Introduction
Endometriosis is a chronic incurable condition affecting an estimated 190 million women worldwide.
1 It is defined by the presence of endometrial-like tissue outside the uterus (lesions), commonly on the peritoneum. Hallmarks of the disease include debilitating pelvic pain and infertility. Management options for endometriosis-associated pain are often unsatisfactory; painful symptoms recur within 5 years following surgical treatment in 40–50% of women,
2 and drug treatments are often ineffective or have unacceptable side-effects.
3 Furthermore, as the mainstay of medical treatments are hormone-based and usually contraceptive, they are inappropriate for women desiring pregnancy, and the hypo-oestrogenic state induced by gonadotropin-releasing hormone agonists can preclude long-term use.
4 Therefore, there is an urgent unmet need for new non-hormonal treatments for endometriosis.
5Research in context
Evidence before this study
We searched PubMed for articles published from database inception to June 1, 2025. We used the search terms “endometriosis” AND “treatments” AND “dichloroacetate” OR “sodium dichloroacetate” OR “dichloroacetic acid”. Three studies were found, which included our published study protocol. The second paper was a summary of our preclinical studies, in which dichloroacetate appeared a promising non-hormonal treatment for endometriosis. The third paper replicated our preclinical findings of elevated pyruvate dehydrogenase kinase 1 and lactate concentrations in endometriosis stromal cells, and that treatment with dichloroacetate inhibited lactate levels. There were no published in vivo studies assessing dichloroacetate in patients with endometriosis. In previous clinical trials, in both paediatric and adult populations with other conditions such as congenital and acquired lactic acidosis, diabetes, and liver cirrhosis, dichloroacetate was effective at reducing systemic lactate levels. In trials of dichloroacetate in glioblastoma, pulmonary hypertension, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome, higher doses of dichloroacetate, or more prolonged treatment regimens resulted in a reversible peripheral neuropathy.
Added value of this study
This study represents the first reported use of dichloroacetate in individuals with endometriosis. The study assessed the feasibility of conducting a trial, using the outcomes of recruitment and retention. The study generates novel insights into dichloroacetate-related adverse effects in this population. Genotyping was also done to assess any association between GSTZ1 haplotypes, drug concentrations, and susceptibility to adverse effects. This study was the first time that genotyping had been performed specifically for this enzyme in patients with endometriosis.
Implications of all the available evidence
Although this trial was not designed to evaluate the efficacy of dichloroacetate or to determine whether it exerts disease-modifying effects in endometriosis—as previously suggested by preclinical models—we have shown the feasibility of recruiting individuals with endometriosis into dichloroacetate-focused clinical research. Although not all retention metrics were achieved, these shortfalls were attributable to necessary adaptations in study delivery imposed by the COVID-19 pandemic, rather than deficiencies in the design of the trial. On this basis, we believe advancing to a randomised placebo-controlled trial assessing dichloroacetate for the treatment of endometriosis with the use of genotyping as a means to mitigate side-effects and optimise treatment tolerability, is appropriate. A further larger, definitive, adequately powered, placebo-controlled trial will ultimately be required to determine whether dichloroacetate is an effective treatment for endometriosis-associated pain. Should efficacy be established, the off-patent status of dichloroacetate could make it a cost-effective therapeutic option, addressing the crucial need for a non-hormonal medical treatment in endometriosis care.
We have previously shown that pelvic peritoneal mesothelial cells recovered from women with endometriosis exhibit substantially higher glycolysis and increased production of lactate compared with pelvic peritoneal mesothelial cells from women without endometriosis.
6,7 Single-cell sequencing of paired eutopic and ectopic endometriosis lesions has confirmed the latter have an altered metabolic signature.
8 In tumours, lactate is a key factor driving cell invasion and angiogenesis,
9 processes also implicated in the establishment and survival of endometriosis lesions. These data prompted us to investigate whether dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, could be a novel non-hormonal therapy for endometriosis. We showed that dichloroacetate normalises pelvic peritoneal mesothelial cell metabolism, reduces lactate secretion, and abrogates endometrial stromal cell proliferation in a co-culture model. In mice with induced endometriosis, dichloroacetate reduced peritoneal fluid lactate production and lesion size.
10 Others have confirmed that dichloroacetate reduces lactate levels and pyruvate dehydrogenase kinase 1 activity in cultured stromal cells from endometriosis lesions.
