Safetxt: a safer sex intervention delivered by mobile phone messaging on sexually transmitted infections (STI) among young people in the UK - protocol for a randomised controlled trial

Introduction Young people aged 16 to 24 have the highest prevalence of genital chlamydia and gonorrhoea compared with other age groups and re-infection rates following treatment are high. Long-term adverse health effects include subfertility and ectopic pregnancy, particularly among those with repeated infections. We developed the safetxt intervention delivered by text message to reduce sexually transmitted infection (STI) by increasing partner notification, condom use and (STI) testing among young people in the UK. Methods and analysis A single-blind randomised trial to reliably establish the effect of the safetxt intervention on chlamydia and gonorrhoea infection at 1 year. We will recruit 6250 people aged 16 to 24 years who have recently been diagnosed with chlamydia, gonorrhoea or non-specific urethritis from health services in the UK. Participants will be allocated to receive the safetxt intervention (text messages designed to promote safer sexual health behaviours) or to receive the control text messages (monthly messages asking participants about changes in contact details) by an automated remote online randomisation system. The primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at 1 year assessed by nucleic acid amplification tests. Secondary outcomes include partner notification, correct treatment of infection, condom use and STI testing prior to sex with new partners. Ethics and dissemination Ethics approval was obtained from NHS Health Research Authority - London – Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the London School of Hygiene & Tropical Medicine. We will submit the results of the trial for publication in peer-reviewed journals. Trial registration number International Standard Randomised Controlled Trials Number: ISRCTN64390461. Registered on 17th March 2016. WHO trial registration data set available at: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN64390461. Trial protocol version 12, 19th July 2018.


Methods and analysis
A single blind randomised trial to reliably establish the effect of the safetxt intervention on chlamydia and gonorrhoea infection at one year. We will recruit 6250 people aged 16-24 years who have recently been diagnosed with chlamydia, gonorrhoea or non-specific urethritis from health services in the UK. Participants will be allocated to receive the safetxt intervention (text messages designed to promote safer sexual health behaviours) or to receive the control text messages (monthly messages asking participants about changes in contact details) by an automated remote online randomisation system.
The primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at one year assessed by nucleic acid amplification tests. Secondary outcomes include partner notification, correct treatment of infection, condom use, and STI testing prior to sex with new partners.

Ethics and dissemination
Ethics approval was obtained from NHS Health Research Authority -London -Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the LSHTM. We will submit the results of the trial for publication in peer reviewed journals.

Trial registration
International Standard Randomised Controlled such as chlamydia and gonorrhoea, and their long-term adverse health effects including ectopic pregnancy and subfertility (1,2). The risk of adverse health effects increases with repeated infections, and re-infection rates following treatment are high: up to 30% for chlamydia and 12% for gonorrhoea at one year (3). Those with an STI are more likely to acquire further STIs and HIV, if exposed. There are marked inequalities in sexual health; STIs are positively associated with lower educational level (4) and living in more deprived areas (1,5,6).
Partner notification, condom use and STI testing can reduce infection and re-infection. There is some evidence that existing interventions delivered face-to-face that target condom use and/or STI testing may be effective, but they are limited in their reach or too costly for widespread application (7). Existing interventions delivered via the media have high reach but their effects have yet to be established (8). Effective ways to increase partner notification in specialist and primary care settings are needed (9,10).
Mobile phones have the potential to provide effective, low cost health behaviour support (11,12). However, evidence for the effect of mobile phone support for safer sex behaviours such as condom use, partner notification and STI testing is equivocal (13)(14)(15). Interventions have targeted testing for STI (16)(17)(18)(19)(20)(21), delaying resumption of sexual activity until 42 days after circumcision (22) and condom use (17,18,23,24), but none have aimed to increase partner notification. The effect of mobile phone based interventions on STI is not known.
The safetxt trial builds on the successful intervention development work and pilot trial (15,26,27). To develop the intervention, we convened a working group including experts in health psychology, contraception research, contraception service provision, IT and the development of interventions delivered by mobile phone. The intervention messages were developed based on: behaviour change theory; evidence-based behaviour change techniques; the content of effective face-to-face safer sex interventions; the factors known to influence safer sex behaviours; the views of 82 young people collected in focus groups and a questionnaire completed by 100 people aged 16-24 (15). The theory and evidence-based intervention is designed to reduce STIs in young people by supporting them in telling a partner about an infection, using condoms and obtaining testing before unprotected sex with a new partner. In a qualitative study with young people, recipients reported that the tone, language, content, and frequency of messages was appropriate (26). Messages reportedly increased knowledge and confidence in how to use condoms and reduced stigma enabling them to tell a partner about an STI. Sharing messages with their partner enabled participants to negotiate condom use.
The pilot trial demonstrated that methods of recruitment, randomisation, intervention delivery and follow-up were successful and that a full-scale randomised controlled trial of the safetxt intervention is feasible (27).

Objectives
The primary objective of this trial is to quantify the effects of the safetxt intervention compared to a control group receiving usual care and messages about trial participation on chlamydia or gonorrhoea infection at one year. Secondary objectives are to determine the effects of safetxt on partner notification and condom use at 4 weeks and on condom use and STI testing at one year.
Which intervention components are effective will be explored by collecting data on the theoretical constructs on the pathway to behaviour change influenced by the intervention components. The cost-effectiveness of the intervention will be established.

Design and setting
Safetxt is a single blind parallel group randomised superiority trial with a 1:1 allocation ratio designed to establish the effects of a safer sex intervention delivered by text message on the cumulative incidence of Chlamydia and gonorrhoea infection at one year. (See Figure 1 for the trial flow chart).
Potential participants testing positive for Chlamydia, gonorrhoea or diagnosed with non-specific urethritis (NSU) will be identified from UK STI testing services by research staff based at the service (a full list of participating services is available at http://safetxt.lshtm.ac.uk/participatingsites/). The intervention is delivered by text message in the community.

Inclusion criteria
Participants will be eligible if they are between 16 and 24 years of age, own a personal mobile phone, are able to provide informed consent, and have either been diagnosed with chlamydia, Interventions:

Safetxt Intervention group
The intervention aims to increase safer sex in three ways: i) encouraging participants to correctly follow STI treatment instructions including informing partner(s) about infection; ii) promoting condom use with new or casual partners; and iii) encouraging participants to obtain testing for STI prior to unprotected sex. Participants in the intervention group will receive regular messages delivered by text message in community settings according to a predetermined schedule. The intervention was informed by the capability, opportunity and motivation model of behaviour (COM-B) (28). It aims to influence the knowledge, beliefs, self-efficacy, skills, social and interpersonal influences that have important effects on motivation, capability and opportunity to reduce sexual risk behaviour.
Over the first ten days participants are sent messages targeting engagement with the intervention,

Control group
Participants in the control group will receive a monthly text message asking for information about changes in postal or email addresses.
All participants will receive usual care and will be free to seek any other existing service or support they wish.
All messages are sent automatically from a large database to an aggregator, which conveys messages to each participant in the community via their network. The success of delivery of messages at each step is monitored by the aggregator and computer system that generates the messages. A member of the trial team will automatically be notified if there is any failure in the delivery of messages. All participants will be able to set embargoed times when they do not want to receive messages. Participants will be able to stop text messages, but continue with the trial follow up, by texting 'stop' to the short code number.

Outcomes
Our primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at one year assessed by nucleic acid amplification tests: urine for men (with additional pharyngeal and anal swabs for MSM) and self-taken vulvo-vaginal swab for women.

