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Abstract
Introduction Colorectal adenoma (CRA) is a precancerous lesion for colorectal cancer. Endoscopic resection is the first-line treatment for CRA. However, CRA recurrence rate is high. This proposed study aims to determine if Chinese herbal medicine (CHM) reduces CRA recurrence.
Methods and analysis This project encompasses an observational, registry-based, cohort study and a nested qualitative study. The cohort study aims to include 364 postpolypectomy CRA participants at Guangdong Provincial Hospital of Chinese Medicine (GPHCM), China, with a follow-up phase of up to 1 year. In addition to routine care, these participants will receive a CHM treatment prescribed by experienced Chinese medicine (CM) clinicians. The CHM treatment encompasses CHM products and CHM formulae according to CM syndromes. The primary outcome is CRA recurrence rate at 1 year after enrolment. Secondary outcomes include characteristics of recurrent CRA, incidence of colorectal polyp (except for CRA), incidence of advanced CRA, incidence of colorectal cancer, improvement of gastrointestinal symptoms commonly seen in CRA patients, faecal occult blood test result, lipid level, fasting plasma glucose level, uric acid level, carcinoembryonic antigen, carbohydrate antigen 19-9, quality of life and safety evaluations. Logistic regression analysis will be used to explore the correlation between exposure and outcome. Qualitative interviews will be conducted among approximate 30 CRA patients from the cohort study and 10 CM practitioners in Department of Gastroenterology at GPHCM. Thematic analysis will be used to analyse qualitative data.
Ethics and dissemination Ethical approval has been obtained from the Human Research Ethics Committee (HREC) of GPHCM (YF2022-320-02) and registered at Royal Melbourne Institute of Technology (RMIT) HREC. The results will be disseminated in peer-reviewed journals and international academic conferences.
Trial registration number ChiCTR2200065713.
- COMPLEMENTARY MEDICINE
- Protocols & guidelines
- Gastrointestinal tumours
- Gastroenterology
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This study includes quantitative and qualitative research components to provide comprehensive understanding of Chinese herbal medicine in reducing colorectal adenoma recurrence.
The quantitative study is a registry-based, real-world study to reflect clinical practice.
The qualitative study contains the perspectives of clinicians and patients to inform better disease management.
Single-centre study design and subsequent recall bias may affect result interpretation.
Introduction
Colorectal adenoma (CRA) is a type of colorectal polyp1 and may develop into colorectal cancer (CRC) in 10–20 years without intervention.2 CRC was the third most common malignancy in 2020.3 There are two types of CRC: sporadic and hereditary, accounting for 60%–65% and 35%–40% cases, respectively.4 5 Reports show that 85%–90% of sporadic CRC develop from CRA,6 hence CRA plays an important role in CRC development.
The European Society of Gastrointestinal Endoscopy and the US Multi-Society Task Force on Colorectal Cancer7 8 recommends endoscopic resection (polypectomy) as first-line CRA management as it can prevent 75% of CRC development.9 However, CRA recurrence rate after polypectomy is high. A multicentre study in China has shown that the 1-year CRA recurrence rate is as high as 59.46% after polypectomy.10 Therefore, the management of CRA recurrence becomes an essential task. Conventional medications can help prevent CRA occurrence or recurrence, however, they have side effects.11–13 For example, some studies show that aspirin can help prevent CRA11 14 but has high risks of gastrointestinal bleeding.15
Finding a safe and effective treatment to reduce CRA recurrence is a current need to improve public health. Studies show that Chinese herbal medicine (CHM) is a potential therapy for reducing colorectal polyp recurrence. Chen et al reported a meta-analysis comprising 17 randomised controlled trials (RCTs) that explored the add-on effect of CHM to conventional medicine.16 Results showed a decreased trend in CRA recurrence in the treatment group 1 year after polypectomy.16 Another meta-analysis including 15 RCTs showed recurrence rate of colorectal polyps and common symptoms (abdominal distension, abdominal pain and hematochezia) decreased using CHM treatment in addition to basic treatment, compared with basic treatment alone.17 Although the meta-analyses findings indicated decreased colorectal polyps in the combination of CHM and conventional therapy groups, the focus was not specifically on CRA. In addition, studies included in meta-analyses, RCTs do not reflect clinical practice of CHM in real-world hospital settings. RCTs follow a rigorous protocol and strict standard of eligibility criteria, so that they narrow the study population and increase the difference between real-world evidence with the poor extrapolation.18 This limits the clinical promotion and recognition of the results in RCTs. Nowadays, real-world evidence is increasingly valued. It can be generated from electronic health records, medical claims and billing data.19 According to the US Food and Drug Administration, real-world data improve the efficiency of clinical trials and provides broader evidence on clinical practice.19 As Chinese medicine (CM) emphasises individualised treatment by following syndrome differentiation, real-world studies can fully take these characteristics of CM treatment into consideration and provide evidence to summarise the effectiveness and safety of CM treatment.20
At the Guangdong Provincial Hospital of Chinese Medicine (GPHCM), China, a chronic disease management clinic has been set up that is mainly for people with CRA after polypectomy to prevent CRA recurrence. In this clinic, patients can receive integrative Chinese and Western medicine. Conducting a cohort study in the clinic is a good opportunity to summarise real-world evidence based on medical records from this clinic and gain an understanding of clinicians’ and patients’ experience.
