Conditions: Opioid-use Disorder
Keywords: buprenorphine naltrexone Vivitrol opioid dependence
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: yes

Brief summary:
This study is an open--label randomized outpatient trial to evaluate feasibility and efficacy of rapid buprenorphine (BUP) discontinuation followed by brief course of treatment with long--acting naltrexone (XR--NTX) and to compare it to the standard method of gradual BUP taper.Individuals with opioid use disorder (OUD) (N=60) who have successfully completed at least 6 months of buprenorphine treatment and do not wish to remain in a long--term buprenorphine maintenance program will be recruited. The first phase includes a 4--week period of stabilization on buprenorphine 4--8 mg at the research clinic to assure that patients are stable, compliant, and free from illicit opioids. Participants that meet the above criteria will be randomized 1:1 to: 1) buprenorphine discontinuation and outpatient transition to XR--NTX with 3 monthly injections, or 2) buprenorphine discontinuation using a gradual 5-week long taper. In both groups participants will receive weekly relapse prevention therapy and will be monitored for the duration of the trial, which is 25 weeks post randomization.

Detailed description:

Arms:
arm 1: Rapid Monday to Friday oral naltrexone-induction procedure arm 2: 5-week buprenorphine taper from maintenance dose of 8, 6, or 4mg

Interventions: intervention 1: Vivitrol intervention 2: Buprenorphine
Intervention descriptions: intervention 1: Oral naltrexone induction procedure followed by Vivitrol intervention 2: 5-week buprenorphine taper

Protocol document:
Prot_ICF_000.pdf: 
 
 
A STRATEGY TO IMPROVE SUCCESS OF TREATMENT 
DISCONTINUATION IN BUPRENORPHINE RESPONDERS 
 
 
NCT03232346 
 
 
 
New York State Psychiatric Institute - Columbia University 
Department of Psychiatry  
Institutional Review Board 
 
Protocol # 7522 
Version April 2, 2019 
 


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Protocol Title:
A Strategy to Improve Success of 
Treatment Discontinuation in 
Buprenorphine Responders
Protocol Number:
7522
First Approval:
07/14/2017
Expiration Date:
07/09/2019
Version Date:
04/02/2019
Clinic:
Substance Treatment And Research 
Services (STARS)
Contact Principal Investigator:
Adam Bisaga, MD
Email: amb107@columbia.edu
Telephone: 646-774-6155
Research Chief:
Frances Levin, 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 proposing an amendment only to an existing protocol
Division & Personnel
Division
What Division/Department does the PI belong to?
SUBSTANCE USE
Within the division/department, what Center or group are you affiliated with, if any? 
SUBSTANCE TREATMENT AND RESEARCH SERVICES
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.
None


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Amendment
Describe the change(s) being made 
1.We are also requesting to collect blood, urine and saliva at Baseline, after randomization (3 weeks after 
1st injection of XR-NTX, or 1 week after completing bup taper), during post randomization month 2 ( 1 
week after 2nd XR-NTX injection, or 4 weeks after completion of bup taper), and at end of study to be 
examined for biomarkers.
Provide the rationale for the change(s) 
Additional study aim.         
Comment on the extent to which the proposed change(s) alter or affect risks/benefits to subjects 
None
Comment on if the proposed change(s) require a modification to the Consent Form (CF)
yes
Procedures
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
   Medically and Psychiatrically Healthy Subjects
   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


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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 application is a pending review or a funding decision
Source of Funding
Federal
Institute/Agency
National Institute on Health
Grant Name
A Strategy to Improve Success of Treatment 
Grant Number
1R21DA042243
Select one of the following
Single Site
Business Office
RFMH
Does the grant/contract involve a subcontract? 
Yes
Subcontracted?
To
Name institution(s)
Columbia University
Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
   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
The current guidelines for buprenorphine (BUP) treatment advocate an open ended, long-term maintenance 
approach. However, many individuals initiating treatment with BUP, particularly youth and those with brief 
history of prescription opioids abuse, expect a short treatment episode and are disappointed that treatment 
extends and may even be indefinite. As such, many patients that responded favorably to treatment intend to 
discontinue medication, whether by deciding unilaterally to stop it, or by a route of physician-directed BUP 
taper. However, it is not known what is a best strategy to assure a successful BUP discontinuation without 


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the risk of relapse.
 
We propose an open--label randomized outpatient trial to evaluate feasibility and
efficacy of rapid buprenorphine (BUP) discontinuation followed by brief course of treatment with long-
-acting naltrexone (XR--NTX) and to compare it to the standard method of gradual BUP taper.
Individuals with opioid use disorder (OUD) (N=60) who have successfully completed at least 6 months of 
buprenorphine treatment and do not wish to remain in a long--term buprenorphine maintenance program 
will be recruited. The first phase includes a 4--week period of stabilization on buprenorphine 2--8 mg at the 
research clinic to assure that patients are stable, compliant, and free from illicit opioids. Participants that 
meet the above criteria will be randomized 1:1 to: 1) buprenorphine discontinuation and outpatient transition 
to XR--NTX with 3 monthly injections, or 2) buprenorphine discontinuation using a gradual 5-week long 
taper. In both groups participants will receive weekly relapse prevention therapy and will be monitored for 
the duration of the trial, which is 25 weeks post randomization. 
The primary outcome will be the percent of patients successfully transitioned off buprenorphine and 
abstinent from any opioids at the 25--week trial endpoint. Secondary outcomes will include measures of 
opioid withdrawal, mood, anxiety and sleep problems, abstinence from other substances, time to relapse or 
dropout, and adverse effects. We hypothesize that more patients will successfully discontinue buprenorphine 
in the group that received XR--NTX. 
This proposed exploratory trial will be able to inform the design of future research and clinical work.  
 
 
Background, Significance and Rationale
Background, Significance and Rationale
The number of individuals with Opioid Use Disorder (OUD) continues to rise with more than 2.5 million 
affected, along with substantial morbidity and mortality. Maintenance treatment with the opioid partial 
agonist buprenorphine or buprenorphine/naloxone (BUP) is becoming a treatment of choice in the primary 
care setting. As many patients who had good treatment response desire to discontinue the medication there 
is a need for evidence on the best strategy to accomplish that. We propose to evaluate whether an addition of 
a short course of a long--acting, injectable naltrexone (XR--NTX) improves the chances of successful BUP 
discontinuation and transition to sustained abstinence off all opioids.
The current guidelines for BUP treatment advocate an open ended, long--term maintenance approach.
However, many individuals initiating treatment with BUP expect a time--limited and short treatment, a
“detoxification--like” experience rather than “methadone--like maintenance treatment,” and are 
disappointed that treatment is protracted and may even be indefinite. This is especially relevant for youth 
and those with brief history of addiction to prescription opioids. More than 60% of patients maintained on 
BUP or methadone expressed interest in discontinuing medication in the near future and more than 70% 
have previously tried that (Winstock et al., 2011). It is not known how many patients with a positive 
treatment response are interested in stopping BUP but more than half of such patient may eventually drop 
out of treatment (Fiellin et al., 2008). It is not well understood to what extent withdrawal--like symptoms 
play a role in relapse and how the addition of a brief course of naltrexone may influence the severity of 


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withdrawal and the success of BUP discontinuation. To our knowledge none of these questions have been 
evaluated experimentally and we believe that it may have a
significant impact on the field considering that up to 1 million patients are treated with BUP every year.
 
Benefits of and challenges associated with buprenorphine discontinuation
Determining when and how individuals can be safely tapered from BUP using a “planned approach” has 
several potential benefits. First, patients may feel encouraged that they may be able to discontinue treatment 
in the near future and therefore will be less likely to discontinue it unilaterally. Second, patients who do not 
need to be maintained on BUP indefinitely and are taken off it, will have lower risk of medication--related 
adverse effects and have lower treatment cost. Third, in areas of the country where BUP providers have 
reached the limits of prescribing for 100 patients, and patients on waiting lists for treatment remain at 
serious risk for overdose and other adverse consequences of use, safely transitioning patients off BUP would 
enable more patients to access treatment. Finally, a number of fee--for--service Medicaid plans have 
implemented lifetime limits on prescriptions for BUP, ranging from 12 to 36 months (Rinaldo and Rinaldo, 
2013), and a strategy that can shorten BUP treatment without compromising outcome may help patients in 
those states.
 
The main challenge to BUP discontinuation is that many patients experience significant and protracted
discomfort, withdrawal--like symptoms with increase in craving as well as mood anxiety and sleep 
disruptions (Dunn et al., 2015). These symptoms emerge even as the dose is being gradually reduced. As a 
result, many will abandon the attempt at discontinuation and resume BUP maintenance. If the patient stops 
medication on their own, and cannot easily resume treatment, they may relapse to illicit opioids. Therefore, 
the question of how to discontinue treatment in patients who favorably responded to BUP is of high 
significance to the field as it may address several important questions with clinical relevance.
Specific Aims and Hypotheses
Specific Aims and Hypotheses
The primary outcome will be the percent of patients successfully transitioned off buprenorphine
and abstinent from any opioids at the 25--week trial endpoint.
 
Secondary outcomes will include measures of opioid withdrawal, mood, anxiety and sleep problems, 
abstinence from other substances, time to relapse or dropout, and adverse effects.
 
Additionally we will examine in biofluid derived extracellular vesicle content for the existence of 
biomarkers related to naltrexone treatment.  
 
We hypothesize that more patients will successfully discontinue buprenorphine in
the group that received XR--NTX.
Description of Subject Population


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Sample #1
Specify subject population
Adults ages 18-60 currently treated with buprenorphine for opioid use disorder 
Number of completers required to accomplish study aims
50
Projected number of subjects who will be enrolled to obtain required number of completers
60
Age range of subject population
18-60
Gender, Racial and Ethnic Breakdown
Both males and females will be recruited. All eligible subjects are accepted; however, past experience with
recruitment for other studies in this population suggests that that the sample will be 75% male, 60%
Caucasian, 30% Hispanic or Latino, and 10% Black or African-American.
Description of subject population
Adults ages 18-60 currently treated with buprenorphine for opioid use disorder
Recruitment Procedures
Describe settings where recruitment will occur
All potential participants will be evaluated at the BSU clinic  at the New York State Psychiatric Institute.
How and by whom will subjects be approached and/or recruited? 
All patients will be seen by one of our psychiatrists or Master's level therapist  for a screening evaluation 
and mental status examination as part of routine admission procedures or BSU clinic . Patients who appear 
to meet criteria are told about the study and offered further evaluation. Final informed consent for the study 
will be obtained after full psychiatric and medical workup is complete. The physicians listed above work 
regular weekly shifts, know the protocol well, and are able to explain study consent to the participant. 
Procedures for training staff physicians in each protocol and consent form include initial presentations by 
the Principal Investigator at weekly staff meetings, and weekly discussion of inclusion/exclusion criteria and 
study eligibility for each screening participant.
How will the study be advertised/publicized? 
Once approved by the IRB, advertisements for study will be placed on the subway and in local newspapers 
and radio stations. Additionally, prospective participants are recruited by word of mouth and through liaison 
to other local clinical services.
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
NCT03232346


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Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
No
Inclusion/Exclusion Criteria
Name the subject group/sub sample
All participants
Create or insert table to describe the inclusion criteria and methods to ascertain them
Inclusion Criteria:
• A documented history of treatment with buprenorphine or buprenorphine/naloxone for at least 6 months 
with sustained abstinence from illicit opioids for at least 3 months. Participants must be maintained on daily 
dose of buprenorphine in the 2--8 mg range.(MINI interview by therapist, Clinical interview by psychiatrist, 
consultation with previous prescriber or the verification patients's self-report with the prescribing records 
(PMP) with patient's permission)
• Aged 18 to 60 years (Clinical interview)
• In otherwise good health based on complete medical history, physical examination, vital signs
measurement, ECG, and laboratory tests (hematology, blood chemistry, urinalysis) within normal
ranges (Medical history and physical examination by psychiatrist or NP, laboratory tests (serum Chem-20 
and CBC, urinalysis), ECG)
• Seeking buprenorphine discontinuation and willing to accept randomization to either taper from
buprenorphine or injection naltrexone (clinical interview)
• Able to give written informed consent to participate in the study
Create or insert table to describe the exclusion criteria and methods to ascertain them
1. Lifetime history of DSM-5 diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder
(MINI interview by therapist, Clinical interview by psychiatrist)
2. Current DSM-5 criteria for any other psychiatric disorder that in the investigator’s judgment is unstable, 
would be disrupted by the study medication, or is likely to require pharmacotherapy or psychotherapy 
during the study period. Concurrent treatment with other psychotropic medication is not exclusionary, as 
long as participants have been stable on their current dose for at least 3 months.
( MINI interview by therapist, Clinical interview and mental status exam by psychiatrist, contact with 
collateral information as needed and available)
3. Individuals who meet DSM-5 criteria for any substance use disorders - severe, other than opioid and 
nicotine use disorder. Physiological dependence on alcohol or sedative-hypnotics is exclusionary.
(MINI interview by therapist, Clinical interview by psychiatrist)
4. A recent history of binge-use of alcohol or sedative-hypnotics (using large amounts in a short time to 
severe intoxication or blackouts).
(Clinical interview by psychiatrist)
5. Pregnancy, lactation, or failure to use adequate contraceptive method in female patients who are currently 
engaging in sexual activity with men.
( Clinical interview by psychiatrist, physical examination and medical history by psychiatrist or NP, urine 
pregnancy test, serum HCG)


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6. Unstable medical conditions, such as AIDS, cancer, uncontrolled hypertension (blood pressure > 140/90), 
uncontrolled diabetes, pulmonary hypertension or heart disease.
(Medical history and physical examination by psychiatrist or NP, laboratory tests (serum Chem-20 and 
CBC, urinalysis), ECG)
7. Legally mandated to participate in a substance use disorder treatment program.
( Participant self-report, Clinical interview by psychiatrist)
8. Current or recent history of significant violent or suicidal behavior, risk for suicide or homicide (MINI 
interview by therapist, Clinical interview by psychiatrist) 
9. History of accidental opioid overdose in the last three years or any other significant history of overdose 
following detoxification within past 10 years defined as an episode of opioid-induced unconsciousness, 
whether or not medical treatment was sought or received.
( MINI interview by therapist, Clinical interview by psychiatrist)
10. Elevated liver function tests (AST and ALT > 3 times the upper limit of normal)
( Laboratory tests -serum Chem-20)
11. Known history of allergy, intolerance, or hypersensitivity to naltrexone or any other study
medications
( Participant self-report, Clinical interview by psychiatrist)
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?
No
Describe procedures used to obtain consent during the screening process 
Potential participants will sign a consent form prior to initiating the screening process. Following review of 
screening informed consent, an evaluation team consisting of a Masters- or Doctoral-level research 
psychologist and psychiatrist meets with potential participants. The baseline evaluation includes a full 
battery of self-report measures, a structured psychiatric evaluation (MINI interview), Hamilton depression 
scale, a physical examination, and laboratory assessments. Medical screening and laboratory work, include 
vital signs, a physical examination, ECG, serum chemistry, liver function tests, complete blood count, and 


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urinalysis obtained by study personnel. Pregnancy tests will be conducted for women.
Describe Study Consent Procedures
After the screening evaluation, the study physician will review the study inclusion/exclusion criteria to 
determine if the participant is eligible for the study based on the screening materials. If the 
participant is eligible for the study, they will be given the consent form to read, and review with the 
consenting physician. The study consent will only be signed after all of the participant's questions are 
asked, and after all the risks and benefits are explained to and understood by the participant. Study 
related procedures will only be initiated after the consent form is signed by both the participant and 
consenting physician. 
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
Blevins, Derek
Brezing, Christina, MD
Kidd, Jeremy
Levin, Frances, MD
Luo, Sean, MD
Mariani, John, MD
Naqvi, Nasir, MD
Shulman, Matisyahu, MD
Vaezazizi, Leila
Wai, Jonathan, MD
Type in the name(s) not found in the above list
Study Procedures
Describe the procedures required for this study
This is an open-label randomized outpatient trial to compare the safety and efficacy of two methods of 
transitioning patients off BUP. Opioid-dependent individuals who have successfully completed at least 6 
months of BUP treatment and do not wish to remain in a long-term BUP maintenance will be screened for 
enrollment. 
 
In the first stage (led-in phase) participants will be maintained on their usual dose of BUP (2-8 mg) at the 
research clinic for 1 month to assure that they are stable, compliant, and free from illicit opioids. Following 
that, participants will be randomly assigned to begin treatment with one of two regimens: 1) rapid BUP 
discontinuation and transition to XR-NTX, or 2) 5-week long BUP taper. Participants randomized to XR-
NTX will receive a total of 3 injections. In both groups, participants will receive weekly individual therapy 
and monitoring for 3 months post-randomization. During months 4-6 participants will be seen twice 


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monthly for therapy and monitoring. The primary outcome will be a binary indicator of discontinuation 
success, the percent of patients successfully transitioned off BUP and abstinent from opioids at the end of 
the trial, 25 weeks after randomization. We hypothesize that success rate will be greater in patients that 
received treatment with XR-NTX.
 
Setting and Screening: This study will be conducted at the BSU clinic at NYSPI where we have previously 
carried out recruitment and treatment of opioid-dependent subjects using similar methodology. A 
combination of radio, print, and Internet advertising will be directed at prospective participants in the New 
York metropolitan area. Screening procedures are standardized for clinical trials including a telephone 
interview, the MINI International Neuropsychiatric Interview, psychiatric evaluation, medical history, 
physical and laboratory examination. The research psychiatrist will offer eligible individuals participation in 
the study and will obtain informed consent.
 
Randomization. We predict that 50 participants (out of 60 enrolled) will complete lead-in phase successfully 
and will be available for randomization. The 1:1 randomization will be stratified by the BUP maintenance 
dose (4 mg/d vs. greater than 4 mg/d) and the type of the primary drug (prescription opioids vs. heroin) 
distributing these potential prognostic factors equally between groups to ensure
comparable representation. The randomization sequence will be carried out by a research pharmacist, 
balanced in random blocks to protect allocation concealment.
 
Regimen 1 will include a rapid Monday to Friday oral naltrexone-induction procedure: last dose of BUP on 
Sat, Sun-Mon 0 mg, Tue 1 mg, Wed 3 mg, Thu 6 mg dose of oral NTX respectively. On Friday, a final 25 
mg dose of oral NTX will be given followed by an injection of XR-NTX (Vivitrol; 380 mg IM). All doses 
of oral NTX will be given in a single or split doses depending on patients’ tolerability of the protocol. 
Throughout the induction adjuvant medications will be administered on standing basis: clonidine 0.1 mg 
qid, clonazepam 0.5 mg qid, and zolpidem 10 mg HS. Additional injections of XR-NTX will be 
administered 4 and 8 weeks after the first injections to participants who provide an opioid-negative urine or 
pass a naloxone challenge test. 
 
Procedures for Missed Doses of Long-acting Naltrexone:Missing a scheduled Vivitrol 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, or as 
soon as possible thereafter, based on clinical judgement( i.e., after a clinical assessment and naloxone 
challenge if indicated). If the patient cannot attend the treatment clinic within that 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 Vivitrol injection, a naloxone challenge will be administered to confirm that the next long-acting 
naltrexone injection will be safely tolerated. 
Regimen 2 will include a 5-week BUP taper from the maintenance dose of 8, 6, 4, or 2mg (wk 1: 6, 5, 3 
2mg/d, wk 2: 4, 4 or 2 mg/d, wk 3: 3, 3 or 2 mgd/, wk 4: 2 mg/d, wk 5: 1 mg/d). A buprenorphine/naloxone 
generic product will be used.  Participants will be offered adjuvant medications, which will be administered 
on standing basis: clonidine 0.1 mg qid, clonazepam 0.5 mg qid, and zolpidem 10 mg HS. Additional 


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injections of XR-NTX will be administered 4 and 8 weeks after the first injections to participants who 
provide an opioid-negative urine or pass a naloxone challenge test.
 