Data collection
The primary outcome will be assessed using Chlamydia and gonorrhoea tests collected by post at one year and clinic records of completed tests. STI test kits for chlamydia and gonorrhoea will be posted (in P650 standard packaging) to respondents. Directions in the pack will ask participants to provide a vaginal swab (women), a urine sample (men), and additional anal and pharyngeal samples (men who have sex with men) and post it in the prepaid and addressed envelope to the laboratory. Test kits will be identified by lab number only, rendering the laboratory staff blind to the participant's allocation. The accredited laboratory will destroy samples after testing is completed.
Results of the STI testing will be reported on the secure trial lab site by lab code only. Clinic records will be checked to identify participants who have had a positive STI diagnosis since joining the study, confirm self-reported STI testing and partner attendance for treatment.
At 4 weeks and at one-year, postal questionnaires will be sent to all participants to collected selfreported data. Non-responders will be contacted by any method the participant agrees to at enrolment (post, email, text message, telephone call). Participants can directly enter self-reported outcome data via a web-based data entry form. Paper based self-reported outcome data or selfreported data collected by telephone will be directly entered into the web-based data entry form by a trial assistant blinded to treatment allocation.
Participants will be sent a £5 unconditional incentive with each postal request i.e. when sending the 4 weeks questionnaire and 1-year test and questionnaire. Participants who return the test sample will be sent £20. See Figure 2 for the Schedule of enrolment, interventions and assessments. All outcome data will be collected on participants who choose to stop messages unless they withdraw from the trial.

Data management
Anonymised research data will be held on a secure system and password protected. All data systems will be set up with checks to alert the trial assistants if data being entered are illogical, inconsistent or incomplete.
Personal details will be stored on a password protected computer held on a secure server at the LSHTM. In accordance with the Data Protection Act of 1998 (30), this information will be stored separately from any anonymised research data, and will be deleted at the end of the study. Any paper data will be locked in a cabinet within a room. All trial procedures are in accordance with the principles of Good Clinical Practice. Essential documents of the sponsor/trial organisers and investigators will be retained for at least ten years after completion of the trial.

Sample size
The study is powered for the primary outcome measure of cumulative incidence of chlamydia and/or gonorrhoea infection at one year. Two main factors determine the number of participants needed for this trial: the estimated event rate, and the size of the treatment effect.
Our estimates are based on the following data: Estimated event rate The estimated event rate for the cumulative incidence of STI at 1 year is 20%, based on the event rate in cohort studies and the pilot trial (3).

Size of treatment effect
Because the intervention can be administered to large populations at low cost, even a modest reduction in treatable STIs would be worthwhile. The trial has therefore been designed to detect a reduction in chlamydia or gonorrhoea infection of 20% versus 16% (RR 0.8), which is similar to the effects of face-to-face safer sex interventions (7).

Sample size calculation
In the pilot trial 2% of the control group viewed messages delivered to intervention participants. estimate any differences between the groups using logistic regression and we will report odds ratios with 95% confidence intervals and p-values, adjusting for key baseline predictors of outcome. These will specified in advance in the SAP. For continuous outcomes, we will use linear regression to test for a difference in mean scores between the arms. All analyses will be based on the intention-to-treat principle.
For the primary analysis Multiple Imputation by Chained Equations (MICE) will be used in order to account for missing data (31). MICE makes appropriate assumptions for accommodating missing data in the analysis based on the predictors of outcome and the predictors of loss to follow up. MICE is recognised as a way of reducing bias and increasing precision of trial results and is increasingly used as the primary analysis in randomised controlled trials (12,31). One hundred imputed datasets will be generated and the point estimates and standard errors will be combined using Rubin's rules. We will perform information-anchored sensitivity analysis using the delta-method (32).

Supplementary analyses.
Before fitting our primary analysis model, we need to identify appropriate auxiliary variables to include in the imputation model. Such auxiliary variables should have information about the missing outcome. Specifically, an independent statistician will use a dataset without the treatment variable and perform regression analyses to identify key predictors of outcomes and which combination of baseline variables and time to negative STI test in clinic should be included as auxiliary variables in the imputation model. We will supplement this by performing and reporting a complete case analysis (where any participants with missing information on any covariate or outcome shall be excluded).

Sub group analyses
A limited number of subgroup analyses will be undertaken adjusting for other key predictors of outcome. Subgroup analyses include: age (16)(17)(18)(19)(20)(21)(22)(23)(24), sexual orientation (men who have sex with men or men and women, men who have sex only with women, women who have sex with men or men and women, women who only have sex with women), ethnic group (Caucasian, Black, other) and age at which left education (16 or under, 17 or over). The subgroups will be analysed by inclusion of an interaction term between treatment group and the subgroup in the appropriate regression model for the outcome. Data will be presented by categories of subgroup using effect estimates and 99% confidence intervals. For each subgroup analysis, missing outcomes will be imputed consistent with the hypothesis of an interaction (33) . At four weeks, each of the five process outcomes were measured using the candidate questionnaire items (3 to 5 items per process outcome). Based on these items, we will carry out confirmatory factor analysis (CFA) to refine and identify a valid measurement model. For the main trial analyses, the final measurement model will be combined with the intervention group allocation, along with key baseline predictors, extending the measurement model to a Multiple Causes Multiple Indicators (MIMIC) model. This model will be used to estimate the effects of the intervention on the five hypothesised process outcomes.

Economic evaluation
The economic modelling required to assess the cost-effectiveness of the intervention will estimate the annual probability of members of the target group acquiring Chlamydia, gonorrhoea and NSU with and without the intervention (based on the experience of those in the control and intervention arms of the trial). Detailed information will be collected on the costs of delivering the intervention. Secondary sources will be used to estimate the future NHS costs avoided as a consequence of avoided infections.

Patient involvement
Patients were involved in the development of the intervention (15) and the design of the trial materials and follow-up procedures (34). A patient of also a member of the Trial Steering Committee. Young people will be involved in the dissemination of the trial results.

Monitoring
The safetxt trial will not have a separate Data Monitoring Committee (DMC). No interim analyses of intervention effects will be conducted since the trial is of a behavioural support intervention unlikely to cause harm, and therefore, there are no stopping rules. Analysis of intervention effects will be conducted once at the end of the trial. The sponsor may audit the trial per their own risk assessment and schedule.
In addition to collecting data on two adverse outcomes (involvement in car accident and experience of partner violence), participants will be asked an open-ended question in the 12 the TSC to consider intensity, causality and expectedness. As appropriate, these will be reported to the sponsor and the Ethics Committee.

Ethics and Dissemination
Ethical approval for this trial was provided by the NHS Health Research Authority -London -Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the LSHTM. All trial participants will provide written informed consent prior to enrolment in the trial. Participants' can withdraw from the trial on request. Participant will receive usual NHS care there is no ancillary care.
Any modifications to the protocol will be approved by the ethics committee prior to implementation. Records of any important modifications will be submitted as an addendum the journal in which this protocol is published.
Trial results will be published open-access in peer-review journals. Authorship will be on the basis of meeting the criteria recommended by the International Committee of Medical Journal Editors (ICMJE).
After the publication of our main trial findings, the anonymised trial dataset will be available on request from the corresponding author.

DISCUSSION
STIs such as Chlamydia and gonorrhoea confer a heavy burden of disease among young people with long term sequelae such as infertility. Safer sex behaviours such as condom use, notifying partner(s) about an existing STI and STI testing reduce the risk of STI, but young people may lack the knowledge, confidence and skills needed to adopt these behaviours. Safer sex interventions delivered by mobile phone are acceptable to young people and show promise in increasing safer sex behaviours, but to date their effects on STI are not reliably known.

Competing interests
The authors declare that they have no competing interests. Participant's Information Sheet safetxt: a randomised controlled trial of a safer sex intervention We are inviting you to take part in a research study. Before you decide, it is important that you know why we are doing the study and what is involved. Please read the following information carefully.

What is the study?
This study is testing whether text messages providing information and tips to increase safer sex helps young people adopt safer sex behaviours.

Why have I been chosen?
You are aged 16-24 and have recently received a positive test result for Chlamydia, gonorrhoea or had a non specific urethritis diagnosis.

Do I have to take part?
No, it is up to you to decide whether to take part.

What will happen if I take part?
After you have had all your questions answered and have agreed to take part, we will ask you to complete a consent form. You can do this on our secure and confidential study website, by filling out a paper version, by text message or by email. We will then ask you to complete a short confidential questionnaire providing details about yourself.
After you have completed the questionnaire, an automated computer system will put you into one of two groups by chance (randomly). One group will receive safer sex text messages for 1-2 weeks, then about 5 messages a month for 11 months. The other group will receive text messages asking you to confirm your contact details. These messages will not be about sexual health. This group will receive one message a month for 12 months.
We will ask you to complete the questionnaire again at 1 and 12 months after signing up. This is to see how things have been for you after joining the study. Also at 12 months we will ask you to provide a sample to test for Chlamydia and gonorrhoea. The testing kit will be sent to you by post. Participating in the study involves returning one urine sample or self-taken swab to test for Chlamydia and gonorrhoea.