Study objectives
The main objective of this study is to evaluate the effectiveness and safety of CHM treatment in reducing CRA recurrence after polypectomy in the hospital setting.
The cohort study aims to identify the:
Characteristics of CHM treatment for CRA recurrence.
Relationship between characteristics of people with CRA and recurrence in people with CRA after polypectomy.
Relationship between CHM treatment and potential biomarkers for CRA recurrence.
The nested qualitative study aims to explore the opinions of CM practitioners and people with CRA on using CHM for reducing CRA recurrence.
Methods and analysis
Overall study design
This is a prospective, observational, registry-based, cohort study of CHM for reducing CRA recurrence with a follow-up phase up to 1 year in GPHCM, with an embedded qualitative study. Details of procedure flow are in figure 1.
Study flow chart. CHM, Chinese herbal medicine. CM, Chinese medicine. CRA, colorectal adenoma.
Cohort study component
Study settings
The study will be conducted at the Colorectal Polyps Clinic at the GPHCM. The Colorectal Polyps Clinic is for people with colorectal polyps after polypectomy and provides integrated disease management.
Study population and sample size
Approximately 70 new people with CRA attend this clinic each month. Recruitment commenced in November 2022 and is estimated to be completed around October 2023.
The study population will consist of 364 adults, male and female, aged 18–75 years inclusive, who have been diagnosed with CRA and had polypectomy within 2 months before enrolment.
This study sample size calculation is based on the primary outcome, CRA recurrence rate. In our recent study,21 CRA recurrence rate after administering a specific CM formula (Tiaochang Xiaoliu Formula) is 45.5%, while that in routine treatment (postoperative care after polypectomy, lifestyle modification and health education) is 61.7%. With the two-sided alpha level of 0.05 and 80% power, we use a test for two proportion and calculate that it needs 145 participants in each group if the ratio of participants in two groups is 1:1. Assuming 20% loss in the follow-up period, we need to enrol 182 participants in each group, totalling 364 participants.
Eligibility criteria
To be eligible to participate, people must:
Be aged between 18 and 75 years inclusive.
Have been diagnosed as having tubular, villous or tubulovillous CRA.22
Have at least one and no more than six histologically confirmed CRA (including tubular, tubulovillous and villous) at a recent colonoscopy.
Have undergone polypectomy within the 2 months before recruitment with no residual adenomas.
Voluntarily participate in the trial.
Sign the consent form.
People with one or more of the following conditions will be excluded:
Adenomas not completely removed during previous colonoscopy.
History of familial adenomatous polyposis or hereditary non-polyposis CRC (Lynch syndrome).
Complicated with CRC (including early and invasive cancer) or had a history of CRC.
History of inflammatory bowel disease, for example, ulcerative colitis and Crohn’s disease.
History of subtotal or total gastrectomy or partial bowel resection.
Severe heart, liver or kidney disease or any cancer disease.
Intolerance to another colonoscopy examination.
Frequent changes in work environment or other circumstances that may lead to lost to follow-up.
Have participated in other clinical trials in the past 3 months.
Pregnancy, breast feeding or expected to become pregnant.