11Dichloroacetate is already used as a treatment for pyruvate dehydrogenase deficiency in neonates and children
12 and has been assessed in phase 2 and 3 trials for multiple conditions including other mitochondrial disorders,
13 pulmonary hypertension,
14 and malignancy.
15,16 Results from these trials informed our choice of dose of 25 mg/kg or less, because some individuals reported a dose-related reversible peripheral neuropathy with higher doses.
17 Notably, response to dichloroacetate can be influenced by the haplotype of the gene that encodes the enzyme
GSTZ1.
17 Carriers of the genetic variant
GSTZ1C are reported to metabolise dichloroacetate faster than non-carriers, which could have implications for the risk of developing side-effects.
18We aimed to perform a single-arm feasibility study of dichloroacetate for the treatment of endometriosis-associated pain. The key questions were whether a subsequent randomised controlled trial could be feasibly conducted, and whether the uncertainties surrounding recruitment and retention could be effectively addressed before proceeding.
Methods
Study design
We conducted a single-centre, single-arm, open-label feasibility study at the Royal Infirmary of Edinburgh, NHS Lothian, UK (EPiC1). Ethics approval for EPiC1 was obtained from Scotland A Research Ethics Committee (19/SS/0063). Following completion of the study, participants were invited to consent to provide an additional blood sample for genotyping of the dichloroacetate metabolising enzyme,
GSTZ1. Ethics approval for genotyping was obtained from West Midlands–Solihull Research Ethics Committee (22/WM/0158). The trial protocol has been published.
19 A patient panel informed the study design and development of patient-facing materials. The trial was registered with
ClinicalTrials.gov (
NCT04046081).
Participants
Participants were recruited from gynaecology outpatient clinics in NHS Lothian, UK. Recruitment was temporarily suspended during 2020 due to the COVID-19 pandemic, forcing some participants to be withdrawn. An anonymised screening log was maintained of potential participants, including reasons for non-eligibility and reasons for not participating if eligible.
The inclusion criteria were premenopausal women aged 18 and older; bodyweight of 50–100 kg; American Society for Reproductive Medicine stage I or II endometriosis surgically confirmed within the past 5 years; and pelvic pain for more than 6 months with an average pain score over the preceding 4 weeks of 4 or more on a numerical rating scale of 0–10. Patients were excluded if they were pregnant, actively trying to conceive, or breastfeeding, or if they had a history of pre-existing peripheral neuropathy, malabsorption, diabetes, or kidney or liver disease. A full list of inclusion and exclusion criteria is given in the protocol.
19 Participants were advised to use effective contraception throughout the trial if they were sexually active. Ethnicity was self-reported. Participants were permitted to use hormonal medication if they had started treatment more than 3 months previously.
All participants provided written informed consent. For women recruited after Aug, 20, 2020, consent was initially obtained by telephone, with written consent obtained at the first study visit.
Procedures
Dichloroacetate was provided in capsules containing 333 mg or 500 mg dichloroacetate powder (Curaltus, Vilnius, Lithuania). The total duration of treatment was 12 weeks.
19 Participants were prescribed dichloroacetate at a dose approximate to 6·25 mg/kg total bodyweight twice daily for 6 weeks. After 6 weeks, if good control of painful symptoms had been achieved, the participant continued the dose without escalation. However, if participants had ongoing painful symptoms and tolerable side-effects, they were asked to increase the dose to an equivalent of 12·5 mg/kg total bodyweight twice daily. If side-effects were experienced at the higher dose, the participant could opt to return to the 6·25 mg/kg total bodyweight dose twice daily. Throughout the study, if a participant had side-effects and no improvement in pain symptoms, they could discontinue treatment. Participants were permitted to take oral analgesics and alternative treatments for pain.
Average pain scores over the preceding 4 weeks were recorded on a 0–10 numerical rating scale for assessment of eligibility. At baseline, after informed consent had been received, we obtained demographics, past medical history, and information about current treatments, and we asked participants to do a urine pregnancy test. We asked participants to complete the Endometriosis Health Profile-30,
20 PainDETECT,
21 Brief Fatigue Inventory,
22 and Pain Catastrophizing Questionnaire,
23 as well as provide recalled average pain scores over the preceding four weeks on a numerical rating scale of 0–10, at baseline and after 6 weeks and 12 weeks of dichloroacetate use. At the end of the 12-week study, and 4 weeks after cessation of dichloroacetate, participants were asked to complete an acceptability questionnaire (11 questions using a 5-point Likert scale) and a perception in change of overall health as rated using a 7-point Likert scale).