Will you compensate me for the time this takes?
We will offer you £5 as compensation for your time at each follow up: for the 1 month questionnaire and the 12 month questionnaire. You will be compensated for your time for returning your 12 month sample.
We do not charge for text messages we send to you.

What are the alternatives?
You do not have to take part.

What are the possible disadvantages in taking part?
Completing the questionnaires and providing a sample will take up some of your time. It is possible that the messages we send could be read by someone else. If you are concerned about this, you can password-lock your phone and delete the messages after you read them. What are the possible benefits of taking part?

Local site logo
We cannot promise that your health will benefit from taking part but you may find the messages helpful and you may learn about safer sex behaviours.

What happens when this study stops?
When the study stops, we will look at the data collected to see if the text messages helped increase safer sex behaviours.

What will happen if I don't want to carry on with the study?
You can stop receiving text messages by texting STOP or pause the text messages by texting PAUSE. You can withdraw at any time by letting the Clinical Trials Unit know (safetxt@LSHTM.ac.uk or freephone 0800 008 7197). You do not have to give a reason for wanting to withdraw.

What if there is a problem?
You can contact the Clinical Trials Unit if there is a problem. If you would like to make a formal complaint, contact Dr Caroline Free who will follow the complaints procedure.

Will my taking part in this study be kept confidential?
Yes. Your answers to the questionnaires will be stored anonymously and your contact details and Chlamydia and gonorrhoea test will be kept confidential. You will be allocated a unique study number when you enrol in the study. We will not inform your parents about your involvement in this research. If you were tested for sexually transmitted infections during the study, we will ask your clinic or GP for your test results. We will also ask for information on whether or not a partner was treated. To keep the messages confidential, password-lock your phone and delete messages after you read them.
Your records will be made available to people authorised to work on the study. They may also need to be made available to people for ensuring that the study is carried our correctly.
With your permission, we will ask your clinic or GP for your test results for sexually transmitted infections after you have finished participating in the study. This is to allow the study researchers to look into long term effects about your sexual health.

What will happen to the samples that I give?
You will post your sample directly to a laboratory to test for Chlamydia and gonorrhoea infection. The laboratory will destroy the samples after they have finished testing. You will be notified if the test shows that there is Chlamydia or gonorrhoea infection. The clinic where you signed up to the study will contact you to arrange treatment.

How long will your data be stored for?
Your data will be kept for 10 years after the trial is completed. However, in accordance with the Data Protection Act of 1998, any personal identifiable data will not be kept longer than necessary and will be deleted within 3 months after you have finished the study.

What will happen to the results of the research study?
The results will be published in a scientific journal so that other people know about it. If you would like a copy of the results please contact the Clinical Trials Unit.
If you want to receive the safer sex messages after your participation in the study, please let us know and we will send them to you.
If the results of the study show that the messages have helped, they will be made available to all young people.

Who is organising and funding the research?
The study is run by Dr Caroline Free (Chief Investigator) from the London School of Hygiene and Tropical Medicine, at the University of London. The UK National Institute for Health Research is funding the trial. I understand that all information I provide will remain confidential in accordance with the Data Protection Act of 1998.
I understand that the information collected about me will be used to support other research in the future, and may be shared anonymously with other researchers.
I agree to take part in the above study.

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 7_____ Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 7_____ Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 7_____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how 7_____ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial n/a____

Data collection methods 18a
Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol 11_____ 18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols 11_____  Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

11-12___
Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol

12-14___
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 13_____ 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) 13_____

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed 14_____ 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial 14_____ Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct 14_____ Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor 14_____ How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

11-12__
Declaration of interests 28 Financial and other competing interests for principal investigators for the overall trial and each study site 18_____ Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators

Methods and analysis
A single blind randomised trial to reliably establish the effect of the safetxt intervention on chlamydia and gonorrhoea infection at one year. We will recruit 6250 people aged 16-24 years who have recently been diagnosed with chlamydia, gonorrhoea or non-specific urethritis from health services in the UK. Participants will be allocated to receive the safetxt intervention (text messages designed to promote safer sexual health behaviours) or to receive the control text messages (monthly messages asking participants about changes in contact details) by an automated remote online randomisation system.
The primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at one year assessed by nucleic acid amplification tests. Secondary outcomes include partner notification, correct treatment of infection, condom use, and STI testing prior to sex with new partners.

Ethics and dissemination
Ethics approval was obtained from NHS Health Research Authority -London -Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the LSHTM. We will submit the results of the trial for publication in peer reviewed journals.

Trial registration
International Standard Randomised Controlled

Strengths and limitations of this study
 The study design is a large randomised trial to assess the effect of 'safetxt', a safer sex intervention delivered by text message, on objectively measured STI (chlamydia and gonorrhoea) infection at one year.
 The use of an independent remote computer-based randomisation system linked to an automated message delivery system ensures allocation concealment.
 The secondary outcomes will assess the effect of the intervention on safer sex behaviours: partner notification, condom use and testing before sex with a new partner.
 The process evaluation will explore which intervention components are effective and has the potential to generate general principles to inform similar interventions in the future.
 The inability to blind participants receiving a behavioural intervention is a limitation of the trial, which could introduce bias in the ascertainment of self-reported outcomes.

Keywords
Sexually transmitted infection (STI); sexual behaviour; young people; mHealth; randomised controlled trial, text message. such as chlamydia and gonorrhoea, and their long-term adverse health effects including ectopic pregnancy and subfertility (1,2). The risk of adverse health effects increases with repeated infections, and re-infection rates following treatment are high: up to 30% for chlamydia and 12% for gonorrhoea at one year (3). Those with an STI are more likely to acquire further STIs and HIV, if exposed. There are marked inequalities in sexual health; STIs are positively associated with lower educational level (4) and living in more deprived areas (1,5,6).
Partner notification, condom use and STI testing can reduce infection and re-infection. There is some evidence that existing interventions delivered face-to-face that target condom use and/or STI testing may be effective, but they are limited in their reach or too costly for widespread application (7). Existing interventions delivered via the media have high reach but their effects have yet to be established (8). Effective ways to increase partner notification in specialist and primary care settings are needed (9, 10).
Mobile phones have the potential to provide effective, low cost health behaviour support (11,12). However, evidence for the effect of mobile phone support for safer sex behaviours such as condom use, partner notification and STI testing is equivocal (13)(14)(15). Interventions have targeted testing for STI (16)(17)(18)(19)(20)(21), delaying resumption of sexual activity until 42 days after circumcision (22) and condom use (17,18,23,24), but none have aimed to increase partner notification. The effect of mobile phone based interventions on STI is not known.
In the UK, 99% of 16-24 year olds are mobile phone users (ONS, 2012) and mobile phone ownership is high across all socio-economic groups. In research leading to this trial, it was demonstrated that interactive support via text message is particularly acceptable in the area of sexual health intervention (15,25,26).
The safetxt trial builds on the successful intervention development work and pilot trial (15,26,27). To develop the intervention, we convened a working group including experts in health psychology, contraception research, contraception service provision, IT and the development of interventions delivered by mobile phone. The intervention messages were developed based on: behaviour change theory; evidence-based behaviour change techniques; the content of effective face-to-face safer sex interventions; the factors known to influence safer sex behaviours; the views of 82 young people collected in focus groups and a questionnaire completed by 100 people aged 16-24 (15). The theory and evidence-based intervention is designed to reduce STIs in young people by supporting them in telling a partner about an infection, using condoms and obtaining testing before unprotected sex with a new partner. In a qualitative study with young people, recipients reported that the tone, language, content, and frequency of messages was appropriate (26). Messages reportedly increased knowledge and confidence in how to use condoms and reduced stigma enabling them to tell a partner about an STI. Sharing messages with their partner enabled participants to negotiate condom use.
The pilot trial demonstrated that methods of recruitment, randomisation, intervention delivery and follow-up were successful and that a full-scale randomised controlled trial of the safetxt intervention is feasible (27).

