Tolerability, Safety, and Activity of SRX246 in Irritable Subjects With Huntington's Disease

• Sponsor: Azevan Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02507284
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH), NeuroNEXT Network (Other)
• Enrollment: 106
• Locations: 22
• Arms: 3
• Actual Duration (Months): 31.4
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study evaluates the tolerability, safety and activity of SRX246 in the treatment of irritability in patients with Huntington's disease. Two-thirds of all participants will receive SRX246, while the other third will receive a placebo.

Condition or Disease	Intervention/Treatment	Phase
Irritable Mood; Huntington's Disease	Drug: SRX246; Drug: Placebo	Phase 2

Detailed Description

SRX246 is a first-in-class vasopressin 1a (V1a) receptor antagonist that crosses the blood-brain barrier following oral administration. The molecule exhibits high affinity and high selectivity for its target receptor. Preclinical pharmacology studies have demonstrated significant CNS effects in models of irritability, including impulsive aggression, depression, and anxiety. In an experimental medicine fMRI study in healthy volunteers, SRX246 treatment significantly attenuated the effect of intranasal AVP in brain circuits known to modulate emotional responses to stimuli that elicit aggression/fear. Together, these findings suggest that SRX246 has potential as a novel therapeutic agent for major neuropsychiatric symptoms seen in HD patients.

This is a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12 week, dose escalation study of SRX246 in irritable Subjects with early symptomatic HD.

Following an initial screening visit, Subjects fulfilling the study inclusion and exclusion criteria will enter a pre-treatment screening phase to permit evaluations to confirm eligibility for inclusion into the study. This screening phase will be no longer than 30 days. At the completion of the screening period, eligible Subjects will be randomized at baseline visit to receive either placebo or final doses of SRX246 of 120 mg twice daily or 160 mg twice daily during the double-blind treatment phase. At baseline, Subjects in the active groups will receive 80 mg twice daily for 2 weeks, then escalate to 120 mg twice daily for 4 weeks. Then one group of Subjects will continue to take 120 mg of SRX246 twice daily for an additional 6 weeks, and the second group of Subjects will increase their dose to 160 mg of SRX246 twice daily for 6 weeks. Total dosing duration is 12 weeks.

Subjects in the placebo group will receive a similar number of capsules that are identical in appearance to the capsules that contain SRX246 during the trial, in order to preserve the blind.

In all groups, dose escalation will occur (stepwise) if patients have not experienced dose-limiting adverse effects. Patients who cannot tolerate their final dose of drug (or placebo) can have this dose reduced without compromising the blinding.

Subjects will have periodic visits either "in-person" or by "telephone", to assess tolerability, safety, and several measures of irritability and other problem behaviors, and clinical assessments for activity signals.

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An Exploratory Phase II Study to Determine the Tolerability, Safety, and Activity of a Novel Vasopressin 1a Receptor Antagonist (SRX246) in Irritable Subjects With Huntington's Disease (HD)
• Actual Study Start Date: May 10, 2016
• Actual Primary Completion Date: Sep 10, 2018
• Actual Study Completion Date: Dec 21, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SRX246 120mg BID SRX246 capsules, administered orally, in divided doses twice daily	Drug: SRX246
Experimental: SRX246 160mg BID SRX246 capsules, administered orally, in divided doses twice daily	Drug: SRX246
Placebo Comparator: Placebo Placebo capsules, administered orally, in divided doses twice daily	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Tolerability, defined as the proportion of completers. [12 weeks]

   Assess the proportion of completers.

Secondary Outcome Measures

1. Safety, defined as the proportion of participants who experience an adverse event. [12 weeks]

   Assess the proportion of participants who experience an adverse event.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male and female Subjects aged 18 years or older

2. Subjects must have clinical features of HD, which can include motor, cognitive, or behavioral symptoms

3. A confirmatory family history of HD; OR CAG repeat expansion ≥ 37

4. Total Functional Capacity (TFC) score of 5-13

5. Evidence of irritability; a score of at least 2 or greater on the severity measure of either the UHDRS Irritability question (30b) or Aggression question (Disruptive or Aggressive Behavior, 31b)

6. Women of childbearing potential (i.e., those not postmenopausal or surgically sterile) must have a negative pregnancy test, be non-lactating and use adequate contraception methods during the study. Adequate birth control includes: abstinence; oral, implanted or injected contraceptives, e.g., birth control pills; intra-uterine device; barrier (vaginal ring or diaphragm/cervical cap with spermicide); transdermal patch. Reliable contraception must have been in use 30 days prior to the Baseline Visit. Partner(s) contraception (e.g., male partner with vasectomy or other surgical contraception) is acceptable.

