Clinical trial NCT04218240
Conditions: Opioid Withdrawal
Sponsor: University of Pennsylvania
Start date: 2020-12-17; Completion date: 2023-08-31
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A phase II double-blind placebo-controlled parallel group clinical trial that will randomize 90 subjects to investigate whether pregabalin (PGB) combined with Lofexidine (LFX) can reduce opioid withdrawal-related subjective effects, and investigate, whether the PGB/LFX combination can increase the proportion of patients with an opioid use disorder (OUD) who complete detoxification and transition to antagonist treatment with extended-release injectable naltrexone (XR-NTX).

Detailed description:
An inpatient detoxification study where pregabalin (PBG) will be given orally at a starting dose of up to 600 mg daily (group 1) tapered to 100 mg daily over 7 days; given with lofexidine (LFX) starting at 2.16 mg daily and declining to 0.72 mg over 7 days. On day 8, subjects are offered an injection of XR-NTX if they provide a urine sample that is negative for opioids and buprenorphine and pass a naloxone challenge. All subjects, regardless of whether or not they receive XR-NTX, will be given a referral and appointment for follow-up treatment when they leave the inpatient detoxification program.

Arms: arm 1: 0.54 mg lofexidine and 200 mg Pregabalin on days 1 -7 with taper for pregabalin and lofexidine starting on day 5 arm 2: 0.54 mg lofexidine and Placebo (PLB) on days 1-7 with taper for lofexidine starting on day 5
Interventions: intervention 1: Pregabalin 200 MG capsules intervention 2: Placebo oral tablet intervention 3: Lofexidine 0.18Mg Tab
Intervention descriptions: intervention 1: oral pregabalin 200 mg capsules given with a taper on day 5 intervention 2: oral Placebo intervention 3: lofexidine 0.18 tab given with a taper starting on day 5

Protocol documents:
Prot_SAP_002.pdf: 
Cover Page 
Title: Pregabalin Plus Lofexidine for the Outpatient Treatment of Opioid 
Withdrawal 
Clinical Trial Number: NCT04218240 
Document Name: Protocol with Analysis Plan 
Document Date: 11/2/2022 


1 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
Protocol V-9.0 
                                                                                                                                               November 2, 2022 
 
 
University of Pennsylvania 
 
 
 
Combining Pregabalin (LYRICA®) with Lofexidine (LUCEMYRATM): 
Can it Increase the Success of Transition to Naltrexone? 
 
 
Protocol Number: 
Regulatory Sponsor: 
834801 
Kyle M. Kampman M.D. 
Department of Psychiatry 
University of Pennsylvania Center for Studies of Addiction 
3535 Market Street Suite 500 
Philadelphia, PA 19104 
215 746 2764 
Funding Sponsor: 
National Institute on Drug Abuse 
National Institutes of Health 
6001 Executive Boulevard Room 5213 
Bethesda Maryland 20892 
301 443 1124 
Study Product: 
Pregabalin 
Lofexidine 
Protocol Number: 
9.0 
IND Number: 
147130 
 
 
 
Date November 2, 2022 


2 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
1.0 SIGNATURE PAGE 
By signing below, the University of Pennsylvania indicates approval of this protocol through the University 
of Pennsylvania’s IRB as well as assurance that this study will be conducted according to the procedures 
described in the protocol, ICH guidelines and Good Clinical Practices, and all applicable regulatory 
requirements. 
 
 
 
Printed Name of Sponsor 
 
 
 
Signature of Sponsor 
 
 
 
Date 
 
 
Investigator’s Agreement 
I have received, read, and understood the information contained in the package insert for LYRICA 
(Pregabalin) and LUCEMYRA (lofexidine). I have read Protocol (IRB protocol number #) and agree to 
conduct the study as written in the protocol. I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol. 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
Signature of Investigator 
 
 
 
Date 
Protocol V-9.0                                                                                                                                                                    November 2, 2022 
 


3 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
2.0 STUDY CONTACTS 
 
Study Contact Information 
 
Name 
Role in Study 
Address and 
Telephone Number 
Email Address 
Kyle Kampman, 
MD 
Principal Investigator 
3535 Market Street, 
Suite 500 
Philadelphia, PA 
19104 
215-746-2764 
kampman@pennmedicine.upenn.edu 
George E. 
Woody, MD 
Medical Monitor 
3535 Market Street, 
Suite 500 
Philadelphia, PA 
19104 
215-746-7702 
woodyg@ pennmedicine.upenn.edu 
Sabrina A. Poole, 
PsyD 
Clinical Project 
Manager 
3535 Market Street, 
Suite 500 
Philadelphia, PA 
19104 
215-746-8802 
spoole@pennmedicine.upenn.edu 
ECG Readings 
For UPENN: 
Kelly Spratt D.O., 
FACP, FACC 
For MOUNTAIN 
MANOR: 
Kelly Spratt, 
D.O., FACP, 
FACC 
For COLUMBIA: 
Kelly Spratt, 
D.O., FACP, 
FACC 
Cardiologist 
Penn-Presbyterian 
Medical Center 
Cardiovascular 
Division 
39th and Market 
Streets 
PHI Building, Suite 2A 
Philadelphia, PA 
19104 
Phone: 215-662-9010 
Fax: 215-662-9733 
Cell: 215-805-3756 
KellyAnne.Spratt@uphs.upenn.edu 
Investigational 
Drug Service 
Central 
Manufacturer/Distributor 
of Pregabalin/Placebo & 
Lofexidine 
3600 Civic Center Dr., 
10th Flr., Philadelphia, 
PA 19104 
Ph: 215-662-7911 
Fax 215-615-1308 
PennIDS@pennmedicine.upenn.edu 
Investigational 
Drug Service 
North 
PPMC Dispensing 
Research Pharmacy 
51 N.39th St., 
103 Mutch Bldg., 
Philadelphia, PA 
19104 
Ph: 215-662-9995 
Fax 215-243-4645 
PennIDSNorth@pennmedicine.upenn.edu 


4 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
2.1 TABLE OF CONTENTS 
 
1.0 
SIGNATURE PAGE 
……………………………………………………………………………………………. 
2 
2.0 
STUDY CONTACTS 
……………………………………………………………………………………………. 
3 
2.1 
TABLE OF CONTENTS 
…………………………………………………………………………………….... 
4 
2.2 
LIST OF TABLES 
……………………………………………………………………………………… 
8 
2.3 
LIST OF FIGURES 
……………………………………………………………………………………… 
8 
3.0 
PROTOCOL SUMMARY 
……………………………………………………………………………………… 
9 
4.0 
SCHEMATICS 
…………………………………………………………………………………………………. 
12 
5.0 
OVERVIEW OF STUDY ASSESSMENTS 
……………………………………………………………… 
13 
6.0 
LIST OF ABBREVIATIONS AND DEFINITIONS 
………………………………………………….…… 17 
7.0 
INTRODUCTIONS 
……………………………………………………………………………………………. 
18 
7.1 
BACKGROUND 
……………………………………………………………………………………………. 
18 
7.1.2 
DETOXIFICATION AND TRANSITION TO XR-NTX 
…………………………………………………….… 19 
7.1.3 
DETOXIFICATION WITH BUPRENORPHINE 
………………………………………………………….…. 19 
7.1.4 
DETOXIFICATION WITH PREGABALIN 
.………………………………………………………………… 19 
7.1.5 
DETOXIFICATION WITH LOFEXIDINE 
……………………………………………………………..….. 20 
7.1.6 
DETOXIFICATION WITH PREGABALIN AND LOFEXIDINE…… 
………………………………………….… 20 
7.2 
INVESTIGATIONAL AGENT…… 
…………………………...……………………..…………………………… 
21 
7.2.1 
PREGABALIN STRUCTURE…………………… 
……………………………………………………………….. 21 
7.2.2 
MECHANISM OF ACTION 
……………………………………………………………………………………..… 
21 
7.2.3 
PHARMACOKINETICS 
………………………………………………………………………… 
22 
7.2.4 
ABSORPTION AND DISTRIBUTION 
………………………………………………………………………… 
22 
7.2.5 
METABOLISM AND ELIMINATION 
………………………………………………………………………… 
22 
7.3 
DOSE RATIONALE AND RISK/BENEFITS 
………………………………………………………………... 
22 
7.3.1 
MEDICATION AND BLINDING… …………………………………………………………………….......………………
22 
7.3.2 
DOSING SCHEDULES 
………..……………………………………………………………………………….. 
23 
7.3.3 
DOSING GUIDELINES 
………………………………………………………………………………………… 
23 
7.3.4 
POTENTIAL RISKS 
……………………………………………………………………………………….. 
24 
7.3.5 
PREGABALIN ASSOCIATED AE’S 
…………………………………………………………………………… 
24 
7.3.6 
MOST COMMON AE’S LEADING TO DISCONTINUATION OF PREGABALIN 
………………………… 24 
7.3.7 
MOST COMMON AE’S IN ALL PRE-MARKETING CONTROLLED PREGABALIN 
…………………
…. 
24 
7.3.8 
AE’S LEADING TO DISCONTINUATION IN CONTROLLED TRIALS OF PREGABALIN 
…………….. 
24 
7.4 
LOFEXIDINE 
…………………………………………………………………………………………………. 
26 
7.4.1 
SAFETY 
……………………………………………………………………………………………………….. 
26 
7.4.2 
METHADONE…………………………. 
………. ……………………………………..……………………………… 26 
7.4.3 
MOST COMMON LOFEXIDINE AES 
……..… ……………………………………………………………………. 
26 
7.4.4 
ECG and VITAL SIGNS 
………………………………………………………………………………………………… 
26 
7.5 
EXTENDED RELEASE NALTREXONE (XR-NTX) 
………………………………………………………… 26 
7.5.1 
INJECTION SITE REACTIONS 
……………………………………………………………………………… 
26 
7.5.2 
PRECIPITATIING OPIOID WITHDRAWAL-XR-NTX 
……………………………… 27 
7.5.3 
NALTREXONE LIVER TOXICITY 
………………………………………………………………………… 27 
7.5.4 
NALTREXONE HEPATIC IMPAIRMENT 
……………………………………………………………………
. 
27 
7.5.5 
NALTREXONE GASTROINTESTINAL EFFECTS 
…………………………………………………………
. 
27 
7.5.6 
NALTREXONE RENAL IMPAIRMENT 
……………………………………………………………………..
. 
27 
7.5.7 
NALTREXONE AND GENDER 
………………………………………………………………………………. 
27 
7.5.8 
NALTREXONE AND DRUG-DRUG INTERACTIONS 
………………………………………………………
. 
27 
7.5.9 
NALTREXONE AND REVERSAL OF BLOCKADE FOR PAIN MANAGEMENT 
…………………………. 27 


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Protocol V9.0                                                                                                                           11/2/2022 
7.5.10 
NALTREXONE AND DEPRESSION AND SUICIDALITY 
……………………………………………….. 28 
7.5.11 
NALTREXONE CONTRAINDICATIONS 
…………………………………………………………………
. 
28 
7.5.12 
OPIOID OVERDOSE FOLLOWING ATTEMPT TO OVERCOME THE XR-NTX BLOCKADE……………. 
  28 
7.5.13 
EOSINOPHILIC PNEUMONIA 
…………………………………………………………………….…..... 28 
7.5.14 
DATA FROM THE RUSSIAN XR-NTX STUDY OF OPIOID DEPENDENT PATIENTS………………   
             28 
 8.0 
STUDY OBJECTIVES 
…………………… 
 28 
8.1 
PRIMARY OBJECTIVES 
…………………………………………………………………………….… 
28 
8.2 
SECONDARY OBJECTIVES 
………………………………………………………………………………… 
28 
8.3 
ASSESSMENT TOOLS USED TO ACHIEVE OBJECTIVES 
…………………………………………… 
29 
9.0 
STUDY DESIGN 
…………………………………………………………………………………………….. 
29 
9.1 
GENERAL DESIGN 
…………………………………………………………………………………………… 
29 
9.1.1 
PHASE 1: OUTPATIENT PRESCREENING (DAY -7 TO DAY -1) 
……………………………………… 29 
9.1.2 
PHASE 2: INPATIENT RANDOMIZATION AND DOSING (DAY 1 THRU DAY 7) 
…………………
… 
30 
9.1.3 
PHASE 3: INPATIENT XR-NTX DOSING (DAY 8 OR 9) 
…………………………………………………   30 
9.1.4 
SUBJECTS WHO REMAIN INPATIENT 
………………………………………………………………… 31 
9.1.5 
PHASE 4: OUTPATIENT FOLLOW-UP VISITS (DAY 10 AND DAY 15) AT CLINIC VISIT 
…………….. 
31 
9.1.6 
OPTIONAL F/U DAY (SECOND XR-NTX INJECTION……………………………………….. 
 
32 
9.2 
PRIMARY STUDY OUTCOME ENDPOINTS 
……………………………………………………………… 32 
9.3 
PRIMARY SAFETY OUTCOME ENDPOINTS 
………………………………………………………….… 
32 
10.0 
SUBJECT SELECTION AND DISCONTINUATION 
……………………………..………………….….... 33 
10.1 
INCLUSION CRITERIA 
……………………………………………………………………………….…….… 
33 
10.2 
EXCLUSION CRITERIA……………………………………………………………... 
…………………………… 
33 
10.3 
SUBJECT RECRUITMENT AND SCREENING............................................ 
…………………………… 
34 
10.3.1 PARTICIPATING CLINICS OR DATA COLLECTION CENTERS....................... 
……………………………. 34 
10.3.2 STUDY TIME TABLE………………………………………………………………..… 
…………………………… 
34 
10.3.3 ENROLLMENT PROJECTIONS……………………………………………………. 
…………………………… 
35 
10.4 
TARGET POPULATION DISTRIBUTION (GENDER, RACE, ETC……………..... 
…………………………… 
35 
10.5 
RECRUITMENT OF FEMALE SUBJECTS…………………………………….....… 
…………………………… 
35 
10.6 
OBTAINING INFORMED CONSENT…………………………………………….… 
…………………………… 
36 
10.7 
SCREEN FAILURES……………………………………………………………….… 
…………………………… 
36 
10.8 
EARLY WITHDRAWAL OF SUBJECTS……………………………………………. 
…………………………… 
36 
10.9 
FOLLOW-UP OF WITHDRAWN SUBJECTS………………………………….….. 
…………………………… 
37 
10.9.1 FOLLOW-UP OF SUBJECTS WHO NEED SECOND INJECTIONS……………... 
…………………………… 
37 
10.10 
DATA COLLECTION……………………………………………………………….… 
…………………………… 
37 
10.10.1 DATA HANDLING & RECORD KEEPING…………………………………………. 
…………………………… 
37 
10.10.2 SOURCE DOCUMENTS…………………………………………………………….. 
…………………………… 
37 
10.10.3 CASE REPORT FORMS (CRFs)……………………………………………………. 
…………………………… 
37 
10.11 
STUDY MEASURES…………………………………………………………………. 
…………………………… 
38 
10.12 
SAFETY ASSESSMENTS…………………………………………………………… 
…………………………… 
39 
10.13 
PROTECTION OF SUBJECTS……………………………………………………… 
…………………………… 
41 
10.13.1 VENIPUNCTURE……………………………………………………………………… 
…………………………… 
41 
10.13.2 RISKS ASSOCIATED WITH STUDY PROCEDURES…………………………… 
…………………………… 
41 
10.13.3 RISK BENEFIT RATIO……………………………………………………………….. 
…………………………… 
41 
10.13.4 MEDICAL MANAGEMENT OF ADVERSE EVENTS 
…………………………… 
41 
11.0 
METHODS FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS 
…………………………… 
41 
11.1 
RANDOMIZATION……………………………………………………………………. 
…………………………… 
41 
11.2 
RANDOMIZATION OF PLACEBO AGENT………………………………………… 
…………………………… 
42 
11.3 
BLINDING OF STUDY DRUG………………………………………………………. 
…………………………… 
42 


6 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
11.4 
RECEIPT OF XR-NTX……………………………………………………………….. 
…………………………… 
42 
11.5 
RECEIPT OF NALOXONE…………………………………………………………… 
…………………………… 
42 
11.6 
PREPARATION AND ADMINISTRATION OF STUDY DRUG………………….. 
…………………………… 
43 
11.7 
COMFORT MEDICATIONS………………………………………………………….. 
…………………………… 
43 
11.8 
PRIOR AND CONCOMITANT MEDICATIONS……………………………………. 
…………………………… 
43 
11.9 
RULING OUT CURRENT PHYSIOLOGIC DEPEND BEFORE XR-NTX ADMINISTRATION 
………… 
43 
12.0 
RECEIVING, STORAGE, DEPENSING AND RETURN………………………….. 
…………………………… 
44 
12.1 
RECEIPT OF PGB, LFX, AND XR-NTX……………………………………………. 
…………………………… 
44 
12.2 
STORAGE OF INVESTIGATIONAL MEDICATION………………………………. 
…………………………… 
44 
12.3 
DISPENSING OF INVESTIGATIONAL MEDICATION…………………………… 
…………………………… 
45 
12.4 
RETURN AND DESTRUCTION OF STUDY DRUG……………………………… 
…………………………… 
45 
12.5 
DISPENSING XR-NTX………………………………………………………………. 
…………………………… 
45 
12.6 
STUDY DRUG ACCOUNTABILITY…………………………………………………. 
…………………………… 
45 
13.0 
STATISTICAL PLAN…………………………………………………………………. 
…………………………… 
46 
13.1 
DATA ANALYSIS……………………………………………………………………… 
…………………………… 
46 
13.2 
SAMPLE SIZE DETERMINATION………………………………………………….. 
…………………………… 
46 
13.3 
STATISTICAL METHODS……………………………………………………………. 
…………………………… 
46 
13.3.1 PRIMARY OUTCOME…………………………………………………………….….. 
…………………………… 
46 
13.3.2 SECONDARY OUTCOMES…………………………………………………………... 
…………………………… 
47 
13.4 
SAFETY OUTCOMES……………………………………………………………… 
…………………………… 
47 
13.4.1 SUICIDALITY…………………………………………………………………………... 
…………………………… 
47 
13.4.2 SEDATION…………………………………………………………………………….. 
…………………………… 
47 
13.4.3 ELEVATED CREATINE KINASE……………………………………………………. 
…………………………… 
47 
13.4.4 EDEMA………………………………………………………………………………… 
…………………………… 
47 
13.5 
TOLERABILITY OUTCOMES……………………………………………………….. 
…………………………… 
47 
13.5.1 ACHINESS……………………………………………………………………………… 
…………………………… 
47 
13.5.2 ANXIETY……………………………………………………………………………….. 
…………………………… 
47 
13.5.3 INSOMNIA………………………………………………………………………………. 
…………………………… 
47 
13.6 
SUBJECT POPULATION FOR ANALYSIS………………………………………… 
…………………………… 
48 
13.7 
ADVERSE EVENT RECORDING AND REDCAP SYSTEM ENTRY 
…………………………… 
48 
13.8 
VITAL SIGNS………………………………………………………………………….. 
…………………………… 
48 
14.0 
DATA MANAGEMENT……………………………………………………………….. 
…………………………… 
48 
14.1 
DATA ACQUISITION AND TRANSMISSION……………………………………… 
…………………………… 
48 
14.1.1 DATA ENTRY METHODS……………………………………………………………. 
…………………………… 
48 
15.0 
SAFETY AND ADVERSE EVENTS………………………………………………… 
…………………………… 
49 


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Protocol V9.0                                                                                                                           11/2/2022 
15.1 
DEFINITION OF ADVERSE EVENTS 
…………………………………………..…………….. 
49 
15.2 
ADVERSE EVENT REPORTING PERIOD 
……………………………………………….………….… 
49 
15.3 
POST STUDY AEs 
…………………………………………..………………………… 
49 
15.4 
ABNORMAL LABORATORY VALUES ……………………………………………………………… 
49 
15.5 
HOSPITALIZATION, PROLONGED HOSPITALIZATION & SURGERY 
………………………………. 
49 
15.6 
RECORDING AEs 
…………………………………………..……………………………….. 
50 
15.7 
REPORTING SERIOUS ADVERSE EVENTS 
………………………………………………..…………. 
50 
15.8 
STUDY SPONSOR AND MEDICAL MONITOR NOTIFICATION BY INVESTIGATOR   
………….………… 
50 
15.9 
REPORTING DEATHS 
…………………………………………..…………………………… 
51 
15.10 OTHER REPORTABLE EVENTS 
…………………………………………..………………….. 
51 
15.11 IRB NOTIFICATION BY INVESTIGATOR 
…………………………………………..…… 
51 
15.12 FDA NOTOFICATION BY SPONSOR 
…………………………………………..……………….. 
51 
16.0 
STUDY MONITORING/AUDITING/AND INSPECTION 
………………………………………….. 
52 
16.1 
STUDY INITIATION  
…………………………………………..………………………….. 
52 
16.2 
MONITORING VISITS 
…………………………………………..………………………….. 
53 
16.3 
MONITORING LOG 
…………………………………………..………………………….. 
53 
16.4 
MONITORING REPORT 
…………………………………………..………………………….. 
53 
16.5 
VISIT 4: CLOSEOUT 
…………………………………………..………………………….. 
53 
17.0 
MEDICAL MONITORING 
…………………………………………..………………..………… 
53 
17.1 
SAFETY AND MEDICAL MONITORING 
………………………………………..…….….……… 
53 
18.0 
ETHICAL CONSIDERATIONS AND SAFETY 
………………………………………..………...……… 
54 
18.1 
GOOD CLINICAL PRACTICE (GCP) 
………………………………………..………...……… 
54 
18.2 
MEDICAL EMERGENCIES 
………………………………………..………...……… 
54 
18.3 
UNBLINDING PROCEDURES 
………………………………………..………...……… 
54 
19.0 
STOPPING RUES 
………………………………………..………...……… 
54 
19.1 
STUDY STOPPING CRITERIA 
………………………………………..……..….……… 
54 
19.2 
MEDICATION DISCONTINUATION CRITERIA 
………………………………………..…….………….. 
55 
20.0 
SUBJECT STIPEND AND REIMBURSEMENTS 
………………………………………..…….…………… 
55 
21.0 
POTENTIAL BENEFITS 
………………………………………..…….…………… 
57 
22.0 
CONFIDENTIALITY 
………………………………………..…….…………… 
57 
22.1 
HIPAA COMPLIANCE 
………………………………………..…….…………… 
57 
23.0 
INDEPENDENT  
………………………………………..…….…………… 
58 
23.1 
DESCRIPTION 
………………………………………..…….…………… 
58 
23.2 
BOARD MEMBER QUALIFICATIONS 
………………………………………..…….…………… 
58 
24.0 
DSMP STUDY MONITORING PLAN 
………………………………………..…….…………… 
59 
25.0 
COVID SAFETY PLAN 
………………………………………..…….…………… 
59 
26.0 
AUDITING AND INSPECTING 
………………………………………..… 
61 
27.0 
FUNDING SOURCE 
………………………………………..…….…………… 
61 
28.0 
DISCLOSURE OF CONFLICT OF INTEREST IN THE 
DSM 
………………………………………..…….…………… 
61 
29.0 
PUBLICATION PLAN 
………………………………………..…….…………… 
61 
 