Objectives
The primary objective of this trial is to quantify the effects of the safetxt intervention compared to a control group receiving usual care and messages about trial participation on chlamydia or gonorrhoea infection at one year. Secondary objectives are to determine the effects of safetxt on partner notification and condom use at 4 weeks and on condom use and STI testing at one year.
Which intervention components are effective will be explored by collecting data on the theoretical constructs on the pathway to behaviour change influenced by the intervention components. The cost-effectiveness of the intervention will be established.

Design and setting
Safetxt is a single blind parallel group randomised superiority trial with a 1:1 allocation ratio designed to establish the effects of a safer sex intervention delivered by text message on the cumulative incidence of chlamydia and gonorrhoea infection at one year. (See Figure 1 for the trial flow chart).
Potential participants testing positive for chlamydia, gonorrhoea or diagnosed with non-specific urethritis (NSU) will be identified from UK STI testing services by research staff based at the service (a full list of participating services is available at http://safetxt.lshtm.ac.uk/participatingsites/). The intervention is delivered by text message in the community. Trial recruitment started on the 1 st April 2016. Completion of follow up and closure of the data set is planned for early spring 2020.

Inclusion criteria
Participants will be eligible if they are between 16 and 24 years of age, own a personal mobile phone, are able to provide informed consent and who, in the 2 weeks prior to their recruitment, have either been diagnosed with chlamydia, gonorrhoea, or NSU, or have started treatment for chlamydia, gonorrhoea or NSU.

Exclusion criteria
Participants will be excluded if they are known to be a sexual partner of someone already recruited to the trial.

Recruitment and consent
Research staff based at STI testing services will identify potential participants. They will provide potential participants with trial information at one of three time points, i.e. when potential participants (i) attend the service and are diagnosed with chlamydia, gonorrhoea or NSU; (ii) receive positive test results for chlamydia or gonorrhoea by phone; or (iii) collect treatment for chlamydia, gonorrhoea or NSU from services.
Research staff will provide potential participants with verbal and written information Strategies for achieving adequate enrolment include site visits, training, feedback and rewards, sharing successful recruiting strategies and newsletters.

Allocation and blinding
Participants will be randomly allocated (1:1 ratio), using a computer-based randomisation system, to a safer sex intervention delivered by text messaging, or to a control group, ensuring allocation concealment. Allocation concealment is ensured as the randomisation system is independent, automated and remote.
An electronic link to the computer-based randomisation programme will result in the generation of a research number and allocation to the intervention or control group. The system will then automatically deliver intervention or control group texts according to the allocation. Given the nature of the intervention, participants will be aware of their assigned group. Research assistants entering data, laboratory staff and researchers conducting the final analysis are masked to allocation until after the analysis is complete. Interventions:

Safetxt Intervention group
The intervention aims to increase safer sex in three ways: i) encouraging participants to correctly follow STI treatment instructions including informing partner(s) about infection; ii) promoting condom use with new or casual partners; and iii) encouraging participants to obtain testing for STI prior to unprotected sex. Participants in the intervention group will receive regular messages delivered by text message in community settings according to a predetermined schedule. The intervention was informed by the capability, opportunity and motivation model of behaviour (COM-B) (28). It aims to influence the knowledge, beliefs, self-efficacy, skills, social and interpersonal influences that have important effects on motivation, capability and opportunity to reduce sexual risk behaviour.
Over the first ten days participants are sent messages targeting engagement with the intervention,  instruction on how to carry out the behaviour; demonstrations of risk reduction behaviour; social support; emotional support; social rewards; non-specific incentives; encouragement to add objects to the environment; anticipated regret; problem solving; action planning techniques; and reframing (29) . The information on safer sexual practices is in accordance with existing guidelines. The

Control group
Participants in the control group will receive a monthly untailored text message asking for information about changes in postal or email addresses. Example control group message: 'Thank you for taking part in the texting study. Remember to let us know if your contact details have changed by replying to this text or emailing safetxt@lshtm.ac.uk' All participants will receive usual care and will be free to seek any other existing service or support they wish.
All messages are sent automatically from a large database to an aggregator, which conveys messages to each participant in the community via their network. The success of delivery of messages at each step is monitored by the aggregator and computer system that generates the messages. A member of the trial team will automatically be notified if there is any failure in the delivery of messages. All participants will be able to set embargoed times when they do not want to receive messages. Participants will be able to stop text messages, but continue with the trial follow up, by texting 'stop' to the short code number.

Outcomes
Our primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at one year assessed by nucleic acid amplification tests: urine for men (with additional pharyngeal and anal swabs for MSM) and self-taken vulvo-vaginal swab for women.

Data collection
The primary outcome will be assessed using chlamydia and gonorrhoea tests collected by post at one year and clinic records of completed tests. STI test kits for chlamydia and gonorrhoea will be posted (in P650 standard packaging) to respondents. Directions in the pack will ask participants to provide a vaginal swab (women), a urine sample (men), and additional anal and pharyngeal samples (men who have sex with men) and post it in the prepaid and addressed envelope to the laboratory. Test kits will be identified by lab number only, rendering the laboratory staff blind to the participant's allocation. The accredited laboratory will destroy samples after testing is completed.
Results of the STI testing will be reported on the secure trial lab site by lab code only. Clinic records will be checked to identify participants who have had a positive STI diagnosis since joining the study, confirm self-reported STI testing and partner attendance for treatment. At 4 weeks and at one-year, postal questionnaires will be sent to all participants to collected selfreported data. Non-responders will be contacted by any method the participant agrees to at enrolment (post, email, text message, telephone call). Participants can directly enter self-reported outcome data via a web-based data entry form. Paper based self-reported outcome data or selfreported data collected by telephone will be directly entered into the web-based data entry form by a trial assistant blinded to treatment allocation.
Participants will be sent a £5 unconditional incentive with each postal request i.e. when sending the 4 weeks questionnaire and 1-year test and questionnaire. Participants who return the test sample will be sent £20. See Figure 2 for the Schedule of enrolment, interventions and assessments. All outcome data will be collected on participants who choose to stop messages unless they withdraw from the trial.

Data management
Anonymised research data will be held on a secure system and password protected. All data systems will be set up with checks to alert the trial assistants if data being entered are illogical, inconsistent or incomplete.
Personal details will be stored on a password protected computer held on a secure server at the LSHTM. In accordance with the Data Protection Act of 1998 (30), this information will be stored separately from any anonymised research data, and will be deleted at the end of the study.
Any paper-based data will be locked in a cabinet within a room. All trial procedures are in accordance with the principles of Good Clinical Practice. Essential documents of the sponsor/trial organisers and investigators will be retained for at least ten years after completion of the trial.

Sample size
The study is powered for the primary outcome measure of cumulative incidence of chlamydia and/or gonorrhoea infection at one year. Two main factors determine the number of participants needed for this trial: the estimated event rate, and the size of the treatment effect.
Our estimates are based on the following data: Estimated event rate The estimated event rate for the cumulative incidence of STI at 1 year is 20%, based on the event rate in cohort studies and the pilot trial (3). Five thousand participants would provide 90% power to detect this difference, allowing for 20% losses to follow-up.
The TSC reviewed the blinded event rate after 546 patients had completed 12 months follow up and recommended an increase in the sample size to 6250 due to a lower than expected event rate of 15.6%.

Analysis
A detailed statistical analysis plan (SAP) will be finalised and submitted to the TSC before the end of the trial and unblinding. For the primary outcome and other binary outcomes, we will estimate any differences between the groups using logistic regression and we will report odds ratios with 95% confidence intervals and p-values, adjusting for key baseline predictors of outcome. These will specified in advance in the SAP. For continuous outcomes, we will use linear regression to test for a difference in mean scores between the arms. All analyses will be based on the intention-to-treat principle.
For the primary analysis Multiple Imputation by Chained Equations (MICE) will be used in order to account for missing data (31). MICE makes appropriate assumptions for accommodating missing data in the analysis based on the predictors of outcome and the predictors of loss to follow up. MICE is recognised as a way of reducing bias and increasing precision of trial results and is increasingly used as the primary analysis in randomised controlled trials (12,31). One hundred imputed datasets will be generated and the point estimates and standard errors will be combined using Rubin's rules. We will perform information-anchored sensitivity analysis using the delta-method (32).

