Dopamine Beta Hydroxylase Deficiency, Multiple Systems Atrophy, Parkinson's Disease, Pure Autonomic Failure, Symptomatic Neurogenic Orthostatic Hypotension
Conditions
Keywords
NOH, OH, PD, MSA, PAF, DBH
Brief summary
Evaluate the clinical efficacy and safety of droxidopa versus placebo over a 17 week (maximum) treatment period in patients with symptomatic NOH.
Detailed description
This is a multi-center, multi-national, randomized, parallel-group, placebo-controlled, double-blind study with a 17 week (maximum) treatment period consisting of an initial, open-label dose titration (up to 2 weeks), followed by a washout period (up to 3 weeks), followed by a 12 week treatment period on a stable dose.
Interventions
DRUGDroxidopa
Droxidopa at 100 mg, 200 mg, 300 mg
DRUGPlacebo
Placebo to match droxidopa capsules and strength designations
Sponsors
Chelsea Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. 18 years and older and ambulatory (defined as able to walk at least 10 meters); 2\. Clinical diagnosis of symptomatic orthostatic hypotension associated with Primary Autonomic Failure (PD, MSA and PAF), Dopamine Beta Hydroxylase Deficiency; 3\. At the Baseline visit (Visit 2), patients must demonstrate: 1. a score of at least 4 or greater on the Orthostatic Hypotension Symptom Assessment (OHSA) Item #1; 2. a fall of at least 20 mmHg in their systolic blood pressure, within 3 minutes of standing; 4\. Provide written informed consent to participate in the study and understand that they may withdraw their consent at any time without prejudice to their future medical care;
Exclusion criteria
* 1\. Score of 23 or lower on the mini-mental state examination (MMSE); 2\. Concomitant use of vasoconstricting agents for the purpose of increasing blood pressure; 1. Patients taking vasoconstricting agents such as ephedrine, dihydroergotamine, or midodrine must stop taking these drugs at least 2 days or 5 half-lives (whichever is longer) prior to their baseline visit (Visit 2) and throughout the duration of the study; 3\. Known or suspected alcohol or substance abuse within the past 12 months (DSM-IV definition of alcohol or substance abuse); 4\. Women who are pregnant or breastfeeding; 5\. Women of child bearing potential (WOCP) who are not using at least one method of contraception with their partner; 6\. Male patients who are sexually active with a woman of child bearing potential (WOCP) and not using at least one method of contraception; 7\. Untreated closed angle glaucoma; 8\. Diagnosis of hypertension that requires treatment with antihypertensive medications (short-acting antihypertensives to treat nocturnal supine HTN are allowed in this study) Any significant uncontrolled cardiac arrhythmia; 9\. History of myocardial infarction, within the past 2 years; 10\. Current unstable angina; 11\. Congestive heart failure (NYHA Class 3 or 4); 12\. 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; 13\. Gastrointestinal condition that may affect the absorption of study drug (e.g. ulcerative colitis, gastric bypass); 14\. Any major surgical procedure within 30 days prior to the Baseline visit (Visit 2); 15\. Previously treated with droxidopa within 30 days prior to the Baseline visit (Visit 2); 16\. Currently receiving any other investigational drug or have received an investigational drug within 30 days prior to the Baseline visit (Visit 2); 17\. 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; 18\. The Investigator has the ability to exclude a patient if for any reason they feel the subject is not a good candidate for the study or will not be able to follow study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Dizziness/ Lightheadedness/ Feeling Faint/ or Feeling Like You Might Blackout (OHSA Item 1) | Change from Randomization to Week 1 | OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. A positive score indicates worsening during the double-blind randomized phase relative to value at randomization, while a negative score indicates an improvement in symptom severity. |
Countries
United States
Participant flow
Recruitment details
61 patients enrolled in the open-label dose titration, 16 patients discontinued in the open-label period and 45 patients continued on to the randomized double-blind treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Open-Label Patients entered open label droxidopa dose titration, but did not proceed into the randomization phase. | 16 |
| Droxidopa Droxidopa 100 mg, 200 mg, 300 mg
Droxidopa: 100 mg, 200 mg and 300 mg capsules 100, 200, 300, 400, 500, 600mg TID dosing for up to 12 weeks of treatment | 22 |
| Placebo Placebo
Placebo: Placebo to match droxidopa capsules and strength designations. 100, 200, 300, 400, 500, 600mg TID dosing for up to 12 weeks of treatment | 23 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind | Adverse Event | 0 | 1 | 1 |
| Double-Blind | Extended Vacation | 0 | 1 | 0 |
| Double-Blind | Protocol Violation | 0 | 0 | 1 |
| Double-Blind | Study Stopped | 0 | 7 | 7 |
| Double-Blind | Supine Hypertension | 0 | 0 | 1 |
| Double-Blind | Withdrawal by Subject | 0 | 2 | 3 |
| Open-label | Adverse Event | 6 | 0 | 0 |
| Open-label | Difficulty attending study visits | 1 | 0 | 0 |
| Open-label | Study Stopped | 4 | 0 | 0 |
| Open-label | Supine Hypertension | 4 | 0 | 0 |
| Open-label | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Open-Label | Droxidopa | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 74.3 years STANDARD_DEVIATION 6.99 | 70.2 years STANDARD_DEVIATION 7.08 | 70.8 years STANDARD_DEVIATION 9 | 70.5 years STANDARD_DEVIATION 8.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 21 Participants | 23 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Primary Diagnosis DBH Deficiency | 0 participants | 0 participants | 0 participants | 0 participants |
| Primary Diagnosis Multiple System Atrophy | 1 participants | 4 participants | 2 participants | 7 participants |
| Primary Diagnosis Parkinson's Disease | 14 participants | 15 participants | 18 participants | 47 participants |
| Primary Diagnosis Pure Autonomic Failure | 1 participants | 3 participants | 3 participants | 7 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 13 Participants | 22 Participants | 21 Participants | 56 Participants |
| Region of Enrollment Canada | 4 participants | 3 participants | 1 participants | 8 participants |
| Region of Enrollment United States | 12 participants | 19 participants | 22 participants | 53 participants |
| Sex: Female, Male Female | 2 Participants | 9 Participants | 7 Participants | 18 Participants |
| Sex: Female, Male Male | 14 Participants | 13 Participants | 16 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 61 | 7 / 22 | 5 / 23 |
| serious Total, serious adverse events | 3 / 61 | 1 / 22 | 3 / 23 |
Outcome results
Primary
Change in Dizziness/ Lightheadedness/ Feeling Faint/ or Feeling Like You Might Blackout (OHSA Item 1)
OHSA item 1 scale range: 0 (none) -10 (worst), likert scale. Change: score at end of study minus score at randomization. A positive score indicates worsening during the double-blind randomized phase relative to value at randomization, while a negative score indicates an improvement in symptom severity.
Time frame: Change from Randomization to Week 1
Population: Patients entering the double-blind, randomized phase and having a visit at week 1 of the double-blind phase were analyzed.~Study was stopped when only 5% of planned participants had completed the study to prevent competition with FDA mandated post-marketing requirement study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Droxidopa | Change in Dizziness/ Lightheadedness/ Feeling Faint/ or Feeling Like You Might Blackout (OHSA Item 1) | -1.1 units on a scale | Standard Deviation 3.2 |
| Placebo | Change in Dizziness/ Lightheadedness/ Feeling Faint/ or Feeling Like You Might Blackout (OHSA Item 1) | -0.5 units on a scale | Standard Deviation 1.8 |