Conditions: Opioid Dependence
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: yes

Brief summary:
The investigators will randomize 50 opioid-dependent participants who have initially failed outpatient induction onto XR-NTX; participants will receive buprenorphine/naloxone on a weekly basis for 30 days. Buprenorphine/naloxone will be dispensed weekly during the 30-day stabilization and twice weekly during taper phase, and all patients who successfully complete the detoxification will be offered induction onto XR-NTX. All participants will receive weekly therapy with a study psychiatrist. All participants will receive open-label medication. The primary outcome of this study will be percentage of patients successfully inducted onto XR-NTX. Secondary outcomes will be time to relapse, defined as opioid use or dropout.

Detailed description:
Buprenorphine induction/stabilization/taper: Buprenorphine induction will be conducted at our STARS clinic and according to current clinical guidelines. Participants who have initially failed outpatient induction onto XR-NTX will receive buprenorphine/naloxone (BUP) on a weekly basis that they will take daily, according to the following schedule: 8/2 mg (Days 1-10), 6/1.5 mg (Days 11-15), 4/1 mg (Days 16-20), 3.0/0.75 mg (Days 21-25), 2.0/0.5 mg (Days 26-30).

Participants will attend the clinic twice weekly and will be assessed for opioid and other substance use (urine toxicology and self-report), vital signs, opioid withdrawal symptoms, opioid cravings, and dose adjustments of buprenorphine will be made as needed by study physicians. If a dose reduction is needed, the stabilization and taper schedule will be adjusted to occur over 30 days.

Participants will be stabilized on, and tapered off, buprenorphine over a 4-week period.Reductions will occur in a graded fashion, with the stabilization dose reduced to 2 mg. This approach to buprenorphine taper is intended to resemble standard clinical practice, in which patients seeking transition off buprenorphine undergo a slow taper. A gradual taper over approximately 4 weeks has established precedent (Sigmon et al. 2013, Ling et al. 2009, Nielsen et al. 2013) as a well-tolerated taper strategy for transitioning off buprenorphine. The purpose is in part to provide a slow transition with minimal withdrawal symptoms. Participants will have at least two study visits a week during the buprenorphine taper, but may be seen more regularly at STARS if deemed clinically necessary.

Naltrexone induction procedure: Participants who successfully complete the taper must then complete a two-day washout (abstinence for opioids, buprenorphine). During this 48-hr period,participants will report to the STARS clinic daily for vital sign monitoring and to receive ancillary medications (clonidine, clonazepam, zolpidem, prochlorperazine) to alleviate withdrawal and discomfort as needed. After abstinence of \>/=48 hours from the last buprenorphine dose, to allow for mu receptor availability, participants will begin the naltrexone induction,using a 4-day ascending taper of oral naltrexone (1, 3, 12, and 25 mg), followed by injection naltrexone . The administration of naltrexone will occur within a detoxification suite provided at STARS, consisting of a private room outfitted with two comfortable reclining lounge chairs for resting, adjustable lighting, and an entertainment system. Participants will be monitored by clinical staff at least every 1-2 hours with frequent vital signs checks and withdrawal assessments. A research psychiatrist or study physician will be present at all times to conduct frequent clinical assessments and provide adjuvant medications and naltrexone. Patients will be monitored on a daily basis (Monday to Friday) for up to 8 hours per day. Transportation home by car service will be provided at the end of the day for any patient deemed to have this clinical need.

On Day 1 of the naltrexone induction,participants are pre-treated with prochlorperazine 10 mg for nausea, followed be the first dose of naltrexone 1mg. Ascending doses of naltrexone will then be titrated upward slowly (3mg, 12mg, 25mg). Adjuvant medications will be available to patients and will include clonidine for myalgias, prochlorperazine for nausea, clonazepam to reduce anxiety and dysphoria, and trazodone or zolpidem for insomnia. Participants will be provided take-home doses of adjuvant medications in small doses and on a tapering schedule for one week post-administration of XR-NTX. Participants will be required to visit the clinic daily and remain there for at least 1 hour to permit close monitoring, with an option to stay as long as necessary to achieve relief of symptoms and medical stability prior to being discharged home.

Once 25 mg of naltrexone has been tolerated, the participant may receive 380 mg IM XR-NTX.

Additionally, for female participants, a urine pregnancy test will be obtained on the day of XR-NTX administration. Prior to administration of XR-NTX, participants who have been non-compliant with the oral naltrexone schedule, accompanied by lapses to opioid use, or in any case for which the challenge appears clinically indicated in the judgment of the study physician or research team, will receive a naloxone challenge prior to XR-NTX administration. Referrals to local treatment providers will be arranged for participants who successfully complete the study and request to continue XR-NTX maintenance

XR-NTX injections: XR-NTX will be administered once naltrexone 25 mg has been tolerated, as an intramuscular injection (380 mg) in one buttock by one of the research psychiatrists or research nurses of STARS, who are currently trained and administer XR-NTX in other protocols. Participants will be observed for at least 2 hours after the first injection. Participants will be offered a second injection at Week 5 (four weeks post-administration of the first injection), and a third injection at Week 9. Prior to receiving second and third injections at STARS, patients will either provide an opioid-negative urine or pass a naloxone challenge test.

At each STARS visit the patient meets with the research assistant to complete research ratings, including self-report of withdrawal, mood, and drug use. Blood samples are drawn according to the protocol for naltrexone serum levels and liver enzymes. The patient provides a urine sample under observation by a staff member at each visit. STARS is staffed by both male and female research assistants so that all urines can be appropriately monitored.

All participants will receive a weekly medication adherence-focused psychosocial intervention informed by relapse prevention strategies we previously developed in Behavioral Naltrexone Therapy and delivered by the study physician (Rothenberg, Sullivan et al. 2002). We have developed a relapse prevention approach which includes an emphasis on compliance with NTX. Participants will receive this therapy during weekly visits in outpatient Weeks 1-12 following induction onto XR-NTX.

Arms:
arm 1: Participants who have initially failed outpatient induction onto XR-NTX will receive buprenorphine/naloxone (BUP) on a weekly basis that they will take daily,

Interventions: intervention 1: Buprenorphine/naloxone
Intervention descriptions: intervention 1: 30 day oral Buprenorphine/naloxone

Protocol document:
Prot_000.pdf: 
Signed copy on file at IRB 
 
             v. 4/19/13 
                                          NEW YORK STATE PSYCHIATRIC INSTITUTE         
INSTITUTIONAL REVIEW BOARD 
MEMORANDUM 
 
 
 
 
 
 
 
 
 
August 13, 2018 
TO: 
 
Dr.  Elizabeth Evans 
FROM: 
Dr. Edward Nunes, Co-Chair, IRB 
 
 
Dr. Agnes Whitaker, Co-Chair, IRB 
 
 
SUBJECT: 
APPROVAL NOTICE:  CONTINUATION   
 
 
Expedited per 45CFR46.110(b)(1)(f)(8)(c) 
 
Your protocol # 6999 entitled BUPRENORPHINE/NALOXONE STABILIZATION AND INDUCTION 
ONTO INJECTION NALTREXONE: AN OUTPATIENT DETOXIFICATION FOR OPIOID DEPENDENCE 
(version date 08-13-18) and Consent Forms have been approved by the New York State 
Psychiatric Institute - Columbia University Department of Psychiatry Institutional Review Board 
from September 8, 2018 to September 7, 2019.   
 
Consent requirements: 
   
  X Not applicable: (RECRUITMENT COMPLETED. DATA BEING ANALYZED) 
    
   45CFR46.117 (c)(2) waiver of documentation of consent for the telephone interview.   
 