Before the COVID-19 pandemic, blood pressure, pulse, respiratory rate, and oxygen saturation were checked at baseline (visit 1) and weeks 2 (visit 2), 6 (visit 3), 8 (visit 4), and 12 (visit 5). Venous blood samples were also obtained at these timepoints, for measurement of dichloroacetate levels. Following the pandemic (March 17–Aug 20, 2020), all these assessments were performed at baseline and weeks 6 and 12 only. Adherence was assessed by the study nurse at each study visit by questioning patients and reviewing dichloroacetate levels.
Dichloroacetate levels were assessed by liquid-chromatography with tandem mass spectrometry. Serum was obtained from venous blood collected in 9 mL Sarstedt Monovette Serum gel tubes (Sarstedt, Leicester, UK); the tubes were centrifuged at 2500 g at 4°C for 10 min and stored at –80°C until liquid-chromatography with tandem mass spectrometry was carried out for analysis of dichloroacetate levels. This method was validated following European Medical Agency guidelines
24 for bioanalytical methods.
All participants were offered genotyping, which enabled exploration of the effect of the
GZTZ1 haplotype on dichloroacetate levels. Sanger sequencing was performed on venous blood samples obtained from the subset of participants who consented. DNA was extracted from venous blood collected in 9 mL EDTA tubes (Sarstedt) using the QIAamp blood mini kit (Qiagen, Manchester, UK) following the manufacturer's instructions. DNA was quantified using the Nanodrop 1000 (Thermo Fisher Scientific, Loughborough, UK) and adjusted to 10 ng/μl. Primers specific to
GSTZ1 single-nucleotide polymorphisms (Thermo Fisher Scientific;
appendix p 1) were analysed using
SNPcheck. Sanger sequencing was performed on Applied Biosystems 3500XL (Thermo Fisher Scientific) in the accredited NHS Lothian Molecular Pathology Department (Edinburgh, UK) under ISO 15189:2012.
Adverse events were assessed at each study visit by the study team in addition to ad hoc reporting by participants. All adverse events were reviewed by the Principal Investigator or delegated to clinicians within the study team who were also responsible for determining the likelihood of association with dichloroacetate use. Known side-effects, including reversible peripheral neuropathy, were not reported as adverse events but were collected in the case report form at each study visit. Persistent peripheral neuropathy was graded according to Common Terminology Criteria for Adverse Events (version 4.0). Grade 3 neuropathy and below was not considered as a serious adverse event.
Outcomes
Our primary outcomes were recruitment and retention. Retention was assessed based on the proportion of recruited participants ever receiving dichloroacetate who at week 6 (visit 3) and week 12 (visit 5) completed the six retention metrics including submitting their average numerical rating scale scores, completing the assessment tools (ie, the Endometriosis Health Profile-30, PainDETECT, Brief Fatigue Inventory, and Pain Catastrophizing Questionnaire), and attending per-protocol blood testing. Recruitment of 50% or more of the eligible patients approached, and retention of 80% or more of the participants who commenced treatment and completed all per-protocol metrics of retention, was deemed acceptable for progression to a subsequent randomised controlled trial based on our previous feasibility studies.
25,26 Secondary outcomes included measures of adherence (ie, self-reported compliance and presence of dichloroacetate in serum), self-reported side-effects, and study acceptability (as per the questionnaire at study end).
Statistical analysis
The emphasis in this study was to establish feasibility, not statistical significance. We aimed to recruit 30 participants. Assuming the target of 50% eligible individuals recruited was achieved, this would allow us a precision of less than 15%. Summary data were used to describe baseline characteristics: for continuous variables mean and SD or median and IQR, and minimum and maximum were reported, and for categorical variables the number (percentage) of individuals was reported. The recruitment and retention rates were reported with exact binomial 95% CIs, due to the small sample size. Questionnaires were scored according to the manuals or author guidelines supplied. A statistical analysis plan was created before any analysis was done (
appendix p 31).
Role of the funding source
The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the results for publication.
Results
Screening of patients began on Nov 19, 2019, and the last participant started dichloroacetate on April 23, 2021. The study ended on Aug 13, 2021. Recruitment was paused during the COVID-19 pandemic from March 17 to Aug 20, 2020. As advised by the funder, participants who were in the first 6 weeks of treatment were withdrawn from the study (ie, two participants). Participants who were in week 7 or later were allowed to continue treatment, but subsequent visits were conducted remotely (five participants).