7. Men must agree not to father a child during the study and one month after and to use contraception. Barrier with spermicide or surgical contraception is acceptable. Partner(s) contraception (e.g., female partner taking birth control pills or surgically sterile) is acceptable.

8. Subjects must be able to swallow study drug capsules whole.

9. Sufficient English skills to complete all assessments without assistance of an English language interpreter. Subjects with HD who cannot read or write might qualify for enrollment in the study. Site PIs will have to decide in each case whether the Subject can understand and fully participate with help from his/her Informant.

10. Availability of a responsible Informant (referred to as a "study partner" in the consent document) who has good English skills, is familiar with the Subject, and is able and willing to comply with all required study procedures, ensuring that the patient attends all study visits and takes the study medicine as instructed. The study partner must spend time with the patient a minimum of 4 times per week on 4 separate days, and must monitor the patient's compliance and adverse events, participate in caregiver assessments, and use the eDiary.

11. Subject has provided written, informed consent or, if Subject lacks the capacity to provide informed consent (as determined by an independent assessment by a qualified healthcare provider not directly involved in other study activities), a legally authorized representative (LAR) has provided written informed consent and the Subject has provided assent.

Exclusion Criteria:

1. Any significant neurologic disease other than HD at Screening.

2. Severe psychotic features or other severe psychiatric symptoms within the last three months which could lead to difficulty complying with the protocol.

3. History of active alcohol or substance abuse within the past two years or Subject is unable to refrain from substance abuse throughout the study.

4. Any chronic disability, significant systemic illness or unstable medical condition at Screening or Baseline that could lead to difficulty complying with the protocol.

5. Use of any investigational drugs within 30 days of Screening.

6. Subject has known allergy to any of the components of study medication.

7. Subject is currently pregnant, breast-feeding and/or lactating.

8. Subject acknowledges present use of illicit drugs at Screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35233
2	UCLA, Neurology Clinic	Los Angeles	California	United States	90095
3	UC Davis Medical Center, Department of Neurology, CTSC Clinical Research Center	Sacramento	California	United States	95817
4	University of Colorado Hospital Translational Research Center	Aurora	Colorado	United States	80045
5	University of Miami, Miller School of Medicine, Jackson Behavioral Health Hospital	Miami	Florida	United States	33136
6	Emory University	Atlanta	Georgia	United States	30329
7	Northwestern Out-Patient Neurology Clinic	Chicago	Illinois	United States	60611
8	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
9	Massachusetts General Hospital	Charlestown	Massachusetts	United States	02129
10	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
11	SUNY Stony Brook Clinical Research Center, Department of Neurology	East Setauket	New York	United States	11733
12	Columbia University Medical Center, New York Presbyterian Hospital	New York	New York	United States	10032
13	University of Rochester Medical Center	Rochester	New York	United States	14618
14	University Medical Arts Building	Cincinnati	Ohio	United States	45219
15	Ohio State University, Wexner Medical Center, Department of Neurology	Columbus	Ohio	United States	43221
16	Oregon Health and Science University	Portland	Oregon	United States	97239
17	University of Pittsburgh Medical Center, Department of Neurology	Pittsburgh	Pennsylvania	United States	15213
18	Vanderbilt Clinical Research Center	Nashville	Tennessee	United States	37232
19	UT Southwestern Medical Center	Dallas	Texas	United States	75390
20	University of Utah, Department of Neurology	Salt Lake City	Utah	United States	84108
21	University of Virginia Health System, Department of Neurology	Charlottesville	Virginia	United States	22908
22	Swedish Neuroscience Institute	Seattle	Washington	United States	98122

Sponsors and Collaborators

• Azevan Pharmaceuticals
• National Institute of Neurological Disorders and Stroke (NINDS)
• NeuroNEXT Network

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Azevan Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02507284
• Other Study ID Numbers: AVN011; 1U44NS090616-01A1
• First Posted: Jul 23, 2015
• Last Update Posted: Jan 13, 2021
• Last Verified: Dec 1, 2019

• Additional relevant MeSH terms: Huntington Disease; SRX246

Study Results

No Results Posted as of Jan 13, 2021