   Signature by the person(s) obtaining consent is required to document the consent process. 
 
   Documentation of an independent assessment of the participant’s capacity to consent is also required. 
 
       
    Approved for recruitment of subjects who lack capacity to consent:   No      Yes    
 
 
    Field Monitoring Requirements:  Routine      Special:                                    
 
√   Only copies of consent documents that are currently approved and stamped by the IRB 
may be used to obtain consent for participation in this study. 
√  A progress report and application for continuing review is required 2 months prior to the  
expiration date of IRB approval. 
√  Changes to this research may be not be initiated without the review and approval of the  
IRB except when necessary to eliminate immediate hazards to participants.  
√  All serious and/or unanticipated problems involving risks to subjects or others must be 
reported immediately to the IRB.  Please refer to the PI-IRB website at http://irb.nyspi.org 
for Adverse Event Reporting Procedures and additional reporting requirements.  
 
CC: 
RFMH Business Office (3 RO1 DA030484-04S1) 
 
 
 
 
EN/AW/Scr 


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Protocol Title:
Buprenorphine/Naloxone Stabilization and 
Induction onto Injection Naltrexone: An 
Outpatient Detoxification for Opioid 
Dependence
Protocol Number:
6999
First Approval:
09/23/2014
Expiration Date:
09/07/2019
Version Date:
08/13/2018
Clinic:
Substance Treatment And Research 
Services (STARS)
Contact Principal Investigator:
Elizabeth Evans, MD
Email: evansel@nyspi.columbia.edu
Telephone: 646-774-6123
Principal Investigator:
Adam Bisaga, MD
Research Chief:
Herbert Kleber, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am submitting an annual continuation without modifications 
Division & Personnel
Division
What Division/Department does the PI belong to?
Substance Abuse
Within the division/department, what Center or group are you affiliated with, if any? 
Substance Treatment and Research Service (STARS)
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 
State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.


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None
Application for Continuation of Research
Status
Current Status of Study: 
All research interventions were completed. Only data analysis is ongoing.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
We are currently analyzing the data and preparing a manuscript.
Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 
the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 
No
Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?
Yes
Is the study covered by a certificate of confidentiality? 
Yes
Certificate expiration date (mm/dd/yyyy) 
9/30/2016
Overall Progress
Approved sample size


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67
Total number of participants enrolled to date
30
Number of participants who have completed the study to date 
8
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
No
Comments / additional information 
Sample Demographics
Specify population
Adults ages 18-60 who meet criteria for opioid use disorder of at least moderate severity
Total number of participants enrolled from this population to date 
30
Gender, Racial and Ethnic Breakdown 
Male
White:16
Hispanic:5
Black:3
Asian: 1
Other: 0
 
Female
White:3
Hispanic:1
Black:1
Asian: 0
Other: 0
Summary of Current Year's Enrollment and Drop-out 
Number of participants who signed consent in the past year
0
Did the investigator withdraw participants from the study? 
No
Did participants decide to discontinue study involvement? 
No
Procedures


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To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Collection of Biological Specimens
   Medication Trial
Population
Indicate which of the following populations will be included in this research
   Adults
   Adults over 50
   Individuals with HIV/AIDS
   Substance Users
Research Support/Funding
Will an existing internal account be used to support the project?
No
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
Funding Source #1
Is the PI of the grant/contract the same as the PI of the IRB protocol? 
Yes
Select one of the following
The grant/contract is currently funded
Source of Funding
Federal
Institute/Agency
NIDA
Grant Name
Improved Strategies for Outpatient Opioid Detoxification
Grant Number
3 R01 DA030484-04S1
Select one of the following
Single Site
Business Office
RFMH
Does the grant/contract involve a subcontract? 
No


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Study Location
Indicate if the research is/will be conducted at any of the following
   Other Columbia University Medical Center Facilities
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research 
Lay Summary of Proposed Research
We will randomize 46 opioid-dependent participants who have initially failed outpatient induction onto XR-
NTX; participants will receive buprenorphine/naloxone on a weekly basis for 30 days. 
Buprenorphine/naloxone will be dispensed weekly during the 30-day stabilization and twice weekly during 
taper phase, and all patients who successfully complete the detoxification will be offered induction onto 
XR-NTX. All participants will receive weekly therapy with a study psychiatrist. All participants will receive 
open-label medication. The primary outcome of this study  will be percentage of patients successfully 
inducted onto XR-NTX. Secondary outcomes will be time to relapse, defined as opioid use or dropout.
Background, Significance and Rationale
Background, Significance and Rationale
Rates of prescription opioids and heroin use and related morbidity and mortality continue to grow at an 
alarming rate (CDC, 2012; SAMHSA, 2013), and there are currently more than 2.5 million individuals 
affected in the U.S. While heroin use remains prevalent, prescription opioid abuse has risen dramatically in 
the past decade (SAMHSA, 2012). There has also been a dramatic increase in unintentional overdose deaths 
(CDC, 2012). Unfortunately, most people with opioid dependence are not receiving treatment (SAMHSA, 
2013). Reasons for this gap between treatment need and delivery include lack of access to opioid 
dependence treatment programs, lack of training for providers such that the healthcare workforce is not, for 
the most part, knowledgeable about effective treatment options. Expanding available treatment options and 
attracting more opioid-dependent individuals into effective treatment represent important public health 
priorities (CASA Columbia, 2012).
Treatment with agonist medication (methadone, buprenorphine) is one effective treatment approach (Ball 
1991; Johnson 2000; Stotts 2009). Since its approval by the US Food and Drug Administration (FDA) in 
2002 as a pharmacotherapy for opioid dependence, buprenorphine is increasingly utilized both by opioid 
treatment centers as well as office-based physicians. While agonist maintenance is currently an effective 
strategy for long-term retention, it may not be a viable option for many individuals for a variety of reasons, 
including preference or access (Rounsaville 2000; Cunningham 2007). Further, the acceptability of opioid 
maintenance treatment is limited by perceived stigma attributed to opioid dependence and its treatment on 
the part of both affected individuals and clinicians (Cicero et al., 2007; Knudsen et al., 2007). Long acting 


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naltrexone (XR-NTX, brand name: Vivitrol), a mu opioid receptor antagonist, completely blocks the effects 
of opioids, and was approved by the FDA in 2010 for relapse to opioid dependence following detoxification 
(O’malley 2007; Krupitsky 2010). Clinical trials have shown retention rates similar to those observed with 
buprenorphine, with little or no opioid use (Brooks et al., 2010; Comer et al., 2006; Hulse et al., 2009; 
Krupitsky et al., 2011, 2012). XR-NTX is an important option for those desiring abstinence from opioids. 
Initiation of naltrexone in patients dependent on opioids is a barrier, as patients must undergo detoxification. 
Inpatient detoxification is not a realistic option for many opioid-dependent patients because of (1) 
occupational or domestic responsibilities which do not permit such an absence, and (2) lack of adequate 
insurance, as carriers have become increasingly unwilling to cover the costs associated with inpatient stays 
for detoxification (Mark et al. 2001). Thus, for XR-NTX to be an effective alternative, and one that is 
readily incorporated into clinical practice, detoxification must occur in a wider range of settings, including 
outpatient. Further, in addition to the growing population on buprenorphine maintenance, buprenorphine is 
also increasingly used to assist with outpatient detoxification (Raistrick 2005; Caldiero 2006). Thus, an 
effective outpatient strategy detoxing from (or with) buprenorphine for purposes of naltrexone induction 
will increase viability of maintenance treatment with XR-NTX. 
 
