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

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

Tracking Information

• First Submitted Date: February 21, 2014
• First Posted Date: February 25, 2014
• Last Update Posted Date: August 25, 2020
• Actual Study Start Date: January 21, 2014
• Actual Primary Completion Date: October 28, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 21, 2014)

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 21, 2014)

• 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
• 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
• 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
• 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy of L-threo DOPS on Orthostatic Hypotension Symptoms and Other Non-motor Symptoms in Patients With MSA
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Multiple System Atrophy

Intervention

• 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
• Drug: placebo
  initial period (4 weeks) followed by 8 weeks

Study Arms

• Experimental: L-Threo DOPS
  patients with Multiple System Atrophy (MSA) after 12 weeks to continued therapy with L-Threo DOPS
  Intervention: Drug: L-Threo DOPS
• Placebo Comparator: placebo
  patients with Multiple System Atrophy (MSA) after 12 weeks to continued therapy with placebo
  Intervention: Drug: placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 24, 2020): 107
• Original Estimated Enrollment (submitted: February 21, 2014): 108
• Actual Study Completion Date: October 28, 2019
• Actual Primary Completion Date: October 28, 2019 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02071459
• Other Study ID Numbers: 12 554 01; 12-018-0200 ( Other Grant/Funding Number: French Ministry of Health, PHRC 2012 )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University Hospital, Toulouse
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Toulouse
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Anne PAVY-LE-TRAON, PHD; CHU Toulouse

• PRS Account: University Hospital, Toulouse
• Verification Date: August 2020