Participants will be regarded as drop-outs if they request to withdraw from the study for any reasons and in any stages of the study.
Exposures
This study is designed as an observational cohort study to evaluate the effectiveness and safety of CHM based on real-world data. No treatments (including specific treatment schedules) will be given to participants by study investigators. To address the study objectives, CHM therapy will be considered as the exposure and therapeutic regimens will be collected. CHM exposure will be defined as CHM products and CHM formulae, but not specific herbs. This is to fully reflect real-world evidence as opposed to evidence for one herb. Treatment types include granule, pill, decoction, powder and paste. Treatment will be decided by clinical practice and participants’ preference. Participants who receive CHM treatments will be classified in the exposure group. CHM exposure level will be calculated based on the cumulative exposure time of CHM during individual follow-up. The mode of CHM administration, treatment type of CHM, time to receive CHM therapy, formula ingredients and total dosage will be explored. Participants who do not take any CHM treatments will be considered as a non-exposure group (non-CHM treatment).
Covariates
Existing evidence23–25 shows there are a range of factors affecting CRA recurrence and incidence of other colorectal neoplasm.
Risk factors are as follows:
Age.
Gender.
Family history of CRC or CRA.
Smoking and alcohol.
Metabolic syndrome and obesity.
Having a flat adenoma.
Diet, including red meat and processed meat consumption, and less fruit and vegetable intake.
Lifestyle factors, including sedentary behaviour, associated with a high risk of CRA recurrence.
Protective factors are as follows:
Medications: metformin and aspirin.
Physical activity: lower risk of CRA occurrence is associated with physical activity beginning in adolescence.
Diet: include fruit and vegetable intake, nutrients obtained from natural food sources rather than solely from dietary supplements.
The above listed covariates will be collected and observed during the follow-up phase.
Quality control of colonoscopy
The following criteria will ensure colonoscopy quality:
Withdrawal time is more than 6 min (including 6).
Boston Bowel Preparation Score is more than 6 points (including 6).
Cecal insertion rate rate reaches 95%.
Endoscopists at GPHCM are proficient in colonoscopy and magnifying staining endoscopy, carrying out more than 1000 colonoscopies.
Outcome measures
The primary outcome will be CRA recurrence rate at 1 year after enrolment, defined by the proportion of participants with one or more recurrent CRAs in each group during the follow-up colonoscopy.
Secondary outcomes include characteristics of recurrent CRA, incidence of other types of colorectal lesions, faecal occult blood and improvement of symptoms to explore the impact of CHM on intestinal health. Metabolic syndrome is reported as a risk factor for recurrent adenomas,23 so metabolic syndrome-related markers (fasting plasma glucose level, lipid level and uric acid level) and tumour markers (carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9)) will be collected to explore any potential effects from taking CHM. Chronic disease can impact a patient’s quality of life, so we will also collect data about quality of life to identify the effects of CHM on general health, physical, psychological and social functions.
Secondary outcome measures are:
Characteristics of recurrent CRA, including the adenoma’s location, number, size, appearance characteristics and histological subtype.
Incidence of colorectal polyp, advanced CRA and colorectal cancer, including the proportion of participants with one or more corresponding colorectal lesion in each group, and corresponding lesion’s location, number, size, appearance characteristics and histological subtype; advanced CRA encompasses those adenomas that meet one or more of the following criteria: adenoma ≥10 mm in size, adenoma with tubulovillous/villous histology and/or adenoma with high-grade dysplasia.23
Improvement of symptoms, referring to expert consensus opinion on quantification standard of symptoms of spleen and stomach diseases (2017)26; this will measure the score of CM symptoms, mainly abdominal pain, abdominal distension, diarrhoea, constipation and haematochezia; divided into four grades: no, mild, moderate and severe, respectively, corresponding 0, 1, 2, 3 points; the sum of each score is the CM symptoms score,
Faecal occult blood test result (FOBT).
Lipid level, including triglycerides, cholesterol, high-density lipoprotein and low-density lipoprotein.
Fasting plasma glucose level.
Uric acid level.
CEA.
CA19-9.
Quality of life (using Short Form Health Survey 36 (SF-36)).
