Clinical Trials of Multivalent Opioid Vaccine Components

Study Overview
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Brief Summary
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Currently, abuse of prescription opioid analgesics and heroin is a serious problem in the U.S. Although several medications, including methadone, buprenorphine, and naltrexone, are available and effective in treating opioid use disorder (OUD), long-term relapse rates remain high. The current study is designed to examine a new approach to treating OUD, namely use of a vaccine targeted against oxycodone [Oxy(Gly)4-sKLH], one of the most commonly abused prescription opioids. The vaccination approach to treating substance use disorders relies on the ability of the vaccine to produce antibodies that bind the target drug in blood and reduce its ability to enter the brain. The long-term goal of this research will be to develop a combined vaccine against oxycodone and heroin. However, in this trial the Oxy(Gly)4-sKLH vaccine will be studied separately. This is a multi-site study, being conducted at the New York State Psychiatric Institute and the Clinilabs clinical research unit (CRU) in Eatontown, New Jersey. The current study proposes to evaluate safety (Aim 1), degree of antibody production (Aim 2), and efficacy (i.e., ability to reduced drug liking following opioid administration) (Aim 3). The oxycodone vaccine (Oxy(Gly)4-sKLH) will be tested in participants with OUD (target # completers = 45 across two study sites). This study will provide a great deal of information about the safety and potential effectiveness of the Oxy(Gly)4-sKLH vaccine in reducing the abuse of opioids.

Detailed Description
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Overview: The proposed study is designed as a Phase 1a/1b clinical trial of an oxycodone vaccine (Oxy(Gly)4-sKLH Conjugate Vaccine, Adsorbed). Healthy adults, aged 18 to 59 years, who meet DSM-5 criteria for OUD but are not seeking treatment for their drug use, and are physically dependent on opioids will be recruited. This study will employ a between-groups, placebo-controlled design (two active vaccine doses, 1 placebo). Immunization will occur at Weeks 0, 3, 6 and 18. The Oxy(Gly)4-sKLH vaccine adsorbed to aluminum adjuvant (Alhydrogel®) or aluminum adjuvant as placebo, will be injected intramuscularly (IM) into the deltoid muscle. Each subject completing the study will participate for 43 weeks including: One Screening Phase (Weeks -6 to -2), two Inpatient Phases (Weeks -2-8 and 18-20), two Outpatient Phases (Weeks 8-18, 20-21), and a Follow Up Phase (Week 21, 23, 30, 34, 38, and 42 (1-week, 1-month, 3-month, 4-month, 5-month, and 6-month follow up). Subjects will be immunized during Weeks 0, 3, 6 and 18 with either Oxy(Gly)4-sKLH (either 100 μg or 400 μg dose; different dose levels will be administered by varying the volume of the 400 μg/mL formulation) adsorbed on aluminum adjuvant or aluminum alone as placebo. Screening Phase (Weeks -6 thru -2): Eligibility for admission into the study will be based on a psychiatric evaluation, physical examination, blood and urine testing, electrocardiogram, drug history assessment, urine drug testing, and ascertainment of physical dependence on opioids via naloxone challenge and/or objective confirmation of opioid withdrawal signs/symptoms Inpatient Phases (Weeks -1-8 & 18-19) Opioid Maintenance and Testing Sessions: During the inpatient phases participants will be maintained on oral morphine 120 mg/day. During testing sessions, intranasal oxycodone (0, 25, 50, and 100 mg/70kg) will be administered during each inpatient phase to assess the ability of the vaccine to reduce positive subjective ratings (e.g., Drug Liking, High, etc.). Intranasal heroin (100 mg/70 kg) and lactose powder (placebo) will be used as positive and negative controls, respectively. In addition to assessing subjective effects, vital signs and other physiological measures are collected throughout the testing period (4.5 hours). The order ofthe different doses will be randomized and one dose of either oxycodone, heroin, or placebo will be given each day on 5 consecutive days. During testing sessions a physician or nurse practitioner will be on the floor for the first hour after IN dosing, and on-call throughout the session. Outpatient Phases (Weeks 9-17, 20-21): Participants will return to the laboratory weekly during the outpatient phases in order to assess titer levels, maintain good contact and to assess drug use, adverse events, and concomitant medication use. Blood tests (hematology, chemistry) and urinalysis will be performed repeatedly throughout the study: just prior to each inpatient phase and during the follow up visits at the end of the study (Weeks 8, 12, 17, 21, 23, and 30). In addition, the following assessments will be completed weekly throughout the study: Physical exam, 12-lead ECG, body weight, vital signs, and standard assessments of depression and suicidal thoughts/behaviors, along with cognitive functioning. The Columbia Suicide Severity Rating Scale (CSSRS) and clinical interviews will be used to provide ongoing assessments of this risk throughout the inpatient and outpatient phases of the study. Discharge (Week 19) and Follow-Up (Weeks 21, 23, 30, 34, 38, and 42): During the last week of the study and/or prior to each inpatient discharge, participants will receive counseling about different treatment options for opioid use disorder. For those participants requesting treatment, appropriate arrangements will be made.