 
 


8 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
30.0 
REFERENCES 
………………………………………..…….…………… 
62 
 
 
 
31.0 
APPENDICES (not attached per copyright) 
………………………………………..…….…………… 
66 
 
MINI-INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW (M.I.N.I.) FOR DSM 5 (SHEEHAN, 1998) 
…………… 
 
CLINICAL GLOBAL IMPRESSION SCALE (CGI; GUY,1976) 
…………… 
 
HAMILTON ANXIETY RATING SCALE (HAM-A; HAMILTON, 1959) 
…………… 
 
HAMILTON DEPRESSION RATING SCALE (HAM-D; HAMILTON, 1960) 
…………… 
 
INSOMNIA SEVERITY INDEX (ISI; BASTIEN, 2001) 
…………… 
 
OPIOID CRAVING VISUAL ANALOG SCALE (VAS; MCMILLAN & GILMORE-THOMAS 1996) 
…………… 
 
PASERO OPIOID-INDUCED SEDATION SCALE (POSS; PASERO, 2009) 
…………… 
 
SUBJECTIVE OPIOID WITHDRAWAL SCALE- GOSSOP (SOWS-G VERNON, 2015) 
…………… 
 
CLINICAL OPIOID WITHDRAWAL SCALE (COWS; WESSON & LING, 2003) 
…………… 
 
TIMELINE FOLLOW-BACK INTERVIEW (TLFB; SOBELL & SOBELL, 1995) 
…………… 
 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) RISK ASSESSMENT VERSION (POSNER 
ET AL., 2008) 
…………… 
 
 
 
 
 
 
32.0 
LIST OF TABLES 
 
33.0 
TABLE 1. OVERVIEW OF STUDY ASSESSMENTS 
………………………………………..…….…… 
13 
34.0 
TABLE 2. LOFEXIDINE DOSING 
………………………………………..…….…… 
23 
35.0 
TABLE 3. PREGABALIN AND PREGABALIN-PLACEBO 
DOSING 
………………………………………..…….…… 
23 
36.0 
TABLE 4. AEs IN TRIALS OF NEUROPATHIC PAIN 
………………………………………..…….…… 
25 
37.0 
TABLE 5. CLINICAL LABORATORY TESTS 
………………………………………..…….…… 
40 
38.0 
TABLE 6. PENN SUBJECT STIENDS AND 
REIMBURSEMENTS 
………………………………………..…….…… 
55 
38.0 
TABLE 7. MMTC SUBJECT STIENDS AND 
REIMBURSEMENTS 
………………………………………..…….…… 
56 
38.0 
TABLE 8. COLUMBIA SUBJECT STIENDS AND 
REIMBURSEMENTS 
 
 
………………………………………..…….…… 
57 
39.0 
LIST OF FIGURES 
 
40.1 
FIGURE 1. STUDY SCHEMATICS 
………………………………………..…….…… 
12 
42.0 
FIGURE 2. MOLECULAR STRUCTURE OF PREGABALIN 
………………………………………..…….…… 
21 
43.0 
FIGURE 3. PROJECTED TIME TABLE 
………………………………………..…….…… 
34 
44.0 
FIGURE 4. ENROLLMENT PROJECTIONS 
………………………………………..…….…… 
35 
 
 
 
 
 
 
 
 


9 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
Title 
Combining Pregabalin (LYRICA®) with Lofexidine (LUCEMYRATM): Can it 
Increase the Success of Transition to Naltrexone? 
Short Title 
Pregabalin and Lofexidine for opioid withdrawal 
Protocol Version 
7.0 
Phase 
Phase 2 
Methodology 
Double-blind placebo-controlled parallel group clinical trial 
Study Duration 
24 months 
Study Centers (3) 
• 
University of Pennsylvania Center for Studies of Addiction in 
Philadelphia Pennsylvania 
• 
Columbia University in New York City, New York 
• 
Mountain Manor in Baltimore, Maryland 
Objective 
(Primary) 
Objective 
(Secondary) 
To investigate whether pregabalin-Lyrica® (PGB) combined with Lofexidine-
Lucemyra® (LFX) can reduce opioid withdrawal-related subjective effects 
To investigate, if the PGB/LFX combination can increase the proportion of 
patients with an opioid use disorder (OUD) who complete detoxification and 
transition to antagonist treatment with extended- release injectable naltrexone 
VIVITROL® (XR-NTX) 
Number of Subjects 
90 subjects. 60 randomized to PGB/LFX; 30 to PGB-PLA/LFX 
Inclusion Criteria 
• 
Male and/or female subjects ≥ 18 years of age 
• 
Meet DSM-5 criteria for an Opioid Use Disorder with physiologic 
features. Have 2 or more of the 11 DSM 5 criteria for opioid 
disorder including tolerance and withdrawal features in the last 12 
months 
• 
Interested in opioid antagonist treatment 
• 
Have used opioids in 20 of the past 30 days 
• 
Have a stable address in the local area; not planning to move; 
have documents for ID check 
• 
Absence of medical or psychiatric conditions that are likely to 
interfere with study participation 
• 
Have a 12 lead ECG demonstrating a QTc ≤450 msec and a 
QRS interval ≤120 msec. The site PI has the final determination 
for inclusion into the study for ECGs unless there is a question 
of QT prolongation or other factors (QTc/Fri uses the Fridericia 
formula (QTc = QT/RR(1/3)).  If consultation is needed, the PENN 
cardiologists and the medical monitor should be contacted. 
• 
If female, have a negative pregnancy test, and uses adequate 
contraception if of childbearing potential 
Exclusion Criteria 
• 
Current psychotic disorder (bipolar I, schizophrenia, major 
depression with psychotic features,) as defined by the MINI 
• 
An alcohol, benzodiazepine, or other sedative disorder with 
physiological features that require medication for detoxification 
• 
History of allergy or other serious adverse event due to treatment with 
pregabalin, XR-NTX, or lofexidine 
3.0 PROTOCOL SUMMARY 


10 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
• 
Pending incarceration in the next 30 days 
• 
Homicidal or otherwise behaviorally disturbed requiring immediate 
attention. 
• 
High Risk for suicide as determined by answering ‘yes’ to questions 
4 and/or 5 on C-SSRS at screening 
• 
Blood pressure <90 mm Hg (systolic) or <60 mm Hg (diastolic). If this value 
is out of normal range, the investigator and a study clinician will decide
subject inclusion or exclusion on a case-by- case basis 
• 
Heart rate and/or pulse<50 bpm at screening-sitting  
• 
An Estimated Glomerular Filtration Rate eGFR<90 mL/min/1.73m2 
• 
A history of, or current seizure disorder (excluding childhood 
febrile seizures) 
• 
Inability to read and/or understand English. For example, does not 
understand the informed consent as demonstrated by failing to answer 
9/10 questions correctly on the quiz 
• 
Pregnant or breastfeeding 
• 
Currently taking sympathomimetic drugs, or a thiazolidinedione 
antidiabetic  
• 
An ALT and/or AST that is at > 4X the top limit of normal 
• 
A Child-Pugh score >7 
• 
Currently receiving opioids for pain management 
• 
In a treatment study where medication was administered in the 
last 30 days. 
• 
Currently using medications that are known to be strong or moderate 
inhibitors of CYP2D6 such as fluoxetine, paroxetine, mirabegron, 
bupropion, quinidine, terbinafine, cimetidine, cinacalcet, duloxetine, 
or fluvoxamine 
• 
In a methadone maintenance or buprenorphine treatment 
program within the last 30 days 
 
Study Product, Dose, 
Route, Regimen 
 
Pregabalin (PGB) or PGB-PLA given orally at a starting dose of up to 400 mg 
on day 1, up to 600 mg daily on Day 2 through Day 4, tapered to 100 mg daily 
by Day 7; Lofexidine (LFX) starts at 1.62 mg on day 1, 2.16 Day 2 through Day 
4, tapering to 0.72 mg by Day 7.  After starting dose on Day 1, both study drug 
doses can be reduced or withheld depending upon patient’s clinical 
observations for Days 1-7. On day 8, subjects are offered an injection of XR-
NTX if they provide a urine sample that is negative for opioids, buprenorphine, 
and fentanyl, and pass a naloxone challenge. All subjects, regardless of 
whether or not they receive XR-NTX, will be given a list of referrals and help 
with making an appointment for follow-up treatment when they leave the 
inpatient detoxification program. 
Comfort Medications 
 
The following “comfort” medications are suggested for treatment of withdrawal 
symptoms that are not suppressed by study medications: ondansetron 4 mg or 
8 mg tid PO PRN for nausea and vomiting, trazodone 100 mg HS PRN 
insomnia, loperamide 2 mg qid PO PRN diarrhea, and a non-steroidal such as 
Ibuprofen 600 mg qid PO PRN for aches and pains or acetaminophen 650 mg 
(2 tablets 325 mg) PO qid PO PRN,  cyclobenzaprine 5 mg tid PO PRN for 
muscle aches and pains, and hydroxyzine 25 mg qid PO PRN  anxiety. In cases 
of QTc prolongation that are not >550ms or judged to require stopping study 
medications, diphenhydramine 50 mg hs PO PRN  may be used for insomnia, 
and  trimethobenzamide 300 mg qid PO PRN for nausea. 


11 
 
 
Protocol V9.0                                                                                                                           11/2/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of subject 
participation and 
medication 
administration 
 
Outpatient screening is used to determine eligibility for the study. It will consist of 
the 30 days prior to inpatient admission for study detoxification and treatment. On 
day 1 of inpatient treatment subjects will be randomized to PGB/LFX or PGB-
PLA/LFX for a 7-day detoxification. On day 8, if the patient completes 
detoxification, continues to be interested in XR-NTX treatment, provides a urine, 
and passes a naloxone challenge, he/she will be offered one injection of XR-NTX 
before hospital discharge. This injection of XR-NTX is optional. If retests must be 
done, such as a repeat of the naloxone challenge, all subjects are eligible to 
remain inpatient until Day 9. All subjects, whether they receive XR-NTX or not, 
will be referred to continuing care and asked to return to the research outpatient 
clinic on days 10 and 15 for follow-up visits. Subjects who cannot find a provider 
may be offered an additional XR-NTX injection up to 5 weeks after the Day 8 
injection. 
Reference therapy 
PGB-Placebo plus lofexidine 
Statistical 
Methodology 
The primary outcome is reduction in subjective withdrawal as measured 
twice/day using the Short Opiate Withdrawal Scale (SOWS- Gossop). SOWS 
scores range from zero to 30. Groups will be compared on 10 or more repeated 
SOWS responses during inpatient treatment using linear mixed-effects 
regression models. The SOWS total will be regressed on a three-level factor for 
site, and a two-level factor for pregabalin dose, with random intercept and 
correlated residuals and a random slope included if necessary for fit. Contrasts 
between the combined groups will be estimated from this model. 
The secondary outcome is an ordinal response indicating completion of detox 
and receipt of antagonist treatment, with levels (1) failure to complete detox, (2) 
completion of detox with failure to receive antagonist treatment, and (3) 
completion of detox and receipt of antagonist treatment. 
 
Note: Study medication will be provided in blister packs that are prepared by the PENN Investigational 
Drug Service and shipped to all three study sites. For the University of Pennsylvania, each blister pack 
will have a patient randomization number and the dosing schedule for each time on each inpatient 
study day, as summarized in the Study Schematics 4.0 below. For the two external sites, patient 
randomization will be generated by the site pharmacy or designated unblinded person, who receives 
the blister packs from the PENN Investigational Drug Service with the dosing schedule for each day.   
The doses for each time of each day will be in separate compartments. Lofexidine will be 0.18 mg pink 
tables; pregabalin or pregabalin placebo will be in capsules.  Blue capsules will contain 100 mg 
pregabalin or placebo; green capsules will contain 25 mg pregabalin or pregabalin placebo. These 
medications have not been used together and it is likely that doses will need to be held or reduced due 
to side effects. The most likely side effect from lofexidine is hypotension and/or bradycardia. The most 
likely side effect from pregabalin is sedation. Thus, in the event of hypotension, the next scheduled 
dose of lofexidine can be reduced or withheld. A similar adjustment can be made for excessive 
sedation (POSS score of 3 or 4; difficult to arouse, slurred speech, etc.) For the PENN site, medication 
counts will be done by the Investigational Drug Service (IDS) pharmacy for each subject. For sites 
outside PENN, medication counts will be done by the site or site pharmacy. 
 


12 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
 
UDS, fentanyl 
UDS, 
fentanyl 
UDS, 
fentanyl 


13 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
5.0 Table 1. Overview of Study Assessments 
 
 
Assessment 
Outpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Outpat 
Outpat 
EOS/
AMA 
VISIT 
(early) 
Screen 
 Day 1 
Day 2 
  Day 3 
  Day 4 
 Day 5 
  Day 6 
Day 7 
Day 8/9†(all 
assessments 
Done both days 
Unless otherwise 
Stated) 
Day 10 
+2 business 
days 
EOSDay 
15 
+2 business 
days 
 
 
Informed Consent 
1X 
Locator Information 
1X 
1X 
Medical History 
1X 
Physical/Weight 
1X 
1X 
 
1X 
 
CBC* with Diff and PLT, 
INR 
1X 
1X 
INR 
Not 
repeated 
1X if no D10 
No INR 
1X  
No INR 
Blood Chemistry, with 
Magnesium and Calcium 
1X 
1X 
Magnesiu
m not 
repeated 
CMP 1X 
IF No Day 10  
1X 
No 
magnesiu
m 
Creatine Kinase 
1X 
1X 
(done at D8- 
only) 
1X 
Estimated 
Glomerular Filtration 
1X 
Child Pugh Score 
1X 
Urinalysis with Reflex 
Microscopy 
1X 
1X 
1X 
Urine Pregnancy Test - F 
1X 
1X 
1X (if done 
at D8-do not 
repeat on 
D9) 
1X 
1X 
UDS 
1X 
1X 
1X 
1X 
1X 
   1X 


14 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
Assessment 
Outpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Outpat 
Outpat 
EOS/
AMA 
VISIT 
(early) 
Screen 
 Day 1 
Day 2 
  Day 3 
  Day 4 
 Day 5 
  Day 6 
Day 7 
Day 8/9†(all 
assessments 
Done both days 
Unless otherwise 
Stated) 
Day 10 
+2 business 
days 
EOSDay 
15 
+2 business 
days 
 
 
 
Fentanyl 
1X 
1X 
1X 
1X 
1X 
1X 
xylazine 
1X 
 
1X 
1X 
1X 
1X 
Alcohol Breathalyzer Test 
1X 
1X 
1X 
 
HEP B & C 
1X 
ECG 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
 
 
MINI 
1X 
Inclusion/Exclusion 
1X 
Randomization Form 
1X 
Visual Analog Scale for 
Craving 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
1X 
 
 
 
Insomnia Severity Index 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
 
SOWS-Gossop 
1X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
1X 
1X 
1X 
 
COWS 
1X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
2X 
1X 
1X 
 
POSS 
3X 
4X 
4X 
4X 
4X 
4X 
4X 
1X 
 
 
 
Naloxone Challenge 
(optional; only if pt. is 
interested and 
detoxed) 
1X 
(if 
positive 
on D8-
repeat on 
D9) 
1X 
Can be 
given to 
AMA Pts 
XR-NTX 
1X 
(if not 
done D8-
do on D9) 
1X 
Can be 
given to 
AMA Pts 
Vital Signs Cont’d next pg. 
 
1X 
8X 
8X 
8X 
8X 
8X 
8X 
8X 
1X BP 
sitting only 
1X BP 
sitting 
1X BP 
sitting only
1X BP 
sitting 


15 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
Assessment 
Outpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Outpat 
Outpat 
EOS/
AMA 
VISIT 
(early) 
Screen 
 Day 1 
Day 2 
  Day 3 
  Day 4 
 Day 5 
  Day 6 
Day 7 
Day 8/9†(all 
assessments 
Done both days 
Unless otherwise 
Stated) 
Day 10 
+2 business 
days 
EOSDay 
15 
+2 business 
days 
 
 
(BP-sitting & standing); 
Pulse 
only  
 
 
only  
 
Adverse Events 
 
1X 
@each  
visit 
1X 
@each 
visit 
1X 
@each 
visit 
1X 
@each 
visit 
1X 
@each 
visit 
1X 
@ea
ch 
visit 
1X 
@each 
visit 
1X 
@visit 
1X 
@visit 
1X 
@visit 
1X 
@visit 
Serious Adverse Events 
 
1X 
@each  
visit 
1X 
@each 
visit 
1X 
@each 
visit 
1X 
@each 
visit 
1X 
@each 
visit 
1X 
@ea
ch 
visit 
1X 
@each 
visit 
1X 
@visit 
1X 
@visit 
1X 
@visit 
1X 
@visit 
Concomitant Medications 
1X 
1X @each 
visit 
1X @each 
visit 
1X @each 
visit 
1X @each 
visit 
1X@each 
visit 
1X @each 
visit 
1X @each 
visit 
1X 
@visit 
1X 
@visit 
1X 
@visit 
1X 
@visit 
Comfort Medications 
1X 
@each  
visit 
1X 
@each 
visit 
1X 
@each 
visit 
1X @each 
   visit 
1X @each  
      visit 
1X @each 
     visit 
1X @each 
     visit 
1X 
@visit 
1X 
@visit 
1X 
@visit 
 
TLFB-
90 
1X 
TLFB-2-wk 
1X 
 
Clinical Global 
Impression Scale 
(CGI) 
1X 
1X 
1X 
1X 
HAM-D 
1X 
1X 
1X 
 
HAM-A 
1X 
1X 
1X 
 
C-SSRS 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
 
Lofexidine/Pregabalin*
* Adherence Pill 
Count 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
 
XR-NTX Adherence 
1X 
End of Study Form 
(EOS) 
 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
1X 
 
1X 
 
 
 
                 EOS only completed 1x when subject completes or drops from study at last study visit 


16 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
ECG=electrocardiogram (QT/Fri corrected for heart rate with Fridericia formula (QTc = QT/RR(1/3)); *CBC=complete blood count with diff; 
PLT, INR (INR at screen only); Chemistry for magnesium need not be done at Day 10; DSM-5=Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition; COWS=Clinical Opioid Withdrawal Scale; SOWS=Short Opioid Withdrawal Scale; UDS=urine drug screen; 
BrAC=breath alcohol concentration; TLFB=Timeline Follow-back; CGI=Clinical Global Impression; C-SSRS=Columbia Suicide Severity 
Rating Scale; HAM- A=Hamilton Anxiety Rating Scale; HAM- D=Hamilton Depression Rating Scale; POSS=Passero Opiate Sedation 
Scale; MINI=Mini International Neuropsychiatric Interview  
 
 
The number prior to X refers to the number of times the procedure is done. Vital signs are done 1X sitting and 1X standing Pre-dose and 
Post-dose at each daily dose scheduled. **Lofexidine/Pregabalin Adherence is done by pharmacy/site collection of bottles per subject and 
blister packs for all doses. † Day 9 is used for retests if needed, but all assessments are again done as per day 8 unless otherwise noted. 
 
Illicit non-study concomitant meds are covered in TLFB; UDS, Fentanyl and xylazine test are done at screen, and Day 1, Day 8, Day 10, Day 15; 
and Early termination. 
 


17 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
6.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
List of Abbreviations 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
aspartate aminotransferase 
BUP/NAL 
Buprenorphine/naloxone 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulation 
CGI 
Clinical Global Impression – Rater Version 
CK 
Creatine Kinase 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EOS 
End of study 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAM-D 
Hamilton Depression Rating Scale (Ham-D; 
Hamilton, 1960) 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
LFX 
Lofexidine 
MAT 
Medication-Assisted Therapy 
MINI 
Mini-International Neuropsychiatric Interview 
(M.I.N.I.) For DSM 5 (Sheehan 1998) 
OUD 
Opioid use disorder 
PGB 
Pregabalin 
POSS 
Pasero Opioid-Induced Sedation Scale (POSS; 
Pasero ,2009) 
QTc 
QT corrected by heart rate 
QTcFri  
QTc Correction using Fridericia formula (QTc = 
QT/RR(1/3)). 
SAE 
Serious adverse event 
SOWS-Gossop 
Short Opiate Withdrawal Scale-Gossop 
(Gossop, 1990) 
TLFB 
Timeline Follow-Back Interview (TLFB; Sobell & 
Sobell, 1995) 
XR-NTX 
Extended-Release Naltrexone 


18 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
7.0 INTRODUCTION 
 
This document is a protocol for a human research study. The study is to be conducted according to 
US and international standards of Good Clinical Practice (FDA Title 21 part 312, International 
Conference on Harmonization guidelines), and applicable government regulations and Institutional 
research policies and procedures. The Principal Investigator is responsible for assuring good 
communications with the study co-investigators as well as the monitor and the clinical staff so that each 
clearly understands and accepts the obligations incurred in undertaking this study. The Principal 
Investigator ensures that the clinical staff understand the nature of the protocol and the requirements 
for an adequate and well-controlled study; the obligation to conduct it in accordance with applicable 
federal and local regulations; obtain informed consent in accordance with 21 CFR Part 50; obtain IRB 
review and approval before the investigation may be initiated, and to ensure continuing review of the 
study by the IRB in accordance with 21 CFR Part 56. 
 
