Clinical trial NCT02741076
Conditions: Opioid-Related Disorders Opiate Addiction Narcotic Abuse Drug Abuse
Sponsor: Member Companies of the Opioid PMR Consortium
Start date: 2016-09-14; Completion date: 2018-04-27
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effect on pain intensity (PI) of structured discontinuation of long-term opioid analgesic therapy compared to continuation of opioid therapy in Suboptimal and Optimal Responders to high-dose, long-term opioid analgesic therapy for chronic low back pain (CLBP).

Detailed description:
This was a multicenter, randomized, double-blind, placebo-controlled study which consisted of a common Screening Visit for all subjects, then different schedules for Optimal and Suboptimal Responders, followed by a common schedule for the Blinded Structured Opioid Discontinuation Period (BSODP) and Follow-up Period.

The original protocol (10 Jan 2016) was amended twice: Amendment 1 (07 Jul 2016) and Amendment 2 (08 Feb 2017). Screening of subjects only started after Amendment 1 approval. Approximately half the subjects were screened under Amendment 1 and half under Amendment 2. The original statistical analysis plan (SAP) was amended twice as well based on the protocol amendments. The current SAP is version 1.3, dated 11 April 2018, which added a section to list the analyses that were not being completed as a result of the premature termination of this study.

The duration of the entire study for each subject was approximately 33 to 37 weeks. For Suboptimal Responders: the study duration included Screening Period of up to 3 weeks, Run-in Period of 1 week, Baseline Period of 1 week, Blinded Structured Opioid Discontinuation Period of 24 weeks, and Follow-up Period of 4 weeks.

For Optimal Responders: the study duration included Screening Period of up to 3 weeks, Observation Period of 1 week, Taper Period up to 2 weeks, Open Label Titration Period of 3 weeks, Blinded Structured Opioid Discontinuation Period of 24 weeks, and Follow-up Period of 4 weeks.

The primary endpoint was the change in the mean Average PI score on the 0-10 Numerical Ratings Scale (NRS) from Baseline to the 1 week period before the Week 12 visit. Data were summarized using descriptive statistics (number of observations \[n\], mean, standard deviation, median, first and third quartiles, minimum, and maximum for continuous variables; and frequency and percentage for categorical variables). Due to the inability to recruit a sufficient number of subjects over an acceptable period of time, the study was terminated prematurely and efficacy analyses were reduced and only a brief summary of the statistical analyses of the primary endpoint in each group (Suboptimal Responders and Optimal Responders) were performed.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER) intervention 2: Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)
Intervention descriptions: intervention 1: Structured discontinuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER) intervention 2: Continuation of opioid therapy (morphine sulfate ER, oxycodone ER, oxymorphone ER)

Protocol documents:
Prot_000.pdf: 
Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
1 
Confidential and Proprietary Information 
1. 
TITLE PAGE 
 
Opioid Post-Marketing Requirement 
(PMR) Consortium  
 
MORPHINE SULFATE ER; OXYCODONE ER; 
OXYMORPHONE ER 
{2065-5} 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, CLINICAL TRIAL OF STRUCTURED OPIOID 
DISCONTINUATION VERSUS CONTINUED OPIOID 
THERAPY IN SUBOPTIMAL AND OPTIMAL RESPONDERS 
TO HIGH-DOSE LONG-TERM OPIOID ANALGESIC 
THERAPY FOR CHRONIC PAIN 
 
 
Original Date: January 10, 2016 
Amendment 1: July 7, 2016 
Amendment 2: February 8, 2017 
 
 
Confidentiality Statement 
The information contained in this document is proprietary and confidential and is the property of 
the member companies of the Opioid PMR Consortium. This document may not—in full or 
part—be passed on, reproduced, published, distributed to any person, or submitted to any 
regulatory authority without the express written permission of the member companies of the 
Opioid PMR Consortium, unless as permitted by a previously executed and effective 
Confidentiality Disclosure Agreement. 
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2. 
SUMMARY OF CHANGES 
Any changes to the protocol after initial approval will be summarized in this section.  
Amendment 1: 
Section 
Original Text 
Revised Text 
Title Page 
This document is the property of the 
Opioid PMR Consortium and may 
not—in full or part—be passed on, 
reproduced, published, distributed to 
any person, or submitted to any 
regulatory authority without the 
express written permission of the 
Opioid PMR Consortium. 
The information contained in this 
document is proprietary and confidential 
and is the property of the member 
companies of the Opioid PMR 
Consortium. This document may not—in 
full or part—be passed on, reproduced, 
published, distributed to any person, or 
submitted to any regulatory authority 
without the express written permission of 
the member companies of the Opioid 
PMR Consortium, unless as permitted by 
a previously executed and effective 
Confidentiality Disclosure Agreement. 
3.0 
Lead Principal Investigator 
 
Synopsis 
(Note: Screening procedures are performed 
over 2 visits no more than 10 days apart.) 
 
 
Adverse events (AEs) will be recorded 
during this period. At the end of the 1-
week Run-In Period, subjects will return to 
the clinic for the Tolerability Visit (Visit 
SR1) to determine whether they tolerated 
the standardized opioid regimen. Subjects 
who did not tolerate the standardized 
opioid regimen or do not have acceptable 
results on screening laboratory tests, 
including the UDT, will be discontinued; 
no dose adjustment of the ER medication 
will be permitted. 
(Note: Screening procedures are 
performed over 2 visits no more than 14 
days apart.) 
 
Adverse events (AEs) will be recorded 
during this period. At the end of the 1-
week Run-In Period, subjects will return 
to the clinic for the Tolerability Visit 
(Visit SR1) to determine whether they 
tolerated the standardized opioid 
regimen. Subjects who did not tolerate 
the standardized opioid regimen will be 
discontinued; no dose adjustment of the 
ER medication will be permitted. 
 
5.0 Table 2 
2.  Screening procedures will be performed over 2 
visits no more than 10 days apart. 
2.  Screening procedures will be performed over 2 
visits no more than 14 days apart. 
5.0 Table 3 
Telephone Calls14 
Telephone Calls15 
5.0 Table 3 
3.  Screening procedures will be performed over 2 
visits no more than 10 days apart. 
3.  Screening procedures will be performed over 2 
visits no more than 14 days apart. 
10.1.1 
Screening 
(Note: Screening procedures will be 
performed over 2 visits no more than 
10 days apart.) 
(Note: Screening procedures will be 
performed over 2 visits no more than 
14 days apart.) 
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Revised Text 
10.1.2 For 
Suboptimal 
Responders 
Only 
Subjects who did not tolerate the 
standardized regimen or do not have 
acceptable results on screening 
laboratory tests or UDT will be 
discontinued; no dose adjustment of the 
ER medication will be permitted. 
Subjects who did not tolerate the 
standardized regimen will be 
discontinued; no dose adjustment of 
the ER medication will be permitted. 
12.1.1 
Screening Visit 
(Same for 
Suboptimal and 
Optimal 
Responders) 
Screening assessments will be carried 
out over 2 visits that are not greater 
than 10 days apart. 
Screening assessments will be carried 
out over 2 visits that are not greater 
than 14 days apart. 
12.1.2 
Suboptimal 
Responders 
Visits Only 
• Discontinue subjects who did not 
tolerate the standardized regimen or 
have unacceptable laboratory results 
– no dose adjustment of the regimen 
is permitted (For study 
discontinuation procedures, see 
section 12.1.6.) 
• Discontinue subjects who did not 
tolerate the standardized regimen – 
no dose adjustment of the regimen 
is permitted (For study 
discontinuation procedures, see 
section 12.1.6.) 
12.1.6 
Study 
Discontinuation 
• Subjects who discontinue between 
Weeks 13 and 24 will complete 
Week 24 assessments and advance to 
the Follow-up period.  At the 
completion of the Follow-up period, 
subjects will be discharged to their 
primary care physician who will 
manage their pain medication. 
 
• Subjects who discontinue between 
Weeks 13 and 24 will complete 
Week 24 assessments and advance 
to the Follow-up period.  For any 
subject who discontinues before 
Week 4, the Medical Monitor 
should be contacted to discuss that 
subject. At the completion of the 
Follow-up period, subjects will be 
discharged to their primary care 
physician who will manage their 
pain medication. 
13.1 
Under each digit the subject should 
write down the corresponding symbol 
as fast as possible. 
Under each digit the subject should 
respond with the corresponding 
symbol as fast as possible. 
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14.5.1 
Reporting 
Adverse Events 
All AEs will be collected by the 
Investigator from the time of signing 
the informed consent through 3 days 
after the last dose of study medication; 
this includes any AEs that are ongoing 
at the time of completion/termination of 
the study. All ongoing AEs must be 
followed until resolution or for 14 days 
after the subject’s last study visit, 
whichever comes first. 
Only SAEs will be collected starting 
at the time of signing the informed 
consent through Screening. Following 
Screening, all AEs will be collected 
by the Investigator through 3 days 
after the last dose of study 
medication; this includes any AEs 
that are ongoing at the time of 
completion/termination of the study. 
All ongoing AEs must be followed 
until resolution or for 14 days after 
the subject’s last study visit, 
whichever comes first.  
Footer 
 
Added: Confidential and 
Proprietary Information 
Appendix B 
Optimal Responders: Open-label 
Taper and Titration Schedule 
Optimal Responders will go through an 
open label taper phase to confirm their 
underlying pain state. Once a certain 
level of flare is confirmed they will 
titrate back to their original dose. Once 
back at their original dose, their 
baseline pin intensity scores will be 
assessed and if stabilized to ≤4 they 
will enter the Blinded Structured 
Discontinuation Period. 
 
Optimal Responders: Open-label 
Taper and Titration Schedule 
Optimal Responders will go through 
an open label taper phase to confirm 
their underlying pain state. After a 
certain level of pain flare is 
confirmed they will titrate their dose 
to control their pain within the 
allowable dose range.   Once the pain 
intensity score is ≤4 for 3 consecutive 
pain scores with satisfaction with pain 
and physical function and acceptable 
side effects, they will enter the 
Blinded Structured Discontinuation 
Period. 
 
Revisions were made to these tables 
to eliminate doses greater than 540 
mg for MSER, 360 mg for OCER, 
and 180 mg for OMER. 
Appendix K 
Colombia 
Columbia 
Appendix L 
 
Replaced EQ-5D-5L UK version with 
US version 
Appendix R 
 
Revised MADDERS forms incorporated 
Appendix T 
 
Revised advice to investigators provided 
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Appendix V 
As a follow-up to the questions we just 
discussed, I want to ask you a few 
questions about the reasons why you 
are leaving this research study. People 
decide to leave research studies for 
many reasons.  For each of the reasons 
listed below, indicate whether this 
contributed to your decision or 
not(“Yes” or “No”).  For those reasons 
where you answered “Yes”, please 
check the box that best indicates how 
important that reason was for you. 
 
As a follow-up to the questions we 
just discussed, I want to ask you a 
few questions about the reasons why 
you are leaving this research study. 
People decide to leave research 
studies for many reasons.  For each of 
the reasons I will read to you, first 
indicate whether this contributed to 
your decision to leave the study or not 
(“Yes” or “No”). Second, for those 
reasons where you answered “Yes”, 
please indicate whether the reason 
was “extremely important”, 
“moderately important”, “a little 
important”, or “not that important” 
for you. 
 
Amendment 2: changes are marked in red bold text in the revised text 
Section 
Original Text 
Revised Text 
Synopsis 
SCREENING 
(Note: Screening procedures are performed over 
2 visits no more than 14 days apart.) 
 
Subjects will be admitted into the study if they 
have non-radicular CLBP which can include 
Quebec Task Force Classification of Spinal 
Disorders Classes 1, 2, 9.2, and 10, for more 
than 12-months duration; have been taking 
extended-release (ER) or long-acting (LA) 
opioids for at least 12 months for their CLBP 
 
 
 
 
Observation Period:…  
their mean Average PI score over the 1 week of 
the period was <4 (with a minimum compliance 
of 4 out of 7 daily PI scores) 
 
Taper Period (up to 2 weeks[+3 days]). 
Subjects with a mean Average PI score ≥5 over 
≥3 consecutive PI scores (excluding missing 
values), 
 
Open-label Titration Period:…  
The dose of index ER opioid will be increased as 
frequently as every 4 days (during telephone or 
office visits) until the mean Average PI score for 
SCREENING 
(Note: Screening procedures are performed over 
2 visits no more than 21 days apart.) 
 
Subjects will be admitted into the study if they 
have non-radicular CLBP which can include 
Quebec Task Force Classification of Spinal 
Disorders Classes 1, proximal radicular (above 
the knee) pain of 2, 9.2, and 10, for more than 
12-months duration; have been taking extended-
release (ER) or long-acting (LA) opioids (or 
doses of immediate-release opioids at least 4 
times a day) for at least 12 months for their 
CLBP 
 
Observation Period:… 
their mean Average PI score over the 1 week of 
the period was <5 (with a minimum compliance 
of 4 out of 7 daily PI scores) 
 
Taper Period (up to 2 weeks[+3 days]). 
Subjects with a mean Average PI score >5 over 
≥3 consecutive PI scores (excluding missing 
values), 
 
Open-label Titration Period:…  
The dose of index ER opioid will be increased as 
frequently as every 4 days (during telephone or 
office visits) until the mean Average PI score for 
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at least 3 consecutive pain scores is <4 (qualify 
for randomization). 
 
Randomization Visit for Optimal Responders 
(Visit OR4).  
Subjects who have completed their titration, 
have achieved a mean Average PI score over 3 
consecutive pain scores of ≤4… 
 
Inclusion Criteria: 2. Have a clinical diagnosis 
of non-radicular CLBP (pain that occurs in an 
area with boundaries between the lowest rib and 
the crease of the buttocks) of Class 1 or Class 2 
based on the Quebec Task Force Classification 
for Spinal Disorders… 
 
 
Inclusion Criteria: 3. Have been taking ER/LA 
opioids for at least 12 months. 
 
 
Exclusion Criteria: 7. Have a body mass index 
(BMI) >40 kg/m2.  
 
 
 
 
Exclusion Criteria: 8. Have clinically significant 
depression based on a score of ≥15 on the Patient 
Health Questionnaire (PHQ-8). 
 
Primary Endpoint… 
For Optimal Responders, the mean Average PI 
score including the Average PI scores during the 
Titration Period that meet the qualification 
criteria (Average PI score ≤4 for 3 consecutive 
non-missing values) plus any scores between the 
last qualification score and the Randomization 
Visit will count as the subject’s baseline Average 
PI score for statistical analysis.  
 
Definition of Baseline… 
For Optimal Responders, the mean Average PI 
score including the Average PI scores during the 
Titration Period that meet the qualification 
criteria (Average PI score ≤4 for 3 consecutive 
non-missing values) plus any scores between the 
final qualification day and the Randomization 
Visit will count as the subject’s baseline Average 
PI score for statistical analysis.   
 
• For Optimal Responders, the subject’s mean 
Average PI score at the end of the Taper 
Period (with added variability based on the 
at least 3 consecutive pain scores is <5 (qualify 
for randomization). 
 
Randomization Visit for Optimal Responders 
(Visit OR4).  
Subjects who have completed their titration, 
have achieved a mean Average PI score over 3 
consecutive pain scores of ≤5… 
 
Inclusion Criteria: 2. Have a clinical diagnosis 
of non-radicular CLBP (pain that occurs in an 
area with boundaries between the lowest rib and 
the crease of the buttocks) of Class 1 or proximal 
radicular (above the knee) pain of Class 2 based 
on the Quebec Task Force Classification for 
Spinal Disorders… 
 
Inclusion criteria: 3. Have been taking ER/LA 
opioids or immediate release opioids (at least 4 
times a day) for at least 12 months. 
 
Exclusion Criteria: 7. Have a body mass index 
(BMI) >45 kg/m2. Anyone with a BMI > 40 but 
< 45 will complete a screening tool (STOPBang 
Questionnaire) to rule out high risk of 
obstructive sleep apnea. 
 
Exclusion Criteria: 8. Have clinically significant 
depression based on a score of > 20 on the 
Patient health Questionnaire (PHQ-8). 
 
Primary Endpoint… 
For Optimal Responders, the mean Average PI 
score including the Average PI scores during the 
Titration Period that meet the qualification 
criteria (Average PI score ≤5 for 3 consecutive 
non-missing values) plus any scores between the 
last qualification score and the Randomization 
Visit will count as the subject’s baseline 
Average PI score for statistical analysis.  
 
 Definition of Baseline… 
For Optimal Responders, the mean Average PI 
score including the Average PI scores during the 
Titration Period that meet the qualification 
criteria (Average PI score ≤5 for 3 consecutive 
non-missing values) plus any scores between the 
final qualification day and the Randomization 
Visit will count as the subject’s baseline Average 
PI score for statistical analysis.   
 
• For Optimal Responders, the subject’s mean 
Average PI score at the end of the Taper 
Period (with added variability based on the 
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variance of the data of the corresponding 
timepoint of missing data). This score will be 
the first 3 days of the mean Average PI score 
used to qualify the subject for entry into the 
Titration Period (i.e., where the mean 
Average PI score is ≥5 over ≥3 consecutive 
days, where this mean Average PI score has 
also increased by ≥1.5 points from the mean 
Average PI score over the 7-day Observation 
Period). 
variance of the data of the corresponding 
timepoint of missing data). This score will be 
the first 3 days of the mean Average PI score 
used to qualify the subject for entry into the 
Titration Period (i.e., where the mean 
Average PI score is >5 over ≥3 consecutive 
days, where this mean Average PI score has 
also increased by ≥1.5 points from the mean 
Average PI score over the 7-day Observation 
Period). 
Section 5 
Figure 1 
 
 
 
 
 
* Baseline PI scores=mean Average PI score 
including the Average PI scores during the 
Titration Period that meet the qualification 
criteria (Average PI score <4 for 3 consecutive 
non-missing values) 
Added: 
ER/LA requirement can be satisfied by use of 
immediate-release opioid at least 4 times a day 
for at least 1 year 
 
* Baseline PI scores=mean Average PI score 
including the Average PI scores during the 
Titration Period that meet the qualification 
criteria (Average PI score <5 for 3 consecutive 
non-missing values) 
Table 3 
footnote 2 
Screening procedures will be performed over 2 
visits no more than 14 days apart. 
Screening procedures will be performed over 2 
visits no more than 21 days apart. 
Table 3 
footnote 5 
At Screening: Height, weight, BMI, pulse rate, 
respiratory rate, and blood pressure. At 
subsequent visit: pulse rate, respiratory rate and 
blood pressure only. 
At Screening: Height, weight, BMI, pulse rate, 
respiratory rate, and blood pressure. At 
subsequent visit: pulse rate, respiratory rate and 
blood pressure only. If BMI >40, complete 
STOPBang Questionnaire and record in source 
documents. Subject cannot continue if apnea risk 
is high. 
Table 3 
footnote 9 
At end of Observation Period: Subjects must 
have had an index ER opioid medication use of 
≥120 mg and ≤540 mg morphine equivalents/day 
(see table in protocol) on average and have had 
80% to 120% compliance over the 1-week 
Observation Period; (ii) have a mean Average PI 
score over the 1 week of the period <4 (with a 
minimum compliance of 4 out of 7 daily PI 
scores); and (iii) still be satisfied with their pain 
and physical function. During or at the end of the 
Taper Period: Subjects must have a mean 
Average PI score ≥5 over ≥3 consecutive scores 
(non-missing values), where this mean Average 
PI score has also increased by ≥1.5 points from 
the mean Average PI score over the 7-day 
Observation Period. Note that if these criteria are 
satisfied at Visit OR2, subject may skip OR2 and 
advance directly to Visit OR3. At the end of 
Titration Period: Subjects must have completed 
their titration and have achieved a mean Average 
PI score over at least 3 consecutive scores (non-
missing values) <4 with acceptable side effects 
and a minimum dose of ≥120 mg and ≤540 mg 
morphine equivalents/day to continue on study. 
At end of Observation Period: Subjects must 
have had an index ER opioid medication use of 
≥120 mg and ≤540 mg morphine equivalents/day 
(see table in protocol) on average and have had 
80% to 120% compliance over the 1-week 
Observation Period; (ii) have a mean Average PI 
score over the 1 week of the period <5 (with a 
minimum compliance of 4 out of 7 daily PI 
scores); and (iii) still be satisfied with their pain 
and physical function. During or at the end of the 
Taper Period: Subjects must have a mean 
Average PI score >5 over ≥3 consecutive scores 
(non-missing values), where this mean Average 
PI score has also increased by ≥1.5 points from 
the mean Average PI score over the 7-day 
Observation Period. Note that if these criteria are 
satisfied at Visit OR2, subject may skip OR2 and 
advance directly to Visit OR3. At the end of 
Titration Period: Subjects must have completed 
their titration and have achieved a mean Average 
PI score over at least 3 consecutive scores (non-
missing values) <5 with acceptable side effects 
and a minimum dose of ≥120 mg and ≤540 mg 
morphine equivalents/day to continue on study. 
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Section 10.1.1 
(Note: Screening procedures will be performed 
over 2 visits no more than 14 days apart.) 
At the Screening Visit, a broad range of patients 
on long-term opioid analgesic therapy for CLBP 
will be evaluated for entry into the study based 
on medical history, physical examination, 
clinical laboratory testing, vital signs, 
electrocardiogram (ECG), PI, urine drug testing 
(UDT), and pregnancy test. Subjects will be 
admitted into the study if they have non-
radicular CLBP which can include Quebec Task 
Force Classification of Spinal Disorders Classes 
1, 2, 9.2, and 10, for more than 12-months 
duration; have been taking extended-release or 
long-acting opioids for at least 12 months for 
their CLBP; have been taking high doses as 
defined in the table below of one of the 
following “index ER opioids”: morphine sulfate 
extended-release (MSER), oxycodone extended-
release (OCER), or oxymorphone extended-
release (OMER) for at least 3 consecutive 
months prior to the Screening Visit. (Subjects 
may also be taking additional ER opioids and/or 
immediate-release (IR) opioids, but the dose of 
any opioids beyond the index ER opioid will not 
be taken into account in the minimum or 
maximum required ER opioid dose for 
enrollment). For subjects taking multiple high-
dose opioids, the Investigator will review all 
opioid use prior to enrollment and determine if 
the subject is still an appropriate candidate for 
the study based on the total amount of opioid the 
subject is receiving.  
(Note: Screening procedures will be performed 
over 2 visits no more than 21 days apart.) 
At the Screening Visit, a broad range of patients 
on long-term opioid analgesic therapy for CLBP 
will be evaluated for entry into the study based 
on medical history, physical examination, 
clinical laboratory testing, vital signs, 
electrocardiogram (ECG), PI, urine drug testing 
(UDT), and pregnancy test. Subjects will be 
admitted into the study if they have non-
radicular CLBP which can include Quebec Task 
Force Classification of Spinal Disorders Classes 
1, proximal radicular (above the knee) pain of 2, 
9.2, and 10, for more than 12-months duration; 
have been taking extended-release or long-acting 
opioids (or doses of immediate-release opioids at 
least 4 times a day) for at least 12 months for 
their CLBP; have been taking high doses as 
defined in the table below of one of the 
following “index ER opioids”: morphine sulfate 
extended-release (MSER), oxycodone extended-
release (OCER), or oxymorphone extended-
release (OMER) for at least 3 consecutive 
months prior to the Screening Visit. (Subjects 
may also be taking additional ER opioids and/or 
immediate-release (IR) opioids, but the dose of 
any opioids beyond the index ER opioid will not 
be taken into account in the minimum or 
maximum required ER opioid dose for 
enrollment). For subjects taking multiple high-
dose opioids, the Investigator will review all 
opioid use prior to enrollment and determine if 
the subject is still an appropriate candidate for 
the study based on the total amount of opioid the 
subject is receiving. 
Section 10.1.3 
Observation Period (1 week)… 
Subjects will be confirmed as Optimal 
Responders and will be allowed to continue in 
the study if (i) their index ER opioid medication 
use was on average in the range shown in the 
table below and they had 80% to 120% 
compliance over the 1-week period; (ii) their 
mean Average PI score over the 1 week of the 
Observation Period was ≤4 (with a minimum 
compliance of 4 out of 7 daily PI scores); and 
(iii) they are still satisfied with their pain and 
physical function. 
 
Taper Period (up to 2 weeks)… 
Subjects with a mean Average PI score ≥5 over 
≥3 consecutive PI scores (excluding missing 
values), where this mean Average PI score has 
also increased by ≥1.5 points from the mean 
Average PI over the 7-day Observation Period, 
Observation Period (1 week)… 
Subjects will be confirmed as Optimal 
Responders and will be allowed to continue in 
the study if (i) their index ER opioid medication 
use was on average in the range shown in the 
table below and they had 80% to 120% 
compliance over the 1-week period; (ii) their 
mean Average PI score over the 1 week of the 
Observation Period was ≤5 (with a minimum 
compliance of 4 out of 7 daily PI scores); and 
(iii) they are still satisfied with their pain and 
physical function. 
 
Taper Period (up to 2 weeks)… 
Subjects with a mean Average PI score >5 over 
≥3 consecutive PI scores (excluding missing 
values), where this mean Average PI score has 
also increased by ≥1.5 points from the mean 
Average PI over the 7-day Observation Period, 
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either off of the index ER opioid pain medication 
entirely or at a reduced dose, will be eligible to 
proceed to the Open-Label Titration Period. 
 
Open-Label Titration Period (up to 3 weeks)… 
The dose of the index ER opioid will be 
increased as frequently as every 4 days (during 
telephone or office [OR3.1 – OR3.6] visits) until 
the mean Average PI score over at least 3 
consecutive pain scores is <4 in order to qualify 
for randomization. 
 
Randomization Visit for Optimal Responders 
(Visit OR4). Subjects who have completed their 
titration, have achieved a mean Average PI score 
over 3 consecutive pain scores of ≤4 with 
satisfaction with their pain and physical function 
and acceptable side effects, and are taking a dose 
of index ER opioid shown in the table below will 
be allowed to continue on study.  
either off of the index ER opioid pain medication 
entirely or at a reduced dose, will be eligible to 
proceed to the Open-Label Titration Period. 
 
Open-Label Titration Period (up to 3 weeks)… 
The dose of the index ER opioid will be 
increased as frequently as every 4 days (during 
telephone or office [OR3.1 – OR3.6] visits) until 
the mean Average PI score over at least 3 
consecutive pain scores is <5 in order to qualify 
for randomization. 
 
Randomization Visit for Optimal Responders 
(Visit OR4). Subjects who have completed their 
titration, have achieved a mean Average PI score 
over 3 consecutive pain scores of ≤5 with 
satisfaction with their pain and physical function 
and acceptable side effects, and are taking a dose 
of index ER opioid shown in the table below will 
be allowed to continue on study.  
Section 10.3.2 
• 
MSIR = Roxane brand of morphine sulfate 
(IR tablets) 
 
• 
MSIR = West-Ward brand of morphine 
sulfate (IR tablets) 
 
Section 10.3.3 
For Optimal Responders, subjects will start the 
standardized regimen during the 2 week Taper 
Period during which study medication will be 
reduced every 3 days until the PI score increases 
as specified. The standardized regimen will 
continue during the 3-week Open-label Titration 
Period. During the Titration Period, the dose of 
the ER opioid will be increased as frequently as 
every 4 days (during telephone or office visits) 
until the mean Average PI score for at least 3 
consecutive pain scores is ≤4. 
For Optimal Responders, subjects will start the 
standardized regimen during the 2 week Taper 
Period during which study medication will be 
reduced every 3 days until the PI score increases 
as specified. The standardized regimen will 
continue during the 3-week Open-label Titration 
Period. During the Titration Period, the dose of 
the ER opioid will be increased as frequently as 
every 4 days (during telephone or office visits) 
until the mean Average PI score for at least 3 
consecutive pain scores is ≤5. 
Section 11.1 
inclusion 
criterion 2 
Have a clinical diagnosis of non-radicular CLBP 
(pain that occurs in an area with boundaries 
between the lowest rib and the crease of the 
buttocks) of Class 1 or 2 of the Quebec Task 
Force Classification for Spinal Disorders 
(subjects with previous surgery or chronic pain 
syndrome, i.e., classes 9.2 or 10, will be allowed 
if their pain does not radiate or radiates only 
proximally) for a minimum of 12 months and… 
Have a clinical diagnosis of non-radicular 
CLBP (pain that occurs in an area with 
boundaries between the lowest rib and the 
crease of the buttocks) of Class 1 or proximal 
(above the knee) radicular pain of Class 2 of the 
Quebec Task Force Classification for Spinal 
Disorders (subjects with previous surgery or 
chronic pain syndrome, i.e., classes 9.2 or 10, 
will be allowed if their pain does not radiate or 
radiates only proximally) for a minimum of 12 
months and… 
Section 11.1 
inclusion 
criterion 3 
Have been taking ER/LA opioids for at least 12 
months; 
Have been taking ER/LA opioids (or immediate 
release opioids (at least 4 times a day) for at 
least 12 months; 
Section 11.2 
exclusion 
criterion 7 
Have a body mass index (BMI) >40 kg/m2.  
Have a body mass index (BMI) >45 kg/m2. 
Anyone with a BMI > 40 but ≤ 45 will complete 
a screening tool (STOPBang Questionnaire) to 
rule out high risk of obstructive sleep apnea 
(Appendix W). 
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Revised Text 
Section 11.2 
exclusion 
criterion 8 
Have a clinically significant depression based on 
a score ≥15 on the Patient Health Questionnaire 
(PHQ-8). 
Have a clinically significant depression based on 
a score ≥20 on the Patient Health 
Questionnaire (PHQ-8). 
Section 12.1.1 
 
 
 
 
sixth bullet 
Screening assessments will be carried out over 2 
visits that are not greater than 14 days apart. 
… 
• Collect vital signs (height, weight, BMI 
[calculated], pulse rate, respiratory rate, and 
blood pressure) 
Screening assessments will be carried out over 2 
visits that are not greater than 21 days apart. 
… 
• Collect vital signs (height, weight, BMI 
[calculated], pulse rate, respiratory rate, and 
blood pressure). Anyone with a BMI > 40 but 
≤ 45 will complete a screening tool 
(STOPBang Questionnaire) to rule out high 
risk of obstructive sleep apnea. 
Section 12.1.3 
OR1 Visit 
(at Week -5) 
seventh 
bullet 
• Subjects will be confirmed as Optimal 
Responders and will be allowed to continue 
in the study if: (i) their index opioid ER 
medication use was in the range shown in the 
table below and they had 80% to 120% 
compliance over the 1-week period; (ii) their 
mean Average PI score over the Observation 
Period was <4 (with a minimum compliance 
of 4 out of 7 daily PI scores); and (iii) they 
are still satisfied with their pain and physical 
function. 
• Subjects will be confirmed as Optimal 
Responders and will be allowed to continue 
in the study if: (i) their index opioid ER 
medication use was in the range shown in the 
table below and they had 80% to 120% 
compliance over the 1-week period; (ii) their 
mean Average PI score over the Observation 
Period was <5 (with a minimum compliance 
of 4 out of 7 daily PI scores); and (iii) they 
are still satisfied with their pain and physical 
function. 
Section 
12.1.3  
OR2 Visit 
(at Week -4) 
First bullet 
• Check criteria for entry into the Titration 
Period: Subjects with a mean Average PI 
score ≥5 over ≥3 consecutive PI scores (non-
missing values), where this mean Average PI 
score has also increased by ≥1.5 points from 
the mean Average PI score over the 7-day 
Observation Period, either off of pain 
medication entirely or at a reduced dose, will 
immediately advance to Visit OR3 (skipping 
Visit OR2) and begin the Open-Label 
Titration Period 
• Check criteria for entry into the Titration 
Period: Subjects with a mean Average PI 
score >5 over ≥3 consecutive PI scores (non-
missing values), where this mean Average PI 
score has also increased by ≥1.5 points from 
the mean Average PI score over the 7-day 
Observation Period, either off of pain 
medication entirely or at a reduced dose, will 
immediately advance to Visit OR3 (skipping 
Visit OR2) and begin the Open-Label 
Titration Period 
Section 
12.1.3 
OR3 Visit 
(at Week -3) 
Ninth bullet  
 
• Check criteria for entry into the Titration 
Period: Subjects with a mean Average daily 
PI score ≥5 over ≥3 consecutive PI scores 
(non-missing values), where this mean 
Average daily PI score has also increased by 
≥1.5 points from the mean Average PI score 
over the 7-day Observation Period, either off 
of pain medication entirely or at a reduced 
dose, will be eligible to proceed to the Open-
Label Titration Period. Subjects who do not 
meet these criteria will be discontinued from 
the study. (For study discontinuation 
procedures, see section 12.1.6.) 
• Check criteria for entry into the Titration 
Period: Subjects with a mean Average daily 
PI score >5 over ≥3 consecutive PI scores 
(non-missing values), where this mean 
Average daily PI score has also increased by 
≥1.5 points from the mean Average PI score 
over the 7-day Observation Period, either off 
of pain medication entirely or at a reduced 
dose, will be eligible to proceed to the Open-
Label Titration Period. Subjects who do not 
meet these criteria will be discontinued from 
the study. (For study discontinuation 
procedures, see section 12.1.6.) 
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Section 
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Revised Text 
Section 
12.1.3 
Telephone 
(or Office) 
Visits every 
4 days (Up 
to 5 
telephone or 
office visits 
from Week 
-3 to 0) 
Sixth and 
seventh 
bullets 
• If the subject does not have a mean Average 
PI score for at least 3 consecutive scores 
(non-missing values) that is <4, increase the 
subject’s dose; increase dose as frequently as 
every 4 days (using Telephone or Office 
Visits) until the mean Average PI score over 
at least 3 consecutive scores (non-missing 
values) is <4 
• When the subject’s mean Average PI score 
over at least 3 consecutive scores (non-
missing values) is <4, schedule the 
Randomization Visit as soon as possible 
(preferably the next day) and keep the subject 
on that ER opioid dose until that visit occurs 
• If the subject does not have a mean Average 
PI score for at least 3 consecutive scores 
(non-missing values) that is <5, increase the 
subject’s dose; increase dose as frequently as 
every 4 days (using Telephone or Office 
Visits) until the mean Average PI score over 
at least 3 consecutive scores (non-missing 
values) is <5 
• When the subject’s mean Average PI score 
over at least 3 consecutive scores (non-
missing values) is <5, schedule the 
Randomization Visit as soon as possible 
(preferably the next day) and keep the subject 
on that ER opioid dose until that visit occurs 
Section 
12.1.3 
Randomizati
on Visit = 
OR4 (at Day 
1) 
Seventh 
bullet 
• Check the criteria for entry into the 
Randomization Period: To continue on study, 
subjects are required to have achieved a mean 
Average PI score ≤4 during the 3 consecutive 
scores (non-missing values) that triggered the 
randomization visit with satisfaction with 
their pain and physical function, and 
acceptable side effects, and be taking a dose 
of index ER opioid in the range listed in the 
table below. 
• Check the criteria for entry into the 
Randomization Period: To continue on study, 
subjects are required to have achieved a mean 
Average PI score ≤5 during the 3 consecutive 
scores (non-missing values) that triggered the 
randomization visit with satisfaction with 
their pain and physical function, and 
acceptable side effects, and be taking a dose 
of index ER opioid in the range listed in the 
table below. 
Section 12.2 
Drugs that are allowed and not allowed as 
concomitant medications for either episodic or 
chronic use are described in this section. 
… 
 
Prohibited Prior Medications 
… 
Prohibited and Allowed Concomitant 
Medications 
… 
Agonist/antagonist analgesics (i.e., pentazocine, 
nalbuphine and butorphanol), buprenorphine, 
methadone, barbiturates, and more than one 
benzodiazepine are prohibited throughout the 
study. 
Alcohol and other concomitant medications that 
are not to be taken in combination with opioid 
analgesics as well as non-prescribed controlled 
substances will NOT be permitted during the 
study except if determined to be appropriate by 
the Investigator.  
Medications and procedures that are allowed and 
not allowed as concomitant medications for 
either episodic or chronic use are described in 
this section. 
… 
Prohibited Prior Medications and Procedures 
… 
Prohibited and Allowed Concomitant 
Medications and Procedures 
… 
Agonist/antagonist analgesics (i.e., pentazocine, 
nalbuphine and butorphanol), buprenorphine, 
methadone, barbiturates, MAO inhibitors, 
investigational drugs, and more than one 
benzodiazepine are prohibited throughout the 
study. 
Alcohol and other concomitant medications that 
are not to be taken in combination with opioid 
analgesics as well as non-prescribed controlled 
substances will NOT be permitted during the 
study except if determined to be appropriate by 
the Investigator.  
Nerve or plexus block, including epidural steroid 
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Revised Text 
injections or facet blocks, botulinum toxin 
injection in the lower back region, chiropractic 
manipulation of the lower back, or any surgical 
procedure (including external or internal nerve 
stimulators) for lower back pain are not allowed 
during the study.  Stimulators that are in place 
prior to study entry are allowed as long as the 
settings are not changed during the study.  
Massage therapy or exercise therapy may 
continue unchanged during the study but new 
massage therapy or exercise therapy is not 
allowed during the study. 
Section 13.2 
For Optimal Responders, the mean Average PI 
score during the Titration Period that meets the 
qualification criteria (Average PI score ≤4 for 3 
consecutive non-missing values) plus any scores 
between the last qualification score and the 
Randomization Visit will count as the subject’s 
baseline Average PI score for statistical analysis. 
For Optimal Responders, the mean Average PI 
score during the Titration Period that meets the 
qualification criteria (Average PI score ≤5 for 3 
consecutive non-missing values) plus any scores 
between the last qualification score and the 
Randomization Visit will count as the subject’s 
baseline Average PI score for statistical analysis. 
Section 17.5 
For Optimal Responders, the mean Average PI 
score during the Titration Period that meets the 
qualification criteria (Average PI score <4 for 3 
consecutive non-missing values) plus any scores 
between the last qualification score and the 
Randomization Visit will count as the subject’s 
baseline Average PI score for statistical analysis. 
For Optimal Responders, the mean Average PI 
score during the Titration Period that meets the 
qualification criteria (Average PI score <5 for 3 
consecutive non-missing values) plus any scores 
between the last qualification score and the 
Randomization Visit will count as the subject’s 
baseline Average PI score for statistical analysis. 
Section 
17.5.1 
• For Optimal Responders, the subject’s mean 
Average PI score at the end of the Taper 
Period (with added variability based on the 
variance of the data of the corresponding 
timepoint of missing data). This score will be 
the first 3 days of the mean Average PI score 
used to qualify the subject for entry into the 
Titration Period (i.e., where the mean 
Average PI score is ≥5 over ≥3 consecutive 
days, where this mean Average PI score has 
also increased by ≥1.5 points from the mean 
Average PI over the 7-day Observation 
Period). 
• For Optimal Responders, the subject’s mean 
Average PI score at the end of the Taper 
Period (with added variability based on the 
variance of the data of the corresponding 
timepoint of missing data). This score will be 
the first 3 days of the mean Average PI score 
used to qualify the subject for entry into the 
Titration Period (i.e., where the mean 
Average PI score is >5 over ≥3 consecutive 
days, where this mean Average PI score has 
also increased by ≥1.5 points from the mean 
Average PI over the 7-day Observation 
Period). 
Section 18.1 
• 
MSIR = Roxane brand of morphine sulfate 
(IR tablets) 
 
• 
MSIR = West-Ward brand of morphine 
sulfate (IR tablets) 
 
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Revised Text 
Appendix B 
Once the pain intensity score is ≤4 for 3 
consecutive pain scores with satisfaction with 
pain and physical function and acceptable side 
effects, they will enter the Blinded Structured 
Discontinuation Period. 
Patient 
group 
Observa
tion 
Period 
Taper 
to Flare 
Flare 
establis
hed 
Titration 
Baseline 
to 
confirm 
stable 
pain ≤4 
Optimal 
Respon
ders 
Current 
medicati
on 
Active 
Open 
Label 
taper 
doses 
(decreas
ed every 
3 days) 
Active Open 
Label titration 
doses back 
towards 
starting dose 
(increased 
every 4 days) 
Active 
dose @ 
entry 
 
Optimal Responders tables: 
[in center] Establish flare: (Average daily PI 
score ≥5; increased by ≥1.5 points for >3 
consecutive days from the mean Average PI). 
Then titrate to stable dose. 
 
[last column] Highest titration dose which 
resulted in a mean Average daily PI score <4 for 
at least 3 consecutive days. 
Once the pain intensity score is ≤5 for 3 
consecutive pain scores with satisfaction with 
pain and physical function and acceptable side 
effects, they will enter the Blinded Structured 
Discontinuation Period. 
Patient 
group 
Observa
tion 
Period 
Taper 
to Flare 
Flare 
establis
hed 
Titration 
Baseline 
to 
confirm 
stable 
pain ≤5 
Optimal 
Respon
ders 
Current 
medicati
on 
Active 
Open 
Label 
taper 
doses 
(decreas
ed every 
3 days) 
Active Open 
Label titration 
doses back 
towards 
starting dose 
(increased 
every 4 days) 
Active 
dose @ 
entry 
 
Optimal Responders tables: 
[in center] Establish flare: (Average daily PI 
score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). 
Then titrate to stable dose. 
 
[last column] Highest titration dose which 
resulted in a mean Average daily PI score ≤5 for 
at least 3 consecutive days. 
Appendix W 
 
NEW: STOPBang Questionnaire 
 
 
 
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3. 
SPONSOR CONTACT INFORMATION 
This section will be completed when the information is available. 
Table 1: 
Sponsor Contact Information 
Role in Study 
Name 
Telephone and Email Address 
Medical Monitor 
Dr. David Schneider 
919-745-2715 
David.Schneider@INCResearch.com  
 
 
 
SAE Reporting Pathway 
 
FAX: 1-877-464-7787 
E-Mail: 
INCDrugSafety@INCResearch.com 
A list of other key study personnel and vendors will be provided separately for your reference. 
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4. 
SYNOPSIS 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
Title 
A randomized, double-blind, placebo-controlled, clinical trial of structured opioid 
discontinuation versus continued opioid therapy in Suboptimal and Optimal 
Responders to high-dose long-term opioid analgesic therapy for chronic pain. 
Phase of 
Development 
Phase 4 
Investigators and 
Study Centers 
Assuming 5 Suboptimal Responder subjects and 5 Optimal Responder subjects are 
randomized (and 20 each screened) per site, this will be a multicenter study conducted 
at approximately 80-100 sites. 
Rationale 
The clinical syndrome of poor response to high-dose long-term opioid therapy is not 
well characterized in the medical literature, but well recognized by the clinical pain 
management community. Characteristics of these patients include, in addition to the 
use of higher doses of opioids for extended periods of time, persistent severe pain 
intensity (PI) ratings, poor physical, psychological, and social function, frequent 
employment difficulties, and aberrant drug-taking behaviors that may or may not be 
sufficient to meet criteria for an addiction disorder. Patients often insist that despite 
their poor clinical status and the lack of an evident response to opioids, continued 
opioid treatment is essential. A traditional treatment for such patients is discontinuation 
of opioid therapy, in which patients have their opioid therapy gradually tapered off, in 
the context of psychological and physical rehabilitative support, often in a structured 
inpatient or outpatient program. Long-term clinical success has been noted in 
uncontrolled and unblinded observational studies, but the efficacy of removal from 
opioid therapy for a well-defined cohort of “Suboptimal Opioid Responders” has never 
been evaluated in a randomized, double-blind, controlled clinical trial. 
One proposed, but as yet unproven, explanation for the phenomenon of Suboptimal 
Responders to higher-dose opioid therapy is opioid-induced hyperalgesia (OIH). 
According to this hypothesis, some patients on long-term opioid therapy for chronic 
pain develop paradoxical hypersensitivity to pain caused by the very opioid treatment 
intended to reduce their pain, resulting in increasing doses, increasing pain intensity, 
increased sensitivity to painful stimuli (hyperalgesia), and according to many 
descriptions, spread of pain beyond the initially painful area. Under this hypothesis, 
removal of opioid therapy would result in improvement of experimental pain 
sensitivity, improvement in pain intensity, and potentially decreased spread of pain 
compared to patients in whom opioid therapy was continued. In addition, it would be 
expected that Suboptimal Responders to opioid therapy have greater experimental pain 
sensitivity and perhaps greater pain spread than Optimal Responders to opioid therapy 
(who presumably do not have OIH). Finally, it would be expected that in contrast to 
Suboptimal Responders, Optimal Responders to opioid therapy will worsen when their 
effective analgesics have been withdrawn, as with any other effective analgesic. 
From a clinical perspective, clinicians need to understand not only whether OIH 
underlies suboptimal responses to opioids in general, but how to identify, among 
patients who are responding poorly to opioids, which patients will improve after 
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Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
withdrawal of opioids. Therefore, it is important to attempt to identify predictors of 
benefit from withdrawal of opioids among Suboptimal Responders. 
The overarching purpose of this research program, which is being conducted to meet 
the U.S. Food and Drug Administration requirements and is one of the 5 Opioid Post 
Marketing Requirement Consortium (OPC) commitments, is to better characterize the 
contribution of OIH to suboptimal responses to opioid therapy. This goal will be 
approached in several different ways. Among a cohort of Suboptimal Responders to 
opioid therapy, the objective will be to evaluate the effect of structured discontinuation 
versus continuation of long-term opioid treatment on pain intensity, pain spread, and 
sensitivity to experimental pain. Predictors of a beneficial response to opioid 
discontinuation will be examined. The impact of structured opioid discontinuation (vs. 
continuation) among the Suboptimal Responders will be indirectly compared to the 
impact of structured opioid discontinuation (vs. continuation) among a cohort of 
Optimal Responders to opioid therapy in order to fully inform the objectives of the 
OPC commitment. Worsening of pain upon discontinuation of opioid therapy in the 
Optimal Responder group will confirm and extend previous observations of the 
efficacy of long-term opioid therapy. Baseline characteristics of Suboptimal and 
Optimal Responders will be compared, particularly with regard to experimental pain 
sensitivity.  
Objectives 
Primary Objective: To evaluate the effect on pain intensity (PI) of structured 
discontinuation of long-term opioid analgesic therapy compared to continuation of 
opioid therapy in Suboptimal and Optimal Responders to high-dose, long-term opioid 
analgesic therapy for chronic low back pain (CLBP).  
Secondary Objective: To evaluate the effect on additional clinical outcomes measures 
of structured discontinuation of long-term opioid analgesic therapy compared to 
continuation of opioid therapy for CLBP in Suboptimal and Optimal Responders to 
high-dose, long-term opioid analgesic therapy at multiple time points. 
Exploratory Objectives:  
• 
To compare experimental pain sensitivity in the opioid discontinuation vs. 
continuation groups in both Suboptimal Responders and Optimal Responders 
(subjects in substudy). 
• 
To determine subject characteristics that predict response to structured 
discontinuation of opioid therapy. 
• 
To determine the effect of opioid discontinuation on certain endocrine function 
tests, sexual function, and the relationship of changes in PI and endocrine 
function to changes in male and female sexual function. 
• 
To determine the effect of opioid discontinuation on neurocognitive function. 
Study Design 
This multicenter, randomized, double-blind, placebo-controlled study will consist of a 
common Screening Visit for all subjects, then different schedules for Optimal and 
Suboptimal Responders, followed by a common schedule for the Blinded Structured 
Opioid Discontinuation Period and Follow-up Period, as illustrated in Figure 1. The 
schedule of procedures for Suboptimal and Optimal Responders is shown in Table 2 
and Table 3, respectively. 
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Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
 
SCREENING 
(Note: Screening procedures are performed over 2 visits no more than 21 days apart.) 
At the Screening Visit, a broad range of patients on long-term opioid analgesic therapy 
for CLBP will be evaluated for entry into the study based on medical history, physical 
examination, clinical laboratory testing, vital signs, electrocardiogram (ECG), pain 
intensity (PI), urine drug testing (UDT), and urine pregnancy test. Subjects will be 
admitted into the study if they have non-radicular CLBP which can include Quebec 
Task Force Classification of Spinal Disorders Classes 1, proximal radicular (above 
the knee) pain of 2, 9.2, and 10, for more than 12-months duration; have been taking 
extended-release (ER) or long-acting (LA) opioids (or doses of immediate-release 
opioids at least 4 times a day) for at least 12 months for their CLBP; have been taking 
high doses as defined here of one of the following “index ER opioids” for their CLBP: 
morphine sulfate extended-release (MSER), oxycodone extended-release (OCER), or 
oxymorphone extended-release (OMER) within the dose range for each index ER 
opioid as shown in the table below, for at least 3 consecutive months prior to the 
Screening Visit.  
 