Official Title
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Phase 1A/1B Clinical Trials of Multivalent Opioid Vaccine Components

Conditions
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Opioid-use Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: Oxy 25 mg
* Drug: OXY 50 mg
* Drug: OXY 100 mg
* Drug: Heroin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. Males and females aged 18 to 59 years. Females must be non-pregnant, non-lactating and either be of non-childbearing potential (i.e. sterilized via hysterectomy or bilateral tubal ligation or at least 1 year post-menopausal) or of childbearing potential but practicing a medically acceptable method of birth control. Meets current DSM 5 criteria for moderate-severe OUD, physical dependence on opioids, and current use of opioids will be in amounts and/or frequencies that meet or exceed those used in the study (3-4 tablets of a prescription opioid medication per day or 1-2 bags of heroin per day). Participants may meet criteria for other behavioral disorders (e.g. gambling) or substance use disorders (e.g., cocaine or marijuana), but cannot be physically dependent on drugs that pose risk of withdrawal that requires medical management such as alcohol or benzodiazepines. Participant must self-identify their opioid of choice as being other than oxycodone, oxymorphone, hydrocodone, and hydromorphone (e.g., a heroin user). In addition, we will only include individuals who have prior experience with intranasal opioid use. Only participants with a minimum use of 1-2 bags of heroin per day and a maximum of 15 bags of heroin per day will be enrolled. Not currently seeking treatment for drug use as defined by urine samples positive for illicit opioids, and at least 2 urine samples negative for buprenorphine and methadone, spaced at least 3 days apart, prior to admission. Willing and able to comply with scheduled visits, dosing plan, laboratory tests, and other study procedures. Patients who weigh less than 300 pounds and /or have less than a maximum girth of 52 inches. Exclusion Criteria: Participation in a clinical trial and receipt of investigational drug(s) during 30 days (or 5 half-lives, whichever is longer) prior to randomization. Sensitivity, allergy, or contraindication to opioids, alum, or any components of the vaccine. Prior exposure to opioid vaccines or vaccines containing Keyhole Limpet Hemocyanin. Use of prescription psychotropic medications that would potentially interfere with study procedures. Women of childbearing age who are pregnant, lactating or, not practicing or willing to begin a medically acceptable method of birth control. Cannot read or understand the self-report assessment forms unaided or are so severely disabled that they cannot comply with the requirements of the study. Medical conditions that may make study participation hazardous: History of seizures or cardiac risk conditions (unstable angina, cardiac arrhythmias, chest pain, strong palpitations (subjectively defined as the feeling that the heart is beating too hard, too fast, skipping a beat, or fluttering). Elevated liver function tests (i.e., AST and ALT > 3 times the upper limit of normal). Impaired renal function (creatinine > 1.2). Hypertension (>140/90). Asthmatic symptoms within the past 3 years. Active hepatitis [e.g. symptomatic with a positive test for hepatitis B (HBsAg), hepatitis C antibody (HCV), HIV1/HIV2 antibody/antigen]. Significant hepatocellular injury as evidenced by elevated bilirubin levels (>1.3), or elevated levels (over 3x the upper limit of normal) of aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT). Creatinine clearance estimated to be less than 60 ml/min. Current gastric disease