Clinical trial NCT02611752
Conditions: Moderate or Severe Opioid Use Disorder
Sponsor: Braeburn Pharmaceuticals
Start date: 2015-10-01; Completion date: 2016-04-01
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Multi-site, randomized, double-blind, repeat-dose Phase 2 study to evaluate the degree and duration of action of multiple doses of CAM2038 in blocking the effects of hydromorphone in patients with moderate or severe opioid use disorder.

Detailed description:
This is a multi-site, randomized, double-blind, repeat-dose Phase 2 study to evaluate the degree and duration of action of multiple doses of CAM2038 q1w in blocking the effects of a mu opioid agonist (hydromorphone) in patients with moderate or severe opioid use disorder. The study will involve 4 phases: Screening, Qualification, Treatment, and Follow-up.

The study will enroll a sufficient number of subjects to ensure that at least 48 subjects complete the study (24 subjects per group with at least 16 females in total). Replacement subjects may be added at the discretion of the sponsor with the agreement of the investigator.

Arms: arm 1: CAM2038 q1w 24 mg will be administered on Day 0 and Day 7. Hydromorphone 0 mg (placebo), 6 mg and 18 mg will be subsequently administered during 4 challenge sessions on Days 1-3, 4-6, 8-10 and 11-13 arm 2: CAM2038 q1w 32 mg will be administered on Day 0 and Day 7. Hydromorphone 0 mg (placebo), 6 mg and 18 mg will be subsequently administered during 4 challenge sessions on Days 1-3, 4-6, 8-10 and 11-13
Interventions: intervention 1: CAM2038
Intervention descriptions: intervention 1: CAM2038 subcutaneous injection

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol 
Braeburn Pharmaceuticals, Inc. 
HS-13-478  
CONFIDENTIAL 
 
Version: 1.0, 01-Oct-2015 
Page 1 of 99 
 
 
Clinical Trial Protocol  
HS-13-478 
A Multiple Dose Opioid Challenge Study to Assess Blockade 
of Subjective Opioid Effects of CAM2038 q1w 
(Buprenorphine FluidCrystal® Subcutaneous Injection 
Depots) in Adults with Opioid Use Disorder 
CAM2038 q1w (buprenorphine FluidCrystal® once-weekly subcutaneous 
injection depot), 50 mg/mL  
IND 114082  
Amendment 1: 2.0, 17-NOV-2015 
 
 
 
 
 
 
CONFIDENTIAL 
This protocol is the property of Braeburn Pharmaceuticals and is intended solely for the 
guidance of the clinical investigation. This protocol may not—in full or part—be passed on, 
reproduced, published, or distributed to any person or entity who is not bound by written 
confidentiality agreement, for any purpose, without the prior consent of Braeburn 
Pharmaceuticals.
BRAEBURN PHARMACEUTICALS, INC.:  
47 Hulfish Street, Suite 441 
Princeton, NJ 08542 


Clinical Trial Protocol 
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HS-13-478  
CONFIDENTIAL 
 
Version: 2.0, 17NOV2015 
Page 2 of 99 
 
Summary of Changes and Justification 
Change and Location Within the Protocol  
Rationale 
Updated version and date of the protocol  
 
pp. 1, 71, 72 and footers throughout 
To reflect amendment date and version of 
protocol 
Updated Principal Investigator title and address 
 
pp. 2 
 
Changed “Principal” to “Primary” 
To reflect title and to include additional 
contact information  
General stylistic changes and clarifications were made to 
the overall study design and plan and subsequently to the 
methodology section of the synopsis to remove 
redundancies and ensure consistent with the rest of the 
document: 
 
Synopsis, pp. 3-4 
 
Section 7, pp. 23-26 
Repetitive text was resulting in confusion 
at CRUs; therefore document was updated 
to remove redundancies and simplify 
descriptions.  
Date subjects will remain in house was updated to 25 days  
 
Synopsis pp. 4, Inclusion/Exclusion pp. 5 
 
Section 7.1, pp. 23 
 
Section 8.1, pp. 35 
Number of days was miscounted in 
original draft 
Benzodiazepines excluded from list of exclusionary list of 
drugs at Screening. 
 
Synopsis Inclusion/Exclusion pp. 5 
 
Section 8.2, pp. 36 
Because opioid-dependent individuals 
often use benzodiazepines, it was decided 
to remove the requirement to test negative 
for benzodiazepines at screening to 
improve enrollment rates/reduce rescreens 
etc.  
Urine alcohol testing removed from protocol only breath 
alcohol testing will be conducted 
 
Synopsis Inclusion/Exclusion pp. 5 
 
Section 8.5, pp. 39 
 
Table 7, pp. 53 
 
Section 10.4.4, pp. 54 
Urine alcohol tests will not be conducted 
based on feedback from the CRUs. 
Details on reference therapy updated to include how the 
product will be supplied  
 
Synopsis, pp. 7 
 
Section 9.2, pp. 40 
Additional details added with respect to 
the hydromorphone product that will be 
used in Hydromorphone Challenge 
Sessions, including the amount and make-
up of the sterile solution that will be 
added to ensure that the total injection 
volume across doses is 1.8 mL. 
Change to the primary endpoint and secondary endpoints 
from “Change from Baseline” to Emax 
 
Synopsis, pp 7 
 
Section 10.7, pp. 58 
 
Section 12.3.3.1, pp. 63-64 
The primary and secondary endpoints 
were updated to reflect a change to the 
analysis which will compare results 
within each hydromorphone challenge 
session, rather than comparison to 
baseline/qualification. 


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Change and Location Within the Protocol  
Rationale 
Change to the definition of completer and safety analysis 
populations. Completer population was updated to include 
all subjects who complete the study (i.e., complete Day 
14). Safety population was updated to include all subjects 
who receive any SC dose of CAM2038.  
 
Synopsis, pp. 8 
 
Section 12.2, pp. 62 
Changes made to include greater detail on 
the subjects that will be included in each 
analysis population. 
Addition of language to permit one additional dose IR 
morphine 30 mg, as needed, for the first 3 days of the 
stabilization portion of the qualification phase, for a total 
daily dose of 150 mg. 
 
Section 7.1, pp 23 
 
Section 7.1.2.1, pp. 24 
 
Table 4, “Footnote z”, pp. 30 
 
Section 7.2, pp. 32 
 
Section 9.1, pp. 40 
 
Section 17.2, pp. 75 
 
CRU determined that some subjects may 
require additional dose during the 
stabilization phase to avoid withdrawal 
effects. Therefore, flexibility to administer 
an additional dose, as needed, was added. 
Added subsection to describe in detail the 
Hydromorphone Challenge Sessions in Section 7.1.4. 
Subsection is referenced in the following sections: 
 
Section 7.1, pp. 23 
 
Section 7.1.2.1, pp. 24 
 
Section 7.1.3.1, pp. 25 
Original protocol repeated details of the 
Hydromorphone Challenge Sessions in 
multiple locations, subsection was added 
to avoid redundancies and errors and 
cross-referenced throughout document. 
Language to permit rescreening at the investigator’s 
discretion was added.  
 
Section 7.1.1, pp. 24 
Language to allow rescreening of subjects 
added at request of clinical sites to 
improve enrollment. 
Option to administer additional treatment, as needed, to 
subjects who do not meet qualification criteria has been 
added based on the standard practices of the 
investigational site.  
 
Section 7.1.2.1, pp. 24 
Language added based on request from 
CRUs. 
Updates to ancillary medications: 1) Addition of language 
to indicate that ancillary medications will be made 
available for symptomatic relief of all episodes of 
withdrawal (precipitated by CAM2038 q1w and other) 
with addition of Table 5 which outlines all allowed 
ancillary meds ; 2) language added to allow 
administration of ancillary medication at check-in for 
symptomatic treatment of withdrawal; 3) language to 
allow ancillary medications (PRNs) as needed, with the 
exception of Hydromorphone Challenge Session days 
starting from midnight (i.e., approximately 9 hours prior 
to dosing) through to the end of the Hydromorphone 
Challenge Session (i.e., approximately 5 hours after 
Update was made to allow for 
administration of additional ancillary 
medications.  


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Change and Location Within the Protocol  
Rationale 
dosing). Once the session has ended, PRNs will be 
permitted. Ancillary medications will also not be 
permitted from midnight on Day -1 (i.e., approximately 9 
hours prior to dosing) until after administration of the first 
dose of CAM2038 on Day 0; 4). 
 
Section 7.1.2.1, pp. 24 
 
Section 9.7, pp. 44 
 
Table 5, pp. 45 
 
Section 10.6.2, pp. 58 
Changes to Table 4 included the following (additions 
bolded): 
 
ET (early termination) added to Day 14 heading 
(i.e., 14/ET) 
 
Serology panel- no testing Day-10 to Day -6. Also 
serology panel was updated to optional. Also 
updated in the following sections: 
o Section 8.2, pp.36 
o Table 7, pp.53 
 
Vital signs will be collected on Day 14/ET 
 
Footnote E: Abbreviated (symptom-directed) 
physical examination performed at the 
investigator’s discretion (height will not be 
measured) 
 
ECG added on Day 7 with Footnote F. Footnote F 
has been updated to the following: ECGs 
performed prior to dosing with CAM2038 q1w.  
 
Footnote G: Urine drug screen will be 
administered at Screening and inpatient check-
in. Additional urine drug screens may be 
performed at the investigator’s discretion. 
 
Footnote H: A serum pregnancy test will be 
performed for all females of childbearing 
potential during Screening and at inpatient 
check-in. Following inpatient check-in and 
throughout the duration of confinement, urine 
pregnancy tests may be administered at the 
Investigator’s discretion. 
 
Footnote I: A urine pregnancy test will be 
performed for all females of child-bearing 
potential only prior to IM hydromorphone 
injection on Day -3 and prior to dosing with 
CAM2038 q1w on Day 0 and Day 7.   
 
Addition of row with “FSH Test” with 
administration at Screening.  
o Footnote J added: If post-menopausal 
females do not have a record of a FSH 
Numerous changes made to footnotes and 
table to ensure consistency and implement 
additions requested by investigators. 
(additions bolded): 
 


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test, post-menopausal females will have 
a FSH test at Screening. 
 
Pulse Oximetry/Cardiac monitoring/Respiratory 
Rate Monitoring added on all study days except 
screening. 
 
Footnote M: Pulse oximetry/Cardiac 
monitoring/Respiratory rate monitoring will 
be included on each Hydromorphone 
Challenge Session day (i.e., Days -3, -2, -1, 1, 2, 
3, 4, 5, 6, 8, 9, 10, 11, 12, and 13). Monitoring 
will be continuous from pre-dose up to 5 hours 
post-dose or longer, if clinically indicated. 
After each dose of hydromorphone, subject’s 
oxygen saturation, respiratory rate, and 
overall safety profile will be reviewed by the 
research/nursing staff to determine whether it 
is safe to proceed with administration of the 
next dose of hydromorphone. 
 
Vital signs added on Day 0 and Day 7 with the 
following Footnote P: On CAM2038 q1w dosing 
days (i.e., Days 0 and 7), vital signs will be 
collected at pre-dose and at 15, 30, and 60 
minutes post-dose, then hourly up to 6 hours 
post-dose. 
 
MADRS added on Days -9,-8, -7, -6, OR -5 to -4 
 
COWS added on Day 1 to3 & 4 to 6 AND Day 7 
and Days 8 to 10 &11 to 13. Footnote T added: 
 
COWS will be administered on each CAM2038 
q1w dosing day, prior to dosing. In order to be 
dosed on Day 0, subjects must have a COWS 
score ≥ 8. If opioid withdrawal occurs after 
dosing with CAM2038 q1w (precipitated 
withdrawal), COWS and OOWS will be collected 
every 4 hours while the subject is awake for at 
least 24 hours after dosing. COWS and OOWS 
will be administered prior to dosing on each 
Hydromorphone Challenge Session day. 
 
OOWS administered on Day 0 and Day 7. 
Footnote U updated: COWS and OOWS will be 
administered prior to dosing on each 
Hydromorphone Challenge Session and as 
needed, if a subject experiences precipitated 
withdrawal following administration of 
CAM203 q1w. 
 
Footnote V: Subjects will be given a short-acting 
oral opioid, IR morphine 30 mg, QID, for a 
minimum of 3 days and a maximum of 7 days 


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prior to the Qualification/Baseline 
Hydromorphone Challenge Session. One 
additional dose of IR morphine 30 mg may be 
administered for the first 3 days of 
stabilization, as needed, at the investigator’s 
discretion. Subjects will not receive their dose 
of oral IR morphine 30 mg for approximately 
12 hours prior to dosing with CAM2038 q1w 
on Day 0.  
 
Footnote W: Subjects will be dosed with either 
CAM2038 q1w 24 mg or 32 mg SC injection 
depending on the subject’s treatment group 
assignment. A second dose of CAM2038 q1w 
will be administered on Day 7. 
 
Pharmacokinetic sampling added on Day 7 and 
Days 8 to 10 & 11 to 13.  
 
Footnote BB: Pharmacodynamic training may 
be administered as frequently as required, but 
all subjects must complete at least one training 
session prior to the Qualification/Baseline 
Hydromorphone Challenge Session. Training 
can only occur prior to or after, but not during 
the Hydromorphone Challenge Sessions. 
 
Row added with Severity of Opioid Withdrawal 
VAS on Days 0 and 7. Footnote DD added: 
Severity of Opioid Withdrawal VAS will be 
administered, as needed, if a subject 
experiences precipitated withdrawal following 
administration of CAM203 q1w. 
*Tracked version numbering is not accurate, please refer 
to clean version. 
Addition of “clinically significant” language to exclusion 
criteria.  
 
Section 7.2, pp.32 
 
Section 8.2, Exclusion Criteria 7 and 12 
Clarification of exclusion criteria at 
request of the investigators. 
Changes made to language within Section 7.2 to be in-line 
with updates to protocol, improve readability and remove 
redundancies.  Details on how to asses withdrawal and 
allowable ancillary meds, deleted and moved to different 
sections. 
 
Section 7.2, pp.32 and 33 
Language in Section 7.2 updated to reflect 
changes in amendment. 
Smoking restrictions updated to restrict smoking for at 
least 30 minutes prior to hydromorphone dosing and allow 
smoking at short breaks (approximately 5-10 minutes in 
duration) at the discretion of the CRU staff. Language 
also added to ensure that if a smoking break is permitted, 
it must not interfere with study procedures. Language 
Based on differences between CRUs, 
language was added to allow greater 
flexibility to allow subjects to smoke at 
the discretion of the investigator. In 
addition, to avoid nicotine withdrawal, 


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Change and Location Within the Protocol  
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updated to allow subjects to use a nicotine-containing 
transdermal system as needed, at the discretion of the 
Investigator. 
 
Section 8.5, pp. 39 
subjects are permitted to use a nicotine-
containing transdermal system as needed.  
Morphine IR 30 mg tablet for oral administration added to 
the list of investigational products and dispensing and 
administration section. Language updated to remove the 
bottle count (i.e., Morphine sulphate will be supplied as 
30 mg tablets. in XX count bottles.) 
 
Section 9.2, pp. 40 
 
Section 9.2.2., pp. 41 
This was missing or included in error in 
original protocol. Corrected in 
amendment. 
Detail on replacement subjects added to indicated that 
replacement subjects will receive the same CAM2038 
q1w treatment as the subject they are replacing. 
 
Section 9.3, pp. 42 
This clarification was added to ensure that 
the two treatment groups are balanced and 
that sufficient subjects are enrolled in 
each. 
Requirements for unblinded staff updated as follows as 
well as to ensure that treatments are volume matched:  
In order to maintain the blind, unblinded staff, not 
otherwise involved in the study will prepare the 
hydromorphone doses so that they are volume-matched 
(1.8 mL, See Section 9.2). 
 
Section 9.6, pp.43 
Clarification added to ensure that 
unblinded staff are not involved in any 
other study procedures. 
Language for subject who require analgesic emergency 
treatment of anesthesia for surgery updated as follows: 
Opioid receptors are likely to be occupied by BPN, which 
may reduce the analgesic effects of an opioid. The 
dissociation of BPN from the receptors may take up to 2 
weeks following the last CAM2038 q1w injection. 
Therefore, subjects requiring analgesic emergency 
treatment or anesthesia for surgery should ideally be 
treated with a non-opioid analgesic. Opioids may be used 
with caution, but as higher doses may be required for 
analgesic effect, there may be a higher potential for 
toxicity with opioid administration. The clinical course 
should be carefully evaluated and fully documented for 
subjects who have a requirement for any opioid analgesic 
for >7 days continually or general anesthesia for surgery 
within 2 weeks of the final dose of CAM2038 q1w. 
 
Section 9.7, pp. 44 
Language updated to include time 
constraints of 2 weeks following last dose 
of CAM2038 q1w, based on expected 
time for buprenorphine to dissociate from 
the opioid receptors. 
Medical history language updated to include only those 
reported conditions affecting major body systems that 
have occurred within the last five years or that the 
Investigator deems clinically significant. 
 
Section 10.1.3, pp. 46 
This clarification was added at the request 
of the CRUs to avoid confusion around 
which medical history events are relevant 
with respect to inclusion.  
Contraceptive requirements updated to include male 
condom with spermicide, and to clarify that female 
Updated to avoid confusion and ensure 
adequate contraceptive practices in place. 


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Change and Location Within the Protocol  
Rationale 
subjects of non-childbearing potential are not required to 
use contraception but must have documentation 
supporting that they are surgically sterile.  
 
Section 10.1.6, pp. 47 
The following language was removed and clarified: 
Retraining of subjects is permitted at the Investigator’s 
Discretion.” 
The following language was added: Study staff are 
encouraged to provide additional subject training as 
needed, to ensure that the subjects comprehend the 
differences between different types of VASs. Training 
dates/times will be documented in the subject’s files.  
Subject training can only occur before VAS 
administration or after the 5 hour Challenge session is 
completed.  The training script will be provided to the 
sites. 
 
Section 10.3, pp. 47 
Language updated to ensure that subjects 
are not trained during the Hydromorphone 
Challenge Sessions 
Language added to include the assessment of opioid 
withdrawal severity if precipitated withdrawal following 
administration of CAM2038 q1w occurs: 
If precipitated withdrawal occurs after administration 
of CAM2038 q1w, subjects will be requested to 
complete a unipolar VAS assessment of opioid 
withdrawal severity. 
Opioid Withdrawal Severity VAS added to Table 6 and 
column “include at pre-dose” removed. 
 
Section 103.1, pp. 48 
 
Table 6, pp. 48 
Scale added in order to assess the risk of 
precipitated withdrawal in subjects 
following study drug treatment. Because 
all PD measures will be collected at pre-
dose, the column “include at pre-dose” 
was removed from Table 6. 
Updates to serious adverse event reporting included 
increase of reporting period to 30 days after early 
termination, the site will be required to also fill out an 
“other concomitant medication and medical history form” 
in the event of an SAE, and the AE form will need to be 
email to the sponsor (or designee) or faxed per 
instructions in the SAE Reporting and Management Plan.   
 
Section 10.4.1.2.1, pp. 50 
This text was updated based on input 
received from the clinical research 
organization. 
Details on clinical laboratory assessments were updated to 
ensure that all protocol-specified laboratory tests on blood 
and urine samples would be performed by each clinical 
site’s local laboratory and that blood volumes would be 
determined by each site’s local laboratory. The following 
text was also added: It is up to the investigator to review 
lab results and determine if the abnormal lab results 
are clinically significant or not. 
 
Section 10.4.3, pp. 52 and 53 
 


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Change and Location Within the Protocol  
Rationale 
The section describing vital signs was separated into 2 
subsection, Section 10.4.5.1 Qualification Phase vital 
signs safety monitoring and Section 10.4.5.2 Treatment 
Phase Vital Signs Safety Monitoring. 
The following language was added to Section 10.4.5.2: 
After each dose of IM hydromorphone during the 
Treatment Phase Hydromorphone Challenge Sessions, 
subject’s oxygen saturation, respiratory rate, and 
overall safety profile will be reviewed by the 
research/nursing staff (as described in Section 7.1.2.1) 
to determine whether it is safe to proceed with 
administration of the next dose of hydromorphone. 
Vital signs assessments will be performed at the visits 
and time points defined in Table 4. 
 
Section 10.4.5, pp.54 and 55 
This section was updated to include 
additional safety precautions prior to 
dosing with hydromorphone as part of the 
challenge session.   
Language describing cardiac monitoring was updated to 
include measurement from inpatient check-in to the end of 
the Treatment Phase (or Early Termination). Language 
was also added to allow cardiac monitoring and pulse 
oximetry equipment to be removed briefly (for hygiene 
purposes), as needed.  
 
Section 10.4.7, pp. 55 
Based on equipment available at the 
CRUs, the term “Continuous” was 
removed and language was added to allow 
subjects to remove the equipment when 
necessary for brief periods. 
Language updated to remove rationale for unipolar VAS 
administration. Language updated to include 
alertness/drowsiness VAS not sedation VAS.  
 
Section 10.5, pp. 56 and 57 
Based on FDA feedback, the Drug Liking 
VAS will be administered as a bipolar 
scale; therefore, rationale for use of 
unipolar Drug Liking VAS was removed. 
Alertness/Drowsiness VAS was added 
and sedation VAS removed, this was an 
error in the original protocol.  
Additional safety measures and withdrawal section 
separate into 2 subsections, Section 10.6.1 Opioid Effects 
and Section 10.6.2 Treating Opioid Withdrawal. The 
following details on treating opioid withdrawal were 
added as follows:  
If opioid withdrawal occurs after dosing with CAM2038 
q1w (precipitated withdrawal), the following assessments 
will be collected every 4 hours while the subject is awake 
for at least 24 hours after dosing to include:  
1) 
COWS,  
2) 
OOWS, 
3) 
VAS assessment of opioid withdrawal severity.  
Treatment will be based upon clinical judgment of the 
medically responsible physician at each site. To ensure the 
safety of subjects, incidences of precipitated withdrawal 
in response to CAM2038 q1w will be followed carefully 
and an amendment of the protocol to ensure subjects are 
 


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Change and Location Within the Protocol  
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in a more advanced state of opioid withdrawal e.g., 
increase required COWS score from 8 to 12, to reduce the 
risk of BPN-related precipitated withdrawal, will be 
considered if more than one incidence occurs.  
Ancillary medications that will be made available for 
symptomatic relief of all episodes of withdrawal 
(precipitated by CAM2038 q1w and other) are 
summarized in Table 5. 
 
Section 10.6.2, pp. 58 
Statistical analysis was updated to further define the way 
in which TEAEs would be displayed.  The following text 
was updated:  
During the Qualification Phase subjects TEAEs will be 
displayed by IR morphine 30 mg treatment or by 
hydromorphone treatment groups i.e., 0 mg 6 mg or 
18 mg - on the days of hydromorphone challenges. 
During the Treatment Phase, TEAEs will be displayed 
by CAM2038 q1w relevant dose and hydromorphone 
relevant dose i.e., 0 mg 6 mg or 18 mg – on the days of 
hydromorphone challenges. TEAEs will be displayed 
by SOC and preferred term. Additionally, TEAEs will be 
tabulated for each treatment group by severity and by 
relationship to the study drug. A listing of SAEs will be 
provided if applicable. 
 
Section 12.3.4.1, pp. 64 and 65 
Based on additional review by the 
statistics group it was determined that the 
TEAEs would be displayed by CAM2038 
dose and by hydromorphone relevant dose 
since specific time of AE may not be 
available.  
Copies of the COWS, OOWS, C-SSRS, and MADRS 
were added in Appendices 17.2 to 17.6, respectively  
 
Appendix 17.2, pp 76 (COWS) 
 
Appendix 17.3, pp. 77 (OOWS) 
 
Appendix 17.4, pp. 78-81 (C-SSRS Baseline) 
 
Appendix 17.5, pp. 82-85 (C-SSRS Since Last 
Visit) 
 
Appendix 17.6, pp. 66-91 (MADRS) 
Details for COWS, OOWS, MADRS, and 
C-SSRS were added to appendices for 
reference purposes.  
 
Stylistic changes including updates to text, correcting 
minor typos, formatting errors, and added abbreviations 
 
Text updated throughout document 
To ensure consistency and remove errors. 
 


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1. 
SPONSOR AND KEY PERSONNEL CONTACT INFORMATION 
ROLE IN STUDY  
NAME 
 CONTACT INFORMATION 
Study Sponsor 
Braeburn Pharmaceuticals, 
Inc. 
47 Hulfish Street, Suite 441 
Princeton, NJ  08542 
Medical Monitor 
Charles Laudadio MD 
pharmmd@gmail.com 
(610) 812-3477 
Sponsor Project Manager 
John Carlos Diaz 
john@braeburnpharma.com 
609.436.9538 (office) 
484.568.3952 (mobile) 
Primary Investigator 
Sharon Walsh PhD 
sharon.walsh@uky.edu 
Robert Straus Behavioral 
Science Building 
845 Angliana Avenue  
Lexington, KY 40508 
 
 


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2. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Braeburn Pharmaceuticals, Inc. 
Name of Investigational Product: 
 CAM2038 q1w (buprenorphine FluidCrystal® once-weekly subcutaneous (SC) injection depot) 
Name of Active Ingredient: buprenorphine (BPN) 
Study Title:  
A Multiple Dose Opioid Challenge Study to Assess Blockade of Subjective Opioid Effects of 
CAM2038 q1w (Buprenorphine FluidCrystal® Subcutaneous Injection Depots) in Adults with Opioid 
Use Disorder 
Objectives: 
The primary objective of this study is:  
 
To evaluate the degree of opioid blocking effects of CAM2038 q1w following administration 
of intramuscular (IM) hydromorphone (6 mg and 18 mg) compared to administration of 0 mg 
IM hydromorphone (placebo) on subjective opioid effects in subjects with opioid use disorder, 
as measured by the Drug Liking visual analog scale (VAS). 
The secondary objectives of this study are:  
 
To evaluate the degree of opioid blocking effects of CAM2038 q1w following administration 
of IM hydromorphone (6 mg and 18 mg) compared to administration of 0 mg IM 
hydromorphone (placebo) on subjective opioid effects in subjects with opioid use disorder, as 
determined by the secondary outcome measures.  
 
To explore the relationship between plasma buprenorphine (BPN) concentration and blockade 
of the subjective opioid effects of hydromorphone. 
 
To examine the safety and tolerability of CAM2038 q1w when co-administered with 
hydromorphone. 
Methodology: 
This is a multi-site, randomized, double-blind, repeat-dose Phase 2 study to evaluate the degree and 
duration of action of multiple doses of CAM2038 q1w in blocking the effects of a mu-opioid agonist 
(hydromorphone) in patients with moderate or severe opioid use disorder. The study will involve 4 
phases: Screening, Qualification, Treatment, and Follow-up.  
Within 4 weeks of initiating screening, subjects will be admitted to a clinical research unit (CRU) for 
the Qualification Phase. Following check in to the CRU, subjects will be transitioned to an oral 
immediate-release (IR) opioid, morphine 30 mg (administered 4 times daily [QID]), for a minimum of 
3 days and a maximum of 7 days. After stabilization on IR morphine 30 mg, all subjects will complete 
a 3-day Qualification/Baseline Hydromorphone Challenge Session which will involve IM 
administration of 3 doses of hydromorphone (Treatment A: 0 mg [placebo], Treatment B: 
6 mg and Treatment C: 18 mg) administered once daily (Day -3, Day -2, and Day -1) in a 
randomized, double blind, crossover manner, with each hydromorphone administration 
separated by approximately 24 hours.  