Safety evaluations, including blood tests, adverse events (AEs) and discomforts related to the exposure (such as diarrhoea, abdominal pain, dizzy and insomnia); blood tests that will be considered safety outcomes are alanine transaminase, aspartate aminotransferase, serum creatinine and blood urea nitrogen.
Enrolment and follow-up visits
Visit 1: initial assessment for enrolment
Participants who are diagnosed with CRA and had a polypectomy within the previous 2 months will be assessed for enrolment (see the Eligibility criteria section, the Exposures section, the Covariates section and the Quality control of colonoscopy section). Investigators will screen invited participants by checking their electronic medical record and interviewing to check for eligibility. Participants will sign informed consent before enrolment. People who meet eligibility requirements and voluntarily participate in the study will attend baseline assessment and follow-up visits. See table 1 for schedule of visits and activities.
Visit schedule
Visits 2–5: follow-up visits
Follow-up visits will occur every 3 months after enrolment. Participants will receive an electronic or paper form to record treatment and symptoms every month. In visits 2, 3 and 5 (at 3, 6 and 12 months after enrolment, respectively), participants will complete SF-36, and a diet and physical activities habits assessment (including food frequency questionnaire, physical activity habits questionnaire and International Physical Activity Questionnaire SF (IPAQ-S).27 The food frequency questionnaire refers to the validated and published food frequency questionnaires and example in the dietary evaluation book,28–30 and is adapted for Guangdong residents. Physical activity is measured by the IPAQ-S in Chinese, which has acceptable reliability and validity,31 32 and physical activity habits questionnaire. The physical activity habits questionnaire is adapted from the published study for physical activity and CRA.33 Participants will also have fasting blood tests at start of study and every 6 months after enrolment and FOBT at start of study and at the 1-year follow-up.
In the final visit, participants will undergo a follow-up colonoscopy. If colorectal lesions are found, they will be removed under endoscopy by polypectomy and the tissue will be sent for biopsy.
Visits 2, 3 and 5 will be on-site visits, and visit 4 (9 months after enrolment) can be on-site or via phone. A flexible visit time±4 weeks before or after the scheduled visit date will be set up. This is to give participants flexibility and reduce dropout and withdraw rates to minimise missing data.
Data collection and management
Structured case report forms (CRFs) will be used to collect data. Participants will complete CRFs by choosing the online or hard copy version according to their preferences. The online version will be sent to participants via Wenjuan.com (www.wenjuan.com) or the chronic disease management clinic app in WeChat. See table 1 for data collection and visit time schedule. Follow-up reminders will be sent to each participant via WeChat or the outpatient management system before the visit time. Investigators will check if CRFs are completed. Collected data will be divided into three parts: participant personal information, exposure information and outcome information.
Participants will be asked to keep diaries to record symptoms and treatments, to reduce potential recall bias in the time between visits. To reduce the rate of lost follow-up, reminders will be sent via WeChat or phone message to participants before the visit time. Investigators will use various methods to reduce the risk of missing data, including regular data checks. Before enrolment, investigators will also receive training on study implementation, use of questionnaires and communication skills with participants to prevent information bias. To reduce confound-bias, covariates will be collected for statistical analysis, including age, gender, diet and lifestyle.
Participant personal information
Demographics: participant number, age, gender, date of birth, address, phone, marital status, occupation, emergency contact and education; collected at baseline visit.
General information: medication, medical history, family history, allergise, pregnancy, alcohol habits, smoking habits, height and weight; collected at baseline visit. Investigators will also record body mass index at each on-site visit.
Symptom: any symptoms will be recorded each month.
CM syndrome: investigators will assess CM syndrome of participants by questionnaire at baseline visit and in visits 2, 3 and 5.
Diet and physical activity habits assessment: participants will complete the lifestyle habits questionnaires at baseline visit and in visits 2, 3 and 5, which includes the diet and physical activity assessment.
Medical records data: diagnoses, results of laboratory and medical imaging examinations will be extracted from medical records during the follow-up period.
Exposure information
Exposure information relates to the therapeutic regimens that participants receive during the follow-up period. It includes CM treatment method, name of CHM formula and its components, CHM products, single Chinese herbs, conventional drugs and corresponding treatment course. Investigators will collect this data via medical records and the participants’ diary during the follow-up phase.