Dose Range 
Morphine sulfate extended-release 
120-540mg 
Oxycodone extended-release 
80-360mg 
Oxymorphone extended-release 
40-180mg 
Subjects may also be taking additional ER opioids and/or immediate-release (IR) 
opioids, but the dose of any opioids beyond the index opioid will not be taken into 
account in the minimum or maximum required ER opioid dose for enrollment. The 
goal will be to have a minimum representation of each index ER opioid, with a 
minimum of ~20% of randomized subjects for each index ER opioid. Subjects taking 
asymmetric dosing of index ER opioids (different dose in the morning and evening) 
will be allowed in the study as long as they meet the dose criterion of index ER opioid 
indicated above and can be converted to symmetric twice-daily dosing. 
Subjects taking acetaminophen (or any acetaminophen-containing product after review 
of concomitant medications) prior to entering the study will be directed to stop taking it 
and only take the study-provided acetaminophen after entering the study. 
Subjects will be classified as Suboptimal Responders or Optimal Responders at the 
Screening Visit as per the following criteria: Suboptimal Responder = Subject whose 
daily Average PI score is ≥6 and who is dissatisfied with his/her pain and physical 
function; Optimal Responder = Subject whose daily Average PI score is ≤4 and who is 
satisfied with his/her pain and physical function. The study design then differs for the 
Suboptimal and Optimal Responder populations as described below. 
 
FOR SUBOPTIMAL RESPONDERS ONLY 
The schedule of procedures for Suboptimal Responders is shown in Table 2. Visits 
specific for Suboptimal Responders are named SR1, SR2, etc. 
Run-In Period (1 week). Subjects classified as Suboptimal Responders at the Screening 
Visit will enter the Run-in Period during which they will be required to discontinue all 
previously prescribed ER and immediate release (IR) opioid medications for the 
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Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
remainder of the study and will receive a standardized regimen supplied as index ER 
opioid plus matching IR opioid depending on the index ER opioid they were taking at 
screening (i.e., either oxycodone extended-release [OCER], OxyContin, plus 
oxycodone IR [OCIR] PRN, morphine sulfate extended-release [MSER], MS Contin, 
plus morphine sulfate IR [MSIR] PRN, or oxymorphone extended-release [OMER], 
Opana ER, plus oxymorphone IR [OMIR] PRN). In the standardized regimen, the 
dose of the ER opioid will be similar to the dose of the index ER opioid taken at 
screening and will remained fixed throughout the period. (Note: Subjects who were 
taking asymmetric doses of the index ER opioid at screening will be placed on a 
symmetric dosage [same dose in the morning and evening] of the standardized 
regimen.)  
The dose of the IR opioid will be limited to no more than twice daily PRN 
administration of OCIR 10 mg, MSIR 15 mg, or OMIR 5 mg, matching the index ER 
opioid each subject is receiving. The maximum dose of PRN IR opioid they are allowed 
per day will remain fixed. Subjects will also be provided acetaminophen as rescue 
medication (500 mg tablets, 1 to 2 tablets PRN every 4 to 6 hours, not to exceed 
6 tablets/day) and will be encouraged to take acetaminophen to manage their pain 
before they use the IR opioid (i.e., only take the IR opioid if the maximum dose of 
acetaminophen is not effective). Subjects will be allowed to continue the non-opioid 
analgesics they had been taking before screening but will not be able to change the 
dose except for acetaminophen as described above. 
Adverse events (AEs) will be recorded during this period. At the end of the 1-week 
Run-In Period, subjects will return to the clinic for the Tolerability Visit (Visit SR1) to 
determine whether they tolerated the standardized opioid regimen. Subjects who did 
not tolerate the standardized opioid regimen will be discontinued; no dose adjustment 
of the ER medication will be permitted. 
Baseline Period (1 week). Subjects will then enter a 1-week Baseline Period during 
which they will self-administer the standardized opioid regimen and record their opioid 
medication intake and PI scores (Average and Worst over past 24 hours on a 0-10 
numerical rating scale (NRS)) daily before bed time. Each subject’s 7-day daily PI 
scores will be averaged and used as the subject’s baseline PI scores (with a minimum 
compliance of 4 out of 7 daily PI scores).  
At the Randomization Visit for Suboptimal Responders (Visit SR2), subjects will 
continue on study if they have (i) a mean Average PI score ≥6 on a 0-10 NRS over the 
1 week of the Baseline Period (with a minimum compliance of 4 out of 7 daily PI 
scores); (ii) compliance with their index ER opioid medication between 80% and 
120%; and (iii) are still dissatisfied with their pain and physical function. Subjects who 
had a baseline mean Average PI score of 10/10 (i.e., 10/10 score every day for the 1 
week of the Baseline Period) will be discontinued. 
The rest of the study will then be similar for both Suboptimal Responders and Optimal 
Responders as described below. 
________________________________________________________
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OPC, 2065-5
Clinical Study Report version: Final
Page 20 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
19 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
 
FOR OPTIMAL RESPONDERS ONLY 
The schedule of procedures for Optimal Responders is shown in Table 3. Visits 
specific for Optimal Responders are named OR1, OR2, etc. 
Observation Period (1 week). Subjects meeting the common screening criteria at the 
end of the Screening Visit and classified as Optimal Responders at the Screening Visit 
will be sent home and told to continue their current medication (including non-index 
ER and IR opioid medications) for 1 week. (Note: Subjects who were taking 
asymmetric doses of the index ER opioid at screening will continue taking asymmetric 
doses of their index ER opioids during this period.) During this period, opioid 
medication intake and PI scores (Average and Worst over past 24 hours on a 0-10 
NRS) will be captured daily before bed time. At the end of the period, subjects will 
return to the clinic (Visit OR1) and all opioid medication use and PI scores will be 
reviewed. Subjects will be confirmed as Optimal Responders and will be allowed to 
continue in the study if: (i) their index ER opioid medication use was, on average, in 
the range shown in the table below  and they had 80% to 120% compliance over the 1-
week period; (ii) their mean Average PI score over the 1 week of the period was <5 
(with a minimum compliance of 4 out of 7 daily PI scores); and (iii) they are still 
satisfied with their pain and physical function. 
 
 
Dose Range 
Morphine sulfate extended-release 
120-540mg 
Oxycodone extended-release 
80-360mg 
Oxymorphone extended-release 
40-180mg 
 
Taper Period (up to 2 weeks[+3 days]). Subjects will be tapered with the same index 
ER opioid they were taking at screening (using study medication provided for the index 
ER opioid; i.e., either  OxyContin, MS Contin, or Opana ER); IR opioid will not be 
used during the Taper Period and any other opioid medication will be discontinued. 
(Note: Subjects who were taking asymmetric doses of ER index opioid at screening 
will be tapered with a symmetric dosage [same dose in the morning and evening] of the 
standardized regimen.) Tapering will start at Visit OR1. Subjects will self-administer a 
tapering dose of the standard index ER opioid matching the one they were taking for up 
to 2 weeks (+ 3 days) and will record PI scores daily. No other ER opioid will be 
allowed. At Visit OR2, the subjects’ overall status (opioid medication dose, PI score, 
etc.) will be reviewed. If the minimum pain requirement has been met either before or 
at Visit OR2, the subject will immediately advance to Visit OR3 (skipping Visit OR2) 
and begin the Open-Label Titration Period. If the minimum pain requirement has not 
been met, the opioid taper will continue.  By Visit OR3, subjects should be completely 
off of their opioid medication if they have not already met the minimum pain 
requirement. Subjects with a mean Average PI score  >5 over ≥3 consecutive PI scores 
(excluding missing values), where this mean Average PI score has also increased by 
≥1.5 points from the mean Average PI score over the 7-day Observation Period, either 
off of their index ER opioid pain medication entirely or at a reduced dose, will be 
eligible to proceed to the Open-Label Titration Period. Subjects who do not meet these 
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Clinical Study Report version: Final
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Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
20 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
criteria, including those subjects who cannot tolerate the tapering of the index ER 
opioid, will be discontinued from the study. 
Open-Label Titration Period (up to 3 weeks). Subjects will be titrated with the same 
index ER opioid they were taking during the Taper Period (supplied as index ER 
opioid plus matching IR opioid; i.e., either OCER (OxyContin) plus OCIR PRN, 
MSER (MS Contin) plus MSIR PRN, or OMER (Opana ER) plus OMIR PRN). The 
dose of index ER opioid will be increased as frequently as every 4 days (during 
telephone or office visits) until the mean Average PI score for at least 3 consecutive 
pain scores is <5 (qualify for randomization). If the dose of the index ER opioid needs 
to be titrated above the baseline dose, the Titration Period may be extended 1 
additional week (+3 days).  The dose of the IR opioid will be limited to no more than 
twice daily PRN administration of OCIR 10 mg, MSIR 15 mg, or OMIR 5 mg, 
matching the index ER opioid each subject is receiving. Subjects will also be provided 
acetaminophen as rescue medication (500 mg tablets, 1-2 tablets PRN every 4 to 
6 hours, not to exceed 6 tablets/day) and will be encouraged to take acetaminophen to 
manage their pain, before they use IR opioid (i.e., only take the IR opioid if the 
maximum dose of acetaminophen is not effective).  
Randomization Visit for Optimal Responders (Visit OR4). Subjects who have 
completed their titration, have achieved a mean Average PI score over 3 consecutive 
pain scores of ≤5 with satisfaction with their pain and physical function and acceptable 
side effects, and are taking a dose of index opioid as shown in the table below will be 
allowed to continue on study.  
 
 
Dose Range 
Morphine sulfate extended-release 
120-540mg 
Oxycodone extended-release 
80-360mg 
Oxymorphone extended-release 
40-180mg 
 
The rest of the study will then be similar for both Suboptimal Responders and 
Optimal Responders.  
CONTINUING FOR BOTH SUBOPTIMAL AND OPTIMAL RESPONDERS 
Blinded Structured Opioid Discontinuation Period (24 weeks). At the Randomization 
Visit (Visit SR2 or OR4), subjects meeting the criteria (described above for each 
population) to enter the Blinded Structured Opioid Discontinuation Period will then be 
randomized to either continue or discontinue opioid therapy, as follows. 
For subjects whose index ER opioid is MSER, the groups will be: 
• 
Morphine Group 1: MSER tablets  + matching placebo tablets to maintain 
MSER dose, but appear as if tapering is occurring; 
• 
Morphine Group 2: Placebo tablets to match MSER tablets + MSER tablets in 
decreasing dose to result in a tapering off of MSER. 
• 
Both groups will be provided with MSIR and acetaminophen. 
For subjects whose index ER opioid is OCER, the groups will be: 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 22 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
21 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
• 
Oxycodone Group 1: OCER tablets + matching placebo tablets to maintain 
OCER dose, but appear as if tapering is occurring; 
• 
Oxycodone Group 2: Placebo tablets to match OCER tablets + OCER tablets 
in decreasing dose to result in a tapering off of OCER. 
• 
Both groups will be provided with OCIR and acetaminophen. 
For subjects whose index ER opioid is OMER, the groups will be: 
• 
Oxymorphone Group 1: OMER tablets + matching placebo tablets to maintain 
OMER dose, but appear as if tapering is occurring; 
• 
Oxymorphone Group 2: Placebo tablets to match OMER tablets + OMER 
tablets in decreasing dose to result in a tapering off of OMER. 
• 
Both groups will be provided with OMIR and acetaminophen. 
Therefore, there will be a total of 4 groups in the Blinded Structured Opioid 
Discontinuation Period:  
• 
Suboptimal Responders, continuation arm 
• 
Suboptimal Responders, discontinuation arm 
• 
Optimal Responders, continuation arm 
• 
Optimal Responders, discontinuation arm 
Randomization will be stratified by responder status (Optimal Responder; Suboptimal 
Responder) and index ER opioid (morphine, oxycodone, or oxymorphone); subject 
recruitment into the study will be adjusted to ensure at least 20% of subjects are on 
oxycodone, at least 20% on morphine, and at least 20% on oxymorphone in the 
Blinded Structured Opioid Discontinuation Period within each cohort (Optimal 
Responders and Suboptimal Responders). The goal is to taper subjects in the 
discontinuation arms of both the Suboptimal Responder and Optimal Responder groups 
off their opioid treatment onto placebo over approximately 3-4 weeks (duration of 
taper will depend on the baseline dose of the index ER opioid). Subjects in the 
continuation arms will be on a fixed-regimen of ER opioid (i.e., the ER opioid dose 
will remain fixed and the maximum dose of PRN IR opioid dose they are allowed per 
day will remain fixed); note that the doses will vary across subjects based on their 
individualized standardized dose. Subjects will also be provided acetaminophen as 
rescue medication (500 mg tablets, 1-2 tablets PRN every 4-6 hours not to exceed 6 
tablets/day) and will be encouraged to take acetaminophen to manage their pain before 
they use IR opioid.  
The dose of the IR opioid will be limited to no more than twice daily PRN 
administration of OCIR 10 mg, MSIR 15 mg, or OMIR 5 mg, matching the index ER 
opioid each subject is receiving. Subjects will return to the clinic at weeks 1, 2, 4, 6, 8, 
12, 16, 20, and 24 (Visits BDP1 through BDP9). A series of assessments will be 
performed at each visit. 
Follow-Up Period (4 weeks). Subjects completing the Blinded Structured Opioid 
Discontinuation Period will be required to advance to and complete the Follow-up 
Period. However, those subjects who discontinue from the Blinded Structured Opioid 
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OPC, 2065-5
Clinical Study Report version: Final
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Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
22 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
Discontinuation Period prior to Week 12 will complete Week 12 study procedures and 
those subjects who discontinue during Weeks 13-23 will complete Week 24 study 
procedures before proceeding to the Follow-Up Period. Subjects will self-administer a 
blinded tapering dose during the Follow-Up Period: Placebo taper for subjects who 
were in the discontinuation arm and active drug taper for subjects who were in the 
continuation arm. Subjects will be followed-up during 2 clinic visits (FUV1 and FUV2, 
and 2 phone calls (during the weeks between Follow-Up Visits). At the end of the 
Follow-up Period, subjects will be transitioned back to their primary care physician.  
Subjects will be instructed not to take any ER opioid medication until they have 
consulted with their primary care physician as they no longer will be opioid-tolerant at 
this time. 
Number of Subjects 
(planned) 
Approximately 3280 subjects will be screened, 820 will be randomized into the 
Blinded Structured Opioid Discontinuation Period (205 subjects per arm per responder 
type will be needed), and it is assumed that approximately 60-70% will complete the 
study. The sample size is calculated to detect a between-group difference (between the 
opioid discontinuation group and the opioid continuation group within each responder 
type) of 0.8 points, assuming a standard deviation of 2.5, a 2-sided 5% significance 
level, and 90% power. 
Entry Criteria at 
Screening 
Inclusion criteria:  Subjects must meet all of the following inclusion criteria to be 
enrolled in the study: 
1. Be male or non-pregnant, non-lactating female aged 18 to 75 years, inclusive. 
2. Have a clinical diagnosis of non-radicular CLBP (pain that occurs in an area 
with boundaries between the lowest rib and the crease of the buttocks) of Class 
1 or proximal radicular (above the knee) pain of Class 2 based on the Quebec 
Task Force Classification for Spinal Disorders (subjects with previous surgery 
or chronic pain syndrome, i.e., classes 9.2 or 10, will be allowed if their pain 
does not radiate or radiates only proximally) for a minimum of 12 months and 
a. For the Suboptimal Responder group, pain must have been present for 
at least several hours a day and have an Average PI score of 6-9 on an 
11-point NRS within the past 24 hours of screening. 
b. For the Optimal Responder group, subjects must have an Average PI 
score of 1-4 on an 11-point NRS within the past 24 hours of screening. 
3. Have been taking ER/LA opioids or immediate release opioids (at least 4 times 
a day) for at least 12 months. 
4. Have been taking one of the 3 index ER opioid drugs around-the-clock at a 
twice-a-day frequency for at least 3 consecutive months at a total daily dose 
within the range shown in the table below. 
 
 
Daily Dose 
Range 
Morphine sulfate extended-
release 
120-540mg 
Oxycodone extended-release 
80-360mg 
Oxymorphone extended-release 
40-180mg 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 24 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
23 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
 
5. Be considered, in the opinion of the Investigator, to be in generally good health 
other than CLBP at screening based upon the results of a medical history, 
physical examination, 12-lead ECG, and laboratory profile. 
6. Speak, read, write, and understand English (to reduce heterogeneity of data), 
understand the consent form, and be able to effectively communicate with the 
study staff. 
7. Have access to the Internet (to access the patient support program). 
8. Voluntarily provide written informed consent. 
9. Be willing and able to complete study procedures. 
Exclusion Criteria:  Subjects who have any of the following will not be enrolled in 
the study: 
1. Have any clinically significant condition that would, in the opinion of the 
Investigator, preclude study participation or interfere with the assessment of 
pain and other symptoms of CLBP or increase the risk of opioid-related AEs.  
2. Have a primary diagnosis of fibromyalgia, complex regional pain syndrome, 
neurogenic claudication due to spinal stenosis, spinal cord compression, acute 
nerve root compression, severe or progressive lower extremity weakness or 
numbness, bowel or bladder dysfunction as a result of cauda equina 
compression, diabetic amyotrophy, meningitis, diskitis, back pain because of 
secondary infection or tumor, or pain caused by a confirmed or suspected 
neoplasm.  
3. Have undergone a surgical procedure for back pain within 6 months prior to 
the Screening Visit. 
4. Have had a nerve or plexus block, including epidural steroid injections or facet 
blocks, within 1 month prior to the Screening Visit or botulinum toxin 
injection in the lower back region within 3 months prior to screening. 
5. Have a history of confirmed malignancy within past 2 years, with exception of 
basal cell or squamous cell carcinoma of the skin that has been successfully 
treated. 
6. Have uncontrolled blood pressure, i.e., subject has a sitting systolic blood 
pressure >180 mm Hg or <90 mm Hg, or a sitting diastolic blood pressure 
>110 mmHg or <40 mm Hg at screening. 
7. Have a body mass index (BMI) >45 kg/m2. Anyone with a BMI > 40 but ≤ 45 
will complete a screening tool (STOPBang Questionnaire) to rule out high risk 
of obstructive sleep apnea. 
8. Have clinically significant depression based on a score of ≥20 on the Patient 
Health Questionnaire (PHQ-8). 
9. Have suicidal ideation associated with actual intent and a method or plan in the 
past year: "Yes" answers on items 4 or 5 of the Columbia-Suicide Severity 
Rating Scale (C-SSRS).  
10. Have a previous history of suicidal behaviors in the past 5 years: "Yes" answer 
(for events that occurred in the past 5 years) to any of the suicidal behavior 
items of the C-SSRS.  
11. Have any lifetime history of serious or recurrent suicidal behavior. (Non-
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Clinical Study Report version: Final
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Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
24 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
suicidal self-injurious behavior is not a trigger for a risk assessment unless in 
the Investigator's judgment it is indicated.) 
12. Have clinically significant abnormality in clinical chemistry, hematology or 
urinalysis, including serum glutamic-oxaloacetic transaminase/aspartate 
aminotransferase or serum glutamic pyruvic transaminase/alanine 
aminotransferase ≥3 times the upper limit of the reference range or a serum 
creatinine >2 mg/dL at screening. 
13. Have severe enough psychiatric or substance abuse disorder to compromise the 
subject’s safety or scientific integrity of the study. 
14. Have on-going litigation associated with back pain or pending applications for 
workers compensation or disability issues or subjects who plan on filing 
litigation or claims within the next 12 months; subjects with settled past 
litigations will be allowed as will subjects who have been on workers 
compensation or disability claims for at least 3 months. 
15. Have used a monoamine oxidase inhibitor within 14 days prior to screening. 
16. Are taking agonist-antagonists (pentazocine, butorphanol or nalbuphine), 
buprenorphine, methadone, barbiturates, or more than one type of 
benzodiazepine within 1 month prior to screening. 
17. Have a positive UDT for illicit drugs (including marijuana), non-prescribed 
controlled substances (opioid or non-opioid), or alcohol at screening. 
18. Have taken any investigational drug within 30 days prior to the Screening Visit 
or are currently enrolled in another investigational drug study. 
Entry Criteria to 
Determine 
Responder Status 
Following successful determination of eligibility, subjects will be assessed against the 
following criteria to determine responder status at the Screening Visit: 
• 
Subjects with an Average PI score ≤4 (as measured on the NRS) at Screening 
who are satisfied with their pain and physical function will be considered 
Optimal Responders 
• 
Subjects with an Average PI score ≥6 (as measured on the NRS) at Screening 
who are dissatisfied with their pain and physical function will be considered 
Suboptimal Responders 
 
• 
Subjects who do not fall into either category will be considered screen failures 
and discontinued from the study. 
Assessments 
• 
Roland-Morris Disability Questionnaire (RMDQ) 
• 
Average PI scores in the past 24 hours on 0-10 NRS 
• 
Worst PI scores in the past 24 hours on 0-10 NRS 
• 
Brief Pain Inventory – Short Form (BPI-SF) 
• 
Regional Pain Scale 
• 
Pain Quality Assessment Scale (PQAS) 
• 
Short-form health survey (EQ-5D-5L) 
• 
Patient Global Impression of Change (PGIC) 
• 
Patient Health Questionnaire-8 (PHQ-8) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
MOS Sleep Scale 
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OPC, 2065-5
Clinical Study Report version: Final
Page 26 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
25 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
• 
Digit Symbol Substitution Test (DSST) 
• 
Quantitative sensory testing (QST) for OIH to measure pain sensitivity to 
experimental thermal stimuli (for subjects enrolled at participating sub-study 
sites) 
• 
Endocrine function tests (eg, free and total testosterone, luteinizing hormone 
(LH), follicle-stimulating hormone [FSH], estradiol [women only], insulin 
growth factor-1 [IGF-1], cortisol, adrenocorticotropic hormone [ACTH], 
dehydroepiandrosterone sulfate [DHEAS], and thyroid-stimulating hormone 
[TSH] [baseline only]) and sexual function scales (International Index of 
Erectile Function [IIEF] for males and Female Sexual Function Index [FSFI] 
for females)  
• 
Subjective Opiate Withdrawal Scale (SOWS)  
• 
Clinical Opioid Withdrawal Scale (COWS) 
• 
Work productivity (Work Productivity and Activity Impairment [WPAI] scale) 
• 
AEs 
• 
Abuse-related events (using the MADDERS™ system) 
• 
Vital signs 
• 
Physical examination 
• 
ECG 
• 
Clinical laboratory parameters 
• 
Pregnancy test  
• 
Quantitative UDT  
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Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
26 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
Endpoints for 
Evaluation 
Primary Endpoint 
Change in the mean Average PI score on the 0-10 NRS from baseline to the 1 week 
period prior to the Week 12 visit. 
For Suboptimal Responders, the mean Average PI score over the 7-day Baseline Period 
will count as the subject’s baseline Average PI score for statistical analysis. 
For Optimal Responders, the mean Average PI score including the Average PI scores 
during the Titration Period that meet the qualification criteria (Average PI score <4 for 
3 consecutive non-missing values) plus any scores between the last qualification score 
and the Randomization Visit will count as the subject’s baseline Average PI score for 
statistical analysis.   
Secondary Endpoints 
Suboptimal Responders 
• 
Change from baseline to Weeks 4, 8, 16, 20, and 24 in 0-10 NRS Average and 
Worst PI scores over 1 week prior to each visit. 
• 
Cumulative response function in percent improvement in PI score at Weeks 12 
and 24 compared to baseline over 1 week prior to each visit. 
• 
Changes from baseline to Weeks 12 and 24 in physical function (RMDQ), 
impact of pain on function (BPI-SF), pain quality (PQAS), pain spread 
(Regional Pain Scale), neuropsychological function (DSST), sleep quality 
(MOS Sleep Scale), mood (PHQ-8), quality of life (EQ-5D-5L) and work 
productivity (WPAI). 
• 
Proportion of subjects with overall clinical benefit at Weeks 12 and 24 defined 
as a composite measure of key clinical endpoints: ≥30% improvement in 
Average PI score and ≥20% improvement in RMDQ and PGIC of moderately 
or better improvement. 
Optimal Responders 
• 
Change from the baseline to Weeks 4, 8, 16, 20, and 24 in 0-10 NRS Average 
and Worst PI scores over 1 week prior to each visit. 
• 
Cumulative response function in percent worsening in PI score at Weeks 12 
and 24 over 1 week prior to each visit compared to baseline. 
• 
Changes from baseline to Weeks 12 and 24 in physical function (RMDQ), 
impact of pain on function (BPI-SF), pain quality (PQAS), pain spread 
(Regional Pain Scale), sleep quality (MOS Sleep Scale), mood  (PHQ-8), 
quality of life (EQ5D), and work productivity (WPAI). 
Exploratory Endpoints  
• 
Change in sensitivity to thermal stimuli on QST  (subjects in substudy) 
• 
Identification of baseline factors predictive of benefit of opioid discontinuation 
among Suboptimal Responders. 
• 
Changes from baseline in endocrine function and sexual function; relationship 
of changes in endocrine function to changes in PI; relationship of baseline 
endocrine status to efficacy of opioid discontinuation. 
• 
Changes from baseline in neurocognitive function as characterized in the 
DSST 
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Clinical Study Report version: Final
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Opioid Post-Marketing Requirement (PMR) Consortium 
08-Feb-2017 
27 
Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
Safety and 
Tolerability 
Safety will be assessed by: 
• 
AEs  
• 
Abuse-related events (using the Misuse Abuse Diversion Drug Event 
Reporting System [MADDERS™]) 
• 
Opioid-specific side effects 
• 
Vital signs  
• 
Clinical laboratory parameters 
• 
Physical examinations  
Additional safety measures will include UDT, C-SSRS, and opioid withdrawal effects 
(measured by COWS, SOWS and withdrawal AEs).  
Statistical Methods 
Study Hypotheses  
Suboptimal Responders: In subjects with chronic pain on high-dose opioid therapy for 
at least 1 year who have a suboptimal response to opioid treatment, structured 
discontinuation results in an improvement in pain compared to continuation of opioid 
treatment.  
Optimal Responders: In subjects with chronic pain on high-dose opioid therapy for at 
least 1 year who have an optimal response to opioid treatment, structured 
discontinuation of opioid treatment results in worsening of pain compared to 
continuation of opioid treatment. 
Separate analyses will be conducted for Suboptimal Responders and Optimal 
Responders, at the 2-sided 0.05 alpha level for each of the 2 primary hypotheses, since 
these are considered 2 different study populations.  
Sample Size  
The primary endpoint is the change from baseline to Week 12 (mean Average PI score 
over the 1 week prior to the Week 12 visit) in 0-10 NRS Average PI score comparing 
the opioid discontinuation group to the opioid continuation group. To detect a between-
group difference of 0.8 points, assuming a standard deviation of 2.5, 5% significance 
level, and 90% power, 205 randomized subjects per arm (410 total randomized) for 
each Responder type will be needed (820 total). Assuming a 3:1 screen failure rate, 
approximately 3280 subjects will need to be screened. 
Statistical Analyses 
A general description of the statistical methods to be used to analyze the efficacy and 
safety data is outlined below. Specific details will be provided in the Statistical 
Analysis Plan (SAP). All statistical comparisons will be 2-sided at the 0.05 alpha level. 
There will be no adjustments for multiplicity. 
Definition of Baseline: 
For Suboptimal Responders, the mean of the Average PI scores over the 7-day 
Baseline Period will count as the subject’s baseline Average PI score for statistical 
analysis. Similarly, the mean of the Worst PI scores over the 7-day Baseline Period 
will count as the subject’s baseline Worst PI score for statistical analysis.  For all other 
assessments, the last non-missing observation prior to the first dose in the Blinded 
Structured Opioid Discontinuation Period will be used as the baseline observation. 
________________________________________________________
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Opioid Post-Marketing Requirement (PMR) Consortium 
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Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
For Optimal Responders, the mean Average PI score including the Average PI scores 
during the Titration Period that meet the qualification criteria (Average PI score <4 for 
3 consecutive non-missing values) plus any scores between the final qualification day 
and the Randomization Visit will count as the subject’s baseline Average PI score for 
statistical analysis. Similarly, the mean Worst PI score including the 3 qualification 
days (as defined above) during the Titration Period plus any days between the 
qualifications days and the Randomization Visit will count as the subject’s baseline 
Worst PI score for statistical analysis. For all other assessments, the last non-missing 
observation prior to the first dose in the Blinded Structured Opioid Discontinuation 
Period will be used as the baseline observation.  
Subject Populations: 
All populations will be defined for Suboptimal Responders and Optimal Responders 
separately.  
Safety Population: Different Safety Populations will be defined to summarize data pre- 
and post-randomization. 
• 
For Suboptimal Responders, the Safety Population Pre-Randomization will 
include all subjects who were enrolled in the study and were switched to the 
standardized regimen (ie, who enter the Run-in Period) and took at least 1 dose 
of study drug. 
• 
For Optimal Responders,  
− The Safety Population Pre-Randomization (Observation Period) will include 
all Optimal Responder subjects who entered the Observation Period. 
− The Safety Population Pre-Randomization (Taper Period) will include all 
Optimal Responder subjects who were enrolled in the study and took at least 
1 dose of study medication during the Taper Period. 
− The Safety Population Pre-Randomization (Titration Period) will include all 
subjects who were enrolled in the study and took at least 1 dose of study 
medication during the Titration Period (ie, who enter the Open-label 
Titration Period.   
For both Suboptimal Responders and Optimal Responders, the Safety Population Post-
Randomization will include all subjects who were randomized and received at least one 
dose of double-blind treatment. Safety will be analyzed separately for these 
populations. Subjects who are randomized to one treatment group but mistakenly 
assigned the medication kit of the other treatment group will be reported “as treated”.  
ITT Population: The ITT Population will include all subjects who were randomized 
and received at least one dose of study drug after randomization. All efficacy analyses 
will be performed using this population. Subjects will be reported in the treatment 
group to which they were randomly assigned. 
Per-protocol Population: The Per-Protocol Population is a subset of the ITT population, 
excluding subjects with protocol deviations that may have an impact on the results of 
the primary efficacy analyses. An additional analysis of the primary efficacy endpoint 
will be performed using this population.  
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Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
The number of subjects included in each study population will be summarized by 
treatment group. Demographic characteristics, including sex, age, age group, race, 
height, and weight, will be summarized by treatment group using descriptive statistics.  
The analysis of the primary endpoint will be in two stages. First, multiple imputation 
will be used for missing data based on the reason for missing data. Missing data 
occurring between observed data points will be imputed using Markov Chain Monte 
Carlo methods to create monotone missing data patterns. For missing data caused by 
discontinuation due to Adverse Events, data will be imputed using  
• 
For Suboptimal Responders, the subject’s baseline Average PI score (with 
added variability based on the variance of the data of the corresponding 
timepoint of missing data).  
• 
For Optimal Responders, the subject’s mean Average PI score at the end of the 
Taper Period (with added variability based on the variance of the data of the 
corresponding timepoint of missing data). This score will be the first 3 days of 
the mean Average PI score used to qualify the subject for entry into the 
Titration Period (i.e., where the mean Average PI score is  >5 over ≥3 
consecutive days, where this mean Average PI score has also increased by ≥1.5 
points from the mean Average PI score over the 7-day Observation Period). 
For missing data caused by discontinuation due to Lack of Efficacy, data will be 
imputed using the subject’s last non-missing weekly mean Average PI score. For 
missing data caused by any other reason, data will be imputed using multiple 
imputation with a regression model for prior weekly Average PI scores and treatment 
group, and utilizing the subject’s observed pain scores in the regression model. Ten 
imputation datasets will be used for this multiple imputation procedure.  
Second, the multiple datasets will be analyzed using mixed model repeated measures 
(MMRM), and the individual imputation dataset results will be combined using 
standard methods. The MMRM analysis will include the fixed effects of treatment 
group, Index ER opioid (morphine, oxycodone, or oxymorphone) group, baseline NRS 
Average PI score, Week, and interaction between treatment group and Week as factors. 
Data up to Week 12 will be included in this analysis. The Restricted Maximum 
Likelihood estimation approach will be used, and the default covariance structure will 
be unstructured. Estimates of the primary endpoint will be shown by treatment group, 
and for the difference between groups (structured discontinuation treatment group 
compared to continuation treatment group), together with 95% confidence interval and 
p-value for the difference.  
Safety Analyses: 
Safety variables will include AEs, abuse-related events, laboratory parameters, vital 
signs, and physical examinations. For the Suboptimal Responders, each safety 
parameter will be assessed separately for the Safety Population Pre-Randomization and 
Post-Randomization, as appropriate. Likewise for the Optimal Responders, each safety 
parameter will be assessed separately for the Safety Population Pre-Randomization 
(Observation Period), the Safety Population Pre-Randomization (Taper Period), and the 
Safety Population Pre-Randomization (Titration Period), as well as the Safety 
Population Post-Randomization. Other safety parameters analyzed will be possible 
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Confidential and Proprietary Information 
Name of Sponsor/Company 
The Opioid Post-Marketing Requirement Consortium 
(OPC) 
Name of Drug/Device 
Morphine sulfate extended-release,  
oxycodone extended-release, or oxymorphone 
extended-release 
Protocol Number 
2065-5 
opioid withdrawal effects (summarized descriptively with COWS and SOWS scores), 
C-SSRS, and UDT.  
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5. 
STUDY DESIGN AND SCHEDULE OF EVENTS 
Figure 1: 
Study Design 
 
wk=week, mo=month, SR=Suboptimal Responder; OR=Optimal Responder.  
ER/LA requirement can be satisfied by use of immediate-release opioid at least 4 times a day for at least 1 year 
* Baseline PI scores=mean Average PI score including the Average PI scores during the Titration Period that meet the qualification criteria (Average PI score <5 for 3 consecutive 
non-missing values) plus any scores between the final qualification day and the Randomization Visit. 
 
Note: In the tables below, blue shading denotes periods of the study that are identical for Optimal and Suboptimal Responders. 
  
Screening Visit 
Common 
screening 
criteria: CLBP; 
ER/LA ≥1 yr; 
index ER opioid 
≥3 mo 
Observation 
Period 
Continue initial 
opioids (1 wk) 
Run-in Period 
Switch to standard 
opioids (1 wk) 
Suboptimal 
Responders 
  PI ≥6 & 
dissatisfied 
Optimal 
Responders 
  PI ≤4 & 
  Satisfied 
Baseline 
Period 
(1 wk) 
Taper Period 
Expected pain flare  
(up to 2 wks) 
Titrate with 
standard 
opioids to 
PI≤4 (up to 
3 wks)
Blinded Structured 
Opioid 
Discontinuation 
Period  
-Continuation arm 
-Discontinuation arm 
(24 wks) 
Follow-up 
Period  
Blinded taper 
(4 wks) 
Random
ization 
of SRs 
Random
ization 
of ORs 
Base-
line* 
OL Titration Period 
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Table 2: 
Schedule of Procedures for Suboptimal Responders 
Period 
Screening  
Run-In  Period 
(1 week) 
Baseline 
Period 
(1 week) 
Random-
ization 
Visit 
Blinded Structured Opioid Discontinuation Period15 
(24 weeks) 
Follow-Up 
Period 
(4 weeks) 
Week 
 
-2 to -1 
-1 
-1 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name1 
Screening 
Visits2 
-- 
SR1 
Tolerabil-
ity Visit 
-- 
SR2 
BDP
1 
BDP
2 
BDP
3 
BDP
4 
BDP
5 
BDP
6 
BDP
7 
BDP
8 
BDP
9 
FUV1 
FUV2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam3 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Vital signs4 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Pregnancy test5 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Quebec Task Force 
Classification for Spinal 
Disorders 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily 24-hr Average and 
Worst PI score in past 24 
hours on NRS 6 
X 
 
--------------X-------------- 
X 
---------------------------------------X------------------------------------------- 
 
 
RMDQ 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
Daily administration of ER 
and IR opioids (phone) 
X7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Check entry or continuation 
criteria8 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drugs9 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect Study Drugs & Drug 
Accountability9 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI-SF 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Online Patient Support 
Program 
 
Acc
ess 
Gran
ted 
--------------------------------------------------------Encourage use of online patient support program------------------------------------------------------------ 
Regional Pain Scale 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
PQAS 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
EQ-5D-5L 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
C-SSRS10 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
PHQ-8 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
MOS Sleep Scale 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
DSST 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
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Table 2: 
Schedule of Procedures for Suboptimal Responders (Continued) 
Period 
Screening  
Run-In  Period 
(1 week) 
Baseline 
Period 
(1 week) 
Random-
ization 
Visit 
Blinded Structured Opioid Discontinuation Period15 
(24 weeks) 
Follow-Up 
Period 
(4 weeks) 
Week 
 
-2 to -1 
-1 
-1 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name1 
Screening
Visits2 
-- 
SR1 
Tolerabil-
ity Visit 
-- 
SR2 
BDP
1 
BDP
2 
BDP
3 
BDP
4 
BDP
5 
BDP
6 
BDP
7 
BDP
8 
BDP
9 
FUV1 
FUV2 
QST for OIH (for subjects 
enrolled at participating sub-
study sites) 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Endocrine laboratory tests 
and sexual function 
questionnaire11 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Abuse-related events 
 
 
----------------------------------------------------------------------------------------X---------------------------------------------------------------------------------- 
Opioid withdrawal (SOWS) 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
 
Opioid withdrawal (COWS) 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
UDT12 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Work productivity (WPAI) 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
AEs13 
 
X 
------------------------------------------------------------------------------------- X ------------------------------------------------------------------------------------ 
Telephone Calls14 
 
 
------------------------------------------------------------------------------------- X ------------------------------------------------------------------------------------ 
Prior/concomitant 
medications 
----------------------------------------------------------------------------------- X ------------------------------------------------------------------------------ 
X 
X 
1.  Visit windows are ±3 days until BDP6, and ±5 days thereafter. 
2.  Screening procedures will be performed over 2 visits no more than 21 days apart. 
3.  Full physical exam at Screening and brief physical exam afterwards. 
4.  At Screening: Height, weight, BMI, pulse rate, respiratory rate, and blood pressure. At subsequent visit: pulse rate, respiratory rate and blood pressure only. If BMI >40, complete STOPBang 
Questionnaire and record in source documents. Subject cannot continue if apnea risk is high. 
5.  Serum pregnancy test at Screening and urine pregnancy test at randomization and final visit.  
6.  Captured once daily by phone at bedtime except at screening when captured in the office. 
7.  Daily dose of opioid and rescue medications at screening will be taken from medical records or medical history.  
8.  At Tolerability Visit (SR1): Subjects who did not tolerate the standardized regimen will be discontinued. At Randomization Visit: Subjects will be included if they have an Average PI score ≥6 on 
0-10 NRS over the Baseline Period (with a minimum compliance of 4 out of 7 daily PI scores), not have an Average PI score each day of the 7-day Baseline Period equal to 10/10 and be 
dissatisfied with their pain and physical function. 
9. Three (3) drugs will be dispensed, collected, and counted: ER opioids, IR opioids, and acetaminophen. 
10. C-SSRS “Lifetime” will be done at Screening and the C-SSRS “Since Last Visit” will be done at 6 weeks and 24 weeks after randomization.  
11. Blood for endocrine function tests will be drawn at Screening and sent to lab but only tested on Randomized subjects. Sexual function questionnaires will be administered when endocrine function 
tests are drawn. 
12. Quantitative UDT for illicit drugs, non-prescribed controlled substances (opioid and non-opioid), and alcohol.  To prevent unblinding, after randomization, results for the index opioid and its 
metabolites will not be provided to the investigator. 
13. Only serious AEs will be collected in the eCRF during Screening. 
14. Phone call every week of the study where a visit is not conducted to check for wellbeing, study drug compliance and safety issues. Changes in medications and AEs obtained during phone calls 
will be captured in the IRT or eCRF as appropriate.  All other information will be captured in source documents. 
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15. The Early Discontinuation Assessment Tool will be administered to any subject who discontinues during the BDP.  
BDP=Blinded Discontinuation Period; FUV=Follow-up Visit 
 
 
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Table 3: 
Schedule of Procedures for Optimal Responders 
Period 
Screen-
ing  
Observation  
Period 
(1 week) 
 
Taper Period 
(up to 2 weeks) 
OL 
Titration 
Period 
(up to 3 
weeks)1 
Random
-ization 
Visit 
Blinded Structured Opioid Discontinuation Period16 
(24 weeks) 
Follow-Up 
Period 
(4 weeks) 
Week 
 
-6 to 
-5 
-5 
-5 to -3 
-3 
-3 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name2 
Screen-
ing Visits3 
-- 
OR1 
OR2 
(wk -4) 
OR3 
Telephone 
or office 
(OR3.1 – 
OR3.6) 
visits every 
4 days 
OR4 
BDP
1 
BDP
2 
BDP
3 
BDP
4 
BDP
5 
BDP
6 
BDP
7 
BDP
8 
BDP
9 
FUV1 
FUV2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Vital signs5 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Pregnancy test6 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Quebec Task Force 
Classification for 
Spinal Disorders 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily 24-hr Average 
and Worst PI score 
in past 24 hours on 
NRS 7 
X 
 
-----X----- 
-----X----- 
---X---- 
X 
--------------------------------------------X-------------------------------------- 
 
 
RMDQ 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Daily dose or 
administration of 
ER and IR opioids 
and rescue meds 
taken (phone) 
X8 
 
-----X8----- 
-----X8----- 
---X8--- 
X8 
--------------------------------------------X8-------------------------------------- 
X8 
X8 
Check entry or 
continuation criteria 
X 
X 
 
X9 
X9 
X9 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
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Table 3: 
Schedule of Procedures for Optimal Responders (Continued) 
Period 
Screen-
ing  
Observation  
Period 
(1 week) 
 
Taper Period 
(up to 2 
weeks) 
OL 
Titration 
Period 
(up to 3 
weeks)1 
Random
-ization 
Visit 
Blinded Structured Opioid Discontinuation Period16 
(24 weeks) 
Follow-Up 
Period 
(4 weeks) 
Week 
 
-6 to -
5 
-5 
-5 to -
3 
-3 
-3 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name2 
Screen-
ing 
Visits3 
-- 
OR1 
OR2 
(wk -
4) 
OR3 
Telephone 
or office 
(OR3.1 – 
OR3.6) 
visits every 
4 days 
OR4 
BDP
1 
BDP
2 
BDP
3 
BDP
4 
BDP
5 
BDP
6 
BDP
7 
BDP
8 
BDP
9 
FUV1 
FUV2 
Dispense Study 
Drugs10 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect Study Drug 
& Drug 
Accountability10 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI-SF 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Online Patient 
Support Program 
 
Ac
ces
s 
Gra
nte
d 
 
 
-----------------------------------------------Encourage use of online patient support program------------------------------------------------------------ 
Regional Pain Scale 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
PQAS 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
EQ-5D-5L 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
C-SSRS11 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
PHQ-8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
MOS Sleep Scale 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
DSST 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
QST for OIH (for 
subjects enrolled at 
participating sub-
study sites) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Endocrine 
laboratory tests and 
sexual function 
questionnarie12 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Abuse-related 
events 
 
 
------------------------------------------------------------------------------------------ X ----------------------------------------------------------------------------------------------- 
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Table 3: 
Schedule of Procedures for Optimal Responders (Continued) 
Period 
Screen-
ing  
Observation  
Period 
(1 week) 
 
Taper Period 
(up to 2 
weeks) 
OL 
Titration 
Period 
(up to 3 
weeks)1 
Random
-ization 
Visit 
Blinded Structured Opioid Discontinuation Period16 
(24 weeks) 
Follow-Up 
Period 
(4 weeks) 
Week 
 
-6 to -
5 
-5 
-5 to -
3 
-3 
-3 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name2 
Screen-
ing 
Visits3 
-- 
OR1 
OR2 
(wk -
4) 
OR3 
Telephone 
or office 
(OR3.1 – 
OR3.6) 
visits every 
4 days 
OR4 
BDP
1 
BDP
2 
BDP
3 
BDP
4 
BDP
5 
BDP
6 
BDP
7 
BDP
8 
BDP
9 
FUV1 
FUV2 
Opioid withdrawal 
(SOWS) 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
 
Opioid withdrawal 
(COWS) 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
UDT13 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
Work productivity 
(WPAI) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
AEs14 
 
X 
------------------------------------------------------------------------------------------ X ---------------------------------------------------------------------------------------------- 
Telephone Calls15 
 
 
------------------------------------------------------------------------------------------ X ---------------------------------------------------------------------------------------------- 
Prior/concomitant 
medications 
---------------------------------------------------------------------------------------- X --------------------------------------------------------------------------------------- 
X 
X 
1 If the dose of the index ER opioid needs to be titrated above the baseline dose, the Titration Period may be extended by 1 additional week (+3 days).   
2.  Visit windows are ±3 days until BDP6, and ±5 days thereafter. 
3.  Screening procedures will be performed over 2 visits no more than 21 days apart.  
4.  Full physical exam at Screening and brief physical exam afterwards. 
5.  At Screening: Height, weight, BMI, pulse rate, respiratory rate, and blood pressure. At subsequent visit: pulse rate, respiratory rate, and blood pressure only. If BMI >40, complete STOPBang 
Questionnaire and record in source documents. Subject cannot continue if apnea risk is high. 
6.  Serum pregnancy test at Screening and urine pregnancy test at randomization and final visit.  
7.  Captured once daily by phone at bedtime except at Screening when captured in the office. 
8.  Daily dose of opioid and rescue medications at screening will be taken from medical records or medical history. Continuation of daily dose of opioid and rescue medications during the 
Observation Period will be confirmed by phone.  Subsequently, confirmation of daily administration of ER and IR opioid study medications will be obtained by phone. 
9.  At end of Observation Period: Subjects must have had an index ER opioid medication use of ≥120 mg and ≤540 mg morphine equivalents/day (see table in protocol) on average and have had 80% 
to 120% compliance over the 1-week Observation Period; (ii) have a mean Average PI score over the 1 week of the period <5 (with a minimum compliance of 4 out of 7 daily PI scores); and (iii) 
still be satisfied with their pain and physical function. During or at the end of the Taper Period: Subjects must have a mean Average PI score  >5 over ≥3 consecutive scores (non-missing values), 
where this mean Average PI score has also increased by ≥1.5 points from the mean Average PI score over the 7-day Observation Period. Note that if these criteria are satisfied at Visit OR2, 
subject may skip OR2 and advance directly to Visit OR3. At the end of Titration Period: Subjects must have completed their titration and have achieved a mean Average PI score over at least 3 
consecutive scores (non-missing values) <5 with acceptable side effects and a minimum dose of ≥120 mg and ≤540 mg morphine equivalents/day to continue on study. 
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10. The non-blinded ER opioid taper dose will be dispensed at OR1 and OR2; Open-label ER opioids, IR opioids, and acetaminophen will be dispensed starting at OR3 (for titration in the Titration 
Period); Double-blind ER opioid and open-label IR opioid and acetaminophen will be dispensed at OR4. Collection and counting of study medication will be done at all visits except OR1. 
11. C-SSRS “Lifetime” will be done at Screening and the C-SSRS “Since Last Visit” will be done at 6 weeks and 24 weeks after randomization.  
12. Blood for endocrine function tests will be drawn at Screening and sent to the lab but tested only on randomized subjects. Sexual function questionnaires will be administered when endocrine 
function tests are drawn. 
13. Quantitative UDT for illicit drugs, non-prescribed controlled substances, and alcohol.  To prevent unblinding, after randomization, results will not be provided to the investigator for the index 
opioid and its metabolites. 
14. Only serious AEs will be collected in the eCRF during Screening. 
15. Phone call every week of the study where a visit is not conducted to check for wellbeing, study medication compliance, and safety issues. Changes in medication and AEs obtained during phone 
calls will be captured in the IRT or eCRF as appropriate.  All other information will be captured in source documents. 
16. The Early Discontinuation Assessment Tool will be administered to any subject who discontinues during the BDP. 
 
