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Efficacy of L-threo DOPS on Orthostatic Hypotension Symptoms and Other Non-motor Symptoms in Patients With MSA (DOPS-AMS)

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ClinicalTrials.gov Identifier: NCT02071459
Recruitment Status : Completed
First Posted : February 25, 2014
Last Update Posted : August 25, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital, Toulouse

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.

Condition or disease Intervention/treatment Phase
Multiple System Atrophy Drug: L-Threo DOPS Drug: placebo Phase 2 Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 107 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluate the Long-term (3 Months) Efficacy of L-threo DOPS (DroxiDopa) on Orthostatic Hypotension Symptoms and Other Non-motor Symptoms in Patients With Multiple System Atrophy (MSA). Comparative Study Versus Placebo
Actual Study Start Date : January 21, 2014
Actual Primary Completion Date : October 28, 2019
Actual Study Completion Date : October 28, 2019


Arm Intervention/treatment
Experimental: L-Threo DOPS
patients with Multiple System Atrophy (MSA) after 12 weeks to continued therapy with L-Threo DOPS
Drug: L-Threo DOPS
initial dose titration period (4 weeks) followed by 8 weeks at the max tolerated dose
Other Name: L DOPS or DroxiDopa

Placebo Comparator: placebo
patients with Multiple System Atrophy (MSA) after 12 weeks to continued therapy with placebo
Drug: placebo
initial period (4 weeks) followed by 8 weeks




Primary Outcome Measures :
  1. Evaluate the efficacy of long term efficacy of L-threo DOPS [ Time Frame: 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 Outcome Measures :
  1. efficacy of L-ThreoDOPS on symptomatic OH [ Time Frame: 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

  2. effects of L-Threo DOPS on motor symptoms [ Time Frame: 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

  3. effect of L-Threo DOPS on dysautonomic symptoms [ Time Frame: 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

  4. safety of high doses of L-ThreoDOPS [ Time Frame: 12 Weeks ]
    Determine the safety of high doses of L-ThreoDOPS in MSA patients based on the occurrence of treatment-emergent adverse events



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Ages Eligible for Study:   30 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02071459


Locations
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France
Centre hospitalier d'Angers
Angers, France, 49933
CHU bordeaux
Bordeaux, France
CHU de Clermont-Ferrand
Clermont-Ferrand, France, 63000
CHU de Dijon
Dijon, France, 21000
CHRU de lille
Lille, France, 59037
CHU de limoges
Limoges, France, 87042
Hôpital La Timone
Marseille, France, 13000
Hôpital G. & R. Laennec
Nantes, France, 44093
Hôpital Pitié-Salpétrière
Paris, France, 75013
CHU de Poitiers
Poitiers, France, 86021
CHU Pontchaillou
Rennes, France, 35033
CHU de Rouen
Rouen, France, 76031
chu de Strasbourg
Strasbourg, France, 67091
Sponsors and Collaborators
University Hospital, Toulouse
Investigators
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Principal Investigator: Anne PAVY-LE-TRAON, PHD CHU Toulouse
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Responsible Party: University Hospital, Toulouse
ClinicalTrials.gov Identifier: NCT02071459    
Other Study ID Numbers: 12 554 01
12-018-0200 ( Other Grant/Funding Number: French Ministry of Health, PHRC 2012 )
First Posted: February 25, 2014    Key Record Dates
Last Update Posted: August 25, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by University Hospital, Toulouse:
L-threo DOPS (DroxiDopa)
Orthostatic Hypotension
Multiple system atrophy
Additional relevant MeSH terms:
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Hypotension, Orthostatic
Multiple System Atrophy
Shy-Drager Syndrome
Hypotension
Atrophy
Pathological Conditions, Anatomical
Vascular Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Droxidopa
Antiparkinson Agents
Anti-Dyskinesia Agents