Outcome measurement
Follow-up colonoscopy and biopsy pathology (if there are colorectal lesions): The colonoscopy will be performed at the end of follow-up. If there are any colorectal lesions, the appropriate endoscopic treatment will be selected according to clinical practice. For example, cold snare polypectomy is indicated for lesion ≤5 mm in size without suspicion of being cancer1 and lesion tissue will be taken for biopsy. The results of colonoscopy and pathology will be obtained, which include the location, number, appearance, size and pathological classification of lesions, as well as the removal method.
FOBT: FOBT is used to detect faecal haemoglobin levels by using immunoassay or the chemical method.24 34 FOBT is the important screening method for CRC and colorectal neoplasm.24 As FOBT is recommended to be conducted at least once a year in China,35 it will be performed annually during the follow-up period.
Lipid level: Triglycerides, cholesterol, high-density lipoprotein and low-density lipoprotein will be collected to assay for lipid level.
Glucose level: Fasting plasma glucose tests will be evaluated.
Uric aacid: Uric acid levels in the blood will be assessed.
Tumour markers: Tumour markers will be assessed through the CEA and CA19-9 tests.
Blood tests will be performed every 6 months.
Quality of life: SF-36 will measure the participants’ quality of life at baseline and every 6 months during the study.
Safety evaluations: AEs related to treatment, including diarrhoea, constipation, abdominal distension and abdominal pain, will be collected at every visit. Liver and kidney function will be tested every 6 months.
Data analysis
SPSS V.26.0 software will be used for data analysis. Frequency tables, percentages or composition ratios are the description of qualitative variables (categorical data and ordinal data). Quantitative variables will be displayed by using mean, SD, median, minimum value and maximum value. P values will be two sided at 95% significance level.
To analyse differences between the two groups, χ2 test, Fisher’s exact test and Wilcoxon rank-sum test will be performed for qualitative variables. T-test and analysis of variance will be used for quantitative data with normal distribution. If quantitative variables do not fit normal distribution, rank-sum test will be performed.
To analyse the correlation between exposure and outcome, logistic regression analysis will be used. Multivariate regression will be used to study the effect of exposure and covariates on outcome. We will eliminate interference by regression analysis to analyse the influence of exposure factors and their influence degree.
First, we will give a clear definition to exposure and list the covariates according to current evidence. Multiple regression models will, respectively, adjust covariates. Next, we will analyse whether the efficacy outcome will change if only participants who have single CRA at the baseline are selected. Finally, we will stratify participants according to gender, age, smoking habits, type of adenoma at baseline and family history of CRA or CRC. Tests of interaction will be also performed in terms of those factors mentioned above.
The incidence of AEs and abnormal indicators of laboratory tests will be included for safety analysis. We will calculate certain, probable/likely and possible AEs. A χ2 test will be used between the exposure and non-exposure groups. Abnormal laboratory results will be recorded. We will determine whether abnormal laboratory results need to be included in the safety test based on the normal range of test indicators and whether they are clinically significant.
Qualitative study
Study design
Semistructured, in-depth interviews will be conducted with CM practitioners and people with CRA from the cohort study. The conduction and reporting will refer to the Consolidated Criteria for Reporting Qualitative Research.36
Study setting
The qualitative study will be conducted in GPHCM, Guangzhou, China.
Sample size
There is no fixed sample size. It is anticipated approximately 10 CM practitioners and 30 people with CRA will be recruited, determined by theoretical or population saturation.37
Participant recruitment
Participants will be divided into CM practitioners and people with CRA. CM practitioners will be recruited in the Gastroenterology Department at GPHCM. They will be eligible to participate if they have clinical experience of using CM or integrative medicine (including CM) for CRA recurrence. Practitioners only using Western Medicine for CRA recurrence will be excluded. Potential participants will be invited to attend the study via WeChat, phone or department meeting. Practitioners will be sampled by age, gender, professional qualification and thoughts about CM theory.
People with CRA from the cohort study who have completed the follow-up period will be regarded as eligible participants. People who withdraw from the cohort study will be excluded. Investigators will explain the study details to potential participants and invite them to participate. People with CRA will be sampled according to gender, age, characteristics of CRA, treatment category, results of follow-up colonoscopy and medical conditions. Once reaching the theoretical or population saturation, the recruitment will be stopped.