BDP=Blinded Discontinuation Period; FUV=Follow-up Visit 
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6. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................ 1 
2. 
SUMMARY OF CHANGES ....................................................................................... 2 
3. 
SPONSOR CONTACT INFORMATION ................................................................. 14 
4. 
SYNOPSIS ................................................................................................................. 15 
5. 
STUDY DESIGN AND SCHEDULE OF EVENTS ................................................. 31 
6. 
TABLE OF CONTENTS ........................................................................................... 39 
7. 
LIST OF ABBREVIATIONS .................................................................................... 44 
8. 
BACKGROUND AND RATIONALE ...................................................................... 47 
9. 
OBJECTIVES AND HYPOTHESIS ......................................................................... 49 
9.1. 
Primary Objective ....................................................................................................... 49 
9.2. 
Secondary Objectives ................................................................................................. 49 
9.3. 
Exploratory Objectives ............................................................................................... 49 
9.4. 
Hypothesis .................................................................................................................. 49 
10. 
INVESTIGATIONAL PLAN .................................................................................... 50 
10.1. 
Study Design .............................................................................................................. 50 
10.1.1. 
Screening .................................................................................................................... 50 
10.1.2. 
For Suboptimal Responders Only .............................................................................. 51 
10.1.3. 
For Optimal Responders Only .................................................................................... 52 
10.1.4. 
Continuing for both Suboptimal and Optimal Responders ........................................ 53 
10.2. 
Selection of Doses ...................................................................................................... 55 
10.3. 
Study Drug Administration ........................................................................................ 56 
10.3.1. 
Study Medications ...................................................................................................... 56 
10.3.2. 
Study Prescribed Drugs .............................................................................................. 56 
10.3.3. 
Study Drug Administration and Dose ........................................................................ 56 
10.4. 
Discussion of Study Design, Including the Choice of Control Groups ...................... 57 
11. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 59 
11.1. 
Subject Inclusion Criteria ........................................................................................... 59 
11.2. 
Subject Exclusion Criteria .......................................................................................... 60 
11.3. 
Replacement Procedures ............................................................................................ 61 
12. 
TREATMENT OF SUBJECTS .................................................................................. 62 
12.1. 
Study Visits ................................................................................................................ 62 
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12.1.1. 
Screening Visit (Same for Suboptimal and Optimal Responders) ............................. 62 
12.1.2. 
Suboptimal Responders Visits Only ........................................................................... 65 
12.1.3 
Optimal Responders Visits Only ................................................................................ 67 
12.1.4 
Continuing for both Suboptimal and Optimal Responders: Blinded Structured 
Opioid Discontinuation Period (24 weeks; from Week 1 to 24) ................................ 71 
12.1.5 
Follow-up Period (4 Weeks; from Week 25 to 28) .................................................... 72 
12.1.6 
Study Discontinuation Procedures ............................................................................. 73 
12.2 
Prior and Concomitant Medications and Procedures ................................................. 74 
12.3 
Study Drug Compliance ............................................................................................. 75 
12.4 
Blinding and Randomization ...................................................................................... 76 
13 
ASSESSMENT OF EFFICACY ................................................................................ 77 
13.1 
Efficacy Measurements .............................................................................................. 77 
13.2 
Endpoints .................................................................................................................... 77 
13.3 
Exploratory Measurements ......................................................................................... 78 
14 
ASSESSMENT OF SAFETY .................................................................................... 79 
14.1 
Definitions .................................................................................................................. 79 
14.1.1 
Adverse Events ........................................................................................................... 79 
14.1.2 
Serious Adverse Events .............................................................................................. 80 
14.2 
Monitoring Adverse Events ........................................................................................ 80 
14.3 
Relationship to Study Drug ........................................................................................ 80 
14.4 
Intensity Assessment .................................................................................................. 81 
14.5 
Reporting Adverse Events and Serious Adverse Events ............................................ 81 
14.5.1 
Reporting Adverse Events .......................................................................................... 81 
14.5.2 
Reporting Serious Adverse Events ............................................................................. 81 
14.5.3 
Follow-Up Procedures for Serious Adverse Events ................................................... 82 
14.6 
Events of Special Interest (EOSI) ............................................................................... 82 
14.6.1 
Overdose/Abuse/Misuse/Diversion/Withdrawal ........................................................ 82 
14.6.1.1 
Terminology ............................................................................................................... 82 
14.6.1.2 
Handling Reports of Overdose/Abuse/Misuse/Diversion/Withdrawal ...................... 83 
14.6.1.3 
Reporting and Classification of Events Using MADDERS® ..................................... 84 
14.6.2 
Pregnancy ................................................................................................................... 84 
14.6.3 
AEs/SAEs Experienced by Non-subjects Exposed to Study Medication .................. 84 
14.7 
Clinical Laboratory Determinations ........................................................................... 85 
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14.8 
Vital Signs .................................................................................................................. 86 
14.9 
Physical Examination ................................................................................................. 86 
14.10 
Other Safety Analyses ................................................................................................ 86 
15 
ASSESSMENT OF PHARMACOKINETICS ........................................................... 88 
16 
ASSESSMENT OF PHARMACODYNAMICS ....................................................... 89 
17 
STATISTICAL CONSIDERATIONS AND METHODS ......................................... 90 
17.1 
Determination of Sample Size .................................................................................... 90 
17.2 
Subject Populations .................................................................................................... 90 
17.2.1 
Safety Population ........................................................................................................ 90 
17.2.2 
ITT Population ............................................................................................................ 91 
17.2.3 
Per-protocol Population .............................................................................................. 91 
17.3 
Subject Disposition ..................................................................................................... 91 
17.4 
Demographics and Other Baseline Characteristics .................................................... 91 
17.5 
Efficacy Analyses ....................................................................................................... 91 
17.5.1 
Primary Efficacy Analysis .......................................................................................... 92 
17.5.2 
Secondary Efficacy Analysis ...................................................................................... 93 
17.5.3 
Exploratory Analyses ................................................................................................. 94 
17.6 
Safety Analyses .......................................................................................................... 95 
17.6.1 
Adverse Events ........................................................................................................... 95 
17.6.2 
Vital Signs .................................................................................................................. 96 
17.6.3 
Clinical Laboratory Parameters .................................................................................. 96 
17.6.4 
Physical Examination ................................................................................................. 96 
17.6.5 
Other Safety Parameters ............................................................................................. 96 
17.7 
Pharmacokinetic Analyses .......................................................................................... 97 
17.8 
Pharmacodynamic Analyses ....................................................................................... 97 
17.9 
Other Data (e.g., Health Economics/QOL, Pharmacogenetics, etc) .......................... 97 
17.10 
Interim Analysis ......................................................................................................... 97 
17.11 
Statistical Software ..................................................................................................... 97 
18 
STUDY DRUG MATERIALS AND MANAGEMENT ........................................... 98 
18.1 
Study Drug Identity .................................................................................................... 98 
18.2 
Study Drug Packaging and Labeling .......................................................................... 98 
18.3 
Study Drug Storage .................................................................................................... 98 
18.4 
Study Drug Preparation .............................................................................................. 99 
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18.5 
Study Drug Accountability ......................................................................................... 99 
18.6 
Study Drug Handling and Disposal ............................................................................ 99 
19 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................................... 100 
19.1 
Source Documents .................................................................................................... 100 
19.2 
Study Monitoring ...................................................................................................... 100 
19.3 
Audits and Inspections ............................................................................................. 100 
19.4 
Institutional Review Board (IRB) ............................................................................ 100 
19.5 
Data Recording and Documentation ........................................................................ 100 
20 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 101 
21 
ETHICS .................................................................................................................... 102 
21.1 
Ethics Review ........................................................................................................... 102 
21.2 
Ethical Conduct of the Study .................................................................................... 102 
21.3 
Subject Information and Consent ............................................................................. 102 
22 
DATA HANDLING AND RECORDKEEPING ..................................................... 104 
22.1 
Data Collection ......................................................................................................... 104 
22.2 
Study Documentation ............................................................................................... 104 
23 
REPORTING AND PUBLICATION ...................................................................... 105 
24 
INVESTIGATOR OBLIGATIONS ......................................................................... 106 
24.1 
Regulatory Documents ............................................................................................. 106 
24.2 
Delegation of Responsibilities and Adequate Resources ......................................... 106 
24.3 
Medical Care of Study Subjects ............................................................................... 107 
24.4 
Use of Investigational Materials ............................................................................... 107 
24.5 
Retention of Records ................................................................................................ 107 
24.6 
Subject Confidentiality ............................................................................................. 108 
25 
TERMINATION OF STUDY .................................................................................. 109 
26 
INVESTIGATOR’S STATEMENT ........................................................................ 110 
27 
REFERENCES ......................................................................................................... 111 
  
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LIST OF TABLES 
Table 1: 
Sponsor Contact Information ..................................................................................... 14 
Table 2: 
Schedule of Procedures for Suboptimal Responders .................................................. 32 
Table 3: 
Schedule of Procedures for Optimal Responders ....................................................... 35 
Table 4: 
Clinical Laboratory Tests ........................................................................................... 85 
 
LIST OF FIGURES 
Figure 1: 
Study Design .............................................................................................................. 31 
 
 
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7. 
LIST OF ABBREVIATIONS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation 
Explanation 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ANCOVA 
Analysis of covariance 
BMI 
Body mass index 
BPI-SF 
Brief Pain Inventory- Short Form 
CFR 
Code of Federal Regulations 
CLBP 
Chronic low back pain 
CMH 
Cochran-Mantel-Haenszel (test) 
COWS 
Clinical Opioid Withdrawal Scale 
CR 
Controlled release 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DHEAS 
Dehydroepiandrosterone sulfate 
DHHS 
Department of Health and Human Services 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSST 
Digit Symbol Substitution Test 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EQ-5D-5L 
EuroQOL 5 dimensions (5 levels of response) instrument 
ER 
Extended release 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICH  
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like growth factor-1 
IR 
Immediate release 
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Abbreviation 
Explanation 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-Treat 
LA 
Long acting 
LAR 
Legally authorized representative 
LH 
Luteinizing hormone 
LOCF 
Last Observation Carried Forward 
MADDERS 
Misuse Abuse Diversion Drug Event Reporting System 
MAO 
Monoamine oxidase 
mmHg 
Millimeter of mercury 
MMRM 
Mixed model repeated measures 
MSER 
Morphine sulfate ER 
MSIR 
Morphine sulfate IR 
NDA 
New Drug Application 
NRS 
Numerical rating scale 
OCER 
Oxycodone ER 
OCIR 
Oxycodone IR 
OIH 
Opioid induced hyperalgesia 
OMER 
Oxymorphone ER 
OMIR 
Oxymorphone IR 
OPC 
Opioid Post-Marketing Requirement Consortium 
OR 
Optimal Responders 
PCS 
Potentially clinically significant 
PGIC 
Patient Global Impression of Change 
PHQ-8 
Patient Health Questionnaire-8 
PI 
Pain Intensity 
PMR 
Post-Marketing Requirement 
PQAS 
Pain Quality Assessment Scale 
PRN 
Pro re nata (as needed) 
QST 
Quantitative sensory testing 
RMDQ 
Roland-Morris Disability Questionnaire 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
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Abbreviation 
Explanation 
SOWS 
Subjective Opiate Withdrawal Scale 
SR 
Suboptimal Responders 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
UDT 
Urine drug testing 
URL 
Uniform resource locator 
WPAI 
Work Productivity and Activity Impairment (questionnaire) 
 
 
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8. 
BACKGROUND AND RATIONALE 
On September 10, 2013, U.S. Food and Drug Administration (FDA) announced class-wide safety 
labeling changes and new postmarketing study requirements for all extended-release and long-acting 
(ER/LA) opioid analgesics intended to treat pain (Department of Health and Human Services 
[DHHS]/FDA website).(1) As part of this announcement, the FDA is requiring approved New Drug 
Application (NDA) application holders for ER/LA opioid analgesics to conduct new postmarketing 
studies to “further assess the known serious risks of misuse, abuse, increased sensitivity to pain 
(hyperalgesia), addiction, overdose, and death”. One of these requirements (2065-5) calls for approved 
ER/LA opioid analgesic NDA application holders to "Conduct a clinical trial to estimate the serious 
risk for the development of hyperalgesia following use of ER/LA opioid analgesics for at least one 
year to treat chronic pain” (FDA announcement). The requirement “strongly encourages you to use the 
same trial to assess the development of tolerance following use of ER/LA opioid analgesics” and 
requests that such studies “include an assessment of risk relative to efficacy”. 
The clinical syndrome of poor response to high-dose long-term opioid therapy is not well characterized 
in the medical literature, but recognized by the clinical pain management community. Characteristics 
of these patients include, in addition to the use of high doses of opioids for extended periods of time, 
persistent severe pain intensity (PI) ratings, poor physical, psychological, and social function, frequent 
employment difficulties, and aberrant drug-taking behaviors that may or may not be sufficient to meet 
criteria for an addiction disorder. Patients often insist that despite their poor clinical status and the lack 
of an evident response to opioids that continued opioid treatment is essential. A traditional treatment 
for such patients is discontinuation of opioid therapy, in which patients have their opioid therapy 
gradually tapered off, in the context of psychological and physical rehabilitative support, often in a 
structured inpatient or outpatient program. Long-term clinical success has been noted in uncontrolled 
and unblinded observational studies, but the efficacy of removal from opioid therapy for a well-defined 
cohort of “Suboptimal Opioid Responders” (designated as Suboptimal Responders in this protocol) has 
never been evaluated in a randomized, double-blind, controlled clinical trial. 
One proposed, but as yet unproven, explanation for the phenomenon of suboptimal response to high-
dose opioid therapy is opioid-induced hyperalgesia (OIH). According to this hypothesis, some patients 
on long-term opioid therapy for chronic pain develop paradoxical hypersensitivity to pain caused by 
the very opioid treatment intended to reduce their pain, resulting in increasing doses, increasing pain 
intensity, increased sensitivity to painful stimuli (hyperalgesia), and according to many descriptions, 
spread of pain beyond the initially painful area. Under this hypothesis, removal of opioid therapy 
would result in improvement of experimental pain sensitivity, improvement in pain intensity, and 
potentially decreased spread of pain compared to patients in whom opioid therapy was continued. In 
addition, it would be expected that Suboptimal Responders to opioid therapy have greater experimental 
pain sensitivity and perhaps greater pain spread than Optimal Responders (patients who require high 
doses of opioid therapy but have good pain control) to opioid therapy (who presumably do not have 
OIH). Finally, it would be expected that in contrast to Suboptimal Responders, Optimal Responders to 
opioid therapy will worsen when their effective analgesics have been withdrawn, as with any other 
effective analgesic. 
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From a clinical perspective, clinicians need to understand not only whether OIH underlies suboptimal 
responses to opioids in general, but how to identify, among patients who are responding poorly to 
opioids, which patients will improve after withdrawal of opioids. Therefore it is important to attempt to 
identify predictors of benefit from withdrawal of opioids among Suboptimal Responders. 
The overarching purpose of this research program is to better characterize the contribution of OIH to 
suboptimal responses to opioid therapy. This goal will be approached in several different ways. Among 
a cohort of Suboptimal Responders to opioid therapy, the objective will be to evaluate the effect of 
structured discontinuation versus continuation of long-term high dose opioid treatment on pain 
intensity, pain spread, and sensitivity to experimental pain. Predictors of a beneficial response to 
opioid discontinuation will be examined. The impact of structured opioid discontinuation (vs. 
continuation) among the Suboptimal Responders will be indirectly compared to the impact of 
structured opioid discontinuation (vs. continuation) among a cohort of Optimal Responders to opioid 
therapy in order to fully inform the objectives of the Post-Marketing Requirement. Worsening of pain 
upon discontinuation of opioid therapy in the Optimal Responder group will confirm and extend 
previous observations of the efficacy of long-term opioid therapy. Baseline characteristics of 
Suboptimal and Optimal Responders will be compared, particularly with regard to experimental pain 
sensitivity. 
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9. 
OBJECTIVES AND HYPOTHESIS 
9.1. 
Primary Objective 
The primary objective is to evaluate the effect on PI of structured discontinuation of long-term opioid 
analgesic therapy compared to continuation of opioid therapy in Suboptimal and Optimal Responders 
to high-dose, long-term opioid analgesic therapy for treatment of chronic low back pain (CLBP).  
9.2. 
Secondary Objectives 
The secondary objective is to evaluate the effect on additional clinical outcomes measures of structured 
discontinuation of long-term opioid analgesic therapy compared to continuation of opioid therapy for 
CLBP in Suboptimal and Optimal Responders to high-dose, long-term opioid analgesic therapy at 
multiple time points. 
9.3. 
Exploratory Objectives 
The exploratory objectives are: 
• To compare experimental pain sensitivity in the opioid discontinuation vs. continuation 
groups  in both Suboptimal Responders and Optimal Responders (subjects in substudy) 
• To determine subject characteristics that predict response to structured discontinuation of 
opioid therapy. 
• To determine the effect of opioid discontinuation on certain endocrine function tests, sexual 
function, and the relationship of changes in PI and endocrine function to changes in male 
and female sexual function 
• To determine the effect of opioid discontinuation on neurocognitive function. 
9.4. 
Hypothesis 
The study hypothesis in Suboptimal and Optimal Responders is as follows: 
Suboptimal Responders: In subjects with CLBP on high-dose opioid therapy for at least 1 year who 
have a suboptimal response to opioid treatment, structured discontinuation results in an improvement 
in pain compared to continuation of opioid treatment.  
Optimal Responders: In subjects with CLBP on high-dose opioid therapy for at least 1 year who have 
an optimal response to opioid treatment, structured discontinuation of opioid treatment results in 
worsening of pain compared to continuation of opioid treatment. 
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10. 
INVESTIGATIONAL PLAN 
10.1. 
Study Design 
This multicenter, randomized, double-blind, placebo-controlled study will consist of a common 
Screening Visit for all subjects, then different schedules for Optimal and Suboptimal Responders, 
followed by a common schedule for the Blinded Structured Opioid Discontinuation Period and Follow-
up Period, as illustrated in Figure 1. The schedule of procedures for Suboptimal and Optimal 
Responders is shown in Table 2 and Table 3, respectively. 
As a convention, whenever there is a requirement for the mean Average PI score to meet a certain 
criterion, the mean of the Average PI scores will be calculated to 1 decimal place prior to applying the 
qualification criterion. 
10.1.1. 
Screening 
(Note: Screening procedures will be performed over 2 visits no more than 21 days apart.) 
At the Screening Visit, a broad range of patients on long-term opioid analgesic therapy for CLBP will 
be evaluated for entry into the study based on medical history, physical examination, clinical 
laboratory testing, vital signs, electrocardiogram (ECG), PI, urine drug testing (UDT), and pregnancy 
test. Subjects will be admitted into the study if they have non-radicular CLBP which can include 
Quebec Task Force Classification of Spinal Disorders Classes 1, proximal radicular (above the knee) 
pain of 2, 9.2, and 10, for more than 12-months duration; have been taking extended-release or long-
acting opioids (or doses of immediate-release opioids at least 4 times a day) for at least 12 months for 
their CLBP; have been taking high doses as defined in the table below of one of the following “index 
ER opioids”: morphine sulfate extended-release (MSER), oxycodone extended-release (OCER), or 
oxymorphone extended-release (OMER) for at least 3 consecutive months prior to the Screening Visit. 
(Subjects may also be taking additional ER opioids and/or immediate-release (IR) opioids, but the dose 
of any opioids beyond the index ER opioid will not be taken into account in the minimum or maximum 
required ER opioid dose for enrollment). For subjects taking multiple high-dose opioids, the 
Investigator will review all opioid use prior to enrollment and determine if the subject is still an 
appropriate candidate for the study based on the total amount of opioid the subject is receiving.  
 
Daily Dose Range 
Morphine sulfate ER 
120-540 mg 
Oxycodone ER 
80-360 mg 
Oxymorphone ER 
40-180 mg 
The goal will be to have a minimum representation of each index ER opioid (a minimum of ~20% of 
randomized subjects for each index ER opioid). Subjects taking asymmetric dosing of index ER 
opioids (i.e., a different dose in the morning and evening) will be allowed in the study as long as they 
meet the dose criterion for their index ER opioid indicated in the table above, and can be converted to 
symmetric twice-daily dosing. 
Subjects taking acetaminophen (or any acetaminophen-containing product after review of concomitant 
medications) prior to entering the study will be directed to stop taking it from their personal supply and 
only take the study-provided acetaminophen after entering the study. 
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Subjects will be classified as Suboptimal Responders or Optimal Responders at the Screening Visit as 
per the following criteria: Suboptimal Responder = Subject whose daily Average PI score is ≥6 and 
who is dissatisfied with his/her pain and physical function; Optimal Responder = Subject whose daily 
Average PI score is ≤4 and who is satisfied with his/her pain and physical function. The study design 
then differs for the Suboptimal and Optimal Responder populations; for Suboptimal Responders only, 
see Section 10.1.2; for Optimal Responders only, go to section 10.1.3. 
10.1.2. 
For Suboptimal Responders Only 
The schedule of procedures for Suboptimal Responders is shown in Table 2. Visits specific for 
Suboptimal Responders are named SR1, SR2, etc.  As a convention, whenever there is a requirement 
for the mean Average PI score to meet a certain criterion, the mean of the Average PI scores will be 
calculated to 1 decimal place prior to applying the qualification criterion. 
Run-In Period (1 week). Subjects classified as Suboptimal Responders at the Screening Visit will 
enter the 1-week Run-in Period during which they will be required to discontinue all previously 
prescribed opioid medications for the remainder of the study and will receive a standardized regimen 
of study medication consisting of index ER opioid plus the matching IR opioid depending on the index 
ER opioid they were taking at screening (i.e., OCER [OxyContin] plus OCIR PRN, MSER [MS 
Contin] plus MSIR PRN, or OMER [Opana ER] plus OMIR PRN). In the standardized regimen, the 
dose of the ER opioid will be similar to the dose of the index ER opioid taken at screening and will 
remain fixed throughout the period. (Note: Subjects who were taking asymmetric doses of the index 
ER opioid at screening will be placed on a symmetric dosage [same dose in the morning and evening] 
of the standardized regimen at this time).  
The dose of the IR opioid will be limited to no more than twice daily PRN administration of OCIR 10 
mg, MSIR 15 mg, or OMIR 5 mg, matching the index ER opioid each subject is receiving. The 
maximum dose of PRN IR opioid they are allowed per day will remain fixed. Subjects will also be 
provided acetaminophen as rescue medication (500 mg tablets, 1-2 tablets PRN every 4-6 hours not to 
exceed 6 tablets/day) and will be encouraged to take study-provided acetaminophen to manage their 
pain before they use the IR opioid (i.e., only take the IR opioid if the maximum dose of acetaminophen 
is not effective).  Personal supplies of acetaminophen should no longer be used for the duration of the 
study.  Subjects will be allowed to continue the non-opioid, non-acetaminophen-containing analgesics 
they had been taking before screening, but will not be able to change the dose except for study-
provided acetaminophen as described above.   
During the Run-In Period, subjects will record daily before bedtime by phone their PI scores and their 
use of ER and IR opioid study medication.  Adverse events (AEs) will be assessed during this period. 
At the end of the 1-week Run-In Period, subjects will return to the clinic for the Tolerability Visit 
(Visit SR1) to determine whether they tolerated the standardized opioid regimen. Subjects who did not 
tolerate the standardized regimen will be discontinued; no dose adjustment of the ER medication will 
be permitted. 
Baseline Period (1 week). Subjects will then enter a 1-week Baseline Period during which they will 
self-administer the standardized opioid regimen and record their PI scores (Average and Worst over 
past 24 hours) on a 0-10 numerical rating scale (NRS) daily before bed time by phone. Each subject’s 
7-day daily PI scores will be averaged and used as the subject’s baseline PI scores (with a minimum 
compliance of 4 out of 7 daily PI scores).  
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At the Randomization Visit for Suboptimal Responders (Visit SR2), subjects will continue on study if 
they have (i) a mean Average PI score (mean of average) ≥6 on 0-10 NRS over the 1 week of the 
Baseline Period (with a minimum compliance of 4 out of 7 daily PI scores); (ii) compliance with their 
index ER opioid medication between 80-120%; (iii) and are still dissatisfied with their pain and 
physical function. Subject who had a baseline mean Average PI score of 10/10 (i.e., 10/10 score every 
day for the 1 week of the Baseline Period) will be discontinued. 
The rest of the study will then be similar for both Suboptimal Responders and Optimal Responders (as 
described in section 10.1.4).  
10.1.3. 
For Optimal Responders Only 
The schedule of procedures for Optimal Responders is shown in Table 3. Visits specific for Optimal 
Responders are named OR1, OR2, etc.   
Observation Period (1 week). Subjects meeting the common screening criteria at the end of the 
Screening Visit and classified as Optimal Responders at the Screening Visit will be sent home and told 
to continue their current medication (including non-index ER and IR opioid medications) for 1 week. 
(Note: Subjects who were taking asymmetric doses of the index ER opioid at screening will continue 
taking asymmetric doses of their ER opioids during this period.) During this period, opioid medication 
intake and PI scores (Average and Worst over past 24 hours on 0-10 NRS) will be captured daily 
before bedtime by phone. At the end of the period, subjects will return to the clinic (Visit OR1) and all 
opioid medication use and PI scores will be reviewed. Subjects will be confirmed as Optimal 
Responders and will be allowed to continue in the study if (i) their index ER opioid medication use 
was on average in the range shown in the table below and they had 80% to 120% compliance over the 
1-week period; (ii) their mean Average PI score over the 1 week of the Observation Period was ≤5 
(with a minimum compliance of 4 out of 7 daily PI scores); and (iii) they are still satisfied with their 
pain and physical function. 
 
Daily Dose Range 
Morphine sulfate ER 
120-540 mg 
Oxycodone ER 
80-360 mg 
Oxymorphone ER 
40-180 mg 
 
Taper Period (up to 2 weeks). Subjects will be tapered with the same index ER opioid they were 
taking at screening (using study medication provided for the index ER opioid; ie, either OxyContin, 
MS Contin, or Opana ER). (Note: Subjects who were taking asymmetric doses of index ER opioid at 
screening will be tapered with a symmetric dosage [same dose in the morning and evening] of the 
standardized regimen.) Tapering will start at Visit OR1. For up to 2 weeks (+ 3 days), subjects will 
self-administer a tapering dose of the standard index ER opioid matching the one they were taking and 
will record PI scores daily before bedtime by phone. No other ER opioid will be allowed; IR opioids 
will not be allowed either during this period, i.e. all previously prescribed opioid medications will be 
discontinued. At Visit OR2 (week -4), the subjects’ overall status (opioid medication dose, PI score, 
vital signs, etc.) will be reviewed. If the minimum pain requirement has been met (see below) either 
before or at Visit OR2, the subject will immediately advance to Visit OR3 (skipping Visit OR2) and 
begin the Open-Label Titration Period. If the minimum pain requirement has not been met, the opioid 
taper will continue. By Visit OR3, subjects should be completely off of their opioid medication if they 
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have not already met the minimum pain requirement. Subjects with a mean Average PI score >5 over 
≥3 consecutive PI scores (excluding missing values), where this mean Average PI score has also 
increased by ≥1.5 points from the mean Average PI over the 7-day Observation Period, either off of the 
index ER opioid pain medication entirely or at a reduced dose, will be eligible to proceed to the Open-
Label Titration Period. Subjects who do not meet these criteria will be discontinued from the study 
(see Study Discontinuation Procedures, section 12.1.6). 
Open-Label Titration Period (up to 3 weeks). Subjects will be titrated with the same index ER opioid 
they were taking during the Taper Period  (supplied as index ER opioid plus matching IR opioid; i.e., 
either OCER [OxyContin] plus OCIR PRN, MSER [MS Contin] plus MSIR PRN, or OMER 
[Opana ER] plus OMIR PRN). The dose of the index ER opioid will be increased as frequently as 
every 4 days (during telephone or office [OR3.1 – OR3.6] visits) until the mean Average PI score over 
at least 3 consecutive pain scores is <5 in order to qualify for randomization. If the dose of the index 
ER opioid needs to be titrated above the baseline dose, the Titration Period may be extended 1 
additional week (+3 days). The dose of the IR opioid will be limited to no more than twice daily PRN 
administration of OCIR 10 mg, MSIR 15 mg, or OMIR 5 mg, matching the index ER opioid each 
subject is receiving. The maximum dose of PRN IR opioid they are allowed per day will remain fixed. 
Subjects will also be provided acetaminophen as rescue medication (500 mg tablets, 1-2 tablets PRN 
every 4-6 hours not to exceed 6 tablets/day) and will be encouraged to take study-provided 
acetaminophen to manage their pain before they use the IR opioid (i.e., only take the IR opioid if the 
maximum dose of acetaminophen is not effective).  Personal supplies of acetaminophen should no 
longer be used for the duration of the study. 
Randomization Visit for Optimal Responders (Visit OR4). Subjects who have completed their 
titration, have achieved a mean Average PI score over 3 consecutive pain scores of ≤5 with satisfaction 
with their pain and physical function and acceptable side effects, and are taking a dose of index ER 
opioid shown in the table below will be allowed to continue on study.  
 
Daily Dose Range 
Morphine sulfate ER 
120-540 mg 
Oxycodone ER 
80-360 mg 
Oxymorphone ER 
40-180 mg 
 
The rest of the study will then be similar for both Suboptimal Responders and Optimal Responders 
(continued below).  
10.1.4. 
Continuing for both Suboptimal and Optimal Responders 
Blinded Structured Opioid Discontinuation Period (24 weeks). At the Randomization Visit (Visit 
SR2 or OR4, Day 1), subjects meeting the criteria (described above for each population) to enter the 
Blinded Structured Opioid Discontinuation Period will then be randomized to either continue or 
discontinue ER opioid therapy, as follows. 
For subjects whose index ER opioid is MSER, the groups will be: 
• Morphine Group 1: MSER tablets  + matching placebo tablets to maintain MSER dose, but 
appear as if tapering is occurring; 
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• Morphine Group 2: Placebo tablets to match MSER tablets + MSER tablets in decreasing 
dose to result in a tapering off of MSER. 
• Both groups will be provided with rescue MSIR and acetaminophen. 
For subjects whose index ER opioid is OCER, the groups will be: 
• Oxycodone Group 1: OCER tablets + matching placebo tablets to maintain OCER dose, but 
appear as if tapering is occurring; 
• Oxycodone Group 2: Placebo tablets to match OCER tablets + OCER tablets in decreasing 
dose to result in a tapering off of OCER. 
• Both groups will be provided with rescue OCIR and acetaminophen. 
For subjects whose index ER opioid is OMER, the groups will be: 
• Oxymorphone Group 1: OMER tablets + matching placebo tablets to maintain OMER dose, 
but appear as if tapering is occurring; 
• Oxymorphone Group 2: Placebo tablets to match OMER tablets + OMER tablets in 
decreasing dose to result in a tapering off of OMER. 
• Both groups will be provided with rescue OMIR and acetaminophen. 
Therefore, there will be a total of 4 groups in the Blinded Structured Opioid Discontinuation Period:  
• Suboptimal Responders, continuation arm 
• Suboptimal Responders, discontinuation arm 
• Optimal Responders, continuation arm 
• Optimal Responders, discontinuation arm 
Randomization will be stratified by responder status (Optimal Responder; Suboptimal Responder) and 
baseline ER opioid (morphine, oxycodone, or oxymorphone); subject recruitment into the study will be 
adjusted to ensure at least 20% of subjects are on oxycodone, at least 20% on morphine, and at least 
20% on oxymorphone in the Blinded Structured Opioid Discontinuation Period within each cohort 
(Optimal Responders and Suboptimal Responders). The goal is to taper subjects (in the discontinuation 
arms of both the Suboptimal Responder and Optimal Responder groups) off their ER opioid treatment 
onto placebo over approximately 3-4 weeks depending on the baseline dose of index ER opioid. 
Subjects in the continuation arms will be on a fixed-regimen of ER opioid (i.e., the ER opioid dose will 
not change); note that the doses will vary across subjects based on their individualized standardized 
dose. Subjects will also be provided acetaminophen as rescue medication (500 mg tablets, 1-2 tablets 
PRN every 4-6 hours not to exceed 6 tablets/day) and will be encouraged to take acetaminophen to 
manage their pain, before they use IR opioid.  
After randomization, the dose of the IR opioid for both Suboptimal Responders and Optimal 
Responders whether randomized to discontinuation or continuation will remain limited to no more than 
twice daily PRN administration of OCIR 10 mg, MSIR 15 mg, or OMIR 5 mg, matching the index ER 
opioid each subject is receiving. Subjects will return to the clinic at weeks 1, 2, 4, 6, 8, 12, 16, 20, and 
24 (Visits BDP1 through BDP9). A series of assessments will be performed at each visit. 
Follow-Up Period (4 weeks). Subjects completing the Blinded Structured Opioid Discontinuation 
Period will be required to advance to and complete the Follow-up Period. However, those subjects who 
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discontinue from the Blinded Structured Opioid Discontinuation Period prior to week 12 will complete 
Week 12 study procedures and those subjects who discontinue during weeks 13-23 will complete 
Week 24 study procedures. Subjects will self-administer a blinded tapering dose during the Follow-up 
Period: Placebo taper for subjects who were in the discontinuation arm and active drug taper for 
subjects who were in the continuation arm. Subjects will be followed-up during 2 clinic visits (at 
Weeks 26 [FUV1] and 28 [FUV2], and 2 phone calls (at Weeks 25 and 27). At the end of the Follow-
up Period, subjects will be transitioned back to their primary care physician.  Subjects will be 
instructed not to take any ER opioid medication until they have consulted with their primary care 
physician as they no longer will be opioid-tolerant at this time. 
10.2. 
Selection of Doses 
Selection of subjects based on the index ER opioid dose: Subjects will be selected on the basis of 
having taken either OCER, MSER, or OMER with a total daily dose as shown in the table below for 
≥3 consecutive months for their CLBP. These doses have been selected because they represent high 
doses of opioids, which is one of the main criteria for selecting subjects for this study.  
 
Daily Dose Range 
Morphine sulfate ER 
120-540mg 
Oxycodone ER 
80-360mg 
Oxymorphone ER 
40-180mg 
Standardized regimen: Prior to the Blinded Structured Opioid Discontinuation Period, subjects’ 
opioid medication regimen will be standardized to study medication supplied as  OCER (OxyContin) 
plus OCIR PRN, or MSER (MS Contin) plus MSIR PRN, or OMER (Opana ER) plus OMIR PRN 
depending on which index ER opioid they were taking at screening. The reason for switching subjects 
to a standardized drug is to have more homogeneous treatment groups and reduce variability due to the 
use of different brands of products. The dose of the IR opioid will be limited to no more than twice 
daily PRN administration of OCIR 10 mg, MSIR 15 mg, or OMIR 5 mg, matching the index ER 
opioid each subject is receiving. (Note: Subjects who were taking asymmetric doses of the index ER 
opioid at screening will be placed on a symmetric dosage [same dose in the morning and evening] of 
the standardized regimen.) All subjects in the continuation arms will be on a fixed-regimen of ER 
opioid (i.e., the ER opioid dose will not change); note that the ER opioid doses will vary across 
subjects based on their individualized standardized dose.  
Importantly, Suboptimal Responders will receive the standardized regimen at a similar dose taken at 
screening in order to maintain the high dose of opioids and the suboptimal response each subject has 
been screened for. No dose adjustments of the ER medication will be permitted during the Run-in 
Period. However, Suboptimal Responders will be discontinued from the study at the end of the Run-in 
Period if they have intolerable side effects.  
For Optimal Responders, no dose adjustment of the ER medication will be permitted during the 
Observation Period. Dose adjustments (titration) will be made regularly in the Open-label Titration 
Period to return each subject to a mean Average PI score ≤4. 
Rescue medication: Subjects will also be provided acetaminophen as rescue medication (500 mg 
tablets, 1-2 tablets PRN every 4-6 hours not to exceed 6 tablets/day) and will be encouraged to take 
acetaminophen to manage their pain before they use the IR opioid, (ie, only take the IR opioid if the 
maximum dose of acetaminophen is not effective). 
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10.3. 
Study Drug Administration 
10.3.1. 
Study Medications 
The study medications are FDA approved and will be provided by the Opioid Post-Marketing 
Requirement Consortium (OPC) as follows: 
• OCER = OxyContin (oxycodone hydrochloride ER tablets) 
• MSER = MS Contin (morphine sulfate ER tablets) 
• OMER = Opana ER (oxymorphone hydrochloride ER tablets)  
Placebos for each of the abovementioned ER drugs will be manufactured by the respective 
manufacturer of the active ER medication and will be identical to the respective drugs in aspect, size, 
and color. 
10.3.2. 
Study Prescribed Drugs 
The following medications are commercially available and will be provided by the OPC in open-label 
fashion as study prescribed drugs: 
• OCIR = Mallinckrodt brand of oxycodone IR tablets 
• MSIR = West-Ward brand of morphine sulfate (IR tablets) 
• OMIR = Opana (Endo brand of oxymorphone hydrochloride IR tablets) 
• Acetaminophen 500 mg tablets 
10.3.3. 
Study Drug Administration and Dose 
The standardized regimen in this study consists of: OCER (OxyContin) plus OCIR PRN, or MSER 
(MS Contin) plus MSIR PRN, or OMER (Opana ER) plus OMIR PRN depending on which index 
ER opioid the subject was taking at screening. The dose of the IR opioid will be limited to no more 
than twice daily PRN administration of OCIR 10 mg, MSIR 15 mg, or OMIR 5 mg, matching the 
index ER opioid each subject is receiving. 
For Suboptimal Responders, subjects will start the standardized regimen during the 1-week Run-in 
Period in an open-label fashion at a similar dose to the index ER opioid taken at screening. During the 
Baseline Period, subjects will continue to self-administer the standardized regimen at the same dose as 
in the Run-in Period (no dose adjustment will be permitted). 
For Optimal Responders, subjects will start the standardized regimen during the 2 week Taper Period 
during which study medication will be reduced every 3 days until the PI score increases as specified. 
The standardized regimen will continue during the 3-week Open-label Titration Period. During the 
Titration Period, the dose of the ER opioid will be increased as frequently as every 4 days (during 
telephone or office visits) until the mean Average PI score for at least 3 consecutive pain scores is <4.  
At the Randomization Visit, all eligible subjects will be randomized to one of the following groups: 
For subjects whose ER opioid is morphine, the groups will be: 
• Morphine Group 1: MSER tablets  + matching placebo tablets to maintain MSER dose, but 
appear as if tapering is occurring; 
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• Morphine Group 2: Placebo tablets to match MSER tablets + MSER tablets in decreasing 
dose to result in a tapering off of MSER. 
For subjects whose ER opioid is oxycodone, the groups will be: 
• Oxycodone Group 1: OCER tablets + matching placebo tablets to maintain OCER dose, but 
appear as if tapering is occurring; 
• Oxycodone Group 2: Placebo tablets to match OCER tablets + OCER tablets in decreasing 
dose to result in a tapering off of OCER. 
For subjects whose ER opioid is oxymorphone, the groups will be: 
• Oxymorphone Group 1: OMER tablets + matching placebo tablets to maintain OMER dose, 
but appear as if tapering is occurring; 
• Oxymorphone Group 2: Placebo tablets to match OMER tablets + OMER tablets in 
decreasing dose to result in a tapering off of OMER. 
Subjects in the continuation arms of both the Suboptimal Responder and Optimal Responder groups 
will be on a fixed-regimen of ER opioid (i.e., the ER opioid dose will not change). 
Rescue medication: Subjects will also be provided acetaminophen as rescue medication (500 mg 
tablets, 1-2 tablets every 4-6 hours PRN, not to exceed 6 tablets/day) and will be encouraged to take 
acetaminophen to manage their pain before they use the IR opioid (ie, only take the IR opioid if the 
maximum dose of acetaminophen is not effective). 
10.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For subjects on high-dose opioids possibly experiencing OIH, a traditional treatment is discontinuation 
of opioid therapy, in which subjects have their opioid therapy gradually tapered off in the structured 
context of psychological and physical rehabilitative support. Although the success of these programs 
has been noted in uncontrolled and unblinded observational studies, the efficacy of removal from 
opioid therapy for a well-defined cohort of “Suboptimal Opioid Responders” has never been evaluated 
in a randomized, double-blind, controlled clinical trial, which is the gold standard for the rigorous 
clinical evaluation of a treatment. Thus, this study uses a placebo-controlled, double-blind, parallel-
arm study design to evaluate the effect of structured opioid discontinuation versus continuation of 
opioid therapy in Suboptimal Responders. A cohort of Optimal Responders is also included in this trial 
to determine the effect of continuation versus discontinuation of opioid therapy in Optimal Responders 
in order to fully inform the objectives of the Post-Marketing Requirement.  
To this end, subjects on a standardized regimen of high-dose opioids will be randomized to (i) continue 
on high-dose opioid (continuation arm) or (ii) taper off their high-dose opioid (discontinuation arm) in 
a double-blind manner.   
In order to maintain the blind in both the continuation and discontinuation arms, the groups have been 
designed as follows: 
• Continuation arm: ER opioid  tablets+ placebo tablets during tapering to maintain the blind 
• Discontinuation arm: Matching placebo tablets for the ER opioid + ER opioid tablets only 
during the first 3-4 weeks after randomization 
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(The ER opioid is either OCER, MSER, or OMER; the IR opioid is either OCIR, MSIR, or OMIR 
matching the ER opioid). IR opioid will only be available at low dosage for infrequent use to manage 
pain not manageable by PRN acetaminophen. 
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11. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
11.1. 
Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be enrolled in the study: 
1. Be male or non-pregnant, non-lactating female aged 18 to 75 years, inclusive; 
2. Have a clinical diagnosis of non-radicular CLBP (pain that occurs in an area with 
boundaries between the lowest rib and the crease of the buttocks) of Class 1 or proximal 
(above the knee) radicular pain of Class 2 of the Quebec Task Force Classification for 
Spinal Disorders (subjects with previous surgery or chronic pain syndrome, i.e., classes 
9.2 or 10, will be allowed if their pain does not radiate or radiates only proximally) for a 
minimum of 12 months and 
− For the Suboptimal Responder group, pain must have been present for at least several 
hours a day and have an Average PI score of 6-9 on an 11-point NRS (as measured on 
the NRS) within the past 24 hours of screening. 
− For the Optimal Responder group, subjects must have an Average PI score of 1-4 on an 
11-point NRS (as measured on the NRS) within the past 24 hours of screening; 
3. Have been taking ER/LA opioids (or immediate release opioids (at least 4 times a day) 
for at least 12 months; 
4. Have been taking one of the 3 index opioid drugs around-the-clock at a twice-a-day 
frequency for at least 3 consecutive months at total daily doses shown in the table 
below. 
 
