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Infectious diseases
Protocol
Addition of daptomycin for the treatment of pneumococcal meningitis: protocol for the AddaMAP study
  1. Pascal Chavanet1,2,
  2. Isabelle Fournel2,3,
  3. Abderrahmane Bourredjem2,3,
  4. Lionel Piroth1,
  5. Mathieu Blot1,
  6. Thibault Sixt1,
  7. Christine Binquet2,3
  1. 1Infectious Diseases Department, University Hospital, Dijon, France
  2. 2INSERM, CIC 1432, Module Epidémiologie Clinique, Dijon, France
  3. 3Centre d'Investigation Clinique, CHU Dijon, Dijon, France
  1. Correspondence to Professor Pascal Chavanet; pascalpychavanet{at}hotmail.com

Abstract

Background The leading cause of acute bacterial meningitis in adults is Streptococcus pneumoniae. This infection is associated with high rates of mortality and morbidity related, among other factors, to the excessive host response to the pneumococcal lysis. Experimental in vitro and in vivo data show that the combination of corticosteroids/third-generation cephalosporins and the non-lytic antibiotic, daptomycin, has synergistic effects with (1) a rapid cerebrospinal fluid sterilisation, (2) less brain damages and (3) less loss of cognitive performances. Despite these encouraging results, daptomycin has never been evaluated in adult patients with pneumococcal meningitis.

Methods and analysis The AddaMAP trial is a phase II, open-label, Simon’s two-stage, multicentre trial that has been designed to assess the efficacy and safety of adding daptomycin (10 mg/kg/d for 8 days) to the recommended treatment (corticosteroids+third generation cephalosporin) in adults with confirmed pneumococcal meningitis. The main endpoint is the disability-free survival (defined as modified Rankin Scale mRS≤2) at day 30. Secondary outcomes are overall mortality, disability at D30 and D90 (mRS, Glasgow Coma Scale and Glasgow Outcome Scales, mini-mental score), hearing loss (Hearing Handicap Inventory Test at D30 and D90, routine audiometric test and Hearing-it test at D30), and quality of life (12-item Short Form Survey and WHO QOL BREF). Seventy-two analysable patients are required.

Ethics and dissemination The study protocol was approved by the Institutional Review Board of the IDF 1 of the ethics committee on 16 January 2018, and authorisation was obtained from the Agence Nationale de Securité des Médicaments et des Produits de Santé on 22 September 2017. The results will be submitted for publication in a peer-reviewed journal.

Trial registration number NCT03480191.

  • clinical trial
  • infectious diseases
  • clinical trials
  • adult intensive & critical care
  • microbiology
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2023-073032

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    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • AddaMAP is a multicentre single-arm phase II study assessing the safety and efficacy of a combined of non-bacteriolytic antibiotic— daptomycin—and recommended treatment for pneumococcal meningitis in adults.

    • Dexamethasone (10 mg) will be started, followed by daptomycin (30 min infusion of 10 mg/kg/d) and cefotaxime or ceftriaxone.

    • Daptomycin will be administered for 8 days if the pneumococcal meningitis is confirmed.

    • The diagnosis of pneumococcal meningitis will be confirmed by microbiological samples according to the French recommendations.

    • There is no control group in this clinical trial.

    Introduction

    The leading cause of acute bacterial meningitis in adults is Streptococcus pneumoniae.1–3 This infection remains associated with a high risk of mortality (20%–30%)1 4–14 and of brain damage, hearing loss or learning disabilities (30%).2 4 15–20 These risks are modulated by the intensity of the bacteriolysis which in turn depends on the host’s genetic profile,21 22 excessive host response23–25 the pneumococcal profile26–28 and especially the bacterial load.29–32 Treatment (dexamethasone and third-generation cephalosporin) should be started immediately.33–35

    Despite these guidelines, approximately half of patients with pneumococcal meningitis are left with a disability, and mortality was as high as 20%.2 12 14 19 20 36

    The decrease in sensitivity of pneumococcal strains to certain antibiotics37 is a potential threat that could lead to different antibiotic therapy proposals, for instance, the addition of daptomycin due to the good in vitro interactions.38 However, this resistance has no clear significance at the moment.39