7.1 BACKGROUND 
 
Extended-release injectable naltrexone (XR-NTX; Vivitrol®), an opioid antagonist treatment 
that was approved by the FDA for the treatment of opioid use disorders (OUDs) in 2010. A single 
injection of 380 mg provides up to four weeks of blockade and has filled a niche created by situations 
in which opioid agonist or partial agonist maintenance (e.g. methadone, buprenorphine-naloxone) 
treatments are unavailable or undesirable due to regulatory or logistical constraints, clinical 
considerations, or patient preference. 
 
Initially met with skepticism, antagonist treatment has attracted interest from an increasing 
number of patients. In a recent cohort of 657 community recruited opioid-using patients, more than 
half, 52.1%, said they would be interested in trying antagonist treatment and possibly extended-
release naltrexone (XR-NTX) (Ahamad et al., 2015).  The authors cited daily heroin injection 
(AOR = 1.53; 95% CI = 1.02–2.31) as positively associated with this decision. Satisfaction with 
agonist treatment and chronic pain were the most common reasons for unwillingness to take XR- 
NTX. A related study assessed 372 opioid addicted individuals undergoing inpatient detoxification 
and the degree to which they would be interested in medication-assisted therapy (MAT). Among the 
202 that expressed interest, 64 (18.5%) preferred methadone, 98 (28%) buprenorphine, 104 (30%) 
XR-NTX, and 80 (23%) preferred “NO MAT” at all, due mostly to negative beliefs about all MATs 
(Uebelacker et al, 2016). 
 
Two recent studies found that XR-NTX treatment was similar in effectiveness to sublingual 
buprenorphine (BUP/NAL). One study, done in the U.S., compared XR-NTX to BUP/NAL in 570 
patients with OUD over 6 months. Though 22% fewer patients started XR-NTX than started 
BUP/NAL, mainly due to failure to complete detoxification, there was no difference between groups in 
the percent of subjects who relapsed to opioids, number of opioid negative urine tests, or number of 
opioid abstinent days among those that started either medication (Lee et al., 2018). In a 12-week trial 
done in Norway, 159 OUD subjects were randomly assigned to XR-NTX or BUP/NAL, 61% 
completed the trial with no significant differences between groups in retention or percent opiate 
negative urine tests (Tanum 2017). A third trial randomized 308 probationers or paroled adult criminal 
justice offenders with OUD to either a 24-week course of XR-NTX (n=153); or 24 weeks of treatment- 
as-usual (n=155) consisting of brief counseling and referrals for community treatment programs. At 6 
months, XR-NTX patients had a longer time to relapse, lower relapse rate, higher rate of opioid- 
negative urine samples, and no overdoses compared to subjects in the treatment-as-usual group 
(Lee et al., 2016). Results showing positive effects of extended-release naltrexone were also found in 
Russian studies when comparing opioid addicted patients that received oral or implantable naltrexone 
in St. Petersburg (Krupitsky et al, 2011; 2012; 2019). 


19 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
7.1.2 Detoxification and Transition to XR-NTX: Although the findings cited above 
suggest patient interest in XR- NTX and its possible effectiveness in reducing time to relapse and 
increasing higher rates of opioid negative urines when used as recommended, methods to increase 
the proportion who complete detoxification and transition from opioid addiction to naltrexone remain 
understudied. 
 
The usual protocol for opioid detoxification is tapering doses of methadone or buprenorphine, or 
suppressing autonomic over activity with an alpha 2 adrenergic agonist, such as clonidine or 
Lofexidine (LFX). The use of αlpha-2 agonists as adjuncts gained popularity when early studies found 
that withholding a single dose of clonidine prior to anesthesia caused a patient to experience an acute 
hypertensive crisis (Brodsky and Bravo, 1976) and it was theorized that α-2 agonists reduce 
withdrawal effects in the central and peripheral nervous systems.  Centrally within the locus 
coeruleus, αlpha-2 agonists were able to produce sedation, analgesia and mild euphoric effects, and 
partially block the sweating, rhinorrhea and objective signs of withdrawal in chronic opioid users but 
did not have much effect on the achiness, insomnia, dysphoria and other subjective symptoms. 
 
Opioid tapers with methadone or buprenorphine are better tolerated compared to treatment with 
alpha 2 adrenergic agonists, but patients interested in XR-NTX treatment need a 7-14-day opioid-free 
interval to avoid having naltrexone precipitate withdrawal, thus leaving time to relapse. Clonidine 
avoids this problem (Gold et al, 1980) but does not have FDA approval for this indication, does not 
decrease the dysphoria and other withdrawal-related subjective effects, and is unpopular with 
patients and physicians alike. Studies by Ling et al (2005) are an example. They show that only 61% 
of inpatients randomized to clonidine detoxification remained in treatment and had opioid negative 
urines at day 13, vs 77% in a buprenorphine detoxified group. Results were even worse in outpatient 
settings where only 5% of clonidine treated patients completed detoxification vs. 29% of those treated 
with buprenorphine only. 
 
7.1.3 Detoxification with Buprenorphine. Combining low and decreasing doses of 
buprenorphine with low and increasing doses of oral naltrexone was also studied as a way to 
transition to naltrexone and the results were positive in an early study where 56% in the experimental 
group transitioned to XR-NTX vs 33% in the buprenorphine group (Sullivan et al, 2017). However, a 
larger trial of 378 patients randomized to one of three regimens: NTX + BUP; NTX + placebo BUP 
(PBO-B); placebo NTX (PBO-N) + PBO-B found no difference in transition to XR-NTX across groups 
(41-46%), although for those inducted onto XR-NTX, the management of opioid withdrawal symptoms 
prior to starting XR-NTX was achieved in a structured outpatient setting using a well-tolerated, fixed- 
dose ancillary medication regimen common to all three groups. (Bisaga et al, 2018). 
7.1.4 Detoxification with Pregabalin. During the time that PGB was available without a 
prescription in Russia, clinicians observed that opioid addicted patients were using it to suppress 
withdrawal when their heroin supply ran out.  These observations led to a study in which 34 heroin-
addicted patients were randomized to detoxification protocols using PGB alone, or clonidine alone 
(Krupitsky et al, 2017). While groups did not differ on baseline clinical or demographic features, 15 of 
the 19 PGB subjects completed treatment (79%) compared to 7 of 15 (47%) in the clonidine group (p 
= 0.05, Fisher exact test), and a Kaplan-Meier Survival Analysis confirmed better retention in the PGB 
group (p = .001). There was no significant group difference in reduced severity of withdrawal, however 
the pregabalin group reported less opioid craving (p= .05), less anxiety (p=0.05), less depression 
(p=0.05), and higher assessments of general health (p < 0.05). Ketorolac was available as needed for 
pain, and the average dose of symptom-triggered ketorolac in the clonidine group was almost twice 
that of the PGB group (60.5 ± 8.2mg vs. 36 ± 7.8mg, (p< 0.05). In addition, the PGB group reported 
less fatigue compared to the clonidine group (16% vs. 47%, p < 0.05) and there was no significant 
difference in AR’s between groups. These findings were consistent with studies using rodent models 
that demonstrated PGB attenuates opioid withdrawal (Vashchinkina et al 2017).


20 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
PGB has a different mechanism of action than alpha-adrenergic receptor agonists as it 
potentiates glutamic acid decarboxylase, an enzyme that catalyzes decarboxylation thus increasing 
the synthesis of GABA, and inhibits calcium influx and release of excitatory neurotransmitters through 
action at the alpha-2-delta subunit of the NMDA receptor (Kämmerer et al, 2012; Freynhagen et al, 
2016). It is rapidly absorbed, reaching a maximum concentration in 10.5 hours that lasts for 8 hours 
and is excreted by the kidneys and not metabolized by the liver, thus unlikely to alter the metabolism 
of other drugs.  It is approved for neuropathic pain, fibromyalgia, adjunctive therapy for adults with 
partial onset seizures and, in Europe, for anxiety (Gajraj, 2007). Side effects occurring in >5% of 
patients are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and difficulty 
concentrating. It can increase the PR interval (http://labeling.pfizer.com/showlabeling.aspx?id=561), 
but only by 3-6 msec and at doses of >300 mg/day. It has a relatively low abuse potential (Schedule 
V) and available without a prescription in Russia until October 2015 when its status was changed to 
the equivalent of U.S. Schedule V due to reports of self-administration to experience opioid-like 
effects or reduce opioid withdrawal (Evoy et al, 2017). 
 
7.1.5 Detoxification with Lofexidine. A third detoxification approach emerged with the 
approval of LFX, a selective alpha 2 adrenergic agonist. Unlike clonidine, it has reduced potency at the 
A subtype of the alpha 2 receptor and is associated with less bradycardia and hypotension (Yu et al, 
2008; Gowing et al, 2016). Though its effects are similar to clonidine, its better safety profile is an 
advantage, especially in outpatient settings where hypotension can be a problem (Kahn et al, 1997; Lin 
et al, 1997; Carnwarth & Hardman, 1998). Like clonidine, it does not target the withdrawal- related 
subjective effects, thus potentiating a greater likelihood for dropout. An inpatient study randomized 
OUD inpatients to detoxification using lofexidine or diazepam. Twenty-seven percent (15/55) of the 
diazepam patients completed 10 days of treatment, vs 46.4% (26/56) of the lofexidine patients, thus 
more effective than diazepam although with much room for improvement (Guo et al, 2018). In a pivotal 
study leading to FDA approval, lofexidine showed a small reduction in subjective effects compared to 
placebo (a 2-point difference on the SOWS-Gossop scale) with significantly greater rates of 
detoxification completion (41% vs 28%; Fishman et al 2018). Again, showing the need for 
improvement, particularly for patients transitioning to antagonist therapy. 
 
7.1.6 Detoxification with Pregabalin and Lofexidine. Here we propose to see if PGB 
can be safely combined with LFX to better reduce the subjective effects of opioid withdrawal and 
increase the proportion that transition to antagonist treatment. Such an approach could lower the 
detoxification hurdle for patients who are interested in antagonist treatment or in settings where agonist 
treatment is unavailable or difficult to access, and reduce overdose risk for those who make the 
transition. This study, will attempt to identify a PGB/LFX combination that reduces withdrawal- related 
subjective effects without generating more SAE’s than LFX, as a precursor to a larger trial. The 
combination of PGB and LFX may result in increased drowsiness, lightheadedness and trouble 
concentrating. 
 
This study is a phase II, double-blind placebo-controlled, study to examine whether: 1) PGB can be 
combined with LFX and reduce opioid withdrawal-related subjective effects; and, 2) if safe and 
effective, can the combination increase the proportion of OUD subjects who transition to XR-NTX. To 
investigate these objectives, preliminary data on the safety and tolerability of PGB/LFX dose 
sequencing, and the reduction of opioid withdrawal-related subjective effects, will be obtained in the 
current trial. We will use a two-arm comparison; PGB/LFX versus LFX/PGB-PLA. If the current trial 
shows that a PGB/LFX combination is likely to be safe effective, and reduces opioid withdrawal 
related subjective effects, we will conduct a second trial in which we will test the PGB/LFX 
combination in a larger sample, under well- powered conditions, to evaluate the results of the current 
trial in relation to the efficacy of the combination to reduce opioid withdrawal-related subjective effects 
and possibly increase the proportion of patients who complete detoxification and transition to XR- 
NTX treatment. The first 2-year component will utilize three sites with inpatient units. Each site will 
recruit around 30 randomized subjects for a total sample size of 90 using DSM-5 criteria to establish 


21 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
OUD with physiologic features diagnosis.  
 
This trial has 4 distinct phases (see 4.0: Figure 1 schematic): 1) Screening (up to 30 days before inpatient 
admission and randomization). Patients who were never randomized and who come back after 30 days must be 
reevaluated and assigned a new screening number; 2) Inpatient Detox (1 – 7) days for medication induction and 
other assessments, 3) Inpatient administration of XR-NTX (Day 8); and, 4) Outpatient Follow-Up (Day 10 and 
Day 15). Dosing for lofexidine and pregabalin will begin at 12:00 on day 1 and be tapered starting at day five. 
This plan will permit dose adjustments for adverse effects, such as BP <90 mmHg systolic or <60 mmHg 
diastolic, a clinically significant drop in standing vs sitting blood pressure, bradycardia <50 bpm, or excessive 
sedation. Subjects that need a procedure repeated can continue inpatient treatment through day 9. The Study 
Schema is seen above in 4.0, Figure 1: Overview of Study Schematics Pregabalin (LYRICA®) plus Lofexidine 
(LUCEMYRATM)”. Study assessments are seen in 5.0 Table 1. 
 
 
7.2 INVESTIGATIONAL AGENT 
7.2.1 Pregabalin Structure (LYRICA®): described chemically as (S)-3-
(aminomethyl)-5- methylhexanoic acid. The molecular formula is 
C8H17NO2 and the molecular weight is 159.23. The chemical 
structure is: 
 
Figure 2. Molecular Structure of Pregabalin 
 
 
It is a white to off-white, crystalline solid with a pKa1 of 4.2 and a pKa2 of 10.6 that is freely 
soluble in water as well as in basic and acidic aqueous solutions. The log of the partition coefficient 
(n-octanol/0.05M phosphate buffer) at pH 7.4 is 1.35. LYRICA (pregabalin) is administered orally and 
supplied as hard gelatin capsules. The study is using the 25 mg strength in green capsules, and 100 
mg strength in blue capsules. The capsule shells contain gelatin and titanium dioxide as well as red 
iron oxide.  The imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium 
hydroxide. 
 
7.2.2 Mechanism of Action. Pregabalin (LYRICA®) binds with high affinity to the 
alpha2- delta site (a subunit of voltage-gated calcium channels) in central nervous system tissues. 
Although its mechanism of action has not been fully elucidated, results with genetically modified 
mice and compounds structurally related to pregabalin (such as gabapentin) suggest that binding to 
the alpha2-delta subunit may be involved in its anti-nociceptive and antiseizure effects in animals. In 
animal models of nerve damage, pregabalin has been shown to reduce calcium- dependent release 
of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing 
calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of 
nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be 
mediated through interactions with descending noradrenergic and serotonergic pathways originating 
from the brainstem that modulate pain transmission in the spinal cord. 
 
While pregabalin is a derivative of the inhibitory neurotransmitter gamma• aminobutyric acid 
(GABA), it does not bind directly to GABAA, GABAB, or benzodiazepine receptors and does not 


22 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
augment GABAA responses in cultured neurons, does not alter rat brain GABA concentration or have 
acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of 
pregabalin increases the density of GABA transporter protein and increases the rate of functional 
GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and 
does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and 
does not inhibit dopamine, serotonin, or noradrenaline reuptake. 
 
7.2.3 Pharmacokinetics. PGB is well absorbed after oral administration, eliminated 
largely by renal excretion, and has an elimination half-life of about 6 hours. 
 
7.2.4 Absorption and Distribution. Following oral administration of PGB under fasting 
conditions, peak plasma concentrations occur within 1.5 hours and oral bioavailability is ≥90% and 
independent of dose. Following single (25 to 300 mg) and multiple-dose (75 to 900 mg/day) 
administration, maximum plasma concentrations (Cmax) and area under the plasma concentration-time 
curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 
24 to 48 hours. 
 
The rate of PGB absorption is decreased when given with food, resulting in a decrease in Cmax 
of approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration 
of PGB with food has no clinically relevant effect on its total absorption of PGB and therefore can be 
taken with or without food. PGB does not bind to plasma proteins. The apparent volume of distribution 
of PGB following oral administration is approximately 0.5 L/kg. PGB is a substrate for a system that is 
responsible for the transport of large amino acids across the blood brain barrier. Although there are no 
data in humans, PGB has been shown to cross the blood brain barrier in mice, rats, and monkeys. In 
addition, PGB has been shown to cross the placenta in rats and is present in the milk of lactating rats. 
 
7.2.5 Metabolism and Elimination. PGB undergoes negligible metabolism in humans. 
Following a dose of radiolabeled PGB, approximately 90% of the administered dose was recovered in 
the urine as unchanged PGB. The N-methylated derivative of PGB, the major metabolite of PGB found 
in urine, accounted for 0.9% of the dose. In preclinical studies, PGB (S-enantiomer) did not undergo 
racemization to the R-enantiomer in mice, rats, rabbits, or monkeys. 
PGB is eliminated from the systemic circulation primarily by renal excretion as unchanged drug 
with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal 
clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because PGB is not 
bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. PGB 
elimination is nearly proportional to creatinine clearance (CLcr). 
 
7.3 DOSING RATIONALE: RISKS AND BENEFITS 
7.3.1 Medication and Blinding US WorldMeds, LLC (Louisville, KY) will provide 
lofexidine (LFX).  Alkermes, Inc. (Waltham, MA) will provide XR- NTX. Each site will have 20 XR-
NTX kits before the study begins to endure immediate availability. The Penn Research Pharmacy will 
prepare blister packs with each day’s planed doses in separate a compartment.  Each compartment 
will be labeled with the dosing time on each inpatient study day.   
Lofexidine will be provided as pink, 0.18 mg tablets; pregabalin as blue capsules for the 
100 mg or placebo doses and as green capsules for the 25 mg or placebo doses.  Medical staff will 
be able to reduce or withhold doses by not removing them from their compartment in the blister pack 
at their scheduled time of administration, after receiving a physician’s order.  Such an order is likely 
to be given after a clinically significant AE that appear to have been study medication-related.  
Examples of possible AE’s are: clinically-significant prolongation of the QTc or QRS; 
clinically significant (>20 mm) drop in blood pressure (BP) compared to the last reading; and/or drop 
in systolic BP of 20 mm or more standing, or 10 mm or more sitting to make it; excessive sedation or 
dizziness (can use manual blood pressure check if considered necessary).  Subjects must exhibit 
mild to moderate opioid withdrawal prior to receiving the first dose of study medication (COWS >/=6, 


23 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
SOWS >/= 4), and pass a naloxone challenge to show they are free of physiologic opioid 
dependence before receiving XT-NTX. 
 
7.3.2 DOSING SCHEDULES  
 
Table 2: LFX Dosing: all tablets are 0.18 mg 
 
Time 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
All 
Groups 
0800 
0.00 
0.54 
0.54 
0.54 
0.54 
0.36 
0.18 
1200 
0.54 
0.54 
0.54 
0.54 
0.36 
0.18 
0.18 
1600 
0.54 
0.54 
0.54 
0.54 
0.36 
0.18 
0.18 
2000 
0.54 
0.54 
0.54 
0.54 
0.36 
0.18 
0.18 
Total 
1.62 
2.16 
2.16 
2.16 
1.62 
0.90 
0.72 
 
 
                     Table 3: PGB and PGB-PLA Dosing (in mg) 
 
Time 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Group 1 
0800 
0 
200 
200 
200 
100 
50 
25 
(PGB) 
1200 
100 
100 
100 
100 
75 
25 
25 
1600 
100 
100 
100 
100 
75 
25 
25 
2000 
200 
200 
200 
200 
150 
100 
25 
Total 
400 
600 
600 
600 
400 
200 
100 
Group 2 
0800 
0 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
(PGB-PLA) 1200 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
1600 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
2000 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
PLAC 
Total 
0 
0 
0 
0 
0 
0 
0 
 
 
7.3.3 Dosing Guidelines:  
 
As stated below investigators may choose to stop or reduce the dose of either Study Medication 
although BP and pulse changes are more likely to be due to lofexidine and sedation due to pregabalin. 
 
- 
Patients can be started and continued on Study Medication if the pulse is 50 or above. Medication 
should be held if the pulse is <50. 
- 
Patients can be started on Study Medications on Day 1 if COWS >/=6 and SOWS >/= 4 
- 
A study physician is required to hold the dose of Study Medication if the systolic BP is < 90 and/or the 
diastolic is <60.  Investigators should hold both lofexidine and pregabalin until the next dosing time 
when they can be restarted if the vitals return to 90/60 or above. 
- 
Hypotension is a potential side effect of lofexidine; sedation, dizziness, or light-headedness are 
potential side effect of pregabalin. A drop of 20 mm or more systolic and/or 10 mm or more diastolic; 
or significant lightheadedness or dizziness, are grounds for holding or reducing a dose of the 
medication that is the most likely cause.  Investigators should use their judgement on which Study 
Medication to hold or reduce and by how much. 
 
  7.3.3.1 The following procedures will minimize risks associated with transient vs. persistent BP 
changes:   
-  
If the BP reading shows a pre-medication sitting and/or standing drop (orthostatic change) of 
more than 20mm systolic, and/or more than 10 mm diastolic, wait 2-3 minutes and repeat the 
sitting and standing BP. 


24 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
-  
If the repeat readings are within the acceptable range as defined by the protocol, dosing can be 
continued as planned.  
-   
If the repeated readings are not within this range as defined by the protocol, hydrate the patient 
and study medication should be administered at the next scheduled dosing time provided they 
are in an acceptable range, as defined by the protocol. Retest the BP within an 
hour.  Depending on the results of the BP retest, the physician has the discretion to give full 
dose, reduced dose, or hold the dose of study medication until the next scheduled dosing time. 
 