Daily Dose Range 
Morphine sulfate ER 
120-540 mg 
Oxycodone ER 
80-360 mg 
Oxymorphone ER 
40-180 mg 
5. Be considered, in the opinion of the Investigator, to be in generally good health other 
than CLBP at screening based upon the results of a medical history, physical 
examination, 12-lead ECG, and laboratory profile. 
6. Speak, read, write, and understand English (to reduce heterogeneity of data), understand 
the consent form, and be able to effectively communicate with the study staff. 
7. Have access to the Internet (to access the patient support program). 
8. Voluntarily provide written informed consent. 
9. Be willing and able to complete study procedures. 
Entry Criteria to Determine Responder Status: Following successful determination of eligibility, 
subjects will be assessed against the following criteria to determine responder status at the Screening 
Visit: 
• Subjects with an Average PI score ≤4 (as measured on the NRS) at Screening who are 
satisfied with their pain and physical function will be considered Optimal Responders; 
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• Subjects with an Average PI score ≥ 6 (as measured on the NRS) at Screening who are 
dissatisfied with their pain and physical function will be considered Suboptimal 
Responders; 
• Subjects who do not fall into either category will be considered screen failures and 
discontinued from the study. 
11.2. 
Subject Exclusion Criteria 
Subjects who have any of the following will not be enrolled in the study: 
1. Have any clinically significant condition that would, in the opinion of the Investigator, 
preclude study participation or interfere with the assessment of pain and other 
symptoms of CLBP or increase the risk of opioid-related AEs.  
2. Have a primary diagnosis of fibromyalgia, complex regional pain syndrome, neurogenic 
claudication due to spinal stenosis, spinal cord compression, acute nerve root 
compression, severe or progressive lower extremity weakness or numbness, bowel or 
bladder dysfunction as a result of cauda equina compression, diabetic amyotrophy, 
meningitis, diskitis, back pain because of secondary infection or tumor, or pain caused 
by a confirmed or suspected neoplasm.  
3. Have undergone a surgical procedure for back pain within 6 months prior to the 
Screening Visit. 
4. Have had a nerve or plexus block, including epidural steroid injections or facet blocks, 
within 1 month prior to the Screening Visit or botulinum toxin injection in the lower 
back region within 3 months prior to screening. 
5. Have a history of confirmed malignancy within past 2 years, with exception of basal 
cell or squamous cell carcinoma of the skin that has been successfully treated. 
6. Have uncontrolled blood pressure, i.e., subject has a sitting systolic blood pressure >180 
mm Hg or <90 mm Hg, or a sitting diastolic blood pressure >110 mmHg or <40 mm Hg 
at screening. 
7. Have a body mass index (BMI) >45 kg/m2.  Anyone with a BMI > 40 but ≤ 45 will 
complete a screening tool (STOPBang Questionnaire) to rule out high risk of 
obstructive sleep apnea (Appendix W). 
8. Have a clinically significant depression based on a score ≥20 on the Patient Health 
Questionnaire (PHQ-8). 
9. Have suicidal ideation associated with actual intent and a method or plan in the past 
year: "Yes" answers on items 4 or 5 of the Columbia-Suicide Severity Rating (C-SSRS). 
10. Have a previous history of suicidal behaviors in the past 5 years: "Yes" answer (for 
events that occurred in the past 5 years) to any of the suicidal behavior items of the C-
SSRS.  
11. Have any lifetime history of serious or recurrent suicidal behavior. (Non-suicidal self-
injurious behavior is not a trigger for a risk assessment unless in the Investigator's 
judgment it is indicated.) 
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12. Have clinically significant abnormality in clinical chemistry, hematology or urinalysis, 
including serum glutamic-oxaloacetic transaminase/aspartate aminotransferase (AST) or 
serum glutamic pyruvic transaminase/alanine aminotransferase (ALT) ≥3 times the 
upper limit of the reference range or a serum creatinine >2 mg/dL at screening. 
13. Have severe enough psychiatric or substance abuse disorder to compromise the 
subject’s safety or scientific integrity of the study. 
14. Have on-going litigation associated with back pain or pending applications for workers 
compensation or disability issues or subjects who plan on filing litigation or claims 
within the next 12 months; subjects with settled past litigations will be allowed as will 
subjects who have been on workers compensation or disability claims for at least 3 
months. 
15. Have used a monoamine oxidase (MAO) inhibitor within 14 days prior to the start of 
study medication. 
16. Are taking agonist-antagonists (pentazocine, butorphanol or nalbuphine), 
buprenorphine, methadone, barbiturates, or more than one type of benzodiazepine 
within 1 month prior to screening. 
17. Have a positive UDT for illicit drugs (including marijuana), non-prescribed controlled 
substances, or alcohol at screening. 
18. Have taken any investigational drug within 30 days prior to the Screening Visit or are 
currently enrolled in another investigational drug study. 
11.3. 
Replacement Procedures 
Subjects who discontinue from the study will not be replaced. 
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12. 
TREATMENT OF SUBJECTS 
12.1. 
Study Visits 
The Schedule of Procedures to be performed at each visit is shown in Tables 2 and 3. Provided below 
are further details where additional instruction about the assessments that will be performed is deemed 
to be needed. Visit windows are ±3 days until BDP6, and ±5 days thereafter. A phone call will be 
conducted every week of the study where a visit is not conducted to check for wellbeing, study drug 
compliance, and safety issues.  Changes in medications and AEs obtained during phone calls will be 
captured in the electronic Case Report Form (eCRF).  All other information will be captured in source 
documents. 
Investigators are encouraged to perform the study procedures at each visit in the order listed. The 
general rationale for the order of the procedures is the following: 
• First, patient-reported outcomes, from the most important as regards to the endpoint 
measured (e.g., BPI-SF) to the least important (e.g., the Work Productivity and Activity 
Impairment [WPAI]), ending with quality of life measures (EQ-5D-5L) so that the subject 
has an overall view of his/her status when completing general health questionnaires 
• Second, performance tasks (e.g., Digit Symbol Substitution Test [DSST]) as they may lead 
to subject fatigue and interfere with capture of the primary data 
• Third, standard procedures associated with subject safety (e.g., recording of AEs, vital 
signs, physical exam, etc.) 
• Fourth, study drug accountability and compliance, which is part of the process of 
identifying potentially abuse-related events 
• Fifth, characterization of any abuse-related AEs, as this may be emotionally laden and 
consume time 
• Sixth, drug dispensing, which may not be done if abuse-related events are identified 
12.1.1. 
Screening Visit (Same for Suboptimal and Optimal Responders) 
Investigators will be expected to maintain screening information on all potential study subjects. This 
will include limited information about the potential subject and the dates and outcome of the screening 
process (i.e., informed consent, demography, subject enrollment status, reason for ineligibility, and 
AEs [SAEs will be recorded in the eCRF]). Investigators will provide information about the study to 
subjects who appear to meet the criteria for participation in the study. 
Screening assessments will be carried out over 2 visits that are not greater than 21 days apart. 
Screening Visit 1 
Determine Eligibility 
• Obtain informed consent;  
• Assign the subject identification number which will consist of 7 digits. The first 3 digits 
represent the study site number followed by ##01, ##02, and so on.  
• Collect demographic data 
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• Collect medical history 
• Obtain confirmation of the subject’s pre-study ER opioid regimen. Confirmation may be 
documentation of verbal confirmation of regimen from a referring clinician, reviewing 
referring physician medical records, checking medical records for subjects of the 
Investigator, or other appropriate methods.  
• Collect vital signs (height, weight, BMI [calculated], pulse rate, respiratory rate, and blood 
pressure). Anyone with a BMI > 40 but ≤ 45 will complete a screening tool (STOPBang 
Questionnaire) to rule out high risk of obstructive sleep apnea. 
• Perform a full physical examination 
• Perform an ECG 
• Classify the subject according to the Quebec Task Force Classification for Spinal Disorders 
• Check prior and concomitant medications 
• Determine daily dose of index ER opioid (from the concomitant medication log) 
• Assess PI using 0-10 NRS by phone 
• Administer BPI-SF 
• Administer the PHQ-8 
• Administer the C-SSRS “Lifetime” 
• Check entry criteria based on abovementioned assessments. A subject who gives written 
informed consent and who satisfies these criteria is considered preliminarily eligible for 
entry into the study.  
Determine Responder Status 
Following successful preliminary determination of eligibility, subjects will be assessed against the 
following criteria to determine responder status: 
• Subjects with an Average PI score ≤4 at Screening (as measured on the NRS) who are 
satisfied with their pain and physical function will be considered Optimal Responders 
• Subjects with an Average PI score ≥6 at Screening (as measured on the NRS) who are 
dissatisfied with their pain and physical function will be considered Suboptimal Responders 
Subjects who do not fall into either category will be considered screen failures and discontinued from 
the study. (For study discontinuation procedures, see section 12.1.6.) The remaining subjects will 
continue as Preliminarily Eligible. 
For All Preliminarily Eligible Subjects 
• Perform clinical laboratory testing 
• Perform a serum pregnancy test for all women of child-bearing age 
• Perform a quantitative UDT for illicit drugs, non-prescribed controlled substances, and 
alcohol 
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• Draw blood for future endocrine testing and send to lab (will be tested later only for 
randomized subjects). Administer sexual function questionnaire (See Appendix S). 
• Administer the Roland-Morris Disability Questionnaire (RMDQ) 
Screening Visit 2 
For all Preliminarily Eligible Subjects 
• Review results from clinical laboratory testing and pregnancy testing 
• Review results from quantitative UDT 
Subjects who do not meet the entry criteria for the protocol will be considered screen failures and 
discontinued from the study. (For study discontinuation procedures, see section 12.1.6.) 
All other subjects will continue according to their responder status: 
For Suboptimal Responders Only: 
• Provide training to the subject on how to use the phone response system 
• Introduce the subject to the Online Patient Support Program (see description in Appendix 
U). The purpose of this program is to support subject retention in the trial as well as 
compliance with study medication, and to provide pain management support during 
medication regimen changes and during medication tapering. Subjects will be provided 
with an URL (uniform resource locator). Participation is not required but will be 
encouraged by the clinic staff. 
• Determine standardized opioid regimen (Refer to the Run-in, Baseline, and Blinded 
Structured Opioid Discontinuation schedule in Appendix B – Dosing Schedule) 
• Dispense open-label standard ER opioid 
• Dispense matching IR opioid medication 
• Discontinue all other opioid medications 
• Discontinue using personal supply of acetaminophen 
• Dispense study-provided acetaminophen 
• Record drug supplied 
For Optimal Responders Only: 
• Provide training to the subject on how to use the phone response system 
• Introduce the subject to the Online Patient Support Program (see description in Appendix 
U). The purpose of this program is to support subject retention in the trial as well as 
compliance with study medication, and to provide pain management support during 
medication regimen changes and during medication tapering. Subjects will be provided 
with an URL (uniform resource locator). Participation is not required but will be 
encouraged by the clinic staff. 
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• Direct optimal responders to continue to take their opioid analgesic medication regimen 
which they were previously taking without any changes until the next visit 
12.1.2. 
Suboptimal Responders Visits Only 
Run-in Period (1 week, from Weeks -2 to -1) 
During the Run-in Period, subjects will: 
• Self-administer the open-label standardized regimen of ER opioid 
• Before bedtime, record via phone the daily Average PI and Worst PI scores in the past 24 
hours 
• Before bedtime, record via phone the daily use of ER opioid and IR opioid  
• Participate in the on-line Patient Support Program 
Tolerability Visit = SR1 (at Week -1) 
At the Tolerability Visit (SR1), the following will be conducted in-clinic: 
• Collect vital signs (pulse rate, respiratory rate, and blood pressure only) 
• Collect AEs 
• Collect concomitant medication data 
• Determine whether any abuse-related events have occurred during the Run-in Period 
• Review the data recorded via phone for daily Average PI and Worst PI scores recorded by 
the subject since the last visit  
• Review the data recorded via phone for the daily use of ER and IR opioids taken by the 
subject since the last visit 
• Collect study drug 
• Perform a pill count for drug accountability (ER opioid, IR opioid, and acetaminophen) 
• Discontinue subjects who did not tolerate the standardized regimen – no dose adjustment of 
the regimen is permitted (For study discontinuation procedures, see section 12.1.6.) 
• Dispense study drug (ER opioid, IR opioid, and acetaminophen) for the Baseline Period 
Baseline Period (1 week, from Week -1 to 0) 
During the Baseline Period, the subject will: 
• Self-administer the open-label standardized regimen of ER opioid 
• Before bedtime, record via the phone the daily Average PI and Worst PI scores in the past 
24 hours 
• Before bedtime, record via the phone the daily use of ER opioid and IR opioid  
• Participate in the on-line Patient Support Program 
Randomization Visit = SR2 (Day 1) 
At the Randomization Visit (SR2), the following will be conducted during a clinic visit: 
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• Collect vital signs (pulse rate, respiratory rate, and blood pressure only) 
• Collect AEs 
• Collect concomitant medication data 
• Collect study drug 
• Perform a pill count for drug accountability (ER opioid, IR opioid, and acetaminophen) 
• Perform a urine pregnancy test for women of child-bearing age 
• Review the data recorded  via phone for daily Average and Worst PI scores by the subject 
since last visit 
• Review the data recorded via phone for the daily use of ER and IR opioids taken by the 
subject since last visit 
• Check the criteria for randomization into the Blinded Structured Opioid Discontinuation 
Period: To continue on study, subjects are required to have a mean Average PI score ≥6 on 
a 0-10 NRS over the 1 week of the Baseline Period (with a minimum compliance of 4 out 
of 7 daily PI scores) and to be dissatisfied with their pain and physical function. Subjects 
who had a baseline mean Average PI score of 10/10 (i.e., 10/10 score every day for the 1 
week of the Baseline Period) will be discontinued. (For study discontinuation procedures, 
see section 12.1.6.) 
For subjects eligible to continue on study, perform the following: 
• Inform the lab to perform the endocrine parameter analysis drawn at Screening 
• Administer the BPI-SF 
• Administer the RMDQ 
• Administer the Regional Pain Scale 
• Administer the Pain Quality Assessment Scale (PQAS) 
• Administer the MOS Sleep Scale 
• Administer the WPAI 
• Administer the EQ-5D-5L 
• Administer the DSST 
• Perform quantitative sensory testing (QST) for OIH (for subjects enrolled at participating 
sub-study sites) 
• Administer the Subjective Opiate Withdrawal Scale (SOWS) 
• Complete the Clinical Opioid Withdrawal Scale (COWS) 
• Determine whether any abuse-related events have occurred during the Baseline Period 
• Randomize the subject using IRT system 
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• Dispense blinded study drug (ER opioid) according to the IRT instructions and matching IR 
opioid and acetaminophen. Instruct the subject to begin treatment with the next scheduled 
dose.  
12.1.3 Optimal Responders Visits Only 
Observation Period (1 week, from Weeks -6 to -5) 
During the Observation Period, subjects will 
• Self-administer the same opioid analgesic regimen they have been taking at screening 
• Before bedtime, record via phone the daily use of opioid analgesics and rescue medication 
taken over the past 24 hours 
• Before bedtime, record via telephone the daily Average and Worst PI scores in the past 24 
hours  
OR1 Visit (at Week -5) 
At the OR1 visit, the following will be conducted during a clinic visit: 
• Collect vital signs (pulse rate, respiratory rate, and blood pressure only) 
• Collect AEs 
• Collect concomitant medication data 
• Review the data recorded via phone for the daily Average and Worst PI scores by the 
subject since last visit 
• Review the data recorded via phone for daily use of opioid and rescue medication taken by 
the subject since last visit 
• Determine whether any abuse-related events have occurred during the Observation Period 
• Subjects will be confirmed as Optimal Responders and will be allowed to continue in the 
study if: (i) their index opioid ER medication use was in the range shown in the table below 
and they had 80% to 120% compliance over the 1-week period; (ii) their mean Average PI 
score over the Observation Period was <5 (with a minimum compliance of 4 out of 7 daily 
PI scores); and (iii) they are still satisfied with their pain and physical function. 
 
Dose Range 
Morphine sulfate ER 
120-540 mg 
Oxycodone ER 
80-360 mg 
Oxymorphone ER 
40-180 mg 
• Dispense open-label study medication (ER opioid dose cards and acetaminophen) for the 
Taper Period (Refer to the Optimal Responders: Open-label Taper and Titration schedule in 
Appendix B – Dosing Schedule) 
• IR opioid is not allowed during the Taper Period 
• Discontinue all other prescribed opioid medications prescribed for the subject 
• Instruct the subject in the use of the Online Patient Support Program 
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Taper Period (up to 2 weeks, from Week -5 to -3) 
During the Taper Period, subjects will: 
• Self-administer the open-label ER opioid taper 
• Before bedtime, record via phone the daily use of ER opioids (IR opioid rescue is not 
allowed during this period) 
• Before bedtime, record via phone the daily Average PI and Worst PI scores in the past 24 
hours  
• Participate in the Online Patient Support Program 
OR2 Visit (at Week -4) 
At Visit OR2 (or before), the following will be conducted: 
• Check criteria for entry into the Titration Period: Subjects with a mean Average PI score  
>5 over ≥3 consecutive PI scores (non-missing values), where this mean Average PI score 
has also increased by ≥1.5 points from the mean Average PI score over the 7-day 
Observation Period, either off of pain medication entirely or at a reduced dose, will 
immediately advance to Visit OR3 (skipping Visit OR2) and begin the Open-Label 
Titration Period 
For subjects continuing in the Taper Period, conduct Visit OR2:  
• Collect vital signs (pulse rate, respiratory rate, and blood pressure only) 
• Collect AEs 
• Determine whether any abuse-related events have occurred since last visit 
• Collect concomitant medication data 
• Review the data recorded via phone for daily use of ER opioid taken by the subject since 
last visit 
• Review the data recorded via phone for daily Average PI and Worst PI scores since last 
visit 
• Collect study drug 
• Perform a pill count for drug accountability (ER opioid and acetaminophen) 
• Dispense additional open-label ER opioid taper medication and acetaminophen 
OR3 Visit (at Week -3) 
At Visit OR3, the following will be conducted: 
• Collect vital signs (pulse rate, respiratory rate, and blood pressure only) 
• Collect AEs 
• Determine whether any abuse-related events have occurred since last visit 
• Collect concomitant medication data 
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• Review the data recorded via phone for daily use of ER opioids taken by the subject since 
last visit 
• Check the daily past 24 hour Average and Worst PI scores from the phone data since last 
visit 
• Collect study drug 
• Perform a pill count for drug accountability  (ER opioid and acetaminophen) 
• Check criteria for entry into the Titration Period: Subjects with a mean Average daily PI 
score  >5 over ≥3 consecutive PI scores (non-missing values), where this mean Average 
daily PI score has also increased by ≥1.5 points from the mean Average PI score over the 7-
day Observation Period, either off of pain medication entirely or at a reduced dose, will be 
eligible to proceed to the Open-Label Titration Period. Subjects who do not meet these 
criteria will be discontinued from the study. (For study discontinuation procedures, see 
section 12.1.6.) 
• For subjects who are continuing into the Titration Period, dispense open-label titration 
medication of the standardized ER opioid corresponding to the subject’s index ER opioid.  
− Also dispense rescue medication (corresponding IR opioid and acetaminophen) for the 
Titration Period 
Open-label Titration Period (up to 3 weeks, from Week -3 to 0) 
During the Open-label Titration Period, subjects will: 
• Self-administer the open-label ER opioid titration regimen  
• Before bedtime, record via phone the daily use of ER and IR opioids  
• Before bedtime, record via phone the daily Average and Worst PI scores in the past 24 
hours before bedtime 
• Participate in the Online Patient Support Program 
Telephone (or Office) Visits every 4 days (Up to 5 telephone or office visits from Week -3 to 0) 
Note: Sites have the option of scheduling Office Visits (OR3.1, OR 3.2, etc.) during this time if they 
believe that is appropriate for the subject’s wellbeing.  Also, if the dose of the index ER opioid needs 
to be titrated above the baseline dose, the Titration Period may be extended by 1 additional week (+3 
days). 
At the Telephone (or Office) Visits, the following will be performed: 
• Collect AEs 
• Determine whether any abuse-related events have occurred since last visit 
• Collect concomitant medication data 
• Review the data recorded via phone for daily Average PI and Worst PI scores by the subject 
since the last visit 
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• Review the data recorded via phone for daily use of ER and IR opioids taken  by the subject 
since the last phone call/visit  
• If the subject does not have a mean Average PI score for at least 3 consecutive scores (non-
missing values) that is <5, increase the subject’s dose; increase dose as frequently as every 
4 days (using Telephone or Office Visits) until the mean Average PI score over at least 3 
consecutive scores (non-missing values) is <5 
• When the subject’s mean Average PI score over at least 3 consecutive scores (non-missing 
values) is <5, schedule the Randomization Visit as soon as possible (preferably the next 
day) and keep the subject on that ER opioid dose until that visit occurs 
Randomization Visit = OR4 (at Day 1) 
At the Randomization Visit (OR4), the following will be conducted during a clinic visit: 
• Collect vital signs (pulse rate, respiratory rate, and blood pressure only) 
• Collect AEs 
• Collect concomitant medication data 
• Perform a urine pregnancy test for women of child-bearing age 
• Review the data recorded via phone for  daily Average and Worst PI scores by the subject 
since last visit 
• Review the data recorded via phone for  daily use of ER and IR opioids taken by the subject 
since the last visit 
• Check the criteria for entry into the Randomization Period: To continue on study, subjects 
are required to have achieved a mean Average PI score ≤5 during the 3 consecutive scores 
(non-missing values) that triggered the randomization visit with satisfaction with their pain 
and physical function, and acceptable side effects, and be taking a dose of index ER opioid 
in the range listed in the table below. 
 
Daily Dose Range 
MS Contin ER 
120-540 mg 
OxyContin ER 
80-360 mg 
Opana ER 
40-180 mg 
For subjects eligible to continue on study, perform the following: 
• Inform the lab to perform endocrine parameter analysis drawn at Screening 
• Administer the BPI-SF 
• Administer the RMDQ 
• Administer the Regional Pain Scale 
• Administer the PQAS 
• Administer the MOS Sleep Scale 
• Administer the WPAI 
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• Administer the EQ-5D-5L 
• Administer the DSST 
• Administer the QST for OIH (for subjects enrolled at participating sub-study sites) 
• Administer the SOWS 
• Complete the COWS 
• Determine whether any abuse-related events have occurred since last visit 
• Randomize the subject using the IRT system 
• Collect study drugs 
• Perform a pill count for drug accountability (ER opioid, IR opioid, and acetaminophen)  
• Dispense blinded study drug (ER opioids) according to the IRT instructions and matching 
IR opioid, and acetaminophen. Instruct the subject to begin treatment with the next 
scheduled dose.  
• Encourage use of online Patient Support Program. 
12.1.4 Continuing for both Suboptimal and Optimal Responders: Blinded Structured Opioid 
Discontinuation Period (24 weeks; from Week 1 to 24) 
During the Blinded Structured Discontinuation Period, subjects will: 
• Self-administer the double-blind standardized ER opioid regimen as directed 
• Before bedtime, record via phone the daily use of ER and IR opioids  
• Before bedtime, record via phone the daily Average and Worst PI scores in the past 24 
hours  
• Participate in the Online Patient Support Program 
 
Clinic visits will occur at Weeks 1, 2, 4, 6, 8, 12, 16, 20, and 24 (BDP visits 1 through 9). A phone call 
will be conducted every week where a visit does not occur (i.e., Weeks 3, 5, 7, 9, 10, 11, 13, 14, 15, 
17, 18, 19, 21, 22, and 23) to check for the subjects wellbeing, study medication compliance, and 
safety issues.  Changes in study medication and AEs obtained during phone calls will be captured in 
the eCRF.  All other information will be captured in source documents. 
Conduct the following assessment at each clinic visit: 
• Check vital signs (pulse rate, respiratory rate, and blood pressure only) 
• Collect AEs 
• Collect concomitant medication data 
• Check the data recorded via phone for daily Average and Worst PI scores by the subject 
since last visit 
• Determine whether any abuse-related events have occurred since last visit 
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• Check the data recorded via phone for daily use of ER opioid and IR opioid taken by the 
subject since last visit  
• Perform a pill count for drug accountability (ER opioid, IR opioid, and acetaminophen) 
• Dispense study medication until next visit 
Conduct the following assessments at specified visits: 
• Conduct a brief physical exam, clinical laboratory testing, endocrine testing and sexual 
function questionnaire (see Appendix S)  at Weeks 12 and 24 
• Administer the BPI-SF, Regional Pain Scale, PQAS, WPAI, EQ-5D-5L, PHQ-8, and 
Patient’s Global Impression of Change (PGIC) at Weeks 12 and 24 
• Administer the RMDQ at Weeks 12 and 24 
• Perform QST for OIH at Weeks 12 and 24 (for subjects enrolled at participating sub-study 
sites) 
• Administer SOWS at Weeks 2, 4, and 6  
• Administer the COWS at Weeks 2 and 4 
• Administer the C-SSRS “Since Last Visit” at Weeks 6 and 24 (review results to determine 
if further risk assessment is necessary) 
• Administer the MOS Sleep Scale and the DSST at Weeks 12 and 24 
• Perform a quantitative UDT at Weeks 4, 12, and 24 for non-prescribed controlled 
substances, illicit drugs, and alcohol. The management of unexpected findings is described 
in the UDT Appendix (Appendix T). If an unexpected finding occurs after a repeat UDT, 
discontinue the subject from the study per the UDT algorithm. (For study discontinuation 
procedures, see section 12.1.6.) 
During weeks without a visit, call the subject to assess subject wellbeing, study medication 
compliance, and safety (check for AEs). Changes in medications and AEs obtained during phone calls 
will be captured in the eCRF.  All other information will be captured in source documents. 
Full information about the reason(s) for dropout of any subject after randomization will be captured in 
the electronic case report form (eCRF) using a special questionnaire (Appendix V) as detailed in 
Section 12.1.6. 
12.1.5 Follow-up Period (4 Weeks; from Week 25 to 28) 
During the Follow-up Period, subjects will  
• Self-administer the double-blind  study medication as directed  
• Before bedtime, record via phone the daily use of ER and IR opioids  
• Participate in the Online Patient Support Program 
There will be 2 clinic visits (at Weeks 26 and 28) and 2 phone calls (at Weeks 25 and 27). 
Follow Up Visit 1 (FUV1; Week 26) and Follow Up Visit 2 (FUV2; Week 28 [final visit]) 
• Collect vital signs (pulse rate, respiratory rate, and blood pressure only) 
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• Collect AEs 
• Determine whether any abuse-related events have occurred since the last visit 
• Check concomitant medications  
• Check the data recorded via phone for daily use of ER opioid and IR opioid taken by the 
subject since last visit  
• Perform a pill count for drug accountability  (ER opioid, IR opioid, and acetaminophen) 
At FUV1 only: 
• Perform SOWS and COWS 
• Dispense double-blind study medication until next visit (Week 28) 
• Instruct the subject to discontinue ER study medication for the last 3 days prior to the final 
visit 
At FUV2 only: 
• Perform a urine pregnancy test for women of child-bearing age 
• Conduct a brief physical exam 
• Collect any remaining medication 
• Discharge the subject at FUV2 to their primary care physician 
− Instruct the subject not to take any ER opioid medication until they see their primary 
care physician (as they are no longer opioid tolerant) 
Phone Calls (Weeks 25 and 27): 
• Check on the subject’s wellbeing (AEs and potential withdrawal symptoms) 
• Check the data recorded via phone for study drug use by the subject since the last visit 
• Changes in medications and AEs obtained during phone calls will be captured in the eCRF.  
All other information will be captured in source documents. 
 
12.1.6 Study Discontinuation Procedures 
Subjects who do not meet the entry criteria for the protocol during Screening will be considered screen 
failures and discontinued from the study.  Investigators will be expected to maintain screening 
information on all potential study subjects. This will include limited information about the potential 
subject and the dates and outcome of the screening process (i.e., informed consent, demography, 
subject enrollment status, reason for ineligibility, and AEs).  Subjects will be discharged to their 
primary care physician.  Opioid medication will be managed as appropriate by their primary care 
physician. 
Subjects who discontinue the study after Screening but before the Randomization Visit will advance to 
the final visit (FUV2), complete all visit assessments, and will be discharged to their primary care 
physician.  Opioid medication will be managed as appropriate by their primary care physician. 
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For subjects who discontinue the study during the Blinded Structured Opioid Discontinuation Period, 
the following should be performed:  
• Subjects who discontinue before Week 12 will complete Week 12 assessments and advance 
to the Follow-up period. At the completion of the Follow-up period, subjects will be 
discharged to their primary care physician who will manage their pain medication. 
• Subjects who discontinue between Weeks 13 and 24 will complete Week 24 assessments 
and advance to the Follow-up period.  For any subject who discontinues before Week 4, the 
Medical Monitor should be contacted to discuss that subject. At the completion of the 
Follow-up period, subjects will be discharged to their primary care physician who will 
manage their pain medication. 
Full information about the reason(s) for dropout of any subject after randomization will be captured in 
the eCRF using a special questionnaire (Appendix V).  If the discontinued subject is unable or 
unwilling to come to the clinic for the discontinuation procedures, the staff will conduct a phone visit 
and complete the following assessments as best possible over the phone: 
• PI according to NRS 
• BPI-SF 
• Regional Pain scale 
• RMDQ 
• EQ-5D-5L 
• PGIC 
12.2 Prior and Concomitant Medications and Procedures 
Medications and procedures that are allowed and not allowed as concomitant medications for either 
episodic or chronic use are described in this section. Medication history, including the use of opioid 
analgesic medication during the previous 1 year and of any other medication during the previous 6 
months, will be recorded at Screening in the eCRF. Thereafter, any changes in concomitant 
medications or new medications added will be recorded in the eCRF.  
Medications taken for hormone replacement therapy including testosterone and estrogen/progesterone-
containing products and erectile dysfunction medications will be recorded in the eCRF. 
Medications and procedures permitted and not permitted during the study are described below: 
Prohibited Prior Medications and Procedures 
• Nerve or plexus block, including epidural steroid injections or facet blocks, within 1 month 
prior to the Screening Visit, or botulinum toxin injection in the lower back region within 3 
months prior to screening 
• MAO inhibitor within 14 days prior to screening 
• Agonist-antagonists (pentazocine, butorphanol or nalbuphine), buprenorphine, methadone, 
barbiturates, or more than one type of benzodiazepine within 1 month prior to screening 
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• Positive UDT for illicit drugs (including marijuana), non-prescribed controlled substances, 
or alcohol at screening. 
• Any investigational drug within 30 days prior to the Screening Visit 
Prohibited and Allowed Concomitant Medications and Procedures 
At Screening, Suboptimal Responder subjects will be required to discontinue all IR and ER opioids 
they had been taking including tramadol and tapentadol and will receive a standardized regimen 
supplied as ER opioid plus matching IR opioid. Optimal Responder subjects will continue to take their 
prescribed opioid regimen during the Observation Period after which those subjects advancing to the 
Taper Period will receive the standardized ER opioid. 
Throughout the study, both Suboptimal Responder and Optimal Responder subjects will be allowed to 
continue the non-opioid, non-acetaminophen containing analgesics they had been taking prior to 
entering the study as concomitant medication at the dose they were taking at Screening. 
Throughout the study (except during the Observation Period for the Optimal Responders), both 
Suboptimal Responder and Optimal Responder subjects will discontinue any personal acetaminophen 
and only take study-provided acetaminophen.  The dose is 500 mg tablets, 1-2 tablets every 4-6 hours 
PRN, not to exceed 6 tablets/day, which provides for a total daily dose (3 grams), well within the 
accepted safety range (<4 grams daily). 
Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine and butorphanol), buprenorphine, 
methadone, barbiturates, MAO inhibitors, investigational drugs, and more than one benzodiazepine are 
prohibited throughout the study. 
Alcohol and other concomitant medications that are not to be taken in combination with opioid 
analgesics as well as non-prescribed controlled substances will NOT be permitted during the study 
except if determined to be appropriate by the Investigator.  
Nerve or plexus block, including epidural steroid injections or facet blocks, botulinum toxin injection 
in the lower back region, chiropractic manipulation of the lower back, or any surgical procedure 
(including external or internal nerve stimulators) for lower back pain are not allowed during the study.  
Stimulators that are in place prior to study entry are allowed as long as the settings are not changed 
during the study.  Massage therapy or exercise therapy may continue unchanged during the study but 
new massage therapy or exercise therapy is not allowed during the study. 
12.3 Study Drug Compliance 
Treatment compliance will be calculated for ER opioids only (since IR opioids and acetaminophen are 
rescue medications taken PRN). Study drug compliance for ER opioids during each period will be 
calculated to determine treatment compliance. Compliance can be calculated using the following 
formula: Divide the number of doses of ER opioids taken by the subject by the number of doses 
required by the protocol for the given period and multiply by 100 to determine the percentage of 
compliance with the protocol. Subjects taking too much or too little study drug should be re-educated 
on the proper use of study drug. Repeated non-compliance (less than 80% or greater than 120%) 
should be evaluated for the need to withdraw the subject.  
Accidental or intentional overdoses should be reported to the Sponsor/designee promptly (see 
section 14.6.1.2, Handling Reports of Overdose/Abuse/Misuse/Diversion/Withdrawal). 
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12.4 Blinding and Randomization 
Following randomization, this study will be conducted as a double-blind investigation. Neither the 
Investigator nor the subject will know the identity of the assigned treatment. Supplies will be prepared 
using matching placebo tablets. Central randomization will be implemented in this study. Subjects will 
be randomly assigned to 1 of 2 treatment groups (continued opioid therapy or structured 
discontinuation of opioid therapy) in a 1:1 ratio based on a computer-generated randomization 
schedule prepared before the study by or under the supervision of the sponsor. The randomization will 
be balanced by using randomly permuted blocks and will be stratified by responder status (Optimal 
Responder; Suboptimal Responder) and Index ER opioid (morphine, oxycodone, or oxymorphone). A 
minimum of 20% of subjects will be randomized into each of the baseline ER opioid strata within each 
responder cohort. The IRT will assign a unique treatment code, which will dictate the treatment 
assignment and study medication for the subject. The requestor must use his or her own user 
identification and personal identification number when contacting the IRT, and will then give the 
relevant subject details to uniquely identify the subject. 
In the case of emergency, the Investigator will have the ability to break the blind at the clinical site for 
the welfare of the subject. Breaking the blind will be accomplished by using the IRT web interface. 
Before breaking the blind, the Investigator should attempt to contact the Medical Monitor to discuss 
the necessity of breaking the blind. The Investigator will be required to make a full written explanation 
of the reason for unblinding the subject and the date. In the event that a subject is unblinded prior to 
contacting the Medical Monitor, the Investigator must provide this information in writing to the 
Medical Monitor as soon as possible. The explanation for breaking the blind will be recorded in the 
eCRF. Breaking the blind at the investigative site will immediately disqualify the subject from further 
participation in the study. In addition, the event(s) leading to emergency unblinding must be reported 
as a SAE according to instructions in section 14.5.2. 
Drug Safety will also have the ability to break the blind for individual subjects in order to fulfill 
regulatory reporting responsibilities.  That information will not be shared with study operational 
personnel. 
Electronic access to the randomization codes in the IRT system will be granted to Drug Supply only.   
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13 
ASSESSMENT OF EFFICACY 
13.1 Efficacy Measurements 
Efficacy will be assessed by the following measurements: 
• PI: Subjects will record the Average PI and Worst PI scores in the past 24 hours on 0-10 
NRS before bedtime each day using the phone system. 
• RMDQ: The RMDQ is an interviewer- or self-administered health status questionnaire that 
measures the level of physical function in subjects with CLBP.(2) 
• BPI-SF: The BPI-SF is a self-administered questionnaire that measures pain severity and 
the impact of pain on daily function.(3) 
• Regional Pain Scale: The Regional Pain Scale is a self-administered questionnaire that 
measures the location and intensity of pain in 38 articular and nonarticular regions.(4)  
• PQAS: The PQAS assesses the different aspects and types of pain (sharp, dull, achy, hot, 
and cold) that a subject experiences. (5)  
• EQ-5D-5L: The EQ-5D-5L is a self-administered general measure of health outcome 
applicable to a wide range of health conditions and treatments.(6) 
• PGIC: The PGIC is a self-administered questionnaire that assesses the subject level of 
improvement/worsening from the beginning to the end of treatment.(7)  
• PHQ-8: The PHQ-8 is an 8-item questionnaire that aims at assessing the level of depression 
of a subject. Each item is scored from 0 = “not at all” to 3= “nearly every day”; the total 
score, which is the sum of the score for each item, can be from 0 to 24. A score ≥10 is 
considered major depression and ≥20 is severe major depression. (8) 
• MOS Sleep Scale: The MOS Sleep Scale is a questionnaire that assesses sleep quality.(9) 
• DSST: Overall neuropsychological function will be assessed using the DSST, a test that is 
sensitive to brain damage, dementia, age, and depression, and is a widely used instrument 
for measuring the neuropsychological effects of opioid therapy. The DSST consists of a 
series of digit-symbol pairs followed by a list of digits. Under each digit the subject should 
respond with the corresponding symbol as fast as possible. The number of correct symbols 
within the allowed time (e.g., 90 or 120 sec) is measured.(10) 
• Work productivity: Work productivity will be assessed by the WPAI questionnaire.(11)  
13.2 Endpoints 
The primary efficacy endpoint is: 
Change in the mean Average PI score on the 0-10 NRS from baseline to the 1 week period prior to the 
Week 12 visit. 
For Suboptimal Responders, the mean Average PI score over the 7-day Baseline Period will count as 
the subject’s baseline Average PI score for statistical analysis. 
For Optimal Responders, the mean Average PI score during the Titration Period that meets the 
qualification criteria (Average PI score <4 for 3 consecutive non-missing values) plus any scores 
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between the last qualification score and the Randomization Visit will count as the subject’s baseline 
Average PI score for statistical analysis.  
Secondary efficacy endpoints are: 
For Suboptimal Responders: 
• Change from baseline to Weeks 4, 8, 16, 20, and 24 in 0-10 NRS Average and Worst PI 
scores over 1 week prior to each visit. 
• Cumulative response function in percent improvement in PI score at Weeks 12 and 24 
compared to baseline over 1 week prior to each visit. 
• Changes from baseline to Weeks 12 and 24 in physical function (RMDQ), impact of pain 
on function (BPI-SF), pain quality (PQAS), pain spread (Regional Pain Scale),  sleep 
quality (MOS Sleep Scale), mood (PHQ-8), quality of life (EQ-5D-5L), and work 
productivity (WPAI). 
• Proportion of subjects with overall clinical benefit at Weeks 12 and 24 defined as a 
composite measure of key clinical endpoints: ≥30% improvement in average daily PI score 
and ≥20% improvement in RMDQ and PGIC of moderately or better improvement. 
For Optimal Responders: 
• Change from baseline to Weeks 4, 8, 16, 20, and 24 in 0-10 NRS Average and Worst PI 
scores over 1 week prior to each visit. 
• Cumulative response function in percent worsening in PI score at Weeks 12 and 24 over 1 
week prior to each visit compared to baseline. 
• Changes from baseline to Weeks 12 and 24 in physical function (RMDQ), impact of pain 
on function (BPI-SF), pain quality (PQAS), pain spread (Regional Pain Scale),  sleep 
quality (MOS Sleep Scale), mood (PHQ-8), quality of life (EQ-5D-5L), and work 
productivity (WPAI). 
13.3 Exploratory Measurements 
Exploratory measurements include: 
• Change in sensitivity to thermal stimuli on QST (subjects in substudy). 
• Identification of baseline factors predictive of benefit of opioid discontinuation among 
Suboptimal Responders. 
• Changes from baseline in endocrine function and sexual function as characterized in the 
male and female questionnaires; relationship of changes in endocrine function to changes in 
PI; relationship of changes in endocrine function to changes in male and female sexual 
function; and relationship of baseline endocrine status to efficacy of opioid discontinuation. 
• Changes from baseline in neurocognitive function as characterized by the DSST 
 
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14 
ASSESSMENT OF SAFETY 
Safety will be assessed by:  
• AEs 
• Abuse-related events (using the Misuse Abuse Diversion Drug Event Reporting System 
[MADDERS]) 
• Opioid-specific side-effects (defined as a subset of all AEs before the database is locked) 
• Vital signs (heart rate and blood pressure only) 
• Clinical laboratory parameters 
• Physical examination 
Additional safety measures will include: 
• UDT 
• C-SSRS 
• Opioid withdrawal effects (measured by SOWS, COWS, and withdrawal AEs) 
14.1 Definitions 
14.1.1 Adverse Events 
An adverse event (AE) is any unfavorable or unintended change in body structure (signs), body 
function (symptoms), laboratory result (eg, chemistry, ECG, X-ray, etc.), or worsening of a pre-
existing condition associated temporally with the use of the study medication whether or not 
considered related to the study medication. Adverse events will be captured once a subject has signed 
the informed consent. AEs include: 
• Changes in the general condition of the subject 
• Subjective symptoms offered by or elicited from the subject 
• Objective signs observed by the Investigator or other study personnel 
• All concurrent diseases that occur after the start of the study, including any change in 
severity or frequency of pre-existing disease 
• All clinically relevant laboratory abnormalities or physical findings that occur during the 
study 
A treatment-emergent AE (TEAE) is any condition that was not present prior to treatment with study 
medication but appeared following treatment, was present at treatment initiation but worsened during 
treatment, or was present at treatment initiation but resolved and then reappeared while the individual 
was on treatment (regardless of the intensity of the AE when the treatment was initiated). 
All AEs, including both observed or volunteered problems, complaints, signs or symptoms must be 
recorded on the AE page of the eCRF, regardless of whether associated with the use of study 
medication. This would include AEs resulting from concurrent illness, reactions to concurrent 
medication use, or progression of disease states (excluding the disease under study). A condition 
present at baseline that worsens after initiation of study treatment will be captured as an AE; the onset 
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date will be the date the event worsened. The AE should be recorded in standard medical terminology 
when possible. 
14.1.2 Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE that: 
• Results in death 
• Is immediately life-threatening (there is an immediate risk of death from the AE as it 
occurred; this does not include an AE that had it occurred in a more serious form may have 
caused death) 
• Results in or prolongs an inpatient hospitalization (Note: a hospitalization for elective or 
pre-planned surgery, procedure, or drug therapy does not constitute an SAE)  
• Results in permanent or substantial disability (permanent or substantial disruption of one’s 
ability to conduct normal life functions)  
• Is a congenital anomaly/birth defect (in offspring of a subject using the study medication 
regardless of time to diagnosis) 
• Is considered an important medical event 
Important medical events are defined as events that, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the other 
serious outcomes. Examples of important medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
14.2 Monitoring Adverse Events 
At each visit, subjects will be queried regarding any AEs that have occurred since the last visit. 
Subjects will be asked to volunteer information concerning AEs with a non-leading question such as, 
“How do you feel?” Study site personnel will then record all pertinent information in the source 
documents and the eCRF. The study drug compliance record should also be reviewed to detect 
potential overdoses (intentional/unintentional). 
14.3 Relationship to Study Drug 
The degree of “relatedness” of the AE to the study medication must be described using the following 
scale:  
• Not related indicates that the AE is definitely not related to the study medication. 
• Unlikely related indicates that there are other, more likely causes and study medication is 
not suspected as a cause. 
• Possibly related indicates that a direct cause and effect relationship between study 
medication and the AE has not been demonstrated, but there is evidence to suggest there is 
a reasonable possibility that the event was caused by the study medication. 
• Probably related indicates that there is evidence suggesting a direct cause and effect 
relationship between the AE and the study medication. 
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It is the Sponsor’s policy to consider “Probably related” and “Possibly related” causality assessments 
as positive causality. “Not related” and “Unlikely related” causality assessments are considered as 
negative causality. 
Assessments will be recorded on the eCRF and must indicate clearly the relationship being assessed. 
For example, an AE that appears during a placebo run-in phase would be assessed with respect to the 
placebo treatment received and/or study procedures conducted during this phase. If the AE continued 
into an active treatment phase, the relationship would be assessed for the active treatment phase only if 
the AE worsened. 
14.4 Intensity Assessment 
The intensity (or severity) of AEs is characterized as mild, moderate, or severe: 
• Mild AEs are usually transient, requiring no special treatment, and do not interfere with the 
subject’s daily activities. 
• Moderate AEs introduce a low level of inconvenience or concern to the subject and may 
interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
• Severe AEs interrupt a subject’s usual daily activity and typically require systemic drug 
therapy or other treatment. 
When the intensity category of an AE changes, the greatest intensity during that continuous episode 
should be recorded.  
14.5 Reporting Adverse Events and Serious Adverse Events 
14.5.1 Reporting Adverse Events 
Throughout the study, AEs will be documented on the source document and on the appropriate page of 
the eCRF whether or not considered treatment-related. This includes any new signs, symptoms, injury 
or illness, including increased severity of previously existing signs, symptoms, injury, or illness. 
Conditions existing prior to screening will be recorded as part of the subject’s medical history. The 
Investigator is responsible for assessing the relationship of AEs to the study medication; relationship 
will be classified as not related, unlikely related, possibly related, or probably related.  
Only SAEs will be collected starting at the time of signing the informed consent through Screening.  
Following Screening, all AEs will be collected by the Investigator through 3 days after the last dose of 
study medication; this includes any AEs that are ongoing at the time of completion/termination of the 
study. All ongoing AEs must be followed until resolution or for 14 days after the subject’s last study 
visit, whichever comes first.  
14.5.2 Reporting Serious Adverse Events 
Any SAE, including death resulting from any cause, which occurs to any subject participating in this 
study must be reported via email or fax by the Investigator using the OPC Clinical Trial Report Form 
for SAEs within 24 hours of first becoming aware of the SAE. SAEs will be collected by the 
Investigator from the time of signing the informed consent through 30 days after the last dose of study 
medication. SAEs that occur within 30 days following cessation of the study treatment, or within 30 
days following premature discontinuation from the study for any reason, must also be reported within 
the same timeframe. Any SAE that is felt by the Investigator to be related to the study medication must 
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be reported regardless of the amount of time since the last dose received. Follow-up information 
collected for any initial report of an SAE must also be reported to the Sponsor within 24 hours of 
receipt by the Investigator.  
All SAEs will be followed until resolution, stabilization of condition, or until follow-up is no longer 
possible. In the event discussion is necessary regarding treatment of a subject, call the Medical 
Monitor (see contact information in section 3). 
All SAEs should be sent via the email address, or faxed to the fax number, provided in section 3. 
The Sponsor will determine whether the SAE must be reported within 7 or 15 days to regulatory 
authorities in compliance with local and regional law. If so, the Sponsor (or the Sponsor’s 
representative) will report the event to the appropriate regulatory authorities. The Investigator will 
report SAEs to the Institutional Review Board (IRB) per their IRB policy. 
14.5.3 Follow-Up Procedures for Serious Adverse Events 
To fully understand the nature of any SAE, obtaining follow-up information is important. Whenever 
possible, relevant medical records such as discharge summaries, medical consultations, and the like 
should be obtained. In the event of death, regardless of cause, all attempts should be made to obtain the 
death certificate and any autopsy report. These records should be reviewed in detail, and the 
Investigator should comment on any event, lab abnormality, or any other finding, noting whether it 
should be considered a serious or non-serious AE, or whether it should be considered as part of the 
subject’s history. In addition, all events or other findings determined to be SAEs should be identified 
on the follow-up SAE form and the Investigator should consider whether the event is related or not 
related to study drug. All events determined to be nonserious should be reported on the eCRF. 
14.6 Events of Special Interest (EOSI) 
14.6.1 Overdose/Abuse/Misuse/Diversion/Withdrawal 
14.6.1.1 
Terminology   
Overdose is the accidental or intentional use of a drug or medicine in an amount that is higher than the 
maximum recommended dose.   
Study Drug Overdose is any accidental or intentional use of study drug in an amount higher than the 
dose indicated by the protocol for that subject.  
Abuse is defined as the taking of the drug for a non-therapeutic use or the use of an illicit drug (or 
substance). 
Misuse is the taking of the drug for a therapeutic use, but not in accordance with the 
indication/dose/route of administration/frequency for which it was prescribed. 
Diversion is any intentional act that results in transferring a prescription medication from lawful to 
unlawful distribution or possession 
Withdrawal is an acute state caused by cessation or dramatic reduction of use of opioid drugs that has 
been heavy and prolonged (typically several weeks or longer). The physiologic reaction frequently 
includes sweating, shaking, headache, drug craving, nausea, vomiting, abdominal cramping, diarrhea, 
inability to sleep, confusion, agitation, depression, anxiety, and other behavioral changes. 
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14.6.1.2 
 Handling Reports of Overdose/Abuse/Misuse/Diversion/Withdrawal 
Overdose: Study drug compliance (see section 12.3) should be reviewed to detect potential instances 
of overdose (intentional or accidental). Any study drug overdose during the study should be noted in 
the IRT. 
All AEs associated with an overdose are considered EOSI and should be reported using the procedures 
detailed in section 14.6.1.3 Reporting and Classification of Events Using MADDERS.  If an EOSI 
associated with an overdose does not meet seriousness criteria, the AE must still be reported within 24 
hours of first becoming aware of the event using the AE form, which will trigger the MADDERS 
supplemental forms.  Those AEs of overdose meeting the seriousness criteria will be handled 
according to the procedures of section 14.5.2 Reporting Serious Adverse Events and by completing the 
MADDERS supplemental forms.  
Follow-up information for AEs associated with an overdose should be reported using the MADDERS 
forms for all events and the SAE forms for serious events. 
Abuse: All incidents and AEs associated with abuse are considered EOSI and should be reported 
using the procedures detailed in section 14.6.1.3  Reporting and Classification of Events Using 
MADDERS.   If an EOSI associated with abuse does not meet seriousness criteria, the AE must still be 
reported within 24 hours of first becoming aware of the event using the AE form, which will trigger 
the MADDERS supplemental forms.  Those AEs of abuse meeting the seriousness criteria will be 
handled according to the procedures of section 14.5.2 Reporting Serious Adverse Events and by 
completing the MADDERS supplemental forms.   
Follow-up information for AEs associated with abuse should be reported using the MADDERS forms 
for all events and the SAE forms for serious events. 
Misuse: All AEs associated with misuse are considered EOSI and should be reported using the 
procedures detailed in section 14.6.1.3  Reporting and Classification of Events Using MADDERS.   If 
an EOSI associated with misuse does not meet seriousness criteria, the AE must still be reported within 
24 hours of first becoming aware of the event using the AE form, which will trigger the MADDERS 
supplemental forms.  Those AEs of misuse meeting the seriousness criteria will be handled according 
to the procedures of section 14.5.2 Reporting Serious Adverse Events and by completing the 
MADDERS supplemental forms.   
Follow-up information for AEs associated with misuse should be reported using the MADDERS forms 
for all events and the SAE forms for serious events. 
Diversion: Even though instances of potential diversion are not considered adverse events, all 
incidences of diversion are considered EOSI and should be reported using the procedures detailed in 
section 14.6.1.3  Reporting and Classification of Events Using MADDERS.  If there is an instance of 
potential diversion, the diversion must be reported within 24 hours of awareness using the appropriate 
MADDERS supplemental forms. 
Follow-up information for instances of potential diversion should using the MADDERS forms. 
Withdrawal: Signs and symptoms of opioid withdrawal are considered EOSI and should be reported 
using the procedures detailed in section 14.6.1.3  Reporting and Classification of Events Using 
MADDERS.   If an EOSI associated with opioid withdrawal does not meet seriousness criteria, the AE 
must still be reported within 24 hours of first becoming aware of the event using the AE form, which 
will trigger the MADDERS supplemental forms.  Those AEs of opioid withdrawal meeting the 
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seriousness criteria will be handled according to the procedures of section 14.5.2 Reporting Serious 
Adverse Events and by completing the MADDERS supplemental forms. 
14.6.1.3 
Reporting and Classification of Events Using MADDERS® 
Potential abuse-related events will be tracked using the Misuse Abuse Diversion Drug Event Reporting 
System (MADDERS®), which is a clinician-based assessment to identify and classify such events 
based on selected AEs and drug accountability discrepancies. The MADDERS® classifies such events 
as abuse, misuse, suicide-related, therapeutic error, none of the above, and unknown.(12) Additional 
modifiers are available for severity of the event, route of administration, tampering, withdrawal, 
addiction-related, diversion, and overdose. Relevant adverse events and certain drug accountability 
discrepancies occurring during the study will trigger specific, detailed forms from the MADDERS 
system.  The MADDERS® will be used to measure potentially abuse-related events throughout the 
study (Appendix R).  
Follow-up information for AEs of special interest should be reported according to the instructions in 
section 14.5.2, Reporting Serious Adverse Events. 
14.6.2 Pregnancy 
Subjects should be instructed to immediately notify the Investigator of any pregnancies. Any 
uncomplicated pregnancy that occurs in a subject during this clinical study will be reported for 
tracking purposes only. All subject pregnancies that are identified during or after this study, where 
the estimated date of conception is determined to have occurred during study drug therapy or within 3 
days of the last dose of study medication need to be reported, followed to conclusion, and the outcome 
reported, even if the subject is discontinued from the study.  Pregnancies that occur in the partner of a 
treated subject (i.e., female partner of male subject) also need to be reported.  The Investigator should 
report all pregnancies within 24 hours using the Initial Pregnancy Report Form, and any pregnancy-
associated SAE using the SAE report form, according to the usual timelines and directions for SAE 
reporting provided in section 14.5.2. Monitoring of the pregnancy should continue until conclusion of 
the pregnancy; 1 or more Follow-up Pregnancy Report Form(s) detailing progress, and a Two-Month 
Follow-up Pregnancy Report Form detailing the outcome, should be submitted. 
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational product 
under study may have interfered with the effectiveness of a contraceptive medication. Likewise, 
elective abortions without complications are not considered AEs. Any SAEs associated with pregnancy 
(e.g., congenital abnormalities/birth defects/spontaneous miscarriages or any other serious events) 
must additionally be reported as such using the SAE report form. Spontaneous miscarriages should 
also be reported and handled as SAEs.  
A subject who becomes pregnant must be withdrawn from the study. Should a subject discontinue 
treatment due to pregnancy, alternative treatment (if available) should be arranged according to 
standard of care, as determined by the Investigator. Attempts to obtain the pregnancy follow-up and 
pregnancy outcome information detailed above are necessary even if a subject discontinues treatment 
because of pregnancy. 
14.6.3 AEs/SAEs Experienced by Non-subjects Exposed to Study Medication 
Non-subjects are persons who are not enrolled in the study but have been exposed to study medication, 
including instances of diversion of study medication. All such AEs/SAEs occurring in non-subjects 
from such exposure will be reported to the OPC Drug Safety Department (when the non-subject 
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agrees) on the appropriate form for serious adverse experiences regardless of whether the event is 
serious or not. Instructions for completing the form for events experienced by non-subjects will be 
provided. SAEs occurring in non-subjects exposed to study medication will be processed within the 
same SAE reporting timelines as described in section 14.5.2. Additionally, the drug accountability 
source documentation at the site should reflect this occurrence. 
14.7 Clinical Laboratory Determinations 
Clinical laboratory tests will be conducted according to the Schedule of Events. Clinical laboratory 
tests will be performed by a designated central laboratory. Each site will be provided with instructions 
on specimen collection, preparation, packaging and transport. Refer to the central laboratory manual 
for further information regarding sample collection, handling, and labeling. The results of the tests will 
be returned to the investigational sites. Clinical laboratory parameters that will be measured in this 
study are listed in Table 4. 
Clinical laboratory test data will be reviewed by the Investigator, or designee, and additional clinical 
laboratory tests may be ordered at his/her discretion (e.g., if the results of any clinical laboratory test 
falls outside the reference range or clinical symptoms necessitate additional testing to ensure safety). 
Any additional testing will be performed by the designated central laboratory. 
Laboratory results will be sent electronically to the designated contract research organization for data 
management. The Investigator will review all abnormal lab results for clinical significance. Any 
abnormal clinical laboratory test result meeting the criteria for clinical significance (refer to central 
laboratory manual) will be recorded as an AE or SAE as appropriate (see sections 14.1.1 and 14.1.2).  
Table 4: 
Clinical Laboratory Tests 
Hematology 
Biochemistry 
Urinalysis 
Hemoglobin 
Glucose 
Glucose 
Hematocrit 
Sodium 
Protein 
Red blood cell 
Potassium 
Specific gravity 
White blood cell (WBC) 
Calcium 
pH 
Platelets 
Chloride 
Ketones 
WBC Differential 
CO2 
Bilirubin 
 