    More than half of treated patients have at least one complication after 48 hours;2 12 this suggests that despite meningeal sterilisation, the rapid lysis cascade of pneumococcus, leading to a dysregulated host response40 41 and then neurological sequelae or death is not sufficiently prevented. Bacteriolysis should be contained or decreased to limit the excessive host response25 42–45 and reduce the persistence of pneumococcal elements within the central nervous system CNS.46 47

    The well-known lipopeptide daptomycin is highly active against susceptible or resistant pneumococci,47–49 and it interacts synergistically with cephalosporins.38 It has a low resistance rate48 and above all, it has been shown to be highly bactericidal but without initiating lysis both in vitro49 and in vivo in murine and rabbit models of meningitis50 51 even against cephalosporin-resistant pneumococci.52 53

    Based on in vivo data from experimental pneumococcal meningitis models, the addition of daptomycin to the recommended combination dexamethasone-cephalosporin is associated with rapid cerebrospinal fluid (CSF) sterilisation and the reduction of (1) the inflammatory response, (2) damage to the blood brain barrier damage,53 54 (3) cognitive impairement54–57 and (4) hearing loss.58 It should be noted that these effects were found to be equal or superior to rifampin58 and similar to other combinations that included daptomycin.59

    Moreover, daptomycin diffuses into CSF60 61 and can cure difficult to treat bacterial meningitis.61–67

    Finally, although acute meningeal inflammation likely only lasts 2–3 days (the duration of the adjunctive corticosteroids) duration of daptomycin treatment proposed in this study is 8 days in accordance with French experts,34 but which is shorter than the European recommendations.33

    Methods and analysis

    Design and setting

    The AddaMAP study is a multicentre prospective open label single-arm Simon’s two stage phase II trial which will investigate the impact of adding daptomycin (10 mg/kg/day for 8 days) to the recommended treatment (corticosteroids+third-generation cephalosporin) on disability-free survival (DFS) in adult patients with confirmed pneumococcal meningitis. Eight university hospitals in France, all participating in the COMBAT cohort,2 will participate in AddaMAP study.

    Study objectives

    The main objective is to evaluate the impact of the addition of daptomycin to the recommended treatment on DFS 30 days after treatment initiation (D30).

    Secondary objectives will evaluate the safety and the efficacy of add-on daptomycin therapy on mortality, disability, hearing loss, quality of life, length of hospital stay at D30 and D90, and on the number of days without antibiotics at D30.

    Endpoints

    The primary outcome is DFS, assessed with the modified Rankin Scale (mRS)68 at D30. The mRS is a clinician-reported measure of global disability that rates patients’ status into six categories, ranging from 0 (no symptoms at all) to 5 (severe disability). DFS will be defined, at D30, as survival with a mRS≤2 which ensures that survival will not be impaired by significant disability subsequent to meningitis.

    Secondary outcomes will include:

    1. Overall mortality at D30 and D90.

    2. Disability level assessed at D30 and D90, with mRS and mini-mental score in surviving patients, and with Glasgow Coma scale and Glasgow Outome Scale in the overall efficacy population.

      The Glasgow Outcome Scale (GOS) is a global scale for functional outcome that divides patient status into five categories and the extended GOS69 is obtained by using a structured interview70 attributing patients into one of eight categories: dead, vegetative state, lower or upper severe disability, lower or upper moderate disability, lower or upper good recovery.

      The Mini Mental State Examination is a tool that can be used to thoroughly assess mental status. It has 11 questions that measure 5 areas of cognitive function: orientation, registration, attention and calculation, recall and language. The maximum score is 30. A score of 23 or lower is indicative of cognitive impairment.

    3. Hearing loss assessed with the Hearing Handicap Inventory test at D30 and D9071 and with routine audiometric tests and the Hearing-it test at D30.