Of 93 women who were identified by screening, 77 patients could be contacted and were approached to participate (
figure), of whom 54 (70%, 95% CI 59–80) were eligible. Of the eligible women, 30 (56%, 95% CI 41–69) were recruited. One participant was withdrawn immediately after consent as their bodyweight was greater than the 100 kg limit for the inclusion criteria. The remaining 29 (97%) participants were prescribed dichloroacetate and were used to calculate subsequent retention metrics. Two (7%) people were lost to follow-up and a further nine (30%) stopped their treatment early (three due to side-effects, two due to unexpected pregnancy, two due to restrictions following the onset of the pandemic, and two due to anxiety). 18 (60%) participants completed all 12 weeks of treatment.
Participant characteristics are reported in
table 1. All participants were female. The initial dose of dichloroacetate was determined by the bodyweight of the participant. At 6 weeks, 19 (83%) of 23 participants still receiving dichloroacetate had had their dose escalated (
appendix p 2).
Of 145 possible study visits that could be completed by the 29 participants who commenced treatment, 128 (88%, 95% CI 82–93) were completed. However, only 19 (66%, 56–89) participants completed all retention metrics, which was predominantly due to missing numerical rating scale scores for pain at week 12, which were returned by 21 participants (72%, 56–89;
table 2;
appendix p 7). The eight people who did not return scores were the two individuals who had been lost to follow-up and six participants who stopped treatment. All other individual metrics for retention had rates of more than 80% (
table 2). Numerical rating scale scores for pain were returned in week 6 by 24 (83%, 69–97) participants, and 27 (93%, 73–98) participants completed some (ie, one to two or three) questionnaires at the final study visit in week 12 (
table 2). Pain scores and questionnaires at baseline, week 6, and week 12 are reported in the
appendix (pp 7–8). Perceived change in analgesic use was reported at weeks 2, 6, 8, and 12 (
appendix p 9).
Acceptability questionnaires were returned by 17 (94%) of the 18 participants who completed 12 weeks of treatment and by five (45%) of the 11 who stopped treatment early (
table 3). Most participants described their experience positively (
table 3).
At week 2, 28 (97%) participants were still taking dichloroacetate; at week 6, 23 (79%); week 8, 22 (76%); and 18 (62%) participants completed all 12 weeks of treatment. Self-reported adherence in those continuing to take dichloroacetate was good with at least 95% of participants, across all weeks, reporting taking all or almost all of their medication (
table 4). For those participants who stopped between visits they could still return their diaries, which would include the dichloroacetate that they had taken before stopping.
At week 6, 24 women were still in the study (one had stopped taking dichloroacetate but had not been withdrawn). Of the per-protocol visits for blood testing (encompassing protocol changes that required some participants not to attend for testing due to COVID-19 restrictions or if they had stopped treatment), 24 (100%; 95% CI 86–100) attended for blood sampling at week 6 and 12 (86%; 57–98) of 14 participants at week 12 attended (
appendix p 3). Testing of venous blood samples confirmed that dichloroacetate had been used in all participants who were tested, except for four blood samples from three participants (
appendix p 3). Two of these participants had low levels of dichloroacetate in the first stage of treatment before undetectable levels later in the study. Both participants reported completion of treatment, although both returned only some of the end of study assessments. A third participant had undetectable levels at week 6 and discontinued treatment before week 12.
No serious adverse events or changes in blood pressure were reported. 12 (41%) of 29 participants reported a total of 21 adverse events (
appendix p 4), of which 12 (57%) were unrelated to dichloroacetate treatment, as determined by the study team. Known side-effects of dichloroacetate were frequently reported (
table 5). The most common side-effect was nausea, reported by 17 (61%) of 28 participants at any time during the trial. 15 (54%) participants reported a tingling sensation, consistent with paraesthesia, or numbness. Most occurrences of these known side-effects were intermittent and mild, but six participants developed persistent symptoms consistent with peripheral neuropathy (
appendix p 5). Four had grade 1 neuropathy and one each had grade 2 and grade 3; in these latter two cases, treatment was stopped by the trial team after dose reduction did not substantially improve symptoms. A further two participants with grade 1 neuropathy stopped treatment early for unrelated reasons: one because of the onset of the COVID-19 pandemic and one from anxiety. All occurrences of peripheral neuropathy fully reversed with the cessation of treatment. One participant who developed neuropathy had a PainDETECT score in keeping with neuropathic pain at baseline, but no other participants who developed neuropathy returned scores in keeping with neuropathic pain at any timepoint. Of the two women who became pregnant during the study and discontinued, one opted for medical termination of the pregnancy in the first trimester (maternal choice, unrelated to study participation). The second continued with her pregnancy: fetal anomaly, cardiac scans, and growth scans were all normal and a healthy baby was born at term.