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Name of Sponsor/Company: Braeburn Pharmaceuticals, Inc. 
Name of Investigational Product: 
 CAM2038 q1w (buprenorphine FluidCrystal® once-weekly subcutaneous (SC) injection depot) 
Name of Active Ingredient: buprenorphine (BPN) 
Following the Qualification/Baseline Hydromorphone Challenge Session, eligible subjects will be 
randomized in a 1:1 ratio to 1 of 2 groups, stratified by gender, to receive CAM2038 q1w at doses of 
24 mg or 32 mg. Subjects will receive once weekly SC injections of CAM2038 q1w for 2 weeks 
(injections on Day 0 and Day 7) and will remain inpatient in the CRU for up to 25 days (including 
Qualification Phase), during which time 4 Hydromorphone Challenge Sessions (3 consecutive days 
each) will be conducted on Days 1 to 3, Days 4 to 6, Days 8 to 10, and Days 11 to 13, respectively. 
Safety and pharmacodynamic assessments will be performed on each day of the Hydromorphone 
Challenge Sessions at multiple timepoints beginning at pre-dose until approximately 5 hours post-dose. 
Plasma samples to quantify BPN and obtain norbuprenorphine levels will also be collected 
approximately 60 minutes prior to hydromorphone dosing on each day of the Hydromorphone 
Challenge Sessions.  
Subjects will be discharged on Day 14 and a follow-up phone interview will be conducted on 
approximately Day 21. 
The degree of hydromorphone dose tolerability will be determined based on the site-specific study 
Investigator’s review of the subject’s oximetry data, vital signs, behavior, and physical demeanor.  
Number of Subjects (Planned):  
The study will enroll a sufficient number of subjects to ensure that at least 48 subjects complete the 
study (24 subjects per treatment group with at least 16 females in total). Replacement subjects may be 
added at the discretion of the sponsor with the agreement of the Investigator(s). 
Criteria for Inclusion/Exclusion: 
Subjects must meet each one of the following inclusion criteria in order to be eligible for participation 
in the study: 
1. Subject must provide written informed consent prior to the conduct of any study-related 
procedures.  
2. Male or female, 18-55 years of age, inclusive.  
3. Subjects with a diagnosis of moderate or severe opioid use disorder (Diagnostic and 
Statistical Manual of Mental Disorders – Fifth Edition [DSM-V]) who are currently 
physically dependent on IV or insufflated opioids, and who are willing to undergo short-
term BPN treatment.  
4. Self-reported opioid-use of a minimum of 21 days in the 30 days prior to Screening. 
5. Positive urine drug screen (UDS) for opioids at Screening or at check-in. If UDS is not 
positive, subjects must present with physical signs of withdrawal, as determined by the 
Investigator. The Investigator may administer a naloxone challenge, in order to confirm 
opioid dependence at the Investigator’s discretion. 


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Name of Sponsor/Company: Braeburn Pharmaceuticals, Inc. 
Name of Investigational Product: 
 CAM2038 q1w (buprenorphine FluidCrystal® once-weekly subcutaneous (SC) injection depot) 
Name of Active Ingredient: buprenorphine (BPN) 
6. Female subjects of childbearing potential must be willing to use a reliable method of 
contraception during the entire study (Screening Visit to Follow-Up phone call).  
7. Female subjects of non-childbearing potential should be surgically sterile (i.e., have 
undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a 
menopausal state (at least 1 year without menses), as confirmed by follicle stimulating 
hormone (FSH) levels. 
8. Male subjects with female partners of childbearing potential must agree to use a reliable 
method of contraception from Screening Visit through at least 3 months after the last dose 
of study drug. Male subjects must also agree not to donate sperm during the study through 
at least 3 months after the last dose of study drug.  
9. Subject is willing and able to comply with the study requirements (including blood 
sampling), complete study assessments, visit the clinic and remain confined in the CRU 
for up to 25 consecutive days. 
Subjects will not be eligible to participate in this study if any one of the following exclusion criteria is 
met: 
1. History or presence of any clinically significant psychiatric, endocrine, hematologic, 
hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal, or 
other major disease or illness at Screening, which in the opinion of the Investigator, 
would jeopardize the safety of the subject or the validity of the study results. 
2. Opioid dependent subjects who are actively seeking treatment for their moderate to severe 
opioid use disorder.   
3. Subjects with positive urine drug screens for buprenorphine, alcohol, barbiturates, or 
methadone on the day of check in to the CRU or breath alcohol.  
4. Aspartate aminotransferase levels >3 X the upper limit of normal, alanine 
aminotransferase levels >3 X the upper limit of normal, total bilirubin >1.5 X the upper 
limit of normal, or creatinine >1.5 X upper limit of normal on the Screening laboratory 
assessments and at inpatient check-in, or other clinically significant laboratory 
abnormalities, which in the opinion of the Investigator, may prevent the subject from 
safely participating in the study. 
5. Any clinically significant abnormality on the basis of medical history, vital signs, physical 
examination, 12-Lead electrocardiogram (QTcF ≥450 msec for males or ≥470 msec for 
females), and laboratory evaluation (including hematology, clinical chemistry, urinalysis, 
and optional serology) at Screening, in the opinion of the Investigator. 
6. Significant symptoms, medical conditions, or other circumstances which, in the opinion 
of the Investigator, would preclude compliance with the protocol, adequate cooperation in 
the study or obtaining informed consent, or may prevent the subject from safely 
participating in study (including, but not limited to, the risks described as precautions, 


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Name of Sponsor/Company: Braeburn Pharmaceuticals, Inc. 
Name of Investigational Product: 
 CAM2038 q1w (buprenorphine FluidCrystal® once-weekly subcutaneous (SC) injection depot) 
Name of Active Ingredient: buprenorphine (BPN) 
warnings, and contraindications in the current version of the Investigator’s Brochure for 
CAM2038). 
7. Subjects will be carefully screened to exclude individuals presenting with or a history of 
clinically significant seizure disorders, history of asthma or other respiratory disorders, 
head injury, hypertension or personal history of cardiovascular disease or clinically 
significant electrocardiogram (ECG). 
8. Current diagnosis of Acquired Immune Deficiency Syndrome (AIDS).  
9. Current diagnosis of chronic pain requiring opioids for treatment. 
10. Subjects who currently meet the criteria for a diagnosis of moderate or severe substance 
use disorder according to DSM-V criteria for any other substances other than opioids, 
caffeine or tobacco.  
11. Pregnant or lactating, or planning to become pregnant during the study.  
12. Clinically significant history of or current evidence of suicidal ideation or active suicidal 
behavior as based on the Columbia-Suicide Severity Rating Scale (C-SSRS; grade 4 or 5). 
13. Hypersensitivity or allergy to BPN or other opioids or excipients of CAM2038. 
14. Intolerance to venipuncture and/or difficulty with venous access, as per the judgment of 
the Investigator/research staff. 
15. Subject is currently using an investigational drug or monoamine oxidase inhibitor 
(MAOI) or has used such within the last 30 days (or 5-times the half-life of the drug, if 
known and longer) prior to first drug administration in the Qualification Phase (i.e., IR 
morphine sulfate). 
16. Requires current use of agents that are strong inhibitors or inducers of cytochrome P450 
3A4 (CYP 3A4), such as some azole antifungals (e.g., ketoconazole), macrolide 
antibiotics (e.g., clarithromycin), or protease inhibitors (e.g., ritonavir, indinavir, and 
saquinavir).  
17. If the subject is currently on probation or has any pending legal action that could prohibit 
participation or compliance in the study. 
18. A subject who, in the opinion of the Investigator, is considered unsuitable or unlikely to 
comply with the study protocol for any reason.  
Investigational Product, Dosage and Mode of Administration: 
 
CAM2038 q1w, 50 mg/mL: 24 and 32 mg (BPN base), 0.48 and 0.64 mL SC injection, 
respectively. SC injections will be performed in the upper buttocks rotating between right and 
left buttocks. 
Reference Therapy, Dosage and Mode of Administration: 
 
Hydromorphone (10 mg/mL; Dilaudid HP®) for IM administration in the deltoid muscle. 


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Name of Sponsor/Company: Braeburn Pharmaceuticals, Inc. 
Name of Investigational Product: 
 CAM2038 q1w (buprenorphine FluidCrystal® once-weekly subcutaneous (SC) injection depot) 
Name of Active Ingredient: buprenorphine (BPN) 
Dilaudid HP® will be supplied as single dose vials for IM administration. Each 1 mL of sterile 
solution contains 10 mg/mL hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% 
citric acid solution. Hydromorphone 18 mg will be delivered via administration of 1.8mL of this 
solution. Hydromorphone 6 mg will be a combination of 0.6 mL Dilaudid HP solution + 1.2 mL ½ 
NS sodium and water for a total injection volume of 1.8 mL. Hydromorphone 0 mg (placebo) will 
be delivered via administration of 1.8 mL of a solution of 0.45% sodium and water.  
 
Morphine Sulfate will be supplied as 30 mg tablets.  
Duration of Study: 
Subjects will participate in the study for approximately 7 weeks, from Screening to Follow-up. 
Criteria for Evaluation: 
Study Endpoints: 
Pharmacodynamic Endpoints 
The primary endpoint of this study is the maximum effect (Emax) of Drug Liking VAS for 
hydromorphone. 
In addition to the primary endpoint of Emax of Drug Liking VAS, the following secondary endpoints 
will be calculated: 
 
Emax of High VAS  
 
Emax of Good Effects VAS  
 
Emax of Bad Effects VAS  
 
Emax of Sedated VAS  
 
Emax of Any Effects VAS  
 
Emax of Desire to use VAS  
Pharmacokinetic Endpoints  
The following pharmacokinetic parameters will be estimated for BPN and norbuprenorphine:  
 
Cmax (maximum plasma concentration) 
 
Ctrough (plasma concentration level 7 days after the latest injection) 
 
Cav (average plasma concentration during a dosing interval)  
Statistical Methods (Data Analysis): 
A sample size of 24 completed subjects will provide 90% power for the CAM2038 32 mg to 
demonstrate no significant difference in the mean Emax score of the Drug Liking VAS compared to 
0 mg hydromorphone at a two-sided 0.05 significance level with a non-significant difference cutoff at 


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Name of Sponsor/Company: Braeburn Pharmaceuticals, Inc. 
Name of Investigational Product: 
 CAM2038 q1w (buprenorphine FluidCrystal® once-weekly subcutaneous (SC) injection depot) 
Name of Active Ingredient: buprenorphine (BPN) 
<=11 points. In the sample size calculation, it was assumed that the true difference was less than or 
equal to 1.5 and the standard deviation was 9.8.  
An additional 24 completed subjects will be enrolled to CAM2038 24 mg group. This sample size will 
provide approximately 83% power for the CAM2038 24 mg to demonstrate no significant difference in 
the mean Emax score of the Drug Liking VAS comparing to 0 mg hydromorphone at a two-sided 0.05 
significance level with a non-significant difference cutoff at <=11 points. In the sample size calculation 
it was assumed that the true difference was less than or equal to 2.5 and the standard deviation was 9.8. 
 
The plan will be to enroll a sufficient number of subjects to ensure that at least 48 subjects complete 
the study (24 subjects per treatment group) by over-enrollment as needed and replacement of subjects 
for those who drop out.  
 
Three populations are defined for the study.  
 
Intent-to-treat (ITT) Population will consist of all subjects who receive study drug and provide 
some post-baseline efficacy values.  
 
Completer Population will include all subjects who complete the study (i.e., complete Day 14). 
The primary efficacy analyses will be based on the Completer Population.  
 
Safety Population will include all subjects who receive any SC dose of CAM2038. All safety 
analyses will be based on the Safety Population. 
 
The primary efficacy variable will be Emax of Drug Liking VAS. This variable will be analyzed via a 
mixed model including subject, hydromorphone challenge dose (A=0 mg, B=6 mg, or C=18 mg), 
Period (1, 2, or 3 to indicate first, second, or third day of each challenge session), challenge session (1, 
2, 3, or 4), where subject will be treated as random effects and the remaining parameters fixed effects. 
The estimated treatment effects, differences in treatment effects (hydromorphone test dose – the 
reference dose of 0 mg), and 95% confidence intervals of the differences will be presented. Blockade 
effects will be claimed if upper bound of the treatment difference is <=11.  
Safety analyses will be based on the evaluation of reported adverse events or laboratory outcomes.  
 


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3. 
TABLE OF CONTENTS 
1. Sponsor and Key Personnel Contact Information ..................................................... 11 
2. Protocol Synopsis .......................................................................................................... 12 
3. Table of Contents .......................................................................................................... 18 
4. List of Abbreviations and Definition of Terms ........................................................... 22 
5. Introduction ................................................................................................................... 24 
5.1. 
Background .............................................................................................................. 24 
5.2. 
Clinical Data ............................................................................................................. 24 
5.2.1. CAM2038 q1w (Once Weekly) .............................................................................. 24 
5.3. 
Study Rationale ........................................................................................................ 30 
6. Study Objectives ........................................................................................................... 31 
6.1. 
Primary Objective .................................................................................................... 31 
6.2. 
Secondary Objectives ............................................................................................... 31 
7. Investigational Plan ...................................................................................................... 32 
7.1. 
Overall Study Design and Plan ................................................................................ 32 
7.1.1. Screening Visits (Day -31 to Day -11): .................................................................. 33 
7.1.2. Qualification Phase ................................................................................................ 33 
7.1.3. Treatment Phase ..................................................................................................... 34 
7.1.4. Hydromorphone Challenge Sessions ..................................................................... 35 
7.1.5. Follow-up Phase ..................................................................................................... 35 
7.2. 
Discussion of Study Design ..................................................................................... 41 
8. Selection of Study Population ...................................................................................... 44 
8.1. 
Inclusion Criteria ...................................................................................................... 44 
8.2. 
Exclusion Criteria ..................................................................................................... 45 
8.3. 
Qualification Criteria ............................................................................................... 46 
8.4. 
Removal of Subjects from Therapy or Assessment ................................................. 47 
8.5. 
Study Restrictions .................................................................................................... 47 
9. Treatments ..................................................................................................................... 49 
9.1. 
Treatment Administration......................................................................................... 49 
9.2. 
Identity of Investigational Products ......................................................................... 49 
9.2.1. Handling, Storage, and Accountability .................................................................. 50 
9.2.2. Dispensing and Administration .............................................................................. 50 
9.3. 
Method of Assigning Subjects to Treatment Groups ............................................... 50 
9.4. 
Selection of Doses .................................................................................................... 51 
9.5. 
Selection and Timing of Dose .................................................................................. 52 


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9.6. 
Blinding .................................................................................................................... 52 
9.7. 
Prior and Concomitant Therapy ............................................................................... 53 
9.8. 
Treatment Compliance ............................................................................................. 54 
10. Study Procedures and Assessments ............................................................................. 55 
10.1. Demographics and Other Baseline Characteristics .................................................. 55 
10.1.1. Informed Consent ................................................................................................... 55 
10.1.2. Demographics ......................................................................................................... 55 
10.1.3. Medical History ...................................................................................................... 55 
10.1.4. Medication History ................................................................................................. 55 
10.1.5. Substance Use and Treatment History ................................................................... 55 
10.1.6. Contraceptive Requirements .................................................................................. 56 
10.2. Eligibility Review .................................................................................................... 56 
10.3. Pharmacodynamic Assessments ............................................................................... 56 
10.3.1. Visual Analog Scales .............................................................................................. 56 
10.4. Safety Assessments .................................................................................................. 57 
10.4.1. Adverse Events and Serious Adverse Events ......................................................... 57 
10.4.2. Pregnancy ............................................................................................................... 60 
10.4.3. Clinical Laboratory Assessments ........................................................................... 60 
10.4.4. Urine Drug Screen and Breath Alcohol Testing ..................................................... 62 
10.4.5. Vital Signs .............................................................................................................. 62 
10.4.6. 12-Lead Electrocardiograms .................................................................................. 63 
10.4.7. Cardiac Monitoring (including Pulse Oximetry) ................................................... 63 
10.4.8. Physical Examination ............................................................................................. 63 
10.4.9. Injection Site Examination ..................................................................................... 63 
10.4.10. 
Clinical Opiate Opioid Withdrawal Scale (COWS) .................................. 64 
10.4.11. 
Objective Opioid Withdrawal Scale (OOWS) ........................................... 64 
10.4.12. 
Columbia-Suicide Severity Rating Scale ................................................... 64 
10.4.13. 
Montgomery-Asberg Depression Rating Scale (MADRS) ....................... 64 
10.5. Appropriateness of Measures ................................................................................... 64 
10.6. Additional Safety Measures and Withdrawal ........................................................... 65 
10.6.1. Opioid Effects......................................................................................................... 65 
10.6.2. Treating Opioid Withdrawal ................................................................................... 66 
10.7. Pharmacodynamic Variables .................................................................................... 66 
10.7.1. Primary Pharmacodynamic Endpoint ..................................................................... 66 
10.7.2. Secondary Endpoints .............................................................................................. 66 
10.8. Drug Concentration Measurements .......................................................................... 66 
11. Data Quality Assurance ................................................................................................ 68 
11.1. Data Collection ......................................................................................................... 68 


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11.2. Study Auditing and Monitoring ............................................................................... 68 
12. Statistical Methods and Determination of Sample Size ............................................ 70 
12.1. Sample Size Determination ...................................................................................... 70 
12.2. Analysis Populations ................................................................................................ 70 
12.3. Statistical Analyses ................................................................................................... 70 
12.3.1. Study Subjects and Demographics ......................................................................... 71 
12.3.2. Exposure ................................................................................................................. 71 
12.3.3. Efficacy Analyses ................................................................................................... 71 
12.3.4. Safety and Tolerability Analyses ............................................................................ 72 
12.3.5. Analysis of Pharmacokinetics ................................................................................ 73 
12.3.6. Multiple Comparisons ............................................................................................ 74 
12.3.7. Interim Analysis ..................................................................................................... 74 
13. Study Administration and Investigator Responsibilities ........................................... 75 
13.1. Regulatory and Ethical Considerations .................................................................... 75 
13.1.1. Ethical Conduct of the Study ................................................................................. 75 
13.1.2. Ethics Approval ...................................................................................................... 75 
13.1.3. Subject Informed Consent ...................................................................................... 75 
13.2. Privacy and Confidentiality ...................................................................................... 76 
13.3. Study and Site Closure ............................................................................................. 76 
13.4. Regulatory Documents and Records Retention ....................................................... 77 
13.5. Delegation of Responsibilities and Adequate Resources ......................................... 77 
13.6. Protocol Amendments .............................................................................................. 78 
13.7. Financial Disclosure ................................................................................................. 78 
14. Sponsor Approval Page ................................................................................................ 79 
15. Investigator Protocol Agreement Page........................................................................ 80 
16. References ...................................................................................................................... 81 
17. Appendices .................................................................................................................... 83 
17.1. Qualification Phase Sample Daily Short-Acting Opioid Administration 
Schedule ................................................................................................................... 83 
17.2. Clinical Opiate Withdrawal Scale (COWS) ............................................................. 84 
17.3. Objective Opioid Withdrawal Scale (OOWS) ......................................................... 85 
17.4. Columbia-Suicide Severity Rating Scale (C-SSRS)- Baseline/Screening ............... 86 
17.5. Columbia-Suicide Severity Rating Scale (C-SSRS)- Since Last Visit .................... 90 
17.6. Montgomery Asberg Depression Rating Scale (MADRS) ...................................... 94 
 


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Table of Tables 
Table 1 
Plasma concentrations of buprenorphine (geometric mean) after 
single subcutaneous administration of CAM2038 q1w to healthy 
subjects under naltrexone blockade .......................................................... 26 
Table 2 
Observed and predicted buprenorphine exposure after single 
administration of SC CAM2038 q1w, SC CAM2038 q4w, and SL 
Subutex® in healthy subjects .................................................................... 27 
Table 3 
Observed and predicted buprenorphine exposure after steady state 
administration of SC CAM2038 q1w, SC CAM2038 q4w, and SL 
Subutex® in healthy subjects .................................................................... 27 
Table 4 
Schedule of Assessments .......................................................................... 37 
Table 5 
Ancillary Medications (PRNs) for Relief of Withdrawal Symptoms ....... 54 
Table 6 
Visual Analog Scale Descriptions ............................................................. 57 
Table 7 
Clinical Laboratory Assessments.............................................................. 61 
 
Table of Figures 
Figure 1 
Observed steady state arithmetic mean Cmax and Ctrough of 
buprenorphine after sublingual administration of Subutex®, and 
observed and predicted steady state plasma concentration profiles 
after subcutaneous administration of CAM2038 q1w and CAM2038 
q4w based on data from Studies HS-11-426 and HS-13-487 
(semi-logarithmic scales) .......................................................................... 28 
Figure 2 
Overview of Study Design ....................................................................... 36 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
AIDS 
Acquired Immune Deficiency Syndrome  
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time 
curve 
AUCinf 
AUC from time 0 to infinity 
BPN 
Buprenorphine 
Cav 
Average plasma concentration during a 
dosing interval 
CFR 
Code of Federal Regulations 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
CRU 
Clinical research unit 
CS 
Clinically significant 
CSR 
Clinical study report 
Css,av 
Average plasma concentration during a 
dosing interval at steady state 
Css,max 
Maximum plasma concentration at steady 
state 
Css,t 
plasma trough concentration at steady state 
Ct  
Plasma concentration at time t; 
CTA 
Clinical Trial Agreement 
Ctrough 
Plasma concentration level 7 days after the 
latest injection 
DSM-V 
Diagnostic and Statistical Manual of Mental 
Disorders – Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form  
EDC 
Electronic data capture 
Emax 
Maximum effect 
FC 
FluidCrystal® 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 


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HIV 
Human Immunodeficiency Virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IM 
Intramuscular 
INR 
International normalized ratio 
IR 
Immediate-release 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous  
MedDRA 
Medical Dictionary of Regulatory Activities 
mIU/ml 
 
milli international units per milliliter 
MOP 
Manual of Procedures 
NCS 
Not clinically significant 
OOWS 
Objective Opioid Withdrawal Scale 
PK 
Pharmacokinetic 
PO 
By mouth 
PRN 
As  needed 
PT 
Prothrombin time 
q1w 
Once weekly 
q4w 
Once monthly 
QID 
4 times daily 
RBC 
Red blood cell 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SL 
Sublingual 
SOC 
System Organ Class 
TID 
Three times daily 
UDS 
Urine Drug Screen 
US 
United States 
 


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5. 
INTRODUCTION 
5.1. 
Background 
Buprenorphine (BPN) is an opioid with mixed agonist-antagonist properties that, together with 
appropriate counseling and psychotherapy, has been shown to be effective in the treatment of 
opioid dependence. Treatment with BPN has been demonstrated to significantly reduce opioid-
positive urines, i.e., to reduce illicit drug use, and increase retention of patients in outpatient 
treatment programs (Johnson et al., 1992; Strain et al., 1994; Schottenfeld et al.,1997; Ling et al., 
1998). 
CAM2038 (BPN FluidCrystal® [FC] subcutaneous [SC] injection depot) once weekly (hereafter 
referred to as CAM2038 q1w) extended release BPN products developed for opioid dependence 
treatment with a target of once-weekly or once-monthly SC dosing, respectively.  
CAM2038 q1w was developed using the proprietary lipid-based and ambient responsive FC 
Injection depot technology. The principle behind the FC Injection depot is a liquid-to-gel phase 
transition, occurring immediately as the lipid based FC system is exposed to in vivo conditions of 
SC tissue. The phase transition proceeds from the outside towards the center of the injected FC 
by absorption of minute quantities of water. Thus, injection of CAM2038 q1w into SC tissue 
results in an immediate and spontaneous formation of controlled BPN release matrix providing 
long-acting release in vivo with a minimum initial burst release. The dual nature of the FC 
system, i.e., a true liquid drug product in vitro before injection and stable gel in vivo after 
injection, enables a ready-to-use drug product in a prefilled syringe. CAM2038 q1w is designed 
for convenient and safe SC injection using a prefilled syringe including a needle safety device 
and with no need for mixing or temperature adjustment prior to administration. In addition, the 
injection volume for CAM2038 q1w is relatively low (from 0.15 to 0.6 mL volume, depending 
on dose and product) and can be administered using a fine gauge needle (23 G). CAM2038 
depots have been designed with a focus on enabling easy administration, dosing flexibility, and 
importantly, minimizing risks of misuse, diversion and poor patient adherence.  
5.2. 
Clinical Data 
5.2.1. 
CAM2038 q1w (Once Weekly)  
SC CAM2038 q1w has so far been investigated after single and repeated doses in 3 clinical 
trials, where a total of 176 human subjects (patients and healthy volunteers) have been exposed 
to the CAM2038 drug products. An initial trial assessed pharmacokinetics, pharmacodynamics 
and safety in opioid dependent patients (Trial HS-07-307). The results showed that CAM2038 
q1w was well tolerated, both locally and systemically. Importantly, no treatment emergent 
serious adverse events (SAEs) were observed and drug-related local tolerability findings were 
limited to 4 of 42 patients (9.5%). Three patients experienced mild injection site pain and 
1 patient exhibited transient injection site inflammation (mild) and injection site pruritus 
(moderate).  


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Two additional clinical trials were subsequently performed in healthy volunteers (under 
naltrexone blockade) to assess the pharmacokinetics and bioavailability of single and repeat 
doses of CAM2038 q1w versus repeated doses of sublingual (SL) BPN (i.e., at steady state) and 
single dose of intravenous (IV) BPN (Trials HS-11-426 and HS-13-487). These two trials 
demonstrated that after administration of the studied doses of CAM2038 q1w, the plasma 
concentrations corresponded to those obtained after administration of SL BPN at approved doses 
(i.e. 8 mg, 16 mg, or 24 mg doses). The BPN levels after administration of CAM2038 q1w were 
furthermore similar in healthy volunteers and patients with opioid dependence. The systemic 
tolerability of CAM2038 q1w was good in both trials and similar to the references, IV and SL 
BPN products, respectively. Local tolerability was very good with no local adverse events (AEs) 
reported in Trial HS-11-426 (Nsafety=60) related to injection site tolerability. Similarly, local 
tolerability was also very good in Trial HS-13-487, featuring 4 repeat SC injections of CAM2038 
q1w into the buttock site.  
Based on these trials, the following main conclusions were drawn regarding clinical properties of 
CAM2038 q1w:  
 Extended BPN release over one week at target plasma concentrations   
 Dose proportionality and flexible/multiple dosing options 
 6- to 8-fold higher bioavailability versus SL BPN 
 BPN plasma concentrations over 7 days within ranges of those produced by 
corresponding SL BPN doses at steady-state (i.e., approved 8 mg, 16 mg, or 24 mg doses) 
 Observed and predicted (repeated dose), Cmax, Cav and Ctrough values for CAM2038 q1w 
within established therapeutic plasma levels of SL BPN (Subutex®) 
 Good safety and systemic tolerability in patients  
 Safety in healthy volunteers comparable to reference IV and SL BPN treatments  
 Good local tolerability in patients and healthy volunteers 
The clinical pharmacokinetic profile and good systemic and local tolerability of CAM2038 q1w 
evidenced in subjects in these 3 trials is also supported by a large body of data generated in non-
clinical pharmacokinetic and toxicology studies in the dog, mini-pig and rat of single and repeat 
SC doses of CAM2038 q1w, including repeat weekly doses of the FC vehicle formulation for 
6 months. SC administration of CAM2038 q1w has been shown to be well tolerated both 
systemically and locally in the non-clinical studies. The treatment-related findings have been 
limited to clinical observations in agreement with and considered related to known 
pharmacological effects of the drug substance BPN, and to reversible, local inflammatory 
reactions at the SC site of injection. The latter findings were similar to the physiological response 
to a foreign body. The FC related injection site findings appeared to be reversible and self-
limiting, and only apparent at the immediate vicinity of test article deposition. In summary, non-
clinical data have indicated no systemic toxicity associated with CAM2038 q1w or the FC 
injection depot vehicle. 
Additional information about CAM2038 can be found in the Investigator’s Brochure. 