Dosing should be given per the protocol scheduled times of 8:00, 12:00, 16:00, and 20:00. However, when 
dosing cannot be given at the protocol scheduled times, Study Medication can be given up to 1 hour pre or 
post the scheduled dose time. On day 1, if dosing cannot be given at the 12:00 scheduled time, after 2 hours, 
wait until the next scheduled 16:00 dose. In case of scheduled dosing changes, medication cannot be 
scheduled less than a minimum of 3 hours apart.  
7.3.4 Potential Risks: These include AEs to PGB, LFX, and XR-NTX (for those who transition to 
it); potential adverse interactions between PGB and LFX; and a small risk from venipuncture. Clinical trials are 
conducted under widely varying conditions thus adverse reaction rates in clinical trials cannot be directly 
compared to rates in clinical trials of another similarly-acting drug, and may not reflect the rates observed in 
clinical practice. 
 
7.3.5 PGB associated AE’s: In controlled and uncontrolled trials across various patient populations 
during premarketing development more than 10,000 patients received PGB; approximately 5000 for 6 months 
or more; over 3100 for 1 year or more; and over 1400 for at least 2 years. 
 
 7. 3. 6  Most common AE’s leading to discontinuation of PGB. In premarketing trials of all 
populations combined, 14% of patients treated with PGB and 7% of patients treated with placebo discontinued 
treatment prematurely due to AEs. AEs most frequently leading to discontinuation were dizziness (4%) and 
somnolence (3%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to 
somnolence. Other adverse reactions that led to discontinuation more frequently in the PGB group compared to 
placebo were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral 
edema (1% each). 
 
7.3.7 Most common AE’s in all pre-marketing controlled PGB studies. In premarketing 
controlled trials of all populations, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and 
"thinking abnormal" (mostly difficulty with concentration/attention) were more commonly reported by subjects 
treated with PGB than placebo (≥5%, twice the placebo rate). 
 
7.3.8 AE’s Leading to Discontinuation in controlled PGB trials. For those of neuropathic pain in 
patients with diabetic neuropathy: 9% of patients treated with PGB and 4% of patients treated with placebo 
discontinued prematurely due to AEs. In the PGB group, the most common reasons for discontinuation were 
dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and 
somnolence. Other reasons for discontinuation with greater frequency in the PGB than placebo groups were 
asthenia, confusion, and peripheral edema. Each led to withdrawal in approximately 1% of patients. Table 4 
lists AEs, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic 
neuropathy in the PGB group for which the incidence was greater than placebo. A majority of PGB patients had 
AEs with a maximum intensity of "mild" or "moderate”. 
 
 
 
 
 
 
 
 
 


25 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4: AE’S in trials of Neuropathic Pain Associated with 
Diabetic Neuropathy in at least 1% of pregabalin-treated 
patients 
 
Body system 
- Preferred term 
75 
mg/day 
[N=77] 
% 
150 
mg/day 
[N=212] 
% 
300 
mg/day 
[N=321] 
% 
600 
mg/day 
[N=369] 
% 
All PGB* 
[N=979] 
% 
Placebo 
[N=459] 
% 
Body as a Whole 
Asthenia 
4 
2 
4 
7 
5 
2 
Accidental injury 
5 
2 
2 
6 
4 
3 
Back pain 
0 
2 
1 
2 
2 
0 
Chest pain 
4 
1 
1 
2 
2 
1 
Face edema 
0 
1 
1 
2 
1 
0 
Digestive System 
Dry mouth 
3 
2 
5 
7 
5 
1 
 
Constipation 
0 
2 
4 
6 
4 
2 
Flatulence 
3 
0 
2 
3 
2 
1 
Metabolic and Nutritional 
Peripheral edema 
4 
6 
9 
12 
9 
2 
Weight gain 
0 
4 
4 
6 
4 
0 
Edema 
0 
2 
4 
2 
2 
0 
Hypoglycemia 
1 
3 
2 
1 
2 
1 
Nervous System 
Dizziness 
8 
9 
23 
29 
21 
5 
Somnolence 
4 
6 
13 
16 
12 
3 
Neuropathy 
9 
2 
2 
5 
4 
3 
Ataxia 
6 
1 
2 
4 
3 
1 
Vertigo 
1 
2 
2 
4 
3 
1 
Confusion 
0 
1 
2 
3 
2 
1 
Euphoria 
0 
0 
3 
2 
2 
0 
Incoordination 
1 
0 
2 
2 
2 
0 
Thinking abnormal† 
1 
0 
1 
3 
2 
0 
Tremor 
1 
1 
1 
2 
1 
0 
Abnormal gait 
1 
0 
1 
3 
1 
0 
Amnesia 
3 
1 
0 
2 
1 
0 
Nervousness 
0 
1 
1 
1 
1 
0 
Respiratory System 
Dyspnea 
3 
0 
2 
2 
2 
1 
Special Senses 
Blurry vision‡ 
3 
1 
3 
6 
4 
2 
Abnormal vision 
1 
0 
1 
1 
1 
0 
* PGB: pregabalin 
† Thinking abnormal primarily consists of events related to difficulty with 
concentration/attention but also includes events related to cognition and language problems 
and slowed thinking. 
 


26 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
7.4 LOFEXIDINE (LFX) 
 
This medication was recently approved by the FDA for opioid detoxification and had been approved 
for the same purpose in the U.K. It is well-absorbed and reaches a peak plasma concentration 3-5 hours 
after a single dose. Administration with food does not alter its pharmacokinetics and about 30% of the 
dose is converted to inactive metabolites during the first pass. Its major metabolites do not influence or 
inhibit CYP450 isoforms except for a slight inhibition of CYP2D6, thus interactions with CYP substrates 
are not expected to be clinically significant. However, we are excluding strong or moderate inhibitors of 
CYP2D6 such as fluoxetine, paroxetine, or mirabegron, bupropion, quinidine, terbinafine, cimetidine, 
cinacalcet, duloxetine, and fluvoxamine. The major contributor to its metabolism is CYP2D6, though 
CYP1A2 and CYP2C19 may also be involved. The elimination half-life is about 12 hours. Nearly all of 
the oral dose is absorbed and accumulation can occur for up to 4 days with repeat dosing. Kidneys are 
the primary route of elimination, and unchanged drug accounts for 15-20% of the dose. 
 
7.4.1 Safety. Concomitant use of LFX may reduce the efficacy of oral naltrexone, therefore 
oral naltrexone cannot be given to patients in this study.   
7.4.2 Methadone and LFX both prolong the QT interval; therefore, methadone cannot be 
given to patients in this study. 
7.4.3 Most common LFX AEs. The most common AE’s (>10%) are orthostatic 
hypotension, bradycardia, hypotension, dizziness, somnolence, sedation and dry mouth. LFX can 
prolong the QT interval and potentiates the sedative effect of benzodiazepines, alcohol and other 
sedating drugs. 
7.4.4 ECG and Vital Signs. ECGs will be reviewed each day before administration of 
the first dose of study medication.  Medication will be withheld if there is clinically significant QTc 
prolongation.  Vital signs will be checked sitting and standing pre-dose and 1-2 hours post dose.  Study 
medication will be withheld if the seated systolic BP is below 90 systolic or below 60 diastolic, and/or if 
the pulse is <50.  A study physician will be contacted for dosing instructions if the seated systolic BP is 
>20 mm, or >10 mm diastolic below the last reading.  Study medications may also be withheld or 
reduced if there is excessive sedation or other clinically significant AE’s that may be caused by study 
medication.  First degree AV block is common and does not indicate a serious problem. Study 
medication should be stopped and the study cardiologist contacted if there is 2nd degree heart block. 
 
           7.5 EXTENDED-RELEASE NALTREXONE (XR-NTX)  
XR-NTX will be offered to all patients who complete detoxification, usually on day 8. It is provided in a 
sealed kit and administered by injection into the gluteal muscle in the upper outer quadrant of the upper 
outer quadrant of the buttock.  Subcutaneous injection may increase the likelihood of severe injection 
site reactions.  To reduce the likelihood of this problem, each needle in the XR-NTX kit is customized 
and no other needle should be used. Needle length may not be adequate in every patient because of 
body habitus and as a result, each participant should be assessed prior to injection to assure that 
needle length is adequate. Patients will be educated to report any injection site reaction and bring it to 
the attention of a clinician and research staff. A physician will examine patients exhibiting abscess, 
cellulitis, necrosis, or swelling to determine if referral to a surgeon is warranted. AEs that have been 
reported in association with XR-NTX treatment are summarized in section 7.5.1 – 7.5.13. 
 
7.5.1 Injection site reactions. These are the most common AEs and were reported in 
50% of the placebo group and 69% of the 380 mg XR-NTX group in alcohol treatment studies. Pain, 
tenderness, induration, swelling, erythema, bruising, or pruritus may follow injections. In some cases, 
injection site reactions may be very severe. In clinical trials for alcohol dependence, one patient 
developed an area of induration that continued to enlarge after 4 weeks and required surgical excision. 
In the post-marketing period, additional cases of injection site reaction with features including induration, 
cellulitis, hematoma, abscess, sterile abscess, and necrosis have been reported. In some cases, these 
problems required surgical intervention, including debridement of necrotic tissue, with some resulting in 
significant scarring. The reported cases were possibly due to excess fatty tissue that interfered with 


27 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
injection into the gluteal muscle. These problems were not observed in the Krupitsky et al study that led 
to FDA approval for opioid dependence (personal communication, Krupitsky, 2011), and not observed in 
the study of XR-NTX for preventing relapse to amphetamine dependence (Runarsdottir et al, 2017). 
 
7.5.2 Precipitating Opioid Withdrawal. XR-NTX will precipitate or exacerbate withdrawal in 
opioid dependent patients unless they have been opioid-free for 7-10 days, and this possibility will be explained to 
study patients. The absence of physiologic dependence will be determined by the study clinicians by observation 
and a COWS scores less than or equal to 10 prior to and 15-20 minutes after a naloxone challenge. If clinically 
significant withdrawal develops, a study physician will treat it with one or more non-narcotic “comfort” medications. 
Note: XRNT may be given to patients after a Naloxone challenge in patients about to go AMA from hospital if the 
naloxone challenge results suggest an absence of physiologic dependence.  
 
 
7.5.3 Liver Toxicity. The most serious adverse effect of XR-NTX is hepatocellular injury, 
which has almost always been associated with oral doses of 1400 to 2100 mg per week. These doses 
result in much greater naltrexone exposure than the 380 mg monthly dose of XR-NTX Data bearing on 
the safety of this dose was seen in a study of actively drinking alcoholics who received a monthly XR-
NTX injections with no evidence of liver toxicity. The study enrolled 624 patients and there were no 
significant differences in ALT, AST, or bilirubin levels between study groups at any post-baseline 
assessment, and the GGT in the 380 mg group was lower compared to placebo at weeks 4, 8, 12, and 
20.  In a subset of patients who were drinking heavily throughout the study, or were obese or taking 
NSAIDs, there was no increase in the frequency of high liver function tests or hepatic-related adverse 
events (Lucey et al, 2008). The Physician’s Desk Reference (PDR) had a “black box” warning about 
XR-NTX and liver damage but removed it in 2013. 
 
7.5.4 Liver Impairment. The pharmacokinetics of XR-NTX have not been shown to 
alter hepatic states in patients with mild to moderate hepatic impairment and dose adjustment is not 
required in these individuals.  XR-NTX pharmacokinetics have not been evaluated in subjects with 
severe hepatic impairment, therefore participants with severe hepatic impairment will be excluded 
from the study. 
 
7.5.5 XR-NTX and Gastrointestinal Effects. The most common have been nausea 
(11% placebo group; 33% XR-NTX), and vomiting (6% placebo; 14% XR-NTX). 
 
7.5.6 XR--NTX and Renal Impairment. A pharmacokinetic analysis indicated that mild 
renal insufficiency (creatinine clearance of 50-80 mL/min) had little or no influence on XR-NTX 
pharmacokinetics and that no dosage adjustment is necessary.  Pharmacokinetics of XR-NTX have not 
been evaluated in subjects with severe renal insufficiency, thus individuals with severe renal abnormalities 
will not be included in this study. 
 
7.5.7  XR-NTX and Gender. In a study of healthy subjects (n=18 females; 18 males), 
gender did not influence the pharmacokinetics of XR-NTX. 
 
7.5.8  XR-NTX and Drug-Drug Interactions. Studies evaluating drug-drug interactions 
have not been performed. 
 
7.5.9   XR-NTX and Reversal of Blockade for Pain Management. In an emergency 
situation, suggestions for pain management are regional anesthesia or non-opioid analgesics. If 
opioids are required, they must be provided in a setting where establishment and maintenance of a 
patent airway and assisted ventilation are readily available from persons trained in the use of 
anesthetic drugs and management of respiratory depression.  


28 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
 
                         7.5.10 Depression and Suicidality. In controlled trials among patients with alcohol 
dependence, AEs of a suicidal nature (ideation, attempts and completed suicides) were infrequent, but 
more common in patients treated with XR-NTX than placebo (1%). In some cases, suicidal thoughts or 
behaviors occurred after study discontinuation but in the context of an episode of depression that 
began while the patient was on the medication. Two completed suicides occurred in alcohol treatment 
studies, both in patients treated with XR-NTX, and depression-related events were more common in 
patients treated with XR-NTX than in those on placebo (1%). However, two studies that have 
specifically examined the relationship between depression and XR-NTX treatment found that 
depression and anxiety decrease in association with detoxification and naltrexone treatment (Mysels et 
al, 2011; Krupitsky et al, 2016)  
 
7.5.11 Naltrexone Contraindications. Patients should not receive XR-NTX if they are 
taking opioid analgesics; have current opioid dependence; are in opioid withdrawal; failed a naloxone 
challenge or have a positive urine screen for opioids; exhibited hypersensitivity to naltrexone, PLG, 
carboxymethylcellulose, or any other components of the diluent; or have acute hepatitis or liver failure. 
 
7.5.12 Opioid Overdose Following an Attempt to Overcome the XR-NTX Blockade. 
Patients will be told that attempting to overcome the blockade by administering large 
doses of opioids may result in fatal overdose. 
 
7.5.13 Eosinophilic Pneumonia. There was one diagnosed, and one suspected case 
of eosinophilic pneumonia in clinical trials. Both required hospitalization and resolved with antibiotics 
and corticosteroids. Should a person receiving Vivitrol ® develop dyspnea and hypoxemia this 
diagnosis should be considered. 
 
7.5.14 Data from the Russian XR-NTX Study of Opioid Dependent Patients: Dr. 
Krupitsky provided the following data from the study that led to FDA approval of XR-NTX for opioid 
dependence (Krupitsky et al, 2011). In that study, 6 of the 126 subjects (4.8%) randomized to 380 mg 
XR-NTX reported injection site pain as compared to one of 124 subjects (0.8%) assigned to XR-NTX 
placebo. ALT in the 380 mg XR-NTX group increased an average of 6.9 IU/L as compared to an 
increase of 5.6 IU/L in the XR-NTX placebo group; AST increased 3.8 IU/L in the XR-NTX 380 mg 
group, and 6.7 IU/L in the XR-NTX placebo group; 63 of the 126 (50%) subjects in the XR-NTX 380 mg 
group reported an AE as compared to 40 of 124 (32%) in the placebo group. Three patients reported 4 
SAEs in the XR-NTX 380 mg group (AIDS/HIV or infections); and 4 reported 5 SAEs in the placebo 
group (2 infections, 1 psychotic disorder, 1 other drug dependence, 1 peptic ulcer). These data 
suggest that the risks associated with XR-NTX among persons with opioid dependence are no 
different or more common that those seen among alcoholics. 
 
 
8.0 STUDY OBJECTIVES 
 
8.1 PRIMARY OBJECTIVES 
 
To determine if PGB can be combined with LFX to reduce opioid withdrawal-related 
subjective effects 
 
8.2 SECONDARY OBJECTIVES 
 
1) 
To determine if PGB plus LFX will result in more successful opiate detoxifications 
Successful detoxification is defined as completing the 7-day regimen/dosing of either 
PBG/LFX or LFX/PGB-PLA without leaving the inpatient unit or otherwise withdrawing from 


29 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
the study; having a SOWS score of less than 6; a COWS score of less than 9; and a urine 
drug screen that is negative for opioids, excluding buprenorphine, and fentanyl. 
2) 
To determine whether PGB plus LFX improves rates of completion of detox and 
receipt of XR-NTX 
 
8.3 ASSESSMENT TOOLS USED TO ACHIEVE OBJECTIVES 
 
The assessment tools used to achieve study objectives are in Table 1.  Effectiveness and safety endpoints, 
based on these assessment tools, are defined in Section 9.2 and 9.4. 
 
9.0 STUDY DESIGN 
This study is a phase II, two-part randomized, double-blind placebo-controlled, study to assess 
the effectiveness of PGB combined with LFX to reduce opioid withdrawal- related subjective effects, 
and to examine whether a PGB/LFX combination can increase the proportion of opioid use 
disordered (OUD) subjects who transition to antagonist treatment (XR-NTX). 
The study will use three sites, each with inpatient units that provide beds and care from nurses 
that will be trained in study procedures and dosing requirements.  Each site will recruit around 30 
randomized subjects, with the Mountain Manor Site and the PENN site possibly recruiting greater 
than 30 subjects, for a total sample size of 90, using DSM-5 to establish an OUD diagnosis with 
physiologic features. This trial has 4 distinct phases (see Figure 1 schematic): 1) Outpatient 
Screening; 2) Inpatient medication induction plus other assessments on Days 1-7; 3) Inpatient XR-
NTX administration on Day 8 or 9; and 4) Outpatient Follow-Up (5 days). Total days in study is 15 
days plus or minus the time taken to complete the initial outpatient screening assessments. 
Randomization will occur before inpatient admission. 
 
9.1  GENERAL DESIGN 
9.1.1  Phase 1: Outpatient Pre-Screening (Up to 30 days before hospital admission). 
Study inclusion and exclusion criteria will be assessed to make sure the subject meets admission 
requirements. Those who meet requirements will be given information and details of the study 
including the timeline, potential risks and benefits, inpatient requirements, confidentiality, and told that 
participation is voluntary. They will be asked to read the informed consent and encouraged to ask 
questions, then given a quiz in which they must answer 9 of 10 answers correctly (three retries 
allowed). Potential subjects will then be asked to sign the informed consent and given a copy.   
- 
 
Once consented, subjects will be screened for up to 30 days to include the following: completion of 
a locator information form, concomitant medications used in the past 30 days, physical, medical 
history, complete blood cell count (CBC) with differential and PLT, INR, CMP with magnesium and 
calcium, urinalysis with reflex microscopy, urine drug screen, a fentanyl urine test, a xylazine urine 
test,  a urine pregnancy test, ECG, creatine kinase test, an eGFR calculation, a Child-Pugh score 
(liver function), MINI assessment for Opioid Use Disorder with physiologic features (e.g. withdrawal), 
Insomnia Severity Index (ISI), Clinical Opioid Withdrawal Scale (COWS), Short Opioid Withdrawal 
Scale (SOWS-G), vital signs (can use manual blood pressure check if considered necessary),  
Timeline Follow- back (TLFB), Clinical Global Impression Scale (CGI), Hamilton Depression and 
Anxiety scales (HAM- D, HAM-A), Columbia-Suicide Severity Rating Scale (CSSR-S), an alcohol 
breathalyzer test, hepatitis B and C tests. Those meeting admission criteria will be asked to report to 
the inpatient unit on Monday through Friday; randomization will occur at hospital admission. Each 
collaborating program will enroll around 30 subjects, 20 to receive pregabalin plus lofexidine and 10 to 
receive placebo pregabalin plus lofexidine. The Pharmacy or designated physician or nurse at each 
site will receive pre-packaged blinded medications from PENN IDS. All study staff will be blinded.  
 
 


30 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
 
 
 
9.1.2 Phase 2: Inpatient Detoxification (Days 1 thru 7). 
 Subjects are admitted to the inpatient unit, randomized to one of the two study medication 
conditions, and will need to demonstrate withdrawal before starting study medications by having 
a COWS >/= 6 and a SOWS >/=  4. LFX and PGB dosing will begin at 12:00 on day 1 and a 
study drug taper will be done from days 5-7. Dose times follow the schedule outlined above and 
adjustments will be made based on BP changes and/or other AEs.  Administration of LFX will be 
withheld or reduced in cases of dizziness or lightheadedness, clinically significant hypotension 
and/or the BP changes described above.  We will explain to participants the importance for 
adequate oral hydration during the consenting process and throughout the detox. Similar 
procedures will be applied to PGB in cases of excessive sedation, dizziness, peripheral edema, 
or other problematic side effects that appear related that medication. 
 