To date, there is no standard buprenorphine detoxification design, and data of duration of buprenorphine 
detoxification, and its impact on treatment outcomes, has been mixed. A review of the literature by Dunn et 
al. in 2011 suggests buprenorphine taper duration is associated with opioid abstinence, but not retention 
(Dunn et al. 2011). However, there are relatively few randomized, clinical trials of taper duration. Some 
trials suggest longer tapers are associated with less withdrawal, less opioid use and better retention (Amass 
et al. 1994; Woody et al. 2008; Sigmon et al. 2013). However, Ling et al. found a larger percentage of 
opioid negative urines in their shorter taper group (Ling et al. 2009). In a recent randomized, double-blind 
trial, Sigmon et al. compared the relative efficacy of 1-,2-, and 4-week buprenorphine tapering regimens and 
subsequent naltrexone induction (Sigmon et al 2013). They found a significant effect of taper duration on 
abstinence, retention, and naltrexone ingestion at the end of their 12-week study (Sigmon et al 2013). 
 
In one of our ongoing studies, Long-acting Injectable Naltrexone Induction: A Randomized Trial of 
Outpatient Opioid Detoxification with Naltrexone vs. Buprenorphine (PI: Adam Bisaga M.D., (#6374) 
opioid-dependent participants are randomized to one of two outpatient detoxification strategies: (1) a 
standard 7-day buprenorphine induction and gradual taper from 8 mg to 0 mg vs. (2) 7-day oral naltrexone 
induction. Both groups receive a single administration of a long-acting injectable naltrexone (XR-NTX): at 
Day 8 for the naltrexone induction group and Day 15 for the buprenorphine group. Thus far, we have 
demonstrated successful outpatient induction onto long-acting injectable naltrexone (XR-NTX) at a rate of 
about 50%; the naltrexone treatment arm has achieved better rates of successful induction onto XR-NTX 
compared to the buprenorphine-assisted detoxification arm, but the difference has not yet reached statistical 
significance (53% vs. 42%).
In another one of our ongoing studies, A Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of 
Naltrexone for use in Conjunction with Buprenorphine in Adults with Opioid Use Disorder Prior to First 
Dose of Vivitrol (PI: Adam Bisaga M.D., ( #7190) opioid-dependent participants are randomized to one of 
three outpatient 8-day detoxificiation schedules: (1) oral naltrexone + buprenorphine (2) oral naltrexone+ 
placebo buprenorphine (3) placebo oral naltrexone + placebo buprenorphine. All three groups receive a 
single administration of a long-acting injectable naltrexone (XR-NTX) on Day 8.
Therefore, in the current pilot study, we would like to implement a procedure for retaining in treatment 
patients who fail the initial attempt at outpatient detoxification and XR-NTX induction. This procedure will 


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be similar to the approach of Sigmon et al. 2013, with a 4-week period of buprenorphine stabilization and 
taper off. Participants will then repeat the detox using a 2-day washout followed by a 4-day ascending taper 
of oral naltrexone (1, 3, 12, and 25 mg), with the purpose of XR-NTX induction. Including a buprenorphine 
maintenance arm allows for a period of stabilization and relief from withdrawal symptoms, followed by a 
taper, with the thought that this may be more tolerable to these individuals that have previously had a 
difficult time modulating and tolerating the distress of the more rapid detoxification.  
 
 
Specific Aims and Hypotheses
Specific Aims and Hypotheses
SPECIFIC AIM #1: To test the efficacy of a second-line treatment for the 50% of opioid-dependent 
individuals who fail their first attempt at outpatient XR-NTX induction. The primary outcome is successful 
induction onto XR-NTX.
EXPORATORY AIMS: We will also examine secondary outcomes retention (time to drop-out); severity of 
opioid withdrawal; and 2-week abstinence at 3rd and 4th weeks after XR-NTX injection.
Description of Subject Population
Sample #1
Specify subject population
Adults 18-60 years old, who meet current DSM-5 criteria for OUD of at least moderate severity
Number of completers required to accomplish study aims
14
Projected number of subjects who will be enrolled to obtain required number of completers
46
Age range of subject population
18-60
Gender, Racial and Ethnic Breakdown
Both genders and all ethnic groups are eligible. It is estimated that the sample will be 75% male, 25% 
female, 50% Caucasian, 30% Hispanic-American, and 15% African-American, and 5% other minorities 
based on data from previous trials.
Description of subject population
Participants will be 46 men and non-pregnant women and meet criteria for opiate dependence. Participants 
will be recruited from the pool of participants that fail XR-NTX induction as part of either protocol #6374: 
Long-acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid Detoxification with 
Naltrexone vs. Buprenorphine or protocol #7190: A Phase 3 Study to Evaluate the Safety, Tolerability, and 
Efficacy of Naltrexone for use in Conjunction with Buprenorphine in Adults with Opioid Use Disorder Prior 


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to First Dose of Vivitrol.
Recruitment Procedures
Describe settings where recruitment will occur
Participants will be recruited from the pool of participants that fail XR-NTX induction as part of one of the 
two trials: Long-acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid 
Detoxification with Naltrexone vs. Buprenorphine (IRB #6374: PI: Adam Bisaga M.D.) or A Phase 3 Study 
to Evaluate the Safety, Tolerability, and Efficacy of Naltrexone for use in Conjunction with Buprenorphine 
in Adults with Opioid Use Disorder Prior to First Dose of Vivitrol (PI: Adam Bisaga M.D.). Participants are 
recruited for that study via IRB-approved advertisements placed in local newspapers and radio stations. 
Additionally, prospective participants are recruited by word of mouth and through liaison to other local 
clinical services. All potential participants will be evaluated at the Substance Treatment and Research 
Service (STARS) at the New York State Psychiatric Institute. All patients are seen by one of our 
psychiatrists or psychologists for a screening evaluation and mental status examination as part of routine 
admission procedures at STARS (Evaluation of Potential Substance Abuse Research Participants, IRB # 
6582R: PI: Mariani). 
How and by whom will subjects be approached and/or recruited? 
Prospective participants will have already been evaluated and recruited at the Substance Treatment and 
Research Service (STARS), and enrolled in protocol #6374 or protocol #7190. Participants who fail XR-
NTX induction will meet with a study psychiatrist, who will offer the participant the option of enrolling in 
the study.
How will the study be advertised/publicized? 
Advertising, recruitment, and screening is covered under the STARS Umbrella Screening protocol
6582R. We will use IRB-approved advertisements to reach our target population.
Do you have ads/recruitment material requiring review at this time? 
No
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number
NCT02294253
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
DA030484-04: “ Long-acting Injectable Naltrexone Induction: A Randomized Trial of Outpatient Opioid 
Detoxification with Naltrexone vs. Buprenorphine.” (IRB# 6374). In the ongoing study funded by 
DA030484-04, we compare a rapid, 7-day induction method (one day of buprenorphine followed by a 
gradual titration of oral naltrexone and injectable naltrexone administration) to a standard 14-day procedure 
(involving a week-long buprenorphine taper followed by a week-long washout and injectable naltrexone 


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administration). To date we have enrolled 110 participants in 3 years of enrollment; recruitment has been 
twice as fast as predicted (based on previous inpatient studies) because of a high level of interest in the 
outpatient procedure.
 