Supplementary analyses.
Before fitting our primary analysis model, we need to identify appropriate auxiliary variables to include in the imputation model. Such auxiliary variables should have information about the missing outcome. Specifically, an independent statistician will use a dataset without the treatment variable and perform regression analyses to identify key predictors of outcomes and which combination of baseline variables and time to negative STI test in clinic should be included as auxiliary variables in the imputation model. We will supplement this by performing and reporting a complete case analysis (where any participants with missing information on any covariate or outcome shall be excluded).

Sub group analyses
A limited number of subgroup analyses will be undertaken adjusting for other key predictors of outcome. Subgroup analyses include: age (16)(17)(18)(19)(20)(21)(22)(23)(24), sexual orientation (men who have sex with men or men and women, men who have sex only with women, women who have sex with men or men and women, women who only have sex with women), ethnic group (Caucasian, Black, other) and age at which left education (16 or under, 17 or over). The subgroups will be analysed by inclusion of an interaction term between treatment group and the subgroup in the appropriate regression model for the outcome. Data will be presented by categories of subgroup using effect estimates and 99% confidence intervals. For each subgroup analysis, missing outcomes will be imputed consistent with the hypothesis of an interaction (33) .

Process outcomes
Candidate questionnaire items were identified for the measurement of the following constructs: attitudes towards partner notification; self-efficacy in telling a partner about an infection; selfefficacy in negotiating condom use; correct condom use self-efficacy; knowledge related to STIs.
At four weeks, each of the five process outcomes were measured using the candidate questionnaire items (3 to 5 items per process outcome). Based on these items, we will carry out confirmatory factor analysis (CFA) to refine and identify a valid measurement model. For the main trial analyses, the final measurement model will be combined with the intervention group allocation, along with key baseline predictors, extending the measurement model to a Multiple Causes Multiple Indicators (MIMIC) model. This model will be used to estimate the effects of the intervention on the five hypothesised process outcomes.

Economic evaluation
The economic modelling required to assess the cost-effectiveness of the intervention will estimate the annual probability of members of the target group acquiring chlamydia, gonorrhoea and NSU with and without the intervention (based on the experience of those in the control and intervention arms of the trial). Detailed information will be collected on the costs of delivering the intervention. Secondary sources will be used to estimate the future NHS costs avoided as a consequence of avoided infections.

Patient involvement
Patients were involved in the development of the intervention (15) and the design of the trial materials and follow-up procedures (34). A patient of also a member of the Trial Steering Committee. Young people will be involved in the dissemination of the trial results.

Monitoring
The safetxt trial will not have a separate Data Monitoring Committee (DMC). No interim analyses of intervention effects will be conducted since the trial is of a behavioural support intervention unlikely to cause harm, and therefore, there are no stopping rules. Analysis of intervention effects will be conducted once at the end of the trial. The sponsor may audit the trial per their own risk assessment and schedule. Harms will be assessed by self-reported data. Car accidents are the only demonstrated harm resulting from text messaging, hence the intention to collect data regarding involvement in road traffic accidents. The safetxt intervention aims to increase partner notification of STI status. Fear of partner violence has been reported to be a barrier to partner notification and partner notification has been identified as a factor which may trigger partner violence. However, no randomised controlled trials targeting increased partner notification detected a difference in partner violence between the control intervention groups. Data will be collected regarding the experience of partner violence at 12 months.
In addition, participants will be asked an open-ended question in the 12 month questionnaire: "Did anything good or bad happen as a result of being involved in the study or receiving the text messages? Please describe." The Clinical Trials Unit will keep detailed records of all adverse events reported. Reports will be reviewed by the Principal Investigator and the TSC to consider intensity, causality and expectedness. As appropriate, these will be reported to the sponsor and the Ethics Committee.

Ethics and Dissemination
Ethical approval for this trial was provided by the NHS Health Research Authority -London - Any modifications to the protocol will be approved by the ethics committee prior to implementation. Records of any important modifications will be submitted as an addendum the journal in which this protocol is published.
Trial results will be published open-access in peer-review journals. Authorship will be on the basis of meeting the criteria recommended by the International Committee of Medical Journal Editors (ICMJE).
After the publication of our main trial findings, the anonymised trial dataset will be available on request from the corresponding author.

DISCUSSION
STIs such as chlamydia and gonorrhoea confer a heavy burden of disease among young people with long-term sequelae such as infertility. Safer sex behaviours such as condom use, notifying partner(s) about an existing STI and STI testing reduce the risk of STI, but young people may lack the knowledge, confidence and skills needed to adopt these behaviours. Safer sex interventions delivered by mobile phone are acceptable to young people and show promise in increasing safer sex behaviours, but to date their effects on STI are not reliably known.
If it proves to be effective, this low-cost intervention could have an important impact in improving sexual health and reducing inequalities among young people in the UK. There is likely to be international interest in the impact of the intervention as short written messages delivered via mobile phones are increasingly used for behavioural support worldwide and sexually transmitted infections remain an important cause of morbidity and mortality.     IR provided expertise on trial design, contributed to the refinement of the study protocol and approved the manuscript.
JB contributed to the development of the intervention, the trial design, the refinement of the study protocol and approved the manuscript.
GH provided fundamental intellectual input into the design of the trial, the refinement of the study protocol and approved the manuscript. SM provided behavioural science expertise, which informed the development of the intervention, contributed to the trial design, the refinement of the study protocol and approved the manuscript.

Competing interests
The authors declare that they have no competing interests.

Ethics approval
Ethics approval for this trial was provided by the NHS Health Research Authority -London -Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the LSHTM.

Trial Sponsor
London School of Hygiene & Tropical Medicine is the main research sponsor for this trial. The sponsor had no role in any aspect of the design and conduct of this study, or the decision to

Participant's Information Sheet safetxt: a randomised controlled trial of a safer sex intervention
We are inviting you to take part in a research study. Before you decide, it is important that you know why we are doing the study and what is involved. Please read the following information carefully.

What is the study?
This study is testing whether text messages providing information and tips to increase safer sex helps young people adopt safer sex behaviours.

Why have I been chosen?
You are aged 16-24 and have recently received a positive test result for Chlamydia, gonorrhoea or had a non specific urethritis diagnosis.

Do I have to take part?
No, it is up to you to decide whether to take part.

What will happen if I take part?
After you have had all your questions answered and have agreed to take part, we will ask you to complete a consent form. You can do this on our secure and confidential study website, by filling out a paper version, by text message or by email. We will then ask you to complete a short confidential questionnaire providing details about yourself.
After you have completed the questionnaire, an automated computer system will put you into one of two groups by chance (randomly). One group will receive safer sex text messages for 1-2 weeks, then about 5 messages a month for 11 months. The other group will receive text messages asking you to confirm your contact details. These messages will not be about sexual health. This group will receive one message a month for 12 months.
We will ask you to complete the questionnaire again at 1 and 12 months after signing up. This is to see how things have been for you after joining the study. Also at 12 months we will ask you to provide a sample to test for Chlamydia and gonorrhoea. The testing kit will be sent to you by post. Participating in the study involves returning one urine sample or self-taken swab to test for Chlamydia and gonorrhoea.

Will you compensate me for the time this takes?
We will offer you £5 as compensation for your time at each follow up: for the 1 month questionnaire and the 12 month questionnaire. You will be compensated for your time for returning your 12 month sample.
We do not charge for text messages we send to you.

What are the alternatives?
You do not have to take part.

What are the possible disadvantages in taking part?
Completing the questionnaires and providing a sample will take up some of your time. It is possible that the messages we send could be read by someone else. If you are concerned about this, you can password-lock your phone and delete the messages after you read them.

What are the possible benefits of taking part?
We cannot promise that your health will benefit from taking part but you may find the messages helpful and you may learn about safer sex behaviours.

What happens when this study stops?
When the study stops, we will look at the data collected to see if the text messages helped increase safer sex behaviours.

What will happen if I don't want to carry on with the study?
You can stop receiving text messages by texting STOP or pause the text messages by texting PAUSE. You can withdraw at any time by letting the Clinical Trials Unit know (safetxt@LSHTM.ac.uk or freephone 0800 008 7197). You do not have to give a reason for wanting to withdraw.