Participants in both regimens will be seen in the clinic for 25 weeks  for follow-up after randomization, 
which will include both the week induction onto Vivitrol in Regimen 1 and the 5 week buprenorphine taper 
in Regimen 2.
 
We will collect 4ml of saliva, 50ml of urine, and 4, 6-7ml blood from subjects at baseline, after 
randomization (3 weeks after 1st injection of XR-NTX, or 1 week after completing bup taper), during 
post randomization month 2 ( 1 week after 2nd XR-NTX injection, or 4 weeks after completion of bup 
taper), and at end of study to be examined for biomarkers. From these we will isolate extracellular 
vesicle-containing pellets and evaluate their contents using advanced -OMICs analyses, in order to 
identify molecular signatures that differ across subjects before and after ending treatment with 
buprenorphine.
 
Study blinding. All participants will receive open-label medication as this is an effectiveness trial of two 
different regimens for managing patients discontinuing BUP treatment, tested as they would be used in 
community-based clinical treatment.
 
Psychotherapy platform. Following study enrollment, all participants will be offered weekly therapy, 
delivered by a therapist, that will follow the Community Reinforcement Approach: CRA (Budney and 
Higgins, 2000). CRA is a skills oriented treatment that emphasizes building a lifestyle which increases the 
opportunities for alternative reinforcers to drug use. CRA has been a central component of the behavioral 
treatment program developed by our group to improve the efficacy of naltrexone based treatments for OUD 
(Nunes et al., 2006; Rothenberg et al., 2002; Sullivan et al., 2015) and we have extensive experience 
implementing this flexible treatment protocol and assuring treatment fidelity. We will offer the following 
modules: Building and enhancing social support network; Social skills and relationship enhancement 
training; Management of mood and emotions; Increasing pleasant activities; Job-seeking skills; and 
Termination (Rothenberg et al., 2002). We will also incorporate a contingency reinforcement schedule to 
reinforce clinic visits to increase frequency of outcomes collection. As patients progress in treatment, we 
will support patient-directed recovery plan focusing on individual’s strengths to build meaningful and 
satisfying life and we will proactively link patients to recovery support resources. We have been 
implementing evidence-based therapy in our clinic for close to 20 years and we have established procedures 
for therapist training, supervision, and treatment fidelity assurance (e.g. recording of therapy sessions).
 
Outpatient Study Visits and Assessments will occur weekly during the period of BUP maintenance and 
taper to ensure adherence and to monitor for abstinence. Study visits will take place daily during XR-NTX 
induction and weekly following injection naltrexone or BUP taper in both regimens for the remainder of the 
study period. Once per week participants will meet with a therapist and complete study assessments. They 
will have scheduled meetings with a study psychiatrist weekly to inquire about medication effects and any 
changes in their medical/psychological condition following medication discontinuation. 
 
Evaluation of Depression and Anxiety symptoms: Participants who meet criteria for a Mood Disorder 
(MDD) of mild to moderate severity or an Anxiety Disorder will be followed closely during detoxification 
and subsequently. Mood and anxiety will be assessed both in therapy sessions and during MD visits. If a 


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patient demonstrates significant symptoms which persist following detoxification, we will offer the 
participant the option of beginning an antidepressant or an anti-anxiety treatment if deemed clinically 
warranted.
 
Managing controlled substances: 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. Dr. Bisaga has obtained his own NYS Controlled Substance license and  a federal 
DEA research license. . 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). 
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
Drop out criteria during the study period include:
 
1) Development of serious psychiatric symptoms as indicated by the Clinical Global Impression (CGI)
improvement score of 6 (much worse than baseline) or greater for 2 consecutive weeks or psychiatric  or 
medical deterioration that cannot be managed safely in the context outpatient treatment offered at the study 
(in cases where the investigator determines that the participant needs immediate study discontinuation).
 
2) If the participant's continued opioid or other drug use places him/her at risk for self-destructive behavior 
or other harm as indicated by a CGI improvement score of 6 or more (much worse than baseline) for 2 
consecutive weeks. In cases where the investigator determines that the participant needs immediate study 
discontinuation for continued opioid or other drug use, participants will be provided with referrals.
 
3) Development of serious medical condition(s) that may or may not be related to study participation
as assessed by weekly visits with the psychiatrist, vital sign measurements, and weekly weight-ins.
 
4) If the participant becomes pregnant as assessed by monthly urine pregnancy testing
 
5) Ongoing non--adherence with recommended clinical visits, absence from study visits for 21 days.
 
Patients who are exited from the trial for any reason will be offered continued treatment in the community 
unless a higher level of care is indicated (inpatient or residential treatment), or the patient requests treatment 
elsewhere, in which care help with arranging referrals will be offered. A clinic staff member, with physician 
backup, is available 24 hours per day by phone in case of emergency. 
 
Participants may be removed from the trial if they repeatedly miss scheduled appointments or clinical


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worsening necessitates more intensive treatment (drop out criteria are defined above). Subjects who
develop serious psychiatric symptomatology (e.g., psychosis, suicidal ideation, severe depressive
symptoms) during the study period will be dropped from the study and appropriate clinical referrals will
be made. A patient who's continued opioid use places them at risk for self-destructive behavior or
otherwise places them at significant risk will be discontinued from the study. This would include, but not be 
limited to, patients who become unconscious after using, engage in destructive or violent behavior while 
intoxicated, report driving while intoxicated, or develop medical complications from their opioid use. In all 
cases where subjects are discontinued from the study, the clinical research staff will assume clinical 
responsibility for the subjects until clinical referrals are operational.
In case that the patient is removed from the research trial for medical reasons, or is requesting
withdrawal from the study, he/she will be retained in open treatment for the remaining study period.
Upon removal of a patient from the trial due to clinical deterioration, the patient will be referred for
appropriate follow-up treatment, in most instances either intensive outpatient or residential treatment.
The PI or a study psychiatrist is available 24 hours/day by phone and/or beeper in case of emergency.
 
 
If a patient is discontinued from the study, or decides to withdraw, or relapses during study the participation, 
the patient will get treated with buprenorphine until they are linked with a referral for continuing 
buprenorphine treatment. Participants will receive a one-week supply of buprenorphine at a time during the 
transition process.  
 
 
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
Urine samples will be collected at every visit, and we will use onsite testing to provide immediate feedback 
on opiate use to the participant and the treatment team. Blood chemistry will be obtained at baseline and end 
of study (week 25). Urine Pregnancy tests will be obtained at baseline, at once monthly (or prior to 
administration of XR-NTX).
 
We will collect 4ml of saliva, 50ml of urine, and 4, 6-7ml blood from subjects at Baseline, after 
randomization (3 weeks after 1st injection of XR-NTX, or 1 week after completing bup taper), during 
post randomization month 2 ( 1 week after 2nd XR-NTX injection, or 4 weeks after completion of bup 
taper), and at end of study to be examined for biomarkers. From these we will isolate extracellular 
vesicle-containing pellets and evaluate their contents using advanced -OMICs analyses, in order to 
identify molecular signatures that differ across subjects before and after ending treatment with 
buprenorphine.


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Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
Physiological Measures
Medical History and Physical Exam: A comprehensive medical history and physical examination will be 
performed during the screening process. All potential participants will be offered the opportunity to be 
referred to receive free HIV risk reduction education, as well as HIV testing and counseling.
 
Pregnancy Testing: Serum pregnancy testing will be performed on all females during screening and urine
pregnancy tests will be performed at baseline and monthly afterwards.
 
Serum laboratory examination: Complete blood count, electrolyte, and liver function tests will be 
performed during the screening process and at the end of study.
 
Urinalysis: Laboratory urinalysis (glucose, protein, ketones, pH, specific gravity, and microscopic analysis) 
will be performed during the screening process and at the end of study.
 
Urine Toxicology: Urine samples will be collected under directly--observed conditions during screening 
and at each study visit. To provide immediate feedback to the participant, the Abuscreen On--Trak system 
(Roche Diagnostics) will be used to identify opiates (morphine, oxycodone, buprenorphine, methadone). In 
addition, the sample will be analyzed for substances of abuse, including THC, alcohol, opioids, cocaine, 
benzodiazepines, amphetamines, and barbiturates.
Vital Signs: Temperature, pulse, and blood pressure will be measured at every study visit for data collection 
and safety monitoring purposes. Height and weight will be measured and baseline body mass index (BMI) 
calculated during screening. Weight will be recorded and monitored at each visit throughout the study 
period.
Interviews
Clinical Global Impression Scale--Observer (CGI): The CGI Severity and CGI Improvement scales 
(Guy, 1976) will be used to measure the overall clinical status of the participant as well as change from 
baseline in symptom severity, functional impairment, and psychiatric symptoms. The CGI Improvement 
scale will be used to determine whether a participant needs to be discontinued from the study and provided 
with an appropriate clinical referral.
Hamilton Depression Scale (HAM--D): This is the standard clinician--rated instrument used to assess
depressive symptoms in clinical trials to assess baseline severity and changes associated with treatment. We 
use a 25--item, structured interview version (SIGH--D--DES) that incorporates the reverse vegetative 
symptoms of the atypical subtype of major depressive disorder (Williams, 1988), but permits calculation of 
the standard 17-- and 21--item scores imbedded in the scale. In addition to mood symptoms, the HAM--D 
has items that measure anxiety, irritability, and insomnia, which are symptoms of interest for this study. The 
HAM--D will be performed at baseline and twice per month thereafter throughout the trial.
Hamilton Anxiety Scale (HAM--A): The HAM--A is a standard clinician--rated instrument used to assess 


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the severity of anxiety symptoms (Maier et al., 1988). The scale consists of 14 items, measuring both 
psychic anxiety and somatic anxiety. The HAM--A will be preformed at baseline and and twice per month 
thereafter throughout the trial.
The MINI International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998) will be performed 
during screening as part of a complete psychiatric diagnostic assessment.
Structured Medication Count Interview is a Timeline Follow--Back assessment of study medication
compliance accounting for each dose of prescribed study medication during the study period. Structured pill 
count interviews will be conducted weekly.
 
Systematic Assessment for Treatment and Emergent Events (SAFTEE): The SAFTEE as modified for 
Project COMBINE (Johnson et al., 2005) will be performed weekly, and twice-monthly during study 
months 4-6 to identify any adverse symptoms. If participants report experiencing adverse symptoms since 
the previous visit, the research nurse will record the symptom as well as the date of onset, severity, and 
resolution (if applicable) and research psychiatrist will review it at least weekly and more frequently if 
symptoms are present.
Timeline Follow--Back (TLFB): The Timeline Followback method (Litten and Allen, 1992) will gather 
self-- reported opioid use data for each day during the month prior to study enrollment and each day during 
the study period. The TLFB confirmed by urine toxicology will be the primary outcome measure of 
psychoactive substance use and will be performed at every study visit.
Therapist Contact Log (TCL): The number and duration of treatment sessions will be documented by the 
therapist on a contact log.
End of Study Form (ESF): At study completion or the point of termination for patients who relapse or 
drop out, the research psychiatrist fills out an End of Study Form, which indicates whether or not a patient 
completed 25 weeks of treatment, the date of termination, the number of weeks of treatment completed from 
randomization to termination, and reasons for early termination, including documented relapse to opiates, 
resumption of buprenorphine maintenance, psychiatric worsening, medical worsening, or lost to follow--up.
 
Self--Report
Clinical Global Impression--Self (CGI--S): The CGI--Self 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). The CGI--S will 
serve as the primary self--reported measure of overall functioning.
Medical Outcomes Study—Sleep Scale (MOS--SS): The MOS--SM is a 12--item measure for 
characterizing the quality of sleep (Hays et al., 2005). Opioid withdrawal, both acute and protracted is 
characterized by insomnia and other sleep disturbances. The MOS--SM will be the primary outcome of 
sleep quality and length and will be collected at each visit.
Craving Scales-- Self: A visual analog scales is used for patients to rate the intensity of craving for opiates 
experienced since the previous visit (Bisaga et al., 2011).


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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 et al., 1970).
Beck Depression Inventory (BDI)-- Self: 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 et al., 1996) and it will be collected weekly, and twice-monthly during study months 4-6.
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 et al., 1987). It will be used to examine occurrence of symptoms 
resembling opiate withdrawal during naltrexone maintenance and will be collected at each visit.
Locator Form-- Self: In order to facilitate the location of drop--outs for follow--up evaluation, a standard 
location form will be administered at baseline and updated monthly. This indicates names, addresses and 
phone numbers of family members and close friends likely to know patients' whereabouts along with 
permission to contact them in the future.
 
 
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?
Yes
Maximum duration of delay to any treatment 
A delay of up to 2 weeks is possible prior to enrollment.
Maximum duration of delay to standard care or treatment of known efficacy
Up to two weeks.
Treatment to be provided at the end of the study
Discharge and aftercare planning and implementation will be incorporated into the study. A Discharge Plan 
will be completed by a clinician and approved by a study physician prior to the End of Study visit. After the 
End of Study, participants will continue in a follow-up phase with once weekly clinic visits with their 
therapist for up to one month in order to facilitate transition and permit overlap with another treatment 
program for aftercare. Discussion of treatment recommendations as well as risks and benefits of accepting 
and refusing referrals will take place and will be documented.  


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Clinical Treatment Alternatives
Clinical treatment alternatives
The major alternatives for long-term treatment of opiate dependence are "drug-free" treatment on either an
outpatient or residential basis, or agonist maintenance with methadone or buprenorphine, all available by
referral. Other options available in the community include either hospital-based detoxification (often 
agonist-assisted) to a "drug-free" state, which is available to the patients by referral, or outpatient methadone 
detoxification, which is available at some methadone clinics. Regardless of treatment, the risk of relapse to 
illicit opiate use is very high once the detoxification is completed without medication-based relapse 
prevention treatment. XR-naltrexone is FDA-approved for relapse prevention treatment of opiate
dependence.
During the initial informed consent process, patients will be informed about alternative treatments and their 
availability, and that they are free to choose among the options, at baseline or at any time during the study.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
Side Effects, Risks, and Interactions of Buprenorphine
Buprenorphine has been associated with adverse effects typical of opioid agonist drugs (e.g. sedation,
constipation, insomnia, headache, nausea), although as a partial agonist such effects are typically less
pronounced than they would be with a full agonist. The most common adverse event associated with the
sublingual administration is oral hypoesthesia. Other adverse events were constipation, headache, 
intoxication, disturbance in attention, palpitations, insomnia, sweating, and blurred vision. Buprenorphine 
by itself has little tendency to suppress respiration and is associated with a low risk of overdose, a safety 
advantage. However, there is a risk of overdose if buprenorphine is combined with sedative drugs such as 
benzodiazepines or alcohol, analogous to the risk of combining such sedating medications with a full 
agonist like methadone. As a partial agonist, buprenorphine can precipitate an acute opioid withdrawal 
reaction if taken within 12--18 hours of another short--acting full opioid agonist, or within 48--72 hours of a 
longer--acting full opioid such as methadone.
Discontinuation of buprenorphine is associated with opioid withdrawal symptoms ranging from mild-
-moderate to more severe reactions. Study physicians have extensive experience, in both research and 


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clinical settings, in administering buprenorphine and in the management of opioid withdrawal symptoms. 
The use of buprenorphine is also associated with the risk of using the medication for the purposes of 
intoxication. In the present study we will use buprenorphine/naloxone combination product, which has 
lower abuse liability. If sublingual buprenorphine is used parenterally, there is a risk of precipitated opioid 
withdrawal. Such an event, if it were to occur, would be short--lived and not life threatening. Participants 
will be warned of this risk and advised not to use the medication in this manner. If it is determined that 
patients have been abusing their buprenorphine in such a manner, they will be declared to have failed BUP 
discontinuation, and a new treatment plan will be developed by the patient’s clinical team, with possibilities 
including transfer to naltrexone or methadone maintenance. To minimize the risk of diversion, medication 
will be dispensed for short time intervals (1--2 weeks of medication at a time).
Buprenorphine is metabolized principally by CYP3A4. Co--administration of other CYP3A4 inhibitors (e.g. 
anti-- retrovirals efavirenz, delavirdine, atazanavir or atazanavir/ritonavir;; the anti--fungal agent 
ketoconazole;; antibiotics erythromycin or clarithromycin) may cause an increase in systemic levels of 
buprenorphine, although this does not usually have clinically significant effects. When a patient being 
prescribed buprenorphine is also receiving other medications, the prescribing physician will check for 
potential interactions ahead of time and monitor during treatment.
 
Side Effects of Extended--Release (XR), Injectable Naltrexone
The most common side effect associated with injectable naltrexone is injection site reaction. XR-naltrexone 
is administered as a gluteal intramuscular injection and injection site reactions, mostly pain, and occur in 
approximately 5% of patients in opioid treatment studies. These reactions are generally mild and include 
pain, tenderness, indurations, bruising, pruritus and swelling. Generally these reactions last 1--3 days. Rare 
skin reactions at the site of the injection have been reported, including sterile abscesses, which may relate to 
inadvertent injection into fatty tissue, rather than muscle. Patients will be informed of this risk, and baseline 
physical evaluation will include examination of the buttock for excessive adiposity. If a patient is examined 
by a physician and found to have an abscess, necrosis, cellulitis or extensive swelling, an appropriate 
surgical referral will be made.
Naltrexone has been associated with reversible hepatocellular injury indicated by elevated liver enzymes 
when administered at doses substantially greater than the 380 mg im per month, dose recommended for 
relapse prevention treatment of opiate dependence and proposed for the present study. When used in 
therecommended dose range in opiate--dependent patients, this risk is remote (Brahen et al., 1988;; Brewer 
and Wong, 2004). 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 three times the 
upper imit of normal are excluded. Injectable naltrexone achieves higher blood levels 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 long--acting preparation, where the naltrexone would be only very slowly 
eliminated, this would prolong exposure to the offending agent. However, the experience with injectable 
naltrexone also suggests it is safe. In our studies with extended--release naltrexone several patients 
experienced elevation in liver enzymes, which were determined to be related to hepatitis C. In the proposed 
study we will use a long--acting, injectable preparation of naltrexone (Vivitrol 380 mg).
Several recent reports have documented that naltrexone pose significantly lower risk of hepatotoxicity than 
previously suspected, even among alcohol-- and opioid--dependent persons including those with HCV 
and/or HIV infection (Lucey et al., 2008;; Mitchell et al., 2012;; Tetrault et al., 2012;; Vagenas et al., 2014). 
These reports were used to support decision taken by FDA in July of 2013 to remove the Boxed Warning on 


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the hepatotoxicity. Other adverse events seen most frequently in association with XR--naltrexone treatment 
for opioid dependence include nasopharingitis, insomnia and toothache (Vivitrol;; Package Insert). 
During the outpatient phase of the study, if a patient misses scheduled injection of Vivitrol and resumes 
regular opiate use, then receiving injectable naltrexone will precipitate opiate withdrawal, which may be 
quite severe in proportion to the time since the last injection and the level of opiate dependence. The 
physician will evaluate the patient and perform a naloxone challenge test to determine whether or not 
naltrexone can be safely resumed. If the naloxone challenge is positive (withdrawal is precipitated), then the 
patient will be removed from the study and offered another treatment option such as agonist maintenance 
(buprenorphine or methadone) according to clinical judgment and the patient’s preferences.
Self--administration of large doses of opiates may over--ride the blockade produced by naltrexone resulting 
in opiate overdosage 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 topped 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. 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.
 
