Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

Parkinson Disease Clinical Trial

Official title:

Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03446807
• Other study ID #: 5170406
• Status: Withdrawn
• Phase: Phase 2
• Start date: December 2021
• Est. completion date: July 1, 2023

Study information

• Verified date: February 2022
• Source: Loma Linda University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: July 1, 2023
• Est. primary completion date: July 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Fatigue
• Multiple System Atrophy
• Parkinson Disease
• Parkinsonian Disorders
• Progressive Supranuclear Palsy
• Shy-Drager Syndrome
• Supranuclear Palsy, Progressive

Intervention

Drug:
• Droxidopa
Droxidopa in 100, 200, and 300mg capsules. Maximum dose to be used in this study is 600mg.
• Placebo Oral Tablet
Placebo capsules to match Droxidopa 100, 200, and 300mg capsules.

Locations

Country	Name	City	State
United States	Loma Linda University Faculty Medical Offices - Neurology Clinic	Loma Linda	California

Sponsors (2)

Lead Sponsor	Collaborator
Loma Linda University	H. Lundbeck A/S

Country where clinical trial is conducted

United States, 

References & Publications (9)

Friedman J, Friedman H. Fatigue in Parkinson's disease. Neurology. 1993 Oct;43(10):2016-8. — View Citation

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. pii: 15025. Epub 2016 Jan 14. — View Citation

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. Review. — View Citation

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. — View Citation

Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA, Mauney J, Feirtag M, Mathias CJ; NOH301 Investigators. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology. 2014 Jul 22;83(4):328-35. doi: 10.1212/WNL.0000000000000615. Epub 2014 Jun 18. — View Citation

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. — View Citation

Mendonça DA, Menezes K, Jog MS. Methylphenidate improves fatigue scores in Parkinson disease: a randomized controlled trial. Mov Disord. 2007 Oct 31;22(14):2070-6. — View Citation

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. — View Citation

Smith KM, Eyal E, Weintraub D; ADAGIO Investigators. Combined rasagiline and antidepressant use in Parkinson disease in the ADAGIO study: effects on nonmotor symptoms and tolerability. JAMA Neurol. 2015 Jan;72(1):88-95. doi: 10.1001/jamaneurol.2014.2472. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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