ALK6428A-301. "A Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of Naltrexone for use 
in Conjunction with Buprenorphine in Adults with Opioid Use Disorder Prior to First Dose of Vivitrol" 
(IRB #7190). In the ongoing study funded by Alkermes Inc., in a randomized double-blind trial, we 
compare three different treatment arms (1) oral naltrexone + buprenorphine, (2) oral naltrexone + placebo 
buprenophine, (3) placebo oral naltrexone + placebo buprenorphine over 8 days, followed by administration 
of XR-NTX. To date we have enrolled 12 participants, randomized 4 , and 1 participant has been 
successfully inducted onto XR-NTX.
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Adults 18-60 years old
Create or insert table to describe the inclusion criteria and methods to ascertain them
1) Age 18-60. 
Method of Ascertainment: Clinical interview 
2) Meets DSM-IV criteria for current opiate dependence disorder of at least six months
duration, supported by urine toxicology OR COWS score > or =6 OR Naloxone Challenge.
Method of Ascertainment: Clinical and MINI interview, urine toxicology or COWS score > or = 6, or 
naloxone challenge. 
3) Voluntarily seeking treatment for opioid dependence.
Method of Ascertainment: Clinical interview. 
4) In otherwise good health based on complete medical history and physical examination.
Method of Ascertainment: Clinical interview and physical examination; vital signs, ECG, laboratory tests 
(hematology,blood chemistry, urinalysis) within normal ranges, including AST or ALT < 3 times normal 
limits.
5) Able to give written informed consent.
Method of Ascertainment: Clinical interview and mental status exam. 
6) Failed outpatient induction onto XR-NTX in Protocol #6374 or Protocol #7190.
Method of Ascertainment: Chart review and clinical interview. 
Create or insert table to describe the exclusion criteria and methods to ascertain them
1) Methadone maintenance treatment or regular use of illicit methadone (> 30 mg per week).
Method of Ascertainment: Clinical interview; urine toxicology
2) Maintenance on, or regular use of,  buprenorphine or other long-acting opioid agonists.
 Method of Ascertainment: Clinical interview; urine toxicology
3.) Pregnancy, lactation, or failure in a sexually active woman to use adequate contraceptive methods.


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Method of Ascertainment:  Clinical Interview, physical examination, urine pregnancy test during screening, 
serum pregnancy test at admission and day 6, at least one day prior to administration of injectable 
naltrexone.
4) Active medical illness which might make participation hazardous, such as untreated hypertension, acute 
hepatitis with AST or ALT > 3 times normal, AIDS, unstable diabetes.
Method of Ascertainment: Clinical Interview, physical examination,laboratory (Chem-20, CBC, urinalysis), 
ECG.
5) Active psychiatric disorder which might interfere with participation or make participation hazardous, 
including DSM-5 Schizophrenia or any psychotic disorder, severe Major Depressive Disorder, or suicide 
risk or 1 or more suicide attempts within the past year.
Method of Ascertainment: Clinical and MINI interview, clinical mental status examination, discussions with 
previous psychiatrist or treatment provider if formerly in treatment.
6) Physiologically dependent on alcohol or sedative-hypnotics with impending withdrawal. Other substance 
use diagnoses are not exclusionary. 
Method of Ascertainment: Clinical and MINI interview; urine toxicology.
7) History of allergic or adverse reaction to buprenorphine, naltrexone, naloxone, clonidine, or clonazepam.
Method of Ascertainment: Clinical interview.
8) Chronic organic mental disorder (e.g. AIDS dementia).
Method of Ascertainment: Clinical Interview, mental status, physical and laboratory examination.
9) History of accidental drug overdose in the last 3 years as defined as an episode of opioid-induced 
unconsciousness or incapacitation, whether or not medical treatment was sought or received.
Method of Ascertainment: Clinical interview.
10) Painful medical condition that requires ongoing opioid analgesia or anticipated
surgery necessitating opioid medications.
Method of Ascertainment: Clinical interview, physical examination.
Waiver of Consent/Authorization
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
No
Waiver of parental consent 
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes


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Indicate NYSPI IRB # 
6582R
Describe Study Consent Procedures
Screening procedures will be standardized and a standard set of instruments will be utilized.
Participants will be recruited from current participants in Protocol #6374 or Protocol #7190 who have failed 
the initial attempt at outpatient injection naloxone induction. Patients will sign consent for the review of 
recently completed assessments including: The MINI International Neuropsychiatric Interview to assess 
current and lifetime DSM-5 diagnoses; a psychiatric evaluation, medical history, and physical and 
laboratory examination. The research psychiatrist will offer eligible patients participation in the study and 
will obtain informed consent.
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Bisaga, Adam, MD
Brezing, Christina, MD
Evans, Elizabeth, MD
Levin, Frances, MD
Luo, Sean, MD
Mariani, John, MD
Naqvi, Nasir, MD
Nunes, Edward, MD
Shulman, Matisyahu, MD
Vaezazizi, Leila
Vaughan, Barney, MD
Williams, Arthur
Type in the name(s) not found in the above list
Study Procedures
Describe the procedures required for this study
Buprenorphine induction/stabilization/taper: Buprenorphine induction will be conducted at our STARS 
clinic and according to current clinical guidelines. Participants who have initially failed outpatient induction 
onto XR-NTX will receive buprenorphine/naloxone (BUP) on a weekly basis that they will take daily, 
according to the following schedule:  8/2 mg (Days 1-10), 6/1.5 mg (Days 11-15), 4/1 mg (Days 16-20), 
3.0/0.75 mg (Days 21-25), 2.0/0.5 mg (Days 26-30).  Participants will attend the clinic twice weekly and 
will be assessed for opioid and other substance use (urine toxicology and self-report), vital signs, opioid 
withdrawal symptoms, opioid cravings,  and dose adjustments of buprenorphine will be made as needed by 
study physicians. If a dose reduction is needed, the stabilization and taper schedule will be adjusted to occur 
over 30 days. Participants will be stabilized on, and tapered off, buprenorphine over a 4-week period. 


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Reductions will occur in a graded fashion, with the stabilization dose reduced to 2 mg. This approach to 
buprenorphine taper is intended to resemble standard clinical practice, in which patients seeking transition 
off buprenorphine undergo a slow taper. A gradual taper over approximately 4 weeks has established 
precedent (Sigmon et al. 2013, Ling et al. 2009, Nielsen et al. 2013) as a well-tolerated taper strategy for 
transitioning off buprenorphine. The purpose is in part to provide a slow transition with minimal withdrawal 
symptoms. Participants will have at least two study visits a week during the buprenorphine taper, but may 
be seen more regularly at STARS if deemed clinically necessary.
 
Naltrexone induction procedure: Participants who successfully complete the taper must then complete a 
two-day washout (abstinence for opioids, buprenorphine). During this 48-hr period, participants will report 
to the STARS clinic daily for vital sign monitoring and to receive ancillary medications (clonidine, 
clonazepam, zolpidem, prochlorperazine) to alleviate withdrawal and discomfort as needed. After 
abstinence of >/=48 hours from the last buprenorphine dose, to allow for mu receptor availability, 
participants will begin the naltrexone induction,using a 4-day ascending taper of oral naltrexone (1, 3, 12, 
and 25 mg), followed by injection naltrexone . The administration of naltrexone will occur within a 
detoxification suite provided at STARS, consisting of a private room outfitted with two comfortable 
reclining lounge chairs for resting, adjustable lighting, and an entertainment system. Participants will be 
monitored by clinical staff at least every 1-2 hours with frequent vital signs checks and withdrawal 
assessments. A research psychiatrist or study physician will be present at all times to conduct frequent 
clinical assessments and provide adjuvant medications and naltrexone. Patients will be monitored on a daily 
basis (Monday to Friday) for up to 8 hours per day. Transportation home by car service will be provided at 
the end of the day for any patient deemed to have this clinical need.
 