Dosing schedules are in Tables 2 and 3. Assessments for Day 1 through 7 include: 
 
1) ECG is obtained before the 12:00 dose of study medications on Day 1 and before the 
08:00 dose of study medications on Day 2-7 
2) VAS is given before the first dose of study medication at 12:00 on Day 1 and before the 
16:00 dose on Day 1. On Day 2-7, the VAS is given before the first dose of study 
medications at 08:00 and before the 16:00 dose of study medications 
3) ISI given before the 12:00 dose of study medications on Day 1, and before the 08:00 
dose of study medications on Days 2-7 
4)    COWS is given around 12:00 on Day 1 before the first dose of study medication; and 
around16:00 before the next dose of study medication. If subject is admitted without 
the requisite withdrawal (COWS >/= 6 and SOWS >/= 4), subsequent COWS and 
SOWS can be administered before the first dose of study medication until dosing 
criteria is met. 
5)    SOWS-G is given around 12:00 on Day 1 before the first dose of study medication; 
and around 16:00 before the next dose of study medication 
6)    POSS is given prior to all doses (08:00, 12:00, 16:00 and 20:00) of study medication 
 7) Sitting and standing blood pressure and pulse are taken prior to each dose of study 
medication and 1 to 2 hours after dosing, (can use manual blood pressure check if 
considered necessary) 
 8)  Weight taken 1x at screen and Day 15 and recorded on the physical form   
 9)   Adverse events/SAEs recorded daily 
10)  Concomitant medication records reviewed and recorded each day 
11)  C-SSRS is given at the end of each study day 
12)  Comfort medications given on a PRN schedule 
 
Successful detoxification is defined as (a) not leaving the inpatient unit before day 8; (b) 
SOWS of 5 or less and COWS of 8 or less; and, (c) urine drug screen negative for opioids, 
excluding buprenorphine, and fentanyl.  
9.1.3 Phase 3: Inpatient XR-NTX Dosing (Day 8 or 9) 
 
On day 8, subjects will be offered an injection of XR-NTX following naloxone challenge starting 
with a split dose an option of 0.2 mg first, wait 10-20 minutes, then 0.6 mg (0.8 mg I.M of naloxone total) An 
injection of Vivitrol is optional, only if the subject is interested in the XR-NTX treatment), and only if the COWS 
does not rise above 10 (COWS) within 15-30 minutes after the challenge. Subjects will be offered a second XR-
NTX dose in the outpatient research clinic 4 to 5 weeks after the Day 8/9 injection if they wish to continue XR-NTX 
and have been unable to find a community provider.  Subjects who fail the naloxone challenge on Day 8 will 
receive symptomatic treatment, observed until symptoms resolve, and be offered an opportunity for a repeat 


31 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
challenge and injection on day 9. Note:  
Note: XRNT may be given to patients after a Naloxone challenge in Pts about to go AMA from 
hospital if the naloxone challenge results suggest an absence of physiologic dependence.  
- 
 
 
The following assessments will be conducted before the XR-NTX injection: 
1) CK test drawn before IM Injection of naloxone (PGB can elevate CK) 
2) Vital Signs (blood pressure sitting) 
3)  Adverse Events Review 
4)  Urine Pregnancy Test 
5)  VAS scale 
6)  ISI 
7)  SOWS-G 
8)  POSS 
9)  UDS 
10) Urine Fentanyl test 
11) urine xylazine test 
12)  COWS 
13) Naloxone Challenge* 
14) Concomitant Medication Review 
15) C-SSRS 
 
ADMINISTRATION OF EXTENDED-RELEASE NALTREXONE 
 
The following assessments will be conducted after the XR-NTX injection: 
 
1) CGI 
2) HAM-A, HAM-D 
3) Inspection of injection site 
4) Comfort medication(s) (PRN) 
  (It is permissible to give comfort medication at visit 8 for Day 8, 9, and at Day 10 for visit 10, 11, 12, 13, 
14 and 15. No comfort medication will be given by the study after Day 15. Comfort medication needed after Day 
15 will be considered non-study follow-up care. Patients can get comfort medications even if they don’t opt for 
XR-NTX). 
 
* Optional. Subject can opt not to receive this treatment. The Study Physician will discuss with the 
subject other available options. All assessments for Day 8 except the challenge and XR-NTX will still 
be collected. 
9.1.4 Subjects who remain inpatient. Subjects who remain inpatient for a Day 9 
naloxone challenge and XR-NTX administration if they are interested but do not qualify on day 8, will 
be given the challenge as per the procedures for Day 8.  Those who fail a second challenge will be 
counted as having an unsuccessful detoxification and be referred to the most appropriate and 
available treatment. Subjects will be discharged after the XR-NTX injection (or failed challenge) and 
asked to return to the study outpatient clinic for their scheduled Day 10, and Day 15 visits according to 
the intent-to-treat design. 
 
9.1.5 Phase 4: Outpatient Follow-up Visit Assessments (Days 10 and 15) 
 
Assessments at Day 10: (NO POSS) 
1) 
CBC with diff and PLT, chemistry, calcium, UA with reflex microscopy (Magnesium and INR 


32 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
need not be repeated). 
2) 
Fentanyl test (urine) 
3) 
Xylazine test (urine) 
4) 
UDS 
5) 
ISI 
6) 
SOWS-Gossop 
7) 
COWS 
8) 
Vital signs 
9) 
Adverse events, concomitant medications 
10) C-SSRS 
11) Comfort Medication (PRN) 
 
Assessments at Day 15: (NO POSS) 
 
1)    Physical/weight 
 
2)    Urine Pregnancy test for women 
 3)     Fentanyl test (urine) 
 4)     xylazine test (urine)   
 
5)  ISI 
6)  SOWS-Gossop  
7)  COWS 
8)  Vital signs 
9)    Adverse events, concomitant medications 
10)     TLFB 
11) CGI 
12) HAM-D 
13) HAM-A 
14) C-SSRS 
15) Comfort Medication (PRN) 
16) UDS 
 
9.1.6 Optional Safety Visit and F/U Day 36 Visit for Second XR-NTX Injection) 
               
 Subjects may be asked to come in after the last Day 15 visit for one safety visit, if the PI or study 
team feels it is necessary, up to 30 days past the end of study visit or 30 days past the F/U Day 36 visit. This 
safety visit may not be needed for all subjects. The assessments collected will include: CBC, CMP, Ufentanyl, 
Uxylazine, and a urine drug screen. Compensation will be given for travel. 
 
Subjects may be scheduled to receive a second XR-NTX dose in the outpatient research clinic up 
to 5 weeks after the Day 8 or 9 injection if they wish to continue XR-NTX and have been unable to find a 
community provider.  Subjects who present for day 36 (+/- 7 days) will undergo the following procedures:  
1. A urine drug screen 
2. Pregnancy test (women) 
3. Naloxone challenge if there is uncertainty about absence of physiologic dependence 
4. XR-NTX injection 
 
9.2  PRIMARY OUTCOME ENDPOINT 
 
Reduction in subjective withdrawal as measured by the SOWS-Gossop. 
 
9.3 SECONDARY ENDPOINTS 
 
Completion of detox and receipt of antagonist treatment 


33 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
 
10.0 SUBJECT SELECTION AND DISCONTINUATION 
 
All subjects will be recruited at the site level through newspaper and social media advertising, 
primary care practices and outpatient facilities, and community referrals. For a more detailed 
description of recruitment procedures, see section 10.3. Once a potential subject has been identified, a 
CRA or another study staff person will screen him/her for admission/exclusion criteria. For respondents 
that appear eligible and are interested in participating, an appointment will be made to come to the 
research facility and review study procedures, expectations, and other information in more detail. 
The CRA or another study staff person will explain the study and the potential subject will be asked to 
read the study enrollment consent, and encouraged to ask questions about anything that is unclear. 
Subjects still interested in participating will be asked to take a 10-item pre-enrollment quiz and correctly 
answer 9 of 10 true/false questions about the study to be eligible to continue (three additional tries 
permitted). A study physician, or other designated clinical staff person will do the medical history and 
physical. A nurse, physician, medical assistant or other designated personnel will draw blood for 
screening labs, arrange for an ECG whose results will be reviewed by the PI at the site, and if a 
problem is found, will transmit a copy to the Study Cardiologist, and/or the study Medical Monitor 
and/or the Lead Study PI to review before a decision is made as to the next step. If Cardiology is used, 
each site should have a decision sent back to the site within 24 hours.  Upon confirmation that all 
medical and inclusion and no exclusion criteria are met, a study staff person will randomize the subject 
and make an appointment for admission to the collaborating inpatient unit.  
 
 
10.1 INCLUSION CRITERIA 
 
1. Male and/or female subjects ≥ 18 years of age 
2.   Meet DSM-5 criteria for an Opioid Use Disorder with physiologic features.  Have 2 or more of the 11 
DSM 5 criteria for opioid disorder including tolerance and withdrawal features in the last 12 months 
3.   Interested in opioid antagonist treatment 
4.   Have used opioids in 20 or more of the last 30 days 
5. Have a stable address in the local area; not planning to move; have documents for ID check 
6. Absence of medical or psychiatric conditions that are likely to interfere with study participation 
7. Have a 12 lead ECG demonstrating a QTc ≤450 msec and a QRS interval ≤120 msec. The site PI 
has the final determination for inclusion into the study for ECGs unless there is a question of QT 
prolongation or other factors (QTc/Fri uses the Fridericia formula (QTc = QT/RR(1/3)).  If consultation 
is needed, the PENN cardiologists and medical monitor should be contacted 
8.  If female, have a negative pregnancy test and use adequate contraception if of childbearing 
potential 
 
10.2 EXCLUSION CRITERIA 
 
1. Current psychotic disorder (bipolar I, schizophrenia, major depression with psychotic 
features,) as defined by the MINI 
2. An alcohol, benzodiazepine, or other sedative use disorder with physiological features that 
require medication for detoxification 
3.  History of allergy or other serious adverse event due to treatment with pregabalin, XR-NTX, or 
lofexidine 
4. Pending incarceration in the next 30 days 
5. Homicidal or otherwise behaviorally disturbed requiring immediate attention  
6. High risk for suicide as determined by answering ‘yes’ to questions 4 and/or 5 on C-SSRS 
at screening 
7. Blood pressure <90 mm Hg (systolic) or <60 mm Hg (diastolic). If this value is out of 


34 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
normal range, the investigator and study Clinician will decide subject inclusion or exclusion 
on a case-by-case basis, (can use manual blood pressure check if considered necessary) 
8.   Heart rate and/or pulse<50 bpm at screening-sitting 
9.   An Estimated Glomerular Filtration Rate eGFR<90 mL/min/1.73m2 
10. A History of, or current Seizure disorder (excluding childhood febrile seizures) 
11. Inability to read and/or understand English. For example, unable to understand the informed 
consent as demonstrated by failing to answer 9/10 questions correctly on the quiz 
12. Pregnant or breastfeeding 
13. Currently taking sympathomimetic drugs, or a thiazolidinedione antidiabetic  
14.  An ALT and/or AST test that is >4X the upper limit of normal  
15. A Child-Pugh score >7 
16. Currently receiving opioids for pain management 
17. In a treatment study where medication was administered in the last 30 days 
18. Currently using medications that are known to be strong or moderate inhibitors of CYP2D6 such 
as fluoxetine, paroxetine, mirabegron, bupropion, quinidine, terbinafine, cimetidine, cinacalcet, 
duloxetine, or fluvoxamine  
19. In a methadone maintenance or buprenorphine treatment program within the last 30 days 
 
Note: Subjects who fail screening for other than medical or severe psychiatric reasons can be reevaluated by 
staff at a later date. 
 
10.3 SUBJECT RECRUITMENT AND SCREENING 
 
10.3.1  Participating Clinics or Data Collection Centers 
 
1. Penn Presbyterian Medical Center Philadelphia PA 
2. New York State Psychiatric Institute, Columbia University New York New York 
    3. Mountain Manor Treatment Center Baltimore Maryland 
 
Subjects will be recruited from: 1) the community in Philadelphia and other out-patient Clinics in 
Philadelphia, 2) the surrounding communities of the New York State Psychiatric institute and other 
outpatient clinic, and, 3) the Mountain Manor area and other clinics through advertising in local media, 
newspapers, social media, flyers, transit advertising, and word-of-mouth. 
 
 
10.3.2 Study time Table 
 
Figure 3: Projected Timetable 
 
 
Months 1-4 
Study Preparation, Final Staff 
Training, IRB Approval 
 
Months 4-22 
Participant Recruitment & Data 
Collection 
Months 23-24 
Data Cleaning, Analysis, 
Manuscript Preparation
 
The proposed study will be completed within 2 Years 
 
• Months 1-4: September 2019 – January 2020 – IND receipt, IRB approval, protocol 
finalization, case report forms finalized, staff hiring and training completed 
• Months 4-22: January 2020 - July 2021: Recruitment, study 
explained and informed consent obtained outpatient follow-up for 
90 participants.  
• Months 23-24: August 2021: Final data clean-up to ensure accuracy and 
completeness. 


35 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
Enrollment Projections 
 
 
 
 
 
 
 
 
 
Expected 
 
10.3.3 Enrollment Projections 
 
Figure 4 : Enrollment Projections 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.4 TARGET POPULATION DISTRIBUTION (GENDER, RACE, ETC.) 
 
Men and women 18+ years of age. We expect the sample to include 30% women and 30-40% minorities 
(predominantly African American). Female-focused recruitment strategies include direct appeals to female 
medical specialties such as OB-GYN offices. Children under the age of 18 will not be included because the 
safety and effectiveness of XR-NTX extended-release naltrexone has not been established in pediatric patients. 
 
 
10.5 RECRUITMENT OF FEMALE SUBJECTS 
 
Lactating or pregnant females are an exclusionary factor for this study. For the purpose of guidance, the 
following methods are considered acceptable means of birth control for this study: 
 
1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition 
of ovulation (oral, intravaginal; transdermal) 
2. Progestogen-only hormonal contraception associated with inhibition of ovulation such as Mirena (a 
progesterone-only IUD) or similarly-acting oral, injectable, or implantable medications; an 
intrauterine device (IUD) or hormone-releasing system; bilateral tubal occlusion 
3. Diaphragm + spermicide; cervical cap; condom; vasectomized partner; sexual abstinence 
 
During the study and for a week after the subject’s final study treatment the research staff will explain 
to the female subject that they will need to take safety measures to prevent pregnancy by not having sex or 
by using a medically accepted method of birth control such as stated above. Before the study begins, the 
research staff will be asked which form of birth control the subject is currently using, or if they have had a 
tubal ligation, bilateral oophorectomy (both ovaries removed), or hysterectomy and thus no longer require 
hormonal or barrier contraceptives to prevent pregnancy. 
 
If during the 7-day dosing phase of this study we find that a female subject has become pregnant, we 
will discontinue all medications, make the appropriate treatment referral, and discharge the subject from the 
medication phase of the study, but ask that she continues to make the 10 and 15-day follow-up visits.  
1.00 
2.00 
3.00 
4.00 
5.00 
6.00 
7.00 
8.00 
9.00 
10.00 
11.00 
12.00 
13.00 
14.00 
15.00 
16.00 
17.00 
18.00 
19.00 
20.00 
21.00 
22 00


36 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
 
10.6 OBTAINING INFORMED CONSENT 
 
Study procedures will be described by research staff and include the following: Description of 
the study medication and how it is normally used; rationale for why it is being studied for opioid 
detoxification; need to begin the study in an inpatient setting; frequency of dosing and length of 
treatment; potential side effects of pregabalin, lofexidine, and XR-NTX; safeguards and emergency 
procedures; and option to receive sustained release injectable naltrexone or be referred to another 
treatment of one’s choice upon study completion. Collection of lab specimens (number of 
venipunctures and urine specimens required) will be reviewed as will eligibility, number and frequency 
of the research interviews and self-assessments, and payments for participation and completion of 
follow-up assessments. 
 
Subjects will be assured that participation is voluntary, withdrawal from the study will not 
jeopardize future treatment, and that if at any time the research or clinical teams feel subjects need 
another treatment they will be referred to the most available treatment of their choice. All subjects will 
be informed of the potential risks and benefits including medication side effects, and that their 
participation may be discontinued at any time because of serious medication side effects, non-
compliance with treatment, new information regarding the safety of study medications, or if continued 
participation is considered to endanger the welfare of subjects or others. 
 
At the end of the consent review session, a 10-item, multiple choice quiz will be given before the 
subject signs the consent. Subjects scoring below 90% correct will receive additional instructions 
regarding the study and consent, and the quiz will be administered until they score at least 9/10 
questions correctly with a review of the one incorrect question (3 retries allowed). Participants will be 
given a copy of the consent form with the name and telephone numbers of the investigative team and 
the Chair of Penn’s Institutional Review Board (IRB) along with a 24-hour emergency contact. 
 
10.7 SCREEN FAILURES 
 
Those who screen fail are defined as those who sign a consent to participate but are not 
randomized because later assessments find that they do not meet study inclusion criteria. An enrolled 
subject is defined as one for whom written informed consent was obtained, all eligibility criteria are 
met, and he/she has been randomized to receive study medication. Screen failures will be given 
referrals to other available treatments. A list of screen failures, not identified by protected health 
information, will be maintained according to the reason of failure throughout the study. The study will 
use screening numbers before randomization numbers are assigned. 
 
10.8 EARLY WITHDRAWAL OF SUBJECTS 
 
All randomized subjects are included in the intent-to-treat analysis. After day 15, or at 
termination for patients who discontinue the trial prematurely, subjects will be asked to complete 
the following procedures and assessments: physical exam, vital signs, weight, adverse events; 
concomitant medications; blood samples for chemistry, CK, CBC with diff and PLT, liver function; 
urinalysis with reflex microscopy, urine drug toxicology screen; a fentanyl urine test, a xylazine 
urine test, a pregnancy test for females; and the Clinical Global Impression. ECG will be obtained 
for early terminators. Subjects will be referred to the most appropriate and available treatment and 
attempts will be made to obtain these data unless the subject requested they not be contacted or 
cannot be located. 
Subjects will be informed at the consent session that medications could be discontinued if (at 
the discretion of the principal investigator or site physician): 1) Intolerable side effects occur, or 2) 
Extreme lab values with a repeat test occur, or that he/she may be discontinued from the study due to 


37 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
development of psychiatric or medical problems that require a more intensive intervention than 
provided by the study.  Examples are psychiatric symptoms that require inpatient treatment (suicidal 
ideation, acute psychosis, acute mania); clinical deterioration or a change in status that requires 
admission to an inpatient medical service; or development of behaviors that compromise safety of the 
subject or staff. Referrals for care will be made and reasons for subject discontinuation from the study 
medication and/or clinical trial will be documented on the End of Study Final Evaluation Form. 
 
10.9  FOLLOW-UP OF WITHDRAWN SUBJECTS 
 
Standard procedures developed at the treatment sites will be used to locate missing subjects. 
They include identification and verification of home and work phone numbers, emergency contacts, 
and persons who might know where they can be reached.  A subject’s phone number will be called 
during screening to make sure it is valid and to make further screening appointments if necessary. 
Subjects who missed an appointment will be re-contacted on the day of the missed appointment by 
phone, then by letter and finally by registered mail. Contacts will be attempted at least twice a week 
for a minimum of two weeks, then less frequently by mail. Subjects are not considered lost to follow 
up until the study has been completed and the database is ready to be closed. All documents 
regarding phone contacts (attempted and connected) will be noted in a study phone contact form 
and placed in the individual’s study binder. 
 
10.9.1 Follow-up of subjects who need second injections. Subjects who might need 
to receive a second injection of XR-NTX because they were unable to connect to a community clinic 
to continue XR-NTX treatment will be offered a second injection up to week 5 at the research clinic. 
Study staff will again refer them to list of clinics that was given to them at the completion of visits 8 or 
9. Subjects will not be paid for a second injection as it is not a formal study visit. 
 
10.10. DATA COLLECTION 
 
10.10.1 Data Handling & Record Keeping. Data will be entered at each site into a 
REDCap program constructed by the Data Management Unit at the Penn Addiction Treatment and 
Research Center. 
 
10.10.2 Source Documents. Source data include all information, original records of 
clinical findings, observations, or other activities in a clinical trial necessary for its reconstruction and 
evaluation. These data are in source documents such as: hospital records, clinic and office charts, 
laboratory notes, memoranda, evaluation checklists, pharmacy records, original data in paper form 
to be recorded into the automated REDCAP instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiche, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at laboratories, or medico-technical 
departments involved in the clinical trial. 
 
10.10.3 Case Report Forms (CRFs). As described in the “assessments” section, they 
include all primary data collection instruments and are entered and checked through the Penn data 
management system (REDCap). This includes all concomitant medications as well as records of 
adverse events. Each site will be responsible for reviewing and maintaining data entry of all case 
report forms into REDCap data system. All adverse events entries and serious adverse events 
entries must be reviewed by the study nursing staff and the site PI.  If the PI cannot resolve the 
serious designation of an event, the site should contact the medical monitor (Dr. Woody). All paper 
sourced assessment documents should be recorded into REDCAP daily. Where ever possible, 
direct entry into RECAP is requested. 
 
