Sustained Effect of Droxidopa in Symptomatic Neurogenic Orthostatic Hypotension (RESTORE)

• ClinicalTrials.gov Identifier: NCT02586623
• Recruitment Status: Completed
• First Posted: October 26, 2015
• Last Update Posted: September 26, 2022
• Sponsor: H. Lundbeck A/S
• Information provided by (Responsible Party): H. Lundbeck A/S

Tracking Information

• First Submitted Date: October 23, 2015
• First Posted Date: October 26, 2015
• Last Update Posted Date: September 26, 2022
• Actual Study Start Date: February 11, 2016
• Actual Primary Completion Date: July 21, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 14, 2017)

Time-to-intervention [ Time Frame: Day 0 to Week 12 of double-blind period ]

Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Period:

• Orthostatic Hypotension Symptom Assessment (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
• Patient stops IMP or withdraws from study for patient-reported lack of efficacy.

The timing of the need for intervention in the above criteria is defined as the first occurrence of a worsening of OHSA Item #1 by ≥ 2 units or when the patient stops taking IMP or withdraws due to a patient-reported lack of efficacy.

Original Primary Outcome Measures (submitted: October 23, 2015)

Time-to-intervention [ Time Frame: Randomization to week 12 ]

Need for intervention is defined as meeting ANY of the following criteria during the Double-Blind Period:

• Orthostatic Hypotension Symptom Assessment (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
• Patient stops IMP or withdraws from study for patient-reported lack of efficacy.

The timing of the need for intervention in the above criteria is defined as the first occurrence of a worsening of OHSA Item #1 by ≥ 2 units or when the patient stops taking IMP or withdraws due to a patient-reported lack of efficacy.

Current Secondary Outcome Measures (submitted: September 14, 2017)

• Time to all cause discontinuation [ Time Frame: Day 0 to Week 12 of double-blind period ]
  Discontinuation for any reason
• Mean change in OHSA item #1 score from Randomization (Visit 6) to all post-Randomization visits [ Time Frame: Day 0 to Week 12 of double-blind period ]
  Mean change in OHSA item #1 score from Randomization (Visit 6) to all post-Randomization visits
• Mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from Randomization (Visit 6) to all post-Randomization visits [ Time Frame: Day 0 to Week 12 of double-blind period ]
  Mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from Randomization (Visit 6) to all post-Randomization visits
• Clinician-rated Clinical Global Impressions - Severity (CGI-S) at all post-Randomization visits (Visits 7-12) [ Time Frame: Week 2 to Week 12 of double-blind period ]
  Clinician-rated Clinical Global Impressions - Severity (CGI-S) scores at all post-Randomization visits (Visits 7-12)
• Patient-rated Clinical Global Impressions - Severity (CGI-S) at all post-Randomization visits (Visits 7-12) [ Time Frame: Week 2 to Week 12 of double-blind period ]
  Patient-rated Clinical Global Impressions - Severity (CGI-S) scores at all post-Randomization visits (Visits 7-12)
• Proportion of patients who need intervention over the 12-week Double-Blind Treatment period [ Time Frame: Day 0 to Week 12 of double-blind period ]
  Proportion of patients who need intervention over the 12-week Double-Blind Treatment period

Original Secondary Outcome Measures (submitted: October 23, 2015)

• Time to all cause discontinuation [ Time Frame: Randomization to week 12 ]
• Mean change in OHSA item #1 score from Randomization (Visit 6) to all post-Randomization visits [ Time Frame: Randomization to week 12 ]
• Mean change in Orthostatic Hypotension Questionnaire (OHQ) composite score from Randomization (Visit 6) to all post-Randomization visits [ Time Frame: Randomization to week 12 ]
• Clinician-rated Clinical Global Impressions - Severity (CGI-S) at all post-Randomization visits (Visits 7-12) [ Time Frame: Randomization to week 12 ]
• Patient-rated CGI-S at all post-Randomization visits (Visits 7-12) [ Time Frame: Randomization to week 12 ]
• Cumulative number of patients who need intervention over the 12-week Double-Blind Treatment period [ Time Frame: Randomization to week 12 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Symptomatic Neurogenic Orthostatic Hypotension

Intervention

• Drug: Droxidopa capsules
  100, 200 or 300 mg
  Other Name: Northera
• Drug: Placebo capsules
  Other Name: Placebo

Study Arms

• Experimental: Open Label Period
  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).
  Intervention: Drug: Droxidopa capsules
• Placebo Comparator: Randomized Period
  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.
  Interventions:

  • Drug: Droxidopa capsules
  • Drug: Placebo capsules

• Publications *: Hauser RA, Favit A, Hewitt LA, Lindsten A, Gorny S, Kymes S, Isaacson SH. Durability of the Clinical Benefit of Droxidopa for Neurogenic Orthostatic Hypotension During 12 Weeks of Open-Label Treatment. Neurol Ther. 2022 Mar;11(1):459-469. doi: 10.1007/s40120-021-00317-5. Epub 2022 Feb 2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 23, 2022): 254
• Original Estimated Enrollment (submitted: October 23, 2015): 482
• Actual Study Completion Date: September 9, 2022
• Actual Primary Completion Date: July 21, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02586623
• Other Study ID Numbers: 16306A; NOH402 ( Other Identifier: NOH402 )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: H. Lundbeck A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: H. Lundbeck A/S
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Email contact via H. Lundbeck A/S; LundbeckClinicalTrials@Lundbeck.com

• PRS Account: H. Lundbeck A/S
• Verification Date: September 2022