      Hearing Handicap Inventory test is a 25-item self-assessment scale composed of two subscales (emotional and social/situational) and is categorised into three categories: (1) no hearing handicap, (2) mild-moderate hearing handicap and (3) significant hearing handicap. The same categorisation will be used for the routine audiometric test and the Hearing-it test.72

    4. Quality of life assessed with the short form 12 (SF12) and WHO QOL BREF at D30 and at D90.

      The SF12 is a generic health status measure and a short form of the SF-36 health survey.73 The WHO QOL BREF is the abbreviated version of the WHOQOL-100, which contains a total of 26 questions.74

    5. Number of days without hospitalisation (including intensive care unit (ICU)) at D30 and D90.

    6. Number of days without antimicrobial therapy at D30.

    The safety endpoint will include frequency and type of side effects related to daptomycin within 30 days after starting daptomycin (particularly intensive care related neuropathy).

    Population

    Eligibility criteria are listed in table 1. All patients full-filling inclusion criteria and who receive the DDC sequence (Dexa-Dapto-Cefotaxime) will be part of the safety population. The efficacy population will be composed of patients with proven pneumococcal meningitis (positive culture or PCR of the CSF or positive pneumococcal antigen (assessed with immunochromatographic test) or a positive blood culture.

    View this table:
    Table 1

    Eligibility criteria

    Data handling

    The investigator, aided by a clinical research technician (CRT), will enter the data directly into an electronic Case Report Form (e-CRF) specifically developed for this study using a clinical data management system (CMDS- CleanWeb). All required information will be entered as and when it is obtained (at screening, between D1 and D8, at D30 and at D90). Automatic checks for missing or inconsistent data will be integrated. These checks will follow the data management plan, jointly defined by the coordinating centre in collaboration with the coordinating investigator. In case of missing or inconsistent data identification, correction requests will be sent to participating centres via the CMDS. If corrections are necessary, they will be made by the CRT or by the investigator directly using CleanWeb.

    The electronic system will ensure the traceability of every change made in the e-CRF.

    A review of data will be performed at the end of the study and may result in additional queries. All queries should be resolved before the final database lock.

    The process of data lock/unlock will be performed according to the procedure set up in the coordinating centre (raw data lock in comma separated values (CSV) format and as an SAS table).

    Data will be securely stored on these servers according to national guidelines.

    Confidentiality

    All data will be captured anonymously in the secured and dedicated CleanWeb database, consistent with the recommendations of the MR01 reference method of the CNIL. At no point will the names of participants or their addresses appear unencrypted. Only the first letter of the family name and the first letter of the first name will be recorded, along with the number of the centre followed by a serial inclusion number. This inclusion number will also be reported on self-administered questionnaires. The follow-up of patients will in part rely on phone call and at sending self-administered questionnaires at D90, which will require access to the patients’ contact information.

    The contact information list as well as the list of correspondence, neither of which will be computerised, will be kept securely in each centre participating in the study.

    During the biomedical study, or at its conclusion, data collected regarding participants that is sent to the sponsor by the investigators (or all other specialists involved) will be anonymised.

    Study procedures

    DDC sequence

    Dexamethasone (30 min infusion of 10 mg) will be started followed by daptomycin (10 mg/kg/d) and cefotaxime or ceftriaxone. The DDC sequence will be administered within the hour following the lumbar puncture, excepted for patients with purpura fulminans, contraindication to lumbar puncture or failure to achieve lumbar puncture. In these patients, the DDC sequence will be administered before lumbar puncture, which will have to be performed as soon as possible. Daptomycin will be administered for 8 days if the pneumococcal meningitis is confirmed.

    Study conduct

    A flow chart for patient after presentation of suspicion of bacterial meningitis is presented in figure 1 and the timing of data collection during the study is presented in online supplemental table.

    Figure 1
    Figure 1

    Flow chart of the AddaMAP trial. *For patients with purpura fulminans, contraindication to lumbar puncture or failure to achieve lumbar puncture, DDC sequence will be administered before lumbar puncture. Lumbar puncture will then have to be performed as soon as a possible.

    Consecutive eligible patients will be identified in each participating emergency unit. If the patient is eligible for the study, the practitioner will present the study to him/her or to his/her surrogate or legal representative. The patient will be preincluded after written consent. Routine biological lab tests for safety will be performed before first daptomycin infusion. DDC sequence will be administered (D1). CSF will be collected from all patients. Gram stain and culture of CSF will be performed. The identification of the pneumococcal antigen will rely on BINAX NowStreptococcus pneumoniae immuno-chromatographic test performed on CSF samples. If bacteriological tests confirm pneumococcal meningitis, daily infusion of daptomycin will be administered for eight consecutive days (except if the renal clearance is below 30 mL/min, in which case daptomycin should be administered every 48 hours). If the pneumococcal origin of the meningitis is ruled out, daptomycin will be stopped. Biological tests for safety will be performed during hospitalisation.

    No treatments are forbidden. However, patients with statin treatment could have an increased creatine phosphokinase levels; temporary suspension of this treatment may be considered during daptomycin treatment.

    The overall management will be carried out without modification of the current recommendations.33 34 A D30 visit will be schedules between D30 and D40 and a D90 visit (end of the study) between D90 and D100 for patients with confirmed pneumococcal meningitis, with collection of endpoint data. Patients for whom pneumococcal meningitis (safety population) will have been ruled out will be called between D30 and D40 in order to collect information about adverse events (AEs). Vital status at D90 will be collected for all patients.

    Patient and public involvement

    No patients involved.

    Oversight and monitoring

    Data safety monitoring board

    The data safety monitoring board will be composed of a statistician experienced in clinical trials, a clinician specialised in infectious diseases, and a pharmacologist, all of whom will be independent of the investigators and sponsor.

    The aim of this board is to ensure patient safety and compliance with the protocol. Its members will oversee the study (AEs, significant event analysis, recruitment, etc…).

    The first meeting will be held immediately before the start of the study, then every 6 months by conference call, or after one suspected unexpected serious adverse reaction.

    Study coordinating centre

    Methodology, data management and study coordination will be provided by the coordinating centre (INSERM CIC1432 of Dijon) which is responsible for preparing study documents with the coordinating investigator, for investigators assistance, site visits, newsletters, committee management (ie, planning meetings, preparing documents for meetings, recording minutes, distributing minutes to all persons concerned), data management, routine quality controls and statistical analysis.

    Steering committee

    The steering committee will comprise the coordinating investigator (Pr Chavanet), the co-coordinating investigator (Dr Blot), the study methodologists and the statistician, the project manager representing the sponsor (CHU Dijon Bourgogne), one representative of the safety and the coordinating clinical research associate. The steering committee will make decisions concerning the study, including administrative and financial aspects and study promotion. The first meeting will be held immediately before starting of the study, then every 6 months, and finally at the end of the study by conference call.

    Quality control and monitoring

    A clinical research assistant mandated by the sponsor will regularly visit each study centre. In all, there will be seven visits per centre (one at the beginning of the study, five during the study and one at the end of the study).

    During these visits, the following elements will be reviewed:

    • Informed consent.

    • Compliance with the study protocol and the procedures that are defined in it.

    • Notification of serious AEs.

    • Traceability of study drugs (pharmacy visit, storage),

    • Quality of data collected in the e-CRF: coherence with source documents (medical files, appointment books, original copies of lab test results, etc).

    • Quality of biological collection.

    Considering the study risk, 100% of cases will be checked. For each visit, a written monitoring report will be drafted. Persons responsible for quality control of biomedical research and duly authorised for this purpose by the sponsor have access, subject to the agreement of the persons concerned, to individual data strictly necessary for this control; they are subject to confidentiality under the conditions defined by Articles 226-13 et 226-14 of the Penal Code. Investigators will make available the documents and individual data strictly required for monitoring, quality control and audit of the biomedical study to persons having right of access, in accordance with the statutory and regulatory provisions in place (clauses L.1121-3 and R.5121-13 of the French Public Health Code).

    An audit may be performed at any time by persons mandated by the sponsor and independently of those in charge of the study. The aim is to ensure the quality of the study, the validity of the results and compliance with the current law and regulations in force.

    Investigators accept to comply with the demands of the sponsor and the competent authorities with regard to an audit or inspection of the study.

    The audit may occur at any stage of the study, from protocol development to publication of results, and to the storage of data used in, or produced by, the study.

    Adverse events

    The safety of daptomycin will be evaluated from inclusion until D30 after initiation of daptomycin.