 
 


38 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
10.11 STUDY MEASURES; SEE TABLES 1 FOR SCHEDULES OF ADMINISTRATION 
 
1. Medical History: Done by the appropriate clinical delegated individual at 
screening 
2. Physical/Weight: Done at Screen; and at Day 15 
3. Pulse and blood pressure: done sitting and standing 1X at screen, done Day 1 
through Day 7 done before receiving Study Medication and 1 - 2 hours after receiving 
medication, 1X on Day 8, 1X (sitting only) on Day 10 (sitting only), and 1X on Day 15 
4. ECG: 1X at Screen, 1X each day for Day 1 through Day 7 
5.   Complete Blood Count with diff and PLT: Done at Screening and Day 10 
6.   Chemistry and calcium: Done at Screening and at Day 10 or Day 15 if not obtained at 
Day 10  
7.   Magnesium Screening (magnesium need not be repeated at EOS) 
8.   Creatine Kinase at screening and Day 8, and early termination 
9.   Hepatitis B and C done at screening 
10. Urinalysis with reflex microscopy: Done at Screening and Day 10 
11. Urine Toxicology Drug Screen. CLIA Waived and FDA approved on-site test with 
Buprenorphine, or get an additional buprenorphine test, done at screen, day 8/9, day 10, 
and day 15. 
12. Urine Fentanyl. Done at Screen, Day 1, Day 8/9, Day 10, and Day 15. 
13. Urine Xylazine .  Done at Screen, Day 1, Day 8/9, Day 10, and Day 15. 
14. Urine pregnancy test: Screen and Day 1, Day 8/9 prior to the XR-NTX injection, and at Day 15 
15. Adverse Events: Collected by research staff at each visit, Day 1 through Day 15 
16. Clinical Global Impression Scale (CGI; Guy,1976): A brief severity rating of 
overall health at time of interview using a 7-point Likert scale. Completed by a study 
staff person and the subject. Administered at day 1, day 8, and EOS 
17. Clinical Opioid Withdrawal Scale (COWS; Wesson & Ling, 2003): An 11-item, staff 
administered instrument that measures objective signs of opiate withdrawal. Done 1X 
at screen, 2X daily Day 1 through Day 7, 2X (naloxone challenge) on Day 8* 
(optional), and 1X on Day 10, and 1X Day 15 
18. Short Opioid Withdrawal Scale (SOWS-Gossop; Gossop, 1990): A 10-item, staff 
administered scale that measures patient’s perceptions of opiate withdrawal. Done 
1X at screen; 2X daily Days 1 - Day 7; and 1X on Days 8, 10, and 15. 
19. CONCOMITANT Medication (CONMEDS): Any prescribed or non-illicit non-Study 
Medications used 30 days before screening, and on Day 1 through EOS 
20. COMFORT Medication: See prescribed medications given for comfort during Day 1 
through Day 7, AND Days 8, 10, and 15 by inpatient or outpatient Staff. Only the 
following comfort medications provided by the study are recommended to be 
given as needed: ondansetron 4 mg or 8 mg tid PO PRN for nausea and vomiting, 
trazodone 100 mg HS PRN insomnia, loperamide 2 mg qid PO PRN diarrhea, and 
a non-steroidal such as Ibuprofen 600 mg qid PO PRN for aches and pains or 
acetaminophen 650 mg (2 tablets 325 mg) PO qid PO PRN,  cyclobenzaprine 5 mg 
tid PO PRN for muscle aches and pains, and hydroxyzine 25 mg qid PO PRN  
anxiety. In cases of QTc prolongation that are not >550ms or judged to require 


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Protocol V9.0                                                                                                                            11/2/2022 
stopping study medications, diphenhydramine 50 mg hs PO PRN  may be used for 
insomnia, and  trimethobenzamide 300 mg qid PO PRN for nausea. These 
medications will come from the standing inventory at each site. Other comfort 
medications can be substituted, however the recommended medications should be 
used first. Any comfort medication that is used must be recorded on the comfort 
medication CRF on whichever day they are used. All comfort meds ingested on 
Day 8 (or Day 9) whether ingested when an inpatient or outpatient should be 
recorded on the comfort medication form for those days.  It is permissible to give 
comfort medication at visit 8 for Day 8, 9, and at Day 10 for visit 10, 11, 12, 13, 14 
and 15. Comfort medications on Day 15 are counted as what was taken on the 
calendar day of day 15. No comfort medication will be given by the study after Day 
15. Comfort medications on Day 15 are counted up to and including what was 
taken at the time of visit on calendar day 15. Comfort medication needed after Day 
15 will be considered non-study follow-up care. Patients can get comfort 
medications even if they don’t opt for XR-NTX). 
21. Hamilton Depression Rating Scale (Ham-D; 1960): A 20-minute, 24- item, research 
staff- administered instrument. Done 1X at screen, 1X Day 8, and 1X Day 15 
22. Hamilton Anxiety Scale (Hamilton A; 1959).  A 5-minute, 14-item, research staff- 
administered instrument. Done at 1X at screen, 1X Day 8, and 1X Day 15 
23. Insomnia Severity Index (ISI; Bastien, 2001). 7-item, research staff administered 
scale; takes about 3 minutes; 1X at screen, 1X Day 1 through Day 7, 1X day 8, 1X 
Day 10, and 1X Day 15 
24. Mini-International Neuropsychiatric Interview for DSM- 5 (MINI; Sheehan 1998): 
Identifies current and lifetime DSM-5 Axis I major psychiatric disorders. Takes about 
20 minutes; administered by trained clinician at Screen. 
25. Opioid Craving Visual Analog Scale (VAS; McMillan & Gilmore-Thomas 1996): Self-
administered 100 mm scale. Done 2X daily Day 1 through Day 7, 1X on Day 8 
26. Pasero Opioid-Induced Sedation Scale (POSS; Pasero, 2009): Brief, study staff 
or designee administered scale. Done 4X daily (before each dose) Day 1 through 
Day 7, 1X on Day 8 
27. Timeline Follow-Back Interview (TLFB; Sobell & Sobell, 1995): A semi-structured staff 
administered interview of self- reported drug use over the past 90 days at screen and 
EOS (2- weeks). 
28. The Columbia–Suicide Severity Rating Scale (C-SSRS) is an assessment tool that 
evaluates suicidal ideation and behavior. It is given at screening and every day from Day 
1 through Day  8, and at day 10 and 15. 
 
10.12 SAFETY ASSESSMENTS 
 
Total number of adverse events leading to medication discontinuation (in judgment of study 
physician), patients reporting at least one adverse event, clinical lab results, ECG, vital signs, weight and 
evidence of worsening (by urine drug screen results and TLFB results) will be considered in assessing safety. 
 
See Table 5 for the list of laboratory tests to be performed. Additional tests may be performed at any 
time during the study as determined necessary by the Investigator or required by local regulations. All study- 
required laboratory assessments will be performed by the site laboratory. 
 
The Site Investigator must review laboratory reports and document this review, and laboratory 
reports must be filed with source documents. Clinically relevant changes that lead to changes in study 


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Protocol V9.0                                                                                                                            11/2/2022 
drug, study participation, or use of concomitant treatment will be recorded as AEs on the AE CRF. 
Clinically significant abnormal laboratory findings are those not associated with the underlying disease 
unless judged by the Investigator to be more severe than expected for the subject's condition. 
 
All laboratory tests with values that are judged significantly abnormal during study participation 
should be repeated. If they do not return to normal/baseline within a period of time judged reasonable by 
the Investigator, the likely cause should be identified, an AE form completed, and the Sponsor notified.  
 
Table 5. Clinical Laboratory Tests to Be Performed for This Study 
 
CBC 
CMP 
Urinalysis 
Hemoglobin 
Urine Color 
Hematocrit 
Appearance 
Red blood cells 
Sodium 
pH 
Mean corpuscular volume 
Potassium 
Specific gravity 
(concentration) 
Mean corpuscular hemoglobin 
Chloride 
Protein 
Mean corpuscular hemoglobin 
concentration 
Carbon Dioxide 
Glucose 
Red blood cell distribution width 
Glucose 
Ketones 
White blood cell count 
Creatinine 
Bilirubin 
White blood cell Differentials: 
Albumin (ALB) 
leukocyte esterase 
Neutrophils 
Total protein 
Nitrite 
Lymphocytes 
Calcium 
Blood 
Monocytes 
Phosphorus 
Urobilinogen 
Eosinophils 
Basophils 
Aspartate aminotransferase 
(AST) 
 
Alanine aminotransferase 
(ALT) 
UA Microscopy 
White blood cell count 
Platelet count 
Total bilirubin 
Red blood cell count 
Epithelial cells 
Alkaline phosphatase 
Bacteria 
Other: 
Blood urea nitrogen 
Yeast 
INR 
Direct Bilirubin 
Crystals 
CK 
 
Cast 
Magnesium 
 
Mucous 
HCV Antibody 
 
 
HBcAb (core) 
 
 
HBsAg (surface antigen) 
 
 
HBsAb (surface antibody) 
 
 


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Protocol V9.0                                                                                                                            11/2/2022 
Subjects who are administratively withdrawn for medical issues will be followed up to document 
the outcome of the event. Subjects who voluntarily withdraw from the medication phase will be 
asked to complete the other visits as scheduled. Subjects who voluntarily withdraw from the study 
and wish no further contact will not be followed up. The reasons for all discontinuations will be 
documented in a study source document.  
 
10.13 PROTECTION OF SUBJECTS 
 
Potential subjects will be screened for conditions that would preclude use of PGB, LFX or 
XR-NTX.  Adverse events will be monitored by medical and research staff on a daily basis. 
Subjects will be given a 24-hour emergency number they can call if necessary.  If the subject is 
discontinued from study treatment due to, an AE, he/she will be followed by medical staff until it 
resolves or becomes stable. Potential subjects will be excluded if they have a history of a severe 
psychiatric disorder (schizophrenia, bipolar I, depression with suicidal attempts); impairment of  
renal function; severe liver disease; participated in a medication study within the last 30 days; 
have an illness which may require hospitalization during the study; history of allergy or other SAE 
due to treatment with PGB, XR-NTX or LFX, taking sympathomimetic drugs, or a 
thiazolidinedione antidiabetic; or impending incarceration;. Pregnant females or women who 
refuse to use acceptable forms of birth control will also be excluded. 
. 
10.13.1  Venipuncture. Venipuncture will be carried out with good aseptic technique 
by a nurse or physician or qualified designated person. 
 
10.13.2  Risks Associated with Study Procedures 
• 
Behavioral Ratings: Risks are minimal and limited to breach of confidentiality or 
becoming anxious or embarrassed by some of the questions. Procedures to protect 
confidentiality and reduce study-related anxieties are described in section 22.0. 
• 
Potential Benefits: Subjects benefit from close medical and psychiatric attention over 
and above that which they receive in an inpatient detoxification. 
 
10.13.3  Risk Benefit Ratio: The first step for transitioning from opioid addiction to 
antagonist treatment is detoxification, often using an alpha-adrenergic agonist such as clonidine or 
LFX. However, patients often drop out due to the dysphoria and other uncomfortable subjective 
effects of withdrawal and do not transition to naltrexone. The recent studies summarized above 
provide data to suggest that PGB can reduce these subjective effects, however the risks and benefits 
of a /LFX combination have not been studied. Both medications are FDA-approved and we have no 
reason to think they cannot be safely used together, but they have not been tested. 
 
Identifying a dosing combination that improves detoxification success and transition to antagonist 
treatment has the potential to improve the number of patients that benefit from its relapse and 
overdose protection effects. For these reasons, we think that the risk/benefit potential of this dosing 
combination is significant in the likely event that it is safe and effective. 
 
10.13.4 Medical Management of Adverse events. Evaluation and management of AE’s may 
include additional medication, transfer to a medical unit, reduction in study of medication, temporary 
cessation of study drug, or early termination from the trial if necessary. 
 
11.0 METHODS FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS 
 
11.1  RANDOMIZATION 
 
Dr. Lynch will develop a program using computer-generated, randomly permuted blocks within each site  
 


42 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
that are stratified according to male/female. Upon completing screening assessments, research 
staff will request randomization be performed by the site research pharmacy. The patient will be 
sequentially assigned to the next treatment based on male/female status. At all sites, patient 
treatment will correspond to a unique randomization number. 
 
Penn IDS will upload the randomization lists into a Treatment Unmasking Program, per IDS 
SOP-309. Access to this trial within the program will be provided to authorized Penn users. In the 
event of an emergency, unmasking can occur at any time using the subject’s assigned randomization 
number. The user will not be unmasked to the treatment of other subjects. For other sites, Dr. Lynch 
will give the randomization list to PENN IDS who will be responsible for maintaining the 
randomization blind. 
 
11.2  RANDOMIZATION OF PLACEBO AGENT 
 
The Penn IDS will prepare the placebo medication as matching blinded capsules containing Lactose 
Monohydrate, Spray-Dried, NF. Blinded placebo capsules will be packaged into blister packs along 
with lofexidine tablets, in separate compartments that are labeled for dosing times on days 1-7 and 
ship them to the research sites. 
 
11.3  BLINDING OF STUDY DRUG 
 
Penn IDS will prepare blinded PGB capsules by over-encapsulation of the drug into shells 
matching the placebo capsules. Blinded PGB capsules will be packaged into blister packs along with 
LFX tablets, in separate compartments that are labeled for dosing times on days 1-7 and ship them to 
the research sites.   
 
11.4 RECEIPT OF XR-NTX  
 
The study will use XR-NTX in 380 mg kits supplied by Alkermes, Inc. Alkermes will ship 
directly to each site a shipment of 20  XR-NTX kits per site. Sites will be responsible for receiving, 
storage, administration, and accountability for each subject. Sites must use the DIMS system for 
accountability of dispensed Vivitrol to control product expiration dates. Sites will also be 
responsible for the destruction and expiration of unused drug (see destruction procedures for XR-
NTX). Accountability, expiration, and destruction will be recorded on a XR-NTX accountability log. 
Each site will administer XR-NTX according to the package insert instructions. 
 
11.5 RECEIPT OF NALOXONE 
 
Subjects will be offered a naloxone challenge on day 8 using 0.8 mg or 1.0 mg I.M. If 
the COWS scores do not rise above 10 within 15-30 minutes, subjects will receive an injection of 
XR-NTX* given by a study nurse (or NP, etc.), physician (or PA, etc.) or other licensed and 
trained health care provider.  Each site will acquire their own supply of naloxone and will be 
responsible for the storage, accountability, and dispensing throughout the trial. (*Naloxone 
challenge and receipt of XR-NTX is optional. Subject can request guidance on another form of 
treatment). 


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Protocol V9.0                                                                                                                            11/2/2022 
 
11.6  PREPARATION AND ADMINISTRATION OF STUDY DRUG 
 
Study medication will be prepared by the Investigational Drug Service at the Hospital of the 
University of Pennsylvania (phone: (215-349-8817). It will be sent to the sites and stored and 
dispensed by their respective research pharmacies/or designated unit at the three sites.  
 
11.7  COMFORT MEDICATIONS 
 
In addition to study medications, subjects can receive, as needed, the following “comfort” medications: 
ondansetron 4 mg or 8 mg tidPO PRN for nausea and vomiting, trazodone 100 mg HS PRN insomnia, 
loperamide 2 mg qid PO PRN diarrhea, and a non-steroidal such as Ibuprofen 600 mg qid PO PRN for aches and 
pains or acetaminophen 650 mg (2 tablets 325 mg) PO qid PO PRN,  cyclobenzaprine 5 mg tid PO PRN for 
muscle aches and pains, and hydroxyzine 25 mg qid PO PRN  anxiety. In cases of QTc prolongation that are not 
>550ms or judged to require stopping study medications, diphenhydramine 50 mg hs PO PRN  may be used for 
insomnia, and  trimethobenzamide 300 mg qid PO PRN for nausea. It is permissible to give comfort medication at 
visit 8 for Day 8, 9, and at Day 10 for visit 10, 11, 12, 13, 14 and 15. No comfort medication will be given by the 
study after Day 15. Comfort medications on Day 15 are counted up to and including what was taken at the time of 
visit on calendar day 15. Comfort medication needed after Day 15 will be considered non-study follow-up care. 
Patients can get comfort medications even if they don’t opt for XR-NTX). 
 
 Each site will maintain records on use of these medications on the Comfort Medication Log. Comfort medications 
will be acquired, stored, and dispensed by each site’s research pharmacy or designated person. Store according 
to the information found in the package insert. 
 
11.8  PRIOR AND CONCOMITANT MEDICATIONS 
 
Prior and concomitant medications are defined as any medications taken before enrolling in 
the study that continues into the study and any medication (not comfort medication or study drugs) 
that are prescribed during the study. They are not the study medications (those provided in the 
blister packs). They must be recorded on the study concomitant medication form and entered into 
the database. For example, a diuretic for hypertension medication. All field (start date, dose, times 
per day, stop date, etc.) must be captured and recorded for the month before the initial screening 
visit through the follow up assessment. 
 
11.9 RULING OUT CURRENT PHYSIOLOGIC DEPENDENCE BEFORE XR-NTX ADMINISTRATION 
 (NALOXONE CHALLENGE)   
 
The COWS will be performed before administering XR-NTX, to assess the subject’s signs/symptoms 
of withdrawal. Naloxone administration should start with a split dose of 0.2 mg first, wait 10-20 minutes, then 
0.6 mg ( 0.8 mg total). Following in the challenge, the patient should be monitored for 15-30 minutes for the 
appearance of opioid withdrawal. The absence of physiologic opioid dependence is seen by COWS scores 
that are < /=10. If clinically significant withdrawal is shown, a study physician will treat it with one or more of 
the approved non-narcotic “comfort” medications. 
 
1. Signs and Symptoms of a positive naloxone challenge might include: 
 
▪ Objective—tearing, sweating, goose bumps, shakes, vomiting, pupillary dilatation, vital sign 
increases 
▪ Subjective—feeling of temperature change, joint and/or muscle pain, bone pain, nausea, 
abdominal cramping, skin crawling 
 
2. If opioid abstinence syndrome is precipitated by naloxone, symptoms will be apparent within a few 


44 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
minutes and maximal within 20 minutes after administration, but the patient must be observed for 
15-30 minutes 
 
If manifestations of opioid withdrawal are evident following the naloxone challenge do not initiate naltrexone 
therapy due to potential risk of precipitating more severe and prolonged withdrawal with XR-NTX; the 
naloxone challenge test may be repeated in 24 hours (inpatient Day 9) in these patients. 
 
If withdrawal symptoms are present, the patient should be treated with withdrawal reducing medication or 
equivalent and observed until symptoms have resolved (about 20 minutes). 
 
If evidence of withdrawal is absent, naltrexone therapy may be initiated. Please note that even minor and/or 
transient GI symptoms following naloxone challenge be considered evidence of withdrawal since patients with 
such symptoms will often develop severe and disturbing GI symptoms if XR-NTX therapy is then initiated. 
 
3. Signs and Symptoms of positive naloxone Challenge might include: 
 
▪ 
Objective—tearing, sweating, goose bumps, shakes, vomiting, pupillary dilatation, vital sign 
increases 
▪ 
Subjective—feeling of temperature change, joint and/or muscle pain, bone pain, nausea, 
abdominal cramping, skin crawling 
 
4. If an opioid abstinence syndrome is precipitated by naloxone, symptoms will be apparent within a 
few minutes and maximal within 20 minutes after administration. 
 
If manifestations of clinically significant opioid withdrawal are evident following the naloxone challenge test, do 
not initiate naltrexone therapy due to potential risk of precipitating more severe and prolonged withdrawal with 
naltrexone; naloxone challenge test may be repeated in 24 hours (inpatient Day 9) in these patients. 
 
If withdrawal symptoms are present, the patient should be treated with the clinically most appropriate 
withdrawal reducing medication and observed until symptoms have resolved (about 20 minutes). 
 
If evidence of withdrawal is absent, naltrexone therapy may be initiated. Please note that even minor and/or 
transient GI symptoms following naloxone challenge be considered evidence of withdrawal since patients with 
such symptoms will often develop severe and disturbing GI symptoms if XR-NTX therapy is then initiated. 
 
12.0 RECEIVING, STORAGE, DISPENSING AND RETURN 
 
12.1 RECEIPT OF PGB, LFX, AND XR-NTX 
 
PGB and LFX will be prepared in blister packs and shipped to the research pharmacies or 
designated persons at each treatment site by the Investigational Drug Service at the University of 
Pennsylvania.  Resupply of packs is requested by email to: PennIDS@pennmedicine.upenn.edu. Upon 
receipt of study treatment medication, an inventory is to be completed and a drug receipt log filled out and 
signed by the person accepting the shipment. It is important that the designated study staff count and 
verify that the shipment contains all items noted in the shipment inventory.  Any damaged or unusable 
study drug in a shipment (active drug or comparator) will be documented in the study files. XR-NTX will be 
shipped by Alkermes directly to the sites. The sites are responsible for destruction of the study medication 
per the site’s documented procedures and regulations for controlled substances. 
 
12.2 STORAGE OF INVESTIGATIONAL MEDICATION 
 
Study medication will be sent from the Penn Research Pharmacy to the sites and stored at their research 


45 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
pharmacies or designated research medication storage sites.  It must be stored at 20°C to 25°C (68°F to 77°F) 
with excursions permitted to 15°C - 30°C (59°F to 86°F).  Each site should maintain temperature records 
throughout the trial and be able to provide them upon request. If sites have a temperature excursion relating to 
study drugs, please contact the Investigational Drug Service at 215-349-8817. 
 
12.3 DISPENSING OF INVESTIGATIONAL MEDICATION 
 
After randomization, study drug will be dispensed to each subject from an assigned blister pack according 
to his/her randomization number at the appropriate times by nurses on the inpatient units at the collaborating 
site. Unused study medication will be collected per site SOP.  
 
 12.4 RETURN AND DESTRUCTION OF STUDY DRUG 
 
All unused study medication is to be saved, documented, and returned to the Research 
Pharmacy or designated person at each site and destroyed at the site according to SOPs for that 
site.  Upon completion of the study, there will be a final reconciliation of study medication that 
was provided, consumed, and returned.  Penn IDS will maintain inventory and subject 
accountability in Vestigo, an electronic, web-based pharmacy research program. A similar 
inventory reconciliation will be performed at each site. If electronic recording is not used at the 
collaborating sites, the research pharmacy or designated person(s) at the site will keep records 
for the reconciliation of administered, spoiled, expired, and unused drug.  Paper logs must be 
signed and dated and any discrepancies noted will be investigated, resolved, and documented. 
Unused study drug will be destroyed in a manner consistent with regulations governing Schedule 
V medications. Medication should not be destroyed until the QA monitor has audited the drug 
accountability log. 
 
12.5 DISPENSING XR-NTX 
 
On day 8 or 9, a 380 mg injection of XR-NTX will be administered according to subjects’ 
consent and evidence that detoxification has been successful, by a negative naloxone 
challenge. Dosing will be maintained in a Drug Accountability Log and recorded in RedCap. 
Subjects who are unable to find an outpatient provider will be offered a second dose of XR-NTX 
up to 5 weeks after day 8 or 9 (day 36 + 7 days). 
 
12.6 STUDY DRUG ACCOUNTABILITY 
 
US WorldMeds LLC will provide LFX and send it to the University of Pennsylvania’s IDS 
pharmacy. Penn IDS will acquire PGB for all sites and the supplies necessary for preparing active and 
placebo blister-packs. Alkermes, INC. will provide XR-NTX and will send it to each collaborating site. 
Comfort medications and naloxone will be acquired separately by each site. 
 
 
All study drug received, dispensed, administered, and returned will be managed by study site 
personnel and site pharmacies for sites, and the Penn Investigational Drug Service for the PENN 
site. Medications must be used only as described in the protocol and by the appropriately licensed 
Investigators named in Form FDA 1572. Study staff will retain the original individual blister-cards, 
including those empty, partially empty, or full, as well as used and unused XR-NTX kits.  Unused 
medications will be collected and handled as per site SOP.  Disposition of any study drug lost or 
damaged must be documented on the site accountability log or by a report by the site pharmacy. 
Unused or expired study drug will be retained at the participating site or pharmacies until the site is 
monitored. After the monitor audit, unused medication can be destroyed according to their usual 
procedures and documented in the regulatory file. 