Data collection
Participants will be scheduled for interviews and sign the written informed consent form. Interviews will be conducted at GPHCM.
Each participant will have one 30–60 min interview. CM practitioners will be asked about their opinions of CHM treatment, how to use CHM and key factors affecting adherence among people with CRA. People with CRA will be asked about their experience of CHM treatment and non-CHM treatment, and factors affecting their adherence.
Interviews will be recorded by audio. Non-verbal details will be recorded by investigators. According to participants’ preference, investigators will use Mandarin or Cantonese to conduct interviews.
Content provided in interviews will be confidential. Investigators will ensure audio files and electronic documents are stored in a locked cabinet or computer with a password. Only investigators will be able to access documents.
Participants can refuse to answer interview questions. If participants are visibly uncomfortable, they will be asked if they want to continue.
Pilot interview
CM practitioners and people with CRA will be interviewed before the main data collection. In the pilot interviews, an interview guide will be developed and validated. Data from pilot interviews will not be included in the final analysis.
Data analysis
Thematic analysis will be applied for data analysis. Interviews will be recorded verbatim in the original text. Investigators will use QSR NVivo software (QSR International) to manage and encode the deidentified transcript. Text is encoded line by line using open encoding to mark common topics. Participants’ personal information will be replaced with their initials. Data analysis will include: (1) reading and re-reading transcripts and related field notes to become familiar with data; (2) setting up original coding; (3) exploring tentative themes; (4) reviewing themes and checking data and (5) defining and naming themes.
Initial data analysis will be performed after each interview to identify whether interview guidelines need to be modified. Initial data analysis will be conducted in the original language of the interview, and the subject and subsubject will be translated into English for further discussion and analysis. Investigators will report data analysis progress regularly to ensure consistency and determine the next analysis phase.
Patient and public involvement
Patients and/or the public will not be involved in the design, conduct, reporting or dissemination of this project.
Ethics and dissemination
This study (version 3) obtained ethical approval from the Human Research Ethics Committee (HREC) of Guangdong Provincial Hospital of Chinese Medicine (YF2022-320-02) and has been registered in HREC of Royal Melbourne Institute of Technology (RMIT). Potential participants will be informed about the study’s purpose and background, and the benefits and risks of participation. People who are willing to participate in the study will be given a patient informed consent form (PICF). Participants and investigators will sign and date the PICF. The signed PICF will be collected before participants enter the study and retained by the investigator. Participants will be given a copy of the PICF. Study procedures will be performed in accordance with the Declaration of Helsinki.
There are no financial and other competing interests during this observational study.
Investigators will submit an updated version of the protocol to the HRECs of GPHCM and RMIT if any essential modifications need be made to the study design and obtain ethics approval. The corresponding update will be uploaded to the Chinese clinical trial registry.
Study findings will be disseminated through national and international peer-reviewed journals, conferences and other events. Participants will be informed of the study results via email or letter.
Ethics statements
Patient consent for publication
Acknowledgments
The authors acknowledge Ms. Louise Pobjoy for editing the manuscript, and the contributions from the China-Australia International Research Centre for Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, and the Gastroenterology Department in Guangdong Provincial Hospital of Chinese Medicine.
References
Footnotes
Contributors YC, YMD, ALZ, CX and BZ contributed to the study design. PH, JM and HZ provided support with data collection and project administration. YC drafted the manuscript. YC, YMD, ALZ, CX and BZ revised the manuscript. All authors read and approved the final manuscript.
Funding This work is supported by RMIT PhD scholarship, the China-Australia International Research Centre for Chinese Medicine, RMIT University. It is also supported by Special support for clinical research from the Guangzhou Science and Technology Plan Project, Guangzhou Key Laboratory for the Prevention and Treatment of Colorectal Inflammation - Cancer Transforming Diseases by Integrated Traditional Chinese and Western Medicine (No.202201020377); State Key Laboratory of Wet Syndrome of Traditional Chinese Medicine, co-established by Guangdong Provincial and Ministry of China, research on Artificial Intelligence Image Acquisition and Recognition of Tongue Coating (grant number SZ2021ZZ2701/B67016 and B67017); and Key Laboratory (Key Laboratory of Spleen and Stomach Diseases Spleen Deficiency Syndrome) of State Administration of Traditional Chinese Medicine.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.