Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

NCT ID: NCT03446807

Last Updated: 2022-03-02

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-31
• Study Completion Date: 2023-07-01

Brief Summary

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

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.

Conditions

Parkinson Disease; Multiple System Atrophy; Progressive Supranuclear Palsy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Droxidopa

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.

Group Type: EXPERIMENTAL

Droxidopa

Intervention Type: DRUG

Droxidopa in 100, 200, and 300mg capsules. Maximum dose to be used in this study is 600mg.

Placebo Oral Tablet

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.

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

Placebo capsules to match Droxidopa 100, 200, and 300mg capsules.

Interventions

Droxidopa

Droxidopa in 100, 200, and 300mg capsules. Maximum dose to be used in this study is 600mg.

Intervention Type: DRUG

Placebo Oral Tablet

Placebo capsules to match Droxidopa 100, 200, and 300mg capsules.

Intervention Type: DRUG

Other Intervention Names

Northera; Placebo

Eligibility Criteria

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)

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

H. Lundbeck A/S

INDUSTRY

Sponsor Role: collaborator

Loma Linda University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Khashayar Dashtipour, M.D. Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Loma Linda University Health

Locations

Loma Linda University Faculty Medical Offices - Neurology Clinic

Loma Linda, California, United States

Countries

United States

References

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Reference Type: BACKGROUND

PMID: 8413960 (View on PubMed)

Friedman JH, Brown RG, Comella C, Garber CE, Krupp LB, Lou JS, Marsh L, Nail L, Shulman L, Taylor CB; Working Group on Fatigue in Parkinson's Disease. Fatigue in Parkinson's disease: a review. Mov Disord. 2007 Feb 15;22(3):297-308. doi: 10.1002/mds.21240.

Reference Type: BACKGROUND

PMID: 17133511 (View on PubMed)

Friedman JH, Beck JC, Chou KL, Clark G, Fagundes CP, Goetz CG, Herlofson K, Kluger B, Krupp LB, Lang AE, Lou JS, Marsh L, Newbould A, Weintraub D. Fatigue in Parkinson's disease: report from a mutidisciplinary symposium. NPJ Parkinsons Dis. 2016;2:15025-. doi: 10.1038/npjparkd.2015.25. Epub 2016 Jan 14.

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Herlofson K, Larsen JP. Measuring fatigue in patients with Parkinson's disease - the Fatigue Severity Scale. Eur J Neurol. 2002 Nov;9(6):595-600. doi: 10.1046/j.1468-1331.2002.00444.x.

Reference Type: BACKGROUND

PMID: 12453074 (View on PubMed)

Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989 Oct;46(10):1121-3. doi: 10.1001/archneur.1989.00520460115022.

Reference Type: BACKGROUND

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Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res. 1995 Apr;39(3):315-25. doi: 10.1016/0022-3999(94)00125-o.

Reference Type: BACKGROUND

PMID: 7636775 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Other Identifiers

5170406

Identifier Type: -

Identifier Source: org_study_id