 Risks of the Rapid Naltrexone Induction Procedure:
In this procedure withdrawal is then precipitated through administration of oral naltrexone and 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 adjunctive medications. In the proposed protocol the risk of severe withdrawal 
has been minimized by starting naltrexone at the very low dose. Opiate withdrawal causes agitation, 
elevated pulse and blood pressure and other signs of sympathetic arousal, and sometimes confusion. 
Clonidine may produce somnolence or hypotension. Clonazepam commonly may produce somnolence. The 
procedure is contraindicated in patients with unstable medical problems or histories of hypersensitivity to 
any of the medications used, and these are exclusions in the proposed study. The procedure is conducted in 
the outpatient setting that permits monitoring of patients for up to 8 hours daily to permit close monitoring 
of vital signs and mental status.
Pregnancy
Buprenorphine and naltrexone are Pregnancy category C agents, although the safety of buprenorphine in 
pregnancy has been supported in clinical trials (Jones et al., 2010). Female participants will be required to 
use adequate methods of birth control (condom with spermicide, diaphragm with spermicide, birth control 
pills) to be included in the study and will be strongly encouraged to use more effective methods like a 
subdermal implant, IUD, or a depot contraceptive injection. Serum pregnancy tests will be evaluated at 
baseline and urine for pregnancy will be tested as clinically indicated during treatment according to standard 
clinical procedures. If a female patient does become pregnant she will be withdrawn from study medication 
and offered continuing treatment with methadone or buprenorphine, which remains the current treatment of 
choice for pregnant opioid dependent patients.
 


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 Randomization to injection naltrexone or buprenorphine taper
The implications of random assignment to treatment conditions will be discussed with patients. One of the 
treatments could be more or less effective for a given patient. The alternative choices of continuing
buprenorphine maintenance outside of the study or injection naltrexone, detoxification and counseling 
without medication (so called “drug--free” treatment), will be discussed with patients, as well as options of 
pursuing such treatments at other treatment programs available to the patients in the New York area. These 
will be discussed with patients at the time of consent, and revisited if Relapse occurs. Patients will also be 
informed, and reminded that the study is voluntary and that they can opt for any of these options at any 
point during the study.
Assessments
The structured interviews, rating scales, and questionnaires should add no physical risk. However, because 
many of the interviews and assessments are time--consuming to complete and involve topics of a sensitive 
nature, some people have found them to be physically or emotionally tiring. Patients are informed prior to 
study entry that they can refuse to answer any questions and that they can request to stop at any time. If a 
participant becomes agitated during any of the interviews or assessments, he or she will be provided with 
therapeutic assistance.
Blood Tests
Blood drawing may cause slight discomfort at site of needle entry, resulting in a small bruise.
 
 
Describe procedures for minimizing risks
Monitoring
Any study of medication efficacy carries risk. However, the investigators have conducted a series of studies 
administering medications to patients with opioid use disorder. Further, Dr. Bisaga has specifically 
conducted a study at the clinic in which the outpatient method of rapid naltrexone induction was developed. 
Other clinic physicians have extensive experience in administering oral and injectable naltrexone to opioid-
-dependent patients as well as experience providing treatment with buprenorphine. Patients are seen weekly 
by a physician until month 4, and twice-monthly during months 4-6 for evaluation of medication and 
side effects, medication compliance therapy, or dose adjustments or adverse effects, and for evaluation of 
safety and emergence of any safety related issues (e.g. pregnancy, clinical worsening including serious 
medical or psychiatric conditions, or worsening of substance use). Adverse Events and Serious Adverse 
Events will be carefully monitored during the study.
 
Relapse during outpatient naltrexone induction
During the detoxification phase of the study, particularly during washout day and during first few days 
when naltrexone is introduced if a patient resumes regular opiate use, then taking naltrexone, particularly 
naltrexone injection, may precipitate opiate withdrawal, which may be severe. Patients will be warned not to 
take the naltrexone if they resumed any level of opiate use, and opiate abstinence will be confirmed by urine 
toxicology prior to administering the next daily dose of naltrexone.
 
Psychiatric Monitoring and Removal from Study


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Participants’ mental and physical status is monitored weekly until study month 4, and twice monthly 
during study months 4-6 by the physician. The psychiatrist will assess appropriateness for continuation in 
the research study on a continuous basis, and will remove from the trial patients with significant clinical 
deterioration or noncompliance of a type that could be dangerous. Although unlikely, it is possible that 
patients may become psychotic or depressed, requiring discontinuation of study medication, and possibly 
psychiatric intervention. The weekly monitoring of patients, along with ongoing evaluations with structured 
assessments, such as the Hamilton Depression Scale, should allow us to detect these psychiatric 
disturbances early and intervene appropriately.
 
Although a patient might potentially attempt to overdose with buprenorphine, individuals who are at 
significant risk for suicidality will be excluded. Further, buprenorphine is a partial agonist and has a ceiling 
effect on respiratory depression; overdoses involving sublingual buprenorphine are rare and typically 
involve taking of toxic amounts of alcohol or benzodiazepines in combination with buprenorphine. Patients 
will be provided with a 1--2 weeks supply of buprenorphine/naloxone throughout the study.
 
Criteria for removal from the study will include: include:
1) Development of serious psychiatric symptoms as indicated by the Clinical Global Impression (CGI) 
improvement score of 6 (much worse than baseline) or greater for 2 consecutive weeks or psychiatric or 
medical deterioration that cannot be managed safely in the context outpatient treatment offered at the study 
(in cases where the investigator determines that the participant needs immediate study discontinuation).
2) If the participant's continued opioid or other drug use places him/her at risk for self-destructive behavior 
or other harm as indicated by a CGI improvement score of 6 or more (much worse than baseline) for 2 
consecutive weeks. In cases where the investigator determines that the participant needs immediate study 
discontinuation for continued opioid or other drug use, participants will be provided with referrals.
3) Development of serious medical condition(s) that may or may not be related to study participation as 
assessed by weekly visits with the psychiatrist, vital sign measurements, and weekly weight-ins.
4) If the participant becomes pregnant as assessed by monthly urine pregnancy testing.
5) Ongoing non--adherence with recommended clinical visits, absence from study visits for 21 days.
 
Patients who are exited from the trial for any reason will be offered continued treatment in the community 
unless a higher level of care is indicated (inpatient or residential treatment), or the patient requests treatment 
elsewhere, in which care help with arranging referrals will be offered. A clinic staff member, with physician 
backup, is available 24 hours per day by phone in case of emergency.
 
 
Patient Education
All patients will be informed through the consent process and consent form and discussions with the 
research psychiatrist of the possible side effects and risks enumerated above. In addition, at weekly visits the 
research nurse or psychiatrist will query about side effects and treatment emergent symptoms. Patients will 
be warned that risks, as yet unknown, may occur when combining study medication with opioids or with 
other street drugs or alcohol. Patients will give informed consent before entering the study. Patients are 


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instructed to call us if any untoward effects occur and are given the phone number of our 24--hour 
answering service. One of the study-- affiliated physicians is on call 24 hours per day to answer questions 
and handle clinical emergencies.
 
Significant Other Contact
Upon entry to the study, the participant is informed that, if s/he agrees, the staff would prefer to have the
contact information of someone who knows them well, to periodically assess how they are doing or to aid in 
case of emergency. Providing this information is not contingent on participating in the study. The 
participant, if he or she agrees, will then inform the individual that they may be contacted by the study staff. 
Only after the participant has informed the individual about the possible contact by the staff will the contact 
information be provided and the consent form addendum be signed.
 
Adverse Events and Serious Adverse Events are carefully monitored during medication studies. The
physician queries the patient and log side effects and other treatment emergent events during the past week, 
recording their severity, what action was taken, and whether they are continuing or resolved. NIDA/VA 
Serious Adverse Event Form and NIDA Serious Adverse Event Tracking and Reporting System (SAETRS, 
on line) is used whenever a serious adverse event occurs. The research physician evaluates the patient, 
completes this form detailing the event, and reports the event immediately to both Investigators’ IRBs and 
to NIDA. SAETRS is a web--based application that helps collect, track, store, analyze and report serious 
adverse events (SAETRS).
Methods to Protect Confidentiality
Describe methods to protect confidentiality
Confidentiality
Patients will be asked to divulge information, such as their drug use or legal, psychiatric or medical 
problems, which are sensitive and could have adverse social consequences if released. This would include 
information released to insurance companies, family members, or made public in any way. Patient records 
are kept in locked files and released only with the patient's consent. We will obtain a Federal Certificate of 
Confidentiality to further safeguard the confidentiality of the participants enrolled in the trial. The 
Certificate of Confidentiality will allow 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. Contact with family members or significant others 
will only be with the patient's express consent. All computer data are stored without names or other uncoded 
identification.
Will the study be conducted under a certificate of confidentiality?
Yes, we will apply for the Certificate of Confidentiality
Direct Benefits to Subjects  
Direct Benefits to Subjects
The potential benefits to patients are cessation of BUP use and achievement of abstinent, opioid--free status


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following successful stabilization off BUP, as well as improvements in daily functioning. Further, the 
knowledge gained from this study will contribute to the effort of finding medication strategies to treat OUD. 
The risks listed above are reasonable in this context. Individual patients may benefit from the treatment they 
receive in the context of the trial. Given the limited efficacy and implementation to date of XR--NTX for 
patients with OUD, the development of additional pharmacotherapy options would be of great public health 
benefit. We believe that measures described above to minimize risks for participants make the balance 
between risk to participants and the potential benefit to participants and others reasonable.
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.
Contingency Management and Subject Compensation: Subjects will be encouraged to come for
the clinical evaluations and for CBT sessions as described in this protocol. To minimize missed
sessions, they will be reimbursed for transportation expenses, for providing data, and for time
spent in completing study assessments in accordance with local site's IRB policies. Contingency
management procedures which have been shown to successfully improve many behaviors
ranging from medication compliance to adherence to protocol activities will be applied to this
study. Subjects will earn chances at each visit to draw vouchers from a prize-bowl. A subject must
complete all visit requirements to be able to draw vouchers at the end of a visit. If study medication is 
discontinued due to adverse events, subject will continue to draw vouchers based on the schedule below as 
long as they continue all other visit requirements are completed. Participants will earn one draw for each 
consecutive visit made, with a bonus 3 draws for every 3 consecutive weeks . If a participant misses a visit, 
their draws are reset. Each draw has a probabilistic chance of yielding one of four outcomes; an encouraging 
statement (e.g. ‘good job’), a small prize valued at $2.50, a large prize valued at $20, or a jumbo prize 
valued at $100. The probability of each particular outcome is fixed for every draw and is based on the 
relative number of slips for each prize category in the prize bowl. Using Petry et al.s (2005) framework each 
prize bowl will have 500 prize slips. 250 slips will be an encouraging statement (50% of the total slips), 209 
will be for small prizes (41.8%), 40 slips will be for large prizes (8%), and 10 slips will be the jumbo prize 
(0.2%). Patients will earn 1 additional draw for every consecutive week of abstinence (all urine samples for 
a treatment week test negative). The increasing number of earned draws during the protocol follows the 
escalating incentive structure employed in other CM based treatments (Higgins et al., 1993). During the 
treatment (contingency management) subjects can earn up to 340 draws from the prize bowl if 
demonstrating 100% attendance during the 25 weeks of the protocol. Total earnings will vary depending 
on attendance. With an expected earning of $2.85 per draw the maximum potential earnings for the CM for 
25 weeks is $969. However, actual observed earnings will be significantly less than the potential maximum 
due to attrition and missed visits.
 


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References
References
Beck, A.T., Steer, R.A., Brown, G.K., 1996. BDI=II Beck Depression Inventory Manual. The           
Psychological Corp. Harcourt Brace & Company, San Antonio, TX.
 
Bisaga, A., Sullivan, M.A., Cheng, W.Y., Carpenter, K.M., Mariani, J.J., Levin, F.R., Raby, W.N., Nunes, 
E.V., 2011. A placebo controlled trial of memantine as an adjunct to oral naltrexone for opioid dependence. 
Drug Alcohol Depend 119, e23--29.
 
Bisaga, A., Sullivan, M.A., Glass, A., Mishlen, K., Carpenter, K.M., Mariani, J.J., Levin, F.R., Nunes, E.V., 
2014. A placebo--controlled trial of memantine as an adjunct to injectable extended--release naltrexone for 
opioid dependence. J Subst Abuse Treat 46, 546--552.
 
Bisaga, A., Sullivan, M.A., Glass, A., Mishlen, K., Pavlicova, M., Haney, M., Raby, W.N., Levin, F.R.,
Carpenter, K.M., Mariani, J.J., Nunes, E.V., 2015. The effects of dronabinol during detoxification and
the initiation of treatment with extended release naltrexone. Drug Alcohol Depend 154, 38--45.
 
Brahen, L.S., Capone, T.J., Capone, D.M., 1988. Naltrexone: lack of effect on hepatic enzymes. J Clin
Pharmacol 28, 64--70. Brewer, C., Wong, V.S., 2004. Naltrexone: report of lack of hepatotoxicity in acute 
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withdrawal during double--blind buprenorphine detoxification. Drug Alcohol Depend 151, 47--55.
 
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Neuroscience 17, 1006--1012.


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BUP DISCO 
Version 04.02.19 
 
1 
NEW YORK STATE PSYCHIATRIC INSTITUTE COLUMBIA UNIVERSITY 
DEPARTMENT OF PSYCHIATRY 
 Informed Consent for Participation in Research  
 
A Strategy to Improve Success of Treatment Discontinuation in Buprenorphine Responders  
 
I. 
Purpose and Overview  
 
You are invited to participate in a research study because you are diagnosed with opioid use disorder, have 
been successfully treated with buprenorphine and would like to stop taking buprenorphine. The main purpose 
of this research study is to evaluate two methods of buprenorphine discontinuation: a standard method of a 
graduated taper compared to a rapid discontinuation and transition onto Vivitrol.  This study is funded by a 
grant from the National Institute on Drug Abuse (NIDA). 
 
Vivitrol is a long-acting injection that contains enough naltrexone to last up to one month; it is approved by 
the FDA for preventing relapse in those with opioid use disorder. It works by blocking the effects of opioids 
and reducing cravings, but is not a controlled substance and has no opioid-like effect itself. You are being 
asked to participate in this study because you are currently prescribed buprenorphine and meet other study 
entry criteria. If you are not eligible, you will be assisted in finding free or low-cost treatment services near 
your home. If you are eligible for the study, you will receive your current dose of buprenorphine for one 
month, and will be randomized to either a five-week gradual taper off buprenorphine, or a week long rapid 
taper followed by an injection of Vivitrol. You will receive individual therapy for 25 weeks, and if you have 
been randomized to receive Vivitrol, you will receive two additional injections.  
This study will also look at biomarkers, which are biological molecules found in blood, which 
can be used to see how well the body responds to treatment for opioid use disorder.  
 
II. 
Voluntary  
 
Participation in this research study is voluntary. If you decide not to participate, or if you later decide to stop 
participating, you will not lose any benefits to which you are otherwise entitled. A decision not to participate 
or withdraw your participation will not affect your current or future treatment at the New York State 
Psychiatric Institute or Columbia University Medical Center. You will be notified of significant new findings 
that may relate to your willingness to continue to participate.  
 
 
III. 
Alternative Treatments/Alternatives to Participation  
 
You do not need to participate in this research study to receive treatment for your opioid use disorder or to 
receive treatment with Vivitrol or buprenorphine. Other treatments are  
available, including methadone maintenance, buprenorphine maintenance, inpatient or other outpatient 
detoxification programs, and "drug-free" treatments including outpatient counseling or residential or 
therapeutic community treatment.  
 
IV. 
Procedures  
Screening 


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The study begins with a screening visit. The medical examinations and laboratory tests for screening 
may be done on one day or over multiple days. You and the study doctor will arrange those times. If 
you agree to be in this study, you will sign this form before any study procedures are done. 
In order to participate in the study you must first have a psychiatric and medical screening, which 
will include questions about your drug use, health, and other problems you may be having. 
Depending on the results of that, you may also have a cardiogram (a test to measure the electrical 
activity of your heart), blood tests, a physical exam, and a urine toxicology screen. After the initial 
screening visit(s), you will be told whether you may be eligible for this research treatment study. The 
screening process may take between a few days to a few weeks depending on the frequency of your 
visits. If you are not eligible, or if you are not interested in taking part in the research treatment, then 
the clinician will assist you in finding treatment for your problems elsewhere. 
If you are eligible for the study, you will come to the clinic once a week to receive your current dose of 
buprenorphine and for monitoring. At the end of this month you will be randomly assigned to one of two 
regimens of stopping buprenorphine: (Regimen 1) rapid discontinuation of buprenorphine followed by 
treatment with Vivitrol or (Regimen 2) a gradual taper off of buprenorphine.  
 
Regimen 1: Rapid Discontinuation + Vivitrol  
You will begin your outpatient visits to the clinic at the beginning of the week, and you will be asked to 
come to the clinic daily (5 visits, at least one hour each day) during this first week, in order to receive 
medications, naltrexone and other medications to reduce the discomfort of withdrawal from opioids. At each 
outpatient visit, you will need to provide an observed urine sample, which will be tested for opiates as well 
as other drugs.  You will have your blood pressure, heart rate, and rate of breathing checked by our staff.  
The anti-withdrawal medication you will receive include: clonidine (a medicine used to treat high blood 
pressure), clonazepam (for anxiety), prochlorperazine (anti-nausea drug), and zolpidem or trazodone (for 
insomnia). If you experience significant withdrawal while at the clinic, you will be strongly encouraged to 
remain at the clinic for observation, and you may receive additional doses of medications.  
 
If you are assigned to Regimen 1, you will be asked to stop taking buprenorphine and you will start taking 
medications to prevent withdrawal. Two days after the last dose of buprenorphine you will start taking 
naltrexone by mouth, first taking very low doses. If you do use buprenorphine or another opioid drug during 
this period, you may receive a naloxone challenge to determine whether it is safe to continue with the rest of 
the dosing schedule.  At the end of the first week, you will receive an intramuscular injection of Vivitrol, a 
long-acting form of naltrexone that lasts in your system for 3-4 weeks.  You will be asked to stay at the clinic 
for at least one hour after receiving this injection, for clinical observation.  
While at the clinic, you will have the opportunity to rest in a private room fitted with lounge chairs, 
adjustable lighting, and an entertainment system. Light snacks and sports drinks such as Gatorade will be 
available to keep you comfortable.  It is important to drink plenty of fluids. Clinical staff will determine any 
changes to your medication necessary for your well-being. The clinic staff will advise you on ways to 
minimize withdrawal symptoms, and you will also meet daily with a therapist who will provide you with 
counseling.  
 
You will be free to leave the clinic each day once you have received all necessary medication doses and have 
been evaluated for medical stability by the clinic nurse and/or psychiatrist. If you experience fatigue or 
medication side effects, car transportation home will be provided to you. After you have received Vivitrol, 
you will continue to come to the clinic once a week to meet with a therapist and psychiatrist for 3 months, 
and twice-monthly during treatment months 4-6. You will also receive two additional injections of Vivitrol 4 


BUP DISCO 
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3 
and 8 week after the first injection.  
 
Regimen 2: Gradual Taper  
If you are assigned to Regimen 2, you will continue receiving buprenorphine on a weekly basis for five 
weeks, with the dose of buprenorphine gradually decreasing to minimize any possible withdrawal. At the end 
of the taper buprenorphine will be stopped.  During this time we ask that you come to the clinic once a week 
so that staff can assess for withdrawal symptoms and so you can meet with a therapist and psychiatrist. After 
you have been tapered off buprenorphine you will continue to come to the clinic once a week to meet with a 
therapist and psychiatrist for 3 months, and twice-monthly during treatment months 4-6. 
 