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5.2.1.1. 
Pharmacokinetics  
Plasma concentrations of BPN (geometric mean) for the first 36 hours post-dose after single SC 
administration of CAM2038 q1w are presented in Table 1, respectively (Study HS-11-426 and 
HS-13-487). Although, the BPN release following CAM2038 q1w SC depot injections have a 
relatively smooth gradual onset relative to SL BPN formulations, BPN peak plasma 
concentrations (Cmax) across doses were observed within the first 24 hours post-dose for both the 
q1w formulation.  
Table 1 
Plasma concentrations of buprenorphine (geometric mean) after single 
subcutaneous administration of CAM2038 q1w to healthy subjects under 
naltrexone blockade 
Time after dose 
(h) 
Plasma concentrations of buprenorphine (ng/mL) 
CAM2038 q1w 8 mg 
CAM2038 q1w 16 mg 
CAM2038 q1w 32 mg 
Pre-dose 
<0.025 
<0.025 
<0.025 
0.5 
0.0759 
0.253 
0.220 
1 
0.119 
0.396 
0.391 
2 
0.257 
0.722 
0.748 
4 
0.568 
1.39 
1.83 
6 
0.767 
1.63 
2.61 
10 
1.40 
2.84 
4.42 
24 
1.65 
2.84 
5.00 
36 
1.11 
2.02 
3.76 
Source: Study HS-11-426 
h = hour; q1w = once weekly 
Table 2 and Table 3 summarize observed and predicted BPN after single dose (Table 2) and 
repeat administration (Table 3) of CAM2038 q1w SC injection and SL BPN (administered as 
Subutex®) in healthy volunteers under naltrexone blockade. Although there are inherent 
differences in the pharmacokinetic profiles for daily-, weekly-, and monthly-administered 
products, pharmacokinetic results from Study HS-11-426 (Study Report HS-11-426) and Study 
HS-13-487 (Interim Study Report HS-13-487) presented below, suggest that the pharmacokinetic 
profiles of the q1w formulation are similar with respect to steady state Cmax and Ctrough of BPN 
after SL administration. Based on these similarities, the current study will examine the opioid-
blocking effects of only the CAM2038 q1w formulation.  


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Table 2 
Observed and predicted buprenorphine exposure after single administration of SC 
CAM2038 q1w, SC CAM2038 q4w, and SL Subutex® in healthy subjects  
 
 
Geometric Mean (geometric CV%) 
 
 
Cmax  
Ct  
AUCinf  
Treatment 
Study 
(ng/mL) 
(ng/mL)a 
(ng*h/mL) 
SC CAM2038 q1w 
 
 
 
 
8 mg  
HS-11-426 
1.7 (36) 
0.30 (26) 
166 (20) 
16 mg  
HS-11-426 
3.1 (49) 
0.61 (25) 
335 (13) 
16 mg  
HS-13-487 
3.1 (46) 
0.58 (25) 
NC 
24 mg 
 
4.2b 
0.86b 
487b 
32 mg  
HS-11-426 
5.3 (45) 
1.1 (24) 
638 (12) 
SC CAM2038 q4w 
 
 
 
 
64 mg  
HS-13-487 
3.8 (60) 
0.45 (57) 
1360 (33) 
96 mg 
 
5.2b 
0.69b 
1960b 
128 mg  
HS-13-487 
6.6 (68) 
0.93 (33) 
2550 (26) 
160 mg 
 
7.9b 
1.2b 
3120b 
SL Subutex 
 
 
 
 
8 mg  
HS-11-426 
4.3 (32) 
0.25 (38) 
NC 
16 mg  
HS-11-426 
6.7 (62) 
0.38 (36) 
NC 
24 mg  
HS-11-426 
7.1 (19) 
0.49 (39) 
NC 
8 mg  
HS-13-487 
4.4 (41) 
0.26 (35) 
NC 
16 mg  
HS-13-487 
5.9 (31) 
0.37 (44) 
NC 
24 mg  
HS-13-487 
8.2 (60) 
0.54 (44) 
NC 
AUCinf = are under the plasma concentration-time curve from time 0 to infinity; Cmax = maximum plasma concentration; Ct = 
plasma concentration at time t; CV = coefficient of variation; NC = Not calculated; SL = sublingual 
a. 
Ct at 7 days for SC CAM2038 q1w, Ct at 1 day (24 hours) for SL Subutex® 
b. 
Predicted from linear regression analysis of logarithmic pharmacokinetic variable vs. logarithmic dose 
 
Table 3 
Observed and predicted buprenorphine exposure after steady state administration 
of SC CAM2038 q1w, SC CAM2038 q4w, and SL Subutex® in healthy subjects 
 
 
Geometric Mean (geometric CV%) 
 
 
Css,max 
Css,av 
Css,t 
Treatment 
Study 
(ng/mL) 
(ng/mL) 
(ng/mL) 
SC CAM2038 q1w 
 
 
 
 
8 mg 
 
1.7a 
1.0b 
0.45 a 
16 mg 
HS-13-487 
4.3 (44) 
2.1 (24) 
0.84 (22) 
24 mg 
 
5.2a 
2.9 b,c 
1.4 a 
32 mg 
 
6.9 a 
3.8 b 
1.8 a 
SC CAM2038 q4w  
 
 
 
 
64 mg 
 
3.9 a 
2.0 b 
1.1 a 
96 mg 
 
5.8 a 
2.9 b,c 
1.6 a 
128 mg 
 
7.8 a 
3.8 b 
2.1 a 
160 mg 
 
9.8 a 
4.6 b,c 
2.7 a 
SL Subutex 
 
 
 
 
8 mg 
HS-11-426 
4.7 (29) 
1.1 (34) 
0.61 (46) 
16 mg 
HS-11-426 
6.3 (49) 
1.6 (37) 
0.79 (58) 
24 mg 
HS-11-426 
7.8 (37) 
2.3 (29) 
1.2 (44) 
8 mg 
HS-13-487 
4.7 (36) 
1.2 (33) 
0.68 (52) 
16 mg 
HS-13-487 
6.7 (47) 
1.9 (33) 
1.1 (46) 
24 mg 
HS-13-487 
8.5 (54) 
2.7 (34) 
1.6 (40) 
Css,max = maximum plasma concentration at steady state; Css,av = average plasma concentration during a dosing interval at steady 
state; Css,t = plasma trough concentration at steady state; CV = coefficient of variation; PK = pharmacokinetic 
a. 
Predicted by simulation from a nonlinear mixed effects pharmacokinetic model describing observed pharmacokinetic data. 
b. 
Predicted and calculated from AUCinf after single dosing and assuming time-independent pharmacokinetic. 
c. 
Predicted from linear regression analysis of logarithmic pharmacokinetic variable vs. logarithmic dose. 


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Figure 1 below provides graphical illustrations of observed and predicted plasma BPN 
concentrations for different doses of CAM2038 q1w, CAM2038 q4w, and SL BPN (Subutex®) 
over 28 days.  
Figure 1 
Observed steady state arithmetic mean Cmax and Ctrough of buprenorphine after 
sublingual administration of Subutex®, and observed and predicted steady state 
plasma concentration profiles after subcutaneous administration of CAM2038 q1w 
and CAM2038 q4w based on data from Studies HS-11-426 and HS-13-487 
(semi-logarithmic scales) 
Figure 1A 
0.1
1
10
100
0
7
14
21
28
SC CAM2038 q1w 16 mg pred 
SC CAM2038 q1w 16 mg obs
SC CAM2038 q4w 64 mg pred 
Ctrough for SL buprenorphine 8 mg at steady state
Cmax for SL buprenorphine 8 mg at steady state
Plasma BPN conc (ng/mL)
Time (days)


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Figure 1B 
 
 
Figure 1C 
0.1
1
10
100
0
7
14
21
28
SC CAM2038 q1w 24 mg pred 
SC CAM2038 q4w 96 mg pred 
Ctrough for SL buprenorphine 16 mg at steady state
Cmax for SL buprenorphine 16 mg at steady state
Plasma BPN conc (ng/mL)
Time (days)
0.1
1
10
100
0
7
14
21
28
SC CAM2038 q1w 32 mg pred 
SC CAM2038 q4w 128 mg pred 
Ctrough for SL buprenorphine 24 mg at steady state
Cmax for SL buprenorphine 24 mg at steady state
Plasma BPN conc (ng/mL)
Time (days)


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Cmax= maximum plasma concentration; Ctrough= trough plasma concentrations; q1w= once weekly dosing 
Geometric mean observed steady state Cmax and Ctrough for Subutex® from HS-11-426 and HS-13-487 
Predicted plasma concentration versus time profiles for CAM2038 q1w from single and repeat dose data in HS-13-487 
Observed steady state plasma concentration versus time profiles for CAM2038 q1w 16 mg from HS-13-487 
Predicted steady state plasma concentration versus time profiles for CAM2038 q4w from single-dose data in HS-13-487 
5.3. 
Study Rationale 
Opioid drug dependence is a major health and social issue and is often a chronic medical 
condition that requires long-term maintenance treatment. An important aim of the treatment 
programs for opioid drug dependence is to reduce illicit drug use, reduce the associated harms 
and stabilize patients pharmacologically to allow them to engage in psychosocial interventions to 
assist in their recovery. Successful treatment can decrease morbidity and mortality, improve 
patients’ quality of life, and reduce the burden on society. Moreover, individuals with opioid use 
disorder often engage in higher risk behaviors such as injecting with used syringes and needles, 
and thus expose themselves to high risk of transmission of infectious diseases, including human 
immunodeficiency virus (HIV) and hepatitis C.  
Clinical studies have reported that BPN is effective at attenuating the effects of subsequently 
administered opioids, including those of acute doses of morphine up to 120 mg for up to 
29.5 hours (Jasinski et al., 1978). Buprenorphine has also demonstrated the ability to dose-
dependently decrease the effects of hydromorphone (Walsh et al., 1995; Bickel et al., 
1988). These studies indicate that BPN (at doses ranging from 2 to 32 mg SL BPN) can attenuate 
the effects of hydromorphone, including subjective effects and euphoria in a dose-dependent 
manner. Furthermore, it was suggested that some therapeutic benefit of opioid attenuation was 
evident after the first dose. 
The present study will investigate the presence, duration, and degree of full mu-opioid agonistic 
effect blockade provided by CAM2038 q1w administered at therapeutic doses for opioid 
maintenance therapy in patients with opioid use disorder.  


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6. 
STUDY OBJECTIVES 
6.1. 
Primary Objective 
The primary objective of the study is:  
 To evaluate the degree of opioid blocking effects of CAM2038 q1w following 
administration of intramuscular (IM) hydromorphone (6 mg and 18 mg) compared to 
administration of 0 mg hydromorphone (placebo) on subjective opioid effects in subjects 
with opioid use disorder, as measured by the primary measure, Drug Liking visual 
analog scale (VAS). 
6.2. 
Secondary Objectives 
The secondary objectives of this study are:  
 To evaluate the degree of opioid blocking effects of CAM2038 q1w following 
administration of IM hydromorphone (6 mg and 18 mg) compared to administration of 
placebo on subjective opioid effects in subjects with opioid use disorder, as determined 
by the secondary outcome measures.  
 To explore the relationship between plasma BPN concentration and blockade of the 
subjective opioid effects of hydromorphone. 
 To examine the safety and tolerability of CAM2038 q1w when co-administered with 
hydromorphone. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
This is a multi-site, randomized, double-blind, repeat-dose Phase 2 study to evaluate the degree 
and duration of action of multiple doses of CAM2038 q1w in blocking the effects of a mu opioid 
agonist (hydromorphone) in patients with moderate or severe opioid use disorder. The study will 
involve 4 phases: Screening, Qualification, Treatment, and Follow-up.  
Within 4 weeks of initiating screening, subjects will be admitted to a clinical research unit 
(CRU) for the Qualification Phase. Following check in to the CRU, subjects will be transitioned 
to a short-acting oral opioid, IR morphine 30 mg, (administered 4 times daily [QID]), for a 
minimum of 3 days and a maximum of 7 days (Qualification Phase described in detail in Section 
7.1.2). One additional dose of IR morphine 30 mg may be administered for the first 3 days of 
stabilization, as needed, at the investigator’s discretion. After stabilization on IR morphine 30 
mg, all subjects will complete a 3-day Qualification/Baseline Hydromorphone Challenge Session 
which will involve IM administration of 3 doses of hydromorphone (Treatment A: 0 mg 
[placebo], Treatment B: 6 mg and Treatment C: 18 mg) administered once daily (Day -3, Day -2, 
and Day -1) in a randomized, double blind, crossover manner, with each hydromorphone 
administration separated by approximately 24 hours (described in detail in Section 7.1.4).  
Following the Qualification/Baseline Hydromorphone Challenge Session, eligible subjects will 
receive CAM2038 q1w at doses of 24 mg or 32 mg (randomized in a 1:1 ratio to 1 of 2 groups). 
Subjects will receive once weekly SC injections of CAM2038 q1w for 2 weeks (injections on 
Day 0 and Day 7) and will remain inpatient in the CRU for up to 25 days (including 
Qualification Phase), during which time 4 Hydromorphone Challenge Sessions (3 consecutive 
days each) will be conducted on Days 1 to 3, Days 4 to 6, Days 8 to 10, and Days 11 to 13, 
respectively. Safety and pharmacodynamic assessments will be performed on each day of the 
Hydromorphone Challenge Sessions at multiple timepoints beginning at pre-dose until 
approximately 5 hours post-dose. Plasma samples to quantify BPN and norbuprenorphine levels 
will also be obtained approximately 60 minutes prior to hydromorphone dosing on each day of 
the Hydromorphone Challenge Sessions.  
Subjects will be discharged on Day 14 and a follow-up phone interview will be conducted on 
approximately Day 21. 
The degree of hydromorphone dose tolerability will be determined based on the site-specific 
study Investigator’s review of the subject’s oximetry data, vital signs, behavior, and physical 
demeanor. 
To ensure adequate enrollment and address potential inconvenience to subjects, all subjects will 
receive appropriate compensation for time and travel expenses related to attendance at study 
visits. All costs of study participation, including study medications will be covered.  
 


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7.1.1. 
Screening Visits (Day -31 to Day -11): 
Medical and eligibility screening will occur within roughly 3 weeks of check in to the inpatient 
Qualification Phase (Day -10, Day -9, Day -8, Day -7, or Day -6). At the first Screening Visit, 
subjects will provide written informed consent to participate in the study before any 
protocol-specified procedures or assessments are completed. Screening will include standard 
medical screening procedures, complete medical/psychosocial history, urine drug screen (UDS) 
and detailed substance use and treatment, using timeline follow-back methods (Fals-Stewart et 
al., 2000), as outlined in Table 4. Screening may occur over several outpatient visits. Subjects 
may be rescreened at the Investigator’s discretion. 
7.1.2. 
Qualification Phase 
7.1.2.1. 
Day -10 to Day -1  
During the Qualification Phase, subjects will be admitted to a CRU for a stabilization period 
starting on Day -10 during which all subjects will be stabilized on a short-acting oral opioid (i.e., 
morphine) to suppress opioid withdrawal. Subjects will receive IR morphine 30 mg, QID for a 
total daily dose of 120 mg; subjects will be permitted to receive an additional dose of IR 
morphine 30 mg dose (total daily dose of 150 mg), as needed (PRN) for the first 3 days only. At 
inpatient check-in, ancillary medications will be made available for symptomatic relief of 
withdrawal (see Table 5Error! Reference source not found.Error! Reference source not 
found. for the list of allowed medications). Subjects will receive IR morphine 30 mg (as outlined 
above) for a minimum of 3 days and a maximum of 7 days prior to entering the 
Qualification/Baseline Hydromorphone Challenge Session, dependent on the individual’s 
underlying level of dependence.  
During this stabilization period, subjects will be monitored carefully for safety. Before each 
scheduled IR morphine 30 mg dose is administered, research/nursing staff will record oxygen 
saturation and respiratory rate and assess the subject for sedation and/or intoxication. If 
respiratory rate drops to <12 breaths per minute or oxygen saturation is <95%, the measurements 
will be repeated and recorded. If either oxygen saturation or respiratory rate remains outside the 
pre-specified parameters or the subject appears sedated or intoxicated, the oral maintenance dose 
of IR morphine 30 mg will be withheld and a study Investigator notified. The withheld dose may 
be administered later (and the administration time recorded) once it is determined that the 
subject’s status has returned to within a safe range.  
On the evening prior to and on the morning of each Qualification/Baseline Hydromorphone 
Challenge Session day i.e., Day -3, Day -2 and Day -1, subjects will not receive their IR 
morphine 30 mg dose; therefore, the last active dose of IR morphine 30 mg will be administered 
a minimum of 12 hours before administration of hydromorphone during the Hydromorphone 
Challenge Session (see sample IR morphine 30 mg administration schedule in Section 17.1).  
On Days -3 to -1, a Qualification/Baseline Hydromorphone Challenge Session will be completed 
(described in Section 7.1.4). The purpose of the Qualification/Baseline Hydromorphone 
Challenge Session is to ensure that subjects can discriminate and show positive subjective effects 
of 6 mg and 18 mg IM hydromorphone compared to IM hydromorphone 0 mg (placebo). After 
completion of each day of the Hydromorphone Challenge Session, subjects will be assessed by 


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research or nursing staff, based upon the same respiratory rate and oxygen saturation criteria 
described above, to determine if it is safe to resume administration of IR morphine 30 mg 
maintenance dosing, with dosing time documented. In the event that IR morphine 30 mg dosing 
is withheld in the afternoon, oral IR morphine 30 mg for the evening dose will be scheduled for 
no later than the original scheduled administration time in order to maintain consistency between 
time of last active dose and hydromorphone dose administration the following day. Subjects who 
are not eligible to continue to the Treatment Phase i.e., do not meet Qualification criteria (Section 
8.3) will be discharged from the CRU at approximately 24 hours after administration of the 
Day -1 IM hydromorphone dose. Prior to discharge, subjects may be offered additional 
treatment, as needed, per the standard practices of the investigational site. Those subjects who 
meet Qualification criteria will proceed to the Treatment Phase.  
7.1.3. 
Treatment Phase 
7.1.3.1. 
Days 0 to 6  
On the morning of Day 0 of the Treatment Phase, subjects will receive one of the following 
treatments (based on randomization in a 1:1 ratio, stratified by gender) to:  
 Group A: CAM2038 q1w 24 mg SC injection 
 Group B: CAM2038 q1w 32 mg SC injection  
Maintenance IR morphine 30  mg will be withheld for at least 12 hours prior to CAM2038 q1w 
dosing; therefore, the Day -1 evening dose and the Day 0 morning dose of IR morphine 30 mg 
will be withheld. The Clinical Opiate Withdrawal Scale (COWS; See Section 17.2) will be 
administered prior to dosing with CAM2038 q1w; in order to be dosed on Day 0, subjects will be 
required to have a COWS score of ≥ 8, indicative of mild withdrawal.  
CAM2038 q1w treatment will be administered at approximately 9:00 am; CAM2038 q1w 
administration instructions for user (IFU) will be provided in the Manual of Procedures (MOP). 
On Days 1 to 3 and Days 4 to 6, subjects will undergo 2 separate Hydromorphone Challenge 
Sessions (described in Section 7.1.4), with each daily challenge dose of IM hydromorphone 
administered at approximately 9:00 am (i.e., approximately 24, 48, 72, 96, 120, and 144 hours 
following Day 0 CAM2038 q1w injection). Safety and pharmacodynamic assessments will be 
conducted immediately following each dose of hydromorphone administered in each 
Hydromorphone Challenge Session (maximum 5 hours after Hydromorphone Challenge 
Session). Plasma samples will also be collected prior to hydromorphone dosing on each day of 
the Hydromorphone Challenge Sessions.  
7.1.3.2. 
Days 7 to 14:  
On the morning of Day 7 (approximately 9:00 am) of the Treatment Phase, each Group (A and 
B) will receive a second dose of CAM2038 q1w according to their assigned treatment group. On 
Days 8 to 10 and Days 11 to 13, subjects will undergo 2 separate Hydromorphone Challenge 
Sessions, with each daily challenge dose of IM hydromorphone administered at approximately 
9:00 am (i.e., approximately 24, 48, 72, 96, 120, and 144 hours following Day 7 CAM2038 q1w 
injection). As in previous sessions, each Hydromorphone Challenge Session will consist of 
subjects receiving 3 doses of IM hydromorphone (0 mg [placebo], 6 mg and 18 mg) in a 


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randomized, crossover manner. Safety and pharmacodynamic assessments will be conducted 
immediately following each dose of hydromorphone administered in each Hydromorphone 
Challenge Session (maximum 5 hours after Hydromorphone Challenge Session). 
Subjects will be discharged on Day 14, if medically acceptable according to the investigator or 
designee. 
7.1.4. 
Hydromorphone Challenge Sessions 
Each Hydromorphone Challenge Session in the Qualification Phase and Treatment Phase will 
consist of the injection of 3 doses of IM hydromorphone 10 mg/mL (0 mg [placebo], 6 mg and 
18 mg) administered once daily over 3 consecutive days in randomized order. Subjects will be 
randomized in a 1:1:1:1:1:1 ratio to 1 of 6 treatment sequences according to two 3 × 3 William 
squares. The following treatment sequences will be used: ABC, ACB, BAC, BCA, CAB, and 
CBA, where A, B, and C are IM Hydromorphone Challenge Sessions with 0 mg (placebo), 6 mg, 
and 18 mg, respectively. The volume of the 0 mg and 6 mg doses of IM hydromorphone will be 
the same as the volume of the 18 mg hydromorphone dose. Safety and pharmacodynamic 
assessments will be performed immediately following each dose of hydromorphone administered 
on each day of the Hydromorphone Challenge Session for a maximum 5 hours after 
Hydromorphone Challenge Session. Plasma BPN and norbuprenorphine levels will also be 
obtained approximately 60 minutes prior to hydromorphone dosing on each day of the 
Hydromorphone Challenge Sessions. After each dose of hydromorphone, subject’s oxygen 
saturation, respiratory rate, and overall safety profile will be reviewed by the research/nursing 
staff (as described in Section 7.1.2.1) to determine whether it is safe to proceed with 
administration of the next dose of hydromorphone. 
7.1.5. 
Follow-up Phase  
Following the last day of the Treatment Phase (i.e., Day 14), plasma BPN levels are expected to 
be approximately 1.4 to 1.8 ng/mL and to gradually taper off; therefore, subjects are not expected 
to experience immediate withdrawal effects at the time of discharge. A follow-up telephone 
interview will be conducted approximately 7 days after discharge from the CRU to obtain 
information on any safety issues including withdrawal effects. 
Subjects will participate in the study for approximately 7 weeks, from Screening to Follow-up. 
An overview of the study design is provided in Figure 2. 
Study assessments and procedures will be performed at the visits and time points outlined in the 
Schedule of Assessments.  
Section 10 provides additional information on the baseline, safety, and pharmacodynamic 
procedures and assessments included in the study. Pharmacodynamic endpoints are described in 
Section 10.7. Statistical analysis is described in Section 12.


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Figure 2 
Overview of Study Design 
 
IR = immediate-release; MS = morphine sulfate; q1w = once weekly dosing; R = randomization


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Table 4 
Schedule of Assessments  
 
Screening 
Inpatient Qualification Phase 
Inpatient Treatment Phase 
Follow-up 
Phone Call  
Visit: 
1 
2 
 
Day: 
-39 to -11 -10, -9, -8, 
-7, OR -6 
-9, -8, -7, -6, 
OR -5 to -4 
-3 to -1 
0 
1 to 3 & 
4 to 6 
7 
8 to 10 & 
11 to 13 
14/ ET 
21 
Assessment 
 
 
 
 
 
 
 
 
 
 
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Reviewb 
X 
X 
 
 
 
 
 
 
 
 
Medical and Medication History 
X 
Xc 
 
 
 
 
 
 
 
 
DSM-V 
X 
 
 
 
 
 
 
 
 
 
Physical Examination (including BMI) 
Xd 
Xe 
 
 
 
 
 
 
Xe 
 
Serology panel (optional) 
X 
 
 
 
 
 
 
 
 
 
Concomitant Meds/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
 
 
Xf 
 
Xf 
 
X 
 
Urine Drug Screeng 
X 
X 
 
 
 
 
 
 
 
 
Breath Alcohol Test 
X 
X 
 
 
 
 
 
 
 
 
 
a Subjects must voluntarily provide written informed consent prior to any study-related procedures being performed. 
b Prior to enrollment in the Qualification Phase of this study, all Inclusion and Exclusion criteria must be met.  
c Brief update on the subject’s medical and medication history since Screening at inpatient check-in only. 
d A complete physical exam of all major body systems will be performed during Screening including height, weight and BMI. 
e Abbreviated (symptom-directed) physical examination performed at the investigator’s discretion (height will not be measured) 
f ECGs performed prior to dosing with CAM2038 q1w  
g Urine drug screen will be administered at Screening and inpatient check-in. Additional urine drug screens may be performed at the investigator’s discretion.  


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Screening 
Inpatient Qualification Phase 
Inpatient Treatment Phase 
Follow-up 
Phone Call  
Visit: 
1 
2 
 
Day: 
-39 to -11 -10, -9, -8, 
-7, OR -6 
-9, -8, -7, -6, 
OR -5 to -4 
-3 to -1 
0 
1 to 3 & 
4 to 6 
7 
8 to 10 & 
11 to 13 
14/ ET 
21 
Pregnancy Test 
Xh 
Xh 
 
Xi 
Xi 
 
Xi 
 
 
 
FSH Testj 
X 
 
 
 
 
 
 
 
 
 
Laboratory Testsk 
X 
X 
 
 
 
 
 
 
X 
 
Pulse Oximetry/Cardiac 
monitoring/Respiratory Rate 
Monitoring  
 
Xl 
X 
Xm 
X 
Xm 
X 
Xm 
 
 
Vital Signsn 
X 
X 
X 
Xo 
Xp 
Xo 
Xp 
Xo 
X 
 
 
h A serum pregnancy test will be performed for all females of childbearing potential during Screening and at inpatient check-in. Following inpatient check-in and 
throughout the duration of confinement, urine pregnancy tests may be administered at the Investigator’s discretion. 
i A urine pregnancy test will be performed for all females of child-bearing potential only prior to IM hydromorphone injection on Day -3 and prior to dosing with 
CAM2038 q1w on Day 0 and Day 7.  
 
j If post-menopausal females do not have a record of a FSH test, post-menopausal females will have a FSH test at Screening. 
k Includes chemistry, hematology, urinalysis and coagulation profile. 
l Before each scheduled IR morphine 30 mg dose is administered, research/nursing staff will record oxygen saturation and respiratory rate and assess the subject 
for sedation and/or intoxication. If respiratory rate drops to <12 breaths per minute or oxygen saturation is <95%, the measurements will be repeated and 
recorded. If either oxygen saturation or respiratory rate remains outside parameters or the subject appears sedated or intoxicated, the oral maintenance dose will 
be withheld and a study Investigator notified. The withheld dose may be administered later (and the administration time recorded) once it is determined that the 
subject’s status has returned to within a safe range. Continuous pulse oximetry and telemetry can be implemented at the Investigator’s discretion. 
m Pulse oximetry/Cardiac monitoring/Respiratory rate monitoring will be included on each Hydromorphone Challenge Session day (i.e., Days -3, -2, -1, 1, 2, 3, 4, 
5, 6, 8, 9, 10, 11, 12, and 13). Monitoring will be continuous from pre-dose up to 5 hours post-dose or longer, if clinically indicated. After each dose of 
hydromorphone, subject’s oxygen saturation, respiratory rate, and overall safety profile will be reviewed by the research/nursing staff to determine whether it is 
safe to proceed with administration of the next dose of hydromorphone. 
n Includes temperature, blood pressure, pulse rate, respiratory rate. 
o On each Hydromorphone Challenge Session day (i.e., Days -3, -2, -1, 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, and 13), vital signs will be collected predose and at 15, 30, 
45, 60, 90, 120 and 180 minutes post-dose and then hourly up to 5 hours post-dose.  
p On CAM2038 q1w dosing days (i.e., Days 0 and 7), vital signs will be collected at pre-dose and at 15, 30, and 60 minutes post-dose, then hourly up to 6 hours 
post-dose. 