Ten participants consented to genotyping, of whom five had developed peripheral neuropathy during treatment (
appendix p 6). One participant's sequencing results did not pass quality control and was not repeated. The two participants who had grade 2 or 3 neuropathy were homozygous for polymorphisms associated with slow metabolism (
GSTZ1B/GSTZ1B and
GSTZ1D/GSTZ1D); the two participants reporting grade 1 neuropathy were heterozygous (both
GSTZ1C/GSTZ1B). Of the other five individuals who underwent genotyping but who did not report neuropathy, one was homozygous for the fast metabolism polymorphism (
GSTZ1C/
GSTZ1C) and four were heterozygous for fast and slow polymorphisms. Of the four participants who were heterozygous, two had not increased their dose and one had dose reduction after escalation for intermittent side-effects. None of the three participants who had undetectable dichloroacetate levels at blood testing underwent genotyping.
Discussion
The EPiC1 study is the first trial reporting the use of dichloroacetate in women with endometriosis. The primary objective was to determine whether women with endometriosis would wish to take part in a study using dichloroacetate. EPiC1 successfully met its prespecified threshold for acceptable recruitment and achieved all but one retention metric. Retention challenges were largely attributable to the COVID-19 pandemic due to the nationwide restrictions on in-person hospital visits. Despite this, participants reported favourably on the acceptability of the study and no serious adverse events were reported. Side-effects such as gastrointestinal upset and paraesthesia were common but consistent with the known safety profile of dichloroacetate, and only three participants stopped treatment because of these side-effects. These findings support further investigation of dichloroacetate as a potential treatment for endometriosis.
The COVID-19 pandemic affected trial delivery, with a halt in recruitment and loss of some follow-up data for seven participants who had already commenced treatment. As follow-up visits for any participant who stopped treatment early were rationalised on resumption of the trial, this could have affected the collection of numerical rating scale scores, which were collected in person at study visits. The collection of numerical rating scale scores was the only retention-related metric not to reach 80%. By contrast, end-of-study questionnaires (which were completed online) were completed by all participants, including those who had stopped treatment, except the two who were lost to follow-up. Recruitment and retention outcomes were broadly comparable with those in a pre-pandemic feasibility study investigating another non-hormonal therapy for endometriosis.
26 The shift to remote delivery for study aspects, including telephone consent and online completion of questionnaires, could improve recruitment and retention in a future randomised controlled trial of dichloroacetate. These strategies might also enhance accessibility for historically under-represented groups, such as those from lower socioeconomic backgrounds, for whom more frequent hospital visits pose logistical and financial barriers to participation.
All participants were advised to use effective contraception if they could become pregnant during study participation. In animal studies, dichloroacetate exposure in utero is associated with an increased rate of miscarriage, cardiac and renal congenital abnormalities, and decreased birthweight.
27,28 Although our study reports the first pregnancy outcomes in women receiving dichloroacetate, and no adverse outcomes occurred in the completed pregnancy, substantially more robust safety data would be needed before dichloroacetate use could be considered in those actively trying to conceive.
Reversible peripheral neuropathy was reported by some participants, despite a lower initial dose of dichloroacetate than the 25–50 mg/kg per day used in previous studies for other indications.
17 However, most occurrences of neuropathy developed after dose escalation, and only two affected participants stopped treatment specifically because of neuropathy, at the instigation of the trial team. For all participants reporting neuropathy, symptoms resolved after treatment cessation, although the time to resolution was typically associated with neuropathy grade. Although previous studies have suggested dichloroacetate-associated neuropathy is broadly dose-dependent,
15,18 no clear plasma concentration threshold has been identified.
17 In our study, the two participants with the highest dichloroacetate serum levels experienced a higher grade of peripheral neuropathy. However, some of those with grade 1 neuropathy had similar dichloroacetate levels to those without a persistent neuropathy, which suggests additional factors could influence susceptibility. Other studies have postulated that age and comorbidities such as diabetes, or chemotherapy-induced peripheral neuropathy, could increase vulnerability to dichloroacetate-related neuropathy.
