Sustained Effect of Droxidopa in Symptomatic Neurogenic Orthostatic Hypotension

Study Overview
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Brief Summary
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To evaluate the time to treatment intervention in patients with Parkinson's Disease (PD), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), Non-Diabetic Autonomic Neuropathy (NDAN) or Dopamine Beta Hydroxylase (DBH) Deficiency who have been previously stabilized with droxidopa therapy for symptoms of neurogenic orthostatic hypotension (NOH) (dizziness, light-headedness, or feelings that they are about to black out)

Detailed Description
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This is a multi-site, placebo-controlled, double-blind, randomized withdrawal, time to intervention study with a duration of up to 36 weeks, consisting of 5 periods: Screening Period: up to 4 weeks duration; Open-Label Titration Period (Titration Period): up to 4 weeks duration; Open-Label Treatment Period (Open-Label Period): 12 weeks duration; Double-Blind Treatment Period (Double-Blind Period): 12 weeks duration; Safety Follow-Up Period: 4 weeks duration

Official Title
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RESTORE: A Clinical Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension to Assess Sustained Effects of Droxidopa Therapy

Conditions
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Symptomatic Neurogenic Orthostatic Hypotension

Intervention / Treatment
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* Drug: Droxidopa capsules
* Drug: Placebo capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older and able to stand (with or without limited assistance) Clinical diagnosis of symptomatic orthostatic hypotension associated with Primary Autonomic Failure (PD, MSA or PAF) or NDAN or DBH Deficiency Score of at least 4 or greater on Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 (measured at Screening [Visit 1] and the first Titration Visit [Visit 2a] prior to dosing) A documented drop of at least 20 millimeters of mercury (mmHg) in SBP, within 3 minutes of standing. This can either be documented in the patient history or assessed during Screening prior to the first Titration Visit (Visit 2a) 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 Additional inclusion criteria for patients taking prescribed droxidopa prior to study entry: Patients who are taking prescribed droxidopa therapy are eligible to participate in the study if they meet the other inclusion criteria and also have been on a stable dose of prescribed droxidopa for at least 2 weeks prior to the Screening Visit (Visit 1). In addition, they must meet either of the following at the Screening Visit (Visit 1): The patient's Visit 1 OHSA Item #1 score is ≥ 7 AND the prescribed dose is ≤ 300 mg three times daily (TID); OR The patient's Visit 1 OHSA Item #1 score is ≤6 AND worsens by ≥ 2 units when retested after washing out of droxidopa for at least 3 days Exclusion Criteria: In the investigator's opinion, the patient is not able to understand or cooperate with study procedures Known or suspected alcohol or substance use disorder within the past 12 months (DSM-5 criteria) Women who are pregnant or breastfeeding Women of childbearing potential (WOCP) who are not using at least one method of contraception with their partner 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 (short-acting antihypertensives to treat nocturnal supine hypertension are allowed in this study) Any significant uncontrolled cardiac arrhythmia History of myocardial infarction or stroke, 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 Any major surgical procedure within the past 30 days Currently receiving any investigational drug or have received an investigational drug within the past 28 days Additional protocol defined exclusion criteria do apply

