A Phase II, Randomised, Placebo-Controlled, Double-Blind, Replicated Crossover, Pilot Study on the Effect of Fipamezole on Neurogenic Orthostatic Hypotension in Patients With Multiple System Atrophy or Parkinson's Disease

This study will be an exploratory, proof of concept, randomised, placebo-controlled, double-blind, multiple crossover study, with an open-label active run-in phase, in patients with multiple system atrophy (MSA) or Parkinson's disease (PD) who can concomitantly be treated with fludrocortisone and antiparkinsonian medication. Three sites in France and one site in Portugal will participate in this study.

During the open-label active run-in phase, a tolerated dose-escalation regimen (either escalating from 30 to 90 or 60 mg tid, or no escalation but fixed dose of 30 mg tid) will be established for each patient. Once the tolerated treatment regimen has been established, patients will then be randomised to the double-blind crossover treatment. Fipamezole and matched placebo tablets are compared in 3 crossover blocks, each block consisting of a total of 28 days: 12 days fipamezole and 12 days placebo in random order, separated by two days of washout. The patients will be randomly assigned to one of the two possible treatment sequences (fipamezole first followed by placebo or placebo first followed by fipamezole).

For efficacy assessments, the patient blood pressure and heart rate is assessed repeatedly when laying still or standing. Impact of orthostatic hypotension on clinical symptoms is assessed with a subjective scale and questionnaire. To explore potential positive or negative impact of fipamezole on disease characteristics, the MSA and PD patients are assessed with UMSARS and UPDRS scales, respectively. Finally, the study includes investigator and patients assessments of CGI-I and PGI-I scales for clinical condition in general.

Fipamezole

Fipamezole is a new antagonist of the pre-synaptic adrenergic alpha-2 receptors and is being investigated for potential use as an adjunctive therapy for PD. Adrenergic alpha-2 receptors inhibit noradrenaline and some other neurotransmitter release from nerve terminals in a tonic manner, and therefore antagonism of this receptor leads in enhanced neurotransmitter release. Alpha-2 receptors are located widely in the body, both in the central nervous system (CNS) and periphery. Pharmacological studies have suggested that either central or peripheral autonomic nervous system is involved in autonomic failure and orthostatic hypotension in MSA and in PD. Neurogenic orthostatic hypotension in these diseases results from decreased delivery of the sympathetic neurotransmitter noradrenaline (or hormonal adrenaline) to vascular adrenergic receptors, either because of blunted CNS control or impaired function of postganglionic sympathetic neurons. Fipamezole is expected to increase noradrenergic (or adrenergic) turnover in specific areas of the brain or in the periphery in MSA and PD and alleviate symptoms related to fall in BP during orthostatism.