Outpatient Treatment 
After stopping buprenorphine, you will continue to be monitored and receive counseling, regardless of the 
regimen you were assigned to. Your visits to the clinic should take between 30 and 60 minutes to meet with a 
counselor and research psychiatrist. These sessions will help you to work on your treatment goals and remain 
abstinent. During each visit, you will fill out several questionnaires and answer questions about your alcohol 
use and other drug use. You will also have your vital signs monitored at every visit. If during the course of 
treatment you resume taking opioids (buprenorphine, heroin or other opioids) and are unable to give an 
opioid-free urine, you will be provided with referrals to alternative treatment programs. If you use opioids 
during the study but are able to receive your next Vivitrol injection you will continue in the program.  
 
Approximately one tablespoon of blood will be drawn at the beginning and end of the study to check your 
liver enzymes. Additionally approximately six tablespoons blood, saliva and urine will be collected at the 
beginning and 3 times throughout the study to check for biochemical markers. You will be asked to give 
supervised urine at every visit to the program throughout the study. The urine samples are tested for drugs, 
and the purpose of this is to help monitor your progress. Results of the urine are discussed at counseling 
sessions. At the beginning, if your liver enzymes are elevated, we may test your blood to determine whether 
you have been infected with viral hepatitis (Hepatitis B, and Hepatitis C). We are required by law to report 
positive hepatitis test results to the Department of Health.  
If you are a woman, approximately one tablespoon of blood will be drawn to check for pregnancy before 
starting treatment. Also, since pregnant women may not participate in this research, women must practice an 
effective method of birth control until the end of the study. You will have a pregnancy urine test monthly.  
 
If you suffer from depression or anxiety, you will have the opportunity to receive therapy to address those 
symptoms. You will also be seeing a psychiatrist who can evaluate your symptoms and may be offered the 
option of taking an antidepressant or anti-anxiety medication.  
 
End of Study 
At the end of Week 25 you will be asked to meet for an hour with the psychiatrist to answer questions, have 
another physical examination and blood test, complete questionnaires, and receive referrals for further 
treatment as part of an aftercare plan outside the clinic. This follow-up care could entail treatment at local 
drug-treatment clinics, other hospital-based treatment programs, or with private medical practitioners or 
therapists. After the study is completed, you will have the option to meet with your therapist weekly for up to 
a month until you have transitioned into the follow-up treatment.  
 
If you remain abstinent throughout the study, we strongly encourage you to continue treatment after study 
completion, and will work with you to help find another treatment provider. If you find difficult to remain 


BUP DISCO 
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4 
abstinent (e.g., have strong cravings) we will offer you an additional month of medication (Vivitrol injection 
or 30-day supply of buprenorphine) and we will provide you with referrals for Vivitrol, buprenorphine, 
methadone, and behavioral treatment options. You should know that when you are provided with referrals, 
both injection and oral forms of naltrexone are available in the community, as well as forms of therapy 
similar to, as well as more intensive than, the behavioral therapy offered in this study. In the event that you 
decide to discontinue from the study, or are withdrawn from the study, you will be treated with 
buprenorphine until you have been transitioned to another buprenorphine treatment program or provider.  
 
The doctors conducting this research study are also responsible for your clinical care. If during the course of 
the study, you have a medical emergency or require urgent medical care, the research medical staff will 
consult with your treating physician(s) regarding any information relevant to your medical care. In the event 
of an emergency or if you have questions while in the study, you can reach the clinic at (646)774-6174 
during regular business hours.  
 
V. 
Risks and Inconveniences  
 
You are entering this study because you have been doing well on buprenorphine, but would like to stop 
taking it. A significant risk of stopping medication like buprenorphine is that you may relapse to use of 
opioids. Relapse is dangerous in several ways including risk of overdose. If you change your mind at any 
point and want to resume buprenorphine, you should let the study staff know and buprenorphine can be 
resumed. As you are reducing the medication, or once you have stopped the medication, if you begin to 
experience cravings or to use opioids, it is important to seek help right away -i.e. let the study staff know 
right away, since medication like buprenorphine can be restarted and can protect you.  
 
Another serious risk of study participation is that after stopping buprenorphine you will lose tolerance to 
opioids and therefore the effects of heroin or another opioid on the body becomes much more potent at a 
lower dosage. This means that resuming use of opioids after detoxifying could cause you to overdose, stop 
breathing and die. If you complete the detoxification and receive injectable naltrexone monthly, it will help 
protect you against death due to opioid overdose by blocking the effects of the drug. However, if you stop 
taking naltrexone, restarting opioids could result in accidental overdose and/or death.  
 
Opioid detoxification carries a moderately high risk of relapse and overdose if you use a significant amount 
of opioids after losing tolerance. We seek to minimize these risks by monitoring you closely with urine drug 
tests and asking about any opioid use. If you do relapse, you will be given referrals for methadone or 
buprenorphine maintenance, or inpatient detoxification and follow-up treatment. There may be a delay of up 
to 2 weeks after your first screening clinic visit and before treatment begins.  
 
Naltrexone 
You will be given naltrexone while your body is still dependent on opioids, which can induce withdrawal 
symptoms. We will use very low doses of naltrexone at the beginning of treatment to minimize the severity 
of withdrawal and prepare your body for naltrexone injection. The withdrawal symptoms are treated with 
clonidine, clonazepam, trazodone, prochlorperazine and zolpidem, but despite their use you may experience 
significant discomfort. The side effects of these medications may include insomnia or possible sleepiness, 
lowered blood pressure which may produce dizziness or a tendency to feel faint, nausea, vomiting, diarrhea, 
muscle and abdominal cramping, irritability, anxiety, and an allergic reaction involving a narrowing of the 
airways in the lungs, similar to what people with asthma sometimes develop.  


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Once you have been stabilized on naltrexone it generally has few side effects. However, it can cause 
irritation to the liver or may occasionally cause or contribute to depressive symptoms. Additional side effects 
may include difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low 
energy, joint muscle pain, or headaches. It is important to note that these symptoms may represent persisting 
withdrawal symptoms, and the psychiatrist who is monitoring you can prescribe medications to reduce the 
discomfort.  
 
If you take small amounts of heroin or other opioids while on naltrexone, you should feel no opioid-like 
effects. However, it is possible to overpower naltrexone if you take large amounts of heroin or other 
opioids. Also, if you miss your Vivitrol injection, it is possible that you may be much more sensitive to 
opioids. This means that amounts of heroin or other opioids that you used to take routinely could 
cause you to overdose, stop breathing and die.  
Naltrexone does not block the effects of other drugs such as cocaine, tranquilizers, or alcohol, and it does not 
reduce the risks when using these substances, such as getting drunk or high.  
You should be aware that you may be more sensitive to the effects of heroin and other opioids upon 
completion of this study, and therefore would be at a greater risk for overdose. This increased sensitivity to 
opiates means that doses of heroin or other opiates that you used to take before entering treatment could be 
enough to cause you to stop breathing and die. Fentanyl and carfentanil are powerful synthetic opioids that 
can be added to heroin without your knowledge and this addition would further increase your risk of 
overdose.  
 
Naloxone Challenge Test 
 If you use opioids prior to receiving the Vivitrol injection, you may be given a naloxone challenge test to 
determine whether or not you are dependent on opioids. We may administer up to 0.8 mg naloxone 
intramuscularly (by injection), which – if you have recently used opioids -can produce a number of 
withdrawal symptoms. You may experience symptoms such as: sweating, restlessness, stomach pain, 
diarrhea, headache, anxiety, nausea, vomiting dizziness, runny nose, yawning, muscle aches, or tremors. We 
will monitor your reactions to naloxone for up to 45 min.  
 
 
Vivitrol  
Risks of Vivitrol are possible irritation (e.g., redness, swelling, possible scarring) or infection at the injection 
site. Injection site reactions have ranged from a small, painless area of hardness to pain, itching, redness, and 
swelling. These reactions have typically resolved spontaneously over a period of 1-3 weeks. Of the 1,000 
naltrexone injections we have administered, three to date caused site swelling and an open sore to develop, 
which became infected and required a minor surgical procedure, antibiotic treatment and wound care. The 
wound healed completely over a period of approximately 3 months, but resulted in a scar.  
Another study risk is that naltrexone may impair the functioning of your liver. Short-term increase of liver 
enzymes can occur, but this is usually reversible. This effect on your liver will resolve after naltrexone leaves 
your body. In addition, administration of naltrexone may increase blood sugar levels, which may produce 
symptoms such as dizziness, increased breathing, dehydration, and seizures. If you experience any of these 
symptoms, it is important that you tell the investigator immediately.  
 
In rare cases, patients who received injectable naltrexone reported developing a form of allergic pneumonia, 
experiencing shortness of breath. If you have trouble breathing, it is important that you let us know right 


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away. In patients treated with the naltrexone injection, we have also observed hives, an allergic reaction of 
the skin with redness and itching. If you develop any of these symptoms it is important to let us know.  
 
If you miss your visit to receive Vivitrol, and/or take opioids, you should come to the clinic immediately. 
There, you will be evaluated to determine if it is safe to restart the naltrexone. You may be asked to take an 
intramuscular injection of naloxone. If your body has become dependent on opioids, this dose will produce 
withdrawal symptoms lasting less than one hour. You may refuse the naloxone challenge but must be able to 
provide an opioid-negative urine or reconsider the challenge within 72 hours in order to determine whether 
you can safely restart naltrexone. If at this point, you are found to be dependent on opioids and unable to 
restart naltrexone, you will be provided with referrals to alternative treatment programs.  
It is very important that you tell your study physician about any other medications you are taking (either 
prescription or non-prescription) before beginning naltrexone. It is also very important that, during the course 
of the study, you tell your research psychiatrist about any other medications you are prescribed or plan to 
take to avoid possible adverse reactions.  
 
Buprenorphine  
When lowering daily doses of buprenorphine, you may experience withdrawal symptoms such as difficulty 
sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint muscle 
pain, headaches, or runny nose. You may also experience a rapid and sudden onset of withdrawal symptoms 
if you crush your take-home buprenorphine pills and inject or snort them. These symptoms would be very 
uncomfortable but short-lived and not life threatening. If this occurs, your psychiatrist would evaluate you 
and provide you with referrals to alternative treatment.  
 
Opioid medications, like buprenorphine, can interact with medicines, such as antidepressants and migraine 
medicines, meant to increase the effects of serotonin, a chemical in the brain. This interaction causes a 
serious response in the brain called serotonin syndrome. If you are taking an opioid along with a medicine 
that increases serotonin and develop symptoms such as agitation, hallucinations, rapid heart rate, fever, 
excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, and/or 
nausea, vomiting, or diarrhea, you should seek medical attention immediately. These symptoms generally 
start within several hours to a few days of taking an opioid with a medicine that increases the effects of 
serotonin in the brain, but symptoms may occur later, especially after either medication is increased in dose.  
 
Taking opioids may lead to a rare, but serious condition where not enough of the hormone called cortisol is 
produced, particularly during stressful conditions when cortisol is usually produced. Consult your study 
doctor or seek medical attention (ensure that you communicate that you are participating in a clinical trial) if 
you experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low 
blood pressure. Long-term use of opioid pain medications may lead to decreased sex hormones. Inform your 
study doctor if you experience signs or symptoms of low libido, impotence, erectile dysfunction, lack of 
menstruation, or infertility. 
 
Comfort Medications 
You will be given comfort medications to help manage your withdrawal during the detoxification. When you 
are taking the comfort medications (clonidine, clonazepam, prochlorperazine, and zolpidem), you should use 
caution when driving a vehicle or operating appliances or machinery. Only the most common risks of each 
comfort medication are highlighted below, so if you would like to learn more about the medications or their 
side effects, please ask your study doctor who can provide you with the Patient Information Sheets. These 
medications may cause some side effects such as sleepiness, lowered blood pressure (which may produce 


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dizziness or a tendency to feel faint), or upset stomach.  
 
Other Risks 
(For females) Both the detoxification procedure and outpatient naltrexone treatment may pose risk to a fetus. 
You will have a pregnancy test before beginning treatment and monthly thereafter to determine that you are 
not pregnant. You will be asked to use adequate birth control throughout your treatment such as: (a) any 
form of hormonal contraception such as Depo-Provera, daily oral contraceptive, transdermal patch or Nuva 
ring, (b) intra-uterine devices, (c) sterilization, or (d) double barrier contraception, which is a combination of 
any two of the following methods: condoms, spermicide, diaphragm. 
 
The only risk to the blood-drawing procedures used in this study is the possibility that slight discomfort 
and/or a small bruise or, rarely, a local infection may develop at the site of the needle puncture. This seldom 
occurs. If taking any medication orally, it is being dispensed to you in packages that are not childproof. Extra 
precautions need to be taken to keep the oral medication away from children.  
 
You will be carefully monitored throughout your participation to minimize the chance of any serious adverse 
side effects. We will provide you with any significant new findings that may develop during the course of the 
study, which may relate to your willingness to continue study participation. If you suspect that you might be 
pregnant, you must inform the study team immediately.  
 
VI. 
Benefits  
 
You may benefit directly from the treatment you receive with reduction in drug use and improvement in 
problems related to your drug use. The findings of the study may help doctors know more about how to treat 
opioid dependence and help others with this problem.  
 
VII. 
Confidentiality  
 
We will do everything we can to keep others from learning about your participation in the research. Your 
private information or biospecimens will only be used for the purposes of this research study, and will 
not be distributed to another investigator for future research studies. Any biospecimens that are 
collected as part of this research will not be used for commercial profit. To further help us protect your 
privacy, the investigators will obtain a Confidentiality Certificate from the Department of Health and Human 
Services (DHHS). With this Certificate, the investigators cannot be forced (for example, by court subpoena) 
to disclose information that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. Disclosure will be necessary, however, upon request of DHHS for the 
purpose of audit or evaluation. A Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research. Note 
however, that if an insurer, employer or other outside party, learns of your participation, and obtains your 
consent to receive research information, then the investigator may not use the Certificate of Confidentiality 
to withhold this information. This means that you and your family must also actively protect your own 
privacy. Finally, the Certificate does not prevent the researchers from reporting suspected or known neglect 
or sexual or physical abuse of a child, or threatened violence to self or others. Such information will be 
reported to the appropriate authorities.  
 
Records will be available to research staff, and to Federal, State and Institutional regulatory personnel (who 
may review records as part of routine audits). Your name and other personal identifying information will be 


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stored in an electronically secure database at New York Psychiatric Institute. Signed consent forms and other 
forms containing identifying information will be kept in a locked file, and all interviews, assessments, etc. 
will be coded with initials and numbers. Electronic data are also coded and are stored on computers that are 
password protected. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.  
 
VIII. 
Study Compensation  
 
During the study, you will receive $10 in cash to help pay for your transportation costs. You will have the 
chance to earn prizes for attending consecutive study visits. Each study visit will result in a draw from the 
prize bowl. Each draw has a chance of getting one of four outcomes: an encouraging statement (e.g. ‘good 
job’), a small prize valued at $2.50, a large prize valued at $20, or a jumbo prize valued at $100. The chance 
of winning a jumbo prize us (0.2 %), the large prize (8%), the small prize (42%), and 50% of the time you 
will get an encouraging statement. You will accumulate an additional draw for each consecutive visit made. 
If you miss a visit your draws will be reset. The maximum amount over 25 weeks you may potentially earn 
for attending all study visits is approximately $969 in cash prizes, and $190 in cash for transportation costs.  
 
We are required by law to report your earnings to the IRS. Therefore, your Social Security Number and 
amount earned will be reported, and you will receive the appropriate IRS form at the end of the year in which 
you were paid. Please note that payment for this study may affect your eligibility for Medicaid and other city 
and state support services. No information about which study you participated in will be provided to the IRS.  
 
IX. 
In Case of Injury  
 
Federal regulations require that we inform participants about our institution’s policy with regard to 
compensation and payment for treatment of research-related injuries. Please be aware that:  
1. The New York State Psychiatric Institute, Columbia University, Research  
Foundation for Mental Hygiene, and New York Presbyterian Hospital will furnish that emergency medical 
care determined to be necessary by the medical staff of this hospital.  
2. You will be responsible for the cost of such care, either personally or through your medical insurance or 
other form of medical coverage.  
3. No monetary compensation for wages lost as a result of injury will be paid to you by the New York State 
Psychiatric Institute, Columbia University, Research Foundation for Mental Hygiene, or by New York 
Presbyterian Hospital.  
4. By signing this consent form, you are not waiving any of your legal rights to seek compensation through 
the courts.  
 
 
 
 
 
 
 
 
 
 


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X. 
Questions  
 
The investigators will answer to the best of their abilities any questions you may have now or in the future 
about the study procedures or about your response to the procedures. You should contact the Principal 
Investigator, Dr. Adam Bisaga, at (646)744-6155 if you have any questions. If a medical emergency occurs 
at night or over the weekend, you should go to the nearest hospital emergency room and have them call 
(914)419-8921.If you have any questions about your rights as a research participant, want feedback, or have 
a complaint, you may call the NYSPI Institutional Review Board (IRB). An IRB is a committee that protects 
the rights of human subjects in research studies). You may call the IRB Main Office at (646) 774-7155 
during regular office hours.  
 
 
 
 
XI. 
Documentation of Consent for Screening 
 
I voluntarily agree to participate in the screening for the research study described above.  
 
Print name : ________________________________________________  
(Participant) 
 
Signed: __________________________________________Date: _________________  
I have discussed the proposed research with this participant including the risks, benefits, and alternatives to 
participation (including the alternative of not participating in the research). The participant has had an 
opportunity to ask questions and in my opinion is capable of freely consenting to participate in this research.  
 
Print name: _______________________________________________  
(Person Designated to Obtain Consent) 
 
 
Signed: ___________________________ Date: __________________  
 
 
Consent for Future Contact 
You permit the Opioid Treatment Research Program staff to contact you in the future. 
 
Print name : ________________________________________________  
(Participant) 
 
Signed: __________________________________________Date: _________________  
 
 
 
 
 
 


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XII. 
Documentation of Study Consent  
 
I voluntarily agree to participate in the research study described above.  
 
Print name: ________________________________________________  
(Participant) 
 
Signed: ______________________________________Date: ______________________  
 
 
I have discussed the proposed research with this participant including the risks, benefits, and alternatives to 
participation (including the alternative of not participating in the research). The participant has had an 
opportunity to ask questions and in my opinion is capable of freely consenting to participate in this research.  
 
 
Print name: _______________________________________________  
(Person Designated to Obtain Consent) 
 
 
 
Signed: ___________________________ Date: ________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ADDENDUM 1 
CONSENT FOR SIGNIFICANT OTHER CONTACT 
It may be important for the staff at the clinic to discuss your problems with a close family member or friend 
to assess how you are doing, to help contact you if you miss a visit, or in case of an emergency. By signing 
this page, you consent to allow the staff to contact the following person(s) to discuss your case throughout 
the course of your treatment. You may refuse to grant this permission, and it will not affect your eligibility 
for treatment in this study.  
Name:_______________________________________Relationship:__________________ 
Address:____________________________________________________________ 
Phone Numbers:______________________________________________________ 
Name:_______________________________________Relationship:__________________ 
Address:____________________________________________________________ 
Phone Numbers:______________________________________________________ 
Name:______________________________________________________________  
 
Significant other contact information refused:____  
Participant Signature:_______________________ Date____________  
 
Investigator Signature:_______________________ Date____________  
 


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NEW YORK STATE PSYCHIATRIC INSTITUTE COLUMBIA UNIVERSITY 
DEPARTMENT OF PSYCHIATRY 
 Informed Consent for Participation in Research  
 
A Strategy to Improve Success of Treatment Discontinuation in Buprenorphine Responders  
 
I. 
Purpose and Overview  
 
You are invited to participate in a research study because you are diagnosed with opioid use disorder, have 
been successfully treated with buprenorphine and would like to stop taking buprenorphine. The main purpose 
of this research study is to evaluate two methods of buprenorphine discontinuation: a standard method of a 
graduated taper compared to a rapid discontinuation and transition onto Vivitrol.  This study is funded by a 
grant from the National Institute on Drug Abuse (NIDA). 
 