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Screening 
Inpatient Qualification Phase 
Inpatient Treatment Phase 
Follow-up 
Phone Call  
Visit: 
1 
2 
 
Day: 
-39 to -11 -10, -9, -8, 
-7, OR -6 
-9, -8, -7, -6, 
OR -5 to -4 
-3 to -1 
0 
1 to 3 & 
4 to 6 
7 
8 to 10 & 
11 to 13 
14/ ET 
21 
Adverse Eventsq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS (baseline/screening) 
X 
 
 
 
 
 
 
 
 
 
C-SSRS (since last visit)r 
 
 
X 
 
X 
 
X 
 
X 
 
MADRSs 
X 
 
X 
 
X 
 
X 
 
X 
 
COWSt 
X 
X 
X 
X 
Xu 
X 
Xu 
X 
X 
 
OOWS 
 
 
 
X 
Xu 
X 
Xu 
X 
X 
 
CAM2038 Injection Site Examination 
 
 
 
 
X 
X 
X 
X 
X 
 
Oral IR Morphine 30 mg Dosingv 
 
X 
X 
X 
 
 
 
 
 
 
CAM2038 q1w SC Injectionw 
 
 
 
 
X 
 
X 
 
 
 
Hydromorphone Challenge Sessionx 
 
 
 
X 
 
X 
 
X 
 
 
 
q Any spontaneously reported adverse events will be recorded after the subject signs the informed consent form.  
r C-SSRS (since last visit) will be administered on Day -4, prior to dosing with CAM2038 q1w on Day 0 and Day 7, and prior to discharge on Day 14/ET.  
s MADRS will be administered at Screening, Day -4, prior to dosing with CAM2038 q1w on Day 0 and Day 7, and prior to discharge on Day 14/ET. 
t COWS will be administered on each CAM2038 q1w dosing day, prior to dosing. In order to be dosed on Day 0, subjects must have a COWS score ≥ 8. If opioid 
withdrawal occurs after dosing with CAM2038 q1w (precipitated withdrawal), COWS and OOWS will be collected every 4 hours while the subject is awake 
for at least 24 hours after dosing. COWS and OOWS will be administered prior to dosing on each Hydromorphone Challenge Session day.  
u COWS and OOWS will be administered prior to dosing on each Hydromorphone Challenge Session and as needed, if a subject experiences precipitated 
withdrawal following administration of CAM203 q1w.  
v Subjects will be given a short-acting oral opioid, IR morphine 30 mg, QID, for a minimum of 3 days and a maximum of 7 days prior to the 
Qualification/Baseline Hydromorphone Challenge Session. One additional dose of IR morphine 30 mg may be administered for the first 3 days of stabilization, 
as needed, at the investigator’s discretion. Subjects will not receive their dose of oral IR morphine 30 mg for approximately 12 hours prior to dosing with 
CAM2038 q1w on Day 0. 
w Subjects will be dosed with either CAM2038 q1w 24 mg or 32 mg SC injection depending on the subject’s treatment group assignment. A second dose of 
CAM2038 q1w will be administered on Day 7.  
x Subjects will be scheduled to receive 3 doses of hydromorphone (0 mg [Placebo], 6 mg, and 18 mg) in a randomized crossover manner over 3 consecutive days. 


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Screening 
Inpatient Qualification Phase 
Inpatient Treatment Phase 
Follow-up 
Phone Call  
Visit: 
1 
2 
 
Day: 
-39 to -11 -10, -9, -8, 
-7, OR -6 
-9, -8, -7, -6, 
OR -5 to -4 
-3 to -1 
0 
1 to 3 & 
4 to 6 
7 
8 to 10 & 
11 to 13 
14/ ET 
21 
Pharmacokinetic sampling 
 
 
 
 
Xy 
Xz 
Xy 
Xz 
Xaa 
 
Pharmacodynamic training/practice 
 
Xbb 
 
 
 
 
 
 
 
 
VAScc 
 
 
 
X 
 
X 
 
X 
 
 
Severity of Opioid Withdrawal VAS 
 
 
 
 
Xdd 
 
X 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
 
Xee 
 
BMI=body mass index; COWS=Clinical Opiate Withdrawal Scale; C-SSRS=Columbia-Suicide Severity Rating Scale; DSM-V = Diagnostic and Statistical 
Manual of Mental Disorders – Fifth Edition; ECG=electrocardiogram; ET=Early Termination; FSH=Follicle Stimulating Hormone; HIV= Human 
Immunodeficiency Virus; MADRS=Montgomery-Asberg Depression Rating Scale; OOWS=Objective Opioid Withdrawal Scale; PD=pharmacodynamic VAS= 
visual analog scale. 
 
y Blood samples will be taken pre-dose and 1, 4, 6 and 8 hours after CAM2038 q1w injection 
z Blood samples will be taken approximately 60 minutes prior to administration of hydromorphone on each of the 3 Hydromorphone Challenge Session days 
during the Treatment Phase (i.e., Days 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, and 13). 
aa Blood samples will be taken approximately 168 hours after CAM2038 q1w injection 
bb Pharmacodynamic training may be administered as frequently as required, but all subjects must complete at least one training session prior to the 
Qualification/Baseline Hydromorphone Challenge Session. Training can only occur prior to or after, but not during the Hydromorphone Challenge Sessions.    
cc On Hydromorphone Challenge Session days (i.e., Day -3, -2, -1, 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, and 13), subjective measures (Drug Liking, Feeling High, Any 
Drug Effects, Good Drug Effects, Bad Drug Effects, Sedated, Desire to Use Opioids VAS) assessments will be performed at predose (up to 15 minutes prior to 
dosing) and at 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240, 270 and 300 minutes post-dose.  
dd Severity of Opioid Withdrawal VAS will be administered, as needed, if a subject experiences precipitated withdrawal following administration of CAM203 
q1w.  
ee Subjects will be discharged on Day 14, if medically acceptable. 


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7.2. 
Discussion of Study Design 
Subjects with opioid physical dependence and moderate to severe opioid use disorder (based on 
criteria defined in the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
[DSM-V]) will be enrolled in this study. Because this is the intended patient population, results 
from this study will be directly applicable to the therapeutic use of CAM2038 q1w in clinical 
practice (i.e., determine the ability of CAM2038 q1w to block illicit opioid effects, which is one 
dimension of opioid maintenance treatment). These subjects are also likely to provide 
meaningful ratings of subjective opioid effects based on their prior opioid use experience. For 
ethical and safety reasons, non-dependent opioid users will not be included, as they are less 
likely to tolerate the higher CAM2038 q1w doses (i.e., no naltrexone blockade) and because it 
would be unethical to produce opioid dependence in an opioid abuser who are not currently 
physically dependent. In addition to the requirement that subjects are “history-qualified” (i.e., 
history of regular opioid use), this study will use a pharmacologic qualification to ensure that 
subjects who meet the drug use history criteria can also distinguish and demonstrate “liking” of 
the subjective euphoric experience of both doses of hydromorphone compared to placebo. 
Therefore, the pharmacologic qualification procedure provides a more objective confirmation of 
drug use history and ensures that subjects can respond appropriately in a laboratory setting as 
well as tolerate the doses of hydromorphone. 
Subjects will be carefully screened to eliminate those presenting with a clinically significant 
history of seizure disorders, history of asthma or other respiratory disorders, head injury, 
hypertension or personal history of cardiovascular disease or clinically significant 
electrocardiogram (ECG). Subjects must not have clinically significant chronic illness (e.g., 
diabetes, liver or kidney disease). Subjects with a known hypersensitivity to any of the study 
drugs or to specific opioids will not be enrolled.  
Studies with opioid-dependent subjects have used a wide array of opioid maintenance drugs and 
doses to stabilize subjects. In the current study, all subjects will be stabilized on a 30 mg dose of 
IR morphine, administered QID (with the option of adding one additional dose of IR morphine 
during the first 3 days of stabilization, as needed) prior to enrollment in the Treatment Phase. 
Administration of IR morphine 30 mg will ensure that any opioids that the subject may have 
recently used will be washed out and will also establish a consistent schedule of opioid 
administration, thereby shortening the duration of opioid washout period required prior to 
administration of the Qualification/Baseline Hydromorphone Challenge Session. Therapeutically, 
patients will be induced with CAM2038 q1w immediately after a short period of abstinence 
(approximately 12 hours) from opioid use as is typical for induction onto buprenorphine; 
therefore, to remain consistent with how the product will be administered clinically, a short-
acting opioid (morphine sulfate) has been selected for stabilization purposes.  
In addition, the 3 to 7 day IR morphine 30 mg stabilization phase will ensure that any opioids 
used prior to check-in will be sufficiently washed out, while also increasing the likelihood that 
subjects will have a similar level of physical dependence to opioids prior to beginning the 
Qualification/Baseline Hydromorphone Challenge. The intention of stabilizing all subjects on IR 


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morphine 30 mg is to attempt to decrease the severity of and discomfort associated with opioid 
withdrawal (Walsh et al., 2015). This will increase the validity of baseline measurement of “drug 
liking” collected after the first administration of hydromorphone (i.e., baseline scores will be less 
likely to be skewed in either direction due to severe withdrawal effects).  
Many studies have evaluated the conditions under which buprenorphine can be administered to 
opioid dependent individuals to avoid the precipitation of withdrawal. Collectively, these studies 
have shown that BPN-precipitated withdrawal is dependent on the following: 1) duration of 
action of the maintenance opioid (whereby precipitated withdrawal is more likely to occur in 
those maintained on long-acting opioids (e.g., methadone) than short-acting opioids (e.g., 
heroin), 2) the time since last opioid maintenance dose (whereby precipitated withdrawal is more 
likely to occur when opioid dosing is recent and more opioid is on board than when time for 
opioid wash-out has occurred and the individual is showing signs of opioid withdrawal, and 3) 
the absolute dose of BPN (whereby a higher BPN dose is more likely to precipitate withdrawal 
compared to a lower dose of BPN). The strategy proposed here addressed each of these 
principles in the following manner: 1) Subjects will be maintained on a short-acting opioid, 
morphine, rather than a long-acting opioid, 2) Morphine will be omitted for a period of ~12 
hours and withdrawal signs and symptoms are expected to emerge during this interval prior to 
CAM2038 q1w administration (subjects will be required to score 8 points or greater on the 
COWS prior to being dosed with CAM2038 q1w on Day 0 (Walsh et al., 2015), and 3) while the 
absolute depot dose of CAM2038 q1w at 24 and 32 mg is high, the more relevant factor is the 
initial concentration exposures following the injection and the rate of onset, whereby a slower 
rate of BPN delivery is associated with decreased likelihood of precipitated withdrawal (Rosado 
et al., 2007). The standard recommended approach (although not necessarily the most commonly 
used in clinical practice) is to begin dosing with 4 mg, wait for 2 hours and, in the absence of 
precipitated withdrawal, administer an additional 4 mg. A 4 mg sublingual tablet of BPN will 
produce a concentration of approximately 2 ng/mL (Cmax) at approximately 1 hour post-dose 
(Ciraulo et al., 2006), while an 8 mg initial dose would produce ~4.3 ng/mL (Cmax) at 
approximately 1.5 hour post-dose (HS-11-426). With respect to the CAM2038 q1w doses 
proposed for testing here, even at the highest dose (32 mg), BPN plasma levels will not exceed 
2 ng/mL until approximately ~4 hours after administration. Thus, the initial BPN concentration 
exposure is predicted to be lower than the exposure typically seen during the first 2-4 hours of 
initial induction with SL products. Moreover, with CAM2038 q1w, concentrations will continue 
to slowly rise, reaching Cmax at approximately 24 hours post-dose. While BPN-precipitated 
withdrawal is a relatively rare occurrence in clinical practice, one strategy employed for 
treatment is to give more BPN. Given the pharmacokinetics of CAM2038 q1w, this potential 
approach for treating BPN-precipitated withdrawal is built into the product design and may serve 
to ameliorate any potential withdrawal effects. However, if withdrawal does occur, specific 
procedures have been included to ensure that subjects are assessed and receive treatment for 
symptoms (See Section 10.6). 
The overall design of the current study is consistent with previously published opioid agonist 
challenge studies, which have investigated the opiate blocking effects of BPN (Jasinski et al., 
1978; Walsh et al., 1995). Based on the pharmacokinetic profile of CAM2038 q1w, specifically 
that BPN peak plasma concentrations are observed within the first 24 hours post-dose, 


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Hydromorphone Challenge Sessions will begin a minimum of 24 hours following the first dose 
of CAM2038 q1w. An additional Hydromorphone Challenge Session will be administered after 
48, 72, 96, 120, and 144 hours post-dose in order to investigate the full duration and magnitude 
of opioid-blockade of the CAM2038 q1w formulation. In order to improve subject retention, the 
study drug will be administered for two weeks with two sets of three Hydromorphone Challenge 
Sessions per week; thereby reducing the inpatient Treatment Phase and the overall duration of 
the study. 
In the current study, subjective “at the moment” assessments using VAS for Drug Liking, Feeling 
High, Any Drug Effects, Good Drug Effects, Bad Drug Effects, Sedated, and Desire to Use 
Opioids will be included to measure the degree and time course of the CAM2038 q1w-induced 
blockade of subjective effects. In addition, pharmacokinetic samples will be collected on each 
Hydromorphone Challenge Session day to measure plasma levels of BPN and norbuprenorphine 
prior to the challenge session. 
Randomization will be used to avoid bias in the assignment of treatment for all the 
Hydromorphone Challenge Sessions and in the assignment of subjects to the 24 mg or 32 mg 
CAM2038 q1w dose groups during the Treatment Phase. Prior to the Qualification/Baseline 
Hydromorphone Challenge Session, subjects will be randomized to 1 of 6 challenge sequences, 
according to two 3 x 3 William squares (ABC, ACB, BAC, BCA, CAB, CBA), and will receive 
one dose of hydromorphone daily over 3 consecutive days, including 2 doses of hydromorphone 
and 1 dose of placebo. This approach has previously been shown to be sensitive to identifying 
dose-related agonist effects, while ensuring that both subjects and staff remain blinded to the 
dose of hydromorphone or placebo being administered, thereby reducing the risk of potential 
expectancy effects. As an additional precaution, subjects will be housed in inpatient research 
units for the duration of the study both for safety monitoring and to ensure that the subjects do 
not use other illicit opioids while enrolled in the study, as this may affect the Hydromorphone 
Challenge Session results.  
Randomization increases the likelihood that known and unknown subject attributes (e.g., 
demographics and baseline characteristics) will be evenly balanced across dose groups and 
enhance the validity of statistical comparisons across dose groups. It was not possible to include 
a placebo control group (CAM2038 SC Placebo injection) in the current study because the 
enrolled population will be physically dependent on opioids and would go into opioid 
withdrawal with placebo administration. Therefore, this study includes a Qualification/Baseline 
Hydromorphone Challenge Session to establish the frequency and magnitude of changes in 
clinical endpoints that may occur in the absence of CAM2038 q1w. 


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8. 
SELECTION OF STUDY POPULATION 
The study will enroll a sufficient number of subjects to ensure that at least 48 subjects complete 
the study (24 subjects per group with at least 16 females in total). Replacement subjects may be 
added at the discretion of the sponsor with the agreement of the Investigator(s).  
8.1. 
Inclusion Criteria 
Subjects must meet each one of the following inclusion criteria in order to be eligible for 
participation in the study: 
1. Subject must provide written informed consent prior to the conduct of any study-
related procedures.  
2. Male or female, 18-55 years of age, inclusive.  
3. Subjects with a diagnosis of moderate or severe opioid use disorder (DSM-V) who 
are currently physically dependent on IV or insufflated opioids, and who are willing 
to undergo short-term BPN treatment.  
4. Self-reported opioid-use of a minimum of 21 days in the 30 days prior to Screening. 
5. Positive UDS for opioids at Screening or at check-in. If UDS is not positive, subjects 
must present with physical signs of withdrawal, as determined by the Investigator. 
The Investigator may administer a naloxone challenge, in order to confirm opioid 
dependence at the Investigator’s discretion. 
6. Female subjects of childbearing potential must be willing to use a reliable method of 
contraception during the entire study (Screening Visit to Follow-Up phone call), as 
defined in Section 10.1.6.  
7. Female subjects of non-childbearing potential should be surgically sterile (i.e., have 
undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a 
menopausal state (at least 1 year without menses), as confirmed by follicle 
stimulating hormone (FSH) levels. 
8. Male subjects with female partners of childbearing potential must agree to use a 
reliable method of contraception from Screening Visit through at least 3 months after 
the last dose of study drug. Male subjects must also agree not to donate sperm during 
the study through at least 3 months after the last dose of study drug.  
9. Is willing and able to comply with the study requirements (including blood 
sampling), complete study assessments, visit the clinic and remain confined in the 
CRU for up to 25 consecutive days. 
 


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8.2. 
Exclusion Criteria 
Subjects will not be eligible to participate in this study if any one of the following exclusion 
criteria is met: 
1. History or presence of any clinically significant psychiatric, endocrine, hematologic, 
hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal, 
or other major disease or illness at Screening, which in the opinion of the Investigator 
would jeopardize the safety of the subject or the validity of the study results. 
2. Opioid dependent subjects who are actively seeking treatment for their moderate to 
severe opioid use disorder.   
3. Subjects with positive urine drug screens for buprenorphine, alcohol, barbiturates, or 
methadone or breath alcohol on the day of check in to the CRU.  
4. Aspartate aminotransferase levels >3 X the upper limit of normal, alanine 
aminotransferase levels >3 X the upper limit of normal, total bilirubin >1.5 X the upper 
limit of normal, or creatinine >1.5 X upper limit of normal on the Screening laboratory 
assessments and at inpatient check-in, or other clinically significant laboratory 
abnormalities, which in the opinion of the Investigator may prevent the subject from 
safely participating in study. 
5. Any clinically significant abnormality on the basis of medical history, vital signs, 
physical examination, 12-lead electrocardiogram (QTcF ≥450 msec. for males or ≥470 
msec. for females), and laboratory evaluation (including hematology, clinical chemistry, 
urinalysis, and serology [optional]) at Screening, in the opinion of the Investigator. 
6. Significant symptoms, medical conditions, or other circumstances which, in the opinion 
of the Investigator, would preclude compliance with the protocol, adequate cooperation in 
the study or obtaining informed consent, or may prevent the subject from safely 
participating in study (including, but not limited to, the risks described as precautions, 
warnings, and contraindications in the current version of the Investigator’s Brochure for 
CAM2038). 
7. Subjects will be carefully screened to exclude individuals presenting with a clinically 
significant history of seizure disorders, history of asthma or other respiratory disorders, 
head injury, hypertension or personal history of cardiovascular disease or clinically 
significant ECG abnormalities. 
8. Current diagnosis of Acquired Immune Deficiency Syndrome (AIDS).  
9. Current diagnosis of chronic pain requiring opioids for treatment. 
10. Subjects who currently meet the criteria for a diagnosis of moderate or severe substance 
use disorder according to DSM-V criteria for any other substances other than opioids, 
caffeine or tobacco.  
11. Pregnant or lactating, or planning to become pregnant during the study.  
12. Clinically significant history of or current evidence of suicidal ideation or active suicidal 
behavior as based on the Columbia-Suicide Severity Rating Scale (C-SSRS; grade 4 or 
5). 


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13. Hypersensitivity or allergy to BPN or other opioids or excipients of CAM2038. 
14. Intolerance to venipuncture and/or difficulty with venous access, as per the judgment of 
the Investigator/research staff. 
15. Subject is currently using an investigational drug or monoamine oxidase inhibitor 
(MAOI) or has used such within the last 30 days (or 5-times the half-life of the drug, if 
known and longer) prior to first drug administration in the Qualification Phase (i.e., IR 
morphine sulfate). 
16. Requires current use of agents that are strong inhibitors or inducers of cytochrome P450 
3A4 (CYP 3A4), such as some azole antifungals (e.g., ketoconazole), macrolide 
antibiotics (e.g., clarithromycin), or protease inhibitors (e.g., ritonavir, indinavir, and 
saquinavir).  
17. If the subject is currently on probation or has any pending legal action that could prohibit 
participation or compliance in the study. 
18. A subject who, in the opinion of the Investigator, is considered unsuitable or unlikely to 
comply with the study protocol for any reason.  
8.3. 
Qualification Criteria 
In addition to the inclusion and exclusion criteria, subjects must meet each one of the following 
criteria in order to be eligible for participation in the Treatment Phase: 
 Maximum effect (Emax) in response to IM hydromorphone 6 mg greater than that of 
placebo on Drug Liking bipolar VAS (response to hydromorphone 6 mg should be 
greater than 55 mm in the VAS and a difference of at least 15 mm between placebo and 
6 mg) and acceptable overall responses to hydromorphone and placebo on the subjective 
measures, as judged by the Investigator or designee.  
 Emax in response to IM hydromorphone 18 mg greater than that of placebo on Drug 
Liking bipolar VAS (greater than 60 mm and a difference of at least 20 mm between 
placebo and 18 mg) and Emax score of at least 20 points, and acceptable overall responses 
to hydromorphone and placebo on the subjective measures, as judged by the Investigator 
or designee.  
 Acceptable placebo response based on Drug Liking bipolar VAS (score between 40 and 
60 mm, inclusive).  
 Subject is able to tolerate IM hydromorphone 6 mg and 18 mg, as judged by the 
Investigator, including ability to complete most pharmacodynamic assessments 
administered within 5 hours post-dose. 
 General behavior suggests that the subject could successfully complete the study, as 
judged by the research site staff. 


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8.4. 
Removal of Subjects from Therapy or Assessment 
A subject is free to withdraw his/her consent and discontinue participation in the study at any 
time for any reason. A subject’s participation must therefore be terminated immediately upon 
his/her request, and the reason(s) for discontinuation appropriately documented. 
A subject must be discontinued from the study for any of the following reasons: 
 Safety reasons, including AEs or significant concomitant illness, injury, or urgent 
surgeries/procedures that would, in the judgment of the Investigator, affect assessments 
of clinical status to a significant extent, require discontinuation of study drug, or both 
 At the request of the Sponsor, regulatory agency, or Institutional Review Board (IRB) 
 Subject is lost to follow-up 
 Subject treatment allocation is unblinded during the Treatment Phase (i.e., individual 
code break; Section 9.6) 
 Death of subject 
A subject may also be discontinued from the study, at the discretion of the Investigator and/or 
Sponsor, for any of the following reasons:  
 Subject refuses or is unable to adhere to the study protocol 
 Protocol violation 
 Pregnancy 
 Requirement for continual use of opioid analgesics >7 days or requirement for general 
anesthesia for surgery 
The Investigator must maintain a record of all subjects who discontinue from the study prior to 
completion; the reason(s) for study discontinuation will be documented. In the event that a 
subject chooses to withdraw from the study, the Investigator should make a reasonable attempt to 
obtain and record the reason(s) for withdrawal, if possible, although the subject is not obligated 
to provide such a reason.  
All efforts should be made by the Investigator to continue collection of safety assessments at the 
protocol-defined intervals, including concomitant medications and AEs in subjects that 
discontinue study drugs, unless the subject withdraws his/her consent at the time of early 
discontinuation. The Investigator should also ask the subject to complete Follow-up phone-call, 
provided that the subject has not withdrawn consent. If a subject refuses to complete Early 
Termination procedures and/or Follow-up, this information will be recorded. 
8.5. 
Study Restrictions 
In addition to the inclusion/exclusion criteria described in Sections 8.1 and 8.2, the subject must 
agree to abide by the following study restrictions:  


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 Subjects will be required to abstain from alcohol for 24 hours prior to Screening and 
before check in to the CRU. Alcohol abstinence will be confirmed with a breath alcohol 
test. 
 Subjects will be asked to abstain from recreational drug use throughout the study, from 
check-in to the CRU until after discharge following the last hydromorphone 
administration in the Treatment Phase.  
 Subjects will not be permitted to consume caffeine-containing beverages on 
Hydromorphone Challenge Session days.  
 Subjects will be asked to abstain from the following foods from 1 week prior to first 
drug administration in the Treatment Phase until after study discharge: grapefruit or 
grapefruit-containing products, pomegranate, pomelo, and star fruit juice/products, as 
well as foods containing poppy seeds,  
 On Hydromorphone Challenge Session days, subjects will be required to abstain from 
smoking for at least 30 minutes prior to hydromorphone dosing. At other times, smoking 
will be permitted at short breaks (approximately 5-10 minutes in duration) at the 
discretion of the CRU staff. If a smoking break is permitted, it must not interfere with 
study procedures. Subjects will be permitted to use a nicotine-containing transdermal 
system as needed, at the discretion of the Investigator.  
 Subjects will be required to abstain from blood donation for 30 days following the 
Follow-up visit. 
 Subjects will be required to follow the informed consent form (ICF) and any clinic rules 
and requirements. 
 Male subjects should refrain from donating sperm for 3 months after the subjects follow 
up visit. 


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9. 
TREATMENTS 
9.1. 
Treatment Administration 
Subjects will be given a short-acting oral opioid, IR morphine 30 mg, QID, for a minimum of 3 
days and a maximum of 7 days prior to the Qualification/Baseline Hydromorphone Challenge 
Session. One additional dose of IR morphine 30 mg may be administered for the first 3 days of 
stabilization, as needed, at the investigator’s discretion. Subjects will not receive IR morphine 
30 mg on the evening and morning prior to hydromorphone dosing in the Qualification/Baseline 
Hydromorphone Challenge Session (Day -3, Day -2, Day -1) and the evening prior to and 
morning of CAM2038 q1w dosing (Day 0).   
Subjects will receive one of the following weekly doses of CAM2038 q1w (BPN FluidCrystal® 
Injection depot for once weekly administration), 24 mg or 32 mg (BPN base), on two separate 
days in the study (Day 0 and Day 7). CAM2038 q1w will be administered by SC injection in the 
subject’s buttocks while rotating between right and left buttocks (0.48 mL or 0.64 mL, 
respectively). 
Hydromorphone (10 mg/mL) will be administered in a randomized manner (placebo, 6 mg and 
18 mg) once daily during each 3-day Hydromorphone Challenge Session. Hydromorphone will 
be administered by 1.8 mL IM injection (described below).  
9.2. 
Identity of Investigational Products 
The following treatments will be used during the study:  
 CAM2038 q1w, 50 mg/mL: 24 and 32 mg (BPN base), 0.48 mL and 0.64 mL SC 
injection. Subcutaneous injections will be performed in the upper buttocks rotating 
between right and left buttocks. 
 Hydromorphone, 10 mg/mL (Dilaudid HP®): 6 and 18 mg for IM administration. 
Intramuscular injections will be performed in the deltoid muscle. 
 Morphine IR 30 mg tablet for oral administration. 
CAM2038 q1w will be supplied as pre-filled syringe with safety device and plunger containing 
the following: BPN, soybean phosphatidylcholine, glycerol dioleate, and ethanol. More 
information regarding the CAM2038 q1w can be found in the Study MOP.  
Dilaudid HP® will be supplied as single dose vials for IM administration. Each 1 mL of sterile 
solution contains 10 mg/mL mg hydromorphone hydrochloride with 0.2% sodium citrate and 
0.2% citric acid solution. 
 For the hydromorphone 18 mg dose, 1.8 mL of this solution will be used. 
 Hydromorphone 6 mg dose will be a combination of 0.6 mL Dilaudid HP solution + 
1.2 mL ½ NS sodium and water for a total injection volume of 1.8 mL. 
 Hydromorphone 0 mg (placebo) will be administered using 1.8 mL of a solution of 0.45% 
sodium and water (1/2 NS).  