Inorganic phosphate 
Urobilinogen 
 
Blood urea nitrogen  
Nitrite 
 
Creatinine 
Blood* 
 
Creatinine clearance  
Leukocytes* 
 
AST 
 
 
ALT 
 
 
Gamma-glutamyl transferase (GGT) 
 
 
Total bilirubin (TBL) (direct bilirubin reflex if 
elevated) 
 
 
Albumin 
 
 
Alkaline phosphatase (ALP) 
 
 
Uric acid 
 
* Microscopic examination will be performed if blood or leukocytes are detected by dipstick. 
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Endocrine function will be assessed by measuring blood levels of free and total testosterone, 
luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol [women only],  insulin-like 
growth factor-1 (IGF-1), cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone 
sulfate (DHEAS), and thyroid-stimulating hormone (TSH) [baseline only].(13)  
For women of childbearing potential, a serum pregnancy test will be performed at Screening, and a 
urine pregnancy test will be performed at Randomization visit and Follow-up visit 2 or termination. If 
necessary, additional urine pregnancy tests can be performed at any time during the study at the 
discretion of the Investigator. Female subjects of childbearing potential must have a negative 
pregnancy test at Screening to be enrolled in the study. Pregnancy tests will be supplied by the 
Sponsor. 
The Investigator will collect urine samples for the screening of (but not limited to) illicit drugs, 
opioids, other controlled prescription drugs, and alcohol. 
14.8 Vital Signs 
Vital sign measurements will be documented as described in the Schedule of Events. These parameters 
include height, body weight, BMI (calculated), pulse rate, respiratory rate, and systolic and diastolic 
blood pressure. All these parameters will be measured at Screening, while only pulse rate, respiratory 
rate, and blood pressure are measured at subsequent visits. Pulse rate, respiratory rate, and blood 
pressure readings will be taken after the subject has been sitting for 5 minutes. Subjects with systolic 
blood pressure greater than 180 mm Hg or less than 90 mm Hg or diastolic blood pressure greater than 
110 mm Hg or less than 40 mm Hg at the Screening Visit or Randomization Visit should be excluded 
from study participation. 
The Investigator will review all vital sign values for clinical significance. Any vital sign value meeting 
the Investigator’s or Sponsor’s criteria for clinical significance will be recorded as an AE or SAE as 
appropriate (see sections 14.1.1and 14.1.2). 
14.9 Physical Examination 
A complete physical examination will be performed at Screening. Additional brief physical 
examinations will be performed at other times as described in the Schedule of Events. All 
examinations will be performed by a physician or health professional listed on the Form FDA 1572 
and licensed to perform physical examinations. 
The Investigator will review all physical exam findings for clinical significance. Any physical exam 
finding meeting the Investigator’s or Sponsor’s criteria for clinical significance will be recorded as an 
AE or SAE as appropriate (see sections 14.1.1 and 14.1.2). 
14.10 Other Safety Analyses 
Other safety parameters analyzed will be:  
• Withdrawal symptoms: The severity of withdrawal symptoms will be measured by the 
SOWS (14) and COWS (15). Withdrawal will also be assessed by the occurrence of typical 
withdrawal AEs, including chills, sweating, tremor, and muscle cramps. 
• UDT: A quantitative UDT for illicit drugs, non-prescribed controlled substances, and 
alcohol will be conducted at Screening and Weeks 4, 12, and 24 after randomization. The 
UDT will be performed by liquid chromatography tandem mass spectrometry (LC-MS/MS) 
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technology.  The management of unexpected findings is described in the UDT Appendix T. 
If an unexpected finding occurs after a repeat UDT, the subject will be discontinued from 
the study. 
• C-SSRS: Risk of suicide will be measured at Screening using the C-SSRS “Lifetime”. 
Subsequent assessments will be performed at Weeks 6 and 24 using C-SSRS “Since Last 
Visit”. 
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15 
ASSESSMENT OF PHARMACOKINETICS 
Not applicable 
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16 
ASSESSMENT OF PHARMACODYNAMICS 
Not applicable. 
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17 
STATISTICAL CONSIDERATIONS AND METHODS 
A general description of the statistical methods to be used to analyze the efficacy and safety data is 
outlined below. Specific details will be provided in the Statistical Analysis Plan (SAP). 
All statistical comparisons will be 2-sided at the 0.05 alpha level, with separate analyses for the 
Suboptimal Responders and the Optimal Responders. There will be no adjustments for multiplicity. 
17.1 Determination of Sample Size 
The primary endpoint is the change from baseline to Week 12 (mean Average PI score over the 1 week 
prior to the Week 12 visit) in 0-10 NRS Average PI score comparing the opioid discontinuation group 
to the continued opioid therapy group. To detect a between-group difference of 0.8 points with 90% 
power, assuming a standard deviation of 2.5, using the two-sided 5% significance level, 205 
randomized subjects per arm for each responder type will be needed; thus a total of 820 subjects will 
need to be randomized into the Blinded Structured Opioid Discontinuation period. Assuming a 3:1 
screen failure rate, approximately 3280 subjects will need to be screened.  
17.2 Subject Populations 
Separate analyses will be conducted for Suboptimal Responders and Optimal Responders since these 
are considered two different study populations. Therefore, all analysis populations will be defined for 
Suboptimal Responders and Optimal Responders separately. 
17.2.1 Safety Population 
Different Safety Populations will be defined to summarize data pre- and post-randomization.  
• For Suboptimal Responders, the Safety Population Pre-Randomization will include all 
subjects who were enrolled in the study and were switched to the standardized regimen 
(i.e., who enter the Run-in Period) and took at least one dose of study drug.  
• For Optimal Responders,  
− The Safety Population Pre-Randomization (Observation Period) will include all 
Optimal Responder subjects who entered the Observation Period. 
− The Safety Population Pre-Randomization (Taper Period) will include all Optimal 
Responder subjects who were enrolled in the study and took at least 1 dose of study 
medication during the Taper Period.  
− The Safety Population Pre-Randomization (Titration Period) will include all Optimal 
Responder subjects who were enrolled in the study and took at least 1 dose of study 
medication during the Titration Period (i.e., who entered the Open-label Titration 
Period). 
For both Suboptimal Responders and Optimal Responders, the Safety Population Post-Randomization 
will include all subjects who were randomized and received at least one dose of double-blind 
treatment.  
Safety will be analyzed separately for these populations. Subjects who are randomized to one treatment 
group but mistakenly assigned the medication kit of the other treatment group will be reported “as 
treated”. 
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17.2.2 ITT Population 
The ITT Population will include all subjects who were randomized and received at least one dose of 
study drug after randomization. All efficacy analyses will be performed using this population. Subjects 
will be reported in the treatment group to which they were randomly assigned. 
17.2.3 Per-protocol Population 
The Per-Protocol Population is a subset of the ITT population, excluding subjects with protocol 
deviations that may have an impact on the results of the primary efficacy analyses. An additional 
analysis of the primary efficacy endpoint will be performed using this population. Further details of the 
Per-Protocol Population definition will be specified in the SAP. 
17.3 Subject Disposition 
The number of subjects included in each study population will be summarized by treatment group. 
Subjects excluded from the safety and efficacy populations will be listed by treatment group. 
The number and percentage of subjects completed and prematurely discontinued during the Blinded 
Structured Opioid Discontinuation Period and up to the end of the study will be presented for each 
responder type and each treatment group. Screen failures (i.e., screened but not randomized subjects) 
and the associated failure reasons will be tabulated overall. Reasons for premature discontinuation as 
recorded on the termination page of the eCRF and collected in the special questionnaire will be 
summarized (number and percentage) by responder type and treatment group for all randomized 
subjects.  
17.4 Demographics and Other Baseline Characteristics 
Demographic characteristics, including sex, age, age group, race, height, and weight, will be 
summarized by responder type and treatment group using descriptive statistics. All screening 
characteristics and medical information, including type and duration of opioid use and duration since 
diagnosis of low back pain, will also be summarized by responder type and treatment group using 
descriptive statistics. The descriptive summaries will include frequency tables for all categorical 
response variables and number, mean, standard deviation, minimum and maximum for all continuous 
variables. 
17.5 Efficacy Analyses 
All efficacy analyses will be conducted separately for Suboptimal and Optimal Responders. 
Definition of Baseline: 
For Suboptimal Responders, the mean of the Average PI scores over the 7-day Baseline Period will 
count as the subject’s baseline Average PI score for statistical analysis. Similarly, the mean of the 
Worst PI scores over the 7-day Baseline Period will count as the subject’s baseline Worst PI score for 
statistical analysis.  
For Optimal Responders, the mean Average PI score during the Titration Period that meets the 
qualification criteria (Average PI score <5 for 3 consecutive non-missing values) plus any scores 
between the last qualification score and the Randomization Visit will count as the subject’s baseline 
Average PI score for statistical analysis. Similarly, the mean Worst PI score including the 3 
qualification days (as defined above) during the Titration Period plus any days between the 
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qualifications days and the Randomization Visit will count as the subject’s baseline Worst PI score for 
statistical analysis.  
For all other assessments, the last non-missing observation prior to the first dose in the Blinded 
Structured Opioid Discontinuation Period will be used as the baseline observation.   
17.5.1 Primary Efficacy Analysis 
The primary endpoint is the change in the mean Average PI score on the 0-10 NRS from baseline to 
the 1 week period prior to the Week 12 visit. 
The analysis of the primary endpoint will be in two stages. First, multiple imputation will be used for 
missing data based on the reason for missing data. Second, the multiple datasets will be analyzed using 
mixed model repeated measures (MMRM), and the individual imputation dataset results will be 
combined using standard methods (e.g., Little & Rubin, 2002) (16). The imputation and analysis are 
described below. 
The imputation of missing data will be based on the reason for treatment discontinuation. Missing data 
occurring between observed data points will be imputed using Markov Chain Monte Carlo methods to 
create monotone missing data patterns. For missing data caused by discontinuation due to Adverse 
Events, data will be imputed using 
• For Suboptimal Responders, the subject’s baseline Average PI score (with added variability 
based on the variance of the data of the corresponding timepoint of missing data).  
• For Optimal Responders, the subject’s mean Average PI score at the end of the Taper 
Period (with added variability based on the variance of the data of the corresponding 
timepoint of missing data). This score will be the first 3 days of the mean Average PI score 
used to qualify the subject for entry into the Titration Period (i.e., where the mean Average 
PI score is  >5 over ≥3 consecutive days, where this mean Average PI score has also 
increased by ≥1.5 points from the mean Average PI over the 7-day Observation Period). 
For missing data caused by discontinuation due to Lack of Efficacy, data will be imputed using the 
subject’s last non-missing weekly mean Average PI score. As PI data are collected electronically daily, 
this data will convey the level of pain as close as possible to the point of discontinuation. For missing 
data caused by any other reason, data will be imputed using multiple imputation with a regression 
model for prior weekly Average PI scores and treatment group, and utilizing the subject’s observed 
pain scores in the regression model. Ten imputation datasets will be used for this multiple imputation 
procedure. 
The analysis of the individual imputation datasets for the primary endpoint will use a MMRM analysis, 
which includes the fixed effects of treatment group, index ER opioid (morphine, oxycodone, or 
oxymorphone) group, baseline NRS Average PI score, Week, and interaction between treatment group 
and Week as factors. Data up to Week 12 will be included in this analysis. The Restricted Maximum 
Likelihood estimation approach will be used, and the default covariance structure will be unstructured. 
If there are convergence problems for this model, other variance-covariance matrix structures will be 
considered. Results from each of the ten imputation datasets will be combined using standard 
methodology, taking into account the within and between imputation components of variability. 
Estimates of the primary endpoint will be shown by treatment group, and for the difference between 
groups (structured discontinuation treatment group compared to continuation treatment group), 
together with 95% confidence interval and p-value for the difference.  
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17.5.2  Secondary Efficacy Analysis 
Secondary analyses for the primary endpoint will include: 
• A descriptive summary of the change in Average PI score from baseline to Week 12, by 
index ER opioid (morphine, oxycodone, or oxymorphone) group. 
• The same analysis described in section 17.5.1 , using the Per-Protocol population.  
• Sensitivity analyses for missing data: (i) Last observation carried forward with analysis of 
covariance (ANCOVA) (model terms of baseline NRS Average PI score, stratification 
parameters, and treatment group); (ii) MMRM of observed data up to Week 12 (with the 
same model terms as the primary analysis model). 
The following endpoints will be analyzed using the same MMRM model as described above for the 
primary endpoint analysis (with corresponding baseline score and stratification parameters as 
covariates), using observed data (without multiple imputation). Data for these analyses will include all 
available timepoints up to Week 24: 
• The change from baseline to Weeks 4, 8, 16, 20, and 24 in the 0-10 NRS Average PI score 
over 1 week prior to each visit 
• The change from baseline to Weeks 4, 8, 12, 16, 20, and 24 in the 0-10 NRS Worst PI score 
over 1 week prior to each visit 
The following endpoints will be analyzed using ANCOVA (with model terms of baseline score, 
stratification parameters, and treatment group) as described above for the primary endpoint analysis, 
using observed data (without multiple imputation): 
• The change from baseline to Weeks 12 and 24 in the RMDQ total score 
• The change from baseline to Weeks 12 and 24 in the BPI-SF Pain Interference Index 
(composite function score), and individual pain inference items (e.g., Pain Interference with 
General Activity, Walking Ability, Sleep, and Normal Work) 
• The change from baseline to Weeks 12 and 24 in the PQAS specific aspects of pain (17 
items), the Overall Unpleasantness of Pain, and the intensity of both Deep and Surface pain 
• The change from baseline to Weeks 12 and 24 in the number of regions of any pain from 
the Regional Pain Scale  
• The change from baseline to Weeks 12 and 24 in sleep quality using the MOS Sleep Scale 
• The change from baseline to Weeks 12 and 24 in mood using the PHQ-8 
• The change from baseline to Weeks 12 and 24 in work productivity in the WPAI. 
The cumulative response function in percent improvement in Average PI score at Weeks 12 and 24 
compared to baseline over 1 week prior to each visit, will be shown by treatment group. The categories 
used will include change from baseline of <0% (any improvement), and ≤10% to ≤50% in steps of 
10%. In addition, the changes from baseline to Weeks 12 and 24 relating to worsening will be shown 
(including >0%, and ≥10% to ≥50% in steps of 10%). 
The overall clinical benefit for the Suboptimal Responders is defined as ≥30% improvement in PI and 
≥20% improvement in RMDQ and PGIC of moderately or better improvement. The proportion of 
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subjects in the Suboptimal Responder group with overall clinical benefit at Weeks 12 and 24 will be 
analyzed using logistic regression for binary endpoints with model terms for baseline Average PI 
score, baseline RMDQ, stratification variables, and treatment group. 
The time to discontinuation due to lack of efficacy and for all reasons will be summarized by treatment 
group using Kaplan-Meier estimates. 
The type of pain (intermittent, variable or stable) collected in the PQAS will be summarized at each 
timepoint, and changes will be summarized. The cumulative response function in percent improvement 
in RMDQ at Weeks 12 and 24 compared to baseline will also be summarized. The cumulative percent 
worsening in RMDQ will also be summarized at Weeks 12 and 24. 
The PGIC scores will be analyzed using the Cochran-Mantel-Haenszel (CMH) row mean score test. 
The percentage of subjects with ‘Much improved/very much improved’ will be presented as 
descriptive statistics. 
The average daily dose of opioid analgesic medication taken during the Blinded Structured Opioid 
Discontinuation Period and during the entire double-blind treatment period will be summarized with 
descriptive statistics by treatment group for each type of formulation (ER/CR and IR). 
The baseline and post-baseline responses in the five dimensions of the EQ-5D-5L questionnaire 
(mobility; self-care; usual activity; pain/discomfort; anxiety/depression) will be summarized by 
treatment group. This summary will use observed data only (no imputation for missing data). An 
additional question, called the EQ-VAS asks the subject to rate their health today using a VAS scale 
from 0 (the worst health you can imagine) to 100 (the best health you can imagine). This will be 
summarized.  
The change from baseline to Weeks 12 and 24 in the impairment endpoints of the WPAI for CLBP 
(WPAI:LBP) will be summarized by treatment group. These endpoints are Activity impairment, 
Overall Work Impairment, Impairment While Working, and Work Time Missed due to Low Back 
Pain. These data will be categorized (0%, >0-5%, >5-10%, >10-25%, >25-50%, >50-75%, >75-
<100%, 100%) and analyzed using the CMH test. This summary will use observed data only (no 
imputation for missing data).  
17.5.3 Exploratory Analyses 
Exploratory analyses are: 
• Change in sensitivity to thermal stimuli on QST (subjects participating in the substudy). 
This will be reported in a separate report of the substudy. 
• Univariate and multivariate regression analyses with each subject characteristic as an 
independent variable to determine the subjects’ characteristics that predict suboptimal or 
optimal response to structured discontinuation of opioid therapy 
• Changes from baseline in endocrine function and sexual function as characterized in the 
male and female questionnaires; relationship of changes in endocrine function to changes in 
PI; relationship of changes in endocrine function to changes in male and female sexual 
function; and relationship of baseline endocrine status to efficacy of opioid discontinuation.  
• Changes from baseline in neurocognitive function as characterized by the number of correct 
responses from the DSST will be analyzed using ANCOVA (with model terms of baseline 
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score, stratification parameters, and treatment group) as described above for the primary 
endpoint analysis, using observed data (without multiple imputation): 
17.6 Safety Analyses 
Safety will be assessed by  
• Occurrence of AEs 
• Occurrence of abuse-related events 
• Occurrence of withdrawal AEs 
• Occurrence of opioid-specific side effects 
• Changes in vital signs 
• Changes in physical examination findings 
• Changes in clinical laboratory parameters 
Additional safety measures will include: 
• Occurrence of abnormal UDT findings 
• Occurrence of C-SSRS findings 
• Occurrence and severity of opioid withdrawal effects as measured by SOWS and COWS. 
17.6.1 Adverse Events 
Version 18.0 or newer of the Medical Dictionary for Regulatory Activities (MedDRA) will be used to 
code AEs. 
An AE (classified by preferred term) that started during the treatment period will be considered a 
TEAE if it was not present prior to the first dose of study drug, or was present prior to the first dose of 
study drug but increased in intensity during the treatment period. If more than 1 AE is reported prior to 
the first dose of study drug and coded to the same preferred term, then the AE with the greatest 
intensity will be used as the benchmark for comparison to the AEs occurring during the treatment 
period which were also coded to that preferred term. Any AE present prior to the first dose of study 
drug that increases in intensity during the treatment period will be re-entered with a new start date of 
the date of increased intensity.  
Descriptive statistics (the number and percentage) for subjects reporting TEAEs in each treatment 
group will be tabulated by system organ class and preferred term; by system organ class, preferred 
term, and severity; and by system organ class, preferred term, and relationship to study drug. If more 
than 1 AE is coded to the same preferred term for the same subject, the subject will be counted only 
once for that preferred term using the most severe and most related occurrence for the summarization 
by severity and by relationship to the study drug. 
The distribution of TEAEs by severity and relationship to study drug will be summarized by treatment 
group. The incidence of common (≥5% of subjects in any treatment group) TEAEs will be summarized 
by preferred term and treatment group and sorted by decreasing frequency in the discontinuation arm. 
SAEs and AEs leading to premature discontinuation of study drug will be summarized by preferred 
term and treatment group, and sorted by decreasing frequency in the discontinuation arm. SAEs will be 
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displayed separately for those events occurring before the first study drug dosing date and all 
subsequent ones. 
Listings will be presented for subjects with SAEs, subjects with AEs leading to discontinuation, and 
subjects who die (if any). 
Although abuse-related events will be reported as AEs, these AEs will be reported separately in a 
descriptive fashion for each group at each visit.  
17.6.2 Vital Signs 
Descriptive statistics for vital signs (i.e., systolic and diastolic blood pressure, pulse rate, respiratory 
rate, and body weight) and their changes from baseline at each visit and at the end of study will be 
presented by treatment group.  
Vital sign values are potentially clinically significant (PCS) if they meet both the observed value 
criteria and the change from baseline criteria. The criteria for PCS vital sign values will be detailed in 
the SAP. The PCS percentages will be calculated relative to the number of subjects with baseline and 
at least one post-baseline assessment. The numerator will be the total number of subjects with at least 
one PCS post-baseline vital sign value. A supportive listing of subjects with post-baseline PCS values 
will be provided including the subject ID, study center, baseline and post-baseline values. A listing of 
all AEs for subjects with PCS vital signs will also be provided. 
17.6.3 Clinical Laboratory Parameters 
Descriptive statistics for clinical laboratory values in International System of Units (SI units) and 
changes from baseline at each assessment time point will be presented by treatment group for each 
clinical laboratory parameter. 
The number and percentage of subjects with PCS post-baseline clinical laboratory values will be 
tabulated by treatment group. The criteria for PCS laboratory values will be detailed in the SAP. The 
PCS percentages will be calculated relative to the number of subjects with available non-PCS baseline 
values and at least one post-baseline assessment. The numerator will be the total number of subjects 
with available non-PCS baseline value and at least one post-baseline PCS value. A supportive listing of 
subjects with post-baseline PCS values will be provided, including the subject ID, study center, 
baseline and post-baseline values. A listing of all AEs for subjects with PCS laboratory values will also 
be provided. 
17.6.4 Physical Examination 
For each body system, the number and percentage of subjects with transitions from normal or not done 
at baseline to abnormal post-baseline will be presented by treatment group. The percentages will be 
calculated relative to the number of subjects having normal or missing assessments at baseline who 
also had a post-baseline physical examination. A listing of physical examination data for all subjects 
will also be provided. 
17.6.5 Other Safety Parameters 
Other safety parameters analyzed will be: 
• UDT findings will be summarized descriptively as the type of abnormal finding. 
• Occurrence of C-SSRS findings after baseline. 
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• Possible opioid withdrawal effects will be summarized descriptively with SOWS scores at 
Weeks 2, 4, and 6 and with COWS scores at Weeks 2 and 4. 
17.7 Pharmacokinetic Analyses 
Not applicable 
17.8 Pharmacodynamic Analyses 
Not applicable 
17.9 Other Data (e.g., Health Economics/QOL, Pharmacogenetics, etc) 
Work productivity will be measured by the WPAI. Analysis of WPAI data are described in the 
secondary efficacy analyses. 
17.10 Interim Analysis 
No interim analysis is planned for this study. 
17.11 Statistical Software 
Statistical analyses will be performed using Version 9.2 (or higher) of SAS® (SAS Institute, Cary, NC). 
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18 
STUDY DRUG MATERIALS AND MANAGEMENT 
18.1 Study Drug Identity 
Study medications will include blinded ER formulations of morphine sulfate, oxycodone HCl, and 
oxymorphone HCl.  
Morphine Sulfate Extended Release (MSER) in strengths of 15, 30, 60, and 100 mg, and 
matching placebos will be supplied by Purdue Pharma L.P.  
Oxycodone HCl Extended Release (OCER) in strengths of 10, 20, 30, 40, 60, and 80 mg, and 
matching placebos will be supplied by Purdue Pharma L.P.  
Oxymorphone HCl Extended Release (OMER) in strengths of 5, 10, 15, 20, 30, and 40 mg, and 
matching placebo will be supplied by Endo Pharmaceuticals. 
Study prescribed drugs that will be used as rescue pain medications will include commercial-image, IR 
formulations of morphine sulfate, oxycodone HCl, oxymorphone HCl, and acetaminophen. 
Morphine sulfate (MSIR) 15 mg will be supplied by West-Ward Laboratories. 
Oxycodone HCl (OCIR) 5 mg will be supplied by Mallinckrodt Pharmaceuticals. 
Oxymorphone HCl (OMIR) 5 mg will be supplied by Endo Pharmaceuticals Inc. 
Acetaminophen 500 mg tablets will be sourced commercially. 
 
18.2 Study Drug Packaging and Labeling 
Blinded ER study drug and matching placebos will be packaged in 20-count blister cards minimally 
labeled with protocol reference, contents (“oxymorphone ER or placebo”, “oxycodone ER or placebo”, 
or “morphine sulfate ER or placebo”), Schedule II designation, storage and appropriate caution 
statements.  Additionally, the supplying company for each product will be listed as the sponsor.  
Open-label MSIR, OCIR, and OMIR will be packaged in 15-count blister cards minimally labeled with 
protocol reference, contents, Schedule II designation, storage and appropriate caution statements.  
Additionally, the supplying company for each product will be listed.  
Acetaminophen will be supplied in commercial bottles with the original manufacturer’s labeling.  An 
auxiliary label will be added with protocol reference, use instructions, storage and appropriate caution 
statements.     
18.3 Study Drug Storage 
All study medications and study prescribed drugs that will be used as rescue medications will be 
provided by OPC representative. Since MSER, OCER, OMER, MSIR, OCIR, and OMIR are Schedule 
II controlled substances according to the Controlled Substances Act of 1970, all study medications and 
study prescribed drugs will be stored in a locked facility with restricted access that meets Drug 
Enforcement Agency requirements. 
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18.4 Study Drug Preparation 
At the time of dispensing, the investigator or designee will use the IRT system to determine which 
material kit(s) for study drug and rescue to dispense to a given subject.  The investigator or designee 
will complete the subject number field on the kit labels. 
18.5 Study Drug Accountability 
The principal investigator is responsible for ensuring accountability of all drugs supplied and 
appropriate storage and allocation of these supplies.  
The investigator is responsible for ensuring that all study medications and study prescribed drug used 
as rescue medications received at the site are inventoried and accountability performed and that 
dispensed drug is recorded in both the CRF and the study drug logs.  The investigator, or designee, will 
verify drug accountability with subjects during site visits.  
18.6 Study Drug Handling and Disposal 
The principal investigator will not supply study medications or study prescribed drugs used as rescue 
medication to any person except those named as sub-investigators on Form FDA 1572, designated 
staff, and subjects in this study and will not dispense study drug or rescue medication from any sites 
other than those listed on Form FDA 1572.  Study drug and rescue medication may not be relabeled or 
reassigned for use by other subjects.  Chain of custody will be followed in accordance with the 
individual site’s standard procedures and will be documented by the site and provided to the Sponsor.  
All unused study drug will be returned, and unit counts will be performed whenever medication is 
returned. The site must account for all study drug received. At the end of the study, all unused drug 
supplies will be returned to the OPC’s packaging vendor.  
 
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19 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
19.1 Source Documents 
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. At a 
minimum, all data required to be collected by the protocol should have supporting source 
documentation for entries in the eCRF, unless the protocol specifies that data can be recorded directly 
on/in the eCRF or other device. 
19.2 Study Monitoring 
A representative of the OPC will meet with the Investigator and his/her staff prior to the entrance of 
the first subject to review study procedures and methods of recording findings in the eCRF.  
After enrollment of the first subject, an OPC representative will be assigned to periodically monitor 
each Investigator site for study progress and to verify that standards of Good Clinical Practice (GCP) 
were followed. The Investigator is expected to prepare for the monitor visit, ensuring that all source 
documents, completed eCRFs, signed consent forms and other study related documents are readily 
available for review. 
19.3 Audits and Inspections 
The Investigator shall permit audits and inspections by the Sponsor, its representatives and members of 
regulatory agencies. The Investigator should immediately notify the Sponsor of an upcoming FDA or 
other regulatory agency inspection. 
19.4 Institutional Review Board (IRB) 
The Investigator shall permit members of the IRB/Independent Ethic Committee (IEC) to have direct 
access to source documents. 
19.5 Data Recording and Documentation 
All data recordings and source documentation (including electronic health records) must be made 
available to the Sponsor (or designee), FDA and any other regulatory agencies that request access to 
study records, including source documents, for inspection and copying, in keeping with federal and 
local regulations. 
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20 
QUALITY CONTROL AND QUALITY ASSURANCE 
Steps to assure the accuracy and reliability of data include the selection of qualified principal 
Investigators and appropriate study centers, review of protocol procedures with the principal 
Investigators and associated personnel prior to start of the study, and periodic monitoring visits 
conducted by the Sponsor or Sponsor representative. 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. 
The Sponsor or its designee will utilize qualified monitors to review and evaluate activities conducted 
at Investigator Sites. 
The data will be entered into the clinical study database and verified for accuracy, following 
procedures defined by the Sponsor (or designee). Data will be processed and analyzed following 
procedures defined by the Sponsor (or designee). 
The study will be monitored and/or audited at intervals to ensure that the clinical study is conducted 
and data are generated, documented (recorded), and reported in compliance with the Study Protocol; 
International Conference on Harmonisation (ICH), E6 consolidated guidelines; and other applicable 
regulations. The extent, nature, and frequency of monitoring and/or audits will be based on such 
considerations as the study objectives and/or endpoints, the purpose of the study, study design 
complexity, and enrollment rate. At the conclusion of a program, a compliance statement will be 
generated by the Sponsor (or designee) listing all audit activities performed during the clinical study. 
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21 
ETHICS 
21.1 Ethics Review 
Approval by the IRB/IEC prior to the start of the study will be the responsibility of the Investigator. A 
copy of approval documentation will be supplied to the OPC representative along with a roster of IRB 
members that demonstrates appropriate composition (a DHHS Assurance Number will satisfy this 
requirement).  
The study protocol, the informed consent form, advertisements, materials being provided to subjects 
and amendments (if any) will be approved to IRB/IECs at each study center in conformance with ICH 
E6, the Code of Federal Regulations (CFR), Title 21, Part 56 and any other applicable local laws. The 
Investigator is responsible for supplying the IRB/IEC with a copy of the current Investigator’s 
Brochure (IB), Package Insert, or Summary of Product Characteristics as well as any updates issued 
during the study. During the course of the study, the Investigator will provide timely and accurate 
reports to the IRB/IEC on the progress of the study, at intervals not exceeding 1 year (or as 
appropriate), and will notify the IRB/IEC of SAEs or other significant safety findings, per the policy of 
the IRB/IEC. At the conclusion of the study, the Investigator will submit a final report or close out 
report to the IRB/IEC and provide a copy to the OPC representative. 
Any amendment to this protocol will be provided to the Investigator in writing by the OPC 
representative. No protocol amendment may be implemented (with the exceptions noted below) before 
it has been approved by the IRB and the signature page, signed by the Investigator, has been received 
by the OPC representative. Where the protocol is amended to eliminate or reduce the risk to the 
subject, the amendment may be implemented before IRB review and approval. However, the IRB must 
be informed in writing of such an amendment and approval obtained within reasonable time limits. 
Deviating from the protocol is permitted only if absolutely necessary for the safety or clinical 
management of the subject, and must be immediately reported to the OPC representative.  
The Investigator will be responsible for supplying updated safety and/or study information to study 
subjects as it becomes available.  
21.2 Ethical Conduct of the Study 
This clinical study is designed to comply with the ICH Guidance on General Considerations for 
Clinical Trials (62 FR 6611, December 17, 1997), Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials for Pharmaceuticals (62 FR 62922, November 25, 1997), Good Clinical 
Practice: Consolidated Guidance (62 FR 25692, May 9, 1997) and 21 CFR parts 50, 54, 56 and 312. 
The study will be conducted in full compliance with ICH E6, the FDA guidelines for GCP and in 
accordance with the ethical principles that have their origins in the Declaration of Helsinki defined in 
21 CFR, 312.120. 
21.3 Subject Information and Consent 
Subjects, after having the study explained to them and an opportunity to have their questions answered 
sufficiently, will give voluntary and written informed consent (in compliance with ICH E6, 4.8 and 
21CFR Parts 50 and 312) before participating in any study-related procedures.  
In addition to obtaining informed consent, the Investigator is responsible for obtaining any additional 
documentation to demonstrate compliance with local privacy laws applicable to activities performed.  
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The consent process shall be recorded in source documents. Signed copies of the informed consent will 
be given to the Subject and originals will be placed in the Investigator study files.  
A unique Subject identification number will be assigned according to section at the time that the 
Subject signs the informed consent form. 
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22 
DATA HANDLING AND RECORDKEEPING 
22.1 Data Collection 
Data collection will involve the use of an electronic data capture (EDC) system to which only 
authorized personnel will have access. The system will be secured to prevent unauthorized access to 
the data or the system. This will include the requirement for a user login and password to enter or 
change data. The level of access to the EDC system will be dependent on the person’s role in the study. 
Study data will be collected from source documents and entered into an eCRF within the EDC system. 
The Investigator will be responsible for ensuring the eCRFs are completed in a timely manner relative 
to the subject’s visit. In addition to periodic monitoring occurring within the system by a Sponsor 
monitor, programmatic edit checks will be used to review EDC data for completeness, logic, and 
adherence to the study protocol. As a result of this monitoring and these checks, queries may be issued 
electronically to the clinical study sites and closed electronically by the monitor, data management 
staff or authorized staff at the study site. Additionally, the Investigator will review eCRFs, ensure all 
missing or corrected data is provided and will sign the eCRF pages with an electronic signature.  
An electronic audit trail will be maintained in the EDC system to track all changes made to data 
entered in the eCRF. Data will be retrievable in such a fashion that all information regarding each 
individual subject is attributable to that subject. Unless otherwise indicated, all data captured in the 
eCRF must first be captured in source documents. Data that can be directly recorded in the eCRF will 
be clearly identified in the section(s) of the protocol that describes the assessment(s). 
In addition, any contact with the subject via telephone or other means that provide significant clinical 
information must be documented in source documents as described above.  
22.2 Study Documentation 
Upon study completion, the complete eCRF, in portable document format (PDF), will be created from 
the EDC system. Study sites will be provided with the PDF of the eCRF for their subjects.  
Upon study completion, the Investigator’s copy of the paper CRF will be retained in each subject’s 
file. 
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23 
REPORTING AND PUBLICATION 
All data generated in this study are the property of the OPC. An integrated clinical and statistical report 
will be prepared at the completion of the study. 
Publication of the results by the Investigator will be subject to mutual agreement between the 
Investigator and the OPC. 
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24 
INVESTIGATOR OBLIGATIONS 
24.1 Regulatory Documents 
The Investigator is responsible for creating and/or maintaining all study documentation required by 
21CFR 50, 54, 56 and 312, ICH, E6 section 8, as well as any other documentation defined in the 
protocol or the Investigator Agreement. The Investigator must maintain the documentation relating to 
this study and permit the OPC representative or a member of a regulatory agency access to such 
records. 
The Investigator must provide the following key documents to the OPC representative prior to the start 
of the study: 
• A completed and signed Form FDA1572. If during the course of the study any information 
reported on the Form FDA 1572 changes, a revised Form FDA1572 must be completed and 
returned to the OPC representative for submission to the FDA. For studies executed outside 
the United States, documentation required by the governing regulatory authority may be 
substituted for the Form FDA 1572. 
• A fully executed contract 
• The Investigator’s Statement page in this protocol signed and dated by the Investigator and 
any subsequent amendment signature pages 
• The IB acknowledgment of receipt page 
• Curricula vitae for the Principal Investigator and all Sub-Investigators listed on Form FDA 
1572, including a copy of each physician’s license (if applicable) 
• A copy of the original IRB/IEC approval for conducting the study. If the study is ongoing, 
renewals must be submitted at yearly intervals or shorter intervals defined by the IRB/IEC. 
All subsequent modifications must be submitted and approved by the IRB, as described in 
section 21.1 
• A copy of the IRB/IEC-approved informed consent form 
• A list of IRB/IEC members or DHHS Assurance Number 
• Laboratory certifications and normal ranges (if local labs are required by the protocol) 
• A financial disclosure agreement completed and signed by the Investigator and all Sub-
Investigators listed on Form FDA 1572. Investigator site staff members who submitted an 
initial financial disclosure are also responsible for informing the OPC representative of any 
changes to their initial financial disclosure form 1 year after the completion of the study. 
A complete list of required regulatory documents will be supplied by the OPC or its representative. 
24.2 Delegation of Responsibilities and Adequate Resources 
The Investigator 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. The Investigator shall delegate tasks 
only to individuals qualified by education, training and experience to perform the delegated tasks. The 
Investigator shall have direct oversight of all delegated activities and shall document delegation of 
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responsibilities. The Investigator is responsible for ensuring all delegated staff members have been 
properly trained on the protocol and their assigned study responsibilities. 
24.3 Medical Care of Study Subjects 
The Investigator and/or a qualified sub-Investigator shall be responsible for the subjects’ medical care. 
Any unrelated medical condition discovered during the course of the study should be communicated to 
the subject so that they may seek appropriate medical care. The Investigator will report all AEs as 
required by the protocol (section 14.5). The Investigator will inform study subjects of new information 
regarding the study drug as it becomes available. 
24.4 Use of Investigational Materials 
The Investigator will acknowledge that the study drug supplies are investigational and as such must be 
used strictly in accordance with the protocol and only under the supervision of the Principal 
Investigator or Sub-Investigators listed on Form FDA1572 (or other regulatory document, depending 
on region). Study drug must be stored in a safe and secure location. At study initiation, a representative 
from the OPC will inventory the study drug at the site. The Investigator must maintain adequate 
records documenting the receipt and disposition of all study supplies. The OPC or its representative 
will supply forms to document total inventory as well as subject specific accountability. The 
Investigator is responsible for monitoring subject’s use of the study drug to ensure compliance with the 
protocol. All study supplies shall be returned to the OPC or its designee (this may include empty 
packaging such as bottles and blister cards). It is the Investigator’s responsibility to ensure that subjects 
return their medication. 
Study drug that has Schedule II designation must be stored in a double-locked area (secure enclosure 
within a locked, controlled access location). 
24.5 Retention of Records 
Federal and local regulations require that the Investigator retain a copy of all regulatory documents and 
records that support the data for this study (e.g., informed consents, laboratory reports, source 
documents, study drug dispensing records) 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 OPC or its representative 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 OPC or its representative 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 (NDA/Marketing Authorization Application).  
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If the Investigator 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 OPC 
or its representative must be notified in writing of the name and address of the new custodian. Study 
records should not be destroyed without consultation with the OPC or its representative. 
24.6 Subject Confidentiality 
All subject records submitted to the OPC or its designee will be identified only by code number. 
Subjects’ names are not to be transmitted to the OPC. The Investigator will keep a Master Subject List 
on which the identification number and the full name, address, and telephone number of each subject 
are listed. It is the Investigators’ responsibility to inform study subjects that representatives of the 
Sponsor, FDA, or other regulatory agencies may review all records that support their participation in 
the study. The Investigator will adhere to all privacy laws to which he/she is subject.  
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25 
TERMINATION OF STUDY 
The Sponsor has the right to suspend or terminate the study at any time. The study may be suspended 
or terminated for any reason. 
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26 
INVESTIGATOR’S STATEMENT 
I agree to conduct the study in accordance with the protocol, and with all applicable government 
regulations and Good Clinical Practice guidance. 
 
 
 
_____/_____/______ 
Investigator’s Signature 
Date 
 
 
 
Printed Name of Investigator 
 
 
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27 
REFERENCES 
1. Department of Health and Human Services (DHHS); US Food and Drug Administration. 
Labeling Supplement and PMR required. Available at: 
www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM367697.pdf  
2. Roland MO, Morris RW. A study of the natural history of back pain. Part 1: Development of a 
reliable and sensitive measure of disability in low back pain. Spine. 1983;8:141-144. 
3. Daut RL, Cleeland CS, Flanery RC. Development of the Wisconsin Brief Pain Questionnaire to 
assess pain in cancer and other diseases. Pain. 1983;17:197-210. 
4. Wolfe F. Pain extent and diagnosis: development and validation of the regional pain scale in 
12,799 subjects with rheumatic disease. J Rheumatol. 2003;30:369-378. 
5. Victor T, Jensen M, Gammaitoni A, Gould E, White R, Galer BS. The dimensions of pain 
quality: factor analysis of the Pain Quality Assessment Scale. Clin J Pain. 2008 24(6): 550-
555.  
6. The EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16:199-208. 
7. Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective 
outcome measures. J Manipul Physiol Ther. 2004;27:26-3. 
8. Kroenke K, Strine TW, Spritzer RL, Williams JB, Berry JT, Mokdad AH. The PHQ-8 as a 
measure of current depression in the general population. J Affect Disord. 2009; 114:163-73. 
9. Hays RD, Stewart AL. Sleep measures. In Stewart AL & Ware JE. (eds.), Measuring 
Functioning and Well-being: The Medical Outcomes Study Approach. Durham, NC: Duke 
University Press, 1992, pp. 235-259. 
10. Wechsler D. The measurement and appraisal of adult intelligence (1st ed.). Baltimore: 
Williams and Wilkins Corporation, 1939. 
11. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. PharmacoEconomics. 1993;4:353-365. 
12. Smith SM, Dart RC, Katz NP, Paillard F, Adams EH, Comer SD, Degroot A, Edwards RR, 
Haddox JD, Jaffe JH, Jones CM, Kleber HD, Kopecky EA, Markman JD, Montoya ID, O'Brien 
C, Roland CL, Stanton M, Strain EC, Vorsanger G, Wasan AD, Weiss RD, Turk DC, Dworkin 
RH; Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, 
Opportunities, and Networks (ACTTION) public-private partnership. Classification and 
definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review 
and recommendations. Pain. 2013;154(11):2287-96. 
13. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009;25:170-
175. 
14. Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new rating 
scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13:293-308. 
15. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 
2003;35(2):253-259. 
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16. Little RJA, Rubin DB. Statistical analysis with missing data (2nd ed.). Hoboken, NJ : John 
Wiley & Sons, Inc., 2002. 
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1 
 
APPENDICES 
 
Appendix A – Quebec Task Force on Spinal Disorders ............................................ 2 
Appendix B – Dosing Schedule ............................................................................... 3 
Appendix C – Roland-Morris Disability Questionnaire (RMDQ) ............................ 24 
Appendix D – Pain Intensity on 0-10 NRS ............................................................. 25 
Appendix E – Brief Pain Inventory- Short Form (BPI-SF) ....................................... 26 
Appendix F – Regional Pain Scale ......................................................................... 28 
Appendix G – Pain Quality Assessment Scale (PQAS) ........................................... 29 
Appendix H – MOS Sleep Scale ............................................................................ 33 
Appendix I – Work Productivity and Activity Impairment (WPAI)......................... 35 
Appendix J – Patient Health Questionnaire Depression Scale (PHQ-8) ................. 37 
Appendix K – Columbia Suicide Severity Rating Scale (C-SSRS) ............................ 38 
Appendix L – EuroQOL 5 Dimensions (EQ-5D-5L) ................................................. 42 
Appendix M – Patient Global Impression of Change (PGIC) ................................. 44 
Appendix N – Subjective Opiate Withdrawal Scale (SOWS).................................. 45 
Appendix O – Clinical Opiate Withdrawal Scale (COWS) ...................................... 46 
Appendix P – Digit Symbol Substitution Test (DSST) ............................................ 48 
Appendix Q – Quantitative Sensory Testing ......................................................... 49 
Appendix R – Abuse-Related Adverse Events (MADDERS) ................................... 51 
Appendix S – Endocrine Function and Sexual Function ........................................ 65 
Appendix T – Urine Drug Testing (UDT) ................................................................ 75 
Appendix U – Online Patient Support Program .................................................... 78 
Appendix V – Early Discontinuation Assessment Tool .......................................... 79 
Appendix W – STOPBang Questionnaire .............................................................. 80 
 
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2 
 
Appendix A – Quebec Task Force on Spinal Disorders 
Classifi-
cation 
Symptoms 
Duration of 
symptoms from 
onset 
Working 
status at time 
of evaluation 
1 
Pain without radiation 
a (<7 days) 
b (7 days – 7 weeks) 
c (>7 weeks) 
 
     W (working) 
     I (idle) 
2 
Pain + radiation to extremity, proximally 
3 
Pain + radiation to extremity, distally* 
4 
Pain + radiation to upper/lower limb, neurological signs 
5 
Presumptive compression of a spinal nerve root on a simple 
roentgenogram (ie, spinal instability or fracture) 
 
 
6 
Compression of a spinal nerve root confirmed by  
-Specific imaging techniques (ie, computerized axial tomography, 
myelography, or magnetic resonance imaging) 
-Other diagnostic techniques (eg, electromyography, venography) 
 
 
7 
Spinal stenosis 
 
 
8 
Postsurgical status, 1-6 months after intervention 
 
 
9 
Postsurgical status, >6 months after intervention 
9.1 Asymptomatic 
9.2 Symptomatic 
 
 
10 
Chronic pain syndrome 
 
     W (working) 
     I (idle) 
11 
Other diagnoses 
 
* Not applicable to the thoracic segment 
 
Reference: Spitzer WO, LeBlanc FE, Dupuis M. Scientific approach to the assessment and management of activity-
related spinal disorders. A monograph for clinicians. Report of the Quebec Task Force on Spinal Disorders. Spine. 
1987;12(7 Suppl):S1–S59.
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3 
 
Appendix B – Dosing Schedule 
Optimal Responders: Open-label Taper and Titration Schedule 
Optimal Responders will go through an open label taper phase to confirm their underlying pain state.  After a certain level of pain flare is confirmed they will 
titrate their  dose to control their pain within the allowable dose range.  Once the pain intensity score is ≤5 for 3 consecutive pain scores with satisfaction with 
pain and physical function and acceptable side effects, they will enter the Blinded Structured Discontinuation Period. 
 