Vivitrol is a long-acting injection that contains enough naltrexone to last up to one month; it is approved by 
the FDA for preventing relapse in those with opioid use disorder. It works by blocking the effects of opioids 
and reducing cravings, but is not a controlled substance and has no opioid-like effect itself. You are being 
asked to participate in this study because you are currently prescribed buprenorphine and meet other study 
entry criteria. If you are not eligible, you will be assisted in finding free or low-cost treatment services near 
your home. If you are eligible for the study, you will receive your current dose of buprenorphine for one 
month, and will be randomized to either a five-week gradual taper off buprenorphine, or a week long rapid 
taper followed by an injection of Vivitrol. You will receive individual therapy for 25 weeks, and if you have 
been randomized to receive Vivitrol, you will receive two additional injections.  
This study will also look at biomarkers, which are biological molecules found in blood, which 
can be used to see how well the body responds to treatment for opioid use disorder.  
 
II. 
Voluntary  
 
Participation in this research study is voluntary. If you decide not to participate, or if you later decide to stop 
participating, you will not lose any benefits to which you are otherwise entitled. A decision not to participate 
or withdraw your participation will not affect your current or future treatment at the New York State 
Psychiatric Institute or Columbia University Medical Center. You will be notified of significant new findings 
that may relate to your willingness to continue to participate.  
 
 
III. 
Alternative Treatments/Alternatives to Participation  
 
You do not need to participate in this research study to receive treatment for your opioid use disorder or to 
receive treatment with Vivitrol or buprenorphine. Other treatments are  
available, including methadone maintenance, buprenorphine maintenance, inpatient or other outpatient 
detoxification programs, and "drug-free" treatments including outpatient counseling or residential or 
therapeutic community treatment.  
 
 
 


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IV. 
Procedures  
Screening 
The study begins with a screening visit. The medical examinations and laboratory tests for screening 
may be done on one day or over multiple days. You and the study doctor will arrange those times. If 
you agree to be in this study, you will sign this form before any study procedures are done. 
In order to participate in the study you must first have a psychiatric and medical screening, which 
will include questions about your drug use, health, and other problems you may be having. 
Depending on the results of that, you may also have a cardiogram (a test to measure the electrical 
activity of your heart), blood tests, a physical exam, and a urine toxicology screen. After the initial 
screening visit(s), you will be told whether you may be eligible for this research treatment study. The 
screening process may take between a few days to a few weeks depending on the frequency of your 
visits. If you are not eligible, or if you are not interested in taking part in the research treatment, then 
the clinician will assist you in finding treatment for your problems elsewhere. 
If you are eligible for the study, you will come to the clinic once a week to receive your current dose of 
buprenorphine and for monitoring. At the end of this month you will be randomly assigned to one of two 
regimens of stopping buprenorphine: (Regimen 1) rapid discontinuation of buprenorphine followed by 
treatment with Vivitrol or (Regimen 2) a gradual taper off of buprenorphine.  
 
Regimen 1: Rapid Discontinuation + Vivitrol  
You will begin your outpatient visits to the clinic at the beginning of the week, and you will be asked to 
come to the clinic daily (5 visits, at least one hour each day) during this first week, in order to receive 
medications, naltrexone and other medications to reduce the discomfort of withdrawal from opioids. At each 
outpatient visit, you will need to provide an observed urine sample, which will be tested for opiates as well 
as other drugs.  You will have your blood pressure, heart rate, and rate of breathing checked by our staff.  
The anti-withdrawal medication you will receive include: clonidine (a medicine used to treat high blood 
pressure), clonazepam (for anxiety), prochlorperazine (anti-nausea drug), and zolpidem or trazodone (for 
insomnia). If you experience significant withdrawal while at the clinic, you will be strongly encouraged to 
remain at the clinic for observation, and you may receive additional doses of medications.  
 
If you are assigned to Regimen 1, you will be asked to stop taking buprenorphine and you will start taking 
medications to prevent withdrawal. Two days after the last dose of buprenorphine you will start taking 
naltrexone by mouth, first taking very low doses. If you do use buprenorphine or another opioid drug during 
this period, you may receive a naloxone challenge to determine whether it is safe to continue with the rest of 
the dosing schedule.  At the end of the first week, you will receive an intramuscular injection of Vivitrol, a 
long-acting form of naltrexone that lasts in your system for 3-4 weeks.  You will be asked to stay at the clinic 
for at least one hour after receiving this injection, for clinical observation.  
While at the clinic, you will have the opportunity to rest in a private room fitted with lounge chairs, 
adjustable lighting, and an entertainment system. Light snacks and sports drinks such as Gatorade will be 
available to keep you comfortable.  It is important to drink plenty of fluids. Clinical staff will determine any 
changes to your medication necessary for your well-being. The clinic staff will advise you on ways to 
minimize withdrawal symptoms, and you will also meet daily with a therapist who will provide you with 
counseling.  
 
You will be free to leave the clinic each day once you have received all necessary medication doses and have 
been evaluated for medical stability by the clinic nurse and/or psychiatrist. If you experience fatigue or 


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medication side effects, car transportation home will be provided to you. After you have received Vivitrol, 
you will continue to come to the clinic once a week to meet with a therapist and psychiatrist for 3 months, 
and twice-monthly during treatment months 4-6. You will also receive two additional injections of Vivitrol 4 
and 8 week after the first injection.  
 
Regimen 2: Gradual Taper  
If you are assigned to Regimen 2, you will continue receiving buprenorphine on a weekly basis for five 
weeks, with the dose of buprenorphine gradually decreasing to minimize any possible withdrawal. At the end 
of the taper buprenorphine will be stopped.  During this time we ask that you come to the clinic once a week 
so that staff can assess for withdrawal symptoms and so you can meet with a therapist and psychiatrist. After 
you have been tapered off buprenorphine you will continue to come to the clinic once a week to meet with a 
therapist and psychiatrist for 3 months, and twice-monthly during treatment months 4-6. 
 
Outpatient Treatment 
After stopping buprenorphine, you will continue to be monitored and receive counseling, regardless of the 
regimen you were assigned to. Your visits to the clinic should take between 30 and 60 minutes to meet with a 
counselor and research psychiatrist. These sessions will help you to work on your treatment goals and remain 
abstinent. During each visit, you will fill out several questionnaires and answer questions about your alcohol 
use and other drug use. You will also have your vital signs monitored at every visit. If during the course of 
treatment you resume taking opioids (buprenorphine, heroin or other opioids) and are unable to give an 
opioid-free urine, you will be provided with referrals to alternative treatment programs. If you use opioids 
during the study but are able to receive your next Vivitrol injection you will continue in the program.  
 
Approximately one tablespoon of blood will be drawn at the beginning and end of the study to check your 
liver enzymes. Additionally approximately six tablespoons blood, saliva and urine will be collected at the 
beginning and 3 times throughout the study to check for biochemical markers. You will be asked to give 
supervised urine at every visit to the program throughout the study. The urine samples are tested for drugs, 
and the purpose of this is to help monitor your progress. Results of the urine are discussed at counseling 
sessions. At the beginning, if your liver enzymes are elevated, we may test your blood to determine whether 
you have been infected with viral hepatitis (Hepatitis B, and Hepatitis C). We are required by law to report 
positive hepatitis test results to the Department of Health.  
If you are a woman, approximately one tablespoon of blood will be drawn to check for pregnancy before 
starting treatment. Also, since pregnant women may not participate in this research, women must practice an 
effective method of birth control until the end of the study. You will have a pregnancy urine test monthly.  
 
If you suffer from depression or anxiety, you will have the opportunity to receive therapy to address those 
symptoms. You will also be seeing a psychiatrist who can evaluate your symptoms and may be offered the 
option of taking an antidepressant or anti-anxiety medication.  
 
End of Study 
At the end of Week 25 you will be asked to meet for an hour with the psychiatrist to answer questions, have 
another physical examination and blood test, complete questionnaires, and receive referrals for further 
treatment as part of an aftercare plan outside the clinic. This follow-up care could entail treatment at local 
drug-treatment clinics, other hospital-based treatment programs, or with private medical practitioners or 
therapists. After the study is completed, you will have the option to meet with your therapist weekly for up to 
a month until you have transitioned into the follow-up treatment.  
 


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If you remain abstinent throughout the study, we strongly encourage you to continue treatment after study 
completion, and will work with you to help find another treatment provider. If you find difficult to remain 
abstinent (e.g., have strong cravings) we will offer you an additional month of medication (Vivitrol injection 
or 30-day supply of buprenorphine) and we will provide you with referrals for Vivitrol, buprenorphine, 
methadone, and behavioral treatment options. You should know that when you are provided with referrals, 
both injection and oral forms of naltrexone are available in the community, as well as forms of therapy 
similar to, as well as more intensive than, the behavioral therapy offered in this study. In the event that you 
decide to discontinue from the study, or are withdrawn from the study, you will be treated with 
buprenorphine until you have been transitioned to another buprenorphine treatment program or provider.  
 
The doctors conducting this research study are also responsible for your clinical care. If during the course of 
the study, you have a medical emergency or require urgent medical care, the research medical staff will 
consult with your treating physician(s) regarding any information relevant to your medical care. In the event 
of an emergency or if you have questions while in the study, you can reach the clinic at (646)774-6174 
during regular business hours.  
 
V. 
Risks and Inconveniences  
 
You are entering this study because you have been doing well on buprenorphine, but would like to stop 
taking it. A significant risk of stopping medication like buprenorphine is that you may relapse to use of 
opioids. Relapse is dangerous in several ways including risk of overdose. If you change your mind at any 
point and want to resume buprenorphine, you should let the study staff know and buprenorphine can be 
resumed. As you are reducing the medication, or once you have stopped the medication, if you begin to 
experience cravings or to use opioids, it is important to seek help right away -i.e. let the study staff know 
right away, since medication like buprenorphine can be restarted and can protect you.  
 
Another serious risk of study participation is that after stopping buprenorphine you will lose tolerance to 
opioids and therefore the effects of heroin or another opioid on the body becomes much more potent at a 
lower dosage. This means that resuming use of opioids after detoxifying could cause you to overdose, stop 
breathing and die. If you complete the detoxification and receive injectable naltrexone monthly, it will help 
protect you against death due to opioid overdose by blocking the effects of the drug. However, if you stop 
taking naltrexone, restarting opioids could result in accidental overdose and/or death.  
 
Opioid detoxification carries a moderately high risk of relapse and overdose if you use a significant amount 
of opioids after losing tolerance. We seek to minimize these risks by monitoring you closely with urine drug 
tests and asking about any opioid use. If you do relapse, you will be given referrals for methadone or 
buprenorphine maintenance, or inpatient detoxification and follow-up treatment. There may be a delay of up 
to 2 weeks after your first screening clinic visit and before treatment begins.  
 
Naltrexone 
You will be given naltrexone while your body is still dependent on opioids, which can induce withdrawal 
symptoms. We will use very low doses of naltrexone at the beginning of treatment to minimize the severity 
of withdrawal and prepare your body for naltrexone injection. The withdrawal symptoms are treated with 
clonidine, clonazepam, trazodone, prochlorperazine and zolpidem, but despite their use you may experience 
significant discomfort. The side effects of these medications may include insomnia or possible sleepiness, 
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muscle and abdominal cramping, irritability, anxiety, and an allergic reaction involving a narrowing of the 
airways in the lungs, similar to what people with asthma sometimes develop.  
 
Once you have been stabilized on naltrexone it generally has few side effects. However, it can cause 
irritation to the liver or may occasionally cause or contribute to depressive symptoms. Additional side effects 
may include difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low 
energy, joint muscle pain, or headaches. It is important to note that these symptoms may represent persisting 
withdrawal symptoms, and the psychiatrist who is monitoring you can prescribe medications to reduce the 
discomfort.  
 
If you take small amounts of heroin or other opioids while on naltrexone, you should feel no opioid-like 
effects. However, it is possible to overpower naltrexone if you take large amounts of heroin or other 
opioids. Also, if you miss your Vivitrol injection, it is possible that you may be much more sensitive to 
opioids. This means that amounts of heroin or other opioids that you used to take routinely could 
cause you to overdose, stop breathing and die.  
Naltrexone does not block the effects of other drugs such as cocaine, tranquilizers, or alcohol, and it does not 
reduce the risks when using these substances, such as getting drunk or high.  
You should be aware that you may be more sensitive to the effects of heroin and other opioids upon 
completion of this study, and therefore would be at a greater risk for overdose. This increased sensitivity to 
opiates means that doses of heroin or other opiates that you used to take before entering treatment could be 
enough to cause you to stop breathing and die. Fentanyl and carfentanil are powerful synthetic opioids that 
can be added to heroin without your knowledge and this addition would further increase your risk of 
overdose.  
 
Naloxone Challenge Test 
 If you use opioids prior to receiving the Vivitrol injection, you may be given a naloxone challenge test to 
determine whether or not you are dependent on opioids. We may administer up to 0.8 mg naloxone 
intramuscularly (by injection), which – if you have recently used opioids -can produce a number of 
withdrawal symptoms. You may experience symptoms such as: sweating, restlessness, stomach pain, 
diarrhea, headache, anxiety, nausea, vomiting dizziness, runny nose, yawning, muscle aches, or tremors. We 
will monitor your reactions to naloxone for up to 45 min.  
 
 
Vivitrol  
Risks of Vivitrol are possible irritation (e.g., redness, swelling, possible scarring) or infection at the injection 
site. Injection site reactions have ranged from a small, painless area of hardness to pain, itching, redness, and 
swelling. These reactions have typically resolved spontaneously over a period of 1-3 weeks. Of the 1,000 
naltrexone injections we have administered, three to date caused site swelling and an open sore to develop, 
which became infected and required a minor surgical procedure, antibiotic treatment and wound care. The 
wound healed completely over a period of approximately 3 months, but resulted in a scar.  
Another study risk is that naltrexone may impair the functioning of your liver. Short-term increase of liver 
enzymes can occur, but this is usually reversible. This effect on your liver will resolve after naltrexone leaves 
your body. In addition, administration of naltrexone may increase blood sugar levels, which may produce 
symptoms such as dizziness, increased breathing, dehydration, and seizures. If you experience any of these 
symptoms, it is important that you tell the investigator immediately.  
 


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In rare cases, patients who received injectable naltrexone reported developing a form of allergic pneumonia, 
experiencing shortness of breath. If you have trouble breathing, it is important that you let us know right 
away. In patients treated with the naltrexone injection, we have also observed hives, an allergic reaction of 
the skin with redness and itching. If you develop any of these symptoms it is important to let us know.  
 
If you miss your visit to receive Vivitrol, and/or take opioids, you should come to the clinic immediately. 
There, you will be evaluated to determine if it is safe to restart the naltrexone. You may be asked to take an 
intramuscular injection of naloxone. If your body has become dependent on opioids, this dose will produce 
withdrawal symptoms lasting less than one hour. You may refuse the naloxone challenge but must be able to 
provide an opioid-negative urine or reconsider the challenge within 72 hours in order to determine whether 
you can safely restart naltrexone. If at this point, you are found to be dependent on opioids and unable to 
restart naltrexone, you will be provided with referrals to alternative treatment programs.  
It is very important that you tell your study physician about any other medications you are taking (either 
prescription or non-prescription) before beginning naltrexone. It is also very important that, during the course 
of the study, you tell your research psychiatrist about any other medications you are prescribed or plan to 
take to avoid possible adverse reactions.  
 
Buprenorphine  
When lowering daily doses of buprenorphine, you may experience withdrawal symptoms such as difficulty 
sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint muscle 
pain, headaches, or runny nose. You may also experience a rapid and sudden onset of withdrawal symptoms 
if you crush your take-home buprenorphine pills and inject or snort them. These symptoms would be very 
uncomfortable but short-lived and not life threatening. If this occurs, your psychiatrist would evaluate you 
and provide you with referrals to alternative treatment.  
 
Opioid medications, like buprenorphine, can interact with medicines, such as antidepressants and migraine 
medicines, meant to increase the effects of serotonin, a chemical in the brain. This interaction causes a 
serious response in the brain called serotonin syndrome. If you are taking an opioid along with a medicine 
that increases serotonin and develop symptoms such as agitation, hallucinations, rapid heart rate, fever, 
excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, and/or 
nausea, vomiting, or diarrhea, you should seek medical attention immediately. These symptoms generally 
start within several hours to a few days of taking an opioid with a medicine that increases the effects of 
serotonin in the brain, but symptoms may occur later, especially after either medication is increased in dose.  
 
Taking opioids may lead to a rare, but serious condition where not enough of the hormone called cortisol is 
produced, particularly during stressful conditions when cortisol is usually produced. Consult your study 
doctor or seek medical attention (ensure that you communicate that you are participating in a clinical trial) if 
you experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low 
blood pressure. Long-term use of opioid pain medications may lead to decreased sex hormones. Inform your 
study doctor if you experience signs or symptoms of low libido, impotence, erectile dysfunction, lack of 
menstruation, or infertility. 
 
Comfort Medications 
You will be given comfort medications to help manage your withdrawal during the detoxification. When you 
are taking the comfort medications (clonidine, clonazepam, prochlorperazine, and zolpidem), you should use 
caution when driving a vehicle or operating appliances or machinery. Only the most common risks of each 
comfort medication are highlighted below, so if you would like to learn more about the medications or their 


BUP DISCO 
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7 
side effects, please ask your study doctor who can provide you with the Patient Information Sheets. These 
medications may cause some side effects such as sleepiness, lowered blood pressure (which may produce 
dizziness or a tendency to feel faint), or upset stomach.  
 
Other Risks 
(For females) Both the detoxification procedure and outpatient naltrexone treatment may pose risk to a fetus. 
You will have a pregnancy test before beginning treatment and monthly thereafter to determine that you are 
not pregnant. You will be asked to use adequate birth control throughout your treatment such as: (a) any 
form of hormonal contraception such as Depo-Provera, daily oral contraceptive, transdermal patch or Nuva 
ring, (b) intra-uterine devices, (c) sterilization, or (d) double barrier contraception, which is a combination of 
any two of the following methods: condoms, spermicide, diaphragm. 
 
The only risk to the blood-drawing procedures used in this study is the possibility that slight discomfort 
and/or a small bruise or, rarely, a local infection may develop at the site of the needle puncture. This seldom 
occurs. If taking any medication orally, it is being dispensed to you in packages that are not childproof. Extra 
precautions need to be taken to keep the oral medication away from children.  
 
You will be carefully monitored throughout your participation to minimize the chance of any serious adverse 
side effects. We will provide you with any significant new findings that may develop during the course of the 
study, which may relate to your willingness to continue study participation. If you suspect that you might be 
pregnant, you must inform the study team immediately.  
 
VI. 
Benefits  
 
You may benefit directly from the treatment you receive with reduction in drug use and improvement in 
problems related to your drug use. The findings of the study may help doctors know more about how to treat 
opioid dependence and help others with this problem.  
 
VII. 
Confidentiality  
 
We will do everything we can to keep others from learning about your participation in the research. Your 
private information or biospecimens will only be used for the purposes of this research study, and will not be 
distributed to another investigator for future research studies. Any biospecimens that are collected as part of 
this research will not be used for commercial profit. To further help us protect your privacy, the investigators 
will obtain a Confidentiality Certificate from the Department of Health and Human Services (DHHS). With 
this Certificate, the investigators cannot be forced (for example, by court subpoena) to disclose information 
that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings. Disclosure will be necessary, however, upon request of DHHS for the purpose of audit or 
evaluation. A Certificate of Confidentiality does not prevent you or a member of your family from 
voluntarily releasing information about yourself or your involvement in this research. Note however, that if 
an insurer, employer or other outside party, learns of your participation, and obtains your consent to receive 
research information, then the investigator may not use the Certificate of Confidentiality to withhold this 
information. This means that you and your family must also actively protect your own privacy. Finally, the 
Certificate does not prevent the researchers from reporting suspected or known neglect or sexual or physical 
abuse of a child, or threatened violence to self or others. Such information will be reported to the appropriate 
authorities.  
 