As per the dosing schedule in the protocol #6374, on Day 1 of the naltrexone induction, participants are pre-
treated with prochlorperazine 10 mg for nausea, followed be the first dose of naltrexone 1mg. Ascending 
doses of naltrexone will then be titrated upward slowly (3mg, 12mg, 25mg). Adjuvant medications will be 
available to patients and will include clonidine for myalgias, prochlorperazine for nausea, clonazepam to 
reduce anxiety and dysphoria, and trazodone or zolpidem for insomnia. Participants will be provided take-
home doses of adjuvant medications in small doses and on a tapering schedule for one week post-
administration of XR-NTX. Participants will be required to visit the clinic daily and remain there for at least 
1 hour to permit close monitoring, with an option to stay as long as necessary to achieve relief of symptoms 
and medical stability prior to being discharged home.
 
Once 25 mg of naltrexone has been tolerated, the participant may receive 380 mg IM XR-NTX. 
Additionally, for female participants, a urine pregnancy test will be obtained on the day of XR-NTX 
administration. Prior to administration of XR-NTX, participants who have been non-compliant with the oral 
naltrexone schedule, accompanied by lapses to opioid use, or in any case for which the challenge appears 
clinically indicated in the judgment of the study physician or research team, will receive a naloxone 
challenge prior to XR-NTX administration. Referrals to local treatment providers will be arranged for 
participants who successfully complete the study and request to continue XR-NTX maintenance.
 
XR-NTX injections:  XR-NTX will be administered once naltrexone 25 mg has been tolerated, as an 
intramuscular injection (380 mg) in one buttock by one of the research psychiatrists or research nurses of 
STARS, who are currently trained and administer XR-NTX in other protocols. Participants will be observed 
for at least 2 hours after the first injection. Participants will be offered a second injection at Week 5 (four 


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weeks post-administration of the first injection), and a third injection at Week 9. Prior to receiving second 
and third injections at STARS, patients will either provide an opioid-negative urine or pass a naloxone 
challenge test. 
 
Clinic visits: At each STARS visit the patient meets with the research assistant to complete
research ratings, including self-report of withdrawal, mood, and drug use. Blood samples are
drawn according to the protocol for naltrexone serum levels and liver enzymes. The patient provides a urine 
sample under observation by a staff member at each visit. STARS is staffed by both male and female 
research assistants so that all urines can be appropriately monitored. The sample is tested immediately for 
opioids with the iScreen system (Instant Technologies, Inc.) Vital signs are also taken. All data are brought 
to the research psychiatrist conducting the therapy, and the therapy session is held. Liver function tests will 
be drawn one week prior to each subsequent injection and at the end of the study(Weeks 4, 8, and 12 
). Serum pregnancy tests will be performed during screening and a urine pregnancy test prior to 
administration of XR-NTX for female participants. Any participant who is experiencing protracted opioid 
withdrawal will be offered clinical contact on a frequent, even daily, basis if needed. For clinical matters 
arising in the evenings or on weekends, participants will have access to the 24-hour emergency 
telephone service at STARS, staffed by physicians familiar with this protocol who can address patients' 
concerns.
 
Behavioral Therapy: All participants will receive a weekly medication adherence-focused psychosocial 
intervention informed by relapse prevention strategies we previously developed in Behavioral Naltrexone 
Therapy and delivered by the study physician (Rothenberg, Sullivan et al. 2002). We have developed a 
relapse prevention approach which includes an emphasis on compliance with NTX. Participants will receive 
this therapy during weekly visits in outpatient Weeks 1-12 following induction onto XR-NTX. We will 
implement our standard procedures for training, supervision, and ongoing fidelity assessments of therapy 
sessions. At study end, participants who have successfully completed the trial and wish to continue injection 
naltrexone maintenance will be referred to local XR-NTX providers or treatment programs. Participants will 
be encouraged to attend 12-step and other self-help groups, as well as other treatment providers, according 
to the selected follow-up plan they have developed with their research therapist and Study MD by Week 12.
Evaluation of dysphoria and antidepressant treatment: During the first week after XR-NTX induction,
the research psychiatrist assists the patient with tapering off anti-withdrawal medications, and
he/she may be continued on zolpidem or trazodone for assistance with sleep. At one visit weekly,
the psychiatrist reviews the history and completes the Hamilton Depression Scale (HAM-D).
Patients who continue to meet criteria for major depression or dysthymia, with HAM-D > 12, are
offered antidepressant treatment based on their past experience with antidepressants, if any, and
an algorithm based on our clinical experience treating opioid-dependent patients (Sullivan et al.
2006). Also, any patient with CGI severity >3 for two consecutive weeks, or CGI >5 in any week,
will trigger evaluation by the study psychiatrist and initiation of antidepressant medication as
clinically indicated.
 
Handling of Missed Doses, Lapses and Relapses
 
Oral Naltrexone: If the patient misses more than 1 day of oral naltrexone during the detoxification


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week, and fails to provide an opioid-negative urine, relapse will be suspected, and, if appropriate,
the psychiatrist will perform a naloxone challenge using 0.8 mg naloxone, administered
intramuscularly. The patient is followed clinically and withdrawal symptoms are assessed over the
next hour. If the challenge is negative, the oral administration of naltrexone will be resumed. If
positive, then oral naltrexone cannot be resumed without risk of precipitating withdrawal, and the patient 
will have relapsed. Based on our experience in previous trials, the results of the naloxone
challenge may be equivocal in some cases. For instance, a patient may tolerate the challenge with
only minimal or mild signs of opiate withdrawal. Any patient who has experienced a recent lapse
but remains compliant with attendance at his/her therapy sessions will be permitted to undergo a
second naloxone challenge within 72 hours of the first failed challenge. Patients who fail two
consecutive naloxone challenges are considered to have relapsed and are referred for inpatient
detoxification or agonist maintenance, as deemed clinically appropriate and in accordance with the
patient’s wishes.
 
XR-NTX: Use of opiates presents different concerns in the management of patients receiving XR-NTX 
maintenance. Failure mode with XR-NTX is similar that a patient misses a scheduled injection, resumes 
using opioids, and becomes re-addicted. However, because of the long duration of action of depot 
naltrexone (full blockade lasts up to 5 weeks after the last injection), a grace period of at least 7 days can be 
expected during which the injection can be rescheduled without risk of relapse. If the patient misses a 
scheduled XR-NTX injection and takes an opioid during at least two of the seven days following the date of 
the scheduled injection, relapse will be suspected. In this case the psychiatrist will perform a naloxone 
challenge, if appropriate, using 0.8 mg naloxone administered intramuscularly. The patient is followed 
clinically and withdrawal symptoms are assessed over the next hour. If the challenge is negative, the 
depot administration of naltrexone will be resumed. If fully positive, then depot naltrexone risks 
of precipitating withdrawal, and the patient will have relapsed. However, because there are blood levels and 
partial blockade beyond Week 5, vulnerability to relapse may be more gradual, and the instance of mild or 
equivocal reactions to naloxone challenge more common. In this instance, a second challenge within 72 
hours, or escalating doses of oral naltrexone over 3 days will be
attempted, and if tolerated, the next injections can be given.
 
Procedures for Missed Doses of XR-NTX: Missing a scheduled XR-NTX injection is the most important 
threat to the success of long-acting naltrexone maintenance. In the event of a patient missing a scheduled 
injection, the clinic staff will immediately attempt to contact the patient to re-establish commitment to the 
naltrexone treatment and reschedule the injection within a 48-hour period. If the patient cannot attend the 
treatment clinic within that two-day time-frame, or cannot be located, the treatment team will use previously 
obtained locator information in an effort to locate the patient through emergency contacts and get him/her in 
for a clinic visit. If opioid use occurs in combination with a missed XR-NTX injection, a naloxone challenge 
will be administered to confirm that the next XR-NTX injection will be safely tolerated.
 