    In case of a serious AE, the investigators musts inform the sponsor by telephone, fax or mail of the onset of the event (whether or not the event is linked to daptomycin), whether it is expected or unexpected. This information must be passed on with 24 working hours following discovery of the serious AE. AEs that are not serious will be recorded in the case report forms.

    In accordance with law relative to public health policy, expected75 and unexpected serious adverse effects must recorded and reported to (1) the competent authority (ANSM for France), (2) the competent Ethics Committee (Comité de Protection des Personnes in France) and (3)- the European Medicines Agency via the Eudravigilance declaration portal. The causal link between the expected or unexpected AE and daptomycin will be investigated.

    Sample size

    The calculation for the sample size is based on 30-day DFS observed in the French COMBAT cohort.2 Using a Simon two-stage design based on a 30-day DFS of 50%, and assuming that the daptomycin add-on therapy would increase the DFS to 65%, with a one-sided alpha risk of 0.1 and a power of 90%, the first stage of the trial should include 40 patients. At the end of the first stage, the study will be stopped for futility if 19 patients or fewer survive without disability at D30. Otherwise, if 20 patients or more survive without disability at D30, inclusions will be pursued until 72 analysable patients are obtained and daptomycin add-on therapy will be considered potentially effective and warrant more extensive investigation (randomised phase III trial) if 42 patients or more survive without disability at the end of the second stage (online supplemental figure). To account for drop-outs, screening failures, which may be particularly frequent in the emergency context, and patients full-filling inclusion criteria but in whom pneumococcal meningitis diagnosis will be ruled out, 128 patients are planned to be included to reach 72 analysable patients.

    Statistical analysis

    Population

    The intention-to-treat (ITT) population will consist of all patients who consented to participate in the study and for whom the diagnosis of pneumococcal meningitis was confirmed. The modified ITT population will include all patients who consented to participate in the study and for whom the diagnosis of pneumococcal meningitis was confirmed and having received the DDC sequence (whatever the order of the drugs) in the 12 hours following the suspicion of pneumococcal meningitis. The PP population will exclude all subjects in the ITT population who meet any of the following criteria:

    • Discontinuation of the protocol before H72 for whatever reason.

    • Patients with major deviations from the protocol.

    • Unmet DDC sequence (daptomycin performed before dexamethasone or after cefotaxime/ceftriaxone).

    • First daptomycin infusion not administered in the first 6 hours following lumbar puncture.

    Safety analyses will be performed on the safety population, which will comprise all patients who consented to participate in the study (including patients with non-confirmed meningitis) and who have been given at least one infusion of the studied treatment.

    Demographic and baseline characteristics

    Patients’ characteristics at baseline will be described as frequencies for categorical variables, and in terms of means (±SD) or medians (IQR) for continuous variables depending on their distribution.

    Primary efficacy analysis

    The main analysis will be conducted on an ITT basis.

    The efficacy of the treatment will be assessed as follows: if 41 or fewer of the 72 patients survive without disability at D30, daptomycin add-on therapy will be considered not worthy of any further investigation in this patient population. Otherwise a phase III clinical trial will be planned. The 95% CI for the D30 DFS will be calculated on the basis of an exact binomial probability. This ITT analysis will be completed with a per-protocol (PP) analysis. The conclusion of the trial will only rely on the ITT analysis.

    An interim analysis at the end of the first stage is planned after the first 40 patients have been included in the safety study.

    Secondary analyses

    Safety and tolerance will be described for each AE. This analysis will be performed on patients that will take at least one dose of the study drug.

    The mortality rate, the proportion of patients with a disability at D30 and at D90, and the proportion of patients with hearing deficit will be expressed as percentages with its 95% CI. The SF-12 scoring algorithms will be used to compute scores for the eight scales and the two summary measurements. The WHOQOL bref score, the number of days without hospitalisation and the number of days without antibiotics at D30 will be expressed as means (±SD) or as medians (IQR), as appropriate. Dead patients will be considered to have been hospitalised and to have received antibiotics between the date of death and D30.

    Ethics and dissemination

    The study protocol was approved by the Institutional Review Board of the IDF 1 ethics committee on 16 January 2018, and authorisation was obtained from the Agence Nationale de Securité des Médicaments et des Produits de Santé on 22 September 2017. The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki and the recommendations of the Good Clinical Practices guidelines.