BUP DISCO 
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8 
Records will be available to research staff, and to Federal, State and Institutional regulatory personnel (who 
may review records as part of routine audits). Your name and other personal identifying information will be 
stored in an electronically secure database at New York Psychiatric Institute. Signed consent forms and other 
forms containing identifying information will be kept in a locked file, and all interviews, assessments, etc. 
will be coded with initials and numbers. Electronic data are also coded and are stored on computers that are 
password protected. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.  
 
VIII. 
Study Compensation  
 
During the study, you will receive $10 in cash to help pay for your transportation costs. You will have the 
chance to earn prizes for attending consecutive study visits. Each study visit will result in a draw from the 
prize bowl. Each draw has a chance of getting one of four outcomes: an encouraging statement (e.g. ‘good 
job’), a small prize valued at $2.50, a large prize valued at $20, or a jumbo prize valued at $100. The chance 
of winning a jumbo prize us (0.2 %), the large prize (8%), the small prize (42%), and 50% of the time you 
will get an encouraging statement. You will accumulate an additional draw for each consecutive visit made. 
If you miss a visit your draws will be reset. The maximum amount over 25 weeks you may potentially earn 
for attending all study visits is approximately $969 in cash prizes, and $190 in cash for transportation costs.  
 
We are required by law to report your earnings to the IRS. Therefore, your Social Security Number and 
amount earned will be reported, and you will receive the appropriate IRS form at the end of the year in which 
you were paid. Please note that payment for this study may affect your eligibility for Medicaid and other city 
and state support services. No information about which study you participated in will be provided to the IRS.  
 
IX. 
In Case of Injury  
 
Federal regulations require that we inform participants about our institution’s policy with regard to 
compensation and payment for treatment of research-related injuries. Please be aware that:  
1. The New York State Psychiatric Institute, Columbia University, Research  
Foundation for Mental Hygiene, and New York Presbyterian Hospital will furnish that emergency medical 
care determined to be necessary by the medical staff of this hospital.  
2. You will be responsible for the cost of such care, either personally or through your medical insurance or 
other form of medical coverage.  
3. No monetary compensation for wages lost as a result of injury will be paid to you by the New York State 
Psychiatric Institute, Columbia University, Research Foundation for Mental Hygiene, or by New York 
Presbyterian Hospital.  
4. By signing this consent form, you are not waiving any of your legal rights to seek compensation through 
the courts.  
 
 
 
 
 
 
 
 


BUP DISCO 
Version 04.02.19 
 
9 
 
 
X. 
Questions  
 
The investigators will answer to the best of their abilities any questions you may have now or in the future 
about the study procedures or about your response to the procedures. You should contact the Principal 
Investigator, Dr. Adam Bisaga, at (646)744-6155 if you have any questions. If a medical emergency occurs 
at night or over the weekend, you should go to the nearest hospital emergency room and have them call 
(914)419-8921.If you have any questions about your rights as a research participant, want feedback, or have 
a complaint, you may call the NYSPI Institutional Review Board (IRB). An IRB is a committee that protects 
the rights of human subjects in research studies). You may call the IRB Main Office at (646) 774-7155 
during regular office hours.  
 
 
 
 
XI. 
Documentation of Consent for Screening 
 
I voluntarily agree to participate in the screening for the research study described above.  
 
Print name : ________________________________________________  
(Participant) 
 
Signed: __________________________________________Date: _________________  
I have discussed the proposed research with this participant including the risks, benefits, and alternatives to 
participation (including the alternative of not participating in the research). The participant has had an 
opportunity to ask questions and in my opinion is capable of freely consenting to participate in this research.  
 
Print name: _______________________________________________  
(Person Designated to Obtain Consent) 
 
 
Signed: ___________________________ Date: __________________  
 
 
Consent for Future Contact 
You permit the Opioid Treatment Research Program staff to contact you in the future. 
 
Print name : ________________________________________________  
(Participant) 
 
Signed: __________________________________________Date: _________________  
 
 
 
 


BUP DISCO 
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10
 
 
 
 
 
XII. 
Documentation of Study Consent  
 
I voluntarily agree to participate in the research study described above.  
 
Print name: ________________________________________________  
(Participant) 
 
Signed: ______________________________________Date: ______________________  
 
 
I have discussed the proposed research with this participant including the risks, benefits, and alternatives to 
participation (including the alternative of not participating in the research). The participant has had an 
opportunity to ask questions and in my opinion is capable of freely consenting to participate in this research.  
 
 
Print name: _______________________________________________  
(Person Designated to Obtain Consent) 
 
 
 
Signed: ___________________________ Date: ________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BUP DISCO 
Version 04.02.19 
 
11
 
 
 
 
 
ADDENDUM 1 
CONSENT FOR SIGNIFICANT OTHER CONTACT 
It may be important for the staff at the clinic to discuss your problems with a close family member or friend 
to assess how you are doing, to help contact you if you miss a visit, or in case of an emergency. By signing 
this page, you consent to allow the staff to contact the following person(s) to discuss your case throughout 
the course of your treatment. You may refuse to grant this permission, and it will not affect your eligibility 
for treatment in this study.  
Name:_______________________________________Relationship:__________________ 
Address:____________________________________________________________ 
Phone Numbers:______________________________________________________ 
Name:_______________________________________Relationship:__________________ 
Address:____________________________________________________________ 
Phone Numbers:______________________________________________________ 
Name:______________________________________________________________  
 
Significant other contact information refused:____  
Participant Signature:_______________________ Date____________  
 
Investigator Signature:_______________________ Date____________  
 


Form #PP2: HIPAA Authorization for Research 4.14.14 
New York State Psychiatric Institute (NYSPI) 
Authorization to Use or Disclose Health Information during a Research Study 
Protocol Number: 
Principal Investigator: 
Name of Study: 
Before researchers can use or share any identifiable health information (“Health Information”) about you as part of the 
above study (the “Research”), the New York State Psychiatric Institute (NYSPI) is required to obtain your authorization. You agree 
to allow the following individuals and entities to use and disclose Health Information about you as described below: 
•
New York State Psychiatric Institute (NYSPI), your doctors and other health care providers, if any, and
•
The Principal Investigator and his/her staff (together “Researchers”).   Researchers may include staff of NYSPI, the New York
State Office of Mental Health (OMH), Research Foundation for Mental Hygiene, Inc. (RFMH), and Columbia University (CU),
provided such staff is a part of the study, and
•
Providers of services for the Research at CU, NYSPI and/or RFMH, such as MRI or PET, or  Central Reference Laboratories 
(NKI), if indicated in the consent form.
1.
The Health Information that may be used and/or disclosed for this Research includes:
All information collected during the Research as told to you in the Informed Consent Form.   
Health Information in your clinical research record which includes the results of physical exams, medical and 
psychiatric history, laboratory or diagnostic tests, or Health Information relating to a particular condition that is related  to 
the Research. 
Additional information may include: 
2.
The Health Information listed above may be disclosed to:
Researchers and their staff at the following organizations involved with this Research: 
The Sponsor of the Research, 
and its agents and contractors (together, “Sponsor”); and  
Representatives of regulatory and government agencies, institutional review boards, representatives of the Researchers 
and their institutions to the level needed to carry out their responsibilities related to the conduct of the research.   
Private laboratories and other persons and organizations that analyze your health information in connection with 
this study 
Other (family members or significant others, study buddies, outside agencies etc.) Specify: 
3.
By giving permission to release your Health Information as described above, you understand that your Health
Information may be disclosed to individuals or entities which are not required to comply with the federal and state privacy laws
which govern the use and disclosure of personal Health Information by NYSPI.   This means that once your Health
Laboratory Corporation of America 


National Institute on Drug Abuse (NIDA)



A Strategy to Improve Success of Treatment Discontinuation in Buprenorphine Responders 
Adam Bisaga M.D.
7522 


Form #PP2: HIPAA Authorization for Research 4.1.14 
Information has been disclosed to a third party which does not have to follow these laws (e.g., a drug company or the Sponsor 
of the Research), it may no longer be protected under the HIPAA or NYS Mental Hygiene Law requirements but is subject to the 
terms of the consent form and may be subject to other state or federal privacy laws or regulations.  
4.
Please note that:
•
You do not have to sign this Authorization form, but if you do not, you may not be able to participate in the study or
receive study related care.  You may change your mind at any time and for any reason. If you do so, you may no
longer be allowed to participate in the study.  If you withdraw this Authorization the research staff and the Sponsor, if this
is sponsored research, may still use or disclose Health Information containing identifying information they already have
collected about you as needed to maintain the reliability of the research.  Any request to withdraw this Authorization
must be made in writing to (enter name and contact information below):
•
While the Research is going on, you may not be allowed to review the Health Information in your clinical research
record that has been created or collected by NYSPI.   When this research has been completed you may be allowed to see
this information.  If it is needed for your care, your Health Information will be given to you or your Doctor.
5.
This Authorization does not have an end date.
6.
You will be given a copy of this form after you have signed it.
I agree to the use and disclosure of Health Information about me as described above: 
__________________________________________                _____________________ 
Signature of Participant/ Legal Representative    
Date 
______________________________________ 
Printed Name of Participant 
______________________________________ 
Relationship of Legal Representative to Participant (if applicable) 
We also ask you or your legal representative to initial the statements below: 
I have received a copy of the NYSPI/OMH Notice of Privacy Practices. 
Adam Bisaga, MD, NYSPI, 1051 Riverside Dr. Unit 66 New York, NY 10032

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
A Strategy to Improve the Success of 
Treatment Discontinuation 
Buprenorphine Responders 
1R21DA042243 
Principal Investigator:  
Adam Bisaga M.D. 
Medical Monitor 
Edward Nunes M.D.  
 
 
Detailed Data and Safety Monitoring Plan 
 
November 15, 2017 
 
 
 


DSM Plan 
Treatment Discontinuation in Buprenorphine Responders 
 
Page 2 of 19 
 
 
 
 
TABLE OF CONTENT 
 
A. PROTOCOL SUMMARY .......................................................................................................... 3 
A1. 
Brief description of the protocol (Study Design) ................................................................. 3 
A2. 
Primary and Secondary Outcome Measures ........................................................................ 4 
A3. 
Inclusion/Exclusion Criteria ................................................................................................ 4 
A4. 
Power calculation and sample size ...................................................................................... 6 
B. TRIAL MANAGEMENT ........................................................................................................... 6 
B1. 
Data Collection Centers ....................................................................................................... 7 
B2. 
Projected Time Table ........................................................................................................... 7 
B3. 
Target Population Distribution ............................................................................................ 7 
C. DATA MANAGEMENT AND ANALYSIS .............................................................................. 7 
C1. 
Data Acquisition and Transmission ..................................................................................... 7 
C2.       Data Entry Methods……………………….………………………………………………8 
C3. 
Data Analysis Plan ............................................................................................................... 9 
D. QUALITY ASSURANCE ........................................................................................................... 9 
D1. 
Procedures in place to ensure the validity and integrity of the data ..................................... 9 
D2. 
Procedures to guarantee the accuracy and completeness of the data, during data 
collection, entry, transmission, and analysis ................................................................................... 9 
E. REGULATORY ISSUES ......................................................................................................... 10 
E1. 
Reporting of Adverse Events ............................................................................................. 10 
E2.      Reporting of IRB actions to NIDA .................................................................................... 10 
E3.      Trial stopping rules ............................................................................................................ 10 
E4.      Disclosure of any potential conflict of interest .................................................................. 10 
F. TRIAL SAFETY ....................................................................................................................... 11 
F1. 
Potential Risks and Benefits of Study Participation .......................................................... 11 
F2.       Collection and Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) 13 
F3. 
Management of SAEs and other study risks ...................................................................... 15 
G. TRIAL EFFICACY .................................................................................................................. 18 
H. DATA AND SAFETY MONITORING PLAN ADMINISTRATION .................................. 18 
H1. 
Responsibility for data and safety monitoring ................................................................... 18 
H2. 
Frequency of DSM ............................................................................................................. 18 
H3. 
Content of DSM report ...................................................................................................... 18 
I. 
DSM BOARD PLAN ................................................................................................................. 19 


DSM Plan 
Treatment Discontinuation in Buprenorphine Responders 
Page 3 of 19 
 
 
A. PROTOCOL SUMMARY  
A1. 
Brief description of the protocol (Study Design) 
The number of individuals with Opioid Use Disorder (OUD) continues to rise with more than 2.5 million 
affected, along with substantial morbidity and mortality. Several effective medications are available to treat 
OUD with buprenorphine becoming the primary medication used in the community. Buprenorphine is 
effective for approximately 50-70% of patients and better results are achieved with the longer duration of 
treatment. However, the prospect of long-term opioid maintenance is not acceptable to some patients and they 
eventually request to stop treatment or discontinue it on their own. As many patients who had good treatment 
response desire to discontinue the medication there is a need to collect evidence about the best strategy to 
accomplish that. Opioid receptor antagonist naltrexone is approved for relapse prevention following 
detoxification off opioids. Naltrexone can be started as a first-line treatment following discontinuation off 
illicit opioids and it may also be used as an adjunct for patients who wish to discontinue buprenorphine 
maintenance and would like to be protected from relapse. We propose an open-label randomized outpatient 
trial to evaluate feasibility and efficacy of rapid buprenorphine discontinuation followed by brief course of 
treatment with long-acting naltrexone (XR-NTX) and to compare it to the standard method of gradual 
buprenorphine taper. 
Individuals with OUD (N=60) who have successfully completed at least 6 months of buprenorphine treatment 
and do not wish to remain in a long-term buprenorphine maintenance program will be recruited. The first 
phase includes a 4-week period of stabilization on buprenorphine 2-8 mg at the research clinic to assure that 
patients are stable, compliant, and free from illicit opioids. Participants that meet the above criteria, 
approximately 50 individuals, will be randomized 1:1 to: Regimen 1) buprenorphine discontinuation and 
outpatient transition to XR-NTX with 3 monthly injections, or Regimen 2) buprenorphine discontinuation 
using a gradual, 5-week long taper. In both groups participants will receive weekly relapse prevention therapy 
and will be monitored for the duration of the trial, which is 25 weeks post randomization.  
Regimen 1 will include a rapid Monday to Friday oral naltrexone-induction procedure: last dose of BUP on 
Sat, Sun-Mon 0 mg, Tue 1 mg, Wed 3 mg, Thu 6 mg dose of oral NTX respectively. On Friday, a final 25 mg 
dose of oral NTX will be given followed by an injection of XR-NTX (Vivitrol; 380 mg IM). All doses of oral 
NTX will be given in a single or split doses depending on patients’ tolerability of the protocol. Throughout 
the induction adjuvant medications will be administered on standing basis: clonidine 0.1 mg qid, clonazepam 
0.5 mg qid, and zolpidem 10 mg HS. Participants will be seen in the clinic daily where they will be monitored 
for up to 8 hours.  
Additional injections of XR-NTX will be administered 4 and 8 weeks after the first injection to participants 
who provide an opioid-negative urine or pass a naloxone challenge test. 
Regimen 2 will include a 5-week BUP taper from the maintenance dose of 8, 6, 4, or 2mg (wk 1: 6, 5, 3 
or 2 mg/d, wk 2: 4, 4 , 2, or 2 mg/d, wk 3: 3, 3, 2, or 1 mg/d, wk 4: 2 or 1 mg/d, wk 5: 1 mg/d). A 
buprenorphine/naloxone generic product will be used.  
Participants in both regimens will be seen in the clinic for 25 weeks for follow-up after randomization, which 
will include both the week induction onto Vivitrol in Regimen 1 and the 5 week buprenorphine taper in 
Regimen 2. 
Additional injections of XR-NTX will be offered to patients who continue to express interest in remaining on 
the medication and are adherent to the time scheduled for the injection (4 weeks after the prior injection). In 
participants who use opioids and test positive, study physician will determine if it is safe to proceed with the 
next injection, which may involve administration of naloxone (0.8 mg im).  
Outpatient Study Visits and Assessments will occur weekly during the period of BUP maintenance and taper 
to ensure adherence and to monitor for abstinence. Study visits will take place daily during XR-NTX 
induction and weekly following injection of XR-NTX or BUP taper in both regimens for the remainder of the 
study period. Once per week participants will meet with a therapist and complete study assessments. At each 


DSM Plan 
Treatment Discontinuation in Buprenorphine Responders 
 
Page 4 of 19 
 
 
 
study visits vitals and a urine toxicology for opioids (morphine, oxycodone, buprenorphine, methadone, 
propoxyphene, and fentanyl), THC, cocaine, benzodiazepines, amphetamines, and metamphetamines will be 
collected. They will have scheduled meetings with a study psychiatrist weekly to inquire about medication 
effects and any changes in their medical/psychological condition following medication discontinuation. 
The primary outcome will be the percent of patients successfully transitioned off buprenorphine and abstinent 
from any opioids at the 25-week trial endpoint. Secondary outcomes will include measures of opioid 
withdrawal, mood, anxiety and sleep problems, abstinence from other substances, time to relapse or dropout, 
and adverse effects. We hypothesize that more patients will successfully discontinue buprenorphine in the 
group that received XR-NTX.  
This proposed exploratory trial will be able to inform the design of future research and clinical work. A 
positive signal that transition from maintenance buprenorphine to XR-NTX is feasible and prevents relapse 
would encourage a larger trial to replicate and perhaps extend to multiple community based treatment settings. 
A feasible, well-tolerated, and effective method of helping patients wishing to discontinue treatment with 
BUP has the potential to expand the population of opioid-dependent individuals benefitting from treatment. 
 
A2. 
Primary and Secondary Outcome Measures  
Primary Outcome: percent of patients successfully transitioned off buprenorphine and abstinent from any 
opioids at the 25-week trial endpoint. 
Secondary Outcomes: 1) Measures of weekly opiate withdrawal (SOWS), mood (Ham-D, BDI), anxiety 
(HAM-A, STAI), and sleep (MOS-SS) (continuous, longitudinal); 2) Time to relapse (survival outcome); 3) 
Continuing abstinence at 12 and 25 weeks (dichotomous); 4) Dichotomous weekly summary measure of use 
(derived by combining urine and self-report, as measured by TLFB) reflecting whether each patient had 
urine-confirmed opiate-free weeks over the course of treatment and urine-confirmed abstinence from all 
drugs (dichotomous, longitudinal); 5) Adverse events (SAFTEE) (dichotomous). 
Covariates/Predictor variables: 1) Length of BUP treatment prior to randomization and the average dose; 2) 
Demographic characteristics (e.g., gender, age); 3) Baseline presence of co-occurring mood or anxiety 
disorders; 4) Baseline severity of opioid use (measured by the primary opioid, route, and quantity of illicit 
opioid use per using day prior to starting BUP treatment); 5) Duration of OUD, 6) Other substance use 
during treatment period. 
  
A3. 
Inclusion/Exclusion Criteria 
The following inclusion/exclusion criteria will be used for selection of participants in the proposed study. 
 