13 Notably, the two participants with higher-grade neuropathy were homozygous for
GSTZ1 haplotypes associated with slow dichloroacetate metabolism (
GSTZ1B and
GSTZ1D). Conversely, the participant who was homozygous for
GSTZ1C had one of the lowest serum levels at week 6, but the other two participants with low dichloroacetate levels were not genotyped, preventing further speculation. Another participant had an early onset of grade 1 peripheral neuropathy, but due to the COVID-19 pandemic stopped treatment in week 3. It is uncertain whether they would have developed more severe symptoms if they had continued with treatment. Of the remaining participants with grade 1 neuropathy, one stopped treatment early due to anxiety unrelated to neuropathy, and two completed the 12-week course, reflecting that these symptoms did not affect adherence. Without including systematic genotyping in our study design, we cannot be certain whether the variations in dichloroacetate levels reflect the underlying
GSTZ1 genotype. However, the potential association between dichloroacetate dose, plasma concentrations, and neuropathy severity suggests a putative role for pharmacogenetics to facilitate dichloroacetate dose adjustment. This strategy is now advocated in other areas for which dichloroacetate could have an application (eg, oncology).
15EPiC1 was not an efficacy study, nor did it incorporate qualitative components, so we were unable to further assess the relationship between reported side-effects, the effect on endometriosis symptoms, and adherence. Hormonal treatments remain the mainstay of medical treatment for endometriosis, but they often cause adverse events such as unscheduled bleeding, effects on mood, and skin disorders.
29 Despite this, patient use and adherence to these treatments continues.
30 A medication with a different side-effect and safety profile might be acceptable to patients, especially if associated with high efficacy.
There was very little ethnic diversity in EPiC1, although participant ethnicity was reflective of Scotland (92·9% White according to the 2022 Scottish census).
31 Greater diversity in the next phase of study (EPiC2) will be important to ascertain more generalisable estimates of acceptability and efficacy, particularly given the potential link between the
GSTZ1 polymorphism and ethnicity.
32 Social deprivation, gender identity, and sexual orientation were not captured, precluding analysis of these factors and their effect on the acceptability of the study. Additionally, the open-label single-arm design could have influenced recruitment and retention. Although we did not specifically assess efficacy, perceived benefit as reflected by the Endometriosis Health Profile-30 scores, analgesia use, and quality of life, could have contributed to retention. Our next planned trial (EPiC2) will address many of these limitations. EPiC2 is a multicentre study with a double-blind, placebo-controlled design, which will incorporate dose modification based on baseline genotyping and bodyweight and will include recruitment from a study site with a more ethnically diverse patient population. Patient-reported outcome measures will be collected digitally, minimising the need for in-person hospital visits. We will assess the effect of a placebo group and blinding on recruitment and retention, of genotyping to minimise side-effects, and generate a signal of efficacy data.
EPiC1 is the first reported use of dichloroacetate in women with endometriosis in whom treatment for 12 weeks with oral dichloroacetate appears acceptable. Side-effects in this population could be influenced by polymorphisms of the GSTZ1 enzyme response for dichloroacetate metabolism. These data support further exploration of dichloroacetate to treat endometriosis-associated pain in this common and debilitating condition, and the EPiC2 study is planned (funding code RG2415).
Contributors
All authors contributed to the conception, design, and delivery of the study. AWH, PTKS, and JPD secured funding. MK, AMD, FC, LCS, and PF were responsible for the day-to-day management of the trial. AWH, JPD, AMD, FC, M-CJ, LHRW, and LJW were the trial management group. LJW performed the statistical analyses, AMD conducted the data cleaning before analysis, and LHRW, LJW, and AMD directly accessed and verified the data with additional clarification from PF. All authors had full access to the data. LHRW, LJW, M-CJ, JPD, and AWH drafted the report, and all authors provided input into editing the manuscript for publication. All authors accept responsibility for the decision to submit for publication. The corresponding author had full access to all of the data and the final responsibility to submit for publication.
Data sharing
The datasets used and/or analysed during this study, including de-identified individual patient data and data dictionaries are available from the corresponding author upon reasonable request. Requests will be assessed for scientific rigour before being granted. Data will be anonymised and securely transferred. A data sharing agreement might be required. The study protocol and statistical analysis plan are included in the
appendix (pp 10, 31).
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