Efficacy, Safety, and Tolerability Study of AVP-786 as an Adjunctive Therapy in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Treatment

A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Tolerability of AVP-786 (Deuterium Modified Dextromethorphan Hydrobromide/Quinidine Sulfate) as an Adjunctive Therapy in Patients With Major Depressive Disorder With an Inadequate Response to Antidepressant Treatment

The objectives of this 10-week study are to evaluate the efficacy, safety, and tolerability of AVP 786 as an adjunctive therapy compared with placebo in patients with major depressive disorder (MDD) who have shown an inadequate response to standard antidepressant treatment. A secondary objective of this study is to assess the pharmacokinetics (PK) of AVP-786 and potential correlations with pharmacodynamic effects.

Study Overview

• Status: Completed
• Conditions: Depressive Disorder, Treatment-Resistant
• Intervention / Treatment: Drug: AVP-786 (d6-dextromethorphan hydrobromide and quinidine sulfate combination); Drug: Placebo

Detailed Description

It is estimated that up to approximately 200 patients will participate in the study at approximately 30 enrolling centers in the US.

Eligible patients for this study must have MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria, and have shown an inadequate response to standard antidepressant treatment.

This is a multicenter, randomized, double-blind, placebo-controlled, study of 10 weeks duration.

Following screening procedures for assessment of inclusion and exclusion criteria, eligible patients will be randomized into the study. Study medication will be administered orally twice a day (BID) (1 capsule in the morning and 1 capsule in the evening, approximately 12 hours apart) throughout the treatment period.

• Study Type: Interventional
• Enrollment (Actual): 206
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
    • Birmingham, Alabama, United States, 35213
  • California
    • Bellflower, California, United States, 90706
    • Costa Mesa, California, United States, 92626
    • Garden Grove, California, United States, 92845
    • Lomita, California, United States, 90717
    • Oceanside, California, United States, 92056
    • Riverside, California, United States, 92506
    • Santa Ana, California, United States, 92706
    • Sherman Oaks, California, United States, 91403
  • Colorado
    • Denver, Colorado, United States, 80239
  • Florida
    • Bradenton, Florida, United States, 34201
    • Jacksonville, Florida, United States, 32256
    • Miami, Florida, United States, 33155
    • Orange City, Florida, United States, 32763
    • Orlando, Florida, United States, 32801
  • Georgia
    • Decatur, Georgia, United States, 30030
  • Illinois
    • Hoffman Estates, Illinois, United States, 60169
  • Indiana
    • Valparaiso, Indiana, United States, 46383
  • Maryland
    • Baltimore, Maryland, United States, 21285
    • Glen Burnie, Maryland, United States, 21061
  • Massachusetts
    • Boston, Massachusetts, United States, 02131
  • New York
    • Brooklyn, New York, United States, 11241
    • New York, New York, United States, 10003
    • Staten Island, New York, United States, 10312
  • Ohio
    • Garfield Heights, Ohio, United States, 44125
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
    • Oklahoma City, Oklahoma, United States, 73103
    • Tulsa, Oklahoma, United States, 74101
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
    • Philadelphia, Pennsylvania, United States, 19139
  • Utah
    • Murray, Utah, United States, 84123

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical diagnosis of major depressive episode ≤ 24 months in duration
• HAM-D17 score ≥ 20.
• Documented to not have a significant (25% or greater) change in QIDS-SR16 score between Screening and Baseline visits.
• Patients have been deemed to have an inadequate response (less than 50% symptom reduction) to at least 1 but no more than 3 adequate antidepressant trials during the current depressive episode.
• Patients must be receiving ongoing treatment with an adequate dose of antidepressants.
• Body Mass Index (BMI) of 18-35 kg/m².

Exclusion Criteria:

• History of myasthenia gravis.

• Have cardiovascular concerns such as:

  • History of complete heart block, QT interval corrected for heart rate (QTc) prolongation, or torsades de pointes.
  • QTc using the Fridericia's formula (QTcF) at screening > 450 msec for males and > 470 msec for females based on central review at the screening visit, unless due to ventricular pacing.
  • Any family history of congenital QT interval prolongation syndrome.
• Known hypersensitivity/intolerance to DM, Q, opiate drugs (codeine, etc.), or any other ingredient of the study medication.

• Pose a current suicide risk, as evidenced by any of the following:

  • It is the judgment of the investigator that the subject may be at risk for suicide.
  • The subject is rated a "yes" to question 4 or question 5 on the Baseline C-SSRS, if the most recent episode occurred within the past 12 months.
  • The subject has attempted suicide within the past 6 months
• Presence of any other current DSM-IV-TR Axis I disorders with the exception of: generalized anxiety disorder (GAD: 300.02), social anxiety disorder (300.23), dysthymic disorder (300.4), or specific phobia (300.29). Patients with co-morbid GAD, social anxiety disorder, or specific phobia are ineligible if the co-morbid condition is clinically unstable, or has been the primary focus of treatment within the 6 month period prior to screening

• Axis I diagnosis of:

  • Delirium, dementia, amnestic, or other cognitive disorder;
  • Schizophrenia or other psychotic disorder, based on the M.I.N.I.;
  • Bipolar I or II disorder, based on the M.I.N.I.
• Clinically significant Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal or histrionic personality disorder.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo capsules administered twice a day over a 10-week period
Experimental: AVP-786	Drug: AVP-786 (d6-dextromethorphan hydrobromide and quinidine sulfate combination); AVP-786 capsules administered twice a day over a 10-week period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Montgomery-Ǻsberg Depression Rating Scale (MADRS) total score	Montgomery-Ǻsberg Depression Rating Scale (MADRS) total score in patients receiving AVP 786 compared with patients administered placebo	Visit 5 (Day 70) Week 10

Secondary Outcome Measures

Outcome Measure	Time Frame
17-item Hamilton Rating Scale for Depression (HAM-D17)	Visit 5 (Day 70) Week 10
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ)	Visit 5 (Day 70) Week 10
16-item Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR16)	Visit 5 (Day 70) Week 10
Sheehan Disability Scale (SDS)	Visit 5 (Day 70) Week 10
Clinical Global Impression of Severity of Illness (CGI-S)	Visit 5 (Day 70) Week 10
Clinical Global Impression of Change (CGI-C)	Visit 5 (Day 70) Week 10
EuroQOL 5 Dimension 5 Level (EQ-5D-5L)	Visit 5 (Day 70) Week 10
Patient Global Impression of Change (PGIC)	Visit 5 (Day 70) Week 10
7-item Generalized Anxiety Disorder (GAD-7)	Visit 5 (Day 70) Week 10

Collaborators and Investigators

• Sponsor: Avanir Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: May 29, 2014
• First Submitted That Met QC Criteria: May 30, 2014
• First Posted (Estimate): June 3, 2014

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: May 11, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Anti-Infective Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Membrane Transport Modulators; Cytochrome P-450 Enzyme Inhibitors; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Respiratory System Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Antitussive Agents; Adrenergic alpha-Antagonists; Dextromethorphan; Quinidine; Quinidine gluconate
• Other Study ID Numbers: 14-AVP-786-201