Inclusion Criteria 
Method of Ascertainment 
1.  Individuals between the ages of 18-60 
ID with birth date 
2.  A documented history of treatment with 
buprenorphine or buprenorphine/naloxone 
for at least 6 months with sustained 
abstinence from illicit opioids for at least 
3 months. Participants must be 
maintained on daily dose of 
buprenorphine in the 2-8 mg range. 
MINI interview by therapist, Clinical interview 
by psychiatrist, consultation with previous 
prescriber or the verification patient's self-report 
with the prescribing records (PMP) with patient's 
permission 


DSM Plan 
Treatment Discontinuation in Buprenorphine Responders 
Page 5 of 19 
 
 
3.  In otherwise good health based on 
complete medical history, physical 
examination, vital signs measurement, 
ECG, and laboratory tests (hematology, 
blood chemistry, urinalysis) within 
normal ranges 
Medical history and physical examination by 
psychiatrist or NP, laboratory tests (serum Chem-
20 and CBC, urinalysis), ECG 
4.  Seeking buprenorphine discontinuation 
and willing to accept randomization to 
either taper from buprenorphine or 
injection naltrexone 
Clinical interview by psychiatrist 
5.  Able to give written informed consent 
to participate in the study 
Clinical Interview by psychiatrist 
 
Exclusion Criteria 
Method of Ascertainment 
1. Lifetime history of DSM-5 diagnosis of 
schizophrenia, schizoaffective disorder, 
or bipolar disorder 
MINI interview by therapist, Clinical interview 
by psychiatrist 
2.  Current DSM-5 criteria for any other 
psychiatric disorder that in the 
investigator’s judgment is unstable, 
would be disrupted by the study 
medication, or is likely to require 
pharmacotherapy or psychotherapy 
during the study period.  
      Concurrent treatment with other 
psychotropic medication that is stable 
for the last 3 months is not 
exclusionary. 
MINI interview by therapist, Clinical interview 
and mental status exam by psychiatrist, contact 
with collateral information as needed and 
available 
3. Individuals who meet DSM-5 criteria for 
any substance use disorder other than 
opioid, nicotine, and alcohol use disorder. 
Physiological dependence on alcohol is 
exclusionary. periods, blackouts)  
MINI interview by therapist, Clinical interview 
by psychiatrist 
 
4.   A recent history of binge-use of alcohol or 
sedative-hypnotics (using large amounts 
in a short time to severe intoxication or 
blackouts).  
Clinical interview by psychiatrist 
 
5. Pregnancy, lactation, or failure to use 
adequate contraceptive method in female 
patients who are currently engaging in 
sexual activity with men 
Clinical interview by psychiatrist, physical 
examination and medical history by psychiatrist 
or NP, urine pregnancy test, serum HCG 
6.  Unstable medical conditions, such as 
AIDS, cancer, uncontrolled hypertension 
(blood pressure > 140/90), uncontrolled 
diabetes, pulmonary hypertension or 
heart disease 
Medical history and physical examination by 
psychiatrist or NP, laboratory tests (serum Chem-
20 and CBC, urinalysis), ECG 


DSM Plan 
Treatment Discontinuation in Buprenorphine Responders 
 
Page 6 of 19 
 
 
 
7.  Legally mandated to participate in a 
substance use disorder treatment program 
Participant self-report, Clinical interview by 
psychiatrist 
8. Current or recent history of significant 
violent or suicidal behavior, risk for 
suicide or homicide 
Participant self-report, Clinical interview by 
psychiatrist, C-SSRS “yes” answers on questions 
5 and/or 4 
8. Currently meets DSM-5 diagnosis for an 
eating disorder or is underweight (BMI 
<18.5) 
MINI interview by therapist, Clinical interview 
by psychiatrist 
9. History of accidental opioid overdose in 
the last year defined as an episode of 
opioid-induced unconsciousness, whether 
or not medical treatment was sought or 
received. 
MINI interview by therapist, Clinical interview 
by psychiatrist 
10.  Elevated liver function tests (AST and 
ALT > 3 times the upper limit of normal) 
or impaired renal function (GFR<60 
ml/min) 
Laboratory tests (serum Chem-20) 
11. Known history of allergy, intolerance, or 
hypersensitivity to naltrexone or any other 
study medications 
Participant self-report, Clinical interview by 
psychiatrist 
 
    A4. Power calculation and sample size 
The primary purpose of this proposed R21 is to estimate the 95% confidence interval (CI) for  
the treatment effect size, in this case the odds ratios of treatment success. The resulting 95% CIs provide 
considerably more information than hypothesis tests; it provides a range of plausible parameter 
estimates.  Such range of effect sizes (especially the estimates from the lower end of the 95% CIs) can be 
used to conservatively estimate potential effect size in larger clinical trials. The following power 
calculations are only in support of this study proposal and for the purpose of sample size calculation. We 
assume that the observed proportion of successful BUP discontinuation in the buprenorphine taper group 
ranges from 30-50% (we assume higher success rate than in the previous buprenorphine taper studies due 
to longer period of stabilization). With 25 subjects in each arm, we have 80% power to detect a significant 
treatment success difference of 37% (e.g. 40% of treatment success in BUP compared to 77% treatment 
success in XR-NTX arm) on 5% level of significance. This is a robust effect that would be clinically 
meaningful. 
The primary aim of this pilot study is to evaluate feasibility, tolerability, acceptability, and safety of two 
methods of discontinuing treatment with buprenorphine. The proposed sample size of 60 enrolled and 50 
individuals randomized to two treatment arms can provide useful information for subsequent confirmatory 
clinical trial. We have chosen this sample size to minimize the cost and also to reach the study end within 
two years. 50 randomized subjects will provide large enough sample size to estimate the potential effect 
size in 95% confidence interval with reasonable precision.  
 
 
B. TRIAL MANAGEMENT  


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    B1. Data Collection Centers 
All data will be collected at one site: New York State Psychiatric Institute’s Outpatient Substance Abuse 
Research Service (STARS)-downtown at 3 Columbus Circle, New York, NY 10019. In our center, we 
have adopted StudyTrax, a comprehensive electronic system for clinical trials, which we will use to collect 
and manage data. As many entry forms and study calendars are already programmed, starting of a study 
can be expedited. Data will be analyzed using SPSS-PC, SAS, and HLM. 
 
    B2. Projected Time Table 
Based on the recent rate of recruitment in our center and the planned sample size the study is estimated to 
take 24 months to complete. 
 
    B3. Target Population Distribution 
We plan to enroll 60 participants into the study.  Both males and females will be recruited.  All eligible 
subjects are accepted; however, past experience with recruitment for other studies in this population, it is 
estimated that the sample will be 75% male, 60% Caucasian, 30% Hispanic or Latino, and 10% Black or 
African-American. These proportions are consistent with the clinical population of heroin or prescription 
opioid users in the city of New York and participants that we recruited in our recent treatment studies. We 
will make every effort to recruit minority patients in order to ensure the generalizability of our findings to 
the overall treatment population. 
 
 
C. DATA MANAGEMENT AND ANALYSIS  
     C1. Data Acquisition and Transmission 
Potential subjects will undergo a screening visit which will include a demographics questionnaire, medical 
history, physical examination, psychiatric evaluation, laboratory testing, and electrocardiogram. The MINI 
International Neuropsychiatric Interview will be conducted to determine current DSM-5 diagnoses. 
Eligible participants will be offered the opportunity to participate in the research treatment study and 
informed consent using the IRB-approved consent form will be obtained by the research psychiatrist. 
This is an open-label randomized outpatient trial to evaluate feasibility and efficacy of a new strategy that 
involves rapid discontinuation of the maintenance buprenorphine dose followed by a brief course of 
treatment with XR-NTX and to compare it to the standard method of gradual buprenorphine taper. All 
patients will be followed for 25 weeks to evaluate longer-term outcomes. This is an exploratory study to 
collect evidence that could be used in designing a definitive efficacy trial.  
The study will be entirely outpatient. Upon study entry, participants will begin clinic visits at the 
Substance Treatment and Research Service (STARS) clinic. All participants will visit the clinic twice 
weekly to provide urine toxicology, report on adverse events, and complete additional assessments (Table 
1). All participants will also receive medical management, a medication adherence focused psychosocial 
intervention that facilitates compliance with study medication and other study procedures, and promotes 
abstinence from opioids and other substances. 
All data will be obtained specifically for research purposes. Data will be entered and maintained in the 
clinical trials electronic database coded with a unique identifier assigned to each participant. Departmental, 
HIPPA-compliant Research Subject Registration System, will however contain participants’ names. 
 


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     C2.  Data Entry Methods 
Data collection will be achieved using a structured, integrated, network-based computerized system. 
Specifically, data management will include: 1) protocol management; 2) patient scheduling; 3) regulatory 
reporting and 4) management of research organizations, personnel, and collaborators. The research staff 
will collect and input data on a daily, basis to reduce the likelihood of errors. Information collection and 
analysis and study-specific data collection will be easily retrievable, organized, and reviewed on an 
ongoing basis as well. 
 


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C3. Data Analysis Plan 
Study Aim #1: To estimate the difference in the rate of successful transition off BUP at 25 weeks post 
randomization between the group that received naltrexone post-buprenorphine and the one that did not. We 
hypothesize that more patients will be transitioned off BUP and stable at the end of trial in the group that 
received XR-NTX. 
Study Aim #2: To determine whether treatment with XR-NTX reduces severity of protracted withdrawal 
seen following BUP discontinuation.  
Significance testing and preliminary analysis:  
All tests for main effects will be performed at two-tailed significance α=5%. We will examine all variables 
for outliers, the distributions of all continuous variables will be checked for normality and if needed 
transformations will be used before applying parametric techniques. The distribution of demographic 
variables and other covariate measures at baseline in the treatment arms will be examined (means, standard 
deviations, proportions and 95% confidence intervals). The analysis will be adjusted by three preselected 
covariates (primary opioid type, length of BUP maintenance, and average dose).  
Primary Analyses  
Subjects treated with XR-NTX will have significantly higher rates of successful transition off BUP at the 
end of study compared to subjects tapered off BUP. The effect of treatment on the primary outcome will be 
examined using logistic regression adjusted for specified covariates (primary opioid type, length of BUP 
maintenance, and average dose), and described using the estimated coefficients of the treatment term in the 
model, the corresponding odds ratios, and 95% confidence intervals. 
Secondary Analyses 
Longitudinal dichotomous and continuous outcomes will be modeled with generalized linear mixed effects 
models using appropriate link function (logit for dichotomous outcomes) with treatment, time, treatment by 
time interaction, and applicable baseline outcome measure as predictors. Time to relapse will be analyzed 
using survival analyses and Kaplan-Meier estimators. Dichotomous outcomes will be analyzed similarly to 
primary hypothesis with logistic regressions. The within subject correlation will be modeled using 
autoregressive AR(1) structure and random effects of subject. Significant time by treatment interaction 
indicates different change over time between treatment groups. If the interaction between time and 
treatment is not found to be significant, the interaction term will be omitted and an overall treatment effect 
will be tested. 
 
D. QUALITY ASSURANCE 
D1. Procedures in place to ensure the validity and integrity of the data 
In order to assure that collected data is valid, all raters undergo an extensive training process prior to 
beginning independent assessments. This involves an initial period when a trainee is a witness to 
evaluations and ratings conducted by an experienced rater. Subsequently trainees will conduct a series of 
evaluations and ratings in the presence of the trainer until a desired proficiency is obtained. Finally, all 
junior raters  will  take  part  in  ongoing  individual  and  group  research  supervision  meetings  where 
evaluation done by a trainee are presented and discussed with senior research staff. 
 
D2. Procedures to guarantee the accuracy and completeness of the data, during data collection, 
entry, transmission, and analysis 
In order to maximize data quality, all ratings and notes will be checked for completeness and accuracy and 
errors or queries are brought back to the raters for correction or clarification the same day or as soon as 
possible thereafter. The clinic has a Quality Assurance person who is responsible for ongoing quality 


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assurance. Every three months, the PI will review the number of participants enrolled, the number who 
completed the protocol, the number who dropped out of the protocol prior to completion (and reason why), 
any adverse events, procedures for assuring participant privacy and confidentiality, and the quality and 
integrity of the data collected. Corrective action will be taken if needed. The Quality Assurance team of the 
New York State Psychiatric Institute also provides semi-annual reviews of all studies to ensure completeness 
of data, and compliance with administrative procedures. This team regularly reports their findings to the IRB, 
and may prevent continuing approval for a study that is shown to have defective documentation of 
procedures. 
 
E. REGULATORY ISSUES  
E1. Reporting of Adverse Events 
All adverse events (AE) reported  by  the  participant  or  observed  by  the  investigator  will  be individually 
listed on the Adverse Event Form (AEF). The signs and symptoms, time of onset, duration, severity, medical 
intervention, follow-up procedures, and suspected relationship to study drug will be reported. Any AE 
(clinical signs and symptoms or laboratory test) associated with the use of study drug, whether or not 
considered drug related, will be documented by the study psychiatrist. 
All AE reports will be reviewed weekly by the clinical research staff, including Dr. Nunes, study Medical 
Monitor and Dr. Mariani, the medical director at STARS, and other staff physicians. If necessary, changes to 
the protocol or consent form to address risks suggested by the AEs will be made. Subsequently these will be 
reported to the Psychiatric Institute IRB. 
In the event of any “serious” and/or “unexpected” adverse drug experiences, the Psychiatric Institute IRB, 
NIDA, and the Food and Drug Administration will be notified within 48 hours. In addition, all serious 
adverse events are reported to the Data and Safety Monitoring Board (DSMB). The DSMB, together with 
Drs. Bisaga and Nunes, will determine whether the seriousness of the event warrants removal of any 
participant from the study. 
 
E2.    Reporting of IRB actions to NIDA 
All proposed changes/amendments to the protocol will be discussed with the NIDA Project Officer prior to 
IRB submission. Amendments will then be filed with the IRB. IRB approval of such amendments and 
updated DSM Plan will be forwarded to the NIDA project officer, and the original amendment approvals will 
be filed in the primary document manual. 
All major IRB actions related to the protocol, will be reported to NIDA via email to the Project Officer (PO) 
Dr. Ann Anderson and the Science Officer (SO) Dr. Tanya Ramey within 48 hours. This communication will 
include a copy of the original communication from the IRB. Reportable actions of the IRB include the initial 
study approval, annual approvals for continuation, approvals of the proposed protocol amendments, and IRB 
responses to the SAE reports. 
 
E3.    Trial stopping rules 
The study Data and Safety Monitoring Board may decide to recommend stopping the trial if there is an 
indication that a substantial proportion of participants are not able to tolerate study medication or if there is 
an unusually high proportion of individuals experiencing SAEs. This may be determined during weekly 
meetings with Dr. Bisaga (PI), Dr. Nunes (MM), and the other study investigators and discussed with  
NIDA’s PO and SO. 
 
E4.    Disclosure of any potential conflict of interest 
Any potential conflict of interest (COI) is reviewed regularly by the IRB.  


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F. TRIAL SAFETY 
F1. Potential Risks and Benefits of Study Participation 
Side Effects, Risks, and Interactions of Buprenorphine 
Buprenorphine has been associated with adverse effects typical of opioid agonist drugs (e.g. sedation, 
constipation, insomnia, headache, nausea), although as a partial agonist such effects are typically less 
pronounced than they would be with a full agonist. The most common adverse event associated with the 
sublingual administration is oral hypoesthesia. Other adverse events were constipation, headache, 
intoxication, disturbance in attention, palpitations, insomnia, sweating, and blurred vision. Buprenorphine by 
itself has little tendency to suppress respiration and is associated with a low risk of overdose, a safety 
advantage. However, there is a risk of overdose if buprenorphine is combined with sedative drugs such as 
benzodiazepines or alcohol, analogous to the risk of combining such sedating medications with a full agonist 
like methadone. As a partial agonist, buprenorphine can precipitate an acute opioid withdrawal reaction if 
taken within 12--18 hours of another short-acting full opioid agonist, or within 48-72 hours of a longer-acting 
full opioid such as methadone. 
Discontinuation of buprenorphine is associated with relapse to use of opioids and risk of overdose. 
Participants who discontinued BUP will be monitored closely for signs of destabilization such as increase in 
cravings, or opioid use initiation. Participants who are unable to maintain abstinence off opioids will be 
offered resumption of maintenance treatment with buprenorphine, and once stable will be transferred to a 
provider in the community.   
Discontinuation of buprenorphine is associated with opioid withdrawal symptoms ranging from mild-
moderate to more severe reactions. Study physicians have extensive experience, in both research and clinical 
settings, in administering buprenorphine and in the management of opioid withdrawal symptoms. The use of 
buprenorphine is also associated with the risk of using the medication for the purposes of intoxication. In the 
present study we will use buprenorphine/naloxone combination product, which has lower abuse liability. If 
sublingual buprenorphine is used parenterally, there is a risk of precipitated opioid withdrawal. Such an 
event, if it were to occur, would be short--lived and not life threatening. Participants will be warned of this 
risk and advised not to use the medication in this manner. If it is determined that patients have been abusing 
their buprenorphine in such a manner, they will be declared to have failed BUP discontinuation, and a new 
treatment plan will be developed by the patient’s clinical team, with possibilities including transfer to 
naltrexone or methadone maintenance.  
To minimize the risk of diversion, medication will be dispensed for short time intervals (1-2 weeks of 
medication at a time). Buprenorphine is metabolized principally by CYP3A4. Co--administration of other 
CYP3A4 inhibitors (e.g. anti-retrovirals efavirenz, delavirdine, atazanavir or atazanavir/ritonavir; the anti-
fungal agent ketoconazole; antibiotics erythromycin or clarithromycin) may cause an increase in systemic 
levels of buprenorphine, although this does not usually have clinically significant effects. When a patient 
being prescribed buprenorphine is also receiving other medications, the prescribing physician will check for 
potential interactions ahead of time and monitor during treatment. 
 
Side Effects of Extended-Release (XR), Injectable Naltrexone 
The most common side effect associated with injectable naltrexone is injection site reaction.  XR-naltrexone 
is administered as a gluteal intramuscular injection and injection site reactions, mostly pain, and occurs in 
approximately 5% of patients in opioid treatment studies. These reactions are generally mild and include 
pain, tenderness, indurations, bruising, pruritus and swelling. Generally these reactions last 1--3 days. Rare 
skin reactions at the site of the injection have been reported, including sterile abscesses, which may relate to 
inadvertent injection into fatty tissue, rather than muscle. Patients will be informed of this risk, and baseline 
physical evaluation will include examination of the buttock for excessive adiposity. If a patient is examined 
by a physician and found to have an abscess, necrosis, cellulitis or extensive swelling, an appropriate surgical 
referral will be made. 


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Naltrexone has been associated with reversible hepatocellular injury indicated by elevated liver enzymes 
when administered at doses substantially greater than the 380 mg im per month, dose recommended for 
relapse prevention treatment of opiate dependence and proposed for the present study. When used in the 
recommended dose range in opiate--dependent patients, this risk is remote (Brahen et al., 1988; Brewer and 
Wong, 2004). 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 three times the upper 
limit of normal are excluded. Injectable naltrexone achieves higher blood levels 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 long-acting preparation, where the naltrexone would be only very slowly eliminated, 
this would prolong exposure to the offending agent. However, the experience with injectable naltrexone also 
suggests it is safe. In our studies with extended--release naltrexone several patients experienced elevation in 
liver enzymes, which were determined to be related to hepatitis C. In the proposed study we will use a long--
acting, injectable preparation of naltrexone (Vivitrol 380 mg). Several recent reports have documented that 
naltrexone pose significantly lower risk of hepatotoxicity than previously suspected, even among alcohol-- 
and opioid-dependent persons including those with HCV and/or HIV infection (Lucey et al., 2008; Mitchell 
et al., 2012; Tetrault et al., 2012; Vagenas et al., 2014). These reports were used to support decision taken by 
FDA in July of 2013 to remove the Boxed Warning on the hepatotoxicity. Other adverse events seen most 
frequently in association with XR--naltrexone treatment for opioid dependence include nasopharingitis, 
insomnia and toothache (Vivitrol; Package Insert). 
During the outpatient phase of the study, if a patient misses scheduled injection of Vivitrol and resumes 
regular opiate use, then receiving injectable naltrexone will precipitate opiate withdrawal, which may be 
quite severe in proportion to the time since the last injection and the level of opiate dependence. The 
physician will evaluate the patient and perform a naloxone challenge test to determine whether or not 
naltrexone can be safely resumed. If the naloxone challenge is positive (withdrawal is precipitated), then the 
patient will be removed from the study and offered another treatment option, such as resumption of 
maintenance treatment with buprenorphine or with methadone according to clinical judgment and the 
patient’s preferences. 
Self-administration of large doses of opiates may over-ride the blockade produced by naltrexone resulting in 
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 at treatment outset and during treatment, when receiving subsequent 
naltrexone injections. Patients who self-administer opiates to the point of somnolence or stupor will be 
removed from the trial and placed back on buprenorphine or referred to inpatient unit for stabilization. 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. 
 