    Any protocol amendments during the study will be communicated and changed accordingly in the relevant registries after approval from the institutional review board.

    In certain emergency situations such as acute bacterial meningitis, it is not possible to go through the informed consent procedure and obtain the consent of the patient or even a legal representative prior to the urgent intervention. Even in these circumstances, consent is not waived but rather postponed.

    The results of this study will be submitted for publication in a peer-reviewed journal, regardless of the outcome, according to the CCMO statement on publication policy. Data will also be presented at national and international conferences.

    Discussion

    While pneumococcal meningitis is relatively rare in the general population, it is a very severe disease; the mortality rate is as high as 20%–30% and up to 40% of patients have sequelae. These poor clinical outcomes may be related to intense pneumococcal lysis and an excessive immune response. Furthermore, considering that antibiotic resistance could be a potential threat, the addition of daptomycin is of interest since this drug is highly bactericidal and synergistic with third generation cephalosporin.38

    Considering its characteristics, daptomycin could be beneficial in this context and the new strategy proposed here is very pragmatic since it consists simply in the addition of daptomycin to the recommended treatment for pneumococcal meningitis. The full therapeutic strategy will thus become: the immediate successive administration of dexamethasone then daptomycin and then cefotaxime (DDC sequence), which is easily feasible in an emergency unit.

    Although daptomycin is widely used, there is no cohort or case series available for the treatment of pneumococcal meningitis. We, therefore, chose to construct a prospective, non-randomised, non-comparative phase II trial; we also chose Simon’s two-stage method to benefit from an interim analysis so as not to overlook a potential futility.

    The proposed phase II trial will allow us to determine whether this strategy has the expected overall effect on 30-day DFS, and it will also help to determine whether some patients with specific profiles are more or less likely to respond to such a strategy or to present adverse effects.

    The results will be compared with the data of previous cohorts in France or in Europe. It is highly likely that the results will be similar to those obtained in other cohorts. This information is of course required before considering the design of phase III randomised controlled trial to confirm or not the efficacy of the proposed DDC sequence compared with the present DC strategy.

    In conclusion, since pneumococcal meningitis is still associated with considerable mortality and morbidity, new strategies likely to limit excessive inflammation are urgently needed. The DDC sequence represents one of these strategies, which will be investigated in the present AddaMAP clinical trial. We are convinced that the DDC sequence, combined with pneumococcal vaccination, will contribute to reducing both the incidence and the severity of this invasive pneumococcal disease.

    Ethics statements

    Patient consent for publication

    Acknowledgments

    The authors thank National Clinical Research Network in Infectiology—RENARCI), Pr X Duval (Clinical Investigation Centre, Bichat Hospital, Paris, France), Dr E Varon (National Reference Center for Pneumococcus, Créteil, France), Pr B Mourvilliers (ICU, Reims, France), Stephen Leib and D Grandgirard (Neuroinfection Lab, Bern, Switzerland) and ESCMID Study Group for Infectious Diseases of the Brain—ESGIB for their assistance in preparation of this study.

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    Footnotes

    • Collaborators E Galizzi, M Carpentier, S Gohier and C Charles.

    • Contributors PC is one of the designers of the study, wrote the scientific and methodological rationale for obtaining the grant, wrote the protocol, is the principal investigator and is the main contributor to the manuscript. PC (along with CB) is responsible for the overall content as guarantor. IF wrote the protocol, ensures the methodological coordination and critically revised the manuscript. AB is responsible for the statistical aspect of the project; in particular, he established the Simon’s plan and calculated the number of subjects required. LP is clinical investigator, served as scientific advisors and critically revised the manuscript. MB is clinical investigator and critically critically reviewed the manuscript. TS is clinical investigator, provided and cared for study patients and critically revised the manuscript. CB is one of the study designers, planned the research and ensures the global coordination of the trial. CB (along with PC) is responsible for the overall content as guarantor.

    • Funding This study is supported by the Clinical Research Hospital Program ID RCB 2017-002888-18 (PHRC-N 2017), France; grant number: PHRCN-16-0225.

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.