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Morphine Sulfate will be supplied as 30 mg tablets. 
Each container of study drug will be clearly labeled with study-specific information meeting all 
the applicable regulatory requirements. 
9.2.1. 
Handling, Storage, and Accountability 
All study drugs will be transported, received, stored, and handled strictly in accordance with the 
container or product label, the instructions provided to the research site, and applicable 
regulations.  
CAM2038 products must be stored according to the requirements outlined in the Study MOP. 
Storage requirements for hydromorphone are provided in the product label (a copy is provided in 
the Study MOP). 
Detailed drug accountability records must be maintained, including the dates shipments are 
received, the quantity of material received, the dates dispensed, the running inventory, and the 
unused quantities returned to the Sponsor’s drug supply vendor at the end of the trial. All unused 
supplies will be checked against the drug accountability records during the study and/or at the 
end of the study. Additional details are provided in the Study MOP. 
Buprenorphine (Schedule III), morphine sulfate and hydromorphone (Schedule II) are controlled 
substances and study drugs must be handled and stored strictly in accordance with restrictions 
related to controlled substances. Study drugs must be kept securely locked with access limited to 
appropriate study personnel, according to applicable regulations. 
9.2.2. 
Dispensing and Administration 
Only eligible subjects participating in the study will receive the study drug. Only authorized 
research site staff may administer the study drugs. Once dispensed, study drug may not be 
relabeled or reassigned for use by other subjects.  
CAM2038 q1w SC injections, hydromorphone IM injections, and IR morphine 30 mg tablets 
will be administered by designated healthcare professional(s) at the CRU. Detailed instructions 
for use will be provided in the Study MOP. 
Investigators will be instructed to treat AEs as they would usually, including pharmacological 
interventions. Any pharmacological interventions provided by the Investigators will be recorded, 
along with the reasons for determining the need for these interventions. Further instructions on 
handling precipitated withdrawal is addressed in Section 10.6. 
9.3. 
Method of Assigning Subjects to Treatment Groups 
Subjects who have provided written informed consent will be assigned a unique number in the 
screening process. This number will be used to identify the subject throughout the study.  
Subjects will be randomized in a 1:1 ratio to 1 of 2 groups (CAM2038 q1w at doses of 24 mg or 
32 mg) stratified by gender. If a subject discontinues from the study, that subject may be replaced 
at the discretion of the Sponsor. The replacement subject will receive the same treatment 


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(CAM2038 q1w) and will follow the same treatment sequence in the Hydromorphone Challenge 
Sessions as the original subject in the Treatment Phase. 
For the Hydromorphone Challenge Sessions, subjects will be randomized in a 1:1:1:1:1:1 ratio to 
1 of 6 treatment sequences according to two 3 × 3 William squares. The following treatment 
sequences will be used: ABC, ACB, BAC, BCA, CAB, and CBA, where A, B, and C are IM 
hydromorphone doses of 0 mg (placebo), 6 mg, and 18 mg, respectively  
9.4. 
Selection of Doses 
The full mu opioid agonist hydromorphone will be used for the opioid challenge sessions. 
Hydromorphone has been commonly employed for this purpose as it has favorable 
pharmacokinetics and is similar to heroin in its time course and pharmacodynamic profile. It has 
a high abuse liability and obviates the challenges of using a Schedule I agent (i.e., heroin). 
Numerous opioid challenge studies have used hydromorphone specifically to examine the ability 
of putative opioid dependence treatments to produce opioid blockade (Walsh et al., 1995; Bickel 
et al., 1988; Strain et al., 1997; Sobel et al., 2004; Ciraulo et al., 2006; Walsh et al., 2006; Lanier 
et al., 2010) so there is a strong precedent for the choice of this compound.  
Initial parenteral doses of hydromorphone for analgesia are 1 to 2 mg subcutaneously or IM 
every 2 to 3 hours PRN (Handelsman et al., 1987; Hydromorphone, 1984). However, 
supratherapeutic doses are needed for challenge studies in opioid abusers. Typically, a lower 
range of supratherapeutic doses can be employed in opioid abusing individuals without physical 
dependence and still produce robust dose-related effects. However, higher supratherapeutic doses 
are needed when investigating responses in active opioid abusers with physical dependence (and 
hence, higher levels of tolerance). Studies that have examined the ability of BPN maintenance 
treatment to produce blockade of hydromorphone effect have varied. For example, one open-
label trial of a depot BPN formulation examined hydromorphone doses of 0 mg and 3 mg (on the 
low end), but this product produced BPN plasma concentrations of under 2 ng/mL (a target range 
generally accepted as the lower therapeutic concentration for blockade, but effective for 
withdrawal suppression). Other studies have employed higher hydromorphone doses during BPN 
and methadone maintenance treatment ranging between 10 mg to 18 mg. In one early study, BPN 
SL solution (estimated to have approximately 30% higher bioavailability over the currently 
marketed tablets) (Handelsman et al., 1987; Hydromorphone, 1984) examined blockade with 
BPN maintenance doses ranging from 2 mg to 16 mg/day using a cumulative SC hydromorphone 
dosing procedure of 0 mg, 6 mg, and 12 mg, for a total challenge dose of 18 mg. A recent study 
examining blockade with another sustained-release BPN product (RBP 6000, Clinical Trials.gov, 
NCT02044094) examined single acute doses of 0 mg, 6 mg and 18 mg. Based upon prior studies 
of methadone and BPN maintenance, the proposed doses are appropriate for opioid challenge 
studies, should be safely tolerated during the Qualification Phase and should reflect attenuated 
responses after stabilization on BPN.  
CAM20138 q1w doses of 24 mg and 32 mg were selected to represent a range of therapeutic 
doses that are being evaluated in Phase III efficacy studies.  


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9.5. 
Selection and Timing of Dose 
During the Treatment Phase, Hydromorphone Challenge Session doses will be administered as 
single IM doses once daily over 3 days, with each daily dose administered at approximately 
9:00 am. CAM2038 q1w SC injections will be administered on Days 0 and 7 at approximately 
9:00 am. The drug administration time should remain consistent (±10 minutes), if possible, on all 
dosing days (CAM2038q q1w and hydromorphone) of the Treatment Phase.  
All subjects will receive standard meals at specified times. Dietary restrictions are described in 
Section 8.5. 
9.6. 
Blinding 
In order to reduce the potential for bias in the study, Hydromorphone Challenge Session 
treatment sequences and CAM2038 q1w treatment group assignments will be double-blinded. 
The subjects will not be aware of the treatment group assignments. The randomization scheme 
will be provided to the site’s unblinded personnel for preparation of the individual subject doses. 
If necessary, personnel from the bioanalytical laboratory will have access to the randomization 
scheme. 
Upon completion of each double-blind, Qualification/Baseline Hydromorphone Challenge 
Session cohort of subjects, the randomization codes for the completed subjects will be unblinded 
to the designated personnel, and the eligibility of subjects to participate in the Treatment Phase 
will be assessed as described in Section 8.3. In order to maintain the blind, unblinded staff not 
otherwise involved in the study will prepare the hydromorphone doses so that they are volume-
matched (1.8 mL, See Section 9.2). 
There is a slight difference in fill volume between the different doses of CAM2038 q1w; 
however, the viscosity is the same. In order to maintain the blind given the differences in color 
fill volume, the following procedures will be implemented: 
 The Injecting staff member and any other staff involved in the injection process will not 
participate in subject evaluations, nor discuss any information regarding the injections with 
the subjects or other study staff. 
 To keep the subjects blinded, appropriate steps will be taken to ensure that the subject is 
unable to view the syringe at any time. 
Under normal circumstances, the blind will not be broken until all subjects have completed 
treatment. In case of emergency, and only if the information is required by the Investigator to 
manage a subject’s medical condition, a subject’s treatment may be unblinded at the site with the 
approval of the Sponsor. Whenever a treatment is prematurely unblinded, the reason, date and 
time of the unblinding, and the individual who broke the blind must be documented. Individual 
code breaks will result in withdrawal of the subject from the study. 


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9.7. 
Prior and Concomitant Therapy 
All non-study medications, including prescription, over-the-counter, or herbal therapies, used by 
the subject will be documented for the 30 days prior to Screening and throughout the study. The 
Investigator will determine if the prior/concomitant medication(s) affect the subject’s eligibility 
to participate or continue to participate in the study. The following restrictions on concomitant 
medications will be in place during the study:  
 Opioid receptors are likely to be occupied by BPN, which may reduce the analgesic 
effects of an opioid. The dissociation of BPN from the receptors may take up to 2 weeks 
following the last CAM2038 q1w injection. Therefore, subjects requiring analgesic 
emergency treatment or anesthesia for surgery should ideally be treated with a non-
opioid analgesic. Opioids may be used with caution, but as higher doses may be required 
for analgesic effect, there may be a higher potential for toxicity with opioid 
administration. The clinical course should be carefully evaluated and fully documented 
for subjects who have a requirement for any opioid analgesic for >7 days continually or 
general anesthesia for surgery within 2 weeks of the final dose of CAM2038 q1w. 
 Buprenorphine is metabolized via CYP3A4. Because CYP3A4 inhibitors may increase 
plasma concentrations of BPN, if CYP3A4 inhibitors such as azole antifungals (e.g., 
ketoconazole), macrolide antibiotics (e.g., erythromycin), and HIV protease inhibitors 
(e.g., ritonavir, indinavir, and saquinavir) are required, the Medical Monitor must be 
consulted. Interactions with CYP3A4 inducers have not been investigated; therefore, it is 
recommended that the use of agents such as phenobarbital, carbamazepine, phenytoin 
and rifampicin be avoided in subjects receiving study treatment. The Medical Monitor 
must be consulted prior to starting subjects on any of these agents. 
 Concomitant use of other narcotic anesthetics, benzodiazepines, phenothiazines, other 
tranquilizers, or other central nervous system (CNS) depressants (including alcohol and 
sedative/hypnotics) may cause respiratory and CNS depression. Use of these substances 
should be minimized during treatment with CAM2038. If these sedatives are required 
during the study, the Medical Monitor must be consulted. Subjects should be advised of 
the danger of concomitant use of sedatives while participating in in the study.  
 Ancillary medications (PRNs) will be allowed as needed throughout the study (see Table 
5), with the exception of Hydromorphone Challenge Session days starting from midnight 
(i.e., approximately 9 hours prior to dosing) through to the end of the Hydromorphone 
Challenge Session (i.e., approximately 5 hours after dosing). Once the session has ended, 
PRNs will be permitted. Ancillary medications will also not be permitted from midnight 
on Day -1 (i.e., approximately 9 hours prior to dosing) until after administration of the 
first dose of CAM2038 on Day 0. 


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Table 5 
Ancillary Medications (PRNs) for Relief of Withdrawal Symptoms  
Symptom 
Treatment 
Dose 
Route of 
Administration 
Dosing 
Schedule 
Anxiety/restlessness 
hydroxyzine 
50-100 mg 
Oral 
Q6H, PRN 
Diarrhea 
bismuth subsalicylate 
(e.g., Pepto-Bismol®) 
30 mL 
Oral 
Q4H, PRN 
Hypotension/sedation 
clonidine 
0.1 mg 
Oral 
Q6H, PRN 
Insomnia 
Zolpidem 
(i.e., Ambien®) 
5 mL 
Oral 
PRN 
Musculoskeletal 
pain/general body 
aches/discomfort 
acetaminophen  
(e.g., Tylenol®) 
650 mL 
Oral 
QID, PRN 
ibuprofen 
400 mg 
Oral 
Q4-6H, PRN 
Nausea/dyspepsia 
alumina, magnesia, 
simethicone 
30 mL 
Oral 
QID, PRN 
Vomiting/severe nausea 
promethazine 
25 mg 
Oral or IM 
Q3-4H, PRN 
IM=intramuscular; PRN=as needed; QID=4 times/daily; Q3-4H= every 3 to 4 hours; Q4H=every 4 hours; Q4-
6=every 4 to 6 hours; Q6H=every 6 hours 
 
On a case-by-case basis, the Investigator is permitted to allow the use of some additional 
concomitant medications not outlined in Table 5Error! Reference source not found., for 
example, to treat an AE, as long as the Investigator determines that the medication will not affect 
the subject’s safety or study integrity (e.g., topical medications). Whenever possible, the 
Investigator should obtain approval from the sponsor’s Medical Monitor prior to administering 
the medication.  
9.8. 
Treatment Compliance 
Study drugs will be administered by study personnel, thus no subject compliance procedures are 
necessary.  


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10. 
STUDY PROCEDURES AND ASSESSMENTS 
All study assessments will be performed at the visits and time points outlined in the Schedule of 
Assessments (Table 4); the following sections outline the details and procedures associated with 
the assessments.  
10.1. 
Demographics and Other Baseline Characteristics 
10.1.1. 
Informed Consent 
The nature of the study and its risks and benefits will be explained to the subject by the 
Investigator or designated study personnel. The subject must voluntarily provide written 
informed consent on an ethics-approved ICF, prior to performing any study-related procedures. 
The subject’s medical records must document that the consent process has been completed and 
that written informed consent has been obtained from the subject prior to the initiation of any 
study-specific procedures. Documentation that the subject was given adequate time to ask the 
Investigator (or designee) questions about their participation in the study and that a signed and 
dated copy of the ICF was provided to the subject should also be included in the medical records 
or clinical chart. 
10.1.2. 
Demographics 
The following demographics will be recorded: age (birthdate), sex, race, and ethnicity. A 
complete psychosocial history will be obtained including: education, employment status, 
marital/significant other status, residential status and legal status/arrest history.  
10.1.3. 
Medical History 
The complete medical history will include histories of acute, chronic, or infectious disease; 
surgical or oncologic histories; and any reported conditions affecting major body systems that 
have occurred within the last five years or that the Investigator deems clinically significant that 
should be included in the subject’s medical history. All findings on medical history will be 
evaluated by the Investigator for clinical significance. Medical histories will be obtained 
according to the site’s standard operating procedures. 
10.1.4. 
Medication History  
All medications (prescription and non-prescription, herbal medications/natural health products, 
or investigational drugs) taken by the subjects during the 30 days prior to Screening will be 
recorded in the source documentation as medication history. Substance Abuse History and 
Treatment History (Section 10.1.5) will be collected separately and stored in the subject’s file. 
10.1.5. 
Substance Use and Treatment History 
A complete history of previous and current illicit drug use, substance abuse/dependence, and 
treatments for any substance use disorders (pharmacologic as well as non-pharmacologic) will be 
obtained. This will include drugs used, type, frequency and patterns of abuse, routes of 
administration, doses, and drug preferences, using a timeline follow-back type of interview 
(Fals-Stewart et al., 2000).  


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10.1.6. 
Contraceptive Requirements 
Female subjects of childbearing potential must be using and willing to continue using medically 
acceptable contraception during the study. Examples of medically acceptable forms of 
contraception include true abstinence, hormonal contraceptives (combined oral pill, patch or 
vaginal ring, intrauterine device or system, progestin implant or injection), bilateral tubal 
ligation, or double-barrier methods (e.g., male condom with spermicide in addition to a 
diaphragm or a contraceptive sponge).  
Female subjects of non-childbearing potential are not required to use contraception and to 
undergo pregnancy tests; however, they must have documentation supporting that they are 
surgically sterile (hysterectomy and/or bilateral oophorectomy/salpingo-oophorectomy, as 
determined by subject medical history) or congenitally sterile, or must be post-menopausal. Post-
menopausal is defined as being amenorrheic for at least 2 years without another cause or 
amenorrheic for at least 1 year without another cause and a documented FSH level ≥50 mIU/mL. 
Male subjects with female partners of childbearing potential must agree to use a medically 
acceptable method of contraception from Screening Visit through at least 3 months after the last 
dose of study drug. Male subjects must also agree not to donate sperm during the study through 
at least 3 months after the last dose of study drug.  
10.2. 
Eligibility Review  
Prior to receiving the first dose of hydromorphone on Day -3, subjects must meet all inclusion 
and not meet any exclusion criteria as outlined in Sections 8.1 and 8.2. 
The Investigator or designee must document that the subjects meet each individual criterion via a 
signed note or eligibility and clinical stability checklist during Screening. Signatures on these 
documents must be dated on or before the date of Day -10.  
10.3. 
Pharmacodynamic Assessments 
All subjects will undergo a scripted training and practice regimen prior to completion of the 
paper and pen subjective measures as outlined in Table 6. 
Testing conditions for pharmacodynamic assessments should remain as consistent as possible 
throughout the Treatment Phase. Subjects will be monitored carefully to ensure that they are 
completing the pharmacodynamic assessments appropriately. Study staff are encouraged to 
provide additional subject training as needed, to ensure that the subjects comprehend the 
differences between different types of VASs. Training dates/times will be documented in the 
subject’s files.  Subject training can only occur before VAS administration or after the 5 hour 
Challenge session is completed.  The training script will be provided to the sites. 
10.3.1. 
Visual Analog Scales 
Each VAS will be scored as an integer from 0 to 100. When appropriate, VASs will be 
administered as bipolar measures, meaning that the neutral point equals 50 (i.e., Drug Liking and 
Alertness/Drowsiness VAS). The neutral point will also be labeled with an anchor, such as 


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“neither like nor dislike.” Unipolar VASs (i.e., High, Good, Bad, and Any Effects VAS) are 
presented with anchors such as “not at all” (score = 0) to “extremely” (score = 100), where the 
neutral point equals 0. The use of a unipolar or bipolar scale is determined by the nature of the 
subjective effect being measured.  
If precipitated withdrawal occurs after administration of CAM2038 q1w, subjects will be 
requested to complete a unipolar VAS assessment of opioid withdrawal severity. 
Table 6 lists the subjective effects VAS question text and response anchors.  
Table 6 
Visual Analog Scale Descriptions 
Scale 
Interpretation 
Description 
Question Text 
Response Anchors 
Balance 
Drug Liking 
At this moment, my liking for this drug is 
0: Strong disliking 
50: Neither like nor 
dislike 
100: Strong liking 
Other effects 
Any Drug Effects 
At this moment, I feel any drug effects 
0: Not at all 
100: Extremely 
Positive 
High 
At this moment, I feel high 
Positive 
Good Drug Effects 
At this moment, I feel good drug effects 
Negative 
Bad Drug Effects 
At this moment, I feel bad drug effects 
Other Effects 
Desire to use opioids 
At this moment, I desire opioids 
0: Definitely not 
100: Definitely so 
Other Effects 
Alertness/Drowsiness 
At this moment, my mental state is 
0: Very drowsy 
50: Neither drowsy 
nor alert 
100: Very alert 
Other Effects 
Opioid Withdrawal 
Severity 
I feel opioid withdrawal 
0: Not at all 
100: Extremely 
 
10.4. 
Safety Assessments 
Safety monitoring will be performed throughout the study for all subjects. All AEs, regardless of 
causality or severity, will be recorded on the AE CRF. CAM2038 injections may be discontinued 
as clinically indicated. 
10.4.1. 
Adverse Events and Serious Adverse Events  
The following definitions, developed in accordance with the United States (US) Code of Federal 
Regulations (CFR) and the International Conference on Harmonization (ICH) Clinical Safety 


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Data Management Guidance for Industry, E2A, will be used for the purpose of identifying AEs 
in this clinical study. 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, 
or increase in severity of a preexisting abnormality, temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
10.4.1.1. Adverse Event Reporting 
All AEs (except for withdrawal symptoms, see below) must be entered on the AE CRF, 
regardless of causality or severity. AEs include new AEs, worsening baseline conditions, 
clinically significant laboratory findings, disease-related signs and symptoms that were not 
present at baseline, and any events or findings that the Investigator feels are clinically significant. 
Withdrawal symptoms will be captured via specified assessments and should not be recorded as 
AEs. 
Disease-related signs and symptoms that are present at baseline should not be recorded as AEs 
unless they worsen in severity or increase in frequency, but rather should be considered and 
recorded as pre-existing conditions. 
Information collected concerning AEs will include the following: 
 Name of the event 
 Onset date 
 Resolution date 
 Severity (i.e., mild, moderate, or severe) 
 Relationship to study drug 
 Action and outcome 
 Seriousness of event 
All AEs will be documented and followed from the time the subject has signed the ICF until 
14 days after the Follow-up Visit (or 30 days after Early Termination). Serious AEs and AEs that 
have been designated as possibly related to study drug will be followed until resolution or 
stabilization. At least 3 attempts will be made to contact the subject and after 3 unsuccessful 
attempts, a certified letter will be sent to the subject address that was provided to the site.  
10.4.1.2. Serious Adverse Event 
A SAE or reaction is any adverse drug experience occurring at any dose that results in any of the 
following outcomes: 
 Death 
 Is life-threatening (at the time of the event) 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 


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 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect (in an offspring) 
 An Important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject and/or may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
All AEs requiring hospitalization or prolongation of a pre-existing hospitalization should be 
reported as SAEs unless they occur greater than 14 days after the Follow-up phone call (or 
30 days after Early Termination) AND are not considered to be drug-related by the Investigator. 
Hospitalizations meeting the following criteria will not be reported as an SAE but must be 
recorded on the appropriate CRF: study specified hospitalization, short-term administrative 
hospitalization for procedures, tests or treatments of conditions that would not otherwise 
constitute an SAE, elective hospitalizations. 
10.4.1.2.1. Serious Adverse Event Reporting 
Serious AEs must be reported to the Sponsor or designee within 24 hours of knowledge of the 
event. All SAEs that occur while a subject is receiving study drug and within 14 days following 
the Follow-up phone call (or 30 days after Early Termination) are reportable within 24 hours. 
During the follow-up period beyond 14 days from Follow-up (or 30 days after Early 
Termination), only those SAEs that are considered to be possibly related to study drug should be 
reported within 24 hours. 
The procedure for reporting a SAE is as follows: 
 Within 24 hours of knowledge of the event, the site must contact the Sponsor (or 
designee) by telephone or facsimile to report the event. 
 The initial report should include all information known at the time of the report 
(additional information can be reported as discovered). Do not delay the initial reporting 
in order to obtain resolution or follow-up information. 
 The site will complete the provided SAE report form that includes the following 
information, as available: 
o Subject ID 
o Basic demographic information (age, gender, weight) 
o Outcomes attributed to the event (death, life-threatening hospitalization [new or 
prolonged], disability, congenital anomaly, required medical intervention to 
prevent permanent impairment/damage, etc.) 
o Onset date and severity of the event 
o Brief description of the event including frequency and severity of symptoms 
leading to diagnosis 
o List of relevant test results and laboratory data 
o Any other relevant history 


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o Whether the study drug was discontinued 
o Whether the assigned treatment oral or injectable therapy was discontinued and/or 
dose titration discontinued, as applicable 
o Investigator’s assessment of causality 
o Other concomitant medication and medical history 
The SAE report form should then be emailed to the Sponsor (or designee) or faxed per 
instructions in the SAE Reporting and Management Plan.  
The Medical Monitor or another representative of the Sponsor may contact the Investigator to 
request additional information regarding the event or to confirm information. All SAEs will be 
entered on the AE CRF. The same nomenclature should be used on both the SAE report and the 
AE CRF. 
Specific instructions for SAE reporting and a copy of an SAE report form are provided in the 
MOP. 
The Investigator is responsible for the complete and timely reporting of all SAEs to the Sponsor 
(or designee), reporting pertinent follow-up information on the SAE, and notifying the 
appropriate IRB/Independent Ethics Committee (IEC) of the occurrence of and details 
surrounding the event. In the event there is a question as to whether the AE is serious, the event 
should be reported. 
10.4.2. 
Pregnancy 
Pregnancies among trial subjects should be reported to the Sponsor or designee as soon as 
possible after learning of the event. Subjects who become pregnant will be withdrawn from the 
study and be referred back to the care of their usual provider or continue in the study after 
discussion with and documentation by the Principal Investigator or his/her designee. Pregnancies 
will be recorded as an AE in the eCRFs. Follow-up information will be obtained where possible 
(with the consent of the subject or their partner) regarding the course and outcome of the 
pregnancy, including any post-natal sequelae in the infant. 
10.4.3. 
Clinical Laboratory Assessments 
All protocol-specified laboratory tests on blood and urine samples will be performed by each 
CRU’s local laboratory. The local laboratory will generate laboratory reports and forward them 
to the clinical site in a timely manner. It is the responsibility of the local medically responsible 
investigator to review and sign all lab reports expeditiously, in order to document appropriate 
safety monitoring of study subjects. The Investigator should sign and date each lab report 
concurrent with her or his review, and should indicate the clinical significance of each 
abnormal/flagged value by noting “NCS” (not clinically significant) or “CS” (clinically 
significant), for example. Notations indicating that a value is clinically significant should also 
include a brief description of the underlying disease or condition that is associated with the 
value, e.g., “CS/mild anemia.” In general, abnormal, clinically significant laboratory values are 
expected to be associated with an item recorded in medical history or with an AE.


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Table 7 
Clinical Laboratory Assessments 
Hematology 
Biochemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Red blood cell (RBC) count  
RBC Morphology 
Mean corpuscular volume  
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration  
Total and differential (absolute) 
white blood cell count 
Platelets 
Sodium 
Potassium 
Magnesium  
Calcium  
Glucose (random) 
Bicarbonate  
Chloride  
Creatinine 
Total protein 
Blood urea nitrogen  
Albumin 
Total bilirubin 
Alanine transferase  
Aspartate transferase  
Lactic dehydrogenase  
Amylase  
Lipase 
Gamma-glutamyl transferase  
Alkaline phosphatase  
Creatine phosphokinase  
Total cholesterol (non-fasting) 
FSH 
Dipstick illicit drug screen 
including buprenorphine, 
barbiturates, benzodiazepines or 
methadone  
Color 
pH 
Specific gravity 
Ketones 
Protein 
Glucose 
Bilirubin 
Nitrite 
Urobilinogen 
Occult blood 
Microscopic examination of 
sediment, only if urinalysis 
dipstick results are abnormal 
 
 
Coagulation 
Prothrombin time (PT), 
International normalized ratio 
(INR) 
Serology testing (optional) 
 
 
HIV-1 and HIV-2 
Hepatitis B surface antigen 
Hepatitis C Antibody (HCVAb) 
 
 
 
Blood and urine samples will be collected, processed, and shipped according to instructions from 
the local laboratory. Additional laboratory samples may be taken at the discretion of the 
Investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure safety. Blood volumes required per draw, laboratory test will be 
determined by each site’s local laboratory. Specific hematology, coagulation, biochemistry, and 
urinalysis assessments are listed in Table 7. It is up to the investigator to review lab results and 
determine if the abnormal lab results are clinically significant. 


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In addition to the clinical laboratory tests, pregnancy testing for the presence of β-human 
chorionic gonadotropin in serum will be performed at the visits defined in Table 4. Results of 
serum pregnancy tests will be reported and determined to be negative prior to study continuation 
and/or dosing. Urine pregnancy testing will be performed prior to the Qualification Phase 
challenge. As an additional precaution, urine pregnancy tests will be administered weekly (on 
Day 0 and Day 7) prior to CAM2038 q1w dosing.  
10.4.4. 
Urine Drug Screen and Breath Alcohol Testing 
Qualitative UDS will be utilized to test for the following drugs of abuse: buprenorphine, 
methadone, tetrahydrocannabinol, oxycodone and other opioids, methamphetamines, 
amphetamines, phencyclidine, oxycodone, propoxyphene, cocaine, barbiturates, and 
benzodiazepines.  
Breath alcohol testing will be performed according to the sites’ standard operating procedures. If 
there is any doubt or concern regarding alcohol use, research site staff may request a breath test 
for alcohol measures at any time during the study. 
Tests will be performed at the visits defined in Table 4. 
10.4.5. 
Vital Signs 
Vital signs will consist of oral body temperature (°C), blood pressure (systolic and diastolic 
blood pressure, mmHg), pulse rate (beats per minute), and respiratory rate (breaths/min) 
collected while sitting with legs uncrossed and feet flat on floor, following a rest period of at 
least 3 minutes.  
10.4.5.1. Qualification Phase Vital Signs Safety Monitoring 
Before each scheduled IR morphine 30 mg dose is administered during the Qualification Phase, 
research or nursing staff will record oxygen saturation and respiratory rate and assess the subject 
for sedation and/or intoxication. If respiratory rate is <12 breaths per minute or oxygen saturation 
is <95% (Section 10.4.7), the measurements will be repeated and recorded. If either oxygen 
saturation or respiratory rate remain outside parameters or the subject appears sedated or 
intoxicated, the oral IR morphine 30 mg maintenance dose will be withheld and a study 
Investigator notified. The withheld dose may be administered later (and recorded) once it is 
determined that the subject’s status has returned to within the safety dosing criteria.  
After the Qualification/Baseline Hydromorphone Challenge Session, subjects will be assessed 
based upon the same safety criteria described above (i.e., respiratory rate, oxygen saturation and 
sedation or intoxication) to determine if it is safe to resume administration of oral IR morphine 
30 mg maintenance dosing. This assessment will be documented. In the event that morphine 
dosing is withheld in the afternoon, evening administration of oral IR morphine 30 mg will be 
scheduled for no later than the original scheduled administration time in order to maintain 
consistency between time of last dose of morphine and Hydromorphone Challenge Session 
dosing the following day.  