such as peptic ulcer disease, gastritis, upper gastrointestinal bleeding, or any gastrointestinal malignancy or precancerous condition. Sleep apnea as assessed by the STOP-Bang questionnaire; those with high risk will be excluded from the study Hemoglobin: Women <11.5; men <13. Newly diagnosed HIV infection or known HIV infection with CD4 counts below normal levels, active tuberculosis, or other immunocompromising diseases. Current chronic pain (persistent for longer than 3 months). Current or history of psychotic disorder or other severe Axis I disorder based on DSM 5 criteria, other than OUD, including physical dependence on drugs that pose risk of withdrawal that requires medical management such as alcohol or benzodiazepines. Participants diagnosed with dysthymia or mild-moderate depression with no recent suicidal ideation may be included. Recent suicidal ideation is defined as thoughts about suicide within the past month. Previous serious or unexpected adverse reaction to a vaccine, including Guillain-Barré syndrome. Use of inhaled corticosteroids, antihistamines, immunosuppressive agents or other medications within 30 days prior to administration of investigational product that might interfere with an immune response. Use of any vaccine, with the exception of influenza vaccine, 30 days prior to administration of study product. Known history of cancer or cancer treatment within 12 months prior to administration of investigational product. Receipt of blood products within 3 months of screening. Anticipated inability to fulfill all visits and examination procedures throughout the study period (approximately 12 months). Individuals who are on medication-assisted treatment for Opioid Use Disorder (e.g., buprenorphine, buprenorphine/naloxone, methadone, naltrexone). Individuals who currently (within the past 3 months) have a temporary restraining order (TRO) against them or against another person. Lactose is used as an excipient in the compounded challenge test articles. History of prior opiate overdose (within the past 2 years) identified by self-report during multiple interviews conducted during the screening process.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: Participants are randomized among three arms i.e., to one of three doses of the opioid vaccine: Placebo, Low and High dose. Under each vaccine condition, the participant is administered 5 intranasal drugs.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Vaccine<br> | Drug: Placebo<br>* Intranasal placebo 0mg<br>Drug: Oxy 25 mg<br>* Intranasal oxycodone 25mg<br>Drug: OXY 50 mg<br>* Intranasal oxycodone 50mg<br>Drug: OXY 100 mg<br>* Intranasal oxycodone 100mg<br>Drug: Heroin<br>* Intranasal heroin 100mg<br>|
| Experimental: Low Dose Vaccine (100 μg)<br> | Drug: Placebo<br>* Intranasal placebo 0mg<br>Drug: Oxy 25 mg<br>* Intranasal oxycodone 25mg<br>Drug: OXY 50 mg<br>* Intranasal oxycodone 50mg<br>Drug: OXY 100 mg<br>* Intranasal oxycodone 100mg<br>Drug: Heroin<br>* Intranasal heroin 100mg<br>|
| Experimental: High Dose Vaccine (400 μg)<br> | Drug: Placebo<br>* Intranasal placebo 0mg<br>Drug: Oxy 25 mg<br>* Intranasal oxycodone 25mg<br>Drug: OXY 50 mg<br>* Intranasal oxycodone 50mg<br>Drug: OXY 100 mg<br>* Intranasal oxycodone 100mg<br>Drug: Heroin<br>* Intranasal heroin 100mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Safety and tolerability of the opioid vaccine. | Beginning from first vaccination through study completion (43 Weeks). | 
| Effects of Vaccine on Intranasal Drug Positive Subjective Effects | Peak self-reported drug Liking. Measured using a visual analog scale (0-100). | Throughout the testing session [i.e., pre-dose baseline (Time 0)- Thru- 4.5 hours post-dose]. |