What if there is a problem?
You can contact the Clinical Trials Unit if there is a problem. If you would like to make a formal complaint, contact Dr Caroline Free who will follow the complaints procedure.

Will my taking part in this study be kept confidential?
Yes. Your answers to the questionnaires will be stored anonymously and your contact details and Chlamydia and gonorrhoea test will be kept confidential. You will be allocated a unique study number when you enrol in the study. We will not inform your parents about your involvement in this research. If you were tested for sexually transmitted infections during the study, we will ask your clinic or GP for your test results. We will also ask for information on whether or not a partner was treated. To keep the messages confidential, password-lock your phone and delete messages after you read them.
Your records will be made available to people authorised to work on the study. They may also need to be made available to people for ensuring that the study is carried our correctly.
With your permission, we will ask your clinic or GP for your test results for sexually transmitted infections after you have finished participating in the study. This is to allow the study researchers to look into long term effects about your sexual health.

What will happen to the samples that I give?
You will post your sample directly to a laboratory to test for Chlamydia and gonorrhoea infection. The laboratory will destroy the samples after they have finished testing. You will be notified if the test shows that there is Chlamydia or gonorrhoea infection. The clinic where you signed up to the study will contact you to arrange treatment.

How long will your data be stored for?
Your data will be kept for 10 years after the trial is completed. However, in accordance with the Data Protection Act of 1998, any personal identifiable data will not be kept longer than necessary and will be deleted within 3 months after you have finished the study.

What will happen to the results of the research study?
The results will be published in a scientific journal so that other people know about it. If you would like a copy of the results please contact the Clinical Trials Unit.
If you want to receive the safer sex messages after your participation in the study, please let us know and we will send them to you.
If the results of the study show that the messages have helped, they will be made available to all young people.

Who is organising and funding the research?
The study is run by Dr Caroline Free (Chief Investigator) from the London School of Hygiene and Tropical Medicine, at the University of London. The UK National Institute for Health Research is funding the trial. I understand that all information I provide will remain confidential in accordance with the Data Protection Act of 1998.
I understand that the information collected about me will be used to support other research in the future, and may be shared anonymously with other researchers.
I agree to take part in the above study.

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 7_____ Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 7_____ Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 7_____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how 7_____ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial n/a____

Data collection methods 18a
Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol 11_____ 18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols 11_____  Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

11-12___
Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol

12-14___
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 13_____ 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) 13_____

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed 14_____ 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59

Methods and analysis
A single blind randomised trial to reliably establish the effect of the safetxt intervention on chlamydia and gonorrhoea infection at one year. We will recruit 6250 people aged 16-24 years who have recently been diagnosed with chlamydia, gonorrhoea or non-specific urethritis from health services in the UK. Participants will be allocated to receive the safetxt intervention (text messages designed to promote safer sexual health behaviours) or to receive the control text messages (monthly messages asking participants about changes in contact details) by an automated remote online randomisation system.
The primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at one year assessed by nucleic acid amplification tests. Secondary outcomes include partner notification, correct treatment of infection, condom use, and STI testing prior to sex with new partners.

Ethics and dissemination
Ethics approval was obtained from NHS Health Research Authority -London -Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the LSHTM. We will submit the results of the trial for publication in peer reviewed journals.

Strengths and limitations of this study
 The study design is a large randomised trial to assess the effect of 'safetxt', a safer sex intervention delivered by text message, on objectively measured STI (chlamydia and gonorrhoea) infection at one year.
 The use of an independent remote computer-based randomisation system linked to an automated message delivery system ensures allocation concealment.
 The secondary outcomes will assess the effect of the intervention on safer sex behaviours: partner notification, condom use and testing before sex with a new partner.
 The process evaluation will explore which intervention components are effective and has the potential to generate general principles to inform similar interventions in the future.
 The inability to blind participants receiving a behavioural intervention is a limitation of the trial, which could introduce bias in the ascertainment of self-reported outcomes.
Partner notification, condom use and STI testing can reduce infection and re-infection. There is some evidence that existing interventions delivered face-to-face that target condom use and/or STI testing may be effective, but they are limited in their reach or too costly for widespread application (7). Existing interventions delivered via the media have high reach but their effects have yet to be established (8). Effective ways to increase partner notification in specialist and primary care settings are needed (9, 10).
Mobile phones have the potential to provide effective, low cost health behaviour support (11,12). However, evidence for the effect of mobile phone support for safer sex behaviours such as condom use, partner notification and STI testing is equivocal (13)(14)(15). Interventions have targeted testing for STI (16)(17)(18)(19)(20)(21), delaying resumption of sexual activity until 42 days after circumcision (22) and condom use (17,18,23,24), but none have aimed to increase partner notification. The effect of mobile phone based interventions on STI is not known.
In the UK, 99% of 16-24 year olds are mobile phone users (ONS, 2012) and mobile phone ownership is high across all socio-economic groups. In research leading to this trial, it was demonstrated that interactive support via text message is particularly acceptable in the area of sexual health intervention (15,25,26).
The safetxt trial builds on the successful intervention development work and pilot trial (15,26,27). To develop the intervention, we convened a working group including experts in health  people by supporting them in telling a partner about an infection, using condoms and obtaining testing before unprotected sex with a new partner. In a qualitative study with young people, recipients reported that the tone, language, content, and frequency of messages was appropriate (26). Messages reportedly increased knowledge and confidence in how to use condoms and reduced stigma enabling them to tell a partner about an STI. Sharing messages with their partner enabled participants to negotiate condom use.
The pilot trial demonstrated that methods of recruitment, randomisation, intervention delivery and follow-up were successful and that a full-scale randomised controlled trial of the safetxt intervention is feasible (27).

Objectives
The primary objective of this trial is to quantify the effects of the safetxt intervention compared to a control group receiving usual care and messages about trial participation on chlamydia or gonorrhoea infection at one year. Secondary objectives are to determine the effects of safetxt on partner notification and condom use at 4 weeks and on condom use and STI testing at one year.
Which intervention components are effective will be explored by collecting data on the theoretical constructs on the pathway to behaviour change influenced by the intervention components. The cost-effectiveness of the intervention will be established.

Design and setting
Safetxt is a single blind parallel group randomised superiority trial with a 1:1 allocation ratio designed to establish the effects of a safer sex intervention delivered by text message on the cumulative incidence of chlamydia and gonorrhoea infection at one year. (See Figure 1 for the trial flow chart).

Inclusion criteria
Participants will be eligible if they are between 16 and 24 years of age, own a personal mobile phone, are able to provide informed consent and who, in the 2 weeks prior to their recruitment, have either been diagnosed with chlamydia, gonorrhoea, or NSU, or have started treatment for chlamydia, gonorrhoea or NSU.

Exclusion criteria
Participants will be excluded if they are known to be a sexual partner of someone already recruited to the trial.

Recruitment and consent
Research staff based at STI testing services will identify potential participants. They will provide potential participants with trial information at one of three time points, i.e. when potential participants (i) attend the service and are diagnosed with chlamydia, gonorrhoea or NSU; (ii) receive positive test results for chlamydia or gonorrhoea by phone; or (iii) collect treatment for chlamydia, gonorrhoea or NSU from services.
Research staff will provide potential participants with verbal and written information Strategies for achieving adequate enrolment include site visits, training, feedback and rewards, sharing successful recruiting strategies and newsletters.

Allocation and blinding
Participants will be randomly allocated (1:1 ratio), using a computer-based randomisation system, to a safer sex intervention delivered by text messaging, or to a control group, ensuring allocation concealment. Allocation concealment is ensured as the randomisation system is independent, automated and remote.
An electronic link to the computer-based randomisation programme will result in the generation of a research number and allocation to the intervention or control group. The system will then automatically deliver intervention or control group texts according to the allocation. Given the nature of the intervention, participants will be aware of their assigned group. Research assistants entering data, laboratory staff and researchers conducting the final analysis are masked to allocation until after the analysis is complete.

Safetxt Intervention group
The intervention aims to increase safer sex in three ways: i) encouraging participants to correctly follow STI treatment instructions including informing partner(s) about infection; ii) promoting condom use with new or casual partners; and iii) encouraging participants to obtain testing for STI prior to unprotected sex. Participants in the intervention group will receive regular messages delivered by text message in community settings according to a predetermined schedule. The intervention was informed by the capability, opportunity and motivation model of behaviour (COM-B) (28). It aims to influence the knowledge, beliefs, self-efficacy, skills, social and interpersonal influences that have important effects on motivation, capability and opportunity to reduce sexual risk behaviour.