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10.4.5.2. Treatment Phase Vital Signs Safety Monitoring 
After each dose of IM hydromorphone during the Treatment Phase Hydromorphone Challenge 
Sessions, subject’s oxygen saturation, respiratory rate, and overall safety profile will be reviewed 
by the research/nursing staff (as described in Section 7.1.2.1) to determine whether it is safe to 
proceed with administration of the next dose of hydromorphone. 
Vital signs assessments will be performed at the visits and time points defined in Table 4. 
10.4.6. 
12-Lead Electrocardiograms 
12-Lead ECGs will be performed after the subject has been resting in a recumbent/supine 
position for at least 3 minutes. The ECG variables will include ventricular heart rate and the PR, 
QRS, QT, and QTcF intervals. The ECGs will be signed and dated by a medically qualified 
individual to confirm review of the ECG and verify whether any abnormalities are clinically 
significant. In general, abnormal, clinically significant ECGs are expected to be associated with 
an item recorded in medical history or with an AE. 
Assessments will be performed at the visits and time points defined in Table 4. 
10.4.7. 
Cardiac Monitoring (including Pulse Oximetry) 
Cardiac monitoring (cardiac rhythm, heart rate) and pulse oximetry will be performed from 
inpatient check-in to the end of the Treatment Phase (or Early Termination) of the study. Data 
will not be recorded in the database, but will be used for real-time safety monitoring. 
Occurrences of oxygen saturation <95%, the measurements will be repeated and recorded as 
AEs. Pulse oximetry/cardiovascular monitoring will be included on each Hydromorphone 
Challenge Session day (i.e., Day -3, -2, -1, 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, and 13). Monitoring 
will be from pre-dose until at least 5 hours post-dose or longer, if clinically indicated. Cardiac 
monitoring and pulse oximetry equipment may be removed briefly (for hygiene purposes), as 
needed.  
Continuous pulse oximetry and telemetry can be performed if the Investigator deems it is 
necessary. 
10.4.8. 
Physical Examination 
A complete physical examination including all major body systems will be performed at 
Screening. At select subsequent study visits, an abbreviated review of systems will be performed 
to capture changes since Screening. 
 Height, weight and BMI will be assessed as described in Table 4. 
10.4.9. 
Injection Site Examination 
CAM2038 injection sites will be examined daily, after each injection, during the Treatment 
Phase for any signs of adverse site reactions. The injection site will be visually inspected daily 
for evidence of erythema, edema, itching, pain, infection, bleeding, abnormal healing and any 
other abnormalities. Injection sites will be examined daily after each injection to determine if any 
site related adverse reactions have occurred. 


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10.4.10. 
Clinical Opiate Opioid Withdrawal Scale (COWS) 
The COWS contains 11 physically observable signs, rated present or absent, based on a timed 
period of observation of the patient by a rater. This scale is a valid and reliable indicator of the 
severity of opiate withdrawal over a wide range of common signs and symptoms (Appendix 
17.2; Wesson, 2003). 
10.4.11. 
Objective Opioid Withdrawal Scale (OOWS) 
The Objective Opioid Withdrawal Scale (OOWS) contains 13 physically observable signs, rated 
present or absent, based on a timed period of observation of the patient by a rater (Appendix 
17.3; Handelsmen et. al. 1987). 
10.4.12. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS will be used to assess both behavior and ideation that tracks all suicidal events, and 
provides a summary of suicidal ideation and behavior. It assesses the lethality of attempts and 
other features of ideation (frequency, duration, controllability, reasons for ideation, and 
deterrents), all of which are significantly predictive of completed suicide.  
Two versions of the C-SSRS will be used in this study: the Baseline/Screening version (6 months 
and lifetime history; Appendix 17.4) and the Since Last Visit version (Appendix 17.5). The 
Screening version of the C-SSRS will be administered at Screening. The Since Last Visit version 
of the C-SSRS will be administered at all subsequent assessment times, as indicated in Table 4, 
by the Investigator or his/her qualified designee (qualified designee is defined as someone that 
has completed the C-SSRS training within the last 2 years). The survey should be administered 
by the same assessor, where possible, throughout the study. 
10.4.13. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
The Montgomery-Asberg Depression Rating Scale (MADRS) will be used to assess subjects for 
the presence of symptoms that are most frequently observed in patients with major depression. 
The scale will be conducted as a clinical interview in which subjects will be required to respond 
to 10 questions. The items will be rated with regards to how the patient has done over the past 
week (Appendix 17.6; Montgomery, 1979). 
10.5. 
Appropriateness of Measures  
As the primary objective of this study is to demonstrate CAM2038 q1w-induced blockade of 
hydromorphone effects; Drug Liking VAS has been chosen as the primary pharmacodynamic 
variable.  
The Drug Liking VAS assesses the response to the question “At this moment, I like this drug.” 
Values for this scale range from 0 (“Strong disliking”) to 100 (“Strong liking”), with 50 as the 
neutral point (“Neither like nor dislike”). This scale has been included to understand the time 
course of CAM2038 q1w-induced blockade of subjective effects of hydromorphone. Additional 
subjective effects VASs will be collected to support findings on the primary measure. The 
subjective effects VAS items will measure positive (Good Drug Effects and High), negative (Bad 


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Drug Effects), and other subjective effects (Any Drug Effects, Desire to Use Opioids, and 
Alertness/Drowsiness VAS) to further assess the pharmacologic response to the Hydromorphone 
Challenge Session injection.  
Pharmacokinetic measures are included to confirm exposure, explore potential relationships 
between pharmacokinetic and subjective measures, and if necessary, to aid in the interpretation 
of unusual responses.  
Standard safety outcomes, such as AEs, ECG, vital signs and clinical laboratory testing will be 
assessed during the study. In addition, respiratory rate and oxygen saturation safety monitoring 
will be included prior to dosing with IR morphine 30 mg and after dosing with hydromorphone.  
10.6. 
Additional Safety Measures and Withdrawal 
10.6.1. 
Opioid Effects  
Buprenorphine and hydromorphone can produce the typical side effect profile of mu opioid 
agonists, and these may include nausea, vomiting, headache, dry mouth, itchiness, drowsiness, 
sweating, dizziness, stimulation, somnolence, lightheadedness, restlessness, a feeling of well-
being, talkativeness, urinary retention and constipation. More serious side effects may include 
allergic reaction and respiratory depression. However, subjects will be opioid-dependent and, 
thus, familiar with these common side effects, and not likely to experience the severe side effects 
such as allergic reaction. 
Physiological and behavioral effects, as well as the emergence of possible side effects, will be 
monitored daily during Hydromorphone Challenge Sessions. Subjects who exhibit 
hypersensitivity (i.e., experience a SAE) following administration of any of the drugs will be 
excluded from further research participation. Heart rate, blood pressure, oxygen saturation and 
respiratory rate will be monitored frequently throughout sessions. However, if a subject 
experiences an allergic reaction, diphenhydramine will be available for oral administration.  
While the risk of significant respiratory depression may be decreased in opioid-dependent 
individuals (due to greater tolerance), standardized criteria for nursing staff and research 
personnel will be employed during the monitoring of individuals. If respiratory rate drops below 
12 breaths/min accompanied by sedation, subjects will be prompted verbally to breathe. This 
approach of physical and verbal stimulation is often sufficient to prompt breathing and restore a 
normal respiratory rate. Subjects will be monitored carefully with a watch-and-wait approach 
and will be accompanied continuously by nursing personnel and evaluated by the staff physician. 
If clinical evaluation determines that a subject’s level of sedation is increasing, naloxone will be 
promptly administered parenterally to produce immediate reversal of the hydromorphone effects. 
Naltrexone will also be available if longer blockade is necessary. 
The study will be conducted in CRUs with trained nursing staff available on site. A crash-cart 
with naloxone will be on site as well. Emergency response will be available by a physician code-
team if needed.  


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10.6.2. 
Treating Opioid Withdrawal 
If opioid withdrawal occurs after dosing with CAM2038 q1w (precipitated withdrawal), the 
following assessments will be collected every 4 hours while the subject is awake for at least 
24 hours after dosing to include:  
1) COWS,  
2) OOWS, 
3) VAS assessment of opioid withdrawal severity.  
Treatment will be based upon clinical judgment of the medically responsible physician at each 
site. To ensure the safety of subjects, incidences of precipitated withdrawal in response to 
CAM2038 q1w will be followed carefully and an amendment of the protocol to ensure subjects 
are in a more advanced state of opioid withdrawal e.g., increase required COWS score from 8 to 
12, to reduce the risk of BPN-related precipitated withdrawal, will be considered if more than 
one incidence occurs.  
Ancillary medications that will be made available for symptomatic relief of all episodes of 
withdrawal (precipitated by CAM2038 q1w and other) are summarized in Table 5Error! 
Reference source not found.Error! Reference source not found..  
10.7. 
Pharmacodynamic Variables 
10.7.1. 
Primary Pharmacodynamic Endpoint 
The primary endpoint of this study is the Emax of Drug Liking VAS. 
10.7.2. 
Secondary Endpoints 
In addition to the primary endpoint of change from baseline in Emax of Drug Liking VAS, the 
following secondary endpoints will be calculated: 
 Emax of High VAS  
 Emax of Good Effects VAS  
 Emax of Bad Effects VAS  
 Emax of Sedated VAS  
 Emax of Any Effects VAS  
 Emax of Desire to use VAS  
10.8. 
Drug Concentration Measurements 
Venous blood samples (6 mL each) will be collected, as indicated in Table 4. Samples will be 
collected, processed, and shipped according to instructions provided in the Study MOP. The 
actual date and time of each blood sample collection will be recorded. 


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Up to 138 mL of total blood volume will be required from subjects for pharmacokinetic 
sampling. Analysis of the plasma samples will be detailed in the Study MOP.  
Plasma samples will be shipped frozen on dry ice from the research site to the designated 
bioanalytical laboratory, as outlined in the Study’s MOP.  
Samples will not be shipped without prior arrangement with the bioanalytical laboratory and/or 
notification to the Sponsor.  
The following pharmacokinetic parameters will be estimated for BPN and norbuprenorphine:  
 Cmax (maximum plasma concentration) 
 Ctrough (plasma concentration level 7 days after the latest injection) 
 Cav (average plasma concentration during a dosing interval).  
 
Details of the pharmacokinetic evaluation will be presented in the SAP. 


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11. 
DATA QUALITY ASSURANCE 
This study will be conducted under Good Clinical Practice (GCP) and all applicable regulatory 
requirements. To ensure compliance, the sponsor or designee may conduct a quality assurance 
audit, as outlined in Section 11.2.  
Actions to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers; the review of protocol procedures with the 
Investigator and study personnel prior to study start; the design of suitable source documents 
with appropriate instructions for use (where applicable); the internal audit of source data 
according to GCP and internal procedures to ensure their accuracy, completeness, and 
verifiability; as well as the periodic site monitoring by the sponsor. The sponsor or designee will 
review source documents for accuracy and completeness during on-site monitoring visits and 
after their return to the sponsor; any discrepancies will be resolved with the Investigator, as 
appropriate.  
Significant and/or repeated non-compliance will be investigated and remedial action instituted 
when appropriate. Failure to comply with remedial actions may result in investigator site 
termination and regulatory authority notification. 
11.1. 
Data Collection  
Source documents include but are not limited to original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, lab results, subject 
diaries, data recorded in automated instruments, microfilm or magnetic media, and pharmacy 
records, etc. This study will use electronic data capture (EDC) or paper CRFs. At a minimum, all 
data required by the protocol should have supporting source documentation for entries in the 
EDC system, unless that data can be recorded directly in the EDC system or other device. 
All CRFs will be completed by the site staff prior to review by the sponsor’s monitor or 
designated representative. The sponsor’s monitor or designated representative will review all 
source records on-site and compare them to the data collected on the CRF. All entries, 
corrections, and alterations will be made by the Investigator or other authorized study personnel. 
All data entries will be verified for accuracy and correctness by independent monitors. The 
electronic data capture system maintains a full audit trail.  
11.2. 
Study Auditing and Monitoring 
Monitoring of the study site (including, but not limited to, reviewing CRFs for accuracy and 
completeness) will be performed by the sponsor’s monitor. The extent, nature, and frequency of 
on-site visits will be based on such considerations as the study objectives and/or endpoints, the 
purpose of the study, study design complexity, and enrollment rate. By signing the protocol, the 
Investigator agrees that, within local regulatory restrictions and institutional and ethical 
considerations, authorized representatives of the sponsor, a regulatory authority, and/or an IRB 
may visit the site to perform audits or inspections, including the drug storage area, study drug 
stocks, drug accountability records, subject charts and source documents, and other records 


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related to study conduct. The purpose of the sponsor audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether the 
study-related activities were conducted, and data recorded, analyzed, and accurately reported 
according to the protocol, the site’s standard operating procedures, GCP guidelines of the ICH, 
and any applicable regulatory requirements. The Investigator should contact the Sponsor 
immediately if contacted by a regulatory agency regarding an inspection. 


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12. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The following sections describe the statistical methods to be used to analyze the efficacy and 
safety. These methods may be revised and updated due to reasons such as regulatory 
requirements or need for further clarifications. The final analysis plan will be documented in a 
formal statistical analysis plan (SAP) that must be finalized before database lock. The SAP will 
include details on how variables will be derived, how missing data will be handled, and how data 
will be presented as well as the details on statistical methods to be used for safety and efficacy 
analyses. The final clinical study report (CSR) will discuss deviations from the SAP, if any. 
12.1. 
Sample Size Determination 
A sample size of 24 subjects will provide 90% power for the CAM2038 32 mg  to demonstrate 
no significant difference in the mean Emax score of the Drug Liking VAS comparing to 0 mg 
hydromorphone at a two-sided 0.05 significance level with a non-significant difference cutoff at 
≤ 11 points. In the sample size calculation it was assumed that the true difference was less than 
or equal to 1.5 and the standard deviation was 9.8.  
An additional group of 24 subjects will be enrolled to CAM2038 24 mg group. This sample size  
will provide approximately 83% power for the CAM2038 24 mg  to demonstrate no significant 
difference in the mean Emax  score of the Drug Liking VAS comparing to 0 mg hydromorphone 
at a two-sided 0.05 significance level with a non-significant difference cutoff at ≤ 11 points. In 
the sample size calculation it was assumed that the true difference was less than or equal to 2.5 
and the standard deviation was 9.8. 
The plan will be to enroll a sufficient number of subjects to ensure that at least 48 subjects 
complete the study (24 subjects per treatment group) by over-enrollment as needed and 
replacement of subjects for those who drop out.  
12.2. 
Analysis Populations 
Three populations are defined for the study:  
 Intent-to-treat (ITT) Population will consist of all subjects who receive study drug and 
provide some post baseline efficacy values.  
 Completer Population will include all subjects who complete the study (i.e., complete 
Day 14). The primary efficacy analyses will be based on the Completer Population.  
 Safety Population will include all subjects who receive study drug. All safety analyses 
will be based on the Safety Population. 
12.3. 
Statistical Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant. 


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Furthermore, the baseline will be the last assessment before the first dosing of the study 
medication. 
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, these 
statistics will typically include the number and percentage of subjects in each category. 
12.3.1. 
Study Subjects and Demographics 
12.3.1.1. Subject Disposition and Discontinuations 
The numbers of subjects randomized, completing, and discontinuing, along with reasons for 
discontinuation, will be tabulated overall and by CAM2038 treatment group (24 mg and 32 mg 
groups) and sequence. The number of subjects in each analysis population will be reported. 
12.3.1.2. Protocol Deviations 
Major protocol deviations will be classified and documented before database lock and will be 
discussed in the CSR. All protocol deviations, both minor and major, will be presented in a data 
listing. 
12.3.1.3. Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, weight, and height) will be 
summarized for each treatment group, sequence, and for the overall population by descriptive 
statistics. Medical history and clinical laboratory tests will be listed. 
Prior and concomitant medications will be summarized by treatment group and sequence by the 
number and percentage of subjects taking each medication, classified using World Health 
Organization Drug Dictionary Anatomical Therapeutic Chemical classes and preferred terms. 
12.3.2. 
Exposure  
Study drug administration will be summarized in terms of exposure in day (last dose date – first 
dose date +1). Descriptive statistics for these quantities, including the mean, SD, minimum, and 
maximum, will be provided by treatment group. 
12.3.3. 
Efficacy Analyses 
Efficacy variables will be summarized and analyzed using both Completer and ITT Populations 
unless otherwise specified. The primary analyses will be based on the Completer Population. 
12.3.3.1. Primary Efficacy Analyses 
The primary efficacy variable will be Emax of Drug Liking VAS. This variable will be analyzed 
via a mixed model including subject, challenge dosing (A=0 mg, B=6 mg, or C=18 mg), Period 
(1, 2, or 3 to indicate first, second, or third day of each challenge session), challenge session (1, 
2, 3, or 4), where subject will be treated as random effects and the remaining parameters fixed 
effects. The estimated treatment effects, differences in treatment effects (test dose – the reference 


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dose of 0 mg), 95% confidence intervals of the differences will be presented. Blockade effects 
will be claimed if upper bound of the treatment difference is ≤11. 
12.3.3.2. Secondary Efficacy Analyses 
The secondary endpoints will include: 
 Emax of High VAS  
 Emax of Good Effects VAS  
 Emax of Bad Effects VAS  
 Emax of Sedated VAS  
 Emax of Any Effects VAS  
 Emax of Desire to use VAS  
These variables will be analyzed using the similar methods discuss for the primary efficacy 
variable analyses.  
COWS and OOWS scores will be summarized. 
12.3.4. 
Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the Safety Population (as defined in 
Section 12.2).  
Safety and tolerability will be assessed through TEAEs; hematologic and laboratory parameters; 
and vital signs measurements.  
No formal statistical comparisons will be performed for safety endpoints. 
12.3.4.1. Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) reporting system. Treatment-emergent AEs are 
defined as any of the following: 
 Non-serious AEs with onset on the date of first dose of treatment with the study drug through 
discharge or Early Termination, whichever occurs first;  
 Serious AEs with onset on the date of first dose of treatment with the study drug through 30 
days after discharge or Early Termination, whichever occurs first; 
 AEs that start before the start of treatment but increase in severity or relationship at the time 
of or following the start of treatment through discharge or Early Termination, whichever 
occurs first. 
The number and percentage of subjects with TEAEs will be displayed for each treatment group. 
During the Qualification Phase subjects TEAEs will be displayed by IR morphine 30 mg 


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treatment or by hydromorphone treatment groups i.e., 0 mg 6 mg or 18 mg - on the days of 
hydromorphone challenges. During the Treatment Phase, TEAEs will be displayed by CAM2038 
q1w relevant dose and hydromorphone relevant dose i.e., 0 mg 6 mg or 18 mg – on the days of 
hydromorphone challenges. TEAEs will be displayed by SOC and preferred term. Additionally, 
TEAEs will be tabulated for each treatment group by severity and by relationship to the study 
drug. A listing of SAEs will be provided if applicable. 
If an AE is considered to be caused by a drug, the Investigator will note which drug caused the 
AE. 
12.3.4.2. Clinical Laboratory Evaluations 
For continuous laboratory parameters, descriptive statistics will be presented for each visit and 
for the changes from Baseline to each subsequent visit by treatment group (CAM2038 q1w of 
24 mg or 32 mg).  
Additionally, clinical laboratory parameters will be categorized as low, normal, or high 
according to laboratory range specifications and the number and percentage of subjects in each 
category will be presented in shift tables. 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. 
12.3.4.3. Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for systolic blood pressure, diastolic blood pressure, 
heart rate, respiratory rate, and oral body temperature. 
12.3.4.4. Physical Examination Findings 
Physical examination data will be presented in the listings. 
12.3.5. 
Analysis of Pharmacokinetics 
Summaries of plasma concentrations of BPN and norbuprenorphine will be presented for the 
Completer Population by treatment group. The following descriptive statistics will be presented at 
each nominal time point: n, arithmetic mean, SD, coefficient of variation percentage (CV%), 
median, geometric mean, geometric CV%, minimum and maximum values. Individual plasma 
concentrations of BPN and norbuprenorphine will be listed for the Safety Population by treatment 
group. Mean plasma concentration-time data will be displayed for the Completer Population in 
linear and semi-logarithmic scales. 
The pharmacokinetic parameter data will be listed and summarized by treatment for the Completer 
Population. Summary statistics will include n, arithmetic mean, SD, CV%, median, geometric 
mean, geometric CV%, minimum and maximum values. 


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12.3.6. 
Multiple Comparisons 
To control for multiple comparisons in the efficacy analyses, the treatment differences between 
Treatments B (hydromorphone 6 mg) and A (0 mg) will be tested at first at a 0.05 significance 
level, followed by the tests between Treatments C (18 mg) and A. Blockade effects for 
hydromorphone 18 mg cannot be claimed unless the blockade effects for 6 mg are established 
first. 
Furthermore, the above tests will be performed for CAM2038 q1w 32 mg first followed by the 
tests for CAM2038 q1w 24 mg. To control for the Type I error rate, opioid agonist blocking 
effects for CAM2038 q1w 24 mg cannot be claimed unless blocking effects for CAM2038 q1w 
32 mg are established. 
12.3.7. 
Interim Analysis 
No interim analyses are planned. 


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13. 
STUDY ADMINISTRATION AND INVESTIGATOR 
RESPONSIBILITIES 
Additional details may be outlined in the Clinical Trial Agreement (CTA) between the sponsor 
and the investigational site.  
13.1. 
Regulatory and Ethical Considerations 
13.1.1. 
Ethical Conduct of the Study 
The Investigator will conduct the study in accordance with GCP and all applicable regulations, 
including, where applicable, the Declaration of Helsinki. The study will also be carried out in 
keeping with applicable national and local laws and regulations. This may include an inspection 
by the sponsor’s representatives and/or regulatory authority’s representatives at any time. 
13.1.2. 
Ethics Approval 
The investigational site’s IRB must meet all relevant regulatory requirements. The study protocol 
and ICF will be reviewed by the IRB prior to enrolling subjects into the study; written approval 
from the committee must be received by the sponsor before drug will be released to the 
Investigator. The Investigator is responsible for submitting all protocol or ICF changes and SAE 
reports to the IRB according to local procedures. At a minimum, all SAEs requiring an 
investigational new drug safety report must be immediately reported. 
In accordance with applicable local regulatory requirements, the Investigator may be obligated to 
provide periodic safety updates on the conduct of the study at his or her research site and 
notification of study closure to the IRB. Such periodic safety updates and notifications are the 
responsibility of the investigator and not of the sponsor. The sponsor will be provided with 
copies of all notifications sent to the IRB. 
All relevant correspondence from the IRB will be forwarded by the respective study site to the 
sponsor in a timely fashion. 
13.1.3. 
Subject Informed Consent 
The Investigator (or authorized designee) will ensure that the subject (or the subject’s legal 
representative) is given full and adequate oral and written information about the nature, purpose, 
potential and possible risks and benefits of the study. Each prospective subject will receive an 
IRB-approved ICF that summarizes the pertinent study information and will be given ample time 
to read the form and ask questions about the study. All information is to be provided in a 
language understandable to the subject and must not include any language that waives the 
subject’s legal rights. Prospective subjects must also be informed of their right to withdraw 
consent without prejudice at any time during the study. If the subject chooses to participate, 
he/she must sign the ICF before any study-related procedures are performed.  
Significant changes to the protocol or product safety information may require a revision of the 
ICF, which must be reviewed and signed by all applicable study subjects. 


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The time that informed consent is obtained must be documented. The investigator must maintain 
the original, signed ICF in the subject’s source documents. A copy of the signed ICF must be 
given to the study subject. 
13.2. 
Privacy and Confidentiality 
The Investigator is responsible for complying with applicable privacy regulations, per his or her 
jurisdiction. Only information identified in this protocol will be collected. The information 
collected will only be used for the purposes identified in this protocol. 
To ensure anonymity and to limit disclosure, subjects will be assigned a unique identifier at their 
first assessment. This identifier will be cross-referenced in the subject’s chart. The identifier will 
not contain any potentially identifiable information. An identifier log will be maintained, linking 
each subject’s name to the corresponding identifier. This log will be stored at the research site in 
a secure location. 
The knowledge gained through this study is the property of the sponsor. The Sponsor, 
representatives and affiliated companies of the sponsor, the IRB, and regulatory agencies (such 
as the United States Food and Drug Administration [FDA]) may inspect medical records related 
to the study to check the validity and accuracy of the data gathered in this study. Subject medical 
records (with subject’s initials and/or date of birth) may be copied. Confidentiality of subject 
records will be maintained except where release of information is required by law.  
The results of this study will be reported in such a manner that subjects will not be identifiable in 
any way. Published reports or presentations will refer to grouped data or coded individual data 
and not to any identifiable individuals. Study reports sent to the sponsor or drug regulatory 
agencies will not include subject names. 
By signing the ICF, the subject consents to the collection, access, use, and disclosure of his or her 
information as described in the ICF document. If a subject withdraws consent, some of the 
subject’s information may still be collected, used, and disclosed by those involved in this study, 
per applicable laws.  
By signing this protocol, the Investigator affirms that he or she will maintain in confidence 
information furnished to him or her by the sponsor and will divulge such information to his or 
her respective IRB or IEC under an appropriate understanding of confidentiality with such board. 
All data will be considered the sole property of the sponsor. Please refer to the CTA for details. 
13.3. 
Study and Site Closure 
Upon completion of the study, all study data will be provided to the Sponsor following review of 
site study records for completeness, and data clarifications and resolutions. Accounting, 
reconciliation, and final disposition of used and unused study drugs, treatment codes, and 
emergency code break envelopes will be performed, as applicable. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason. If such action is taken, the Sponsor will discuss this with 


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the Investigator (including the reasons for taking such action) at that time. The Sponsor will 
promptly inform any other investigators and/or institutions conducting the study, if the study is 
suspended or terminated for safety reasons and will inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by applicable 
regulations, the Investigator will inform the IRB promptly and provide the study subjects with 
the reason for the suspension or termination. If the study is prematurely discontinued, all study 
data will be returned to the Sponsor.  
13.4. 
Regulatory Documents and Records Retention 
The Investigator(s) are responsible for creating and/or maintaining all study documentation 
required by 21 CFR 50, 54, 56 and 312, ICH E6 section 8, as well as any other documentation 
defined in the protocol or CTA. The Investigator(s) must provide key documents to the Sponsor 
prior to the start of the study. A complete list of required regulatory documents will be supplied 
by the Sponsor or its representative. 
Federal and local regulations require that the Investigator(s) retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is the 
longest period of time: 
 A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the subject of the investigation; or 
 A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 
application for a research or marketing permit for the study drug for the purposes that 
were the subject of the investigation. 
The Sponsor will notify investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the sponsor that the entire clinical investigation (not merely the 
investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 
of the Investigational New Drug application/Clinical Trial Authorization or request for marketing 
approval (New Drug Application/Marketing Authorization Application).  
If the Investigator(s) retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the sponsor. 
13.5. 
Delegation of Responsibilities and Adequate Resources 
The Investigator(s) should have adequate time to conduct the study properly and should have an 
adequate number of qualified staff to assist with the conduct of the study.  


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The term “Investigator” used throughout this protocol refers to the principal investigator and/or 
qualified sub-investigators. However, the Investigator(s) may delegate responsibilities to other 
investigational site personnel. The Investigator(s) shall delegate tasks only to individuals 
qualified by education, training and experience to perform the delegated tasks. The 
Investigator(s) shall have direct oversight of all delegated activities and shall document 
delegation of responsibilities. The Investigator(s) is responsible for ensuring all delegated staff 
have been properly trained on the protocol and their assigned study responsibilities. A delegation 
log identifying all delegated duties and the individual to whom they have been delegated will be 
maintained at the investigational site.  
13.6. 
Protocol Amendments 
Approval of a protocol amendment by the investigator’s IRB must be obtained before 
implementation of the protocol amendment, unless a change is necessary to eliminate an 
apparent immediate hazard to the subject or when the change involves logistical or 
administrative aspects of the study. The protocol amendment must be signed and dated by both 
the sponsor and the Investigator(s). The Sponsor or designee will submit protocol amendments to 
the appropriate regulatory authorities, if required. 
13.7. 
Financial Disclosure 
Clinical investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR § 
54.2, a clinical investigator is a listed or identified investigator or sub-investigator who is directly 
involved in the treatment or evaluation of research subjects. The term also includes the spouse 
and each dependent child of the investigator. In addition, investigators must promptly update 
financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study. 


