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Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

Primary Purpose

Parkinson Disease, Multiple System Atrophy, Progressive Supranuclear Palsy

Status

Withdrawn

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Droxidopa

Placebo Oral Tablet

About this trial

This is an interventional treatment trial for Parkinson Disease focused on measuring fatigue, Droxidopa

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Loma Linda University Faculty Medical Offices - Neurology Clinic

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Droxidopa

Placebo Oral Tablet

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

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

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

Secondary Outcome Measures

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

Efficacy of Droxidopa on motor and non-motor symptoms of Parkinsonism as determined by the Unified Parkinson's Disease Rating Scale (UPDRS)

Full Information

NCT ID

NCT03446807

First Posted

February 20, 2018

Last Updated

February 14, 2022

Sponsor

Loma Linda University

Collaborators

H. Lundbeck A/S

1. Study Identification

Unique Protocol Identification Number

NCT03446807

Brief Title

Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

Official Title

Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Withdrawn

Why Stopped

Sponsor Decision to terminate

Study Start Date

December 2021 (Anticipated)

Primary Completion Date

July 1, 2023 (Anticipated)

Study Completion Date

July 1, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Loma Linda University

Collaborators

H. Lundbeck A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Parkinson Disease, Multiple System Atrophy, Progressive Supranuclear Palsy

Keywords

fatigue, Droxidopa

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Masking Description

The first phase is double-blind and the second phase is open label.

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Droxidopa

Arm Type

Experimental

Arm Description

Arm Title

Placebo Oral Tablet

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Droxidopa

Other Intervention Name(s)

Northera

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo Oral Tablet

Other Intervention Name(s)

Placebo

Intervention Description

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

Primary Outcome Measure Information:

Title

Efficacy of Droxidopa on fatigue in subjects with Parkinsonism as determined by completion of Visual Analogue Fatigue Scale (VAFS)

Description

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

Time Frame

Change between baseline and 12 weeks

Title

Efficacy of Droxidopa on fatigue in subjects with Parkinsonism as determined by completion of Visual Analogue Fatigue Scale (VAFS)

Description

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

Time Frame

Change between 18 weeks and 28 weeks

Title

Efficacy of Droxidopa on fatigue in subjects with Parkinsonism as determined by completion of Visual Analogue Fatigue Scale (VAFS)

Description

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

Time Frame

Week 29

Secondary Outcome Measure Information:

Title

Efficacy of Droxidopa on motor and non-motor symptoms of Parkinsonism as determined by the Unified Parkinson's Disease Rating Scale (UPDRS)

Description

Time Frame

Change between baseline and 12 weeks

Title

Efficacy of Droxidopa on motor and non-motor symptoms of Parkinsonism as determined by the Unified Parkinson's Disease Rating Scale (UPDRS)

Description

Time Frame

Change between 18 weeks and 28 weeks

Title

Efficacy of Droxidopa on motor and non-motor symptoms of Parkinsonism as determined by the Unified Parkinson's Disease Rating Scale (UPDRS)

Description

Time Frame

Week 29

10. Eligibility

Sex

All

Minimum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Khashayar Dashtipour, M.D. Ph.D.

Organizational Affiliation

Loma Linda University Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

Loma Linda University Faculty Medical Offices - Neurology Clinic

City

Loma Linda

State/Province

California

ZIP/Postal Code

92354

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Lundbeck is funding this study and will be providing the study drug. If Lundbeck requests, they will be provided with protocol, statistical analysis plan, clinical study report, and any other study data they request. All adverse events will be reported to Lundbeck.

IPD Sharing Time Frame

The data will be available to Lundbeck from the start of the study through it's completion.

IPD Sharing Access Criteria

This material will be provided to Lundbeck in person, not electronically.

Citations:

PubMed Identifier

8413960

Citation

Friedman J, Friedman H. Fatigue in Parkinson's disease. Neurology. 1993 Oct;43(10):2016-8. doi: 10.1212/wnl.43.10.2016.

Results Reference

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PubMed Identifier

17133511

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. doi: 10.1002/mds.21240.

Results Reference

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PubMed Identifier

27239558

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;2:15025-. doi: 10.1038/npjparkd.2015.25. Epub 2016 Jan 14.

Results Reference

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PubMed Identifier

17674415

Citation

Mendonca 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. doi: 10.1002/mds.21656.

Results Reference

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PubMed Identifier

25420207

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.

Results Reference

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PubMed Identifier

24944260

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.

Results Reference

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PubMed Identifier

12453074

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. doi: 10.1046/j.1468-1331.2002.00444.x.

Results Reference

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PubMed Identifier

2803071

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. doi: 10.1001/archneur.1989.00520460115022.

Results Reference

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PubMed Identifier

7636775

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. doi: 10.1016/0022-3999(94)00125-o.

Results Reference

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Safety and Efficacy of Droxidopa for Fatigue in Patients With Parkinsonism

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