46 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
13.0 STATISTICAL PLAN 
 
13.1  DATA ANALYSES 
 
Kevin Lynch, PhD, the CSA Statistician, and his staff will perform data analyses. Prior to 
analyses, standard data screening/cleaning procedures will be applied. These procedures will 
screen the data for data-entry errors, check for outliers, assess the extent and pattern of missing 
data, and check that appropriate assumptions of normality are met whenever necessary. 
 
13.2  SAMPLE SIZE DETERMINATION 
 
Power Analyses: The primary goal of this study is to determine if the PBG/LFX combination 
versus LFX/PGB-PLA is safe and effective in OUD individuals, and shows a reduction in opioid–
related withdrawal effects greater than lofexidine alone. To assist in this determination, we 
provide power for the primary comparison of longitudinal subjective withdrawal measures, 
comparing the groups on rate of decrease across days, using a linear group by time effect for the 
mixed effects models described above. We have one primary outcome, so use an alpha level of 
0.05, and we use two- sided tests. 90 subjects, approximately 30 from each of three sites (MMTC 
and PENN might have more than 30), who will be randomized into two groups, with 30 assigned 
to LFX/PGB-PLA, and 60 to LFX plus a starting daily dose of 400 mg of PGB and increasing to 
600mg PGB on day 2. Assuming an overall dropout rate of 40%, and within-subjects’ correlations 
of 0.5, the methods of Hedeker et al (Hedeker, Gibbons and Waternaux, 1999) show that this 
provides 80% power for a group by linear time interaction effect of Cohen’s d=0.44 standard 
deviations between the two groups. 
 
13.3 STATISTICAL METHODS 
 
13.3.1 Primary Outcome - Reduction in SOWS-Gossop criterion. The primary outcome will be 
reduction in subjective withdrawal as measured by the SOWS - Gossop (scores range from zero to 30). The 
groups will be compared on the 14 repeated SOWS-Gossop responses obtained during the seven-day 
detoxification period, using linear mixed-effects regression models; the SOWS-Gossop total will be regressed on 
a three-level factor for site, and a two-level factor for medication group, with time and group by time effects. The 
covariance structure will include a random intercept and correlated residuals, with a random slope included if 
necessary for fit. Contrasts between the PGB group and the PGB-PLA group will be estimated from the model. 
Exploratory analyses of heterogeneity of dose effects across sites will be performed including a site by dose 
interaction term in the main model. 
These models will provide valid estimates and tests if any missing data is statistically ignorable (Laird, 
1998). Dropout may be associated with reports of subjective withdrawal, and will be ignorable if available 
subjective scores prior to dropout are predictive of dropout. To assess possible effects of non-ignorability on 
inference, we will perform sensitivity analyses using pattern- mixture models and selection models. For pattern 
mixture models, subjects are grouped on the basis of their pattern of missing data. Usually, rarely occurring 
patterns are grouped, so as to keep the number of pattern-groups at a manageable level. This grouping defines a 
nominal variable, which is then used as a predictor in the analyses, although a covariate representing 
missingness on a continuous scale can also be used. The regression coefficients associated with this variable, 
and its interactions with the other predictors, quantify how response-predictor relationships differ across the 
different patterns of missingness. Overall predictor effects may be found by averaging over the patterns (Little, 
1993). For longitudinal data, subjects are usually stratified according to the visit after which they dropped out. 
Hedeker and Gibbons (1997), and Hedeker and Rose (2000), apply these methods to mixed effects models in 
longitudinal data. Selection models (Little, 1995; Kenward, 1998; Verbeke and Molenberghs, 2000) take a 
different approach, by explicitly modeling the probability of drop out, and incorporating the predicted probabilities 


47 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
into the main longitudinal analysis. Heuristically, this can be thought of as a two-stage process, but usually the 
two steps are performed as part of a single model. Any approach to non-ignorability requires us to make 
assumptions on the variables associated with missing data, and on the form of the relationship between the 
variables and dropout. Comparisons between the predictions of the primary analyses, and each set of pattern 
mixture and selection models, provides some evidence for assessing the sensitivity of results to missing data. 
 
 
13.3.2 Secondary Outcomes. Completion of and receipt of antagonist treatment: Our 
completion threshold criterion is based on the study of Fishman et al (2019), where completion of 
detoxification was defined as “proportion of participants completing the study, defined as having 
received at least 1 dose of study medication on day 7 and completing the 3.5- hour post dose 
SOWS-Gossop assessment on day 7. Receipt of antagonist treatment will be defined as 
completion of the process to receive antagonist treatment and receipt of the first dose.  
 
We will define a three-category ordinal response: (1) failure to complete detoxification, (2) 
completion with failure to start antagonist treatment, (3) completion and receipt of antagonist 
treatment. We will compare these groups using ordinal logistic regression models, with a three- 
level factor for site, and a two-level factor for medication group, as the explanatory variables. 
13.4 SAFETY OUTCOMES 
13.4.1 Suicidality. We will compare the groups on presence of active suicidal ideation on the basis 
of the C-SSRS, which will be administered daily. We define Active Suicidal Ideation to be an endorsement of 
either Question 4 (active ideation without plan) or 5 (active ideation with plan). If there is sufficient variability 
in these repeated binary outcomes, we will compare the groups using a mixed effects logistic regression 
model, similar to the linear mixed effects models described above for the primary outcome; if variability is too 
low, we will use a (non-mixed-effects) logistic regression model to compare the groups on proportion of 
participants reporting active ideation at any time in the period 
13.4.2 Sedation. The POSS will be administered four times a day on dose days, yielding a set of 
repeated measures on the POSS score for each participant. We will compare the groups on this score, using 
linear mixed effects models similar to those described above for the primary outcome. 
13.4.3 Elevated Creatine Kinase. On day 8 of detoxification, participants will be classified as having 
elevated creatine kinase if their level is more than three times their screening level. We will compare groups 
on this response using a logistic regression model with site and group as explanatory variables. 
13.4.4 Edema. We will compare groups on the proportion of participants whose study medications 
were discontinued due to peripheral edema, using a logistic regression model with site and group as the 
explanatory variables. 
 
13.5 TOLERABILITY OUTCOMES 
 
13.5.1 Achiness. The SOWS-Gossop scale will be administered twice a day. Item 10 yields an 
ordinal measure of achiness. We will use mixed effects ordinal logistic regression models, with site and 
group as the main explanatory variables, to compare the groups on their probabilities of the different 
ordinal levels. 
 
13.5.2 Anxiety. Item 1 of the SOWS-Gossop yields an ordinal measure of anxiety, and we will 
compare the groups using mixed effects logistic regression models as for the Achiness item above. 
 
13.5.3 Insomnia. The Insomnia Severity Index will be administered daily during detoxification, 
and yields a total score. We will compare the groups on the score using linear mixed effects models 
similar to those described for the primary outcome. 


48 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
 
13.6 SUBJECT POPULATION FOR ANALYSIS 
 
All subjects who are randomized will be analyzed according to the Intent-to-Treat study design. 
 
13.7 ADVERSE EVENT RECORDING AND REDCAP SYSTEM ENTRY 
 
AE names will be recorded based on the Medical Dictionary for Regulatory Activities (MedDRA) preferred 
terms found in the REDCap Database. Information regarding adverse events (AEs) will be recorded in 
REDCap and on an adverse event log and will include the following: 
• 
AE Description 
• 
AE Code 
• 
Expectedness 
• 
Date of Onset/ Change in Severity 
• 
Continuous or Intermittent 
• 
Severity 
• 
Seriousness 
• 
Study Drug Relatedness 
• 
Action Taken Regarding Study Drug 
• 
Other Actions Taken 
• 
Outcome 
Coding will be from a list of terms provided to each site formulated using MedDRA medical terminology. 
 
 
13.8 VITAL SIGNS 
Vital sign data (HR and BP) will be presented as summary statistics of maximum (max) absolute values, 
max change from baseline, and time to max value during the 1-hour period after each dose of study 
medication. Data will be compared between groups and within groups by study day by Wilcoxon rank sum 
statistic. Effects will be considered statistically significant at a two-sided p < 0.05. 
 
14.0 DATA MANAGEMENT 
 
14.1  DATA ACQUISITION AND TRANSMISSION 
 
14.1.1  Data Entry Methods. This study will use the University of Pennsylvania REDCap 
(Research Electronic Data Capture) data system for data entry capture. REDCap is a widely-used, 
secure web application that can be used to build and manage surveys and databases online. It provides 
audit trails for tracking data manipulation and user activity, and provides Data Queries options for 
documenting and controlling the process of resolving data issues using a data resolution workflow option. 
 
Data will be collected by trained study staff using standardized forms with a study number to 
identify the participant. A code linking the participant to the study group will be kept confidential in a 
password protected database. The Physician, nurse practitioner, clinical research coordinator and 
Clinical Research assistants (CRAs) at each site will be responsible for collecting and checking clinical 
data at their site. All data entered will be cross-checked by an independent research monitor assigned to 
the project ensuring that all fields are completed appropriately, the database is complete and accurate, 
and corrections are done according to GCP requirement. Any inconsistencies/deviations will be 
documented and reviewed by the PI and reported to the required oversight departments IRBs etc.). 
 
 
 


49 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
 
15.0 SAFETY AND ADVERSE EVENTS 
 
15.1  DEFINITION OF ADVERSE EVENT (AE) 
 
Any symptom, sign, illness, or experience that develops or worsens during the course of the 
study. Abnormal results of diagnostic procedures are considered AEs if they result in study 
withdrawal, are associated with a serious adverse event, lead to additional treatment or further 
diagnostic tests, and/or are considered by the investigator to be of clinical significance. Normal 
withdrawal events are not recorded as AEs unless extreme or exacerbated. 
 
15.2  ADVERSE EVENT REPORTING PERIOD 
 
The period during which AEs must be reported begins at study screening and ends at the 
last follow-up. 
 
15.3  POST-STUDY AEs 
 
At the last scheduled follow-up, the investigator and /or clinical staff will instruct each subject 
to report any subsequent event(s) that the subject or the subject’s physician or treatment staff 
believes might reasonably be related to study participation. The investigator should notify the 
study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated participation that may reasonably be related to the study. The sponsor 
should also be notified if the investigator becomes aware of the development of cancer or a 
congenital anomaly in a subsequently conceived offspring of a subject that has participated in the 
study.  Patients who become pregnant during the study should be followed up to determine if there 
was any evidence of fetal harm or an abnormality. 
 
15.4  ABNORMAL LABORATORY VALUES 
A laboratory abnormality should be documented as an AE if any of the following conditions 
are met: 1) A repeat test confirms it; 2) It suggests a previously undetected disease and/or organ 
toxicity; 3) It requires active management; e.g. discontinuation of medication, more frequent 
follow-up assessments, further diagnostic investigation, etc. 
 
15.5  HOSPITALIZATION, PROLONGED HOSPITALIZATION & SURGERY 
 
Any AE that results in hospitalization or prolonged hospitalization will be reported as a 
SAE unless it involves detoxification for relapse to opioid dependence since they are common 
and expected in studies involving opioid addicted individuals. Any condition that requires surgery 
should be documented as an AE or SAE, depending on the need and length of hospitalization. 
However, neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an AE in the following circumstances: 
• Hospitalization or prolonged hospitalization is for diagnostic or elective surgical 
procedures for a preexisting condition. 
• Hospitalization or prolonged hospitalization is required for the study. 
• Hospitalization or prolonged hospitalization for treatment of the disease 
addressed by the study unless it is a worsening or increase in the expected 
frequency of admissions. 
 
 
 


50 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
15.6  RECORDING AE’s 
 
At each patient contact the research team will seek information on AEs by questioning 
and, as appropriate, by examination. Information on AEs will be recorded in a source document 
and the appropriate CRF. The course of each event will be followed until resolution, stabilization, 
or it has been determined that study treatment or participation is not the cause. SAEs that are 
ongoing at the end of the study will be followed up to determine their outcome. Any SAE that 
occurs after the study and is considered possibly related to it is to be recorded and reported. 
 
15.7  REPORTING SAE’s 
 
The Penn IRB considers disability, hospitalization or prolongation of hospitalization, 
congenital defects, and life-threatening events to be SAEs that must be reported (orally, e-mail, 
fax) to the Penn IRB when they are identified if judged related or possibly related to the study, or 
unexpected. In such cases, a report to the Penn IRB and NIDA is to be filed within 5 working 
days. When additional information is available, a follow-up and/or final SAE report is to be filed. If 
the report is a narrative, the minimum necessary information at the time of the initial report 
should include: identifier, subject number, description of event, date of onset, current status, if 
study treatment was discontinued, reason why the event was serious, and whether it was related 
to study treatment or procedures. Copies of each report and documentation of IRB notification 
and receipt will be kept in the study file. 
 
15.8  STUDY SPONSOR NOTIFICATION BY INVESTIGATOR 
 
A serious adverse event must be reported to the study sponsor (Penn) by fax, email 
or telephone within 72 hours of when the event is reported to any of the study staff. A Serious 
Adverse Event (SAE) form must be completed by the investigator and faxed or emailed to the 
study sponsor within 72 hours. The investigator will keep a copy of this SAE form on file at the 
study site. Report serious adverse events by phone and facsimile to the study sponsor: 
 
Kyle M. Kampman, M.D. 
kampman@upenn.edu 
(Sponsor) 
215-506-3799 beeper 
215-746-2988 fax 
George E. Woody, M.D. 
woodyg@upenn.edu 
215-746-7702 
215-746-2988 fax 
(Medical Monitor) 
 
At the time of the initial report, the following information should be provided: 
 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Whether study treatment was 
discontinued 
• 
The reason why the event is classified 
as serious 
• 
Current status 
• Investigator assessment of the 
association between the event and 
study treatment 
 
Within the following 48 hours, the investigator must provide further information on the serious 


51 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
adverse event in the form of a written narrative if such information has been received. This should 
include a copy of the completed Serious Adverse Event form, and any other diagnostic information 
that will assist the understanding of the event. Significant new information on ongoing serious adverse 
events should be provided promptly to the study sponsor. 
 
 
15.9  REPORTING DEATHS 
 
The Penn IRB requires that investigators report a death within 24 hours of staff becoming aware 
of it, if it was unexpected or indicates that participants or others are at increased risk of harm. Other 
deaths are to be reported within 72 hours regardless of whether they were related to study 
participation. 
 
15.10  OTHER REPORTABLE EVENTS 
 
The following are also reportable to the Penn IRB: 
• Any AE that, even without detailed analysis, represents a SAE that is rare 
in the absence of drug exposure (i.e. agranulocytosis, hepatic necrosis, 
Stevens-Johnson syndrome). 
• Any AE that would cause a change in the product information, protocol or 
informed consent, or would prompt IRB action to assure protection of human 
subjects. 
• Information that indicates a change to the risks or benefits of the research, in 
terms of severity or frequency as, for example: safety monitoring indicates that a 
side effect is more severe or more frequent than expected; new information shows 
that an arm of the study is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a study medication. 
• Breach of confidentiality 
• Protocol change that was taken to eliminate an apparent immediate hazard. 
• The research team cannot resolve a participant complaint indicating unexpected risks. 
• Protocol violation (an accidental or unintentional deviation from the protocol) 
that in the opinion of the investigator placed one or more participants at 
increased risk or affects their rights or welfare. 
• Reporting results: After final data are analyzed, the team will prepare reports 
for scientific, peer-reviewed journals describing the clinical outcomes. The data 
will be made available, after publication, to other scientists who wish to 
perform additional analyses. 
 
15.11  IRB NOTIFICATION BY INVESTIGATOR 
 
Reports of all serious adverse events (including follow-up information) must be submitted to the IRB 
based on the IRBs current AE/SAE reporting requirements and timeline for reporting (e.g. 5 business days). 
Copies of each report and documentation of IRB notification and receipt will be kept in the study regulatory 
binder. 
 
15.12  FDA NOTIFICATION BY SPONSOR 
 
The study sponsor (Penn) shall notify the FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use of the drug as soon as 
possible based on the FDAs current SAE reporting requirements and timeline for reporting (e.g. no 
later than 7 calendar days from the sponsor’s original receipt of the information). 
 


52 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
If a previous adverse event not initially deemed reportable is later found to fit the criteria for 
reporting, the study sponsor (Penn) will submit the adverse event in a written report to the FDA as 
soon as possible based on the requirements and timeline (e.g. but no later than 15 calendar days 
from the time the determination is made). 
 
 
16.0 STUDY MONITORING/AUDITING/AND INSPECTION 
 
A research monitor will be selected by the sponsor and assigned to this trial and be responsible 
for completing the monitoring process. A CV for the monitor will be obtained, updated bi-annually, and 
kept in the regulatory binder to document the monitor’s qualifications. Monitors will meet with the sponsor 
and review the protocol, CRF and the monitoring checklists that are completed by study staff. 
On-site or remote monitoring will include: 
• compliance with ICH and GCP(R2) oversight 
• regulatory and protocol compliance 
• data quality 
• participant safety 
• source data verification 
• review and analysis of eligibility requirements 
• informed consent procedures 
• adverse events and all associated documentation 
• review of study drug administration/treatment 
• regulatory files, protocol departures reporting 
• pharmacy records 
• response assessments 
• data management (data entry timelines for assessments as defined by the protocol) 
 
16.1  STUDY INITIATION VISIT 
 
The Principal Investigator will be responsible for assuring via personal contact with co- 
investigators, the monitor, and clinical staff that the research team understands and accepts the 
obligations incurred in the undertaking of this clinical trial. 
The Principal Investigator and monitor will meet with the clinical staff (research nurses and 
study technician) to ensure they understand and accept the following: the nature of the protocol and the 
requirements for an adequate and well-controlled study; obligation to conduct the investigation in 
accord with 21 CFR Parts 312, 511, 812, 813 and any other applicable regulations; obligation to obtain 
informed consent in accord with 21 CFR Part 50; obligation to obtain IRB review and approval of a 
clinical investigation before the investigation is initiated and ensure continuing review of the study by 
the IRB in accord with 21 CFR Part 56; and keep the sponsor informed of IRB approvals and 
subsequent actions concerning the study. 
Training will consist of an explanation of the protocol and review of the CRF. In addition, the 
duties of each member of the staff outlined in all applicable regulations will be reviewed. All questions 
will be answered. 
A report of the Study Initiation will be written by the monitor detailing the visit, specifically noting 
the information reviewed with the clinical staff and any questions generated during the training. The 
report will be filed in the regulatory binder. A copy of the Study Initiation Report will be sent to the 
Office of Human Research, University of Pennsylvania School of Medicine, Room 150 Anatomy- 
Chemistry Building, Philadelphia, PA 19104-6061. 
 
 


53 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
16.2 MONITORING VISITS 
 
Monitoring will be conducted in accord with University of Pennsylvania Sponsor-Investigator 
Standard Operating Procedure PM 504. Enrollment will be complete when 90 patients are 
randomized into the trial. Approximately 2 patients/site will be randomized per month and monitoring 
visits conducted periodically throughout the study. The first visit will occur no more than two weeks 
after the first patient is entered. Subsequent visits will be conducted quarterly, as described below. 
• 
Visit 1: Initiation Visit 
• 
Visit 2: Approximately 25% of subjects to be randomized have completed the trial and 100% 
Source Document Verification for the first two randomized subjects 
• 
Visit 3: Approximately 50% of subjects to be randomized have completed the trial. 
• 
Visit 4: Approximately 100% of subjects to be randomized have completed the trial. This visit 
serves as the closeout-monitoring visit. 
If a greater than 10% error rate is noted during the data review, the monitor will source data verify 100% of the 
data on a larger sample at the following monitoring visit 
 
16.3  MONITORING LOG 
 
At the beginning of each monitoring visit, the monitor and any representative of the Sponsor 
participating in monitoring must sign and date the monitoring log. 
 
16.4  MONITORING REPORT 
 
All monitoring visits will be documented on the Monitor’s Report and Visit Checklist. The original 
report for each visit will be filed in the regulatory binder and copies of the report will be sent to the Data 
Safety Monitoring Board (DSMB) and the Office of Human Research at the aforementioned address. 
 
16.5  VISIT 4: CLOSE-OUT VISIT 
 
Monitoring visits can be documented on the Visit Report form located on the Penn Office of Human 
Research (OHR) website. The monitor and investigator will review the report and file it in the Monitoring 
Binder. In addition to the Monitoring Visit Report, the monitor will write a letter to the PI addressing each 
component of the visit and queries will be given to the study staff to complete within the next month. 
 
 
17.0 MEDICAL MONITORING 
 
17.1 SAFETY AND MEDICAL MONITORING 
 
The Site Principal Investigator will oversee the safety of the study at his/her site. The Study PI 
and the Medical Monitor will oversee safety procedures at each site. Safety monitoring will include 
assessment and reporting of adverse events as noted above, as well as construction and 
implementation of a site data and safety-monitoring plan (see section 9 Auditing, Monitoring and 
Inspecting). Medical monitoring will include a regular assessment of the number and type of serious 
adverse events. The Medical Monitor for this study is Dr. George Woody. 
 


54 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
18.0 ETHICAL CONSIDERATIONS AND SAFETY 
 
18.1  GOOD CLINICAL PRACTICE (GCP) 
 
This study will be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312; International Conference on Harmonization guidelines) 
and all applicable governmental regulations and institutional policies and procedures. The 
protocol and any amendments will be submitted to NIDA, and the Penn IRB for approval before 
procedures are changed unless they require immediate action to protect participants’ safety. All 
subjects will be given a copy of the informed consent describing the study with sufficient 
information for them to make an informed decision about participation. Any information obtained 
in connection with the study that can be used to identify participants will be kept confidential. An 
informed consent will be written and submitted along with the protocol for review by the Penn 
IRB if this study is funded. No procedures will be done unless the participant has reviewed and 
been given the opportunity to ask questions about the purpose and procedures used in the study 
and understand its risks and benefits. All participants must sign the informed consent in order to 
participate in the study. 
 