Ages Eligible for Study
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Minimum Age: 18 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: Open Label Period<br>Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally. During the Open Label Titration Period, patients will first receive 100 mg TID and their dose will be raised (in 100 mg increments) at subsequent visits until optimal dose is determined. During the Open Label Treatment Period, patients will receive active droxidopa100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to the patient's individual dose at the end of the Open-Label Titration Period). | Drug: Droxidopa capsules<br>* 100, 200 or 300 mg<br>* Other names: Northera;|
| Placebo Comparator: Randomized Period<br>Active droxidopa 100, 200, 300, 400, 500, or 600 mg three times daily (TID) orally (equal to patients individual dose at the end of the Open-Label Period) or matching placebo. | Drug: Droxidopa capsules<br>* 100, 200 or 300 mg<br>* Other names: Northera;Drug: Placebo capsules<br> <br> * Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Intervention | Kaplan-Meier estimates are presented for time to treatment intervention. The estimates represent the quartiles of the survival time, where 50% corresponds to the median time to need for treatment intervention. Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Treatment Period: OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; OR OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early discontinuation; OR participant stops IMP or withdraws from study for patient-reported lack of efficacy. | Randomization (Day 0) up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Needed Intervention During the 12-week Double-Blind Treatment Period | Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Treatment Period: OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) AND lack of efficacy as judged by the investigator; OR OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at 2 consecutive visits; OR OHSA Item #1 ≥2 unit worsening from Randomization (Visit 6) at the visit before early discontinuation; OR participant stops IMP or withdraws from study for patient-reported lack of efficacy. | Randomization (Day 0) up to Week 12 | 
| Time To All-cause Discontinuation | Kaplan-Meier estimates are presented for time to all-cause discontinuation. The estimates represent the quartiles of the survival time, where 50% corresponds to the median time to discontinuation. Time to all-cause discontinuation was defined as the time from randomization to withdrawal or last contact date. | Randomization (Day 0) up to Week 12 | 
| Change From Randomization To All Post-randomization Visits in Orthostatic Hypotension Symptom Assessment (OHSA) Item #1 Score | The OHSA scale was designed to rate symptoms occurring specifically as a result of low blood pressure (BP), on average, over the past week using an 11-point scale (0 to 10), with more severe symptoms scoring higher. A score of zero indicates that the symptom was not experienced, and 10 is the worst possible. The scale was used to assess six symptoms: 1) Dizziness, lightheadedness, feeling faint, or feeling like you might black out, 2) problems with vision, 3) weakness, 4) fatigue, 5) trouble concentrating, and 6) head/neck discomfort. Scores for each activity and a composite score for all six activities were tabulated. A mean negative change from baseline means that symptoms have improved. A mean positive change from baseline means that symptoms have gotten worse. | Randomization (Day 0); Weeks 2 to 12 | 
| Change From Randomization To All Post-randomization Visits in Orthostatic Hypotension Questionnaire (OHQ) Composite Score | The OHQ composite score was a mean of the OHSA composite and the Orthostatic Hypotension Daily Activity Scale (OHDAS) composite scores. The OHDAS was designed as a measure of quality of life. It uses an 11-point scale to assess whether orthostatic hypotension (OH) interfered with four types of activities: 1) standing for a short time, 2) standing for a long time, 3) walking for a short time, and 4) walking for a long time. A zero rating means that over the preceding week the activity was performed with no interference and a 10 rating means that orthostatic hypotension completely interfered with the activity. Scores for each activity and a composite score for all four activities were tabulated. A mean negative change from baseline means that symptoms have improved. A mean positive change from baseline means that symptoms have gotten worse. | Randomization (Day 0); Weeks 2 to 12 | 
| Clinician-rated Clinical Global Impressions - Severity (CGI-S) | The CGI-S was developed to provide global measures of the severity of a participant's clinical condition during clinical studies. The CGI-S was utilized by both the clinician and the participant to provide an impression of the participant's current state of OH. The severity of the participant's current illness was rated by the clinician on a 7-point scale ranging from 1 (normal, no OH) to 7 (among those patients most extremely ill with OH). | Weeks 2 to 12 | 
| Participant-rated CGI-S | The CGI-S was developed to provide global measures of the severity of a participant's clinical condition during clinical studies. The CGI-S was utilized by both the clinician and the participant to provide an impression of the participant's current state of OH. The severity of the participant's current illness was rated by the participant on a 7-point scale ranging from 1 (normal, no OH) to 7 (most extremely ill with OH). | Weeks 2 to 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease, Multiple System Atrophy, Pure Autonomic Failure, Primary Autonomic Failure, Dopamine Beta Hydroxylase Deficiency