Risks of the Rapid Naltrexone Induction Procedure 
In this procedure withdrawal is then precipitated through administration of oral naltrexone and 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 adjunctive medications. In the proposed protocol the risk of severe withdrawal has 
been minimized by starting naltrexone at the very low dose. Opiate withdrawal causes agitation, elevated 
pulse and blood pressure and other signs of sympathetic arousal, and sometimes confusion. Clonidine may 
produce somnolence or hypotension. Clonazepam commonly may produce somnolence. The procedure is 
contraindicated in patients with unstable medical problems or histories of hypersensitivity to any of the 
medications used, and these are exclusions in the proposed study. The procedure is conducted in the 
outpatient setting that permits close monitoring of vital signs and mental status for up to 8 hours daily.  
 
 


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Pregnancy 
Buprenorphine and naltrexone are Pregnancy category C agents, although the safety of buprenorphine in 
pregnancy has been supported in clinical trials (Jones et al., 2010). Female participants will be required to use 
adequate methods of birth control (condom with spermicide, diaphragm with spermicide, birth control pills) 
to be included in the study and will be strongly encouraged to use more effective methods like a subdermal 
implant, IUD, or a depot contraceptive injection. Serum pregnancy tests will be evaluated at baseline and 
urine for pregnancy will be tested as clinically indicated during treatment according to standard clinical 
procedures. If a female patient does become pregnant she will be withdrawn from study medication and 
offered continuing treatment with methadone or buprenorphine, which remains the current treatment of 
choice for pregnant opioid dependent patients. 
 
Randomization to injection naltrexone or buprenorphine taper 
The implications of random assignment to treatment conditions will be discussed with patients. One of the 
treatments could be more or less effective for a given patient. The alternative choices of continuing 
buprenorphine maintenance outside of the study or injection naltrexone, detoxification and counseling 
without medication (so called “drug-free” treatment), will be discussed with patients, as well as options of 
pursuing such treatments at other treatment programs available to the patients in the New York area. These 
will be discussed with patients at the time of consent, and revisited if relapse occurs. Patients will also be 
informed, and reminded that the study is voluntary and that they can opt for any of these options at any point 
during the study. 
 
Assessments 
The structured interviews, rating scales, and questionnaires should add no physical risk. However, because 
many of the interviews and assessments are time-consuming to complete and involve topics of a sensitive 
nature, some people have found them to be physically or emotionally tiring. Patients are informed prior to 
study entry that they can refuse to answer any questions and that they can request to stop at any time. If a 
participant becomes agitated during any of the interviews or assessments, he or she will be provided with 
therapeutic assistance. 
 
Other Risks 
Blood draws may cause slight discomfort at the site of needle entry, can result in infection at the site if 
hygienic/sterile techniques aren't used, or can result in a small bruise. 
Participants will receive cash card compensation and incentives during the study that could pose a risk of 
providing more available funds to purchase illicit opioids. However, the form of compensation- a cash card 
limits this risk. 
 
Potential Benefits of the Proposed Research 
Participants will receive up to 25 weeks of free treatment. 
 
F2. Collection and Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) 
Definitions 
An adverse event is any unwanted experience or event occurring during the course of a clinical trial. An 
adverse event is defined as unexpected whenever the nature and severity of the event is not consistent with 
the known product information. 
 
Relationship to Study Drug 
The investigator will document his/her opinion of the relationship of the event to the study drug as follows: 


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None- the event can be readily explained by the participant’s underlying medical condition or concomitant 
therapy, and no relationship exists between the study drug and the event. In this event, an alternative 
etiology must be indicated. 
Unlikely-the temporal relationship between the event and the administration of the study drug is uncertain 
and the event can be probably explained by the participant’s medical condition or other therapies. 
Possible- there is some temporal relationship between the event and the administration of the study drug 
and the event cannot be explained by the participant’s medical condition or other therapies. 
Probable- the temporal relationship is compelling between the administration of the study drug and the 
event cannot be explained by the participant’s medical condition or other therapies. 
 
Severity 
Adverse events should be graded for severity and noted in the description of the event. A severity category 
of mild, moderate or severe, as defined below, should be determined and entered on the appropriated AEF. 
Mild- causing no limitation of usual activities.  
Moderate- causing some limitation of usual activities.  
Severe- causing inability to carry out usual activities  
 
Definition of Serious Adverse Event (SAE) 
An SAE is any AE, occurring at any dose and regardless of causality that:  
• 
Results in death 
• 
Is life-threatening; the subject is at immediate risk of death from the reaction as it occurs.  
• 
Is significantly or permanently disabling or incapacitating;  
• 
Requires or prolongs inpatient hospitalization;  
• 
Results in permanent disability; results in a congenital anomaly;  
Significant medical events that may not result in death, be immediately life threatening, or require 
hospitalization may be considered to be SAEs when, based on the medical judgment, they may jeopardize 
the participant and may require intervention to prevent one of the outcomes defined above as SAE.     
 
Reporting of Serious or Unexpected Adverse Events 
In the event of any “serious” and/or “unexpected” adverse drug experiences during this study, the 
Principal Investigator will notify the following: 
Amy Bennett-Staub, Department of Quality Management New York State Psychiatric Institute 1051 
Riverside Drive, Unit 101 New York, NY 10032 
In addition to the report to quality management, relevant data on the event and any available follow-up 
reports will be reported to NIDA’s Project Officer Dr. Ann Anderson via email and also via using the 
Serious Adverse Event Tracking and Reporting System (SAETRS) within 72 hours of the event 
occurrence. The initial notification will indicate that the event occurred and the IRB/DSMB was notified. 
The PI will follow-up with the PO as the evaluation of the SAE proceeds, on whether the SAE was related 
or not to the trial.  These follow-ups will occur as the evaluation moves forward, and not wait until the 
final conclusions are determined. 
The Investigator will also provide written notification of the SAE to the IRB. The Incident Review 
Committee will also review the SAE and suggest appropriate actions and, if necessary, study 
modifications. 
The DSMB and study PI will determine whether the seriousness of the event warrants removal of any 
participant from the study. Appropriate diagnostic and therapeutic measures will be instituted and the 
participant will be kept under observation for as long as is medically indicated. IRB actions following the 


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occurrence of an SAE will be reported to NIDA. Any conflict of interest in the data and safety monitoring 
will be disclosed. The SAEs and AEs will be reviewed by the DSMB on a regular basis. 
 
F3. Management of SAEs and other study risks 
Procedures for Minimizing Risks: 
   1) Screening Procedures 
In order to minimize the risk associated with the study, subjects undergo a comprehensive medical and 
psychiatric evaluation during the screening procedure. The baseline medical evaluation consists of a 
physical examination, blood chemistry profile (including liver function tests), complete blood count, 
urinalysis, serum pregnancy test, urine toxicology and is designed, along with the clinical history, to detect 
chronic and/or unstable medical illnesses. A comprehensive psychiatric assessment is performed during the 
screening process, and is intended to detect and assess all past and current psychiatric disorders. The 
eligibility criteria (see above) are designed to minimize the medical and psychiatric risks to participants by 
excluding those for whom participation would place them at an increased risk. Special attention will be 
given to patient's concurrent use of medications. Participants on medications that meet exclusion criteria 
will not be included in the study. If participants have recently completed another study at STARS, we will 
ensure, as with other medications, that there are no drug-drug interactions with the possible recent 
exposure to other study medications or will ensure proper time for wash-out between studies. 
   2) Study Procedures 
Participants will be informed about the possible side effects and risks (listed above) of taking 
buprenorphine and extended-release naltrexone both alone and in combination with other medications 
through extensive discussions with staff psychiatrist during the consent process. Participants will be told to 
contact the clinic if they experience any adverse effects and given the number for the 24-hr physician on-
call. Participants' mental status and physical health are monitored weekly during the study period by a 
psychiatrist. Vital signs will be obtained at each study visit. At clinic visits, a physician will assess 
participants for signs and symptoms of adverse effects of study medications, noting which if any 
symptoms are present, the severity of the symptoms, make adjustments to study medication dose, 
discontinue study medication, or withdraw the participant from the study if needed.  
Female participants who are engaging in sexual activity with men must use adequate methods of 
contraception which will be discussed repeatedly during the screening process. Serum pregnancy tests will 
be conducted during screening and urine pregnancy tests will be performed monthly during the study. If a 
female participant does become pregnant or wishes to become pregnant, study medication will be 
immediately discontinued, she will be withdrawn from the study, and offered continuing non-
pharmacological treatment (psychotherapy). 
3) Procedures to Minimize Other Risks: 
With regards to the risks of blood draws, only staff trained in phlebotomy will draw blood from participants 
to minimize risks of infection. Participants will be warned of the possible associated discomfort and slight 
bruising following blood draws. They can decline blood draws at any time.  
We aim to reduce the risk of using cash card reimbursements and incentives to buy drugs by keeping 
reimbursements at a low monetary value. The monetary incentives for completion of study related activities 
are felt to be modest, appropriate, and limited and also in card form. This payment schedule has been used 
successfully in treatment studies in our clinic and others with no observed effect of increased drug use. 
With regards to risks associated with interviews, rating scales, and questionnaires, patients are informed 
that they may refuse to answer any questions and may ask to stop at any time. If participants become upset 
during the interviews/assessments, assistance will be made available to them. 
   4) Relapse during outpatient naltrexone induction 


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During the detoxification phase of the study, particularly during washout day and during first few days when 
naltrexone is introduced if a patient resumes regular opiate, including buprenorphine, use then taking 
naltrexone, particularly naltrexone injection, may precipitate opiate withdrawal, which may be severe. 
Patients will be warned not to take the naltrexone if they resumed any level of opiate use, and opiate 
abstinence will be confirmed by urine toxicology prior to administering the next daily dose of naltrexone. 
5) Procedures for Missed Doses of Long-acting Naltrexone: Missing a scheduled Vivitrol 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, or 
as soon as possible thereafter, based on clinical judgement ( i.e., after a clinical assessment and naloxone 
challenge if indicated). If the patient cannot attend the treatment clinic within that 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 Vivitrol injection, a naloxone challenge will be administered to confirm that the 
next long-acting naltrexone injection will be safely tolerated. 
6) Relapse during post-medication follow-up phase 
It is possible that some patients may have difficulty remaining abstinent after XR-NTX or buprenorphine 
are discontinued. All participants will be monitored closely during the follow-up period for signs of 
destabilization such as increase in cravings, or opioid use initiation. Participants who are unable to maintain 
abstinence off opioids will be offered resumption of maintenance treatment with buprenorphine, and once 
stable will be transferred to a provider in the community.  
 
Psychiatric Monitoring and Removal from Study 
Participants’ mental and physical status is monitored weekly by the physician. The psychiatrist will assess 
appropriateness for continuation in the research study on a continuous basis, and will remove from the trial 
patients with significant clinical deterioration or noncompliance of a type that could be dangerous. Although 
unlikely, it is possible that patients may become psychotic or depressed, requiring discontinuation of study 
medication, and possibly psychiatric intervention. The weekly monitoring of patients, along with ongoing 
evaluations with structured assessments, such as the Hamilton Depression Scale, should allow us to detect 
these psychiatric disturbances early and intervene appropriately. 
Although a patient might potentially attempt to overdose with buprenorphine, individuals who are at 
significant risk for suicidality will be excluded. Further, buprenorphine is a partial agonist and has a ceiling 
effect on respiratory depression; overdoses involving sublingual buprenorphine are rare and typically involve 
taking of toxic amounts of alcohol or benzodiazepines in combination with buprenorphine. Patients will be 
provided with a 1--2 weeks supply of buprenorphine throughout the study at a time. 
 
Patient Education 
All patients will be informed through the consent process and consent form and discussions with the research 
psychiatrist of the possible side effects and risks enumerated above. In addition, at weekly visits the research 
nurse or psychiatrist will query about side effects and treatment emergent symptoms. Patients will be warned 
that risks, as yet unknown, may occur when combining study medication with opioids or with other street 
drugs or alcohol. 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. One of 
the study-- affiliated physicians is on call 24 hours per day to answer questions and handle clinical 
emergencies. 
 
 


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Opioid Overdose Responder Training  
The Substance Abuse Treatment and Research Service (STARS) is a registered opioid overdose prevention 
program through the New York State Department of Health since June 2015. Our program is in 
compliance with 10 NYCRR 80.138 that permit non-patient specific prescriptions for naloxone, as well as 
shared access to and use of naloxone by appropriately trained individuals. As part of this program we offer 
free intranasal naloxone and training for overdose responders to any patient who self-identifies as an 
opioid user. 
 
Significant Other Contact 
Upon entry to the study, the participant is informed that, if s/he agrees, the staff would prefer to have the 
contact information of someone who knows them well, to periodically assess how they are doing or to aid in 
case of emergency. Providing this information is not contingent on participating in the study. The participant, 
if he or she agrees, will then inform the individual that they may be contacted by the study staff. Only after 
the participant has informed the individual about the possible contact by the staff will the contact information 
be provided and the consent form addendum be signed. 
 
Study Discontinuation 
Criteria for removal from the study will include: 
(1) substantial alcohol and other drug use that endangers the patient or requires a higher level of care such as 
inpatient or residential treatment; (2) psychiatric or medical deterioration that cannot be managed safely in 
the context outpatient treatment offered at the study clinics (e.g., acute suicide risk, acute medical 
problems); (3) Ongoing non-adherence with recommended clinical visits, absence from the clinic for more 
than 21 days; and (4) Pregnancy.  
Patients who are exited from the trial for any reason will be offered a continued treatment in the community 
unless a higher level of care is indicated (inpatient or residential treatment), or the patient requests treatment 
elsewhere, in which care help with arranging referrals will be offered. Participants will be offer a weekly 
supply of buprenorphine for up to 30 days if they are being transitioned to another treatment program if they 
are removed from the trial. A clinic staff member, with physician backup, is available 24 hours per day by 
phone in case of emergency. 
Participants may be removed from the trial if they repeatedly miss scheduled appointments or clinical 
worsening necessitates more intensive treatment (drop out criteria are defined above). Subjects who 
develop serious psychiatric symptomatology (e.g., psychosis, suicidal ideation, severe depressive 
symptoms) during the study period will be dropped from the study and appropriate clinical referrals will be 
made. A patient who’s continued opioid use, places them at risk for self-destructive behavior or otherwise 
places them at significant risk will be discontinued from the study. This would include, but not be limited 
to, patients who become unconscious after using, engage in destructive or violent behavior while 
intoxicated, report driving while intoxicated, or develop medical complications from their opioid use. In all 
cases where subjects are discontinued from the study, the clinical research staff will assume clinical 
responsibility for the subjects until clinical referrals are operational. 
In case that the patient is removed from the research trial for medical reasons, or is requesting withdrawal 
from the study, he/she will be retained in open treatment for the remaining study period. Upon removal of a 
patient from the trial due to clinical deterioration, the patient will be referred for appropriate follow-up 
treatment, in most instances either intensive outpatient or residential treatment. The PI or a study 
psychiatrist is available 24 hours/day by phone and/or beeper in case of emergency. 
If a patient is discontinued from the study, or decides to withdraw, or relapses during study the 
participation, the patient will get treated with buprenorphine until they are linked with a referral for 
continuing buprenorphine treatment. Participants will receive a one-week supply of buprenorphine at a 
time during the transition process.  


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 Management of SAE’s  
Serious adverse events (SAEs), as defined by the FDA, will be systematically evaluated at each clinic visit. 
Any SAE, whether or not related to study medication, will be reported to the IRB and NIDA. The initial 
SAE report will be followed by submission of a completed SAE report to both institutions. 
In the event that a patient either withdraws from the study or the investigator decides to discontinue a 
patient due to SAE, the patient will have appropriate follow-up medical monitoring. Monitoring will 
continue until the problem requiring hospitalization has resolved or stabilized with no further change 
expected, is clearly unrelated to study medication, or results in death. Outcome of SAEs will be reported to 
NIDA as soon as this information becomes available. A summary of the SAEs that occurred during the 
previous year will be included in the annual progress report to NIDA. 
 
G. TRIAL EFFICACY 
Interim analyses are not planned for this study. 
 
H. DATA AND SAFETY MONITORING PLAN ADMINISTRATION  
H1. Responsibility for data and safety monitoring 
The study Principal Investigator, Dr. Adam Bisaga, is primarily responsible for the data and safety 
monitoring. He will be assisted by Dr. Edward Nunes, study Medical Monitor, and other STARS staff 
physicians. 
 
H2. Frequency of DSM 
Ongoing data and safety monitoring will be conducted weekly during research meetings. Every three 
months, the PI and the medical monitor will review the number of patients enrolled, the number who 
completed the protocol, the number who dropped out of the protocol prior to completion (and reason why), 
any adverse events, procedures for assuring patient privacy and confidentiality, and the quality and 
integrity of the data collected. Corrective action will be taken if needed.  IRB protocols and informed 
consent documents will be reviewed annually by the IRB. Reports of enrollment and retention and 
reporting of adverse events are required with these renewals. In addition, all studies involving human 
subjects are periodically and systematically reviewed by the New York State Quality Assurance Staff. 
These procedures assure protocol compliance by conducting unannounced reviews of participants' research 
charts, comparing research charts to the IRB protocol. All serious adverse events will be reported to the 
DSMB in a timely fashion. This report will also be forwarded to the NIDA’s Project Staff Dr. Ann 
Anderson (PO) upon receipt. 
In addition, a separate Data Safety and Monitoring Board (DSMB; see below for details) will meet yearly. 
H3. Content of DSM report 
Annually, the DSMB will prepare and submit a report to NIDA. This report will include the following: 
1. Brief description of the trial 
2. Baseline socio-demographic characteristics 
3. Retention and disposition of study participants 
4. Q.A. Issues 
5. Regulatory Issues 
6. AEs 
7. SAEs 
8. Efficacy 


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I. DSM BOARD PLAN 
 
The proposed study will have a Data Safety and Monitoring Board (DSMB), that will be chaired by Dr. 
Frances Levin, a Division Chief, and will include Dr. Herbert Kleber, a senior investigator in the Division, 
and Dr. John Mariani who is a Director of the research clinic. In addition, Dr. Erik Gunderson, an 
experienced investigator based in the University of Virginia School of Medicine, who published research 
involving buprenorphine maintenance, will join the DSMB. The DSMB will meet before the study launch 
and annually afterwards to conduct initial and ongoing study review and review all Adverse Events that 
occurred in the study. The DSMB will meet within a week of the occurrence of any Serious Adverse Event 
(SAE). For each SAE, the Principal Investigator and covering physician will present a synopsis of how it 
occurred and how the incident was handled clinically. In this way the team can assess how the event was 
managed and if there are any recommendations that will maintain the high quality of the care that we 
provide to our research participants. All DSMB members will be ask to submit in writing any potential 
conflict of interest pertaining to the study. DSMB will prepare a report to NIDA in response to any SAE 
review meetings, and will submit a DSM report annually (as outlined above in section H3).