Control group
Participants in the control group will receive a monthly untailored text message asking for information about changes in postal or email addresses. Example control group message: 'Thank you for taking part in the texting study. Remember to let us know if your contact details have changed by replying to this text or emailing safetxt@lshtm.ac.uk' All participants will receive usual care and will be free to seek any other existing service or support they wish. The control group is not attention matched as during the pilot work young people reported that it was irritating to receive the same number of messages as the intervention group about another health topic, when they had just been diagnosed with an STI. If the trial shows a benefit it is possible that this could be due to simply receiving the number of messages involved in the intervention, rather than the message content. However, given the lack of effect of some mobile phone message based interventions in sexual health this seems unlikely (14) All messages are sent automatically from a large database to an aggregator, which conveys messages to each participant in the community via their network. The success of delivery of messages at each step is monitored by the aggregator and computer system that generates the messages. A member of the trial team will automatically be notified if there is any failure in the delivery of messages. All participants will be able to set embargoed times when they do not want to receive messages. Participants will be able to stop text messages, but continue with the trial follow up, by texting 'stop' to the short code number.

Outcomes
Our primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at one year assessed by nucleic acid amplification tests: urine for men (with additional pharyngeal and anal swabs for MSM) and self-taken vulvo-vaginal swab for women.

Data collection
The primary outcome will be assessed using chlamydia and gonorrhoea tests collected by post at one year and clinic records of completed tests. STI test kits for chlamydia and gonorrhoea will be posted (in P650 standard packaging) to respondents. Directions in the pack will ask participants to provide a vaginal swab (women), a urine sample (men), and additional anal and pharyngeal samples (men who have sex with men) and post it in the prepaid and addressed envelope to the laboratory. Test kits will be identified by lab number only, rendering the laboratory staff blind to the participant's allocation. The accredited laboratory will destroy samples after testing is completed.
Results of the STI testing will be reported on the secure trial lab site by lab code only. Clinic records will be checked to identify participants who have had a positive STI diagnosis since joining the study, confirm self-reported STI testing and partner attendance for treatment.
At 4 weeks and at one-year, postal questionnaires will be sent to all participants to collected selfreported data. Non-responders will be contacted by any method the participant agrees to at enrolment (post, email, text message, telephone call). Participants can directly enter self-reported outcome data via a web-based data entry form. Paper based self-reported outcome data or selfreported data collected by telephone will be directly entered into the web-based data entry form by a trial assistant blinded to treatment allocation.
Participants will be sent a £5 unconditional incentive with each postal request i.e. when sending the 4 weeks questionnaire and 1-year test and questionnaire. Participants who return the test sample will be sent £20. See Figure 2 for the Schedule of enrolment, interventions and assessments. All outcome data will be collected on participants who choose to stop messages unless they withdraw from the trial.

Data management
Anonymised research data will be held on a secure system and password protected. All data systems will be set up with checks to alert the trial assistants if data being entered are illogical, inconsistent or incomplete.
Personal details will be stored on a password protected computer held on a secure server at the LSHTM. In accordance with the Data Protection Act of 1998 (32), this information will be stored separately from any anonymised research data, and will be deleted at the end of the study.
Any paper-based data will be locked in a cabinet within a room. All trial procedures are in accordance with the principles of Good Clinical Practice. Essential documents of the sponsor/trial organisers and investigators will be retained for at least ten years after completion of the trial. The study is powered for the primary outcome measure of cumulative incidence of chlamydia and/or gonorrhoea infection at one year. Two main factors determine the number of participants needed for this trial: the estimated event rate, and the size of the treatment effect.

Sample size
Our estimates are based on the following data: Estimated event rate The estimated event rate for the cumulative incidence of STI at 1 year is 20%, based on the event rate in cohort studies and the pilot trial (3).

Size of treatment effect
Because the intervention can be administered to large populations at low cost, even a modest reduction in treatable STIs would be worthwhile. The trial has therefore been designed to detect a reduction in chlamydia or gonorrhoea infection of 20% versus 16% (RR 0.8), which is similar to the effects of face-to-face safer sex interventions (7).

Sample size calculation
In the pilot trial 2% of the control group viewed messages delivered to intervention participants. Five thousand participants would provide 90% power to detect this difference, allowing for 20% losses to follow-up.
The TSC reviewed the blinded event rate after 546 patients had completed 12 months follow up and recommended an increase in the sample size to 6250 due to a lower than expected event rate of 15.6%.

Analysis
A detailed statistical analysis plan (SAP) will be finalised and submitted to the TSC before the end of the trial and unblinding. For the primary outcome and other binary outcomes, we will estimate any differences between the groups using logistic regression and we will report odds ratios with 95% confidence intervals and p-values, adjusting for key baseline predictors of outcome. These will specified in advance in the SAP. For continuous outcomes, we will use linear regression to test for a difference in mean scores between the arms. All analyses will be based on the intention-to-treat principle. For the primary analysis Multiple Imputation by Chained Equations (MICE) will be used in order to account for missing data (33). MICE makes appropriate assumptions for accommodating missing data in the analysis based on the predictors of outcome and the predictors of loss to follow up. MICE is recognised as a way of reducing bias and increasing precision of trial results and is increasingly used as the primary analysis in randomised controlled trials (12,33). One hundred imputed datasets will be generated and the point estimates and standard errors will be combined using Rubin's rules. We will perform information-anchored sensitivity analysis using the delta-method (34).

Supplementary analyses.
Before fitting our primary analysis model, we need to identify appropriate auxiliary variables to include in the imputation model. Such auxiliary variables should have information about the missing outcome. Specifically, an independent statistician will use a dataset without the treatment variable and perform regression analyses to identify key predictors of outcomes and which combination of baseline variables and time to negative STI test in clinic should be included as auxiliary variables in the imputation model. We will supplement this by performing and reporting a complete case analysis (where any participants with missing information on any covariate or outcome shall be excluded).

Sub group analyses
A limited number of subgroup analyses will be undertaken adjusting for other key predictors of outcome. Subgroup analyses include: age (16)(17)(18)(19)(20)(21)(22)(23)(24), sexual orientation (men who have sex with men or men and women, men who have sex only with women, women who have sex with men or men and women, women who only have sex with women), ethnic group (Caucasian, Black, other) and age at which left education (16 or under, 17 or over). The subgroups will be analysed by inclusion of an interaction term between treatment group and the subgroup in the appropriate regression model for the outcome. Data will be presented by categories of subgroup using effect estimates and 99% confidence intervals. For each subgroup analysis, missing outcomes will be imputed consistent with the hypothesis of an interaction (35) .

Process outcomes
Candidate questionnaire items were identified for the measurement of the following constructs: attitudes towards partner notification; self-efficacy in telling a partner about an infection; selfefficacy in negotiating condom use; correct condom use self-efficacy; knowledge related to STIs.
At four weeks, each of the five process outcomes were measured using the candidate questionnaire items (3 to 5 items per process outcome). Based on these items, we will carry out confirmatory factor analysis (CFA) to refine and identify a valid measurement model. For the

Economic evaluation
The economic modelling required to assess the cost-effectiveness of the intervention will estimate the annual probability of members of the target group acquiring chlamydia, gonorrhoea and NSU with and without the intervention (based on the experience of those in the control and intervention arms of the trial). Detailed information will be collected on the costs of delivering the intervention. Secondary sources will be used to estimate the future NHS costs avoided as a consequence of avoided infections.

Patient involvement
Patients were involved in the development of the intervention (15) and the design of the trial materials and follow-up procedures (36). A patient of also a member of the Trial Steering Committee. Young people will be involved in the dissemination of the trial results.