Patient 
group 
Observation 
Period 
Taper to Flare 
Flare 
established 
Titration 
Baseline to 
confirm stable 
pain ≤5 
Optimal 
Responders 
Current 
medication 
Active Open 
Label taper 
doses 
(decreased 
every 3 days) 
Active Open Label 
titration doses back 
towards starting 
dose (increased 
every 4 days) 
Active dose @ 
entry 
 
The tables below shows dosing paradigms for a variety of expected doses. Most probable doses in BOLD (doses achieved with same dosage strengths).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 
 
Optimal Responders: Morphine Sulfate ER (MSER) Open-label Taper and Titration Schedule 
 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
ER MORPHINE
Total 
Daily 
Dose @ 
entry
Patient 
group
Closest BID 
dose
Taper Days 1-
3
Taper Days 
4-6
Taper Days 
7-9
Taper 
Days 10-12
Taper Days 
13-14
Titration 
Step 1 
(4 days)
Titration 
Step2
(4 days)
Titration 
Step 3
(4 days)
Titration Step 
4 
(4 days)
Titration Step 
5 
(4 days)
Titration Step 6 
(4 days)
Titration Step 7 
(4 days)
Baseline Period
Tablet Strengths
15 mg
30 mg
60 mg
100 mg
No Drug
15A
No Drug
15A
No Drug
15A
No Drug
15A
No Drug
15A
No Drug
15A
No Drug
30A
60A/30A
60A/60A
60A
15A
30A
30A/15A
30A
30A/15A
30A
200mg - 
229mg
Optimal 
Responders
230mg - 
259mg
Optimal 
Responders
60A/30A
60A/15A
60A
30A
30A/15A
60A/15A
60A/15A
60A
100A
60A/60A
60A/30A
60A
15A
15A
30A
30A/15A
60A/15A
30A/15A
30A
120mg - 
149mg
Optimal 
Responders
Optimal 
Responders
150mg - 
179mg
100A/30A
100A/60A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
60A/15A
30A
60A
100A
100A/30A
30A
15A
30A
60A
60A/30A
60A/60A
100A/30A/15A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
30A
15A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
180mg - 
199mg
Optimal 
Responders
60A/30A
60A/60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
100A
60A/15A
30A/15A
60A
N/A
100A/30A
100A/30A/15A
100A/30A
100A
60A/15A
30A/15A
15A
30A/15A
60A/15A
100A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
290mg - 
319mg
Optimal 
Responders 100A/30A/15A
100A/15A
60A/30A
60A
30A
60A
60A/30A
100A/15A
100A/30A/15A
60A/60A/60A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
260mg - 
289mg
Optimal 
Responders
100A/60A
60A/60A/60A
100A/60A/30A
100A/100A
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5 
 
 
Optimal Responders: Morphine Sulfate ER (MSER) Open-label Taper and Titration Schedule (Cont’d) 
ER MORPHINE
Total 
Daily Dose 
@ entry
Patient 
group
Closest BID 
dose
Taper Days 1-
3
Taper Days 
4-6
Taper Days 
7-9
Taper Days 
10-12
Taper Days 
13-14
Titration 
Step 1 
(4 days)
Titration 
Step2
(4 days)
Titration 
Step 3
(4 days)
Titration Step 
4 
(4 days)
Titration Step 
5 
(4 days)
Titration Step 6 
(4 days)
Titration Step 7 
(4 days)
Baseline Period
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
No Drug
30A
No Drug
30A
No Drug
30A
No Drug
30A
No Drug
30A
No Drug
30A
No Drug
30A
520mg - 
540mg
Optimal 
Responders 100A/100A/60A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
100A/100A
100A/100A/60A
100A/60A
100A/100A
100A
100A/60A
30A
100A
460mg - 
519mg
Optimal 
Responders 100A/100A/30A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
100A/100A/60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
100A/60A/30A
100A/100A/30A
100A/30A
100A/60A/30A
60A/30A
100A/30A
30A
60A/30A
430mg - 
459mg
Optimal 
Responders 100A/100A/15A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
100A/100A/60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
100A/60A/15A
100A/100A/15A
100A/30A
100A/60A/15A
60A/30A
100A/30A
30A
60A/30A
400mg - 
429mg
Optimal 
Responders
100A/100A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
100A/100A/30A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
100A/60A
100A/100A
100A/15A
100A/60A
60A/15A
100A/15A
30A
60A/15A
380mg - 
399mg
Optimal 
Responders 100A/60A/30A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
100A/100A/15A 100A/100A/60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
100A/30A/15A
100A/60A/30A
100A
100A/30A/15A
60A/15A
100A
30A
60A/15A
320mg - 
349mg
360mg - 
379mg
Optimal 
Responders
Optimal 
Responders
100A/60A/30A
100A/60A
60A/60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
100A/60A
60A/60A/60A
60A/60A
100A/30A
60A/30A
60A
30A
60A
60A/30A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
60A/30A
60A
30A
60A
60A/30A
100A/30A
60A/60A/60A
100A/100A
100A/100A/15A
100A/100A/30A
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OPC, 2065-5
Clinical Study Report version: Final
Page 119 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
6 
 
Optimal Responders: Oxycodone ER (OCER) Open-label Taper and Titration Schedule 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
ER OXYCODONE
Total 
Daily 
Dose @ 
entry
Patient 
group
Closest BID 
dose
Taper Days 1-
3
Taper Days 
4-6
Taper Days 
7-9
Taper 
Days 10-12
Taper Days 
13-14
Titration 
Step 1 
(4 days)
Titration 
Step2
(4 days)
Titration 
Step 3
(4 days)
Titration Step 
4 
(4 days)
Titration Step 
5 
(4 days)
Titration Step 6 
(4 days)
Titration Step 7
(4 days)
Baseline Period
Tablet Strengths
10 mg
20 mg
30 mg
40 mg
60 mg
No Drug
10A
80 mg
No Drug
10A
No Drug
10A
No Drug
10A
No Drug
10A
No Drug
10A
No Drug
20A
80A
60A/30A
180mg - 
199mg
Optimal 
Responders
100mg - 
109mg
Optimal 
Responders
140mg - 
149mg
Optimal 
Responders
150mg - 
179mg
Optimal 
Responders
80mg - 
99mg
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
80A
60A
30A
40A
20A
30A
10A
20A
30A
40A
20A
30A
10A
20A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
40A
Optimal 
Responders
30A/20A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A/30A
40A
30A/20A
110mg - 
139mg
Optimal 
Responders
60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
80A
40A
60A
30A
40A
20A
30A
10A
20A
40A/30A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
60A/30A
30A/20A
40A/30A
40A
30A/20A
30A
40A
10A
30A
80A/30A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
60A/40A
60A
80A
40A
60A
20A
40A
10A
20A
60A/60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
200mg - 
219mg
Optimal 
Responders
60A/40A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
40A
80A/60A
80A/40A/30A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
60A/60A
80A
60A/40A
60A
80A
40A
60A
20A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
80A/30A
40A/30A
60A/30A
40A
40A/30A
20A
40A
10A
20A
N/A
60A/30A
60A/40A
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 120 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
7 
 
Optimal Responders: Oxycodone ER (OCER) Open-label Taper and Titration Schedule (Cont’d) 
ER OXYCODONE
Total 
Daily Dose 
@ entry
Patient 
group
Closest BID 
dose
Taper Days 1-
3
Taper Days 
4-6
Taper Days 
7-9
Taper Days 
10-12
Taper Days 
13-14
Titration 
Step 1 
(4 days)
Titration 
Step2
(4 days)
Titration 
Step 3
(4 days)
Titration Step 
4 
(4 days)
Titration Step 
5 
(4 days)
Titration Step 6 
(4 days)
Titration Step 7
(4 days)
Baseline Period
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
No Drug
20A
No Drug
20A
No Drug
20A
No Drug
30A
No Drug
30A
No Drug
30A
No Drug
30A
360mg
Optimal 
Responders
60A/60A/60A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
80A/60A
60A/60A/60A
60A/30A
80A/60A
60A
60A/30A
30A
60A
340mg - 
359mg
Optimal 
Responders
80A/80A/10A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
80A/60A
80A/80A/10A
60A/40A
80A/60A
60A
60A/40A
30A
60A
320mg - 
339mg
Optimal 
Responders
80A/80A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
60A/60A/60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
60A/60A
80A/80A
60A/30A
60A/60A
60A
60A/30A
30A
60A
300mg - 
319mg
Optimal 
Responders
80A/40A/30A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
80A/80A/10A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
60A/60A
80A/40A/30A
60A/30A
60A/60A
60A
60A/30A
30A
60A
280mg - 
299mg
Optimal 
Responders
80A/60A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
80A/80A
60A/60A/60A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
60A/40A
80A/60A
40A/30A
60A/40A
40A
40A/30A
20A
40A
60A/60A
240mg - 
279mg
Optimal 
Responders
220mg - 
239mg
Optimal 
Responders
80A/30A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
80A/60A
80A
80A/30A
60A
80A
40A
60A
20A
40A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
80A/40A/30A
60A/30A
60A/60A
40A/30A
60A/30A
40A
40A/30A
20A
40A
80A/80A
80A/80A/10A
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 121 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
8 
 
Optimal Responders: Oxymorphone ER (OMER) Open-label Taper and Titration Schedule 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
ER OXYMORPHONE
Total 
Daily 
Dose @ 
entry
Patient 
group
Closest BID 
dose
Taper Days 1-
3
Taper Days 
4-6
Taper Days 
7-9
Taper 
Days 10-12
Taper Days 
13-14
Titration 
Step 1 
(4 days)
Titration 
Step2
(4 days)
Titration 
Step 3
(4 days)
Titration Step 
4 
(4 days)
Titration Step 
5 
(4 days)
Titration Step 6 
(4 days)
Titration Step 7
(4 days)
Baseline Period
Tablet Strengths
5 mg
10 mg
15 mg
20 mg
30 mg
No Drug
5A
40 mg
No Drug
5A
No Drug
5A
No Drug
5A
No Drug
10A
No Drug
10A
No Drug
10A
No Drug
10A
20A
15A/10A
40mg - 
49mg
Optimal 
Responders
50mg - 
59mg
Optimal 
Responders
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A
30A
15A
20A
10A
15A
5A
10A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
20A/15A
20A
15A/10A
15A
20A
10A
15A
5A
10A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
60mg - 
69mg
Optimal 
Responders
30A
70mg - 
79mg
Optimal 
Responders
20A/15A
80mg - 
89mg
Optimal 
Responders
40A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A
15A/10A
30A
20A
15A/10A
10A
20A
5A
10A
30A/20A
90mg - 
99mg
Optimal 
Responders
30A/15A
100mg - 
109mg
Optimal 
Responders
30A/20A
110mg - 
119mg
Optimal 
Responders
40A/15A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
30A/15A
30A
20A/15A
20A
30A
10A
20A
5A
10A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
30A
40A
20A
30A
15A
20A
10A
15A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A/15A
20A/15A
30A/15A
15A/10A
20A/15A
15A
15A/10A
10A
15A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
30A/30A
40A
30A/20A
30A
40A
20A
30A
10A
20A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A/30A
40A
40A/15A
30A
40A
20A
30A
10A
20A
40A/40A/10A
N/A
30A/15A
30A/20A
40A/15A
30A/30A
40A/30A
40A/40A
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 122 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
9 
 
 
Optimal Responders: Oxymorphone ER (OMER) Open-label Taper and Titration Schedule (Cont’d) 
ER OXYMORPHONE
Total 
Daily Dose 
@ entry
Patient 
group
Closest BID 
dose
Taper Days 1-
3
Taper Days 
4-6
Taper Days 
7-9
Taper Days 
10-12
Taper Days 
13-14
Titration 
Step 1 
(4 days)
Titration 
Step2
(4 days)
Titration 
Step 3
(4 days)
Titration Step 
4 
(4 days)
Titration Step 
5 
(4 days)
Titration Step 6 
(4 days)
Titration Step 7
(4 days)
Baseline Period
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
No Drug
10A
No Drug
10A
No Drug
10A
No Drug
15A
No Drug
15A
No Drug
15A
No Drug
15A
180mg
Optimal 
Responders
30A/30A/30A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
40A/30A
30A/30A/30A
30A/20A
40A/30A
30A
30A/20A
15A
30A
170mg - 
179mg
Optimal 
Responders
40A/30A/15A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
40A/30A
40A/30A/15A
30A/20A
40A/30A
30A
30A/20A
15A
30A
160mg - 
169mg
Optimal 
Responders
40A/40A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
30A/30A/30A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
60A
40A/40A
30A/15A
60A
30A
30A/15A
15A
30A
150mg - 
159mg
Optimal 
Responders
40A/20A/15A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A/30A/15A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
60A
40A/20A/15A
30A/15A
60A
30A
30A/15A
15A
30A
140mg - 
149mg
Optimal 
Responders
40A/30A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A/40A
30A/30A/30A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
30A/20A
40A/30A
40A
30A/20A
15A/10A
40A
10A
15A/10A
130mg - 
139mg
Optimal 
Responders
30A/20A/15A
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A/20A/15A
40A/30A/15A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
30A/20A
30A/20A/15A
40A
30A/20A
15A/10A
40A
10A
15A/10A
120mg - 
129mg
Optimal 
Responders
30A/30A
Highest Titration 
dose which resulted 
in a mean Average 
daily PI score ≤5 for 
at least 3 consecutive 
days
Establish Flare: (Average daily PI score >5; increased by ≥1.5 points for ≥3 
consecutive days from the mean Average PI). Then titrate to stable dose.
40A/40A
30A/15A
30A/30A
20A/15A
30A/15A
15A/10A
20A/15A
10A
15A/10A
40A/40A/20A
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 123 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
10 
 
Run-in, Baseline and Blinded Structured Opioid Discontinuation Schedule   
The Drug Supply Logistics Team is planning to package in blister cards by dose strength to afford the most flexibility for retaining patients on their dose at entry 
to the study and enabling a variety of taper schedules. 
In general, the taper will be managed with a double-dummy design where patients maintaining dose get placebo doses added during the taper weeks. Patients 
being discontinued will switch to placebo versions of their dose at entry and will have active taper doses added. 
This design ensures both the Maintain and the Discontinue arms will be dosed with the same number of identical tablets as they progress through the study, 
thus maintaining the blind. 
 
Patient 
group 
Baseline Period 
Taper wks 
Study Duration 
Maintain 
Active dose @ 
entry 
Active dose @ entry 
PLUS 
Placebo taper doses 
Active dose @ 
entry 
Discontinue 
Active dose @ 
entry 
Placebo dose @ entry 
PLUS 
Active taper doses 
Placebo dose @ 
entry 
 
The tables below shows dosing paradigms for a variety of expected doses. Most probable doses in BOLD (doses achieved with same dosage strengths) 
 
 
 
________________________________________________________
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_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 124 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
11 
 
Blinded Structured Opioid Discontinuation Schedule - Morphine Sulfate ER 
ER MORPHINE
Total Daily 
Dose @ 
entry
Closest BID 
dose @ entry
Patient group
Baseline Period
Taper wk 1
Taper wk 2
Taper wk 3
Taper wk 4
Study Duration
Tablet Strengths
60A
60A
60A
60A
60A
60A
15 mg
30P/15P
30P
15P
15P
30 mg
60A
60P
60P
60P
60P
60P
60 mg
30A/15A
30A
15A
15P
100 mg
60A/15A
60A/15A
60A/15A
60A/15A
60A/15A
60A/15A
60P
30P/15P
30P
15P
60A/15A
60P/15P
60P/15P
60P/15P
60P/15P
60P/15P
60A
30A/15A
30A
15A
60A/30A
60A/30A
60A/30A
60A/30A
60A/30A
60A/30A
60P/15P
30P/15P
30P
15P
60A/30A
60P/30P
60P/30P
60P/30P
60P/30P
60P/30P
60A/15A
30A/15A
30A
15A
100A
100A
100A
100A
100A
100A
60P/15P
60P
30P
15P
100A
100P
100P
100P
100P
100P
60A/15A
60A
30A
15A
60A/60A
60A/60A
60A/60A
60A/60A
60A/60A
60A/60A
60P/30P
60P
30P
15P
60A/60A
60P/60P
60P/60P
60P/60P
60P/60P
60P/60P
60A/30A
60A
30A
15A
100A/30A
100A/30A
100A/30A
100A/30A
100A/30A
100A/30A
100P
60P/15P
30P/15P
15P
100A/30A
100P/30P
100P/30P
100P/30P
100P/30P
100P/30P
100A
60A/15A
30A/15A
15A
100A/30A/15A
100A/30A/15A
100A/30A/15A
100A/30A/15A
100A/30A/15A
100A/30A/15A
100P/15P
60P/30P
60P
30P
100A/30A/15A
100P/30P/15P
100P/30P/15P
100P/30P/15P
100P/30P/15P
100P/30P/15P
100A/15A
60A/30A
60A
30A
Maintain
Discontinue
60
90
120
100
Discontinue
130
Maintain
Discontinue
Maintain
Discontinue
Maintain
145
Maintain
Discontinue
Discontinue
Maintain
75
Maintain
Discontinue
120mg - 
149mg
290mg - 
319mg
260mg - 
289mg
230mg - 
259mg
200mg - 
229mg
180mg - 
199mg
150mg - 
179mg
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 125 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
12 
 
Blinded Structured Opioid Discontinuation Schedule - Morphine Sulfate ER (Cont’d) 
ER MORPHINE
Total Daily 
Dose @ 
entry
Closest BID 
dose @ entry
Patient group
Baseline Period
Taper wk 1
Taper wk 2
Taper wk 3
Taper wk 4
Study Duration
 
100A/60A
100A/60A
100A/60A
100A/60A
100A/60A
100A/60A
60P/60P
60P/30P
60P
30P
100A/60A
100P/60P
100P/60P
100P/60P
100P/60P
100P/60P
60A/60A
60A/30A
60A
30A
60A/60A/60A
60A/60A/60A
60A/60A/60A
60A/60A/60A
60A/60A/60A
60A/60A/60A
100P/30P
60P/30P
60P
30P
60A/60A/60A
60P/60P/60P
60P/60P/60P
60P/60P/60P
60P/60P/60P
60P/60P/60P
100A/30A
60A/30A
60A
30A
100A/60A/30A
100A/60A/30A
100A/60A/30A
100A/60A/30A
100A/60A/30A
100A/60A/30A
100P/30P/15P
100P
60P/15P
30P
100A/60A/30A
100P/60P/30P
100P/60P/30P
100P/60P/30P
100P/60P/30P
100P/60P/30P
100A/30A/15A
100A
60A/15A
30A
100A/100A
100A/100A
100A/100A
100A/100A
100A/100A
100A/100A
100P/60P
100P/15P
60P/15P
30P
100A/100A
100P/100P
100P/100P
100P/100P
100P/100P
100P/100P
100A/60A
100A/15A
60A/15A
30A
100A/100A/15A
100A/100A/15A
100A/100A/15A
100A/100A/15A
100A/100A/15A
100A/100A/15A
100P/60P/15P
100P/30P
60P/30P
30P
100A/100A/15A
100P/100P/15P
100P/100P/15P
100P/100P/15P
100P/100P/15P
100P/100P/15P
100A/60A/15A
100A/30A
60A/30A
30A
100A/100A/30A
100A/100A/30A
100A/100A/30A
100A/100A/30A
100A/100A/30A
100A/100A/30A
100P/60P/30P
100P/30P
60P/30P
30P
100A/100A/30A
100P/100P/30P
100P/100P/30P
100P/100P/30P
100P/100P/30P
100P/100P/30P
100A/60A/30A
100A/30A
60A/30A
30A
100A/100A/60A
100A/100A/60A
100A/100A/60A
100A/100A/60A
100A/100A/60A
100A/100A/60A
100P/100P
100P/60P
100P
30P
100A/100A/60A
100P/100P/60P
100P/100P/60P
100P/100P/60P
100P/100P/60P
100P/100P/60P
100A/100A
100A/60A
100A
30A
180
Maintain
Discontinue
160
Maintain
Discontinue
360mg - 
379mg
320mg - 
359mg
Maintain
Discontinue
200
Maintain
Discontinue
380mg - 
399mg
400mg - 
429mg
430mg - 
459mg
215
Maintain
Discontinue
190
Maintain
Discontinue
520mg - 
540mg
260
Maintain
Discontinue
460mg - 
519mg
230
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 126 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
13 
 
Blinded Structured Opioid Discontinuation Period – Oxycodone ER 
ER OXYCODONE
Total Daily 
Dose @ 
entry
Closest BID 
dose @ entry
Patient group
Baseline Period
Taper wk 1
Taper wk 2
Taper wk 3
Taper wk 4
Study Duration
Tablet Strengths
40A
40A
40A
40A
40A
40A
10 mg
30P
20P
10P
10P
20 mg
40A
40P
40P
40P
40P
40P
30 mg
30A
20A
10A
10P
40 mg
30A/20A
30A/20A
30A/20A
30A/20A
30A/20A
30A/20A
60 mg
40P
30P
20P
10P
80 mg
30A/20A
30P/20P
30P/20P
30P/20P
30P/20P
30P/20P
40A
30A
20A
10A
60A
60A
60A
60A
60A
60A
40P
30P
20P
10P
60A
60P
60P
60P
60P
60P
40A
30A
20A
10A
40A/30A
40A/30A
40A/30A
40A/30A
40A/30A
40A/30A
30P/20P
40P
30P
10P
40A/30A
40P/30P
40P/30P
40P/30P
40P/30P
40P/30P
30A/20A
40A
30A
10A
80A
80A
80A
80A
80A
80A
30P/30P
40P
20P
10P
80A
80P
80P
80P
80P
80P
30A/30A
40A
20A
10A
60A/30A
60A/30A
60A/30A
60A/30A
60A/30A
60A/30A
40P/30P
40P
20P
10P
60A/30A
60P/30P
60P/30P
60P/30P
60P/30P
60P/30P
40A/30A
40A
20A
10A
60A/40A
60A/40A
60A/40A
60A/40A
60A/40A
60A/40A
80P
60P
40P
20P
60A/40A
60P/40P
60P/40P
60P/40P
60P/40P
60P/40P
80A
60A
40A
20A
70
90
Maintain
Discontinue
Maintain
Discontinue
80
Maintain
Discontinue
50
Maintain
Discontinue
100
Maintain
Discontinue
200mg - 
219mg
Maintain
Discontinue
180mg - 
199mg
150mg - 
179mg
140mg - 
149mg
110mg - 
139mg
100mg - 
109mg
80mg - 99mg
40
Maintain
Discontinue
60
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 127 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
14 
 
Blinded Structured Opioid Discontinuation Period – Oxycodone ER (Cont’d) 
ER OXYCODONE
Total Daily 
Dose @ 
entry
Closest BID 
dose @ entry
Patient group
Baseline Period
Taper wk 1
Taper wk 2
Taper wk 3
Taper wk 4
Study Duration
80A/30A
80A/30A
80A/30A
80A/30A
80A/30A
80A/30A
80P
60P
40P
20P
80A/30A
80P/30P
80P/30P
80P/30P
80P/30P
80P/30P
80A
60A
40A
20A
60A/60A
60A/60A
60A/60A
60A/60A
60A/60A
60A/60A
60P/30P
40P/30P
40P
20P
60A/60A
60P/60P
60P/60P
60P/60P
60P/60P
60P/60P
60A/30A
40A/30A
40A
20A
80A/60A
80A/60A
80A/60A
80A/60A
80A/60A
80A/60A
60P/40P
40P/30P
40P
20P
80A/60A
80P/60P
80P/60P
80P/60P
80P/60P
80P/60P
60A/40A
40A/30A
40A
20A
80A/40A/30A
80A/40A/30A
80A/40A/30A
80A/40A/30A
80A/40A/30A
80A/40A/30A
60P/60P
60P/30P
60P
30P
80A/40A/30A
80P/40P/30P
80P/40P/30P
80P/40P/30P
80P/40P/30P
80P/40P/30P
60A/60A
60A/30A
60A
30A
80A/80A
80A/80A
80A/80A
80A/80A
80A/80A
80A/80A
60P/60P
60P/30P
60P
30P
80A/80A
80P/80P
80P/80P
80P/80P
80P/80P
80P/80P
60A/60A
60A/30A
60A
30A
80A/80A/10A
80A/80A/10A
80A/80A/10A
80A/80A/10A
80A/80A/10A
80A/80A/10A
80P/60P
60P/40P
60P
30P
80A/80A/10A
80P/80P/10P
80P/80P/10P
80P/80P/10P
80P/80P/10P
80P/80P/10P
80A/60A
60A/40A
60A
30A
60A/60A/60A
60A/60A/60A
60A/60A/60A
60A/60A/60A
60A/60A/60A
60A/60A/60A
80P/60P
60P/30P
60P
30P
60A/60A/60A
60P/60P/60P
60P/60P/60P
60P/60P/60P
60P/60P/60P
60P/60P/60P
80A/60A
60A/30A
60A
30A
Maintain
120
Discontinue
110
Maintain
Discontinue
Maintain
Discontinue
Maintain
Discontinue
170
Maintain
Discontinue
180
Maintain
240mg - 
279mg
220mg - 
239mg
300mg - 
319mg
320mg - 
339mg
340mg - 
359mg
360mg
280mg - 
299mg
140
Maintain
Discontinue
Discontinue
150
160
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
 
 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 128 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
15 
 
Blinded Structured Opioid Discontinuation Period – Oxymorphone ER 
ER OXYMORPHONE
Total Daily 
Dose @ 
entry
Single BID 
dose @ entry
Patient group
Baseline Period
Taper wk 1
Taper wk 2
Taper wk 3
Taper wk 4
Study Duration
Tablet Strengths
20A
20A
20A
20A
20A
20A
5 mg
15P
10P
5P
5P
10 mg
20A
20P
20P
20P
20P
20P
15 mg
15A
10A
5A
5P
20 mg
15A/10A
15A/10A
15A/10A
15A/10A
15A/10A
15A/10A
30 mg
20P
15P
10P
5P
40 mg
15A/10A
15P/10P
15P/10P
15P/10P
15P/10P
15P/10P
20A
15A
10A
5A
30A
30A
30A
30A
30A
30A
15P/10P
20P
10P
5P
30A
30P
30P
30P
30P
30P
15A/10A
20A
10A
5A
20A/15A
20A/15A
20A/15A
20A/15A
20A/15A
20A/15A
30P
20P
10P
5P
20A/15A
20P/15P
20P/15P
20P/15P
20P/15P
20P/15P
30A
20A
10A
5A
40A
40A
40A
40A
40A
40A
30P
20P
15P
10P
40A
40P
40P
40P
40P
40P
30A
20A
15A
10A
30A/15A
30A/15A
30A/15A
30A/15A
30A/15A
30A/15A
20P/15P
15P/10P
15P
10P
30A/15A
30P/15P
30P/15P
30P/15P
30P/15P
30P/15P
20A/15A
15A/10A
15A
10A
Discontinue
30
40
25
Maintain
Discontinue
Maintain
35
Maintain
Discontinue
Maintain
Discontinue
45
Maintain
Discontinue
20
Maintain
Discontinue
90mg - 99mg
80mg - 89mg
70mg - 79mg
60mg - 69mg
50mg - 59mg
40mg - 49mg
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 129 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
16 
 
Blinded Structured Opioid Discontinuation Period – Oxymorphone ER (Cont’d) 
ER OXYMORPHONE
Total Daily 
Dose @ 
entry
Single BID 
dose @ entry
Patient group
Baseline Period
Taper wk 1
Taper wk 2
Taper wk 3
Taper wk 4
Study Duration
30A/20A
30A/20A
30A/20A
30A/20A
30A/20A
30A/20A
40P
30P
20P
10P
30A/20A
30P/20P
30P/20P
30P/20P
30P/20P
30P/20P
40A
30A
20A
10A
40A/15A
40A/15A
40A/15A
40A/15A
40A/15A
40A/15A
40P
30P
20P
10P
40A/15A
40P/15P
40P/15P
40P/15P
40P/15P
40P/15P
40A
30A
20A
10A
30A/30A
30A/30A
30A/30A
30A/30A
30A/30A
30A/30A
30P/15P
20P/15P
15P/10P
10P
30A/30A
30P/30P
30P/30P
30P/30P
30P/30P
30P/30P
30A/15A
20A/15A
15A/10A
10A
30A/20A/15A
30A/20A/15A
30A/20A/15A
30A/20A/15A
30A/20A/15A
30A/20A/15A
30P/20P
40P
15P/10P
10P
30A/20A/15A
30P/20P/15P
30P/20P/15P
30P/20P/15P
30P/20P/15P
30P/20P/15P
30A/20A
40A
15A/10A
10A
40A/30A
40A/30A
40A/30A
40A/30A
40A/30A
40A/30A
30P/20P
40P
15P/10P
10P
40A/30A
40P/30P
40P/30P
40P/30P
40P/30P
40P/30P
30A/20A
40A
15A/10A
10A
40A/20A/15A
40A/20A/15A
40A/20A/15A
40A/20A/15A
40A/20A/15A
40A/20A/15A
30P/30P
30P/15P
30P
15P
40A/20A/15A
40P/20P/15P
40P/20P/15P
40P/20P/15P
40P/20P/15P
40P/20P/15P
30A/30A
30A/15A
30A
15A
40A/40A
40A/40A
40A/40A
40A/40A
40A/40A
40A/40A
30P/30P
30P/15P
30P
15P
40A/40A
40P/40P
40P/40P
40P/40P
40P/40P
40P/40P
30A/30A
30A/15A
30A
15A
40A/30A/15A
40A/30A/15A
40A/30A/15A
40A/30A/15A
40A/30A/15A
40A/30A/15A
40P/30P
30P/20P
30P
15P
40A/30A/15A
40P/30P/15P
40P/30P/15P
40P/30P/15P
40P/30P/15P
40P/30P/15P
40A/30A
30A/20A
30A
15A
30A/30A/30A
30A/30A/30A
30A/30A/30A
30A/30A/30A
30A/30A/30A
30A/30A/30A
40P/30P
30P/20P
30P
15P
30A/30A/30A
30P/30P/30P
30P/30P/30P
30P/30P/30P
30P/30P/30P
30P/30P/30P
40A/30A
30A/20A
30A
15A
60
Maintain
Discontinue
50
Maintain
Discontinue
55
Maintain
Discontinue
120mg - 
129mg
110mg - 
119mg
100mg - 
109mg
70
Maintain
Discontinue
75
Maintain
Discontinue
180mg
90
Maintain
Discontinue
80
Maintain
Discontinue
130mg - 
139mg
140mg - 
149mg
150mg - 
159mg
160mg - 
169mg
170mg - 
179mg
85
Maintain
Discontinue
65
Maintain
Discontinue
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 130 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
17 
 
Follow-Up Period 
The Drug Supply Logistics Team is planning to package in blister cards by dose strength to afford the most flexibility for retaining patients on their dose at entry 
to the study and enabling a variety of taper schedules. 
The taper will be managed in a blinded fashion. Patients on active study drug will be switch through active taper doses while patients on placebo during the 
study will receive a placebo taper pack.  
 
 
 
 
 
 
 
Taper applied at end of study or at any point when a patient chooses to discontinue after being randomized to study drug. 
 
 
 
 
 
 
 
 
Patient 
group
Study Period 
(after structured 
discontinuation)
Taper wks 25-28
End of Study
Maintain
Active dose @ 
entry
Active taper doses
No drug
Discontinue
Placebo dose @ 
entry
Placebo taper doses
No drug
 
The tables below shows dosing paradigms for a variety of expected doses. Most probable doses in BOLD (doses achieved with same dosage strengths) 
 
 
 
 
 
 
 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 131 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
18 
 
Follow-Up Period - Morphine Sulfate ER 
ER MORPHINE
Single BID 
dose in study
Patient group
Study Period
Taper wk 25
Taper wk 26
Taper wk 27
Taper wk 28
End of Study - Off 
Drug
Tablet Strengths
15 mg
30 mg
60 mg
100 mg
30A
30P
60P
60P/30P
100P/15P
100P/30P/15P
100A/60A
60A/60A
60A/30A
60A
60P/60P
100P/60P
30A
30P
60P
60P/30P
100P
100P/30P
100A/30A/15A
100A/15A
60A/30A
60A
15A
15P
30P/15P
60P/15P
60P/30P
60P/60P
100A/30A
100A
60A/15A
30A/15A
15A
15P
30P
60P
60P/15P
100P
60A/60A
60A/30A
60A
30A
15A
15P
30P
60P
60P/15P
60P/30P
100A
60A/15A
60A
30A
15A
15P
30P
30P/15P
60P
60P/15P
60A/30A
60A/15A
30A/15A
30A
60A
30A/15A
30A
60P
30P/15P
30P
30P/15P
145
Maintained
Discontinued
160
Maintained
Discontinued
120
Maintained
Discontinued
130
Maintained
Discontinued
90
Maintained
Discontinued
100
Maintained
Discontinued
60
Maintained
Discontinued
75
Maintained
Discontinued
15A
15P
15P
15P
30P
15P
60A/15A
60A
30A/15A
30A
15A
 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
________________________________________________________
_______________________________________________________
_______________________________________________________
OPC, 2065-5
Clinical Study Report version: Final
Page 132 of 194


Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
19 
 
Follow-Up Period - Morphine Sulfate ER (Cont’d) 
ER MORPHINE
Single BID 
dose in study
Patient group
Study Period
Taper wk 25
Taper wk 26
Taper wk 27
Taper wk 28
End of Study - Off 
Drug
 
100P/100P/60P
100P/100P
100P/60P
100P
30P
60P/30P
30P
100A/100A/60A
100A/100A
100A/60A
100A
30A
100P/100P
100P/60P
100P/15P
60P/15P
30P
100A/100A/15A
100A/60A/15A
100A/30A
60A/30A
30A
Maintained
Discontinued
Maintained
100A/100A/30A
100A/60A/30A
100A/30A
100P/100P/30P
100P/60P/30P
100P/30P
30A
30P
60P
60P/30P
100A/60A/30A
100A/30A/15A
100A
60A/15A
30A
100P/60P/30P
100P/30P/15P
100P
60P/15P
30P
100A/100A
100A/60A
60A/60A/60A
100A/30A
60A/30A
60A
100P/30P
60P/60P/60P
60A/30A
30A
100A/15A
60A/15A
30A
100P/100P/15P
100P/60P/15P
100P/30P
60P/30P
30P
180
Maintained
Discontinued
190
200
215
230
260
Discontinued
Maintained
Discontinued
Maintained
Discontinued
Maintained
Discontinued
 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
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Follow-Up Period - Oxycodone ER 
ER OXYCODONE
Single BID 
dose in study
Patient group
Study Period
Taper wk 25
Taper wk 26
Taper wk 27
Taper wk 28
End of Study - Off 
Drug
Tablet Strengths
10 mg
20 mg
30 mg
40 mg
60 mg
80 mg
60P/30P
40P/30P
40P
20P
10P
10A
20A
40A
40A/30A
60A/30A
40P/40P
30P/30P
40P
20P
10P
10A
20A
40A
30A/30A
40A/40A
40P/30P
30P/20P
40P
30P
10P
10A
30A
40A
30A/20A
40A/30A
60P
40P
30P
20P
10P
10A
20A
30A
40A
60A
30P/20P
40P
30P
20P
10P
10A
20A
30A
40A
30A/20A
10P
40P
30P
20P
10P
10P
40A
30A
20A
10A
90
Maintained
Discontinued
70
Maintained
Discontinued
80
Maintained
Discontinued
50
Maintained
Discontinued
60
Maintained
Discontinued
40
Maintained
Discontinued
 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
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Follow-Up Period - Oxycodone ER (Cont’d) 
ER OXYCODONE
Single BID 
dose in study
Patient group
Study Period
Taper wk 25
Taper wk 26
Taper wk 27
Taper wk 28
End of Study - Off 
Drug
 
180
Maintained
Discontinued
60P/60P/60P
80A/60A
60A/30A
60A
30A
80P/60P
60P/30P
60P
30P
80A/60A
60A/40A
60A
30A
80P/60P
60P/40P
60P
30P
30P
60A/60A
60A/30A
60A
30A
60P/60P
60P/30P
60P
30P
140
Maintained
Discontinued
150
Maintained
Discontinued
160
Maintained
Discontinued
170
Maintained
Discontinued
60A/40A
40A/30A
40A
20A
60P/40P
40P/30P
40P
20P
60A/60A
60A/30A
60A
30A
20P
40P
40P/30P
60P/30P
60P/60P
80A/60A
80A/40A/30A
80A/80A
80A/80A/10A
60A/60A/60A
80P/60P
80P/40P/30P
80P/80P
80P/80P/10P
60P/60P
60P/30P
60P
60A/60A
60A/30A
40A/30A
40A
20A
20P
40P
60P
80P
80P/30P
80A/30A
80A
60A
40A
20A
20P
40P
60P
80P
60P/40P
60A/40A
80A
60A
40A
20A
110
Maintained
Discontinued
120
Maintained
Discontinued
100
Maintained
Discontinued
 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
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Follow-Up Period - Oxymorphone ER 
ER OXYMORPHONE
Single BID 
dose in study
Patient group
Study Period
Taper wk 25
Taper wk 26
Taper wk 27
Taper wk 28
End of Study - Off 
Drug
Tablet Strengths
5 mg
10 mg
15 mg
20 mg
30 mg
40 mg
40P/15P
40P
30P
20P
10P
40A/15A
40A
30A
20A
10A
30P/20P
40P
30P
20P
10P
10A
20A
30A
40A
30A/20A
30P/15P
20P/15P
15P/10P
15P
10P
30A/15A
20A/15A
15A/10A
15A
10A
40P
30P
20P
15P
10P
40A
30A
20A
15A
10A
5P
10P
20P
30P
20P/15P
20A/15A
30A
20A
10A
5A
5P
10P
20P
15P/10P
30P
30A
15A/10A
20A
10A
5A
15P/10P
20P
15P
10P
5P
15A/10A
20A
15A
10A
5A
20P
15P
10P
5P
5P
20A
15A
10A
5A
5P
50
Maintained
Discontinued
55
Maintained
Discontinued
40
Maintained
Discontinued
45
Maintained
Discontinued
30
Maintained
Discontinued
35
Maintained
Discontinued
20
Maintained
Discontinued
25
Maintained
Discontinued
 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
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Follow-Up Period - Oxymorphone ER (Cont’d) 
ER OXYMORPHONE
Single BID 
dose in study
Patient group
Study Period
Taper wk 25
Taper wk 26
Taper wk 27
Taper wk 28
End of Study - Off 
Drug
 
40A/30A
30A/20A
30A
15A
30P/30P/30P
40P/30P
30P/20P
30P
15P
30A/30A/30A
40A/30A
30A/20A
30A
15A
40P/30P/15P
40P/30P
30P/20P
30P
15P
40A/30A/15A
30A
15A
40P/40P
30P/30P
30P/15P
30P
15P
40A/40A
90
Maintained
Discontinued
30A/20A
40A
15A/10A
10A
30P/20P/15P
30P/20P
40P
15P/10P
10P
30A/20A/15A
30A/20A
40A
15A/10A
10A
40P/30P
30P/20P
40P
15P/10P
75
Maintained
Discontinued
80
Maintained
Discontinued
85
Maintained
Discontinued
30A/30A
30A/15A
30A
15A
40P/20P/15P
30P/30P
30P/15P
30P
15P
40A/20A/15A
30A/30A
30A/15A
30P/30P
30P/15P
20P/15P
15P/10P
10P
65
Maintained
Discontinued
70
Maintained
Discontinued
10P
40A/30A
30A/30A
30A/15A
20A/15A
15A/10A
10A
60
Maintained
Discontinued
 
All doses represent single BID dose in mg 
 
 
 
 
 
 
 
 
 
 
A = Active; P = Placebo 
 
 
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Appendix C – Roland-Morris Disability Questionnaire (RMDQ) 
When your back hurts, you may find it difficult to do some of the things you normally do. 
This list contains some sentences that people have used to describe themselves when they have back pain. 
When you read them, you may find that some stand out because they describe you today. As you read the list, 
think of yourself today. When you read a sentence that describes you today, mark the box next to it. If the 
sentence does not describe you, then leave the space blank and go on to the next one. Remember, only mark 
the sentence if you are sure that it describes you today. 
1. 
 
I stay at home most of the time because of the pain in my back. 
2. 
 
I change position frequently to try and make my back comfortable. 
3. 
 
I walk more slowly than usual because of the pain in my back. 
4. 
Because of the pain in my back, I am not doing any of the jobs that I usually do around the house. 
5. 
 
Because of the pain in my back, I use a handrail to get upstairs. 
6. 
 
Because of the pain in my back, I lie down to rest more often. 
7. 
 
Because of the pain in my back, I have to hold on to something to get out of a reclining chair. 
8. 
 
Because of the pain in my back, I ask other people to do things for me. 
9. 
 
I get dressed more slowly than usual because of the pain in my back. 
10.  
I only stand up for short periods of time because of the pain in my back. 
11.  
Because of the pain in my back, I try not to bend or kneel down. 
12.  
I find it difficult to get out of a chair because of the pain in my back. 
13.  
My back hurts most of the time. 
14.  
I find it difficult to turn over in bed because of the pain in my back. 
15.  
My appetite is not very good because of the pain in my back. 
16.  
I have trouble putting on my socks (or stockings) because of the pain in my back. 
17.  
I only walk short distances because of the pain in my back. 
18.  
I sleep less because of the pain in my back. 
19.  
Because of the pain in my back, I get dressed with help from someone else. 
20.  
I sit down for most of the day because of the pain in my back. 
21.  
I avoid heavy jobs around the house because of the pain in my back. 
22.  
Because of the pain in my back, I am more irritable and bad tempered with people. 
23.  
Because of the pain in my back, I go upstairs more slowly than usual. 
24.  
I stay in bed most of the time because of the pain in my back. 
Note to users: 
The score of the RDQ is the total number of items checked – i.e. from a minimum of 0 to a maximum of 24. 
It is acceptable to add boxes to indicate where patients should mark each item. 
The questionnaire may be adapted for use on-line or by telephone. 
Reference: Roland MO, Morris RW. A study of the natural history of back pain. Part 1: Development of a reliable and 
sensitive measure of disability in low back pain. Spine. 1983;8:141-144. 
 
 
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Appendix D – Pain Intensity on 0-10 NRS 
 
 
 
 
 
0            1             2             3             4             5             6             7              8            9            10 
No 
pain 
Worst 
pain 
imaginable 
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Appendix E – Brief Pain Inventory- Short Form (BPI-SF) 
The BPI-SF is shown in its entirety.  However, for this study, questions 2 and 7 are not relevant and that 
information will not be collected. 
 
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Reference: Daut RL, Cleeland CS, Flanery RC. Development of the Wisconsin Brief Pain Questionnaire to assess pain in 
cancer and other diseases. Pain. 1983;17:197-210. 
 
 
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Appendix F – Regional Pain Scale 
 
Reference: Wolfe F. Pain extent and diagnosis: development and validation of the regional pain scale in 12,799 subjects 
with rheumatic disease. J Rheumatol. 2003;30:369-378. 
 
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Appendix G – Pain Quality Assessment Scale (PQAS) 
 
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Reference: Victor T, Jensen M, Gammaitoni A, Gould E, White R, Galer BS. The dimensions of pain quality: factor analysis 
of the Pain Quality Assessment Scale. Clin J Pain. 2008;24:550-555. 
 
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Appendix H – MOS Sleep Scale 
 
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Reference: Hays RD, Stewart AL. Sleep measures. In Stewart AL & Ware JE. (eds.), Measuring Functioning and Well-being: 
The Medical Outcomes Study Approach. Durham, NC: Duke University Press, 1992, pp. 235-259. 
 
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Appendix I – Work Productivity and Activity Impairment (WPAI) 
 
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Reference: Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity 
impairment instrument. PharmacoEconomics. 1993;4:353-365 
 
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Appendix J – Patient Health Questionnaire Depression Scale (PHQ-8) 
 
Reference: Kroenke K, Strine TW, Spritzer RL, Williams JB, Berry JT, Mokdad AH. The PHQ-8 as a measure of current 
depression in the general population. J Affect Disord. 2009;114:163-73. 
 
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Appendix K – Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS Lifetime: 
 
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C-SSRS Since Last Visit:
 
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Reference: Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin G, Greenhill L, Shen 
S, Mann JJ. The Columbia-Suicide Severity Rating Scale: Initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psych. 2011;168:1266-1277.   
 
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Appendix L – EuroQOL 5 Dimensions (EQ-5D-5L) 
 
 
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Reference: The EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health 
Policy. 1990;16:199-208. 
 
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Appendix M – Patient Global Impression of Change (PGIC) 
√ (Check) the box you feel most closely describes any change you have experienced in your low back pain since 
you entered the study. Choose only ONE response. 
□ 1. Very Much Improved 
□ 2. Much Improved 
□ 3. Minimally Improved 
□ 4. No Change 
□ 5. Minimally Worse 
□ 6. Much Worse 
□ 7. Very Much Worse 
Reference: John T. Farrara JT, Young JP, LaMoreaux L, et al.  Clinical importance of changes in chronic pain intensity 
measured on an 11-point numerical pain rating scale. Pain 2001;94:149-158. 
 
 
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Appendix N – Subjective Opiate Withdrawal Scale (SOWS) 
Instructions to patient:  Based on the way you feel now, rate each of the 16 symptoms on a scale for 0 to 4, 
where:  
0 = not at all  
1 = a little  
2 = moderately 
3 = quite a bit  
4 = extremely 
 
___________________________________________ 
1. I feel anxious 
2. I feel like yawning 
3. I’m perspiring 
4. My eyes are tearing 
5. My nose is running 
6. I have goose flesh 
7. I am shaking 
8. I have hot flashes 
9. I have cold flashes 
10. My bones and muscles ache 
11. I feel restless 
12. I feel nauseous 
13. I feel like vomiting 
14. My muscles twitch 
15. I have cramps in my stomach 
16. I feel like shooting up now 
______________________________________________ 
Scoring: the sum of the scores on each item is the total SOWS score. The minimum SOW score is 0 and the 
maximum is 64. 
Reference: Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new rating scales for opiate 
withdrawal. Am J Drug Alcohol Abuse. 1987;13:293-308. 
 
 
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Appendix O – Clinical Opiate Withdrawal Scale (COWS) 
For each item, write in the number that best describes the patient’s signs or symptom. Rate on just the 
apparent relationship to opiate withdrawal.  For example, if heart rate is increased because the patient was 
jogging just prior to assessment, the increase pulse rate would not add to the score. 
 
Patient’s Name:___________________________                         Date: ______________ 
                                                                                       
Item 
Score 
Resting Pulse Rate: ______ (record beats per minute)                    
Measured after patient is sitting or lying for one minute  
0 pulse rate 80 or below 
1 pulse rate 81-100 
2 pulse rate 101-120 
4 pulse rate greater than 120 
 
Sweating: over past ½ hour not accounted for by room temperature or 
patient activity. 
0 no report of chills or flushing 
1 subjective report of chills or flushing 
2 flushed or observable moistness on face 
3 beads of sweat on brow or face 
4 sweat streaming off face 
 
Restlessness: Observation during assessment 
0 able to sit still 
1 reports difficulty sitting still, but is able to do so 
3 frequent shifting or extraneous movements of legs/arms 
5 Unable to sit still for more than a few seconds 
 
Pupil size: 
0 pupils pinned or normal size for room light 
1 pupils possibly larger than normal for room light 
2 pupils moderately dilated 
5 pupils so dilated that only the rim of the iris is visible 
 
Bone or Joint aches: If patient was having pain previously, only the 
additional component attributed to opiates withdrawal is scored 
0 not present 
1 mild diffuse discomfort 
2 patient reports severe diffuse aching of joints/ muscles 
4 patient is rubbing joints or muscles and is unable to sit still because of 
discomfort 
 
Runny nose or tearing: Not accounted for by cold symptoms or allergies 
0 not present 
1 nasal stuffiness or unusually moist eyes 
2 nose running or tearing 
4 nose constantly running or tears streaming down cheeks  
 
 
 
 
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Item 
Score 
GI Upset: over last ½ hour 
0 no GI symptoms 
1 stomach cramps 
2 nausea or loose stool 
3 vomiting or diarrhea 
5 Multiple episodes of diarrhea or vomiting 
 
Tremor: observation of outstretched hands 
0 No tremor 
1 tremor can be felt, but not observed 
2 slight tremor observable 
4 gross tremor or muscle twitching 
 
Yawning: Observation during assessment 
0 no yawning 
1 yawning once or twice during assessment 
2 yawning three or more times during assessment 
4 yawning several times/minute 
 
Anxiety or Irritability: 
0 none 
1 patient reports increasing irritability or anxiousness 
2 patient obviously irritable anxious 
4 patient so irritable or anxious that participation in the assessment is 
difficult 
 
Gooseflesh skin: 
0 skin is smooth 
3 piloerection of skin can be felt or hairs standing up on arms 
5 prominent piloerection 
 
 
Total scores 
 
 with observer’s initials 
 
 
 
 
Score:  
5-12 = mild;  
13-24 = moderate;  
25-36 = moderately severe; 
More than 36 = severe withdrawal 
 
Reference: Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003;35:253-259. 
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Appendix P – Digit Symbol Substitution Test (DSST) 
 
Reference: Wechsler D. The measurement and appraisal of adult intelligence (1st ed.). Baltimore: Williams and Wilkins 
Corporation, 1939. 
 
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Appendix Q – Quantitative Sensory Testing 
Background 
In addition to clinical outcomes, opioid-induced hyperalgesia (OIH) will be evaluated in a sub-study at 
interested and qualified sites by using quantitative sensory testing (QST) methods to assess pain sensitivity 
during certain study visits. The procedure is described in detail in the study specific procedure manual for the 
OIH QST Algorithm. All study staff participating in the QST sub-study will be trained on the QST procedure.  
Subjects will sign a separate informed consent for participation and are not required to participate after being 
informed of the risks, benefits, and requirements of the sub-study. 
 
The QST Procedure 
The procedure is based on 4 tests, in which thermal stimuli will be administered via a thermode to the 
subject’s hand or arm by using the Q-Sense CPM Device (Medoc, Ramat Yishai, Israel). Subjects will report the 
pain they perceive from each stimulus, and the study staff will capture these reports on source documents. 
The 4 QST tests are: (1) Phasic heat Pain Intensity (PPI); (2) Tonic heat Pain Intensity (TPI); (3) Conditioned Pain 
Modulation (CPM) and (4) Temporal Summation (TS).  
 
Training Session 
 
At the beginning of the study visit, participants will be exposed to a short training session. The training session, 
lasting approximately 10 minutes, will allow participants to practice the use of the scoring scale and to address 
questions regarding the procedure. The training session will include a detailed description of the study tests 
and instructions on how to rate pain intensity during the procedure. The results of the training session will be 
captured in the system but not entered into the data capture system or used for the statistical analysis. 
 
Phasic Heat Pain Intensity 
 
In order to assess pain intensity in response to a phasic (short) heat pain stimulus, the thermode will be 
attached to the thenar eminence of the non-dominant hand. The temperature will be increased gradually from 
baseline until it reaches the destination temperature of 47°C, which will then be maintained consistently for a 
duration of 3 seconds. The maximal pain intensity reported by the subject will be recorded. 
 
The Phasic Heat Pain Intensity test outcome is a single pain score.  
 
Tonic Heat Pain Intensity 
 
In order to assess pain intensity in response to tonic (long) heat pain stimulation, the thermode will be 
attached to the volar aspect of the dominant arm. The thermode temperature will be increased to 46°C and 
will remain constant for 60 seconds, after which the temperature will be reduced back to baseline. During the 
60-second stimulus, subjects will report their pain intensity (0–100 on the Numerical Pain Scale [NPS]) every 20 
seconds (at 0, 20, 40, and 60).  
 
The Tonic Heat Pain Intensity test outcomes are recorded as four pain ratings, collected at times 0, 20, 40, and 
60 seconds.  
 
Conditioned Pain Modulation (CPM) Test 
 
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CPM is conducted by the administration of two types of stimuli, a test stimulus and a conditioning stimulus. At 
the beginning, the test stimulus is administered alone, and the pain intensity reported by the subject is 
recorded. This test is followed by the administration of the conditioning stimulus to a separate, remote part of 
the body. While the conditioning stimulus is administered, another test stimulus is given and the pain intensity 
reported by the subject is recorded. 
 
The test-pain stimulus is a 30-second stimulus delivered to the volar aspect of the dominant forearm and set at 
45.6°C. Pain intensity (NPS) will be recorded at seconds 0, 15, and 30. After a 60-second break, the 
conditioning stimulus, lasting approximately 40 seconds, will be administered to the volar aspect of the non-
dominant forearm at of 46.3°C. A few seconds after initiation of the conditioning stimulus, the test-pain 
stimulus will be repeated, and pain intensity (NPS) will be recorded in the same manner.  
 
The CPM outcomes to be collected are 6 pain scores, 3 for each test stimulus (at time 0, 15, and 30 seconds, 
for each test stimulus). 
 
Temporal Summation (TS) test 
 
The TS test will be induced by applying a rapid set of 4 identical stimuli, each lasting 0.1 second, at 46.5°C 
intensity to the ventral section of the non-dominant forearm. Thermode temperature will oscillate between 
46.5°C and 44°C a total of 4 times, and stimuli will be separated by 2.5 seconds. The thermode temperature 
will decline to the device baseline temperature (32 °C) after reaching the last peak temperature. Following 
each stimulus, participants will rate their pain using the NPS (0–100).  
 
The TS outcomes are 4 pain scores, one per stimulus.  
 
 
 
 
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Appendix R – Abuse-Related Adverse Events (MADDERS) 
Description 
Potentially abuse-related events will be identified, assessed, and quantified using the Misuse, Abuse, and 
Diversion Drug Event Reporting System (MADDERSTM), which identifies and characterizes such events 
according to a classification system developed in the context of the FDA-ACTTION initiative (Smith 2013). 
Events are identified for further evaluation on the occurrence of specific adverse events (such as abuse, 
overdose, respiratory arrest, etc.), or significant drug accountability discrepancies. Events triggering will be 
outlined in the MADDERSTM User’s Manual. When such an event occurs, investigators and study staff, having 
been trained on the system, complete a clinician-based assessment to capture information and classify 
whether the event was abuse, misuse, suicide-related, therapeutic error, unknown, or none of the above, 
with further supplemental designations for tampering, withdrawal, addiction-related, diversion, and 
overdose.  
The output of the system is count data for each type of event and their total, which can be compared 
between groups in a study, as well as the event characteristics as captured by the supplemental forms. The 
result of the process is a more accurate classification of potentially abuse-related events than can be 
achieved by standard methods, to avoid either overestimation, underestimation, or mischaracterization of 
product risks. 
The system components consist of: 
• 
Triggering Adverse Events List 
o A list of specific adverse event terms and definitions that, if documented by the investigator, 
lead to completion of a “Supplemental Adverse Event Form” 
• 
Drug Accountability Discrepancy Threshold 
o A criterion for drug accountability discrepancies that, if documented during a study visit, lead 
to completion of a “Supplemental Drug Accountability Form” 
• 
Supplemental Adverse Event Form 
o A clinician-reported assessment that directs the clinician on what information to capture at 
the time of a triggering adverse event to inform the correct classification of the event 
• 
Supplemental Drug Accountability Form 
o A clinician-reported assessment that directs the clinician on what information to capture at 
the time of a drug accountability discrepancy to inform the correct classification of the event 
• 
Medication Use Survey  
o A clinician-reported assessment that directs the clinician on what information to capture at 
the end of study or at an early termination visit to inform of any potential MADDERSTM events 
that might not have been captured 
The 3 forms that will need to be completed are presented in the following pages.  The remaining 
information will be provided in the User’s Manual. 
Reference: Smith SM, Dart RC, Katz NP, Paillard F, Adams EH, Comer SD, Degroot A, Edwards RR, Haddox JD, Jaffe JH, 
Jones CM, Kleber HD, Kopecky EA, Markman JD, Montoya ID, O'Brien C, Roland CL, Stanton M, Strain EC, Vorsanger G, 
Wasan AD, Weiss RD, Turk DC, Dworkin RH; Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, 
Opportunities, and Networks (ACTTION) public-private partnership. Classification and definition of misuse, abuse, and 
related events in clinical trials: ACTTION systematic review and recommendations. Pain. 2013;154:2287.  
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Supplemental Adverse Event Form 
 
 
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Supplemental Drug Accountability Form 
 
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Medication Use Survey 
 
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Appendix S – Endocrine Function and Sexual Function 
Endocrine function will be assessed at screening, and 12 and 24 weeks post-randomization, in all participants.  
Participants will be encouraged to attend the clinic and have blood drawn as early in the morning as practical, 
and to fast prior to their morning blood draw.  Data will be captured on customary time to bed, customary 
awakening time, and time blood is drawn, to account for variability in actual blood drawing time.  In female 
patients, data will be captured on type of birth control (including IUDs, implants, etc.), menopausal status, the 
date the last menstrual period began, and during the study the onset dates of all menstrual periods.  The 
timing of blood draws will be performed according to the study schedule irrespective of the timing of the 
menstrual cycle. 
The endocrine endpoints will be as follows: 
• 
HPG axis: Total testosterone, free testosterone (assayed using the equilibrium dialysis 
method), FSH, LH, and, in women, estradiol 
• 
HPA axis: ACTH, cortisol, dehydroepiandrosterone sulfate (DHEAS) 
• 
Growth hormone axis: IGF-1 
• 
Thyroid function: TSH (only at screening) 
Questionnaires (following this description) regarding sexual function (International Index of Erectile Function 
[IIEF] in males and Female Sexual Function Index [FSFI] in females) will be obtained at the same time that 
endocrine blood samples are drawn.  Changes in sexual function will be correlated to changes in endocrine 
function. 
Procedure:  
At a morning visit in fasted subjects (who ideally have been seated and resting quietly for 30 min), obtain 
blood for total testosterone, free testosterone, FSH, LH, estradiol (women only), IGF-1, cortisol, ACTH, DHEAS, 
and TSH (baseline only).   
Anticipated results:  
Participants who stop opioids, compared to those continued on opioids, will:  
1) Show increases in testosterone and free testosterone (and estradiol in women).  The increases in 
these hormones will likely be accompanied by increases in FSH/LH, suggesting that opioids act at 
the hypothalamic level to affect gonadal function. Improvements in gonadal function may 
correlate with improved sexual function. 
2) Show increases in cortisol, ACTH and DHEAS 
3) Show increases in IGF-1 
Potential Confounders:  
Potential confounders include any steroid use (inhaled steroids, topical steroids, oral steroids, injected into 
joints--effects will suppress the HPA axis for up to a year), phase of the menstrual cycle, whether a woman is 
pre- versus post-menopausal, use of hormones or oral contraceptives, smoking, age, sex, other medical 
illnesses, body mass index (particularly important in interpreting IGF-1), duration of opioid use, and specific 
opioid being used.  These factors should be assessed in a detailed history. 
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Appendix T – Urine Drug Testing (UDT) 
Appendix: Urine Drug Testing Procedures and Management of Unexpected Findings 
 
General Procedure 
Urine Drug Testing (UDT) will be performed according to the Schedule of Procedures of the protocol. Testing 
will be performed for the presence of the following drugs: 
• 
Illegal drugs 
• 
Non-prescribed controlled substances (opioid and non-opioid) 
• 
Alcohol 
Following randomization, index drugs and their metabolites will NOT be tested to avoid unblinding of the 
subject or the investigator. 
 
Management of Unexpected Findings 
Unexpected finding will be managed according to the following table: 
 
 
Unexpected 
Result/Report 
Possible Explanation 
Recommended Action 
Comment 
1 
UDT positive for 
non-study opioid 
medication 
• If not prescribed, 
patient acquired 
opioids from other 
sources (doctor 
shopping, street) 
• Report indicates detection of non-
study opioid.  Details of the non-
study opioid are provided.  
Investigator to determine whether 
result is appropriate based on 
patient’s prescribed rescue 
regimen and phase of study. 
• Unscheduled visit:  Investigator 
performs “Supplemental 
Evaluation” (see below) if result is 
not appropriate. 
• Since repeated consumption of 
prohibited medications against 
instructions creates a patient 
safety issue, patient is terminated 
from study per sponsor guidelines 
upon second event 
• Example: patient has codeine 
in his urine.  Report indicates 
presence of codeine.  
Investigator understands that 
after randomization codeine is 
inappropriate and follows 
unscheduled visit and related 
procedures. 
• Example: patient on oxycodone 
ER and codeine rescue at 
Screening has codeine in their 
urine.  Investigator 
understands that this is 
acceptable and takes no 
action. 
2 
UDT positive for 
non-opioid 
controlled 
medication 
• If not prescribed, 
patient acquired 
non-opioids from 
other sources 
(doctor shopping, 
street) 
• Report indicates detection of 
“non-opioid controlled 
substance.”   Identity of substance 
is provided. 
• Unscheduled visit:  Investigator 
performs “Supplemental 
Evaluation” (see below) if this is a 
non-prescribed medication. 
• Since repeated consumption of 
prohibited or non-prescribed non-
opioid controlled medications is 
against instructions creates a 
patient safety issue, patient is 
terminated from study per 
sponsor guidelines upon second 
event. 
• Example: patient on any 
regimen has diazepam in urine.  
Investigator reviews prescribed 
concomitant medications to 
determine if  patient was 
prescribed diazepam 
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Unexpected 
Result/Report 
Possible Explanation 
Recommended Action 
Comment 
3 
UDT positive for 
illicit drugs (e.g., 
cocaine, heroin) or 
alcohol (not 
cannabis;  
see below) 
• Patient is abusing 
the detected 
substance 
• Cannabis is positive 
for dronabinol 
(Marinol®) or 
medical marijuana 
• Report indicates detection of 
specified illicit substance. 
• Unscheduled visit:  Investigator 
performs “Supplemental 
Evaluation” (see below) 
• Counsel patient that repeated 
similar results may lead to 
discontinuation from study 
• Since repeated consumption of 
prohibited medications against 
instructions creates a patient 
safety issue, patient is terminated 
from study per sponsor guidelines 
upon second event 
• Example: patient has cocaine in 
urine. 
4 
UDT positive for 
cannabis 
• Medical marijuana 
• Recreational 
marijuana 
• Report indicates detection of 
cannabis 
• Unscheduled visit:  Investigator 
performs “Supplemental 
Evaluation” (see below) 
• Counsel patient based on 
investigator judgment 
• Termination from study based on 
investigator judgment 
•  
5 
Failed specimen 
validity test (e.g. 
creatinine, specific 
gravity) 
• Patient added 
water to sample 
 
• Send report to investigator, 
indicating that “urine specimen 
was not valid”, suggesting 
adulteration 
• Unscheduled visit: Investigator 
performs “Supplemental 
Evaluation” (see below) 
• Review treatment agreement and 
counsel patient that repeated 
similar results may lead to 
discontinuation from study. 
• Consider supervised collection or 
temperature testing 
• Since repeated masking of urine 
testing raises the likelihood of a 
patient safety issue, patient is 
terminated from study per 
sponsor guidelines upon second 
event 
• Algorithm constructed to be 
general in terms of the type of 
specimen validity test result 
that will generate this report, 
since specimen validity testing 
may vary across lab vendors 
 
 
 
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Supplemental Evaluation and Intervention 
• 
Bring patient in for unscheduled visit to discuss test results in non-judgmental manner. 
• 
Take a detailed history of the patient’s medication use for the preceding 7 days (e.g., could learn that 
patient ran out of study medication several days prior to test or that a legitimate supplemental 
prescription had been provided). 
• 
Ask patient if they took any non-prescribed medications, and if so, which ones, doses, etc. 
• 
Ask about medical prescription of dronabinol or medical marijuana if cannabis detected. 
• 
Ask patient if they’ve given the drug to others. 
• 
Monitor compliance with pill counts. 
• 
Check Prescription Monitoring Program (PDMP) data if available for recent non-study pain medication 
prescriptions. 
• 
Repeat UDT is not required but may be performed at discretion of investigator if that will improve 
management of subject. 
• 
Review treatment agreement (brief form to be used) and counsel patient that repeated similar results may 
lead to discontinuation from study. 
• 
If patient is terminated from the study, advance subject to follow-up period. 
 
 
 
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Appendix U – Online Patient Support Program 
Unfortunately, several barriers stand in the way of face-to-face pain treatment for millions of people, including 
inadequate finances, reluctance to seek treatment, and reduced access in rural areas. A highly cost-effective 
avenue for making inroads into this problem is the use of technology as a supplement to the traditional 
administration of services. Technology-based programs are affordable, self-paced, and are available 24 hours 
a day to people with reduced access to traditional treatment, such as people living in rural areas, with 
communication or other disabilities, with busy or inflexible schedules, or who lack child care, transportation, or 
insurance coverage. 
The Online Patient Support Program uses easy-to-use computer-based tools to aid in treatment for chronic 
pain and depression. These tools help people manage psychological, social, and health-related problems that 
are often treated in health care settings and in during clinical trials. The tools provide a uniquely dynamic 
foundation for learning such as online assessments and the scoring and reporting of data, interactive learning, 
electronic messaging, in-stream video, online discussion forums, as well as online data tracking and graphing. 
Features such as self-assessment, homework exercises, and self-monitoring can be created to suit the specific 
goals of a program. The program was created by two psychologists, Dr. Linda Ruehlman and Dr. Paul Karoly.  
Reference: Ruehlman LS, Karoly P, Enders C. A randomized controlled evaluation of an online chronic pain self-
management program. Pain. 2012;153:319-30. 
 
 
 
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Appendix V – Early Discontinuation Assessment Tool 
As a follow-up to the questions we just discussed, I want to ask you a few questions about the reasons why you 
are leaving this research study. People decide to leave research studies for many reasons.  For each of the 
reasons  I will read to you, first indicate whether this contributed to your decision to leave the study (“Yes” or 
“No”). Second, for those reasons where you answered “Yes”, please indicate whether the reason was 
“extremely important”, “moderately important”, “a little important”, or “not that important”  for you. 
 
Each question is initially answered “Yes” or “No” by circling 
the word.  If “Yes” is chosen, then indicate the importance 
Extremely 
important 
Moderately 
important 
A little 
important 
Not that 
important 
1) 
Too much pain                                    
Yes   No 
□ 
□ 
□ 
□ 
2) 
Side effects from medications                               
Yes   No 
□ 
□ 
□ 
□ 
3) 
Feeling sick from medication withdrawal               Yes   No 
□ 
□ 
□ 
□ 
4) 
Anxiety or nervousness                                                Yes   No 
□ 
□ 
□ 
□ 
5) 
Trouble sleeping                                                            Yes   No 
□ 
□ 
□ 
□ 
6) 
Transportation problems                                              Yes   No 
□ 
□ 
□ 
□ 
7) 
Study procedures are too uncomfortable                 Yes   No 
□ 
□ 
□ 
□ 
8) 
Study procedures require too much of my time      Yes   No 
□ 
□ 
□ 
□ 
9) 
Cannot take time from work or other obligations  Yes   No 
□ 
□ 
□ 
□ 
10) 
Do not like not knowing what medication I am on Yes   No 
□ 
□ 
□ 
□ 
11) 
Prefer to receive medical care elsewhere                Yes   No 
□ 
□ 
□ 
□ 
12) 
Need treatment that is not allowed in this study    Yes   No 
□ 
□ 
□ 
□ 
13) 
Moving too far from the research center                  Yes   No 
□ 
□ 
□ 
□ 
14) 
Developed a new medical condition                          Yes   No 
□ 
□ 
□ 
□ 
15) 
Do not want to be in an experiment any longer      Yes   No 
□ 
□ 
□ 
□ 
16) 
Want to go back on opioid medications                    Yes   No 
□ 
□ 
□ 
□ 
17) 
Do not like the research center                                   Yes   No 
□ 
□ 
□ 
□ 
Please add any additional comments:  
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
How has your pain changed during this study? 
Increased 
Remained the same 
Decreased 
Severity of pain 
□ 
□ 
□ 
Area of pain 
□ 
□ 
□ 
Sensitivity to pain 
□ 
□ 
□ 
 
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Opioid Post-Marketing Requirement (PMR) Consortium 
 
 
 
 
Study {2065-5} 
08-Feb-2017 
 
Confidential and Proprietary Information 
 
80 
 
Appendix W – STOPBang Questionnaire  
Please answer the following questions below to determine if you are at risk for obstructive sleep apnea (OSA): 
 
Scoring Criteria: 
 
For general population 
Low risk of OSA:  
 
Yes to 0 - 2 questions 
Intermediate Risk of OSA:  
Yes to 3 - 4 questions 
High Risk of OSA: 
 
Yes to 5 - 8 questions 
or Yes to 2 or more of 4 STOP questions + male gender 
or Yes to 2 or more of 4 STOP questions + BMI > 35kg/m2 
or Yes to 2 or more of 4 STOP questions + neck circumference 17 inches / 43cm in 
male or 16 inches / 41cm in female 
 
Modified from Chung F et al. Anesthesiology 2008; 108:812-21, Chung F et al Br J Anaesth 2012; 108:768–75, Chung F et al 
J Clin Sleep Med Sept 2014  
“With permission from University Health Network, www.stopbang.ca” 
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SAP_001.pdf: 
1004904A 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 1 of 72 
Sponsor Name: 
Opioid Post-Marketing Requirement (PMR) 
Consortium 
Protocol Number and Title: 
2065-5: A Randomized, Double-Blind, 
Placebo-Controlled Clinical Trial of 
Structured Opioid Discontinuation versus 
Continued Opioid Therapy in Suboptimal and 
Optimal Responders to High-Dose Long-Term 
Opioid Analgesic Therapy for Chronic Pain 
Protocol Version and Date: 
Original Protocol: 10 Jan 2016 
Amendment 1: 07 Jul 2016 
Amendment 2: 02 Feb 2017 
INC Research Project Code: 1004904A 
Author: 
Laura Truskowski 
Principal Biostatistician 
SAP Version: 
1.3 
SAP Version Date:  
11 April 2018 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to the Opioid PMR 
Consortium. Acceptance of this document constitutes agreement by the recipient that no 
information contained herein will be published or disclosed without prior written authorization 
from an official of the Opioid PMR Consortium.  However, this document may be disclosed to 
appropriate Institutional Review Board and Ethics Committees or duly authorized representatives 
of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, INC Research 
should be notified promptly. 
 
 
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Clinical Study Report version: Final
Page 2 of 73


100490.fA 
Opioid PMR (00$0ftlum 
Protocol: 2065·5 
SAPv1.l 
Statistical Analysis Plan 
:nc 
Research" 
_.......,..,_ ......... 
Version: 
1.3 
Version Date: 
...:..1.:...1 
_____ _ 
I confirm that I have reviewed this document and agree with the content. 
Lead Biostattsticfan 
Laura Truskowski 
Principal Biostatistician 
Di 
a Meske 
APPROVALS 
IHC ResHrch 
on behalf of the Opioid PMR Consortium 
03.007A.01 
Thts document ts proprietary and confidential to INC Research LLC, 
INC Re$eardl O LLC 
Page2of72 
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Clinical Study Report version: Final
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 3 of 72 
TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 7 
2. 
PURPOSE ..................................................................................................... 10 
2.1. 
Responsibilities ................................................................................................................. 10 
2.2. 
Timings of Analyses .......................................................................................................... 10 
3. 
STUDY OBJECTIVES AND HYPOTHESES ................................................. 11 
3.1. 
Primary Objective .............................................................................................................. 11 
3.2. 
Secondary Objective ......................................................................................................... 11 
3.3. 
Exploratory Objectives ...................................................................................................... 11 
3.4. 
Hypotheses ......................................................................................................................... 11 
4. 
STUDY DESCRIPTION ................................................................................. 12 
4.1. 
Subject Selection ............................................................................................................... 12 
4.2. 
Brief Description ................................................................................................................ 12 
4.2.1. 
Suboptimal Responders .................................................................................................. 12 
4.2.2. 
Optimal Responders ........................................................................................................ 13 
4.2.3. 
Blinded Structured Opioid Discontinuation Period and Follow-up................................... 14 
4.3. 
Determination of Sample Size .......................................................................................... 14 
4.4. 
Treatment Assignment and Blinding ............................................................................... 14 
4.5. 
Administration of Study Medication ................................................................................ 15 
4.6. 
Study Procedures and Flowchart ..................................................................................... 16 
5. 
ENDPOINTS .................................................................................................. 23 
5.1. 
Primary Efficacy Endpoint ................................................................................................ 23 
5.2. 
Secondary Efficacy Endpoints ......................................................................................... 23 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 4 of 72 
5.3. 
Exploratory Measurements ............................................................................................... 24 
5.4. 
Assessment of Safety........................................................................................................ 25 
6. 
ANALYSIS SETS .......................................................................................... 26 
6.1. 
Safety Sets .......................................................................................................................... 26 
6.2. 
Randomized Set ................................................................................................................. 26 
6.3. 
Intent-to-treat Set ............................................................................................................... 27 
6.4. 
Per-protocol Set ................................................................................................................. 27 
6.5. 
Protocol Deviations ........................................................................................................... 28 
7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 29 
7.1. 
General Methods ................................................................................................................ 29 
7.2. 
Key Definitions ................................................................................................................... 29 
7.2.1. 
Definition of Baseline ....................................................................................................... 29 
7.2.2. 
Mean Pain Intensity Scores ............................................................................................. 30 
7.2.3. 
Treatment Emergence for Adverse Events ..................................................................... 30 
7.3. 
Visit Windows ..................................................................................................................... 30 
7.4. 
Pooling of Study Sites ....................................................................................................... 31 
7.5. 
Subgroups .......................................................................................................................... 31 
8. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 32 
8.1. 
Subject Disposition and Withdrawals .............................................................................. 32 
8.2. 
Demographics .................................................................................................................... 33 
8.3. 
Baseline Characteristics ................................................................................................... 33 
8.4. 
Medical History .................................................................................................................. 34 
8.5. 
Prior and Concomitant Medications ................................................................................ 34 
8.5.1. 
Pre-randomization Prior Medications .............................................................................. 35 
8.5.2. 
Post-randomization Concomitant Medications ................................................................ 35 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 5 of 72 
9. 
EFFICACY ..................................................................................................... 36 
9.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 36 
9.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 37 
9.2.1. 
Secondary Analyses of the Primary Endpoint ................................................................. 37 
9.2.2. 
Analysis of Pain Intensity Secondary Endpoints ............................................................. 38 
9.2.3. 
Analysis of Scale Score Secondary Endpoints ............................................................... 38 
9.3. 
Additional Efficacy Analyses ............................................................................................ 41 
9.3.1. 
Cumulative Response Function – Mean Average PI ...................................................... 41 
9.3.2. 
Cumulative Response Function – RMDQ ....................................................................... 41 
9.3.3. 
Overall Clinical Benefit – Suboptimal Responders .......................................................... 42 
9.3.4. 
Time to Discontinuation Due to Lack of Efficacy ............................................................. 42 
9.3.5. 
Patient Global Impression of Change .............................................................................. 42 
9.3.6. 
EuroQOL 5 Dimensions (5 Levels of Response) Instrument .......................................... 43 
9.4. 
Exploratory Efficacy Analyses ......................................................................................... 43 
9.4.1. 
Subject Characteristics Predictive of Response.............................................................. 44 
9.4.2. 
Digit Symbol Substitution Test......................................................................................... 44 
9.4.3. 
Changes in Endocrine and Sexual Function ................................................................... 44 
10. 
ANALYSIS OF PHARMACOKINETICS .................................................... 46 
11. 
ANALYSIS OF PHARMACODYNAMICS .................................................. 47 
12. 
SAFETY ..................................................................................................... 48 
12.1. 
Extent of Exposure ............................................................................................................ 48 
12.2. 
Treatment Compliance ...................................................................................................... 48 
12.3. 
Adverse Events .................................................................................................................. 49 
12.4. 
Laboratory Evaluations ..................................................................................................... 53 
12.5. 
Vital Signs ........................................................................................................................... 54 
12.6. 
Physical Examination ........................................................................................................ 55 
12.7. 
Urine Drug Testing ............................................................................................................. 55 
12.8. 
Subjective Opiate Withdrawal Scale ................................................................................ 55 
12.9. 
Clinical Opiate Withdrawal Scale ..................................................................................... 55 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 6 of 72 
12.10. 
Columbia-Suicide Severity Rating Scale .................................................................... 56 
12.10.1. 
Suicidal Behavior ........................................................................................................ 56 
12.10.2. 
Suicidal Ideation .......................................................................................................... 56 
12.10.3. 
Suicidality .................................................................................................................... 57 
13. 
INTERIM ANALYSES ................................................................................ 58 
14. 
END OF STUDY STATISTICAL ANALYSIS PLAN MODIFICATIONS ..... 59 
15. 
REFERENCE LIST .................................................................................... 62 
16. 
PROGRAMMING CONSIDERATIONS ...................................................... 63 
16.1. 
General Considerations .................................................................................................... 63 
16.2. 
Table and Listing Format .................................................................................................. 63 
16.2.1. 
General ........................................................................................................................ 63 
16.2.2. 
Headers ....................................................................................................................... 63 
16.2.3. 
Display Titles ............................................................................................................... 64 
16.2.4. 
Column Headers ......................................................................................................... 64 
16.2.5. 
Body of Data Display ................................................................................................... 64 
17. 
QUALITY CONTROL ................................................................................. 67 
18. 
INDEX OF TABLES ................................................................................... 68 
19. 
INDEX OF LISTINGS ................................................................................. 72 
 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 7 of 72 
1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description  
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BPI-SF 
Brief Pain Inventory – Short Form 
BSODP 
Blinded Structured Opioid Discontinuation Period 
CI 
confidence interval 
CLBP 
chronic low back pain 
CMH 
Cochran-Mantel-Haenszel 
COWS 
Clinical Opiate Withdrawal Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DHEAS 
dehydroepiandrosterone sulfate 
DSST 
Digit Symbol Substitution Test 
EQ-5D-5L 
EuroQOL 5 dimensions (5 levels of response) instrument 
ER 
extended-release 
FDA 
Food and Drug Administration 
FSFI 
Female Sexual Function Index 
ICH 
International Conference on Harmonization 
IIEF 
International Index of Erectile Function 
IR 
immediate release 
IRT 
interactive response technology 
ITT 
Intent-to-Treat 
LA 
long-acting 
LBP 
lower back pain 
LOCF 
last observation carried forward 
LSMeans 
least squares means 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 8 of 72 
Abbreviation 
Description  
MADDERS 
Misuse Abuse Diversion Drug Event Reporting System 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed model repeated measures 
MOS 
Medical Outcomes Study 
MSER 
morphine sulfate extended-release 
MSIR 
morphine sulfate immediate-release 
NRS 
numerical rating scale 
OCER 
oxycodone extended-release 
OCIR 
oxycodone immediate-release 
OMER 
oxymorphone extended-release 
OMIR 
oxymorphone immediate-release 
OPC 
Opioid PMR Consortium 
PCS 
potentially clinically significant 
PGIC 
Patient Global Impression of Change 
PHQ-8 
Patient Health Questionnaire Depression Scale 
PI 
pain intensity 
PID 
pain intensity difference 
PMR 
Post-Marketing Requirement 
PP 
Per-protocol 
PQAS 
Pain Quality Assessment Scale 
PRN 
pro re nata (as needed) 
PT 
preferred term 
QST 
quantitative sensory testing 
RMDQ 
Roland-Morris Disability Questionnaire 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 9 of 72 
Abbreviation 
Description  
SD 
standard deviation 
SE 
standard error 
SI 
International System of Units 
SOC 
System Organ Class 
SOWS 
Subjective Opiate Withdrawal Scale 
TEAE 
treatment emergent adverse event 
UDT 
urine drug testing 
VAS 
visual analog scale 
WHODD 
World Health Organization Drug Dictionary 
WPAI 
Work Productivity and Activity Impairment scale 
 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 10 of 72 
2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives. 
2.1. 
Responsibilities 
INC Research will perform the statistical analyses and is responsible for the production 
and quality control of all tables, figures and listings.  
2.2. 
Timings of Analyses 
The analysis of safety and efficacy is planned after all subjects complete the final study 
visit or terminate early from the study. No interim analysis is planned. 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 11 of 72 
3. 
STUDY OBJECTIVES AND HYPOTHESES 
3.1. 
Primary Objective 
The primary objective is to evaluate the effect on pain intensity (PI) of structured 
discontinuation of long-term opioid analgesic therapy compared to continuation of 
opioid therapy in Suboptimal and Optimal Responders to high-dose, long-term opioid 
analgesic therapy for treatment of chronic low back pain (CLBP). 
3.2. 
Secondary Objective 
The secondary objective is to evaluate the effect on additional clinical outcomes 
measures of structured discontinuation of long-term opioid analgesic therapy compared 
to continuation of opioid therapy for CLBP in Suboptimal and Optimal Responders to 
high-dose, long-term opioid analgesic therapy at multiple time points. 
3.3. 
Exploratory Objectives 
The exploratory objectives are: 
• 
To compare experimental pain sensitivity in the opioid discontinuation vs. 
continuation groups in both Suboptimal Responders and Optimal Responders 
(subjects in substudy) 
• 
To determine subject characteristics that predict response to structured 
discontinuation of opioid therapy 
• 
To determine the effect of opioid discontinuation on certain endocrine function 
tests, sexual function, and the relationship of changes in PI and endocrine 
function to changes in male and female sexual function 
• 
To determine the effect of opioid discontinuation on neurocognitive function 
 
3.4. 
Hypotheses 
The study hypotheses for Suboptimal and for Optimal Responders are as follows: 
Suboptimal Responders: In subjects with CLBP on high-dose opioid therapy for at least 1 
year who have a suboptimal response to opioid treatment, structured discontinuation 
results in an improvement in pain compared to continuation of opioid treatment. 
Optimal Responders: In subjects with CLBP on high-dose opioid therapy for at least 1 
year who have an optimal response to opioid treatment, structured discontinuation of 
opioid treatment results in worsening of pain compared to continuation of opioid 
treatment. 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 12 of 72 
4. 
STUDY DESCRIPTION 
4.1. 
Subject Selection 
Subjects enrolled in the study must have been taking extended release (ER) or long-
acting (LA) opioids or doses of immediate-release opioids at least 4 times a day for at 
least 12 months for non-radicular chronic low back pain (CLBP). The enrolled subjects 
must also have been taking high doses as defined in the table below of one of the 
following “index ER opioids” for their CLBP: morphine sulfate ER (MSER), oxycodone ER 
(OCER), or oxymorphone ER (OMER) for at least 3 consecutive months before the 
Screening Visit. The goal is to have a minimum representation of each index ER opioid 
(a minimum of approximately 20% of randomized subjects for each). Specific inclusion 
and exclusion criteria are listed in the Protocol. 
Index ER Opioid 
Daily Dose Range 
Morphine sulfate ER 
120-540 mg 
Oxycodone ER 
80-360 mg 
Oxymorphone ER 
40-180 mg 
 
A subject will be classified at the Screening Visit as an Optimal Responder if his daily 
Average PI score is ≤4 and he is satisfied with his pain and physical function. A subject 
will be classified as a Suboptimal Responder if his daily Average PI score is ≥6 and he is 
dissatisfied with his pain and physical function. 
Approximately 820 subjects will be randomized into the Blinded Structured Opioid 
Discontinuation Period (BSODP). For each Responder type, 205 subjects per arm will be 
needed. 
4.2. 
Brief Description 
This multicenter, randomized, double-blind, placebo-controlled study will consist of a 
common Screening Visit for all subjects, then different schedules for Optimal and 
Suboptimal Responders, followed by a common schedule for the BSODP and Follow-up 
Period. 
4.2.1. 
Suboptimal Responders 
Subjects classified as Suboptimal Responders at the Screening Visit will enter a 1-week 
Run-in Period during which they will be required to discontinue all previously prescribed 
opioid medications for the duration of the study and will receive a standardized regimen 
of study medication consisting of the index ER opioid plus the immediate-release (IR) 
opioid matching the index ER opioid they were taking at screening. 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 13 of 72 
At the end of the 1-week Run-in Period, Suboptimal Responders will return to the clinic 
for a Tolerability Visit to determine whether they tolerated the standardized opioid 
regimen. 
Suboptimal Responders who tolerated the regimen will then enter a 1-week Baseline 
Period during which they will self-administer the standardized opioid regimen and 
record their PI scores (Average and Worst over the past 24 hours) on a 0-10 numerical 
rating scale (NRS) daily before bedtime. Each subject’s 7-day daily PI scores will be 
averaged and used as the subject’s baseline PI scores. 
At the Randomization Visit, Suboptimal Responders will continue on study if they have 
(i) a baseline mean Average PI score (mean of average daily score) ≥6; (ii) compliance 
with their index ER opioid study medication between 80-120%; and (iii) are still 
dissatisfied with their pain and physical function. Subjects who had a baseline mean 
Average PI score of 10/10 (i.e., they recorded a 10 every day) will be discontinued. 
4.2.2. 
Optimal Responders 
Subjects classified as Optimal Responders at the Screening Visit will enter a 1-week 
Observation Period, where they will be told to continue their current medication 
(including non-index ER and IR opioid medications). At the end of the Period, subjects 
will return to the clinic and be confirmed as Optimal Responders if (i) their index ER 
opioid medication use was ≥120 to ≤540 mg morphine equivalents/day on average with 
80-120% compliance over the Observation Period; (ii) their mean Average PI score was 
≤5; and (iii) they are still satisfied with their pain and physical function. 
Optimal Responders will then enter a Taper Period of up to 2 weeks. Subjects will be 
tapered with the same index opioid they were taking at screening (using study 
medication provided for the index ER opioid). No other ER opioid will be allowed, nor 
any IR opioid. Subjects with a mean Average PI score >5 over 3 or more consecutive PI 
scores (excluding missing values) , which has also increased by ≥1.5 points from the 
mean Average PI over the 7-day Observation Period ,will be allowed to continue. 
Subjects who reach 2 weeks with their index ER medication tapered to 0 without 
meeting these criteria will be discontinued. 
Optimal Responders who meet the criteria from the Taper Period will proceed to an 
Open-Label Titration Period of up to 3 weeks. The index ER opioid (supplied as ER 
opioid plus matching IR opioid) will be titrated with increases as frequently as every 4 
days until the mean Average PI score over at least 3 consecutive pain scores is ≤5 and 
the dose of index ER opioid is ≥120 mg and ≤540 mg morphine equivalents/day in order 
to qualify for randomization. 
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1004904A 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
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03.007A.01     
  INC Research © LLC 
Page 14 of 72 
4.2.3. 
Blinded Structured Opioid Discontinuation Period and Follow-up 
All subjects who qualify for randomization will be randomized to either continue or 
discontinue opioid therapy during the BSODP lasting 24 weeks. Subjects will return to 
the clinic at Weeks 1, 2, 4, 6, 8, 12, 16, 20, and 24 for a series of assessments at each 
visit. 
Subjects in the discontinuation arms will be completed tapered off their opioid 
treatment over approximately 3-4 weeks, depending on the baseline dose of the index 
ER opioid. 
Subjects who complete the BSODP will advance to a 4-week Follow-up Period. However, 
those subjects who discontinue from the BSODP before Week 12 will complete Week 12 
study procedures and those subjects who discontinue during Weeks 13-23 will complete 
Week 24 study procedures before proceeding to the Follow-up Period. During the 
Follow-up Period, subjects will self-administer a blinded taper of placebo for subjects in 
the discontinuation arm and active drug taper for subjects in the continuation arm. 
4.3. 
Determination of Sample Size 
The primary efficacy endpoint is the change from baseline to Week 12 (mean Average PI 
over the week before the Week 12 visit) in 0-10 NRS Average PI score comparing the 
opioid discontinuation group to the continued opioid therapy group. To detect a 
between-group difference of 0.8 points with 90% power, assuming a standard deviation 
(SD) of 2.5, using a two-sided 5% significance level, 205 randomized subjects per arm 
for each Responder type will be needed, for a total of 820 subjects. The calculation is 
based on a 2-sample t-test with equal variances assumed between the two groups. It is 
assumed that approximately 60-70% of the subjects will complete the study. Assuming a 
3:1 screen failure rate, approximately 3280 subjects will need to be screened. Subjects 
who discontinue from the study will not be replaced. 
4.4. 
Treatment Assignment and Blinding 
Subjects are randomized in a 1:1 ratio to either the continued opioid therapy arm or the 
structured discontinuation of opioid therapy arm. Central randomization will be used, 
stratified by Responder status (Optimal Responder, Suboptimal Responder) and Index ER 
opioid (morphine, oxycodone, or oxymorphone). A minimum of 20% of subjects will be 
randomized into each of the baseline ER opioid strata within each Responder cohort. 
The interactive response technology (IRT) system will assign a unique randomization 
number which will dictate the treatment assignment and matching study drug kit for 
the subject. 
In case of emergency, the Investigator will have the ability to break the blind at the 
clinical site for the welfare of the subject. Breaking the blind will be accomplished by 
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1004904A 
 
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03.007A.01     
  INC Research © LLC 
Page 15 of 72 
using the IRT web interface. The Investigator should discuss the necessity of breaking 
the blind with the Medical Monitor first. 
4.5. 
Administration of Study Medication 
The study medications are Food and Drug Administration (FDA) approved and will be 
provided by the Opioid PMR Consortium (OPC) as follows: 
• 
OCER: OxyContin® (oxycodone hydrochloride ER tablets) 
• 
MSER: MS Contin® (morphine sulfate ER tablets) 
• 
OMER: Opana® ER (oxymorphone hydrochloride ER tablets) 
 
Placebos for each of the abovementioned ER drugs will be manufactured by the 
respective manufacturer of the active ER medication and will be identical to the 
respective drugs in aspect, size, and color. 
Associated IR medications (oxycodone immediate-release (OCIR), morphine sulfate 
immediate-release (MSIR), and oxymorphone immediate-release (OMIR)) are 
commercially available and will be provided by the OPC in open-label fashion as study 
prescribed drugs: 
• 
OCIR: Mallinckrodt brand of oxycodone IR tablets 
• 
MSIR: West-Ward brand of morphine sulfate (IR tablets) 
• 
OMIR: Opana® (Endo brand of oxymorphone hydrochloride IR tablets) 
 
The dose of the IR opioids will be limited to no more than twice daily as needed (PRN) 
administration of OCIR 10 mg, MSIR 15 mg, or OMIR 5 mg, matching the index ER opioid 
each subject is receiving. 
Subjects will also be provided acetaminophen as rescue medication (500 mg tablets, 1-2 
tablets every 4-6 hours PRN, not to exceed 6 tablets/day). Subjects will be encouraged 
to take acetaminophen to manage their pain before they use the IR opioid. 
Subjects in the continuation arm will receive tablets of their index ER opioid plus 
matching placebo tablets to maintain the opioid dose at a fixed regimen, but appear as 
if tapering is occurring. 
Subjects in the structured discontinuation arm will receive placebo tablets matching the 
index ER opioid tablets plus index ER opioid tablets in decreasing dose to result in a 
tapering off the index ER opioid. 
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4.6. 
Study Procedures and Flowchart 
Figure 1: 
Study Design
 
wk=week, mo=month, SR=Suboptimal Responder; OR=Optimal Responder. 
ER/LA requirement can be satisfied by use of immediate-release opioid at least 4 times a day for at least 1 year  
* Baseline PI scores=mean Average PI score including the Average PI scores during the Titration Period that meet the qualification criteria (Average PI score <5 
for 3 consecutive non-missing values) plus any scores between the final qualification day and the Randomization Visit. 
 
Note: In the tables below, blue shading denotes periods of the study that are identical for Optimal and Suboptimal Responders. 
 