Currently the study is run under the NYS Controlled Substance license # 0400081 held by the NYS OMH and the DEA 
Researcher Registration # PN0093461 held by the NYSPI Pharmacy Department. As soon as the joint PI, Dr. Adam 
Bisaga, obtains his own NYS Controlled Substance license and DEA Researcher Registration # the projects will be run 
under both his researcher specific NYS license, his DEA Researcher Registration and the NYS/OMH license and NYSPI 
DEA Researcher Registration. The drug stock of controlled substances for each project will be ordered, maintained and 
prepared under the Institutional registration at the NYSPI Pharmacy (OMH/NYS Controlled Substance license # 
0400081). Packaged drugs (kits) will be transferred to the Principal Investigator (Dr. Adam Bisaga) using a DEA 222 form 


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with the address where the study will take place (e.g. 3 Columbus Circle, Suite 1408, NY, NY 10019). Drugs or kits for 
individual patients will be transferred from the Institutional registration (#0400081) to the investigator registration using 
DEA 222 forms and transported by Marcia Loughran, FNP (supervisor of controlled substance activity) to the 3 
Columbus Circle Suite 1408, NY, NY 10019 research site. Drug will then be kept in the wall mounted, double-door, double 
locked storage cabinets at 3 Columbus Circle until it is given to the participant.
 
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
 Criteria for Study Dropout During the Buprenorphine Stabilization/Taper:
1. Participant is unable to tolerate sublingual buprenorphine/naloxone as demonstrated by continued opioid 
use.
2. Participant in unable to tolerate a buprenorphine taper, as indicated by moderate or severe withdrawal 
(COWS score 13-36). 
3. Participant refuses continued buprenorphine/naloxone maintenance.
4. Participant requests withdrawal from study to receive agonist maintenance or to pursue other
treatment options.
5. Participant experiences medical or psychiatric worsening of a condition deemed to make further
study participation hazardous. 
6. Participant is absent from study visits for 10 days.
 
Criteria for Study Dropout During the Detoxification are as follows:
1. Participant is unable to tolerate oral naltrexone as demonstrated by continued opioid use or a failed 
naloxone challenge.
2. Participant demonstrates moderate or severe opioid withdrawal in response to 25 mg oral naltrexone 
(COWS score 13-36).
3.Participant in unable to tolerate a buprenorphine taper, as indicated by moderate or severe withdrawal 
(COWS score 13-36). 
4. Participant refuses XR-NTX injection.
5. Participant requests withdrawal from study to receive agonist maintenance or to pursue other
treatment options.
6. Participant experiences medical or psychiatric worsening of a condition deemed to make further
study participation hazardous. 
7. Participant is absent from study visits for 7 days.
 
Criteria for Study Dropout following Detoxification:
1. Relapse to opioid dependence; patient resumes opioid use for more than 3 days and is unable
to provide an opioid-negative urine or to pass a naloxone challenge.
2. Binges of opioid use resulting in overdose or severe somnolence, or in attempts to override the
blockade.
3. Clinical deterioration rendering further study participation hazardous (e.g. significant worsening


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of medical or psychiatric condition, elevation of liver enzymes to >3 times normal, dangerous
escalation of non-opioid drug or alcohol use).
4. Participant's continued opiate use places him or her at risk for harm for self-destructive behavior
or other harm as indicated by and Opiate CGI improvement score of 6 or greater for two
consecutive weeks.
5. Non-compliance with study procedure (missing at least 6 consecutive visits or 2 weeks). 
 
The Principal Investigator may also decide to administratively withdraw participants who show other 
clinically significant worsening of medical or psychiatric symptoms, evidence of significant discomfort 
related to the withholding of rescue medication, any behavior which suggests significant risk from attempts 
to over-ride blockade or subject request.
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
Serum pregnancy testing will be performed during screening.  For patients whose screening bloodwork 
(CBC, basic metabolic panel, liver function tests) for #6374  or #7190 were completed more than 90 days 
ago, these labs will be redrawn.  Liver function tests will be performed during screening and at 4 weeks 
following administration of each XR-NTX injection. Urine toxicology screens, conducted at each visit, will 
serve as an objective marker of current opioid use.
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Ongoing Psychiatric and Medical Assessments: The research psychiatrist will conduct weekly assessments 
of the psychiatric and medical status of the study participants. Participants who meet criteria for clinical 
worsening or the development of unacceptable medical or psychiatric risks will be removed from the trial 
and referred for appropriate treatment.
Study Assessments 
Adverse Effects measures: The Systematic Assessment for the Treatment and Emergent Events (SAFTEE) 
(Johnson et al. 2005) adapted for buprenorphine and XR-NTX injections will be performed weekly to 
identify adverse symptoms.
Clinical Status measures: The Clinical Global Impression Scale-Observer (CGI) (Guy 1976) will be used to 
measure the overall clinical status of the participant as well change from baseline in the symptom severity. 
The Clinical Global Impression-Self (CGI-S) is a two-item scale that asks the subject to rate his or her 
current level of symptoms and estimate changes from baseline (Guy 1976).
 
Medical Evaluation and Monitoring: A medical history and physical exam will be performed during 
screening. Serum pregnancy testing will be performed during screening and urine pregnancy testing will be 
performed monthly during the study. Complete blood count, electrolyte, urinalysis, and liver function tests 


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will be performed during screening and monthly during the study. Height and weight will be measured and 
baseline body mass index (BMI) calculated during screening. Temperature, pulse, blood pressure, and 
weight will be measured at every study visit.
 
Mood and Anxiety measures: A structured interview version of the Hamilton Depression Scale (HAM-D) 
(Williams 1988) will be used to assess mood and anxiety symptoms at baseline and changes associated with 
treatment.
Psychiatric Evaluation and Diagnosis: The MINI International Neuropsychiatric Interview will 
be performed during screening and as part of a complete psychiatric diagnostic assessment.
Opiate Craving Scales- Self: A visual analog scales is used for patients to rate the intensity of craving 
experienced over the previous week for opiates (Bisaga, Sullivan et al. 2011).
Spielberger State-Trait Anxiety Test (SSTAT)- Self: The SSTAT is a well-validated measure of anxiety 
consisting of two self-rated subscales, one rating Trait anxiety and the other State anxiety (Spielberger, 
Gorsuch et al. 1970).
Beck Depression Inventory (BDI): The BDI is a 21-item self-report questionnaire. It has been used in many 
studies and validly and reliably assesses depression in many patient groups including substance abusers 
(Beck, Steer et al. 1996).
Subjective Opiate Withdrawal Scale (SOWS)- Self: The SOWS is a 19-item self-report scale reliably 
eliciting severity of common physical and mental symptoms of opiate withdrawal, and also yielding a total 
withdrawal severity score (Handelsman, Cochrane et al. 1987). It will be used to examine occurrence of 
symptoms resembling opiate withdrawal during naltrexone maintenance.
Risk Assessment Battery (RAB) The RAB provides a self-report measure of drug use, injection-related risk 
behavior, and sexual risk during the preceding six months (Navaline, Snider et al. 1994). 
 
