Phase IIa Study of AV411, a Glial Activation Inhibitor, for Opioid Withdrawal

Study Overview
=================
Brief Summary
-----------------
Repeated use and/or abuse of opioid medications is generally associated with a characteristic withdrawal syndrome that develops after cessation of drug administration. The present study is designed to evaluate the effectiveness of AV411 to alter opioid-induced withdrawal symptoms.

Detailed Description
-----------------
Opioid-induced cytokine release and glial activation has been proposed to directly contribute to the affective and physiological aspects of withdrawal. Furthermore, cytokine release following opioid administration has been hypothesized to be a limiting factor in both the duration and magnitude of opioid-induced analgesia. The two primary goals of our study are to assess AV411's ability to 1) reduce the opioid-withdrawal syndrome and 2) increase and prolong the analgesic effects of the mu-opioid agonist, oxycodone. To explore whether AV411 decreases opioid-induced glial cell activation, some participants assigned to the placebo and high dose AV411 groups (n = 6 for each dose condition) will be studied twice with [11C]PK11195, a positron emission tomography (PET) radiotracer used to measure the peripheral benzodiazepine receptor (PBR) in the human brain. The PBR is a receptor located on the mitochondria of the microglia and can be used to examine microglial activation in various brain regions.

Official Title
-----------------
The Safety, Tolerability and Preliminary Efficacy of AV411, a Glial Activation Inhibitor, in Heroin Abusers Under Conditions of Morphine Maintenance and Withdrawal

Conditions
-----------------
Opioid-Related Disorders

Intervention / Treatment
-----------------
* Drug: AV411
* Drug: Placebo (PCB)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults between the ages of 21 and 45 Current dependence on heroin according to (Diagnostic and Statistical Manual) DSM-IV criteria Non-treatment seeking Exclusion Criteria: Female participants who are currently pregnant or breastfeeding. Lack of effective birth control 10 days before Study Day 1 (15 days prior to the first PET scan) Self-reported use of methadone, buprenorphine, or levo-alpha-acetylmethadol (LAAM) in the past 14 days Participants who have a positive history of neurological illness (including epilepsy) or those who have received anti-convulsant therapy during the past 5 years Liver disease requiring medication or medical treatment, and/or aspartate or alanine aminotransferase levels greater than 3 times the upper limit of normal Gastrointestinal or renal disease that would significantly impair absorption, metabolism or excretion of study drug, or require medication or medical treatment Neurological or psychiatric disorders including psychosis, bipolar disorder, organic brain disease, any seizure history or other disorders that require treatment or that could make study compliance difficult Positive tuberculosis (PPD) TB skin test along with a clinical history and chest X-ray indicative of active tuberculosis. (Individuals who have a positive PPD test and have a negative chest X-ray, are not symptomatic for tuberculosis, and do not require anti-tuberculosis therapy will be eligible to participate. Participants will be asked if they ever tested positive for tuberculosis. If so, they will not be given a PPD and a chest X-ray and clinical history will be used for evaluation purposes). Presence or positive history of severe medical illness or any cardiovascular disease or heart abnormality, such as low hemoglobin (Hb < 13 g/dL in males, Hb < 11 g/dL in females), or BP > 150/90. Requirement for any of the following medications (current or within the past 4 weeks): psychotropics (including sedative/hypnotics, antidepressants, neuroleptics), anticonvulsants, antihypertensives, antiarrhythmics, or antiretroviral medications,. Participants on any current psychoactive prescription medications will be excluded. Current dependence (by DSM-IV criteria) on methadone, LAAM, or buprenorphine Participants for whom detoxification is not clinically recommended such as those with a significant history of overdose following detoxification Participation in an investigational drug study within the past 3 months Hypersensitivity to any of the medications used in this study Participants who are positive for HIV or chronic active hepatitis Metal implants or paramagnetic objects contained within the body which may interfere with the MRI scan, as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologists: Guide to MR procedures and metallic objects Shellock Frank G., Lippincott Williams & Wilkins Healthcare, Philadelphia, 2001. Lifetime exposure to radiation in the workplace, or participation in nuclear medicine procedures, including research protocols, in the past year Positive Allen Test indicating lack of collateral blood flow to hand History of Reynaud's syndrome

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>This group will receive placebo drug | Drug: Placebo (PCB)<br>* Placebo drug will be administered orally twice a day (BID) for two consecutive weeks<br>* Other names: PCB or 0 mg;|
| Experimental: Low-dose AV411<br>This group will receive a low dose of AV411 | Drug: AV411<br>* Low (20 mg), and high dose (40 mg) of AV411 will be administered orally twice a day (BID) for two consecutive weeks<br>* Other names: ibudilast;|
| Experimental: High-dose AV411<br>This group will receive a high dose of AV411 | Drug: AV411<br>* Low (20 mg), and high dose (40 mg) of AV411 will be administered orally twice a day (BID) for two consecutive weeks<br>* Other names: ibudilast;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective Opioid Withdrawal Scale Score (SOWS) | Measures severity of opioid withdrawal in opioid dependent populations (0-64). Larger values indicate more severe withdrawal. | Measured at the end of each two-week maintenance period (i.e., Placebo, Low AV411, High AV411). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Effects of AV411 on the Analgesic Effects of Oxycodone. | The McGill Pain Questionnaire (Melzack, 1987) was used to assess pain experience immediately following the immersion of the hand in 4 degree Celsius water. Scores were added across all 15 items to generate a sum score, which ranged between 15 and 60. Larger scores indicate greater pain levels. | Measured at the end of each AV411 of the three two-week maintenance periods | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
opioid withdrawal, analgesia