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14. 
SPONSOR APPROVAL PAGE 
A MULTIPLE DOSE OPIOID CHALLENGE STUDY TO ASSESS 
BLOCKADE OF SUBJECTIVE OPIOID EFFECTS OF CAM2038 Q1W 
(BUPRENORPHINE FLUIDCRYSTAL® SUBCUTANEOUS INJECTION 
DEPOTS) IN ADULTS WITH OPIOID USE DISORDER 
 
Version: 2.0 
Date: 17-NOV-2015 
Braeburn Pharmaceuticals, Inc. 
 
 
 
 
Sponsor Representative 
Full Title 
 
Date 
 


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15. 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
A MULTIPLE DOSE OPIOID CHALLENGE STUDY TO ASSESS 
BLOCKADE OF SUBJECTIVE OPIOID EFFECTS OF CAM2038 Q1W 
(BUPRENORPHINE FLUIDCRYSTAL® SUBCUTANEOUS INJECTION 
DEPOTS) IN ADULTS WITH OPIOID USE DISORDER 
 
Version: 2.0 
Date: 17-NOV-2015 
I have read this protocol and I agree to conduct the study in accordance with the protocol and 
with all applicable government regulations and International Conference on Harmonisation/Good 
Clinical Practice guidances. 
 
 
Principal Investigator’s 
Name 
 
(please print or type) 
 
 
 
 
Principal Investigator’s Signature 
 
Date (DD-MMM-YYYY) 


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16. 
REFERENCES 
1. Bickel WK, StitzerML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE. 
Buprenorphine: Dose-related blockade of opioid challenge effects in opioid dependent 
humans. J Pharmacol Exp Ther 1988; 247:47-53. 
2. Ciraulo, D., Hitzemann, R., Somoza, E., Knapp, C., Rotrosen, J, Sarid-Segal, O., Ciraulo, 
AM, Greenblatt, D., Chiang, C.N. Correia CJ. Pharmacokinetics and Pharmacodynamics 
of Multiple Sublingual Buprenorphine Tablets in Dose-Escalation Trials. Journal of 
Clinical Pharmacology. 2006; 46:179-192 
3. Walsh SL, Bigelow GE, Strain EC. Effects associated with double-blind omission of 
buprenorphine/naloxone over a 98-h period. Psychopharmacology (Berl). 
2006;189(3):297-306. 
4. Duke AN, Bigelow GE, Lanier RK, Strain EC. Discriminative stimulus effects of 
tramadol in humans. J Pharmacol Exp Ther. 2011; 338, 255–262. 
5. Fals-Stewart W, O'Farrell TJ, Freitas TT, McFarlin SK, Rutigliano P. The timeline 
followback reports of psychoactive substance use by drug-abusing patients: psychometric 
properties. J Consult Clin Psychol. 2000; 68:134–144. 
6. Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new 
rating scales for opiate withdrawal. American Journal of Drug and Alcohol Abuse, 13(3). 
Pp 293-308 (1987) 
7. Hydromorphone hydrochloride injection [package insert]. Lake Forest, IL: Hospira, Inc; 
1984. 
8. Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the 
analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen 
Psychiatry 1978; 35(4):501-16. 
9. Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of buprenorphine treatment for opioid 
dependence. JAMA 1992; 267(20):2750-2755. 
10. Lanier RK, Lofwall MR, Mintzer MZ, Bigelow GE, Strain EC. Physical dependence 
potential of daily tramadol dosing in humans. Psychopharmacology (Berl). 2010; 211(4): 
457-466. 
11. Ling W, Charuvastra C, Collins JF, Batki S, Brown LS Jr, Kintaudi P, Wesson DR, 
McNicholas L, Tusel DJ, Malkerneker U, Renner JA Jr, Santos E, Casadonte P, Fye C, 
Stine S, Wang RI, Segal D. Buprenorphine maintenance treatment of opiate dependence: 
a multicenter, randomized clinical trial. Addiction. 1998; 93(4):475-86. 
12. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry 1979; 134(4):382–89 


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13. Roland CL, Setnik B, Pixton GC, Webster L. Measurement of drug-liking in abuse 
potential studies: A comparison of bipolar vs. unipolar visual analog scales. Drug 
Alcohol Depend. 2014; 140:e188. 
14. Rosado J., Walsh S.L., Bigelow G.E. and Strain E.C. (2007) Sublingual 
buprenorphine/naloxone precipitated withdrawal in subjects maintained on 100 mg of 
daily methadone, Drug and Alcohol Dependence, 90: 261-269. 
15. Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR. Buprenorphine vs 
methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. 
Arch Gen Psychiatry 1997; 54(8):713-20. 
16. Sobel BF, Sigmon SC, Walsh SL, Johnson RE, Liebson IA, Nuwayser ES, Kerrigan JH, 
Bigelow GE. Open-label trial of an injection depot formulation of buprenorphine in 
opioid detoxification. Drug Alcohol Depend. 2004; 73(1):11-22. 
17. Strain EC, Stitzer mL, Liebson IA, Bigelow GE. Comparison of Buprenorphine and 
Methadone in the treatment of Opioid dependence. Am J Psychiatry 1994; 151(7):1025-
1030. 
18. Strain EC, Walsh SL, Preston KL, Liebson IA, Bigelow GE. The effects of 
buprenorphine in buprenorphine-maintained volunteers. Psychopharmacology (Berl). 
1997;129(4):329-338. 
19. Walsh SL, Preston KL, Bigelow GE, Stitzer mL. Acute administration of buprenorphine 
in humans: partial agonist and blockade effects. J Pharmacol Exp Ther 1995; 274:361-
372. 
20. Walsh SL, Nuzzo PA, Lofwall MR, Holtman JR. The relative abuse liability of oral 
oxycodone, hydrocodone and hydromorphone assessed in prescription opioid abusers. 
Drug Alcohol Depend. 2008; 98, 191–202. 
21. Walsh SL, Nuzzo PA, Elayi C, Lofwall MR. Intranasal buprenorphine alone and in 
combination with naloxone: Reinforcing efficacy and abuse liability in physically 
dependent opioid abusers. Presented at the College on Problems of Drug Dependence, 
Scottsdale, Arizona, June, 2015. 
22. Wesson DR, Ling W J Psychoactive Drugs 2003; 35(2): 253-9 
 
 


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17. 
APPENDICES 
17.1. 
Qualification Phase Sample Daily Short-Acting Opioid 
Administration Schedule  
During the Qualification Phase, subjects will be administered IR morphine 30 mg QID for a 
minimum of 3 days and a maximum of 7 days. For the first 3 days of stabilization, subjects will 
be permitted to receive one additional dose of IR morphine 30 mg, as needed at the discretion of 
the Investigator. Therefore, subjects will be permitted to receive a maximum of 150 mg IR 
morphine per day for the first 3 days, after which the total daily dose will be reduced to 120 mg.  
A sample schedule for the 3 Qualification/Baseline Hydromorphone Challenge Session days 
(Day -3, Day -2, and Day-1) is provided below.  
Time 
 
8:30 am 
Start of session (pre-dose Hydromorphone Challenge Session procedures) 
9:00 am  
Hydromorphone Challenge dose administered, IM 
9:00 am – 2:00 pm  
Hydromorphone Challenge Session study procedures  
2:00 pm  
Morphine IR 30 mg dose administered, orally (after all challenge procedures are 
completed) 
8:00 pm  
Morphine IR 30 mg dose administered, orally 
 
 
 
Each morning prior to the start of the Hydromorphone Challenge Session, the COWS (Appendix 
17.2) and OOWS (Appendix 17.3) will be administered and the score recorded to assess the 
degree of opioid withdrawal that the subject may be experiencing. 
 
 


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17.2. 
Clinical Opiate Withdrawal Scale (COWS) 
 
 


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17.3. 
Objective Opioid Withdrawal Scale (OOWS) 
 
 
 


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17.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS)- 
Baseline/Screening 
 
 


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17.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS)- Since Last Visit 
 


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17.6. 
Montgomery Asberg Depression Rating Scale (MADRS)  
 


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SAP_001.pdf: 
HS-13-478 
Phase II 
 
A Multiple Dose Opioid Challenge Study to Assess Blockade of 
Subjective Opioid Effects of CAM2038 q1w (Buprenorphine 
FluidCrystal® Subcutaneous Injection Depots) In Adults with 
Opioid Use Disorder 
Statistical Analysis Plan (SAP) 
 
 
Sponsor 
BRAEBURN PHARMACEUTICALS 
47 Hulfish Street, Suite 441 
Princeton, NJ 08542 
Tel:  (609) 751-5375 
Fax:  (609) 921-2156 
 
 
Version Final 1.01 
 
June 13, 2016 
 
 
 


BRAEBURN PHARMACEUTICALS CONFIDENTIAL 
Version 1.01—13 June, 2016 
HS-13-478 SAP 
Page 2 of 22 
SPONSOR APPROVAL 
The undersigned have reviewed the format and content of this prospective statistical analysis plan (SAP) 
and have approved it for use to analyze the HS-13-478 data. 
BRAEBURN PHARMACEUTICALS 
Sonnie Kim, Pharm.D. 
Print Name 
Signature 
Date 
Print Name 
Signature 
Date 
Print Name 
Signature 
Date 
STATISTICIAN 
Michael Chen, PhD 
Print Name 
Signature 
Date 
June 13, 2016


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TABLE OF CONTENTS 
1.0 
DOCUMENT HISTORY ........................................................................................................................ 5 
2.0 
LIST OF ABBREVIATIONS ................................................................................................................. 5 
3.0 
INTRODUCTION ..................................................................................................................................... 6 
4.0 
STUDY DESCRIPTION ......................................................................................................................... 6 
4.1 
Study Objectives .......................................................................................................................... 6 
4.2 
Study Treatments ........................................................................................................................ 6 
4.3 
Study Design ................................................................................................................................. 6 
5.0 
ANALYSIS POPULATIONS ................................................................................................................. 7 
6.0 
GENERAL CONVENTIONS................................................................................................................. 7 
6.1 
Definition of Baseline ................................................................................................................. 8 
6.2 
Software ......................................................................................................................................... 8 
6.3 
Changes to Planned Analyses ................................................................................................... 8 
7.0 
DESCRIPTION OF THE STUDY POPULATIONS ....................................................................... 8 
7.1 
Disposition..................................................................................................................................... 8 
7.2 
Demographic and Baseline Characteristics ....................................................................... 10 
7.3 
Medical History ........................................................................................................................ 10 
8.0 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................................ 10 
9.0 
EFFICACY ANALYSES ...................................................................................................................... 10 
9.1 
Primary Efficacy Outcome – emax Drug liking VAS ........................................................ 11 
9.1.1 
derivation of EMAX DRUG LIKING VAS ........................................................................ 11 
9.1.2 
Primary Analysis ...................................................................................................................... 12 
9.1.3 
missing value imputation ....................................................................................................... 12 
9.1.4 
supportive Analyses ................................................................................................................ 12 
9.2 
Secondary Efficacy Outcomes ............................................................................................... 12 
9.3 
Interim Analyses ...................................................................................................................... 13 
9.4 
Adjustments for Multiplicity ................................................................................................. 13 
9.5 
PK/PD  relationships ............................................................................................................... 13 
9.6 
Power and Sample Size Justification ................................................................................... 13 
10.0 
SUMMARIES OF PHARMACOKINETIC ANALYSIS ............................................................. 13 
11.0 
SUMMARIES OF MEASURES OF SAFETY ................................................................................ 14 
11.1 
Extent of Exposure .................................................................................................................. 14 
11.2 
Adverse Events ......................................................................................................................... 14 
11.3 
Laboratory Assessments ......................................................................................................... 15 
11.4 
columbia suicide severity rating scale (cssr-s) ................................................................... 15 
11.5 
montgomery-asberg depression rating scale (madrs) ..................................................... 15 
11.6 
Vital Signs .................................................................................................................................. 15 


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11.7 
Physical Exam ........................................................................................................................... 16 
11.8 
12-Lead Electrocardiogram (ECG) ..................................................................................... 16 
11.9 
Injection Site Examination .................................................................................................... 16 
12.0 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS .............................. 16 
13.0 
DATA QUALITY ASSURANCE ....................................................................................................... 16 
14.0 
REFERENCES ....................................................................................................................................... 16 
15.0 
APPENDICES ......................................................................................................................................... 17 
15.1 
Appendix A - List of Tables, Listings, and Figures ......................................................... 17 
15.2 
Appendix B - Imputation Algorithm for Partial and Missing Dates ........................... 21 
 


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1.0 
DOCUMENT HISTORY 
Version 
Date  
Changes made since previous version 
0.01 
10 November, 2015 
First draft 
Final 1.00 
17 February, 2016 
Final after incorporated all comments 
Final 1.01 
13 June, 2016 
To clarify languages and remove certain summaries that cannot 
be performed because data were not collected. 
 
2.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
AUC 
AUC0-168h 
Adverse Event 
Area under the plasma concentration-time curve 
AUC beween time 0 and 168 hours after latest injection 
BMI 
BW 
Cav 
Cmax 
Body Mass Index 
Body Weight  
Average plasma concentration during a dosing interval 
Maximum plasma concentration 
COWS 
Clinical Opioid Withdrawal Scale 
CRF 
Case Report Form (may include electronic data capture systems or paper forms) 
CSR 
Ctrough 
CV% 
Clinical Study Report 
Plasma concentration 7 days after the latest injection 
Coefficient of variation percentage 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
PK 
Pharmacokinetics 
PT 
MedDRA Preferred Term 
SAE 
SD  
Serious Adverse Event 
Standard Deviation 
SL BPN 
Sublingual Buprenorphine or Buprenorphine/Naloxone 
SOC 
MedDRA System Organ Class 
SOWS 
Subjective Opioid Withdrawal Scale 
TEAE 
Tau () 
Treatment-Emergent Adverse Event 
Dosing interval 
VAS 
Visual Analog Scale 
 


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3.0 
INTRODUCTION 
This statistical analysis plan (SAP) is based on Protocol HS-13-478, Amendment 1, dated Nov 10, 2015. 
The purpose of this document is to provide details on study populations and on how the variables will be 
derived, how missing data will be handled, as well as details on statistical methodologies to be used to 
analyze the safety and efficacy data from the study.   
 
The document may evolve over time, for example, to reflect the requirements of protocol amendments or 
regulatory requests.  However, the final SAP must be finalized, approved by the Sponsor, and placed on 
file before database is locked and treatment codes are unblinded.  Deviations from the approved plan will 
be noted in the clinical study report. 
 
4.0 
STUDY DESCRIPTION 
4.1 
STUDY OBJECTIVES 
The primary objective of this study is: 
 
To evaluate the degree of opioid blocking effects of CAM2038 q1w following administration of 
intramuscular (IM) hydromorphone (6 mg and 18 mg) compared to administration of 0 mg IM 
hydromorphone (placebo) on subjective opioid effects in subjects with opioid use disorder, as 
measured by the Drug Liking visual analog scale (VAS). 
The secondary objectives of this study are: 
 
To evaluate the degree of opioid blocking effects of CAM2038 q1w following administration of 
IM hydromorphone (6 mg and 18 mg) compared to administration of 0 mg IM hydromorphone 
(placebo) on subjective opioid effects in subjects with opioid use disorder, as determined by the 
secondary outcome measures. 
 
To explore the relationship between plasma buprenorphine (BPN) concentration and blockade of 
the subjective opioid effects of hydromorphone. 
 
To examine the safety and tolerability of CAM2038 q1w when co-administered with 
hydromorphone.  
4.2 
STUDY TREATMENTS  
In this study, subjects will be randomized to one of two treatment groups in a 1:1 ratio to receive either 
CAM2038 1qw 24 mg or CAM2038 1qw 32 mg.  Subjects within both CAM2038 1qw dosing groups 
will be randomized to one of 6 sequences of ordered hydomorphone challenge sessions: A/B/C, A/C/B, 
B/A/C, B/C/A, C/A/B, and C/B/A, where A, B, and C denote hydromorphone 0 mg, 6 mg, and 18 mg.   
4.3 
STUDY DESIGN 
This is a multi-site, randomized, double-blind, repeat-dose Phase 2 study to evaluate the degree and 
duration of action of multiple doses of CAM2038 q1w in blocking the effects of a mu-opioid agonist 
(hydromorphone) in patients with moderate or severe opioid use disorder. The study will involve 4 
phases: Screening, Qualification, Treatment, and Follow-up. 
 


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Within approximately 3 weeks of initiating outpatient screening, subjects will be admitted to a clinical 
research unit (CRU) for the Qualification Phase. Following check in to the CRU, subjects will be 
transitioned to an oral immediate-release (IR) opioid, morphine 30 mg, 4 times daily (QID) for a 
minimum of 3 days and a maximum of 7 days prior to the Qualification/Baseline Hydromorphone 
Challenge Session, which consists of 3 consecutive days of testing. During the Qualification/Baseline 
Hydromorphone Challenge Session, subjects will not receive their late evening or early subjects will not 
receive their late evening or early the following morning Morphine -IR; therefore, the last active dose of 
morphine therefore, the last active dose of morphine -IR will be administered a minimum of 12 hours 
before administration of the hydromorphone challenge doses.  
 
Following the 3-day Qualification/Baseline Hydromorphone Challenge Session (Days -3 to -1), eligible 
subjects will be randomized in a 1:1 ratio to one of 2 groups to receive CAM2038 q1w at doses of 24 mg 
or 32 mg, stratified by gender. Subjects will receive two, once weekly injections of CAM2038 q1w, 7 
days apart, (injections on Day 0 and Day 7) and will remain inpatient in the CRU for a total of 
approximately 3 weeks, during which time, 1 qualification/baseline Hydromorphone Challenge session 
will occur prior to CAM2038 administration then 4 Hydromorphone Challenge Sessions (3 consecutive 
days each with dose randomized) will be conducted on Days 1 to 3, Day 4 to 6, Days 8 to 10, and Days 
11 to 13 after the first CAM2038 administration. Each Hydromorphone Challenge Session will consist of 
3 doses of hydromorphone 10 mg/mL IM injections (doses of 0 mg [placebo], 6 mg and 18 mg) 
administered on 3 consecutive days in randomized order. Eligible subjects will be randomized in a 
1:1:1:1:1:1 ratio to 1 of 6 treatment sequences according to two 3 × 3 William squares. The following 
treatment sequences will be used: ABC, ACB, BAC, BCA, CAB, and CBA, where A, B, and C are IM 
hydromorphone doses, 0 mg (placebo), 6 mg, and 18 mg, respectively. The doses, 0 mg (placebo), 6 mg 
or 18 mg, will be administered once daily during the hydromorphone challenge sessions. Safety 
assessments will be conducted immediately following each dose of hydromorphone administered in each 
Challenge Session and scheduled pharmacodynamic evaluations will occur over approximately 5 hours 
post dose. Plasma BPN and norbuprenorphine (NorBPN) levels will also be obtained approximately 60 
minutes prior to hydromorphone dosing (predose) on each day of the Hydromorphone Challenge 
Sessions. 
 
Subjects will be discharged on Day 14 and a follow-up phone interview will be conducted on Day 21. 
The degree of hydromorphone dose tolerability will be determined based on the site-specific study 
Investigator’s review of the subject’s oximetry data, vital signs, behavior, and physical demeanor.   
  
5.0 
ANALYSIS POPULATIONS 
Three populations are defined for the study. Intent-to-treat (ITT) population will consist of all subjects 
who receive study drug and provide some post baseline efficacy values. Completer population will 
include all subjects who complete the study. The primary efficacy analyses will be based on the 
Completer population. Safety population will include all subjects who receive study drug. All safety 
analyses will be based on the Safety population.     
 
6.0 
GENERAL CONVENTIONS 
Unless otherwise stated, all analyses will be performed using SAS Version 9 and all hypothesis tests will 
be conducted at a two-sided significance level of 0.05.  P-values will be presented with 3 decimals and p-
values that are less than 0.001 will be presented as <0.001. 
 


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Continuous (non survival related) data will be summarized using descriptive statistics: number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum.  Frequencies and 
percentages will be used to summarize categorical (discrete) data.  Presentations of categorical data will 
generally suppress percentages for items where the count is zero in order to draw attention to the nonzero 
counts.  In general, mean, standard deviation, median, minimum, maximum, and percentages will be 
presented with one decimal. 
 
Unless otherwise stated, confidence intervals, when presented, will be constructed at the two-sided 95% 
level.   
 
Summaries of plasma concentrations of BPN and norbuprenorphine will be presented for the Completer 
population by treatment group. The following descriptive statistics will be presented at each nominal time 
point: n, arithmetic mean, SD, coefficient of variation percentage (CV%), median, geometric mean, 
geometric CV%, minimum and maximum values. Individual plasma concentrations of BPN and 
norbuprenorphine will be listed for the Safety population by treatment group. Mean plasma concentration-
time data will be displayed for the Completer population in linear and semi-logarithmic scales. 
 
The pharmacokinetic parameter data will be listed and summarized by treatment for the Completer 
population. Summary statistics will include n, arithmetic mean, SD, CV%, median, geometric mean, 
geometric CV%, minimum and maximum values. 
 
Data listings will present all data collected on CRFs by study drug, center, and subject number.   
6.1 
DEFINITION OF BASELINE 
Unless otherwise stated, the last observed measurement prior to or on the date of randomization will be 
considered the baseline measurement.  If multiple observations are made during baseline, the baseline will 
be defined as average of the observations obtained during the baseline phase. 
6.2 
SOFTWARE 
Analyses will be conducted using SAS Version 9.2 or higher.   
6.3 
CHANGES TO PLANNED ANALYSES 
Draft versions of the SAP will be numbered sequentially as Version 0.0i.  The final approved version will 
be numbered as Version 1.00.  Revisions after the “Final” version will be numbered as Version 1.0x.  The 
Clinical Study Report will document any changes made after the final version approved before data base 
lock and treatment unblinding. 
 
7.0 
DESCRIPTION OF THE STUDY POPULATIONS 
All tables, figures, and listings must include a population descriptor (e.g., ITT, Safety or Completer) in 
the title. 
7.1 
DISPOSITION 
Subject disposition summaries will be presented by treatment arm (CAM2038 q1w 24 mg and CAM2038 
q1w 32 mg) and sequence (ABC, ACB, BAC, BCA, CAB, and CBA) and will include the number of 
subjects randomized, the number and percentage of randomized subjects in each of the predefined 
populations, as well as the number and percentage of subjects who complete the study.  The summaries 
will also include the reasons for early discontinuation from the study.   


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Disposition summaries will be presented for each of the predefined populations separately. 


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7.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
A summary of demographics and baseline characteristics will be presented by treatment arm, sequence, 
and overall for the ITT, Completer and safety populations.  The demographic characteristics will consist 
of age, sex, ethnicity, and race using descriptive statistics. 
 
Demographic data including age, race, ethnicity, and gender, as well as baseline clinical characteristics 
will be summarized. Age will be calculated based on the following conditional algorithm:  
 
Has the patient had his/her birthday this year? 
o Yes, then AGE = (year of informed consent) – (year of birth). 
o No, then AGE = (year of informed consent) – (year of birth) – 1. 
 
Clinical baseline characteristics summarized will include, if available, BW, BMI, type of primary opioid 
use (heroin, prescription opioid pain relievers, other), years of drug use, when first diagnosed with opioid 
dependence, proportion of patients previously treated for opioid dependence, duration of buprenorphine 
treatment, duration of 8 mg or less buprenorphine treatment, and dose of buprenorphine treatment prior to 
randomization. Clinical baseline characteristics will summarized by treatment group, sequence, and 
overall. 
7.3 
MEDICAL HISTORY 
Medical history will be coded using MedDRA dictionary. A medical history listing will be presented.   
 
8.0 
PRIOR AND CONCOMITANT MEDICATIONS 
All medications recorded on the CRFs will be coded using the WHO DRUG Dictionary Enhanced.  Prior 
and concomitant medications will be summarized by treatment arm in the safety population by anatomical 
therapeutic chemical (ATC) Class Level 4 and WHO Drug base substance preferred name. 
 
Prior medications are defined as medications with stop dates occurring before the date of first 
administration of any study treatment component.  Concomitant medications are defined as medications 
with start dates occurring on or after the date of first administration of any study treatment component and 
no more than 30 days after the last administration of any study treatment component. Medications with 
start and stop dates that bracket the date of first administration of any study treatment component will be 
summarized as both prior and concomitant medications. 
 
Medications that clearly stopped prior to date of first administration of any study treatment component 
will be included in the prior medications table, and medications that clearly started on or after date of first 
administration of any study treatment component will be included in the concomitant medications table.  
All other medications will be included in both the prior and concomitant medications tables. 
 
Prior and Concomitant medication will be summarized for the safety population. 
 
9.0 
EFFICACY ANALYSES 
Many of the efficacy variables are visual analog scale (VAS) based.  Each VAS will be scored as an 
integer from 0 to 100. When appropriate, VASs will be administered as bipolar measures, meaning 


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that the neutral point equals 50 (i.e., Drug Liking and Alertness/Drowsiness VAS). The neutral point 
will also be labeled with an anchor, such as “neither like nor dislike.” Unipolar VASs (i.e., High, Good, 
Bad, and Any Effects VAS) are presented with anchors such as “not at all” (score = 0) to “extremely” 
(score = 100), where the neutral point equals 0. The use of unipolar scale is determined by the 
nature of the subjective effect being measured. If precipitated withdrawal occurs after 
administration of CAM2038, patients will have a unipolar VAS assessment of opioid withdrawal 
severity. 
 
The table lists the subjective effects VAS question text and response anchors. 
 
Interpretation Include  
Pre-
dose 
Description 
Question Text 
Response Anchors 
Balance 
No 
Drug Liking 
At this moment, my liking 
for this drug is 
0: Strong disliking 
50: Neither like nor 
dislike 100: Strong 
liking  
Other effects  
No  
Any Drug Effects  
At this moment, I feel any 
drug effects  
0: Not at all  
100: Extremely  
Positive  
Yes  
High  
At this moment, I feel high  
Positive  
No  
Good Drug Effects  
At this moment, I feel good 
drug effects  
Negative  
No  
Bad Drug Effects  
At this moment, I feel bad 
drug effects  
Other Effects  
Yes  
Desire to use opioids  
At this moment, I desire 
opioids  
0: Definitely not  
100: Definitely so  
Other Effects  
Yes  
Alertness/Drowsiness  At this moment, my mental 
state is  
0: Very drowsy  
50: Neither drowsy 
nor alert  
100: Very alert  
9.1 
PRIMARY EFFICACY OUTCOME – EMAX DRUG LIKING VAS 
The primary efficacy variable will be Emax of Drug Liking VAS.   
9.1.1 DERIVATION OF EMAX DRUG LIKING VAS 
Four hydromorphone challenge sessions (3 consecutive days each with dose randomized) will be 
conducted on Days 1 to 3, Day 4 to 6, Days 8 to 10, and Days 11 to 13 after the first CAM2038 
administration. Each Hydromorphone Challenge Session will consist of 3 doses of hydromorphone 10 
mg/mL IM injections (doses of 0 mg [placebo], 6 mg and 18 mg) administered on 3 consecutive days in 
randomized order.  The drug liking VAS will be rated by the subjects at predose and at 5, 10, 15, 30, 45, 


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60, 75, 90, 120, 150, 180, 210, 240, 270 and 300 minutes post-dose.  The primary efficacy variable Emax 
of drug liking VAS will be the maximum of the above post-dosing drug liking VAS scores. 
9.1.2 PRIMARY ANALYSIS 
The primary analysis of the primary efficacy variable, Emax of drug liking VAS, will be performed using 
the completer population.  This variable will be analyzed via a mixed model including sequence (ABC, 
ACB, BAC, BCA, CAB, CBA), dosing (challenge dosing A=0 mg, B=6 mg, or C=18 mg), period (1, 2, 
or 3 to indicate first, second, or third day of each challenge session), session (challenge session 1, 2, 3, or 
4), and dosing-by-session interaction as fixed effects, and subject as random effects. The maximum 
likelihood estimation will be used to estimate the parameters.  Specifically, the following pseudo SAS 
codes will be used for the analysis: 
 
proc mixed data=Efficacy_Data method=ml; 
class SubjectID ChallengeDose Sequence Period Session; 
model Emax=Sequence ChallengeDose Period Session  ChallengeDose*Session; 
random SubjectID / Subject= SubjectID; 
LSMEANS ChallengeDose*Session/diff cl alpha=0.05; 
Run; 
 
The estimated treatment effects, differences in treatment effects (test dose – the reference dose of 0 mg), 
95% confidence intervals of the differences will be presented. Blockade effects will be claimed if the 
upper bound of the treatment difference is <=11. 
 
