Title: A comparison of fludrocortisone, midodrine or usual care to treat orthostatic hypotension – a multi-arm multi-stage randomised controlled trial: CONFORM-OH
Funder: Department of Health and Social Care

Abstract: Orthostatic hypotension (OH) is a drop in blood pressure (BP) on standing up from a sitting or lying position. The drop in BP can lead to unpleasant symptoms such as dizziness, fainting and falls. It is a common problem, affecting one in five older people and one in three people with Parkinson’s disease._x000D_ _x000D_ Doctors usually treat OH without tablets and medicines, instead giving patients advice on drinking more water, wearing compression stockings and performing muscle tensing exercises (known as non-drug therapies). When these non-drug therapies don’t help, patients are offered medication. The two most commonly used drugs for OH are fludrocortisone and midodrine. However, there has been very little research on whether these treatments work. So nobody really knows what the ideal treatment is for OH._x000D_ _x000D_ To find out what the best treatment is, we will conduct a clinical trial to compare fludrocortisone and midodrine to non-drug therapies (known as usual care). We plan to recruit 366 participants with OH in 20 different hospitals. First we will try simple treatments, such as standing up slowly, avoiding dehydration and reducing medications that cause OH. If the OH persists after one month (four weeks), participants will be put randomly into one of three treatment groups – usual care, fludrocortisone or midodrine. People with OH have told us that symptoms are the most important outcome to them, so we will measure any change in symptoms in all three groups after six months on treatment. We will continue to look at the effects on quality of life, daily activities, falls, BP, side effects and costs to the NHS, for a total of 12 months._x000D_ _x000D_ A novel feature of this trial is that after the 200th participant we will perform a provisional review of the effectiveness of the treatments. This will allow us to stop one of the study treatments if it is ineffective and focus on the one with most potential. We will also run a nine-month pilot of the study (a small scale version of the study) to identify and resolve any problems before continuing with the main trial. _x000D_ _x000D_ People with OH were a crucial part of how we chose the most important outcomes, when to measure them and how much improvement to look for. They have also helped to write this summary. People with OH will continue to work with the researchers in the development of trial documents, protocol, and research management. People with OH have told us that they are not confident to join management groups within the trial. They would prefer an advocate who visits them at home and contributes to meetings on their behalf. Patients and participants frequently do not hear about research results. Continued patient involvement will be an important part of how we develop a plan to get the results out, in an understandable way, to patients with OH and the doctors treating them.

Lay abstract: Orthostatic hypotension (OH) is a common condition, characterised by a significant drop in blood pressure (BP) on standing. It results in a reduced quality of life (QOL) and a high risk of falls, but there is little evidence to guide treatment._x000D_ _x000D_ Primary Objective_x000D_ Determine whether fludrocortisone or midodrine improve symptoms and are cost-effective compared to usual care in adults with OH._x000D_ _x000D_ Secondary Objectives_x000D_ Determine whether fludrocortisone or midodrine:_x000D_ - Improve QOL, activities of daily living (ADLs) and standing BP _x000D_ - Reduce falls _x000D_ - Are safe _x000D_ - Reduce NHS and social service costs _x000D_ _x000D_ Methods_x000D_ Design: Pragmatic, multi-arm, multi-stage, parallel group, prospective, randomised, open label, superiority clinical trial with a 10-month internal pilot._x000D_ Setting: Secondary care (falls, geriatric and movement disorders clinics)_x000D_ Inclusion: Adults aged >18 years, with symptomatic OH: _x000D_ • Drop in systolic BP of >/=20mmHg and/or a drop in diastolic BP of >/=10mmHg, within three minutes of standing upright _x000D_ • Score of >/=2 on the Orthostatic Hypotension Questionnaire (The OHQ is composed of 10 items relating to symptoms of OH)_x000D_ • Willing and able to provide informed consent prior to any trial procedures taking place_x000D_ Exclusion: OH due to acute/reversible causes; use of fludrocortisone/midodrine in last six months; current/planned pregnancy; terminal illness/life expectancy <12 months; allergy to trial medication; contra-indication to study interventions; supine hypertension; unable to stand; unable to communicate in English; unable to comply with trial procedures; currently in another trial that would interfere with CONFORM-OH trial outcomes._x000D_ _x000D_ Interventions:_x000D_ A) Fludrocortisone: 50 to 400 mcg daily plus usual care _x000D_ B) Midodrine: 2.5 mg BD to 10 mg TDS plus usual care_x000D_ Control (usual care): Non-drug therapy (advice on trigger avoidance, water and salt intake, counter-manoeuvres and compression garments standardised via provision of written advice leaflet)._x000D_ _x000D_ Primary Outcome:_x000D_ Change in symptoms (OHQ score) from baseline, at six months._x000D_ _x000D_ Secondary Outcomes:_x000D_ • OHQ, ADLs (Nottingham Extended Scale) and QOL (EQ-5D-5L) at three, six and 12 months_x000D_ • Falls_x000D_ • Lying Standing BP (LSBP)_x000D_ • Hospital admissions_x000D_ • Adverse Events (AEs) and Adverse Reactions (ARs)_x000D_ • Quality Adjusted Life Years (QALYS)_x000D_ • Use of health services (HSSU)_x000D_ • Costs to the NHS, personal social services and the patient_x000D_ • Research costs_x000D_ • Incremental cost per QALY_x000D_ • Recruitment procedures, trial design and eligibility criteria, from the Screening Log_x000D_ • Adherence to treatment allocation, and crossover at each data collection time point_x000D_ • Reasons for crossover and withdrawal, during pilot_x000D_ • Use of secondary health care resource_x000D_ • Cost of accessing care, by participants and their families_x000D_ _x000D_ Randomisation_x000D_ Participants will be randomised to a study arm in a 1:1:1 ratio. Minimisation will ensure balance across age groups, aetiology (neurogenic or non-neurogenic OH) and centre. Assessment of outcomes will be unblinded._x000D_ _x000D_ Sample Size_x000D_ 122 participants per arm, assuming attrition of 15%, one sided 2.5% Type 1 error and 90% power to detect a difference of 1.0 in the OHQ._x000D_ _x000D_ Analysis_x000D_ An interim analysis will be conducted after 200 participants have been randomised. If a treatment arm is ineffective compared to control, it will be dropped. A linear mixed-effects model will be used for primary analysis of the main trial. QALYs will be calculated from EQ-5D-5L._x000D_ _x000D_ Pilot_x000D_ A 10-month pilot will assess recruitment, attrition, follow-up and overall viability._x000D_ _x000D_ Timelines_x000D_ Month 0-6: Set-up; Month 7-15: Pilot; Month 13-36: Recruitment; Month 26: Interim analysis; Month 37-49: Follow-up; Month 50-51: Data clean; Month 52-60: Analysis and Final Report._x000D_ _x000D_ Impact and dissemination_x000D_ Evidence in this area is likely to change clinical practice. Our co-applicants are well positioned to influence guidelines and disseminate findings to the clinical community. Results will be disseminated to patient support groups’ blogs and newsletters, and regional public engagement events.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE