Multiple System Atrophy
Conditions
Keywords
L-threo DOPS (DroxiDopa), Orthostatic Hypotension, Multiple system atrophy
Brief summary
Evaluate the effects of L-Threo DOPS on orthostatic hypotension symptoms and other non-motor symptoms in patients with Multiple System Atrophy (MSA) after 12 weeks following randomization to continued therapy with droxidopa or placebo.
Detailed description
Background : Multiple system atrophy (MSA) is a rare, sporadic progressive neurodegenerative disorder, rapidly leading to severe disability and impairment of quality of life. MSA is characterized by a variable combination of a poor levodopa parkinsonism and /or cerebellar ataxia and autonomic failure (cardiovascular and / or bladder and sexual dysfunction) (Gilman et al, 2008). The prevalence is approximately 4-5 cases per 100 000 inhabitants. Orthostatic hypotension (OH) is one of the major symptoms of MSA, present in a large majority of patients, leading to significant disability because of impaired balance, falls and possibly syncope. Drugs available to treat OH in this disease are very limited. L-ThreoDOPS (L DOPS or DroxiDopa) is an orally administered synthetic catecholamine acid that is converted to the sympathetic neurotransmitter norepinephrine (NE) through a single step of decarboxylation by the endogenous enzyme 3,4-dihydroxyphenylalanine (DOPA) decarboxylase. It prevents symptoms related to OH by central and/peripheral mechanisms. This drug is currently developed for "neurogenic OH" by Chelsea Therapeutics on the basis of short duration placebo-controlled randomized trials. Besides an expected effect on OH, L-DOPS may also, by noradrenergic stimulation, improve some motor and non-motor symptoms common and disabling in MSA patients such as akinesia and fatigue. In this context, the French reference center for MSA and the 12 national centers with identified skills to manage this disease, propose to conduct a national multicenter randomized clinical trial versus placebo to evaluate the long term efficacy (3 months) of L-threo DOPS on the OH and other non-motor symptoms in MSA patients.
Interventions
DRUGL-Threo DOPS
initial dose titration period (4 weeks) followed by 8 weeks at the max tolerated dose
DRUGplacebo
initial period (4 weeks) followed by 8 weeks
Sponsors
University Hospital, Toulouse
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* MSA patients (possible or probable, MSA-P or C (according to revised criteria, Gilman et al 2008)). * Aged 30 to 80 years, * Able to walk at least 10 meters * With symptomatic OH (score of at least 3 at one of the items of Part I of the OH scale (OHQ)) * Documented fall in systolic blood pressure of at least 20 mmHg, and/or in diastolic blood pressure of at least 10 mmHg, within 3 minutes after standing. * Able to fill in the evaluation questionnaires with or without help * With no significant problems with swallowing. * Stable anti-parkinsonian, dysautonomia and depression treatments for the 4 weeks before the study and during the entire study * Signed written informed consent for the present study.
Exclusion criteria
* Dementia (DSM-IV, Mini-Mental State Examination (MMSE) \< 24/30) * Concomitant use of vaso-constrictive drugs, other than midodrine. Patients taking vasoconstrictor agents such as ephedrine, dihydroergotamine, must stop taking these drugs at least 2 days or 7 half-lives prior to their baseline visit (Visit 1); the association with midodrine may be kept at a stable dose not exceeding 3 tablets (7.5 mg) / day if the patient has no CV history. This will be discussed case by case with the coordinating center and the safety committee of this study. * Taking anti-hypertensive medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the efficacy of long term efficacy of L-threo DOPS | 12 weeks | Evaluate the efficacy of long term efficacy of L-threo DOPS (droxidopa) in MSA patients (probable or possible - cerebellar (C) or parkinsonian (P) type) with symptomatic NOH as measured by the relative change in mean score of Orthostatic Hypotension Symptom Assessment (OHSA) (Part I of the questionnaire on the symptoms OH (OHQ) (Kaufmann et al., 2011)) 12 weeks following randomization to therapy with droxidopa or placebo (including 8 weeks to maximum tolerated dose). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| efficacy of L-ThreoDOPS on symptomatic OH | 12 weeks | Evaluate and compare the efficacy of L-ThreoDOPS on symptomatic OH (measured by the relative change in mean score of Item 1 of the Orthostatic Hypotension Symptom Assessment (OHSA)) in MSA patients 4, 8 and 12 weeks following randomization to continued therapy with droxidopa or placebo |
| effects of L-Threo DOPS on motor symptoms | 12 weeks | Evaluate the effects of L-Threo DOPS on motor symptoms (UMSARS I and II) in MSA patients after 12 weeks following randomization to continued therapy with droxidopa or placebo |
| effect of L-Threo DOPS on dysautonomic symptoms | 12 weeks | Evaluate the effect of L-Threo DOPS on dysautonomic symptoms (COMPASS) in MSA patients after 4, 8 and 12 weeks following randomization to continued therapy with droxidopa or placebo |
| safety of high doses of L-ThreoDOPS | 12 Weeks | Determine the safety of high doses of L-ThreoDOPS in MSA patients based on the occurrence of treatment-emergent adverse events |
Countries
France
Contacts
PRINCIPAL_INVESTIGATORAnne PAVY-LE-TRAON, PHD
University Hospital, Toulouse
Outcome results
None listed