The same methodology will be used to analyze CAM2038 q1w 24 mg and 32 mg separately. 
9.1.3 MISSING VALUE IMPUTATION 
Missing scores will not be imputed, unless otherwise stated. 
9.1.4 SUPPORTIVE ANALYSES 
As a supportive analysis, the primary efficacy variable will be analyzed based on ITT subjects using the 
same methodology. 
9.2 
SECONDARY EFFICACY OUTCOMES 
In addition to the primary endpoint of change from baseline in Emax of Drug Liking VAS, the following 
secondary endpoints will be calculated: 
 
High VAS Emax 
 
Good Effects VAS Emax 
 
Bad Effects VAS Emax 
 
Sedated VAS Emax 
 
Any Effects VAS Emax 
 
Desire to use VAS Emax  
 
All these variables will be analyzed via the same methodology used to analyze the primary efficacy 
variable. 
 
The follow secondary efficacy variables will be summarized by CAM2038 treatment group on the 
scheduled days that they are measured: 
 
Clinician-Rated Opioid Withdrawal Scale (COWS); 
 
Subjective Opioid Withdrawal Scale (SOWS); 


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9.3 
INTERIM ANALYSES 
No interim analyses will be performed. 
9.4 
ADJUSTMENTS FOR MULTIPLICITY 
The study involves multiple comparisons.  Procedures will be used to control for the overall Type I error 
rate at the significance level of 0.05. The following ordered comparisons of blocking effect will be tested 
at the 0.05 level of significance: 
 
1. Hydromorphone 6 mg vs Hydromorphone 0 mg for CAM2038 q1w 32 mg; 
2. Hydromorphone 6 mg vs Hydromorphone 0 mg for CAM2038 q1w 24 mg; 
3. Hydromorphone 18 mg vs Hydromorphone 0 mg for CAM2038 q1w 32 mg; 
4. Hydromorphone 18 mg vs Hydromorphone 0 mg for CAM2038 q1w 24 mg; 
 
Blockade effect cannot be claimed unless all preceding blocking effects, if any, are established. 
9.5 
PK/PD  RELATIONSHIPS 
The relationship between plasma BPN concentration and blockade of the subjective opioid effects of 
hydromorphone will be explored as appropriate. 
9.6 
POWER AND SAMPLE SIZE JUSTIFICATION 
A sample size of 24 subjects will provide 90% power for the CAM2038 32 mg to demonstrate no 
significant difference in the mean Emax score of the Drug Liking VAS comparing to 0 mg hydromorphone 
at a two-sided 0.05 significance level with a non-significant difference cutoff at ≤ 11 points. In the sample 
size calculation it was assumed that the true difference was less than or equal to 1.5 and the standard 
deviation was 9.8. 
 
Additional 24 subjects will be enrolled to CAM2038 24 mg group. This sample size will provide 
approximately 83% power for the CAM2038 24 mg to demonstrate no significant difference in the mean 
Emax score of the Drug Liking VAS comparing to 0 mg hydromorphone at a two-sided 0.05 significance 
level with a non-significant difference cutoff at ≤ 11 points. In the sample size calculation it was assumed 
that the true difference was less than or equal to 2.5 and the standard deviation was 9.8.  
 
The plan will be to enroll a sufficient number of subjects to ensure that approximately 48 subjects 
complete the study (24 subjects per treatment group) by over-enrollment as needed. 
 
10.0 SUMMARIES OF PHARMACOKINETIC ANALYSIS 
Pharmacokinetic endpoints include:  
The following pharmacokinetic parameters will be estimated for BPN and norbuprenorphine:  
 
Cmax (maximum plasma concentration) 
 
Ctrough (plasma concentration level 7 days after the latest injection) 
 
Cav (average plasma concentration during a dosing interval) 
Cav will be calculated as (AUC0-168h/), where AUC0-168h is the area under the plasma concentration-time 
curve (AUC) between time 0 and 168 hours after latest injection and  the dosing interval (168 hours). 
AUC0-168h will be calculated using the linear trapezoidal method up to Cmax and the logarithmic 
trapezoidal method for the remainder of the curve up to 168 hours after latest injection.  


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The PK parameters will be calculated using Phoenix WinNonlin Version 6.3 (or higher). The actual 
sampling times relative to dosing rather than the nominal times will be used in the calculations.   
BPN and norbuprenorphine plasma concentrations over time as well as all above PK parameters will be 
summarized by dose (32 mg and 24 mg) separately. 
 
11.0 SUMMARIES OF MEASURES OF SAFETY 
Safety analyses will be performed for the safety population.  Safety evaluations will be based on the 
incidence, intensity, and type of adverse events, as well as on clinically significant changes in the 
subject’s physical examination, vital signs, and clinical laboratory results, Injection site examination and 
wound care.  Safety variables will be tabulated and presented by study drug actually received. 
 
Because there is no pre-specified safety outcome defined in terms of AEs, clinically relevant laboratory 
parameters, or vital signs, any formal comparisons between the treatment arms with respect to specific 
safety parameters will be post-hoc. 
11.1 EXTENT OF EXPOSURE 
Summary statistics (number and percentage) of weeks of exposure to study drug (frequency of number of 
injections received) will be tabulated by treatment group.  
11.2 ADVERSE EVENTS 
Each AE and SAE term recorded on the case report forms (CRFs) by primary system organ class (SOC) 
and will be mapped to a preferred term using the MedDRA dictionary.  The investigator will assess AE 
severity and relationship to the study treatment. 
 
A treatment emergent adverse event (TEAE) is defined as any AE with an onset date on or after date of 
randomization, or any ongoing event on the date of first dose that worsens in severity after date of 
randomization. Only TEAEs with an onset date prior to date of last dose + 30 days will be tabulated in 
summary tables.  For the purpose calculating treatment emergence and inclusion in summary tables, 
incomplete onset dates will be imputed as detailed in Appendix B.   
 
AEs will be summarized by the number and percent of subjects in each primary SOC and preferred term.  
Patients will be counted only once for each primary SOC and each preferred term. Summary tables of 
AEs by primary SOC, preferred term and intensity will be provided. If a subject has more than one AE 
coded to the same preferred term, the subject will be counted only once for that preferred term by using 
the event with the highest intensity. Similarly, if a subject has more than one AE within a primary SOC 
category, the subject will be counted only once in that SOC category by using the event with the highest 
intensity. AEs by primary SOC, preferred term and relationship to study drug will be provided as well. If 
a subject has more than one AE coded to the same preferred term, the subject will be counted only once 
for that preferred term by using the most related event. Similarly, if a subject has more than one AE 
within a primary SOC category, the subject will be counted only once in that primary SOC category by 
using the most related event. In addition, serious adverse events (SAE) by primary SOC and preferred 
term will be provided. Deaths and SAEs will be summarized similarly to AEs. All adverse event tables 
will also include the total number of events, counting multiple events per patient. 
 
AEs will be presented by treatment group (CAM2038 q1w of 24 mg or 32 mg and by hydromorphone 
treatment groups i.e., 0 mg 6 mg or 18 mg – during qualification period- and CAMP2038 relevant 
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be attributed to a hydromorphone dose, if the AE occurred within one hour of the dosing (if the time of 
the AE is missing, the AE will be attributed to CAM2038). Summaries of these AE subsets will be 
presented for the following categories: 
 
Study drug related 
 
Intensity 
 
Relationship to injection (Suspected or Not Suspected) 
 
Suspected to be study drug related by intensity 
 
Serious 
 
AEs which led to discontinuation 
 
SAEs which led to discontinuation 
 
AEs occurring in 5% or greater of any treatment group (by preferred term) 
 
In the AE summary, preferred terms within each SOC will appear in alphabetical order.   
 
Frequencies for deaths and hospitalizations will also be summarized by treatment group and overall. 
 
 
 
Other safety analyses will be performed as appropriate 
11.3 LABORATORY ASSESSMENTS 
Chemistry, Hematology, Urinalysis and Coagulation Profile will be assessed at baseline and Week 24 (see 
Section 10.4.3 for a complete list of parameters to be assessed).  Summary statistics for these parameters 
will be presented by visit for the actual value and change from baseline for each test in each laboratory 
category (Hematology, Chemistry, Urinalysis, and Coagulation Profile). Shift tables will be presented for 
shifts from baseline lab categories to end of study laboratory category.  The three laboratory categories 
will be:  L (below lower bound of normal range), N (within normal range), and H (above higher bound of 
normal range).    
If a lab value is reported using a non-numeric qualifier (e.g., less than (<) a certain value, or greater than 
(>) a certain value), the given numeric value will be used in the summary statistics, ignoring the non-
numeric qualifier. 
If a subject has repeated laboratory values for a given time point, the value from the first evaluation at that 
time point will be used for summarization purposes. For the purpose of determining baseline, the last 
nonmissing observation on or prior to randomization will be used.  The Week 24 values will be the last 
post-baseline value on or prior to Week 24. 
11.4 COLUMBIA SUICIDE SEVERITY RATING SCALE (CSSR-S)  
Summary of Columbia Suicide Severity Ratings will be provided by CAM2038 group and by the 
scheduled day the measurements are obtained. 
11.5 MONTGOMERY-ASBERG DEPRESSION RATING SCALE (MADRS) 
Summary of Montgomery-Asberg Depression Rating will be provided by CAM2038 group and by the 
scheduled day the measurements are obtained. 
11.6 VITAL SIGNS 


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Vital signs will consist of blood pressure (systolic and diastolic blood pressure, mmHg), pulse rate (beats 
per minute), and respiratory rate (breaths/min), and oxygen saturation (%) collected while sitting, 
following a rest period of at least 3 minutes.  Vital sign values and change from  baseline in the vital signs 
will be summarized for each treatment group. 
11.7 PHYSICAL EXAM 
Number and percent of subjects with abnormal physical exam findings at Screening will be summarized 
by CAM2038 group and body system for each treatment group and overall. Physical Exam data for each 
subject will also be presented in a listing. 
11.8 12-LEAD ELECTROCARDIOGRAM (ECG) 
12-Lead ECGs will be performed at screening and at Week 24 after the subject has been resting in a 
recumbent/supine position for at least 3 minutes. The ECG variables will include ventricular heart rate 
and the PR, QRS, QT, QTcB and QTcF intervals. The ECGs will be signed and dated by a medically-
qualified individual to confirm review of the ECG and verify whether any abnormalities are clinically 
significant.  
 
Number and percent of subjects in each ECG finding category (normal, abnormal not clinically 
significant, and abnormal and clinically significant), will be summarized for each visit by each treatment 
group and overall. Summary statistics will be presented for the actual value and change for each ECG 
parameter. 
 
The results will be summarized by CAM2038 group. 
11.9 INJECTION SITE EXAMINATION  
The injection site will be visually inspected for evidence of erythema, edema, itching, pain, infection, 
bleeding, abnormal healing and any other abnormalities.     
 
12.0 IDENTIFICATION AND SUMMARY OF PROTOCOL 
DEVIATIONS 
Major protocol deviations from entry criteria and treatment compliance will be summarized as far as they 
can be extracted from numeric or coded study data. 
 
13.0 DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be ensured by verification and cross check of the CRFs against 
the investigator’s records by the study monitor (source document verification) and by the maintenance of 
a drug–dispensing log by the investigator.  Collected data will be entered into a computer database and 
subject to electronic and manual quality assurance procedures. 
 
14.0 REFERENCES 


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15.0 APPENDICES 
15.1 APPENDIX A - LIST OF TABLES, LISTINGS, AND FIGURES  
List of Tables 
Number 
Title 
TABLE 14.1.1.1 
Disposition of Randomized Patients (Safety Population) 
TABLE 14.1.1.2 
Disposition of Randomized Patients (ITT Population) 
TABLE 14.1.1.3 
Disposition of Randomized Patients (Completer Population) 
TABLE 14.1.2 
Demographics (Safety Population) 
TABLE 14.1.3 
Baseline Clinical Characteristics (Safety Population) 
TABLE 14.1.4 
Summary of Psychiatric History (Safety Population) 
TABLE 14.1.5.1 
Prior Medications (Safety Population) 
TABLE 14.1.5.2 
Concomitant Medications (Safety Population) 
TABLE 14.1.6 
Substance Abuse Treatment History (Safety Population) 
TABLE 14.2.1.1a 
Analysis Results for Primary Efficacy Variable Emax of Drug Liking VAS for 
CAM2038 32 mg (Completer Population) 
TABLE 14.2.1.1b 
Analysis Results for Primary Efficacy Variable Emax of Drug Liking VAS  for 
CAM2038 24 mg (Completer Population) 
TABLE 14.2.1.2a 
Analysis Results for Primary Efficacy Variable Emax of Drug Liking VAS for 
CAM2038 32 mg (ITT Population) 
TABLE 14.2.1.2b 
Analysis Results for Primary Efficacy Variable Emax of Drug Liking VAS for 
CAM2038 24 mg (ITT Population) 
TABLE 14.2.2.1a 
Analysis Results for Primary Efficacy Variable Emax of High VAS for 
CAM2038 32 mg (Completer Population) 
TABLE 14.2.2.1b 
Analysis Results for Primary Efficacy Variable Emax of High VAS for 
CAM2038 24 mg (Completer Population) 
TABLE 14.2.2.2a 
Analysis Results for Primary Efficacy Variable Emax of High VAS for 
CAM2038 32 mg (ITT Population) 
TABLE 14.2.2.2b 
Analysis Results for Primary Efficacy Variable Emax of High VAS for 
CAM2038 24 mg (ITT Population) 
TABLE 14.2.3.1a 
Analysis Results for Primary Efficacy Variable Emax of Good Effects VAS for 
CAM2038 32 mg (Completer Population) 
TABLE 14.2.3.1b 
Analysis Results for Primary Efficacy Variable Emax of Good Effects VAS for 
CAM2038 24 mg (Completer Population) 
TABLE 14.2.3.2a 
Analysis Results for Primary Efficacy Variable Emax of Good Effects VAS for 
CAM2038 32 mg  (ITT Population) 
TABLE 14.2.3.2a 
Analysis Results for Primary Efficacy Variable Emax of Good Effects VAS for 
CAM2038 24 mg  (ITT Population) 
TABLE 14.2.4.1a 
Analysis Results for Primary Efficacy Variable Emax of Bad Effects VAS for 
CAM2038 32 mg  (Completer Population) 
TABLE 14.2.4.1b 
Analysis Results for Primary Efficacy Variable Emax of Bad Effects VAS for 
CAM2038 24 mg  (Completer Population) 
TABLE 14.2.4.2a 
Analysis Results for Primary Efficacy Variable Emax of Bad Effects VAS for 
CAM2038 32 mg  (ITT Population) 


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TABLE 14.2.4.2b 
Analysis Results for Primary Efficacy Variable Emax of Bad Effects VAS for 
CAM2038 24 mg  (ITT Population) 
TABLE 14.2.5.1a 
Analysis Results for Primary Efficacy Variable Emax of Sedated Effects VAS 
for CAM2038 32 mg  (Completer Population) 
TABLE 14.2.5.1b 
Analysis Results for Primary Efficacy Variable Emax of Sedated Effects VAS 
for CAM2038 24 mg  (Completer Population) 
TABLE 14.2.5.2a 
Analysis Results for Primary Efficacy Variable Emax of Sedated Effects VAS 
for CAM2038 32 mg  (ITT Population) 
TABLE 14.2.5.2b 
Analysis Results for Primary Efficacy Variable Emax of Sedated Effects VAS 
for CAM2038 24 mg  (ITT Population) 
TABLE 14.2.6.1a 
Analysis Results for Primary Efficacy Variable Emax of Any Effects VAS for 
CAM2038 32 mg  (Completer Population) 
TABLE 14.2.6.1b 
Analysis Results for Primary Efficacy Variable Emax of Any Effects VAS for 
CAM2038 24 mg  (Completer Population) 
TABLE 14.2.6.2a 
Analysis Results for Primary Efficacy Variable Emax of Any Effects VAS for 
CAM2038 32 mg  (ITT Population) 
TABLE 14.2.6.2b 
Analysis Results for Primary Efficacy Variable Emax of Any Effects VAS for 
CAM2038 24 mg  (ITT Population) 
TABLE 14.2.7.1a 
Analysis Results for Primary Efficacy Variable Emax of Desire to Use VAS for 
CAM2038 32 mg  (Completer Population) 
TABLE 14.2.7.1b 
Analysis Results for Primary Efficacy Variable Emax of Desire to Use VAS for 
CAM2038 24 mg  (Completer Population) 
TABLE 14.2.7.2a 
Analysis Results for Primary Efficacy Variable Emax of Desire to Use VAS for 
CAM2038 32 mg  (ITT Population) 
TABLE 14.2.7.2b 
Analysis Results for Primary Efficacy Variable Emax of Desire to Use VAS for 
CAM2038 24 mg  (ITT Population) 
TABLE 14.2.10.1a 
Summary of Change from Baseline in Clinical Opiate Withdrawal Scale 
(COWS) for CAM2038 32 mg (Completer Population) 
TABLE 14.2.10.1b 
Summary of Change from Baseline in Clinical Opiate Withdrawal Scale 
(COWS) for CAM2038 24 mg (Completer Population) 
TABLE 14.2.10.2a 
Summary of Change from Baseline in Clinical Opiate Withdrawal Scale 
(COWS) for CAM2038 32 mg (ITT Population) 
TABLE 14.2.10.2b 
Summary of Change from Baseline in Clinical Opiate Withdrawal Scale 
(COWS) for CAM2038 24 mg (ITT Population) 
TABLE 14.2.11.1a 
Summary of Change from Baseline in Objective Opioid Withdrawal Scale 
(OOWS) for CAM2038 32 mg (Completer Population) 
TABLE 14.2.11.1b 
Summary of Change from Baseline in Objective Opioid Withdrawal Scale 
(OOWS) for CAM2038 24 mg (Completer Population) 
TABLE 14.2.11.2a 
Summary of Change from Baseline in Objective Opioid Withdrawal Scale 
(OOWS) for CAM2038 32 mg (ITT Population) 
TABLE 14.2.11.2b 
Summary of Change from Baseline in Objective Opioid Withdrawal Scale 
(OOWS) for CAM2038 24 mg (ITT Population) 
TABLE 14.2.12.1a 
Summary of BPN and norpuprenorphine Concentrations for CAM2038 32 mg 
(Completer Population) 
TABLE 14.2.12.1b 
Summary of BPN and norpuprenorphine Concentrations for CAM2038 24 mg 
(Completer Population) 
TABLE 14.2.12.2a 
Summary of PK Parameters for CAM2038 32 mg (Completer Population) 


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TABLE 14.2.12.2b 
Summary of PK Parameters for CAM2038 24 mg (Completer Population) 
TABLE 14.3.1 
Summary of CAM2038 Exposure (Safety Population) 
TABLE 14.3.2 
Summary of All Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Hydromorphone During Qualification Period (Safety Population) 
TABLE 14.3.3.1 
Summary of All Adverse Events by System Organ Class, Preferred Term, and 
Intensity for CAM2038 Doses and Overall (Safety Population) 
TABLE 14.3.3.1.2 
Summary of All Adverse Events by System Organ Class, Preferred Term, and 
Intensity for Hydromorphone and CAM2038 24 mg (Safety Population) 
TABLE 14.3.3.1.3 
Summary of All Adverse Events by System Organ Class, Preferred Term, and 
Intensity for Hydromorphone and CAM2038 32 mg (Safety Population) 
 
 
 
 
TABLE 14.3.4.1.1 
Summary of All Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Study Drug for CAM2038 Doses and Overall (Safety Population) 
TABLE 14.3.4.1.2 
Summary of All Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Study Drug for Hydromorphone and CAM2038 24 mg (Safety 
Population) 
TABLE 14.3.4.1.3 
Summary of All Adverse Events by System Organ Class, Preferred Term, and 
Relationship to Study Drug for Hydromorphone and CAM2038 32 mg (Safety 
Population) 
 
 
 
 
TABLE 14.3.5 
Summary of All Suspected to Be Drug Related Adverse Events by System Organ 
Class and Preferred Term for CAM2038 Doses and Overall (Safety Population) 
 
 
 
 
TABLE 14.3.6 
Summary of Most Common (at least 5%) Adverse Events by System Organ 
Class and Preferred Term for CAM2038 Doses and Overall (Safety Population) 
 
 
 
 
TABLE 14.3.7 
Summary of All Serious Adverse Events by System Organ Class and Preferred 
Term for CAM2038 Doses and Overall (Safety Population) 
 
 
 
 
TABLE 14.3.8 
Summary of All Adverse Events That Lead to Study Discontinuation by System 
Organ Class and Preferred Term for CAM2038 Doses and Overall (Safety 
Population) 
 
 
 
 
TABLE 14.3.9 
Summary of All Serious Adverse Events That Lead to Study Discontinuation by 
System Organ Class and Preferred Term for CAM2038 Doses and Overall 
(Safety Population) 
 
 
 
 
TABLE 14.3.10 
Summary of All Deaths and Hospitalizations for CAM2038 Doses and Overall 
(Safety Population) 
TABLE 14.4 
Summary of Columbia Suicide Severity Ratings by CAM2038 Doses and Time 


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(Safety Population) 
TABLE 14.5 
Summary of Montgomery-Asberg Depression Rating by CAM2038 Doses and 
Time (Safety Population) 
TABLE 14.6.1.1 
Summary of Clinical Hematology Data by CAM2038 Doses and Time (Safety 
Population) 
TABLE 14.6.1.2 
Shift from Baseline in Laboratory Tests: Hematology by CAM2038 Doses 
(Safety Population) 
TABLE 14.6.2.1 
Summary of Clinical Chemistry Data by CAM2038 Doses (Safety Population) 
TABLE 14.6.2.2 
Shift from Baseline in Laboratory Tests: Chemistry by CAM2038 Doses (Safety 
Population) 
TABLE 14.6.3.1 
Summary of Clinical Coagulation Profile Data by CAM2038 Doses (Safety 
Population) 
TABLE 14.6.3.2 
Shift from Baseline in Laboratory Tests: Coagulation Profile by CAM2038 
Doses (Safety Population) 
TABLE 14.6.4 
Number (%) of Patients with Abnormal Physical Examination Findings by 
CAM2038 Doses (Safety Population) 
TABLE 14.6.5 
Summary of Vital Signs by CAM2038 Doses at Each Visit (Safety Population) 
TABLE 14.6.6 
Summary of 12-Lead ECG Conclusions by CAM2038 Doses (Safety Population) 
TABLE 14.6.7 
Summary of 12-Lead ECG Individual Parameters by CAM2038 Doses (Safety 
Population) 
 
 
 
 
 
List of Listings 
 
Number 
Title 
LISTING 16.2.1 
Patient Meets Inclusion Criteria 
LISTING 16.2.2 
Eligibility for Randomization 
LISTING 16.2.3 
Patient Randomization 
LISTING 16.2.4.1 
Demographics 
LISTING 16.2.4.2 
Medical History 
LISTING 16.2.4.3 
Psychiatric History  
LISTING 16.2.5.1 
CAM2038 Injection 
LISTING 16.2.5.2 
Injection Site Examination/ Treatment Compliance 
LISTING16.2.6.1 
COWS, C-SSRS, MADRS, and OOWS Scales 
LISTING16.2.6.2 
VAS Scales 
LISTING16.2.7.1 
Adverse Events 
LISTING16.2.7.2 
Serious Adverse Events 
LISTING16.2.7.3 
Adverse Events That Lead to Study Drug Discontinuation 
LISTING16.2.7.4 
Adverse Events That Have Death as the Outcome 
LISTING16.2.7.1 
Death Report 
LISTING16.2.7.1 
Prior and Concomitant Medications/Procedures 
LISTING16.2.8.1 
Lab Test Samples 
LISTING16.2.8.2 
Clinical Hematology 
LISTING16.2.8.3 
Clinical Chemistry 
LISTING16.2.8.4 
Clinical Coagulation Profile 


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LISTING16.2.8.5 
Urine Collection/Toxicology 
LISTING16.2.8.6 
Pregnancy Test 
LISTING16.2.8.7 
Physical Examination 
LISTING16.2.8.8 
Vital Signs 
LISTING16.2.8.9 
12-Lead ECG 
LISTING16.2.8.10 
Patient Disposition 
LISTING16.2.8.11 
Protocol Deviations 
LISTING16.2.8.12 
Plasma concentrations 
LISTING16.2.8.13 
PK Data 
List of Figures 
 
Number 
Title 
Figure 14.1.1.1 
Drug Liking VAS Over Time by Challenge Session for CAM2038 32 mg 
(Completer Population)  
Figure 14.1.1.2 
Mean Emax of Drug Liking VAS Over Challenge Sessions for CAM2038 32 mg 
(Completer Population) 
Figure 14.1.1.3 
Mean Emax of Drug Liking VAS vs Mean CAM2038 Concentration Over 
Challenge Sessions for CAM2038 32 mg (Completer Population)  
Figure 14.1.2.1 
Drug Liking VAS Over Time by Challenge Session for CAM2038 24 mg 
(Completer Population)  
Figure 14.1.2.2 
Mean Emax of Drug Liking VAS Over Challenge Sessions for CAM2038 24 mg 
(Completer Population) 
Figure 14.1.2.3 
Mean Emax of Drug Liking VAS vs Mean CAM2038 Concentration Over 
Challenge Sessions for CAM2038 24 mg (Completer Population)  
Figure 14.1.3a 
Mean (±MSE) Concentration over Time for CAM2038 32 mg (linear and semi-
logarithmic graphs, Completer Population) 
Figure 14.1.3b 
Mean (±MSE) Concentration over Time for CAM2038 24 mg (linear and semi-
logarithmic graphs, Completer Population) 
Figure 14.1.3c 
Individual Concentrations over Time for CAM2038 32 mg (linear and semi-
logarithmic graphs, ITT Population) 
Figure 14.1.3d 
Individual Concentrations over Time for CAM2038 24 mg (linear and semi-
logarithmic graphs, ITT Population) 
15.2 APPENDIX B - IMPUTATION ALGORITHM FOR PARTIAL AND 
MISSING DATES  
This section describes missing date imputation methods. 
 
For Adverse Events 
 
If onset date is completely missing, onset date is set to date of randomization. 
If (year is present and month and day are missing) or (year and day are present and month is missing): 
 
If year = year of randomization, then set month and day to month and day of randomization 
 
If year < year of randomization, then set month and day to December 31. 
 
If year > year of randomization, then set month and day to January 1. 
If month and year are present and day is missing: 
 
If year=year of randomization and  
 
If month = month of randomization then set day to day of first dose 


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 
If month < month of first dose then set day to last day of month 
 
If month > month of first dose then set day to first day of month 
 
If year < year of randomization then set day to last day of month 
 
If year > year of randomization then set day to first day of month 
 
For all other cases, set onset date to date of randomization. 
 
For Concomitant Medications 
 
Start Date:  If start date is completely missing and end date is not prior to randomization, then the 
medication will be classified as concomitant. If start date is completely missing and end date is prior to 
randomization, then the medication will be classified as prior. 
 
If (year is present and month and day are missing) or (year and day are present and month is missing) then 
set month and day to January 1.  If year and month are present and day is missing then set day to first day 
of month. 
 
End Date:  If end date is completely missing then the medication will be classified as concomitant. 
If (year is present and month and day are missing) or (year and day are present and month is missing) then 
set month and day to December 31.  If year and month are present and day is missing then set day to last 
day of the month. 
 
Note: that if both start and end dates are missing then the medication will be classified as concomitant.