18.2  MEDICAL EMERGENCIES 
 
Patients that have a medical emergency during the study will be told to consult a study 
physician, their primary care provider, or go to the nearest emergency room and tell them when they last 
received study medication. Patients will be given a wallet card that identifies them as participating in a 
medication study and possibly receiving PGB, LFX, or XR-NTX. The subject can ask them to call the 
telephone numbers listed on the wallet card for further instructions or information. In the event that a 
patient is hurt or injured as a result of participation in the study, he/she is to contact the investigator listed 
on the consent form. In the event of physical injury resulting from research procedures, treatment will be 
provided without cost to the patient, but financial compensation is not otherwise offered from the 
University of Pennsylvania or the participating site. If the patient has an illness or injury that is not directly 
related to study participation, the patient’s insurance or will be responsible for the cost of medical care. 
 
18.3  UNBLINDING PROCEDURES 
 
All research staff will be blind to the medication status until the end of the study. An off-site statistician 
will work with the Penn research pharmacist in setting up the randomization sequences. The patient will be 
sequentially assigned to the next treatment based on male/female status. At Penn IDS, the treatment will 
correspond to a unique randomization number. 
 
Penn IDS will upload the randomization lists into a Treatment Unmasking Program, per IDS SOP-309. 
Access to this trial within the program will be provided to authorized Penn users. In the event of an emergency, 
unmasking can occur at any time using the subject’s assigned randomization number. The user will not be 
unmasked to the treatment of other subjects. The subject, or treating physician can call the site PI to notify him 
or her of the medical emergency and request a release of authorization of medical information for the non- 
study treating physician. Study personnel will follow-up with an attempt to secure written authorization from the 
subject, if possible, for the authorization to release medical information to the stated non-study physician. 
 
19.0 STOPPING RULES 
 
19.1  STUDY STOPPING CRITERIA 
 
In addition to oversight by the University of Pennsylvania IRB and Office of Human Research, 


55 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
the trial will be conducted under the supervision of a Data Safety and Monitoring Board, as outlined 
below in section 8.6.1. This independent board will review the study every 6 months. The DSMB is 
charged with monitoring the safety of participants and the quality of the data, as well as the appropriate 
termination of studies either when significant benefits or risks have been uncovered or when it appears 
that a clinical trial cannot be concluded successfully. The DSMB will review all adverse events and will 
have access to unblinded data in order to determine the association between adverse events and study 
medication. If a pattern of significant adverse events is uncovered that suggests that the risks of 
continuing the trial outweigh the expected benefits of the trial then the DSMB will recommend that the 
study be stopped. 
 
19.2  MEDICATION DISCONTINUATION CRITERIA 
 
All randomized subjects are included in the intent-to-treat analysis. All subjects who 
prematurely discontinue treatment will be scheduled for a final evaluation and end-of trial visit (unless 
these two fall within 2 weeks of each other), and the follow up visit. Subjects are not dropped from all 
study activity unless they request to not be contacted or cannot be located for assessment. 
 
Subjects will be informed at the consent session that medications may be held or discontinued due to 
intolerable side effects, hypotension or other problematic cardiovascular effects, or extreme lab values 
confirmed by a repeat test. (AST or ALT levels greater than 4 times upper limit of normal; elevated BUN, 
creatine kinase, or other evidence of renal damage). Subjects will also be informed at the consent session that 
he or she may be discontinued from study treatment due to: 1) Development or exacerbation of significant 
psychiatric or medical symptoms which necessitate admission to a medical unit or an intervention different 
from that provided by the protocol; 2) Clinical deterioration for any reason or a clinical status which 
necessitates inpatient admission; 3) Prolonged QTc after repeat ECG; 4) Blood pressure is less than 90 mm 
Hg (systolic) or less than 60 mm Hg (diastolic). For sitting to standing blood pressure (orthostatic change), if 
there is a change in systolic blood pressure of more than 20mm or diastolic blood pressure more than 10mm  
HG, the dosing nurse or physician may hold the lofexidine or pregabalin dose until the next dose and then 
recheck (can use manual blood pressure check if considered necessary). If at any point blood pressure is less 
than 90/60 the nurse or physician should also hold the lofexidine or pregabalin dose and consult a study 
physician. If for any dose, the blood pressure results remain below the previously stated minimum mmHg by 
the next scheduled dose, the next dose may be reduced or withheld. Dosing discontinuations can be 
discussed with the Lead PI and the medical monitor if it impacts subject continuation in the dosing part of the 
study. The reason the subjects misses their next dose of Study Medication or discontinues from Study 
Medication must be documented in the subject’s casebook 
 
20.0 SUBJECT STIPEND AND REIMBURSEMENTS 
 
Each site will reimburse subjects as per the procedures below: 
 
TABLE 6: PENN SUBJECT STIPENDS AND REIMBURSEMENTS 
 
Screen 
Day1 
Day2 
Day3 
Day4 
Day5 
Day6 Day7 Day8 
Day9 
Day10 Day15 
InPatient 
Admission 
InPt 
InPt 
InPt 
InPt 
InPt 
InPt 
InPt 
VIVITROL 
InPt 
optional 
F/up 
F/up 
50.00 
125 
125 
125 
125 
125 
125 
125 
125 
125 
50 
50 
10.00 
10.00 
10.00* 
10.00* 
10.00 
10.00 
Total 
60.00 
135.00 
125 
125 
125 
125 
125 
125 
135.00 
135.00 
60.00 
60.00 
 
 
This study will use Greenphire ClinCard as the payment method. The patient’s social security 
number will be collected but not used or stored in any data records kept by the research study 


56 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
staff. Subjects will receive $50 for completing screening assessments and a maximum of $10.00 
total for travel reimbursement for screening. During this inpatient phase of the study, patients will 
be reimbursed $125.00 per day for completing assessment for a possible total of up to $1000.00, 
plus $20.00 for travel on days 1 and 8 (admission and discharge) for a total of $1200. If subjects 
are inpatient for 9 days, however, as seen in Table 8 above, the maximum reimbursement for 
completing all assessments for screening and the 9 inpatient days will be $1175, plus a total of 
$20.00 for travel reimbursement for Screening on Days 1 and 9 for a maximum total for completing 
all assessments of $1205.00. For the follow-up visits-Day 10 and Day 15, subjects will receive 
$50.00 for completing all outpatient assessment for a total of up to $100.00, plus a total of $20.00 
for travel reimbursement for a total of $120.00. The maximum that a subject can receive for 
screening, a 9-day inpatient stay completing all assessments, plus outpatient visits and travel 
reimbursement is $1325.00 for the study. The maximum that a subject can receive for the 8-day 
inpatient stay, completing all assessments plus travel reimbursement is $1200.00. 
 
TABLE 7: MOUNTAIN MANOR SITE SUBJECT STIPENDS AND REIMBURSEMENTS 
 
 
 
Screen 
Day1 
InPt  
Admt 
Day
2 
InPt  
Day
3 
InPt  
Day
4 
InPt  
Day
5 
InPt  
Day6 
InPt 
Day7 
InPt 
Day 
8 
InPt 
VIVITROL 
Day 
9 
Possible)  
InPt 
VIVITROL 
Day 
10 
F/up 
Day 
15 
F/up 
Assessments 
Total 
50 
125 
125 
125 
125 
125 
125 
125 
125 
125 
50 
50 
Travel 
10 
10 
 
 
 
 
 
 
10* 
10* 
10* 
10* 
Total 
60 
135 
125 
125 
125 
125 
125 
125 
135 
135 
60 
60 
 
This study will use Clinical Trials Payer (CT Payer) gift cards as the method of payment.  
• 
Subjects will receive $50 for completing assessments during the screening visit.  
• 
During the inpatient phase of the study, upon completion of all assessments on each inpatient day, 
patients will be compensated $125.00 (Days 1-8; possibly including day 9).  
 
• 
For the follow-up visits-Day 10 and Day 15, subjects will receive $50.00 for completing all 
assessments. In addition, subjects will receive $10.00 reimbursement for travel for the screening visit, 
for travel on the day of inpatient admission and discharge*, and travel for the day 10 and day 15 follow-
up visits. The maximum that a subject can receive for a 9-day inpatient stay plus outpatient visits, and 
travel reimbursement is $1325.00. The maximum that a subject can receive for the average 8-day 
inpatient stay and completing assessments plus travel reimbursement is $1200.00. You will only receive 
reimbursement for travel if you are traveling to or from the treatment center for study related reasons. 
You will receive your CT Payer Card and be reimbursed during screening but will not be reimbursed for 
other study procedures until you are released from inpatient care. 
 
Please note: In order to be compensated for participation in this study, you must provide your Social 
Security Number. Additionally, please note that the University of Pennsylvania is required to report to 
the IRS any cumulative payments for participation in research studies that exceed a total of $600 in a 
calendar year. 
 
 
TABLE 8: COLUMBIA SITE SUBJECT STIPENDS AND REIMBURSEMENTS 
 
 
Screen 
Day1 
Day2 
Day3 
Day4 
Day5 
Day6 
Day7 
Day8 
Day 9 
Day10 
Day 15 
 
InPt Admt 
InPt 
InPt 
InPt 
InPt 
InPt 
InPt 
InPt 
 optional 
OutPt 
OutPt 


57 
 
 
Protocol V9.0                                                                                                                            11/2/2022 
VIVITROL 
F/up 
F/up 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
10.00 
10.00 
 
 
 
 
 
 
    10.00 
10.00* 
 10.00 
 10.00 
Total 
 
 
 
 
 
 
 
 
 
 
 
60.00 
60.00 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
60.00 
60.00 
60.00 
60.00 
 
You will be paid during the study. The study involves time-consuming assessments that are not included 
in usual treatment and you will be paid for the time and travel needed to complete assessments. You 
will receive $50 for completing assessments during the screening visit. During the inpatient phase of the 
study, upon completion of all assessments on each inpatient day, you will be compensated $50 for a 
possible total of up to $450 if you are inpatient for 9 days, however as seen above, the expected average 
inpatient stay is 8 days. For the follow-up visits-Day 10 and Day 15, you will receive $50 for completing 
each outpatient assessment for a total of up to $100. In addition, you will receive $10 reimbursement for 
travel for the screening visit, travel on inpatient admission day and discharge from inpatient, and $50 for 
the day 10 and day 15 follow-up visits. The maximum that you can receive for a 9 day inpatient stay plus 
outpatient visits, and travel reimbursement is $650.00 for the study. The maximum that you can receive 
for the average 8-day inpatient stay and completing assessments plus travel reimbursement is $600.00. 
 
Please note: In order to be compensated for your participation in this study, you must provide your 
Social Security Number. For compensation of $600 or more, we are required by law to reports your 
earning to the IRB. 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 not that 
payments 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. 
 
21.0 POTENTIAL BENEFITS 
 
This study is designed to identify a non-opioid detoxification medication protocol that is easy to 
use, does not require special licensing, and can increase the chances that opioid addicted patients 
are able to transition to naltrexone. If hypotheses are confirmed the study will have identified a 
medication that is more effective than current options for detoxifying opioid addicted patients. 
 
22.0 CONFIDENTIALITY 
 
22.1  HIPAA COMPLIANCE 
 
All research staff have HIPAA training, support the privacy of clinical and research data 
collected as part of any study, and follow NIH policy in use and disclosure of protected health 
information in a manner that respects privacy in accord with the “Privacy Rule” under the Health 
Insurance Portability and Accountability Act (HIPAA) and other applicable laws. All subjects sign a 
HIPAA-authorization form, receive a copy of this form, and receive a notice of the site’s privacy 
practice. HIPAA signed forms are retained in locked file cabinets with patients’ source documents. 
 
Information about study subjects will be kept confidential and managed according to requirements 
of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require 
a signed subject authorization informing the subject of the following: 
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 


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• 
The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts should be 
made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 
 
No information about subjects will be disclosed to others without the subject’s prior written 
permission, except as stated in the informed consent, or if necessary to protect the rights or welfare 
of a subject in accordance with the law. Names or unique identifying information are never used in 
the publication of research data. Procedures designed to maintain confidentiality include: (1) formal 
training for all research staff on the importance of confidentiality; (2) procedures to protect a patient’s 
confidentiality; and (3) formal mechanisms limiting access to information that can link data to 
individual patients. Data forms that include identifying information are kept in locked cabinets. Only 
the unique identification (ID) number, assigned at the time of initial contact represents patients 
during data entry, data transfer, analyses, or other file management procedures. To facilitate 
tracking, a password-protected computer file on a secure server is maintained containing the 
identity of patients, ID numbers, and information about how they can be reached. This file, however, 
contains no clinical data. All data are stored in a securely locked area accessible only to authorized 
research personnel. The Principal Investigator (PI) is required to allow trial-related monitoring, 
audits, IRB review, and regulatory inspection by providing direct access to source documents. The 
FDA, IRB, and other regulatory authorities will also have access to source documents. We inform 
subjects of this access in the informed consent. HIPAA regulations are followed. 
 
 
23.0 INDEPENDENT DATA AND SAFETY MONITORING BOARD 
 
23.1  DESCRIPTION 
 
A safety monitoring board has been established at the Center for the Studies of Addiction with the 
following purpose (according to NIDA guidelines): to assure that the safety of study subjects is protected 
while the scientific goals of the ongoing studies are being met. The DSMB is charged with monitoring 
safety of participants and quality of the data, as well as the appropriate termination of studies when 
significant benefits or risks have been uncovered or a clinical trial cannot be concluded successfully. 
 
23.2  BOARD MEMBER QUALIFICATIONS 
 
All board members will meet NIDA requirements regarding background and experience, and 
none will have ethical conflicts, including financial interest related to study outcome. Individuals invited 
to serve on the board will disclose any potential conflicts in writing. The board will meet every six months 
(unless more frequent meetings are deemed necessary) and will be chaired by James McKay, M.D., a 
faculty member within the Department of Psychiatry at the University of Pennsylvania. Other members 
of the board include faculty of the University of Pennsylvania School of Medicine, Department of 
Psychiatry.  
 
When the current study is reviewed, Dr. Kampman will prepare and submit a summary report 
on the trial status, followed by a closed session under the direction of Dr. McKay. Issues related to 
recruitment, subject safety and efficacy, whether the primary study question is being answered, 
conflict of interest, confidentiality, and ongoing study review (including AEs, SAEs, and regulatory 
issues) will be assessed. Following each DSM Board meeting, Dr. McKay will make recommendations 
to Dr. Kampman, and a final report (edited by all Board members) will be prepared and submitted to 
NIDA, the Penn IRB, and (if required) the FDA. In addition to semiannual reviews, at the occurrence of 


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the second medication associated serious adverse event or after the first fatal medication associated 
adverse event the protocol will be reviewed by the DSMB the DSMB to consider modifications to the 
protocol or discontinuation. 
 
24.0 DSMP STUDY MONITORING PLAN 
 
This study has a monitoring plan on file with NIDA. The investigator will allocate adequate 
time for such monitoring activities and also ensure that the monitor or other compliance or quality 
assurance reviewer is given access to all the above noted study-related documents and study 
related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct 
the monitoring visit. 
 
25.0 COVID SAFETY PLAN 
 
a. Risk for COVID Procedures: 
1. COVID PRECAUTIONS – University of Pennsylvania 
  
I. 
When you bring your study subjects in for their visit to 3535 for their screening visit, you 
should perform a nasal swab for ROUTINE SARS-CoV-2 testing. This should be ordered and 
sent to the Presby lab. The results will be back within 24 hours. 
II. The Director of Infection Control at PPMC, and the Infection Control team will provide 
guidance to the 4WS and 5 WS units on best practices for screening and managing the 
patients. The Infection Preventionist staff person is tasked with oversight for IC related topics 
for Behavioral Health.  
III. Through the Infection Preventionist staff person, the infection Control team will alert WS 4 
team that a test within 24-48 hours is acceptable within the context of your planned study 
admissions.  
IV. Once the patient is admitted, they will be quarantined for 72 hours in a single room, re-
tested, and if negative, will then be released from quarantine into a semi private room. 
 
 
2. COVID PRECAUTIONS – MOUNTAIN MANOR Treatment Center 
 
I. 
Outpatient Screening 
Standard Covid screening questions and Covid testing will be incorporated into the screening 
visit. Study staff will follow standard infection control procedures including wearing masks 
and distancing, during consent and assessments. 
II. Treatment center admission 
Patients receive Covid screening questions and Covid testing on the day of admission. 
Admitted patients are admitted in cohorts, separated from the general treatment population 
until Covid results are known. Patients who test Covid negative are integrated into the 
general treatment population. Patients who test positive are placed in medical isolation until 
an appropriate disposition can be arranged. Study staff and usual care clinical staff follow 
standard infection control procedures including wearing masks, use of other PPE as 
appropriate, and distancing. 
III. Post discharge follow-up 
Any post discharge study assessments may be obtained remotely by telehealth platform as 
appropriate. 
 
3. COVID Precautions – Columbia University 
There are risks of exposure to coronavirus 2019 (COVID-19). At this time, there is still a significant 
risk of infection from COVID-19 whenever entering a public setting or interacting with others. 


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Participation in this research study also carries additional risks. We will discuss additional risks due to 
COVID-19 with participants prior to beginning the study. NYSPI will test for COVID-19 prior to any 
participant entering the unit and also on the first day when a participant enters the unit. Please see 
COVID-19 test SOP. Below are additional precautions we are taking due to COVID-19. 
 
I. All research at NYSPI has been modified to reduce in-person visits and procedures.  
- We now use technology (telephone and computer) to perform all possible research 
procedures (such as obtaining consent, clinical interviews, symptom scales, and other 
tests) remotely. 
- We are recommending that only tests and procedures that cannot be performed remotely 
should take place in-person. If the participant prefers an in-person meeting for a specific 
visit or procedure, we encourage him/her to discuss this possibility with the study team. 
II. We are monitoring research participants and staff for signs and symptoms of COVID-
19. 
- The participant will be contacted by study staff on the day prior to your visits and asked 
whether they have any symptoms consistent with COVID-19. Upon their arrival to NYSPI, 
we will again ask the participant questions about any possible COVID-19 symptoms and 
take their temperature. 
- If they are having any symptoms of COVID-19, we will postpone the visit and recommend 
that they see a medical professional for evaluation. 
- All staff are required to self-monitor themselves for any possible symptoms of COVID-19 
and are instructed to stay home and not come to work if they are sick in any way. 
III. We are taking extra precautions at NYSPI to reduce the risk of COVID-19 infection. 
- When the participant enters NYSPI, he/she will be required to wear a face covering. If they 
do not have one, they will be given a surgical face mask. 
- Staff will wear masks and other personal protective equipment as appropriate to the 
procedure (e.g., gowns, gloves). 
- The participant will be asked to maintain physical distancing (at least 6 feet space between 
them and other people) while at NYSPI where possible unless specific research 
procedures require temporarily being closer to study staff. 
- Alcohol-based hand sanitizer will be provided at the building entrance and many other 
areas. 
- We are restricting visitor access to only those who are essential for our participants’ care. 
- Visitors will be screened for fever and symptoms of COVID-19 prior to entry and will be 
asked to wear face coverings and limit their movement within NYSPI. 
IV. We have increased our routine cleaning and disinfection procedures in order to 
further protect research participants and staff from COVID-19 at NYSPI. 
- All equipment used by participants (e.g., blood pressure cuffs, EKG machine) will continue 
to be thoroughly disinfected before and after each participant’s use. 
V. 
Procedures for admission to the inpatient unit: 
- All participant must present to the unit with evidence of a negative COVID test. On the day 
of admission the participant will be brought directly to the back of the dorm area. The 
participant must be wearing a mask and will be assigned to a single room. The participant 
will remain in this room for at least the first 24 hours. All meals will be brought to them by 
unit staff, any assessments will be done in their room with staff wearing PPE, and they can 
have their telephone during that time so they can call family/friends and play games. Of 
note, the telephone will not be available after the first 24 hours. There will be no smoking 
breaks escorted by research staff until after the 24 hour isolation period is complete. After 
the first 24 hours staff will provide a new mask to them daily which they are encouraged to 
wear at all times while in public places. 
- Upon admission, the unit staff will send off a COVID nasal swab to New York Presbyterian 
for analysis. Once that returns negative and 24 hours has elapsed the participant can enter 


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the day area. If the COVID test is positive 1) research procedures will be halted, and 2) a 
clinical decision involving the Clinical Director will be made regarding appropriate next 
steps. 
 
The participant will be made aware that they will also have a COVID antibody (serum) test 
drawn soon after admission. They will have an additional nasal swab COVID test prior to 
discharge from the unit.  
 
26.0 AUDITING AND INSPECTING 
 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, 
the sponsor, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.). The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).  Participation as an 
investigator in this study implies acceptance of potential inspection by government regulatory 
authorities and applicable University compliance and quality assurance offices. 
 
27.0 FUNDING SOURCE 
 
This study is sponsored through a grant from the US National Institute on Drug Abuse. 
 
 
28.0 DISCLOSURE OF CONFLICT OF INTEREST IN THE DSM 
 
All University of Pennsylvania investigators conducting clinical trials are required to submit a Financial 
Disclosure Form. This form is submitted either in connection with submission of a grant application or 
proposal transmittal form to the Office for Research Services (ORS), or with submission of a protocol to the 
Institutional Review Board (IRB) for approval. The IRB or the ORS review disclosures to determine if it 
appears that the investigator has a Significant Financial Interest related to the conduct of the study. 
Significant Financial Interests are referred to the University Conflict of Interest Standing Committee (CISC). 
There are currently no conflicts of interest for the Principal Investigators. 
 
29.0 PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor. Any investigator 
involved with this study is obligated to provide the sponsor with complete test results and all data 
derived from the study. 
 
 
 
 
 
 
 
 
 
 
 


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30. APPENDICES