Monitoring
The safetxt trial will not have a separate Data Monitoring Committee (DMC). No interim analyses of intervention effects will be conducted since the trial is of a behavioural support intervention unlikely to cause harm, and therefore, there are no stopping rules. Analysis of intervention effects will be conducted once at the end of the trial. The sponsor may audit the trial per their own risk assessment and schedule. Harms will be assessed by self-reported data. Car accidents are the only demonstrated harm resulting from text messaging, hence the intention to collect data regarding involvement in road traffic accidents. The safetxt intervention aims to increase partner notification of STI status. Fear of partner violence has been reported to be a barrier to partner notification and partner notification has been identified as a factor which may trigger partner violence. However, no randomised controlled trials targeting increased partner notification detected a difference in partner violence between the control intervention groups. Data will be collected regarding the experience of partner violence at 12 months.
In addition, participants will be asked an open-ended question in the 12 month questionnaire: "Did anything good or bad happen as a result of being involved in the study or receiving the text messages? Please describe." The Clinical Trials Unit will keep detailed records of all adverse  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 16 events reported. Reports will be reviewed by the Principal Investigator and the TSC to consider intensity, causality and expectedness. As appropriate, these will be reported to the sponsor and the Ethics Committee.

Ethics and Dissemination
Ethical approval for this trial was provided by the NHS Health Research Authority -London -Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the LSHTM. All trial participants will provide written informed consent prior to enrolment in the trial. Participants' can withdraw from the trial on request. Participant will receive usual NHS care there is no ancillary care.
Any modifications to the protocol will be approved by the ethics committee prior to implementation. Records of any important modifications will be submitted as an addendum the journal in which this protocol is published.
Trial results will be published open-access in peer-review journals. Authorship will be on the basis of meeting the criteria recommended by the International Committee of Medical Journal Editors (ICMJE).
After the publication of our main trial findings, the anonymised trial dataset will be available on request from the corresponding author.

DISCUSSION
STIs such as chlamydia and gonorrhoea confer a heavy burden of disease among young people with long-term sequelae such as infertility. Safer sex behaviours such as condom use, notifying partner(s) about an existing STI and STI testing reduce the risk of STI, but young people may lack the knowledge, confidence and skills needed to adopt these behaviours. Safer sex interventions delivered by mobile phone are acceptable to young people and show promise in increasing safer sex behaviours, but to date their effects on STI are not reliably known.
RK is a member of the Trial Management Group, is are responsible for the day-to-day management of the trial, contributed to the trial design, the refinement of the study protocol and approved the manuscript.
PE is the trial statistician who provides general statistical oversight, contributed to the statistical analysis plan, contributed to the trial design, the refinement of the study protocol and approved the manuscript.
RF contributed to the development of the intervention, provided input on the trial outcome measures, contributed to the trial design, the refinement of the study protocol and approved the manuscript.
PB contributed to the development of the intervention, contributed to the trial design, the refinement of the study protocol and approved the manuscript.
FH adapted the intervention messages for men who have sex with men, contributed to the trial design, the refinement of the study protocol and approved the manuscript.
KW contributed to the development of the intervention, provided input on the trial outcome measures, contributed to the trial design, the refinement of the study protocol and approved the manuscript.
IR provided expertise on trial design, contributed to the refinement of the study protocol and approved the manuscript.
JB contributed to the development of the intervention, the trial design, the refinement of the study protocol and approved the manuscript.
KT leads the economic evaluation, contributed to the trial design, the refinement of the study protocol and approved the manuscript.
KD contributed to the development of the intervention, contributed to the trial design, the refinement of the study protocol and approved the manuscript.
KP is a member of the Trial Management Group, is are responsible for the day-to-day management of the trial, contributed to the trial design, the refinement of the study protocol and approved the manuscript.

Funding
This trial is funded by the National Institute for Health Research Public Health Research (NIHR PHR) Programme (project number 14/182/07). The funding body have no role in any aspect of the design and conduct of this study, or the decision to submit the report for publication.

Competing interests
The authors declare that they have no competing interests.

What is the study?
This study is testing whether text messages providing information and tips to increase safer sex helps young people adopt safer sex behaviours.

Why have I been chosen?
You are aged 16-24 and have recently received a positive test result for Chlamydia, gonorrhoea or had a non specific urethritis diagnosis.

Do I have to take part?
No, it is up to you to decide whether to take part.

What will happen if I take part?
After you have had all your questions answered and have agreed to take part, we will ask you to complete a consent form. You can do this on our secure and confidential study website, by filling out a paper version, by text message or by email. We will then ask you to complete a short confidential questionnaire providing details about yourself.
After you have completed the questionnaire, an automated computer system will put you into one of two groups by chance (randomly). One group will receive safer sex text messages for 1-2 weeks, then about 5 messages a month for 11 months. The other group will receive text messages asking you to confirm your contact details. These messages will not be about sexual health. This group will receive one message a month for 12 months.
We will ask you to complete the questionnaire again at 1 and 12 months after signing up. This is to see how things have been for you after joining the study. Also at 12 months we will ask you to provide a sample to test for Chlamydia and gonorrhoea. The testing kit will be sent to you by post. Participating in the study involves returning one urine sample or self-taken swab to test for Chlamydia and gonorrhoea.

Will you compensate me for the time this takes?
We will offer you £5 as compensation for your time at each follow up: for the 1 month questionnaire and the 12 month questionnaire. You will be compensated for your time for returning your 12 month sample.
We do not charge for text messages we send to you.

What are the alternatives?
You do not have to take part.

Local site logo
We cannot promise that your health will benefit from taking part but you may find the messages helpful and you may learn about safer sex behaviours.

What happens when this study stops?
When the study stops, we will look at the data collected to see if the text messages helped increase safer sex behaviours.

What will happen if I don't want to carry on with the study?
You can stop receiving text messages by texting STOP or pause the text messages by texting PAUSE. You can withdraw at any time by letting the Clinical Trials Unit know (safetxt@LSHTM.ac.uk or freephone 0800 008 7197). You do not have to give a reason for wanting to withdraw.

What if there is a problem?
You can contact the Clinical Trials Unit if there is a problem. If you would like to make a formal complaint, contact Dr Caroline Free who will follow the complaints procedure.

Will my taking part in this study be kept confidential?
Yes. Your answers to the questionnaires will be stored anonymously and your contact details and Chlamydia and gonorrhoea test will be kept confidential. You will be allocated a unique study number when you enrol in the study. We will not inform your parents about your involvement in this research. If you were tested for sexually transmitted infections during the study, we will ask your clinic or GP for your test results. We will also ask for information on whether or not a partner was treated. To keep the messages confidential, password-lock your phone and delete messages after you read them.
Your records will be made available to people authorised to work on the study. They may also need to be made available to people for ensuring that the study is carried our correctly.
With your permission, we will ask your clinic or GP for your test results for sexually transmitted infections after you have finished participating in the study. This is to allow the study researchers to look into long term effects about your sexual health.

What will happen to the samples that I give?
You will post your sample directly to a laboratory to test for Chlamydia and gonorrhoea infection. The laboratory will destroy the samples after they have finished testing. You will be notified if the test shows that there is Chlamydia or gonorrhoea infection. The clinic where you signed up to the study will contact you to arrange treatment.

How long will your data be stored for?
Your data will be kept for 10 years after the trial is completed. However, in accordance with the Data Protection Act of 1998, any personal identifiable data will not be kept longer than necessary and will be deleted within 3 months after you have finished the study.

What will happen to the results of the research study?
The results will be published in a scientific journal so that other people know about it. If you would like a copy of the results please contact the Clinical Trials Unit.
If you want to receive the safer sex messages after your participation in the study, please let us know and we will send them to you.
If the results of the study show that the messages have helped, they will be made available to all young people.
I understand that the information collected about me will be used to support other research in the future, and may be shared anonymously with other researchers.
I agree to take part in the above study. Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities 19_____ 5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee) 19_____ Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory) 6_____

Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained 6_____ Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

6-7_____
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered 8-9_____ 11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease) 14_____ 11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests) n/a_____ 11d Relevant concomitant care and interventions that are permitted or prohibited during the trial 9_____ Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended

9-10___
Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) Figure 2___

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 7_____ Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 7_____ Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 7_____ Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how 7_____ 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial n/a____

Methods: Data collection, management, and analysis
Data collection methods 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol 11_____ 18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols 11_____  Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

11-12___
Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol

12-14___
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 13_____ 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) 13_____

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed 14_____ 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial 14_____ Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct 14_____ Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor 14_____ How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial