Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of Droxidopa for the treatment of fatigue in patients with Parkinsonism by the Visual Analog Fatigue Scale (VAFS). This is a randomized, placebo-controlled, double-blind clinical trial for 3 months where half the subjects will receive placebo and the other half will receive Droxidopa. Following this will be a wash-out period of 7 days and then all subjects will receive Droxidopa for 3 months during the open-label phase.

Detailed Description
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Parkinsonism, is a group of symptoms seen in several diseases, including Parkinson's Disease. In Parkinsonism, a patient may become stiff, have smaller and slower movements, develop a tremor (shaking of the arms or legs), have decreased facial expression, and a softer voice. Fatigue is a common symptom that causes suffering and stress in diseases that affect the brain. Over 50% of patients with Parkinsonism report fatigue as one of their top three symptoms that make their life more difficult. Currently, there are no evidence-based guidelines for treating fatigue in Parkinson's Disease, and no effective medications or therapeutic modalities exist for fatigue symptoms in patients with Parkinson's Disease. Droxidopa (also known by the trade name NORTHERA) is a safe and well tolerated medication which has been approved in USA for the treatment of orthostatic dizziness or light headedness in patients with a clinical diagnosis of symptomatic Neurogenic Orthostatic Hypotension associated with primary autonomic failure (Parkinson's Disease and Multiple System Atrophy), Dopamine Beta Hydroxylase Deficiency, or Non Diabetic Autonomic Neuropathy. Fatigue may be due to diminished levels of norepinephrine in Parkinson's Disease. The locus coeruleus, one of the major sources of norepinephrine, is affected during the preclinical phase of Parkinson's Disease during stage 2 of Braak pathology staging. Norepinephrine is the final metabolite of dopamine, therefore by adding exogenous norepinephrine, it may be possible to control some of the motor and non-motor symptoms of Parkinsonism. Norepinephrine is the final metabolite of droxidopa, and it is still unclear if it passes the blood-brain barrier. This pilot study is to measure the efficacy and safety of droxidopa in Parkinsonism patients with fatigue.

Official Title
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Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

Conditions
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Parkinson Disease, Multiple System Atrophy, Progressive Supranuclear Palsy

Intervention / Treatment
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* Drug: Droxidopa
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 50 years or older. Clinical diagnosis of Parkinsons Disease or Atypical Parkinsonism (including multiple system atrophy (MSA), PSP) Fluent in English Reported fatigue and must have a mean VAFS score of 4 or more at baseline Written informed consent Exclusion Criteria: Inability to understand or cooperate with study procedures Alcohol or substance use disorder within the past 12 months (as per Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria) Women who are pregnant or breastfeeding Women of childbearing potential (WOCP) as indicated by one of the following: Sustained supine hypertension greater than or equal to 180 mmHg systolic or 110 mmHg diastolic. Sustained is defined as the average of 3 observations each at least 10 minutes apart with the patient having been supine and at rest for at least 5 minutes prior to each measurement Untreated closed angle glaucoma Diagnosis of hypertension that requires treatment with antihypertensive medications Any significant uncontrolled cardiac arrhythmia History of myocardial infarction, within the past 2 years Current unstable angina Congestive heart failure (NYHA Class 3 or 4) Diabetic autonomic neuropathy History of cancer within the past 2 years other than a successfully treated, non-metastatic cutaneous squamous cell or basal cell carcinoma or cervical cancer in situ Gastrointestinal condition that may affect the absorption of Investigational Medicinal Product (e.g. ulcerative colitis, gastric bypass) Any major surgical procedure within 30 days prior to the first titration visit. Currently receiving any investigational drug or have received an investigational drug within 28 days prior to the first titration visit Any condition or laboratory test result, which in the Investigator's judgment, might result in an increased risk to the patient, or would affect their participation in the study Dementia or non-treated depression Subjects who have a mean VAFS score of less than 4 at baseline Vulnerable populations Uncontrolled intercurrent illnesses including, but not limited to severe lung disease, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic cardiac arrhythmia, and situations that would limit compliance with study requirements will be excluded Orthostatic hypotension (OH)

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Droxidopa<br>The Droxidopa starting dose for all eligible patients in the Titration Periods are 100mg three times daily (TID). Doses will be titrated by 100mg TID; increments will be made weekly until the optimal dose is achieved or the subject doesn't notice an improvement in their subjective fatigue on a higher dose compared to the most recent dose. Half of the subjects will be on Droxidopa for 3 months during the double-blind phase. All subjects will be on Droxidopa for 3 months during the open-label phase. | Drug: Droxidopa<br>* Droxidopa in 100, 200, and 300mg capsules. Maximum dose to be used in this study is 600mg.<br>* Other names: Northera;|
| Placebo Comparator: Placebo Oral Tablet<br>The placebo starting dose for all eligible patients in the Titration Period is 100mg TID. Doses will be titrated by 100mg TID; increments will be made weekly until the optimal dose is achieved. Half of the subjects will be on placebo for 3 months during the double-blind phase. | Drug: Placebo Oral Tablet<br>* Placebo capsules to match Droxidopa 100, 200, and 300mg capsules.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Droxidopa on fatigue in subjects with Parkinsonism as determined by completion of Visual Analogue Fatigue Scale (VAFS) | Subjects will complete the VAFS which measures level of fatigue with zero being equivalent to energetic with no fatigue to ten being worst possible fatigue | Change between baseline and 12 weeks | 
| Efficacy of Droxidopa on fatigue in subjects with Parkinsonism as determined by completion of Visual Analogue Fatigue Scale (VAFS) | Subjects will complete the VAFS which measures level of fatigue with zero being equivalent to energetic with no fatigue to ten being worst possible fatigue | Change between 18 weeks and 28 weeks | 
| Efficacy of Droxidopa on fatigue in subjects with Parkinsonism as determined by completion of Visual Analogue Fatigue Scale (VAFS) | Subjects will complete the VAFS which measures level of fatigue with zero being equivalent to energetic with no fatigue to ten being worst possible fatigue | Week 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Droxidopa on motor and non-motor symptoms of Parkinsonism as determined by the Unified Parkinson's Disease Rating Scale (UPDRS) | The UPDRS is a composite measurement of motor and non-motor symptoms divided into six domains. Domain I measures Mentation, Behavior and Mood. Domain II measures Activities of Daily Living. Domain III measures Motor Examination. Domain IV measures Complications of Therapy. Domain V is Modified Hoehn and Yahr Staging. Domain 6 is Schwab and England Activities of Daily Living Scale | Change between baseline and 12 weeks | 
| Efficacy of Droxidopa on motor and non-motor symptoms of Parkinsonism as determined by the Unified Parkinson's Disease Rating Scale (UPDRS) | The UPDRS is a composite measurement of motor and non-motor symptoms divided into six domains. Domain I measures Mentation, Behavior and Mood. Domain II measures Activities of Daily Living. Domain III measures Motor Examination. Domain IV measures Complications of Therapy. Domain V is Modified Hoehn and Yahr Staging. Domain 6 is Schwab and England Activities of Daily Living Scale | Change between 18 weeks and 28 weeks | 
| Efficacy of Droxidopa on motor and non-motor symptoms of Parkinsonism as determined by the Unified Parkinson's Disease Rating Scale (UPDRS) | The UPDRS is a composite measurement of motor and non-motor symptoms divided into six domains. Domain I measures Mentation, Behavior and Mood. Domain II measures Activities of Daily Living. Domain III measures Motor Examination. Domain IV measures Complications of Therapy. Domain V is Modified Hoehn and Yahr Staging. Domain 6 is Schwab and England Activities of Daily Living Scale | Week 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fatigue, Droxidopa