Control, Fludrocortisone or Midodrine for the treatment of Orthostatic Hypotension (CONFORM-OH): Results from an internal pilot randomised controlled trial

Background Orthostatic hypotension (OH) is a common debilitating condition characterised by a significant drop in blood pressure (BP) on standing upright. Adults with OH are typically offered non-pharmacologic therapies, either alone or in combination with medication. The two most used agents are fludrocortisone and midodrine. There is a lack of good quality evidence for any of these treatments, all of which are in widespread clinical use. The aim of this internal pilot trial was to evaluate recruitment, attrition, treatment crossover and quality of outcomes.

The trial was designed as a pragmatic, open label, randomised, prospective, multicentre, superiority, multi-arm internal pilot. Within the 10-month pilot, a target of 64 adults with OH from 14 sites, was required to evaluate feasibility of recruitment, attrition, crossover and data collection. Participants were randomised to one of three treatments: non-drug therapies (control), fludrocortisone plus non-drug therapies or midodrine plus non-drug therapies. Outcomes measured included symptoms, quality of life, activities of daily living, postural BP, use of health and care services, falls and safety. Participants received treatment and were followed-up for 12 months. Pre-planned criteria to progress from internal pilot were defined for recruitment, retention, crossover and outcome completion.

Between the 3rd December 2021 and 31st August 2022, 13 participants were randomised from four of nine recruiting centres. Redeployment of clinical and research staff, due to COVID-19, limited the number of available sites. Participants already receiving fludrocortisone or midodrine accounted for 120 of 233 eligible participants being excluded. Due to the low sample size the rates of attrition and crossover are of limited value. Apart from the falls diaries, completion rates of the outcome measures were high. Due to low recruitment rates the pilot did not progress to the planned multi-arm multi-stage trial.

In its current design, this trial was not feasible. The main barriers to success were participants already receiving treatment and redeployment of clinical and academic staff during and after the COVID-19 pandemic. Trial registration ISRCTN 87213295, 23/07/2021, https://doi.org/10.1186/ISRCTN87213295 Key messages regarding feasibility The clinical and cost effectiveness of different treatment strategies for orthostatic hypotension is unknown. People with orthostatic hypotension tend to be older, have multiple long-term conditions and take multiple medications. There is uncertainty around recruitment of this population, attrition rates, potential crossover of treatments and completion of multiple outcome measures. Redeployment of clinical and research staff during COVID-19 and the post-COVID period meant that trial delivery was not feasible. Recent or current exposure to one of the trial interventions precluded a large proportion of participants being eligible. A flexible and pragmatic trial protocol was not sufficient to overcome these barriers. The number and timing of outcome measures appears to be appropriate and feasible. Competing Interest Statement The authors have declared no competing interest. Clinical Trial ISRCTN 87213295, 23/07/2021, https://doi.org/10.1186/ISRCTN87213295 Clinical Protocols https://www.isrctn.com/ISRCTN87213295 Funding Statement This study was funded by the UK NIHR Health Technology Assessment (NIHR127385) programme. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the UK NHS Health Research Authority Newcastle and North Tyneside 1 Research Ethics Committee (reference 21/NE/0083). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Availability of data and materials A de-identified dataset will be prepared and stored by Newcastle University. Requests for data sharing will be subject to request which should provide a clear purpose, analysis plan, how the results will be disseminated, and who the authors will be. Data transfer will be subject to completion of a Data Sharing Agreement between Newcastle University and the end users. List of abbreviations - OH - orthostatic hypotension - BP - blood pressure - PD - Parkinson’s disease - NICE - National Institute for Health and Care Excellence - NIHR HTA - National Institute for Health and Care Research Health Technology Assessment - CONFORM-OH - Control, fludrocortisone or midodrine for orthostatic hypotension - OHQ - Orthostatic hypotension questionnaire - NEADL - Nottingham extended activities of daily living - MEDDRA - Medical Dictionary for Regulatory Activities - QALY - Quality adjusted life year