Please attach copies, unless standard instruments are used
Off label and investigational use of drugs/devices
Choose from the following that will be applicable to your study 
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
No
Treatment to be provided at the end of the study
At the conclusion of the protocol, the participants will be offered supportive therapy for at


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least one additional month or until an appropriate referral for on-going treatment is made. If the patient
is interested to continue on XR-NTX, we will try to work with the patient’s insurance to provide
coverage to continue XR-NTX. If the patient wishes to be on oral naltrexone, we will provide
him/her with a 30-day supply of oral medication, and will help patients to obtain referrals to
treatment providers in the community.
Participants who had no response to naltrexone treatment, such as those who continued using
opioids while on naltrexone as well as those who stopped taking naltrexone (missed scheduled
injections) and/or resumed opioids after missing naltrexone, are considered to be at very high risk
of a full relapse and overdose. These individuals will be immediately directed toward either
inpatient detoxification followed by a residential treatment, or toward agonist maintenance with either 
buprenorphine/naloxone or methadone. Methadone maintenance treatment is widely available in
the community; however, access to buprenorphine treatment is more restricted. 
 
 In order to minimize the risk of relapse due to the lack of access to the medication and the gap between 
treatment providers we would like to offer 2-week supply buprenorphine/naloxone 8mg to participants who 
are in the process of being referred out to either inpatient treatment or an agonist maintenance program. We 
will continue to provide additional support including frequent, daily if needed visits at our clinic for a 
maximum of 2 weeks. 
Clinical Treatment Alternatives
Clinical treatment alternatives
Naltrexone maintenance and Relapse Prevention Therapy are effective and accepted treatments
for opioid dependence. The major alternatives for outpatients with opioid dependence would be
either methadone or buprenorphine/naloxone maintenance, which has a high success rate for patients
willing to take it; injection naltrexone maintenance without research procedures; outpatient methadone
detoxification; or inpatient detoxification followed by "drug-free" outpatient or residential
counseling. Both inpatient and detoxification methods are associated with high relapse rates in the absence 
of antagonist maintenance.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
Risks of the Buprenorphine-Clonidine-Naltrexone Procedure: In this procedure, opiate-dependent
patients are stabilized for 30 days on the partial opiate agonist buprenorphine. During subsequent
administration of naltrexone and throughout the detoxification, withdrawal symptoms are treated
with clonidine, an alpha-2-adrenergic receptor agonist which reduces sympathetic nervous system
output produced by opiate withdrawal, clonazepam, a benzodiazepine which reduces the anxiety
and dysphoria and permits sleep, and other prn medications such as trazodone or zolpidem for
insomnia. Opiate withdrawal causes agitation, elevated pulse and blood pressure and other signs
of sympathetic arousal, and sometimes confusion. Clonidine may produce somnolence or


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hypotension. Clonazepam commonly may produce somnolence. An extremely rare potential side effect of 
trazodone is priapism .The procedure is conducted in a setting equivalent to a day hospital, with a STARS 
study physician present at all times, to permit close monitoring of vital signs and mental status.
 
Buprenorphine taper: The risks associated with buprenorphine dose reduction are minimal. During the 
buprenorphine taper, opioid withdrawal symptoms (e.g., anxiety, muscle aches, rhinorrhea) may emerge. If 
the participant does not tolerate well this discomfort, he or she will meet with the study physician, and 
discuss options (i.e. receiving more adjuvant medications, modifying a given daily dose of buprenorphine). 
The participant will also be offered the option of discontinuing the taper and transitioning to buprenorphine 
maintenance at a dose of buprenorphine/naloxone that is comfortable, which would mean discontinuation 
from the study and would be considered a treatment failure in terms of achieving opioid-free status. 
Medications will be dispensed by medical staff trained in the use of opioids, and in the management of 
adverse effects of opioids. The doses proposed for use in the current application are within the 
recommended dose range for treating opioid addiction.
 
Buprenorphine diversion and abuse:The use of buprenorphine in opioid-abusing, opioid-dependent 
volunteers is also associated with the risk of using the medication for the purposes of getting high. If 
sublingual buprenorphine is crushed and used parenterally, there is a risk of precipitated opioid withdrawal, 
due to the release of the sequestered naloxone. Attempts to administer buprenorphine by injection have also 
been associated with granulomatous reactions and infections. Participants will be warned of the risks of 
diversion and abuse and advised not to use the medication in this manner. They will also be warned of the 
risks of accidental ingestion.   If it is determined that patients have been abusing their buprenorphine in such 
a manner, they will be removed from the study and referred to methadone maintenance.
 
Side Effects of Naltrexone: The possible side effects of naltrexone may include difficulty sleeping,
anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint muscle
pain, and headaches. It is important to note that these symptoms may represent protracted opioid
withdrawal symptoms. The most common adverse events associated with XR-NTX in clinical trials
for alcohol dependence were nausea, vomiting, headache, dizziness, asthenic conditions and
injection site reactions. Cases of urticaria, angioedema, and anaphylaxis have been observed with
use of XR-NTX. 
Naltrexone has been associated with reversible hepatocellular injury indicated by elevated liver
enzymes when administered at doses substantially greater than the 50 mg per day dose
recommended for maintenance treatment of opiate dependence and proposed for the present
studies. When used in the recommended dose range in opiate-dependent patients, this risk is
remote (Brahen et al 1988). Naltrexone is therefore contraindicated in patients with acute hepatitis
or liver failure, and such patients are excluded from the study. Patients with hepatic enzyme levels
greater than two times the upper limit of normal are therefore excluded. Liver enzymes will be
repeated frequently. Depot naltrexone achieves higher bloodlevels than oral naltrexone initially,
but these should remain lower than levels associated with hepatitis. If naltrexone-induced hepatitis were to 
occur in the setting of a long-acting preparation,where the naltrexone would be only very slowly eliminated, 
this would prolong exposure to the offending agent. However, our experience with long-acting naltrexone 
also suggests it is safe. In our studies with long-acting naltrexone several patients experienced elevation in 
liver enzymes, which were determined to be related to hepatitis C. One patient developed diabetes mellitus,


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which was deemed unlikely to be study related. In the proposed study we will use a long-acting,
injectable preparation of naltrexone (Vivitrol 380 mg). This preparation has been used in a large
clinical trials as a treatment for alcohol dependence and is considered to have a good safety
profile (Garbutt et al 2005). XR-NTX is currently approved by the FDA for the treatment of alcohol
dependence. 
If a patient misses a scheduled injection of XR-NTX and resumes regular opiate use, then taking a dose of 
naltrexone will precipitate opiate withdrawal, which may be quite severe in proportion to the time since the 
last naltrexone dose and the level of opiate dependence. Patients will be warned not to take the naltrexone if 
they have missed their dose for more than a week and resumed opiate use for more than two days. They will 
be
instructed instead to contact their therapist and/or research psychiatrist, who will see the patient
and perform a naloxone challenge test to determine whether or not naltrexone can be safely resumed. 
Patients who fail two consecutive naloxone challenges (withdrawal is precipitated), are considered to have 
relapsed and are referred for inpatient detoxification .
Self-administration of large doses of opiates may over-ride the blockade produced by naltrexone
resulting in an opiate overdose with its attendant risks, including respiratory depression and death.
Patients will be warned of the severe danger of using opiates, including trying to over-ride the
blockade. Also patients who have stopped naltrexone and resume opiates will not be tolerant
initially, so that the quantities of opiates self-administered prior to treatment, when they were
tolerant, may be quite dangerous in the non-tolerant state. Patients will be warned of this. Patients
who self-administer opiates to the point of somnolence or stupor will be removed from the trial and
referred to inpatient detoxification or agonist maintenance treatment. Until such patients are
accepted for treatment elsewhere, they will remain in treatment at our clinic, where they will be
offered therapy and treated in the open label manner for the duration of trial.
In the event of a medical emergency requiring opiate analgesia, a patient on naltrexone will
require higher doses of opiates than normally administered. Patients will be informed of this and
will be given a naltrexone medication card to carry in their wallet.
Naloxone Challenge Test: This test will be performed under the supervision of a study physician
and will take approximately 45 min to complete. The risks of a dose of 0.2-0.8 mg naloxone
administered IM are the signs and symptoms associated with opioid withdrawal (“gooseflesh,”
“vomiting,” “tremor,” “uncontrollable yawning,” etc.). These will be assessed every 10 min. for up to
45 min. During the procedure, we will measure blood pressure and heart rate before and up to 30
min. after the naloxone dose. 
Pregnancy: Both the buprenorphine-clonidine-naltrexone procedure and naltrexone maintenance
are considered contraindicated in pregnancy. Several small case series (Hulse et al., 2001; 2004)are 
reassuring in suggesting favorable pregnancy outcomes in women detoxified and maintained
on naltrexone while pregnant. However, standard practice suggests methadone maintenance is
the treatment of choice for opioid dependent pregnant women, and we do not consider the small
size of these case series sufficient to amend that recommendation. Absence of pregnancy will be
confirmed at baseline and monthly during the study with urinary HCG. During the inpatient
detoxification period, a serum (quantitative) pregnancy test will be obtained on admission and
repeated on the day prior to administration of depot naltrexone. For women, regular use of an
adequate contraception method (diaphragm with spermicide, condom with spermicide, birth
control pills) is required for inclusion in the study. Patients who become pregnant during the trial


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will be removed from the trial and treated as clinically indicated.
Blood Tests: Blood drawing may cause slight discomfort at site of needle entry, resulting in a small
bruise. Other risks include patients' discomfort with being asked uncomfortable questions or the
psychological distress that may occur if a patient agrees to be tested for HIV.
 
Risks associated with receiving vouchers or cash equivalents: An incentive system is being used
to compensate patients for their time and travel and to encourage compliance with study
procedures. For that purpose we have adopted procedures used widely in the context of
Contingency Management Therapy. We believe that using low-value incentives is essential to
maximize participation in study-related procedures, including nursing and physician visits for
safety monitoring, study outcomes collection, and therapy participation. Risks that participants will
attempt to use study payments to purchase drugs, though still present, are rather small with
current procedures.
Describe procedures for minimizing risks
The exclusion criteria of this study are designed to minimize the risks to participants.
Patients are excluded if they have severe psychiatric illness (mood disorder with functional
impairment or suicide risk, schizophrenia) which might interfere with their ability to participate in
the outpatient therapy. A history of drug overdoses will be exclusionary. Pregnancy, lactation, or
failure to practice a reliable birth control method is exclusionary, and patients are instructed to
inform their psychiatrist immediately if they suspect they may be pregnant. Urine HCG is tested
during screening and monthly throughout the trial. Serum (quantitative) pregnancy test will be
obtained during screening. The baseline medical evaluation includes physical examination, blood
chemistry profile (including liver function tests), complete blood count, urinalysis (including HCG),
and electrocardiogram, urine toxicology, and naloxone challenge if opiate dependence diagnosis
is unclear. The evaluating psychiatrist reviews all these and takes a medical history. Any disorders
which might make buprenorphine-clonidine-naltrexone or naltrexone maintenance hazardous,
such as uncontrolled hypertension, diabetes, heart disease, hepatitis with transaminase levels
greater than three times the upper limit of normal, renal disease, or advanced AIDS are exclusionary. 
Patients with acute hepatitis infection and increasing liver function tests during screening
will be excluded from study participation. The patient will be assisted in obtaining appropriate
medical evaluation and treatment, and may be eligible for the research study once the problem is
controlled. History of an allergic reaction to any of the medications used is an exclusion criterion.
Patient Education: All patients will be informed through the informed consent form and discussions
with the research psychiatrist of the possible side effects and risks enumerated above. In
addition, at weekly visits the psychiatrist will query side effects in general, and events of specific
concern including missing naltrexone doses in conjunction with resumed opiate use or heavy
opiate use in an effort to over-ride the blockade, and the risk of overdose and death in these
situations. Patients will give informed consent before entering the study. Patients are instructed
to call us if any untoward effects occur and are given the phone number of our 24-hour answering
service.
Patient Monitoring and Removal from Study: The psychiatrist and/or therapist will assess
appropriateness for continuation in the research study on a continuous basis, and will remove


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from the trial patients with significant clinical deterioration or noncompliance of a type which could
be dangerous. 
Methods to Protect Confidentiality
Describe methods to protect confidentiality
A Certificate of Confidentiality has been acquired for this study from the National Institute on Drug
Abuse to offer protection for the privacy of subjects by protecting identifiable research information
from forced disclosure (e.g., through a subpoena or court order). The Certificate of Confidentiality
allows investigators and others with access to research records to refuse to disclose information that could 
identify subjects in any civil, criminal, administrative, legislative, or other
proceeding, whether at the Federal, State, or local level. The Certificate of Confidentiality is
granted for studies that collect information that, if disclosed, could damage subjects' financial,
employability, insurability, or reputation, or have other adverse consequences.
We use coded records (i.e. initials and numbers), store signed consent forms in a locked safe, and
try, to the best of our ability to maintain confidentiality. Only coded records will be entered into the
computer and the security of electronic data is ensured at the level of the server, the user, and the
database. We do, however, point out to prospective patients, that we cannot assure that their drug
histories and other personal records might not become know. 
Will the study be conducted under a certificate of confidentiality?
Yes, we have already received a Certificate of Confidentiality
Direct Benefits to Subjects  
Direct Benefits to Subjects
Participants may benefit from many of the components of  the treatment that they receive, including 
buprenorphine stabilization, induction onto injection naltrexone, naltrexone maintenance, and components 
of behavioral therapy.
 
Further, because participants are recruited from the pool of participants that fail XR-NTX induction 
as part of one of two trials, an additional potential benefit is a decrease in time to treatment following 
study discontinuation from the parent protocols (IRB #6734 or IRB #7190). Immediately following 
discontinuation from the initial protocol, participants are eligible for the current protocol and if 
enrolled can be stabilized on buprenorphine, thereby potentially reducing overdose risk, in a more 
timely fashion than if referred to treatment in the community. 
 
 


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Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Participants will receive $10 for completion of study assessments at each visit and will receive 
compensation for travel ($5 per visit).  They will also be offered $25 for completing a follow-up visit at 
week 12 and will receive $5 for travel. Thus participants could earn up to $480 for completion of study 
assessments and reimbursement for travel.
References
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Garbutt JC, Kranzler HR, O’Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, Loewy JW, Ehrich 
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treatment    in the pregnant heroin user. Int J Gynaecol Obstet 85(2)170-1.
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SAP_001.pdf: 
Study Title: Buprenorphine/Naloxone Stabilization and Induction onto Injection 
Naltrexone 
Principal Investigator: Adam Bisaga, MD 
ID: 6999 
NCT02294253 
 
 
 
August 13, 2018 
 
 
Statistical Analysis:   
This is a single-arm, open-label, pilot study evaluating whether individuals with opioid use 
disorder who were unable to tolerate a rapid transition to XR-naltrexone would tolerate a slow 
four-week buprenorphine taper and XR- naltrexone induction.  
Study objective was to evaluate the feasibility of the slow-transition protocol and to obtain 
descriptive data regarding baseline demographics and treatment outcomes in such patients. 
Analytical plan include: 1) percent of participant who completed the transition, 2) time to relapse 
defined as daily opioid use for 5 days or study dropout, and 3) descriptive statistics on baseline 
characteristics comparing participants who successfully initiated XR-NTX and those who did not 
initiate XR-NTX. Summary statistics will include frequency, percentages, and where relevant 
averages.