 
  
Screening Visit 
Common 
screening 
criteria: CLBP; 
ER/LA ≥1 yr; 
index ER opioid 
≥3 mo 
Observation 
Period 
Continue initial 
opioids (1 wk) 
Run-in Period 
Switch to standard 
opioids (1 wk) 
Suboptimal 
Responders 
  PI ≥6 & 
dissatisfied 
Optimal 
Responders 
  PI ≤4 & 
  Satisfied 
Baseline 
Period 
(1 wk) 
Taper Period 
Expected pain flare  
(up to 2 wks) 
Titrate with 
standard 
opioids to 
PI≤4 (up to 
3 wks)
Blinded Structured 
Opioid 
Discontinuation 
Period  
-Continuation arm 
-Discontinuation arm 
(24 wks) 
Follow-up 
Period  
Blinded taper 
(4 wks) 
Random
ization 
of SRs 
Random
ization 
of ORs 
Base-
line* 
OL Titration Period 
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Table 1: 
Schedule of Procedures for Suboptimal Responders 
Period 
Screening  
Run-In  Period 
(1 week) 
Baseline 
Period 
(1 week) 
Random-
ization 
Visit 
Blinded Structured Opioid Discontinuation Period15 
(24 weeks) 
Follow-Up Period 
(4 weeks) 
Week 
 
-2 to -1 
-1 
-1 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name1 
Screening 
Visits2 
-- 
SR1 
Tolerability 
Visit 
-- 
SR2 
BDP1 
BDP2 
BDP3 
BDP4 
BDP5 
BDP6 
BDP7 
BDP8 
BDP9 
FUV1 
FUV2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam3 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Vital signs4 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Pregnancy test5 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Quebec Task Force Classification 
for Spinal Disorders 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily 24-hr Average and Worst 
PI score in past 24 hours on NRS 
6 
X 
 
--------------X-------------- 
X 
---------------------------------------X------------------------------------------- 
 
 
RMDQ 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
Daily administration of ER and 
IR opioids (phone) 
X7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Check entry or continuation 
criteria8 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drugs9 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect Study Drugs & Drug 
Accountability9 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI-SF 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Online Patient Support Program 
 
Acce
ss 
Gran
ted 
--------------------------------------------------------Encourage use of online patient support program------------------------------------------------------------ 
Regional Pain Scale 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
PQAS 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
EQ-5D-5L 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
C-SSRS10 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
PHQ-8 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
MOS Sleep Scale 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
DSST 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
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Table 1: 
Schedule of Procedures for Suboptimal Responders (Continued) 
Period 
Screening  
Run-In  Period 
(1 week) 
Baseline 
Period 
(1 week) 
Random-
ization 
Visit 
Blinded Structured Opioid Discontinuation Period15 
(24 weeks) 
Follow-Up Period 
(4 weeks) 
Week 
 
-2 to -1 
-1 
-1 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name1 
ScreeningVi
sits2 
-- 
SR1 
Tolerabil-
ity Visit 
-- 
SR2 
BDP1 
BDP2 
BDP3 
BDP4 
BDP5 
BDP6 
BDP7 
BDP8 
BDP9 
FUV1 
FUV2 
QST for OIH (for subjects 
enrolled at participating sub-
study sites) 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Endocrine laboratory tests and 
sexual function questionnaire11 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Abuse-related events 
 
 
----------------------------------------------------------------------------------------X---------------------------------------------------------------------------------- 
Opioid withdrawal (SOWS) 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
 
Opioid withdrawal (COWS) 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
UDT12 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Work productivity (WPAI) 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
AEs13 
 
X 
------------------------------------------------------------------------------------- X ------------------------------------------------------------------------------------ 
Telephone Calls14 
 
 
------------------------------------------------------------------------------------- X ------------------------------------------------------------------------------------ 
Prior/concomitant medications 
----------------------------------------------------------------------------------- X ------------------------------------------------------------------------------ 
X 
X 
1.  Visit windows are ±3 days until BDP6, and ±5 days thereafter. 
2.  Screening procedures will be performed over 2 visits no more than 21 days apart. 
3.  Full physical exam at Screening and brief physical exam afterwards. 
4.  At Screening: Height, weight, BMI, pulse rate, respiratory rate, and blood pressure. At subsequent visit: pulse rate, respiratory rate and blood pressure only. If BMI > 40, complete STOPBang 
Questionnaire and record in source documents. Subject cannot continue if apnea risk is high. 
5.  Serum pregnancy test at Screening and urine pregnancy test at randomization and final visit.  
6.  Captured once daily by phone at bedtime except at screening when captured in the office. 
7.  Daily dose of opioid and rescue medications at screening will be taken from medical records or medical history.  
8.  At Tolerability Visit (SR1): Subjects who did not tolerate the standardized regimen will be discontinued. At Randomization Visit: Subjects will be included if they have an Average PI score ≥6 on 0-
10 NRS over the Baseline Period (with a minimum compliance of 4 out of 7 daily PI scores), not have an Average PI score each day of the 7-day Baseline Period equal to 10/10 and be dissatisfied 
with their pain and physical function. 
9. Three (3) drugs will be dispensed, collected, and counted: ER opioids, IR opioids, and acetaminophen. 
10. C-SSRS “Lifetime” will be done at Screening and the C-SSRS “Since Last Visit” will be done at 6 weeks and 24 weeks after randomization.  
11. Blood for endocrine function tests will be drawn at Screening and sent to lab but only tested on Randomized subjects. Sexual function questionnaires will be administered when endocrine function 
tests are drawn. 
12. Quantitative UDT for illicit drugs, non-prescribed controlled substances (opioid and non-opioid), and alcohol.  To prevent unblinding, after randomization, results for the index opioid and its 
metabolites will not be provided to the investigator. 
13. Only serious AEs will be collected in the eCRF during Screening. 
14. Phone call every week of the study where a visit is not conducted to check for wellbeing, study drug compliance and safety issues. Changes in medications and AEs obtained during phone calls will 
be captured in the IRT or eCRF as appropriate.  All other information will be captured in source documents. 
15. The Early Discontinuation Assessment Tool will be administered to any subject who discontinues during the BDP.  
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BDP=Blinded Discontinuation Period; FUV=Follow-up Visit 
Table 2: 
Schedule of Procedures for Optimal Responders 
Period 
Screen 
-ing  
Observation  
Period 
(1 week) 
 
Taper Period 
(up to 2 weeks) 
OL Titration 
Period 
(up to 3 
weeks)1 
Random-
ization 
Visit 
Blinded Structured Opioid Discontinuation Period16 
(24 weeks) 
Follow-Up Period 
(4 weeks) 
Week 
 
-6 to -
5 
-5 
-5 to -3 
-3 
-3 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name2 
Screen 
-ing  
Visits3 
-- 
OR1 
OR2 (wk 
-4) 
OR3 
Telephone or 
office (OR3.1 
– OR3.6) visits 
every 4 days 
OR4 
BDP1 
BDP2 
BDP3 
BDP4 
BDP5 
BDP6 
BDP7 
BDP8 
BDP9 
FUV1 
FUV2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Vital signs5 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Pregnancy test6 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Quebec Task Force 
Classification for 
Spinal Disorders 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily 24-hr Average 
and Worst PI score in 
past 24 hours on NRS 7 
X 
 
-----X----- 
-----X----- 
---X---- 
X 
--------------------------------------------X-------------------------------------- 
 
 
RMDQ 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
Daily dose or 
administration of ER 
and IR opioids and 
rescue meds taken 
(phone) 
X8 
 
-----X8----- 
-----X8----- 
---X8--- 
X8 
--------------------------------------------X8-------------------------------------- 
X8 
X8 
Check entry or 
continuation criteria 
X 
X 
 
X9 
X9 
X9 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
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Table 2: 
Schedule of Procedures for Optimal Responders (Continued) 
Period 
Screen-
ing  
Observation  Period 
(1 week) 
 
Taper Period 
(up to 2 weeks) 
OL Titration 
Period 
(up to 3 
weeks)1 
Random-
ization 
Visit 
Blinded Structured Opioid Discontinuation Period16 
(24 weeks) 
Follow-Up Period 
(4 weeks) 
Week 
-6 to -5 
-5 
-5 to -3 
-3 
-3 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name2 
Screen-
ing  
Visits3 
-- 
OR1 
OR2 
(wk -4) 
OR3 
Telephone or 
office (OR3.1 
– OR3.6) visits 
every 4 days 
OR4 
BDP1 
BDP2 
BDP3 
BDP4 
BDP5 
BDP6 
BDP7 
BDP8 
BDP9 
FUV1 
FUV2 
Dispense Study 
Drugs10 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect Study Drug & 
Drug Accountability10 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI-SF 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Online Patient Support 
Program 
 
Acc
ess 
Gra
nte
d 
 
 
-----------------------------------------------Encourage use of online patient support program------------------------------------------------------------ 
Regional Pain Scale 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
PQAS 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
EQ-5D-5L 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
C-SSRS11 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
PHQ-8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
MOS Sleep Scale 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
DSST 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
QST for OIH (for 
subjects enrolled at 
participating sub-
study sites) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Endocrine laboratory 
tests and sexual 
function 
questionnarie12 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Abuse-related events 
 
 
------------------------------------------------------------------------------------------ X ----------------------------------------------------------------------------------------------- 
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Table 2: 
Schedule of Procedures for Optimal Responders (Continued) 
Period 
Screen-
ing  
Observation  Period 
(1 week) 
 
Taper Period 
(up to 2 weeks) 
OL Titration 
Period 
(up to 3 
weeks)1 
Random-
ization 
Visit 
Blinded Structured Opioid Discontinuation Period16 
(24 weeks) 
Follow-Up Period 
(4 weeks) 
Week 
-6 to -5 
-5 
-5 to -3 
-3 
-3 to 0 
0 
1 
2 
4 
6 
8 
12 
16 
20 
24 
26 
28 
Month 
 
 
 
 
 
 
0 
 
0.5 
1 
1.5 
2 
3 
4 
5 
6 
6.5 
7 
Visit Name2 
Screen-
ing 
Visits3 
-- 
OR1 
OR2 
(wk -4) 
OR3 
Telephone or 
office (OR3.1 
– OR3.6) visits 
every 4 days 
OR4 
BDP1 
BDP2 
BDP3 
BDP4 
BDP5 
BDP6 
BDP7 
BDP8 
BDP9 
FUV1 
FUV2 
Opioid withdrawal 
(SOWS) 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
X 
 
Opioid withdrawal 
(COWS) 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
PGIC 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
UDT13 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
Work productivity 
(WPAI) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
AEs14 
 
X 
------------------------------------------------------------------------------------------ X ---------------------------------------------------------------------------------------------- 
Telephone Calls15 
 
 
------------------------------------------------------------------------------------------ X ---------------------------------------------------------------------------------------------- 
Prior/concomitant 
medications 
---------------------------------------------------------------------------------------- X --------------------------------------------------------------------------------------- 
X 
X 
1 
If the dose of the index ER opioid needs to be titrated above the baseline dose, the Titration Period may be extended by 1 additional week (+3 days).   
2.  Visit windows are ±3 days until BDP6, and ±5 days thereafter. 
3.  Screening procedures will be performed over 2 visits no more than 21 days apart.  
4.  Full physical exam at Screening and brief physical exam afterwards. 
5.  At Screening: Height, weight, BMI, pulse rate, respiratory rate, and blood pressure. At subsequent visit: pulse rate, respiratory rate, and blood pressure only. If BMI > 40, complete STOPBang 
Questionnaire and record in source documents. Subject cannot continue if apnea risk is high. 
6.  Serum pregnancy test at Screening and urine pregnancy test at randomization and final visit.  
7.  Captured once daily by phone at bedtime except at Screening when captured in the office. 
8.  Daily dose of opioid and rescue medications at screening will be taken from medical records or medical history. Continuation of daily dose of opioid and rescue medications during the Observation 
Period will be confirmed by phone.  Subsequently, confirmation of daily administration of ER and IR opioid study medications will be obtained by phone. 
9.  At end of Observation Period: Subjects must have had an index ER opioid medication use of ≥120 mg and ≤540 mg morphine equivalents/day (see table in protocol) on average and have had 80% to 
120% compliance over the 1-week Observation Period; (ii) have a mean Average PI score over the 1 week of the period <5 (with a minimum compliance of 4 out of 7 daily PI scores); and (iii) still 
be satisfied with their pain and physical function. During or at the end of the Taper Period: Subjects must have a mean Average PI score >5 over ≥3 consecutive scores (non-missing values), where 
this mean Average PI score has also increased by ≥1.5 points from the mean Average PI score over the 7-day Observation Period. Note that if these criteria are satisfied at Visit OR2, subject may 
skip OR2 and advance directly to Visit OR3. At the end of Titration Period: Subjects must have completed their titration and have achieved a mean Average PI score over at least 3 consecutive 
scores (non-missing values) <5 with acceptable side effects and a minimum dose of ≥120 mg and ≤540 mg morphine equivalents/day to continue on study. 
10. The non-blinded ER opioid taper dose will be dispensed at OR1 and OR2; Open-label ER opioids, IR opioids, and acetaminophen will be dispensed starting at OR3 (for titration in the Titration 
Period); Double-blind ER opioid and open-label IR opioid and acetaminophen will be dispensed at OR4. Collection and counting of study medication will be done at all visits except OR1. 
11. C-SSRS “Lifetime” will be done at Screening and the C-SSRS “Since Last Visit” will be done at 6 weeks and 24 weeks after randomization.  
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12. Blood for endocrine function tests will be drawn at Screening and sent to the lab but tested only on randomized subjects. Sexual function questionnaires will be administered when endocrine 
function tests are drawn. 
13. Quantitative UDT for illicit drugs, non-prescribed controlled substances, and alcohol.  To prevent unblinding, after randomization, results will not be provided to the investigator for the index 
opioid and its metabolites. 
14. Only serious AEs will be collected in the eCRF during Screening. 
15. Phone call every week of the study where a visit is not conducted to check for wellbeing, study medication compliance, and safety issues. Changes in medication and AEs obtained during phone 
calls will be captured in the IRT or eCRF as appropriate.  All other information will be captured in source documents. 
16. The Early Discontinuation Assessment Tool will be administered to any subject who discontinues during the BDP. 
 
BDP=Blinded Discontinuation Period; FUV=Follow-up Visit 
 
 
 
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5. 
ENDPOINTS 
5.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in the mean Average PI score on the 0-10 
NRS from baseline to the 1 week period before the Week 12 visit. 
5.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
For Suboptimal Responders: 
• 
Changes from baseline to Weeks 4, 8, 16, 20, and 24 in 0-10 NRS mean Average 
PI scores over 1 week before each visit 
• 
Changes from baseline to Weeks 4, 8, 12, 16, 20, and 24 in 0-10 NRS mean Worst 
PI scores over 1 week before each visit 
• 
Cumulative response function in percent improvement in PI score at Weeks 12 
and 24 compared to baseline over 1 week before each visit 
• 
Changes from baseline to Weeks 12 and 24 in physical function as measured by 
the Roland-Morris Disability Questionnaire (RMDQ) score 
• 
Changes from baseline to Weeks 12 and 24 in the impact of pain on function as 
measured by the Brief Pain Inventory – Short Form (BPI-SF) score 
• 
Changes from baseline to Weeks 12 and 24 in pain quality as measured by the 
Pain Quality Assessment Scale (PQAS) score 
• 
Changes from baseline to Weeks 12 and 24 in pain spread as measured by the 
Regional Pain Scale 
• 
Changes from baseline to Weeks 12 and 24 in sleep quality as measured by the 
Medical Outcomes Study (MOS) Sleep Scale 
• 
Changes from baseline to Weeks 12 and 24 in mood as measured by the Patient 
Health Questionnaire Depression Scale (PHQ-8) 
• 
Changes from baseline to Weeks 12 and 24 in quality of life as measured by the 
EuroQOL 5 dimensions (5 levels of response) instrument (EQ-5D-5L) 
• 
Changes from baseline to Weeks 12 and 24 in work productivity as measured by 
the Work Productivity and Activity Impairment (WPAI) scale 
• 
Patient Global Impression of Change (PGIC) at Weeks 12 and 24 
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• 
Proportion of subjects with overall clinical benefit at Weeks 12 and 24 defined as 
a composite measure of key clinical endpoints: ≥30% improvement in mean 
Average PI score, ≥20% improvement in RMDQ, and PGIC of moderately or better 
improvement 
For Optimal Responders: 
• 
Changes from baseline to Weeks 4, 8, 16, 20, and 24 in 0-10 NRS mean Average 
PI score over 1 week before each visit 
• 
Changes from baseline to Weeks 4, 8, 16, 12, 20, and 24 in 0-10 NRS mean Worst 
PI scores 
• 
Cumulative response function in percent worsening in PI score at Weeks 12 and 
24 over 1 week before each visit compared to baseline 
• 
Changes from baseline to Weeks 12 and 24 in physical function as measured by 
the RMDQ score 
• 
Changes from baseline to Weeks 12 and 24 in the impact of pain on function as 
measured by the BPI-SF score 
• 
Changes from baseline to Weeks 12 and 24 in pain quality as measured by the 
PQAS score 
• 
Changes from baseline to Weeks 12 and 24 in pain spread as measured by the 
Regional Pain Scale 
• 
Changes from baseline to Weeks 12 and 24 in sleep quality as measured by the 
MOS Sleep Scale 
• 
Changes from baseline to Weeks 12 and 24 in mood as measured by the PHQ-8 
• 
Changes from baseline to Weeks 12 and 24 in quality of life as measured by the 
EQ-5D-5L 
• 
Changes from baseline to Weeks 12 and 24 in work productivity as measured by 
the WPAI scale 
• 
PGIC at Weeks 12 and 24 
 
5.3. 
Exploratory Measurements 
Exploratory measurements include: 
• 
Change in sensitivity to thermal stimuli on quantitative sensory testing (QST) in 
substudy subjects 
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• 
Identification of baseline factors predictive of benefit of opioid discontinuation 
among Suboptimal Responders 
• 
Changes from baseline in endocrine function and sexual function as 
characterized in the male and female questionnaires; relationship of changes in 
endocrine function to changes in PI; relationship of changes in endocrine 
function to changes in male and female sexual function; and relationship of 
baseline endocrine status to efficacy of opioid discontinuation 
• 
Changes from baseline in neuropsychological function as characterized by the 
Digit Symbol Substitution Test (DSST) 
 
5.4. 
Assessment of Safety 
Safety will be assessed by: 
• 
Adverse events (AEs) 
• 
Abuse-related events (using the Misuse Abuse Diversion Drug Event Reporting 
System [MADDERS™]) 
• 
Opioid-specific side-effects 
• 
Vital signs (heart rate, blood pressure, and respiratory rate only) 
• 
Clinical laboratory parameters 
• 
Physical examination 
 
Other safety measures will include: 
• 
Urine drug testing (UDT) 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Opioid withdrawal effects (measured by the Subjective Opiate Withdrawal Scale 
[SOWS], the Clinical Opiate Withdrawal Scale [COWS], and withdrawal AEs) 
 
________________________________________________________
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6. 
ANALYSIS SETS 
Separate analyses will be conducted for Suboptimal Responders and Optimal Responders 
since these are considered two different study populations. Therefore, all analysis sets 
will be defined for Suboptimal Responders and Optimal Responders separately. 
6.1. 
Safety Sets 
Different Safety Sets will be defined to summarize data pre- and post-randomization. 
• 
For Suboptimal Responders, the Safety Set Pre-Randomization will include all 
subjects who were enrolled in the study and were switched to the standardized 
regimen (i.e., who enter the Run-in Period) and took at least one dose of study 
drug.  
• 
For Optimal Responders: 
— The Safety Set Pre-Randomization (Observation Period) will include all 
Optimal Responder subjects who entered the Observation Period. 
— The Safety Set Pre-Randomization (Taper Period) will include all Optimal 
Responder subjects who were enrolled in the study and took at least 1 dose 
of study medication during the Taper Period. 
— The Safety Set Pre-Randomization (Titration Period) will include all Optimal 
Responder subjects who were enrolled in the study and took at least 1 dose 
of study medication during the Titration Period (i.e., who enter the Open-
label Titration Period) 
 
For both Suboptimal Responders and Optimal Responders, the Safety Set Post-
Randomization will include all subjects who were randomized and received at least one 
dose of double-blind treatment. 
Safety will be analyzed separately for these analysis sets. Subjects who are randomized 
to one treatment group but mistakenly assigned the medication kit of the other 
treatment group for over half their time in the study will be reported “as treated”. 
6.2. 
Randomized Set 
The Randomized Set will include all subjects who were randomized into the BSODP. The 
analysis set will be summarized in the disposition tables and will be the analysis set for 
the summary of protocol deviations to indicate subjects who were randomized but did 
not receive study drug in the BSODP. 
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6.3. 
Intent-to-treat Set 
The Intent-to-treat (ITT) Set will include all subjects who were randomized and 
received at least one dose of study drug after randomization. All efficacy analyses will 
be performed using this analysis set. Subjects will be reported in the treatment group 
to which they were randomly assigned. 
6.4. 
Per-protocol Set 
The Per-protocol (PP) Set is a subset of the ITT set. It will include subjects who have at 
least 6 weeks of valid mean Average PI scores, not including baseline, but including a 
valid Week 12 mean Average PI score (a valid mean is calculated from 2 or more daily 
Average PIs). 
In addition, the subjects must have satisfied the following inclusion criteria:  
• 
Have a clinical diagnosis of non-radicular CLBP for a minimum of 12 months and 
— For Suboptimal Responders, pain must have been present for at least several 
hours a day and have an Average PI score of 6-9 within the past 24 hours of 
screening 
— For Optimal Responders, subjects must have an average PI score of 1-4 within 
the past 24 hours of screening; 
• 
Have been taking ER/LA opioids (or immediate release opioids at least 4 times a 
day) for at least 12 months 
• 
Have been taking one of the 3 index opioid drugs around-the-clock at a twice-a-
day frequency for at least 3 consecutive months 
Also, subjects in the PP Set must not have violated the following exclusion criteria at 
the time of randomization: 
• 
Have a primary diagnosis of fibromyalgia, complex regional pain syndrome, 
neurogenic claudication due to spinal stenosis, spinal cord compression, acute 
nerve root compression, severe or progressive lower extremity weakness or 
numbness, bowel or bladder dysfunction as a result of cauda equina 
compression, diabetic amyotrophy, meningitis, diskitis, back pain because of 
secondary infection or tumor, or pain caused by a confirmed or suspected 
neoplasm 
• 
Have undergone a surgical procedure for back pain within 6 months prior to the 
Screening Visit 
• 
Have had a nerve or plexus block, including epidural steroid injections or facet 
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blocks, within one month prior to the Screening Visit or botulinum toxin 
injection in the lower back region within 3 months prior to screening 
The subjects must also not have more than 2 instances of medication compliance 
outside of the 80%-120% range at each compliance assessment after randomization. 
Protocol deviations and other criteria for inclusion in the PP Set will be assessed before 
unblinding. 
6.5. 
Protocol Deviations 
Protocol deviations will be categorized and graded as important or not important. 
Protocol deviations will be summarized for the Randomized Set. The summary will show 
the frequency and percentage of subjects with any protocol deviation by treatment 
group and for all subjects. Each category of deviation will also be summarized, counting 
subjects with at least one deviation in the category. A comprehensive listing of protocol 
deviations will be provided. 
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7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
7.1. 
General Methods 
All summary tables will be presented separately for Suboptimal and Optimal 
Responders, as determined at Screening. 
All efficacy analyses will be conducted separately for Suboptimal and Optimal 
Responders, without adjustments for multiplicity. Safety analyses will be presented 
according to the defined Safety Sets Pre- and Post-Randomization. 
Summary statistics for continuous variables will include number of subjects, mean, SD, 
median, first and third quartiles, minimum, and maximum by treatment group. 
Summary statistics for categorical variables will include the number of subjects with 
data, and frequencies and percentages for each category by treatment group. Unless 
stated otherwise, percentages will be based on the number of subjects with nonmissing 
observations at that time point. 
All analyses will be performed using SAS® version 9.3 or higher unless otherwise 
specified.  
All demographic, background, efficacy, and safety data collected as part of this study 
will be included in subject data listings. Listings will be by Responder type and 
randomized treatment group within Responder type. 
7.2. 
Key Definitions 
7.2.1. 
Definition of Baseline 
For PI scores, baseline will be defined differently for Suboptimal and Optimal 
Responders. 
For Suboptimal Responders, the mean of the available Average PI scores over the 7-day 
Baseline Period will count as the subject’s baseline Average PI score for statistical 
analysis. Similarly, the mean of the Worst PI scores over the 7-day Baseline Period will 
count as the subject’s baseline Worst PI score for statistical analysis. At least 4 out of 7 
scores must be present. 
For Optimal Responders, the mean of the Average PI scores during the Titration Period 
that meet the qualification criteria (Average PI score ≤5 for 3 consecutive non-missing 
values) and any scores between the last qualification score and the Randomization Visit 
will count as the subject’s baseline Average PI score for statistical analysis. Similarly, 
the mean of the Worst PI scores over the 3 qualification days (as defined above) during 
the Titration Period and any scores between the qualification score and the 
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Randomization Visit will count as the subject’s baseline Worst PI score for statistical 
analysis. 
The baseline mean PI scores (Average and Worst) will be rounded to one decimal place. 
For all other assessments, the last non-missing observation before the first dose in the 
BSODP will be used as the baseline observation. For example, if an assessment is 
collected at screening and at randomization and the randomization assessment is 
missing, then the screening value will be used. 
7.2.2. 
Mean Pain Intensity Scores 
Subjects are asked to rate their pain daily before bedtime using the 0-10 NRS based on 
Worst pain and Average pain over the past 24 hours. For the scheduled post-
randomization visits, mean Average PI and mean Worst PI at the visit will be defined as 
the means of the respective PI scores over the 7 days preceding the visit. If there is only 
one daily PI score available over the 7 days before a particular visit, the mean will not 
be calculated and the data point will be considered missing. The means will be rounded 
to one decimal place before analysis. 
7.2.3. 
Treatment Emergence for Adverse Events 
Each AE occurring before randomization into the BSODP will be classified into the Pre-
Randomization period (defined by the Safety Sets) for which it was treatment emergent 
according to its start date and time relative to the start and end dates and times of 
each period. Any AE that was not present before the start date and time of each period, 
or was present before but increased in intensity during the period will be considered 
treatment emergent. 
For all subjects, treatment-emergent adverse events (TEAEs) in the Post-Randomization 
Period will be those that started or worsened on or after the date and time of the first 
dose of double-blind treatment in the BSODP up to 28 days after the subject’s last visit 
date. 
Further detail on classifying AEs as TEAEs and the handling of partial or missing AE start 
dates and times is given in Section 12.3. 
7.3. 
Visit Windows 
Visit windows specified in the protocol are ±3 days up to the Week 12 visit of the BSODP 
and ±5 days thereafter. However, in general, data points for visits falling outside of 
these windows will still be mapped to the named scheduled visit, except for data 
recorded as a discontinuation visit in the BSODP. These will be mapped to the next 
scheduled visit for the assessment after the last scheduled visit. 
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If 2 or more data values have the same visit designation, the one closest to the target 
day will be used. If the 2 values are equidistant from the target day, the earlier value 
will be used. 
For PI scores, weekly means will be calculated for each week using the 7 days up the 
seventh day of each week (i.e., Day 1-7 for Week 1, Day 8-14 for Week 2) as long as 
there are 2 or more scores present during the week. The mean score for each week may 
not coincide with scheduled visits. However, for Week 12, the mean Average and Worst 
PI scores will be calculated from the scores taken on the day of the Week 12 visit and 
the preceding 6 days. Daily PI scores from days used in the Week 11 calculation will not 
be used in the Week 12 mean, so there must be 2-7 days of scores present to calculate a 
valid Week 12 mean. The Week 24 mean PI scores will be similarly determined. 
7.4. 
Pooling of Study Sites 
No pooling of study sites will be specified for analysis, as terms for site will not be 
included in the statistical models. 
7.5. 
Subgroups 
Study data will be summarized and analyzed separately for Optimal Responders and 
Suboptimal Responders. Descriptive summaries of the values and mean changes from 
baseline to Week 12 in mean Average PI will be presented by index ER opioid within 
each Responder group. 
The primary efficacy analysis will be repeated for subgroups defined by sex and 
(separately) by age (<=65 years, >65 years) within each Responder group. 
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8. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
8.1. 
Subject Disposition and Withdrawals 
Subject disposition will be summarized separately for the Pre- and Post-Randomization 
periods, as well as separately for Optimal and Suboptimal Responders. 
Pre-randomization, the separate summaries of subject disposition for each Responder 
type will be based on all subjects entering each period who were classified to each 
Responder type. This count will be the denominator for percentages in each section of 
the table. For Suboptimal Responders, the frequencies and percentages of subjects 
randomized into the BSODP, not randomized into the BSODP, and the reasons for 
discontinuation before randomization will be presented. 
For Optimal Responders, the frequencies and percentages of subjects entering each 
period Pre-Randomization (Observation, Taper, and Open-label Titration) will be 
presented. The frequencies and percentage of subjects discontinuing during the period 
and reasons for discontinuation will be also be presented for each period, including 
discontinuations before randomization. 
The summaries of subject disposition Post-Randomization for each Responder type will 
be based on all randomized subjects and will be by treatment group and overall. For 
each column, the number of subjects randomized into each treatment group and overall 
will be the denominator for percentages and will be tabulated first, without 
percentages. 
The frequencies and percentages of subjects in each post-randomization analysis set 
will be tabulated below the frequencies of randomized subjects. 
The frequencies and percentages of subjects who completed the BSODP and who 
prematurely discontinued during the BSODP will be presented. The specific reasons for 
early discontinuation will be shown, also with frequencies and percentages. “Other” 
reasons for discontinuation will be summarized as one category, rather than by separate 
text categories.  
The frequencies and percentages of subjects randomized into the BSODP who enter and 
do not enter the Follow-up Period will be summarized, with reasons for not entering 
also summarized. Subjects completing and discontinuing from the Follow-up Period will 
be summarized with frequencies and percentages including reasons for discontinuation. 
The denominator for percentages in this section of the disposition summary will be the 
number of subjects who enter the Follow-up Period. 
A flow chart showing the numbers of subjects entering each period and moving on to 
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the next or discontinuing will be provided. 
For subjects who discontinue from the BSODP, the Early Discontinuation Assessment 
Tool will be summarized with frequencies and percentages of subjects responding yes 
and no to each question. For each question, the level of importance will also be 
summarized with frequencies and percentages of subjects responding yes to the 
question. 
The categories of change in pain will be summarized for severity of pain, area of pain, 
and sensitivity of pain. 
8.2. 
Demographics 
Demographics include age, sex, race, ethnicity, baseline height and weight, and body 
mass index (BMI). 
Age in years will be calculated from the date of informed consent and the date of birth. 
Height and weight values in inches and pounds, respectively, will be used in summaries 
and listings. Units for BMI will be kg/m2. 
The demographic summaries will be by treatment group, including an all subjects 
column. Age, height, weight and BMI will be summarized with descriptive statistics for 
quantitative assessments. Sex, race, and ethnicity will be summarized with frequencies 
and percentages. Age will also be categorized as <25 years, 25-49 years, 50-64 years, 
and >=65 years and summarized. 
Separate demographic summaries will be produced for the Safety Set Post-
Randomization, ITT, and PP Sets within each Responder type. 
8.3. 
Baseline Characteristics 
Baseline characteristics to be summarized by treatment group and overall are: 
• 
Baseline Average PI 
• 
Baseline Worst PI 
• 
Index ER Opioid 
• 
Duration of Use of Index ER Opioid 
• 
Quebec Task Force on Spinal Disorders Classification 
• 
Time Since Diagnosis of CLBP 
 
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The PI scores, duration of index ER opioid use, and time since diagnosis of CLBP will be 
summarized with descriptive statistics for quantitative assessments. The remaining 
baseline disease characteristics are qualitative and will be summarized with frequencies 
and percentages of subjects in each category. 
Separate summaries will be produced for the Safety Set Post-Randomization, ITT, and 
PP Sets within each responder type. 
8.4. 
Medical History 
Medical history will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA). Summaries by System Organ Class (SOC) and Preferred Term (PT) 
will be produced for the Safety Set Post-Randomization. The summaries will be in 
alphabetical order by SOC and by PT within each SOC. Subjects will be counted once on 
the overall level (any medical history), SOC level, and PT level. 
8.5. 
Prior and Concomitant Medications 
Medications taken before and during the study will be coded according to the World 
Health Organization Drug Dictionary (WHODD). Summaries of medications will be by 
Anatomical Therapeutic Chemical (ATC) level 3 and preferred drug name within ATC 
level 3. If the level 3 term is not available, the level 2 term will be used. Subjects 
taking a medication multiple times will be counted only once on the ATC level and on 
the preferred drug name level. Drugs will appear in alphabetical order by ATC level 3 
term and preferred drug name within the ATC term. 
Medications will be classified as prior to enrollment (started before the signing of 
informed consent, regardless of stop date), as prior within each of the periods defined 
by the Safety Sets Pre-Randomization (continued past the start and end dates of the 
period or started on the start date of the period or before the end date), or 
concomitant within the BSODP. A particular medication may be classified as being in 
more than one period. 
If the start date is partial, then it will be imputed using the same rules as for AEs listed 
in Section 12.3.  If the stop date is partial and the medication was not classified as prior 
or concomitant in a period using the start date alone, then the stop date will be 
imputed as follows for determination of concomitance within a period only: 
• 
If the day is missing, then the last day of the month and year will be used. If this 
date is after the last date of the latest period the subject entered where the 
months are the same, then the last such date will be used. This causes the 
medication to be considered concomitant in the latest period which ends with 
the same medication stop month. 
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• 
If the day and month are missing, then the last day of the year will be used.  If 
this date is after the last date of the latest period the subject entered and the 
years are the same, then the last such date will be used. This causes the 
medication to be considered concomitant in the latest period which ends with 
the same medication stop year. 
• 
If the stop date is completely missing, then it will be set to the last date of the 
latest period into which the subject entered, such that it will be considered 
concomitant in that period. 
 
8.5.1. 
Pre-randomization Prior Medications 
Prior medications taken before randomization and before study enrollment will be 
summarized. 
Medications will be classified as prior to enrollment (started before the signing of 
informed consent, regardless of stop date), or as prior within each of the periods 
defined by the Safety Sets Pre-Randomization as described in Section 8.5. A particular 
medication may be classified as being in more than one period. 
8.5.2. 
Post-randomization Concomitant Medications 
Post-randomization concomitant medications will be summarized by treatment group. 
The classification of medications as post-randomization concomitant is described in 
Section 8.5. A particular medication may be classified as being in more than one period. 
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9. 
EFFICACY 
All efficacy analyses will present descriptive statistics and, when appropriate, statistical 
tests to compare the 2 treatment groups to which subjects were randomized. All 
statistical comparisons will be 2-sided at the 0.05 alpha level, with separate analyses 
for the Suboptimal Responders and the Optimal Responders. There will be no 
adjustments for multiplicity. 
9.1. 
Primary Efficacy Endpoint and Analysis 
The primary efficacy endpoint is the change from baseline to the 1 week period before 
the Week 12 visit in the mean Average PI. The primary analysis will be performed using 
the ITT Set. 
The analysis of the primary efficacy endpoint will be in two stages. First, multiple 
imputation will be used for missing data based on the reason for missing data. Second, 
the multiple datasets will be analyzed using mixed model repeated measures (MMRM), 
and the individual imputation dataset results will be combined using standard methods 
(e.g., Little & Rubin, 2002). The imputation and analysis are described below. 
Missing data occurring between observed data points for a given subject will be imputed 
using Markov Chain Monte Carlo (MCMC) methods as provided by the SAS MI procedure to 
create monotone missing data patterns for each subject. 
Multiple imputation (MI) will then be used to create 10 complete datasets from the 
monotonic datasets for the mean Average PI data using regression models with terms for 
treatment group and each subject's previous weekly mean Average PI scores. This step 
generates imputed values for subjects who discontinue the study for any reason using all 
subjects in the dataset. 
Values imputed by multiple imputation in these 10 datasets will then be replaced by 
alternate imputed values specifically for subjects who discontinue due to AEs and for 
subjects who discontinue due to Lack of Efficacy. 
For subjects who discontinue due to AEs, missing weekly mean Average PIs after 
discontinuation will be imputed by Responder type as follows: 
• 
For Suboptimal Responders: a randomly generated response from a normal 
distribution with a mean equal to the subject's baseline Average PI score and 
variance as calculated from all subjects at the corresponding time point of 
missing data within the Suboptimal Responders. 
• 
For Optimal Responders: a randomly generated response from a normal 
distribution with a mean equal to the subject's mean Average PI score over the 
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first 3 days at the end of the Taper Period which qualified the subject for entry 
into the Titration Period (i.e., the mean Average PI score is >5 for ≥3 
consecutive days and has increased by ≥1.5 points from the mean Average PI 
over the 7-day Observation Period). The variance for the randomly generated 
score will be calculated from all subjects at the corresponding time point of 
missing data within the Optimal Responders. This mean Average PI score is used 
as a conservative imputation, as it will be worse than the baseline mean Average 
PI score for an Optimal Responder.  
 
For missing mean Average PI scores caused by discontinuation due to lack of efficacy, 
data will be imputed using the subject's last non-missing weekly mean Average PI score. 
All imputed PI scores will be rounded to one decimal place. Any imputed values >10 will 
be set to 10, and any imputed values <0 will be set to 0. 
The analysis of the individual imputation datasets for the primary endpoint will use an 
MMRM analysis which includes the fixed effects of treatment group, index ER opioid 
(morphine, oxycodone, or oxymorphone), Week, and the interaction between treatment 
group and Week as factors, and baseline Average PI as a covariate. Data up to Week 12 
will be included in this analysis. The Restricted Maximum Likelihood estimation 
approach will be used, and the default covariance structure will be unstructured. If 
there are convergence problems for this model, other variance-covariance matrix 
structures will be considered, such as Toeplitz, auto-regressive, and compound 
symmetry. 
The MMRM results from each dataset will be combined using the SAS MIANALYZE 
procedure to generate a single test statistic and p-value for the primary test of 
significance. Model-based least squares means (LSMeans) of the changes from baseline 
for the 2 treatment groups and for the difference in means will be presented with their 
standard errors (SE) and 95% confidence intervals (CI), as estimated from MIANALYZE. 
Summary statistics obtained from the MI results will be provided for the mean Average 
PI values at each visit and changes from baseline to each visit. 
9.2. 
Secondary Efficacy Endpoints and Analyses 
9.2.1. 
Secondary Analyses of the Primary Endpoint 
The primary efficacy endpoint of change from baseline to Week 12 in mean Average PI 
will be summarized separately for each of the 3 index ER opioids with descriptive 
statistics. These summaries will include the imputed values. 
The analysis described in Section 9.1 will be repeated for the PP Set. The same 10 
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imputation datasets created for the ITT Set analysis will be used for this analysis, but 
restricted to the PP Set. 
Two sensitivity analyses of the primary efficacy endpoint using the ITT Set will be 
performed as follows: 
i) 
Missing mean Average PI values will be imputed using the last observation 
carried forward (LOCF). Analysis of covariance (ANCOVA) will be used to 
assess the treatment difference in change from baseline to Week 12. The 
model will include terms for baseline Average PI, index ER opioid, and 
treatment group. 
ii) 
The same MMRM model as used for the primary analysis will be applied to the 
observed data up to Week 12 without imputation of missing values. LSMeans 
with SEs and 95% CIs will be presented for the changes from baseline to Week 
12 by treatment group and for the treatment difference. 
9.2.2. 
Analysis of Pain Intensity Secondary Endpoints 
Change from baseline to Weeks 4, 8, 16, 20, and 24 in mean Average PI score and 
change from baseline to Weeks 4, 8, 12, 16, 20, and 24 in mean Worst PI score will be 
summarized with descriptive statistics, without imputation of missing values. An MMRM 
model as described for the primary efficacy analysis (without imputation of missing 
values) will be fitted and used to generate LSMeans, SEs, and 95% CIs for each time 
point by treatment group and for the treatment difference. P-values will be provided 
for the treatment difference at each week. 
9.2.3. 
Analysis of Scale Score Secondary Endpoints 
The changes from baseline to Weeks 12 and 24 in the scale scores will be analyzed using 
ANCOVA with terms for baseline score as a covariate, index ER opioid, and treatment 
group. There will be no imputation of missing values. LSMeans with SEs and 95% CIs will 
be presented for the changes from baseline to each visit by treatment group and for the 
treatment difference. 
The scales and scoring algorithms are described in the following sections. 
9.2.3.1. 
Roland-Morris Disability Questionnaire 
The RMDQ used in this study is a series of 24 statements that can be used to describe 
the subject's back pain on the day the questionnaire is administered. The score for the 
RMDQ is the sum of the marked statements, so ranges from 0-24, where 0 = no disability 
and 24 = maximum disability. 
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9.2.3.2. 
Brief Pain Inventory – Short Form 
The BPI-SF is a 9-item self-administered questionnaire used to evaluate the severity of a 
subject's pain and the impact of this pain on the subject's daily functioning. The subject 
is asked to rate their worst, least, average, and current pain intensity (0-10), list 
current treatments and their perceived effectiveness, and rate the degree that pain 
interferes with general activity, mood, walking ability, normal work, relations with 
other persons, sleep, and enjoyment of life on a 0-10 point scale (0 = does not 
interfere, 10 = completely interferes). 
The 0-10 pain intensity scores will be summarized separately for worst, least, and 
average over the past 24 hours, and for pain right now. A composite Pain Index will be 
calculated as the mean the 4 pain intensities, rounded to one decimal place. 
Each of the 7 pain interference scores will be summarized separately. If at least 4 of 
the 7 components are answered, then a composite Pain Interference Index will be 
calculated as the mean of the non-missing individual pain interference scores, rounded 
to one decimal place. 
9.2.3.3. 
Pain Quality Assessment Scale 
The PQAS is a 20-item instrument developed to quantify the quality and intensity of 
pain associated with all types and categories of pain problems, including nociceptive 
and neuropathic pain. Seventeen items measure intensities of various aspects or types 
of pain on 0-10 scales (0=not intense, 10 = most intense). The other 3 items quantify the 
unpleasantness of pain and the intensity of deep pain and surface pain, also on 0-10 
scales. All items and changes from baseline will be summarized separately, without any 
overall score. 
In addition, the final question on the PQAS addresses time quality of pain, described as 
intermittent, variable, and stable. Type of pain will be summarized with a shift table 
with frequencies and percentages showing baseline type across the columns and type at 
Week 12 and Week 24 across the rows. Total columns and rows will be included to show 
the distribution at each visit. Each shift table by Responder type, treatment group, and 
week will be restricted to subjects who have a response at baseline and at the visit, 
which will be the denominator for percentages. 
9.2.3.4. 
Regional Pain Scale 
The Regional Pain Scale measures the location and intensity of pain in 38 articular and 
nonarticular regions. The intensity of pain or tenderness is indicated on a scale of None, 
Mild, Moderate, and Severe. All items are expected to have a response, even if the 
response is None. The measure for each visit and change from baseline is the number of 
regions with pain of Mild or higher. 
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In addition, each region will be summarized with shift tables from baseline to each visit 
(baseline severity across the columns by severity at each visit down the rows). Rows and 
columns for totals will be included. The denominators for percentages in each shift 
table will be the number of subjects with a response at the visit and at baseline for the 
region. 
9.2.3.5. 
Medical Outcomes Study Sleep Scale 
The MOS Sleep Scale is a 12-item questionnaire which measures sleep quality in 7 scales 
over the past 4 weeks: sleep disturbance, snoring, sleep short of breath or headache, 
sleep adequacy, sleep somnolence, and 2 sleep problems indexes. In addition, the 
average hours of sleep over the past 4 weeks is recorded as a raw measure and also 
coded as an optimal sleep index. 
The MOS will be scored and the sleep scales calculated according to the MOS Sleep Scale 
User's Manual v1.0 (Spritzer and Hays, 2003). 
9.2.3.6. 
Patient Health Questionnaire Depression Scale (PHQ-8) 
The PHQ-8 is an 8-item questionnaire that aims at assessing the level of depression of a 
subject. Each item is scored from 0 = “not at all” to 3= “nearly every day”; the total 
score, which is the sum of the scores for each item, can be from 0 to 24. A score ≥10 is 
considered major depression and ≥20 is severe major depression. 
The total score will be considered missing if more than 1 item is missing. If only 7 of the 
8 questions are answered, the sum will be weighted up by multiplication by 8/7. 
9.2.3.7. 
Work Productivity and Activity Impairment 
The WPAI used in this study is for the specific health problem of lower back pain (LBP). 
The questionnaire consists of 6 questions regarding the past 7 days: 
1. Currently employed 
2. Hours of work missed due to LBP 
3. Hours of work missed for other reasons 
4. Hours actually worked 
5. Degree LBP affected productivity while working (0-10) 
6. Degree LBP affected regular activities (0-10) 
 
Questions 2-5 are skipped if the subject was not employed during the past week (7 
days). 
Outcomes from the WPAI:LBP are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity. Referring the responses to 
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questions 2-6 as Q2-Q6, respectively, the impairment percentages are calculated as: 
% work time missed due to LBP = 100*Q2/(Q2+Q4) 
% impairment while working due to LBP = 10*Q5 
% overall work impairment due to LBP = 100*{Q2/(Q2+Q4) + [(1-(Q2/(Q2+Q4)))*(Q5/10)]} 
% activity impairment due to LBP = 10*Q6 
In addition to the ANCOVA and summaries of actual and changes from baseline, the 4 
percentages will be categorized as 0%, >0-5%, >5-10%, >10-25%, >25-50%, >50-75%, >75%-
<100%, 100% and summarized with frequencies and percentages. Differences between 
the treatment groups in the distributions will be assessed using a Cochran-Mantel-
Haenzsel (CMH) test stratified by index ER opioid with row mean scores, appropriate for 
ordered categories. 
9.3. 
Additional Efficacy Analyses 
Additional efficacy analyses stated in the protocol are described in the following 
sections. No imputation of missing data will be employed for any of these analyses. 
9.3.1. 
Cumulative Response Function – Mean Average PI 
For the Suboptimal Responders, the cumulative response function in percent 
improvement in mean Average PI score at Weeks 12 and 24 relative to baseline over 1 
week before each visit will be shown by treatment group. Since reduction in mean 
Average PI represents improvement, the pain intensity difference (PID), defined as 
baseline Average PI – mean Average PI at visit, expressed as a percentage of baseline, 
will be used. The categories used will include percent PID relative to baseline of >0% 
(any improvement), and ≥10% to ≥50% in steps of 10% as a decreasing function. If 
sufficient subjects show improvement ≥50%, additional cut points will be added. 
For the Optimal Responders, the worsening from baseline represented by the actual 
changes from baseline to Weeks 12 and 24 as percentages of baseline will also be shown 
(including >0% (any worsening), and ≥10% to ≥50% in steps of 10%), similarly to the 
summary for improvement. 
9.3.2. 
Cumulative Response Function – RMDQ 
For the Suboptimal Responders, the cumulative response function in percent 
improvement in RMDQ score (0-24) at Weeks 12 and 24 relative to baseline over 1 week 
before each visit will be shown by treatment group. Since reduction in RMDQ score 
represents improvement, the negative of change from baseline will be expressed as a 
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percentage of baseline and summarized similarly to mean Average PI. 
Likewise, for Optimal Responders, worsening in RMDQ score as a percentage of baseline 
will be summarized. 
9.3.3. 
Overall Clinical Benefit – Suboptimal Responders 
The overall clinical benefit for the Suboptimal Responders is defined as ≥30% 
improvement in mean Average PI and ≥20% improvement in RMDQ and PGIC of 
moderately or better improvement. The proportion of subjects in the Suboptimal 
Responder group with overall clinical benefit at Weeks 12 and 24 will be analyzed using 
logistic regression for binary endpoints with model terms for baseline Average PI, 
baseline RMDQ, index ER opioid, and treatment group. Subjects who are missing data 
for any of the components defining overall clinical benefit will be excluded from the 
analysis for the week with missing data. 
9.3.4. 
Time to Discontinuation Due to Lack of Efficacy 
The time to discontinuation due to lack of efficacy starting from Day 1 of the BSODP and 
for any reason will be summarized by treatment group using Kaplan-Meier estimates of 
the survival function. Median and quartile times will be shown with 95% CIs. 
Subjects who complete the BSODP will be censored on the last day of the period (~24 
weeks). For the summaries of subjects who discontinue to lack of efficacy, subjects who 
do not discontinue or discontinue for other reasons will be censored on their last day of 
contact within the BSODP. 
9.3.5. 
Patient Global Impression of Change 
The PGIC is a self-administered questionnaire that assesses the subject's level of 
improvement/worsening from the beginning to the end of treatment. Subjects are asked 
to select the category of change that most closely describes any change experienced in 
the pain in their painful areas from the beginning of the BSODP to Week 12 and to Week 
24. 
The scale has levels describing change as: 
Very much improved 
Much improved 
Minimally improved 
No change 
Minimally worse 
Much worse 
Very much worse 
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The frequencies and percentages of subjects reporting each category of change will be 
summarized by treatment group at each visit. Differences in the distributions between 
treatment groups will be assessed with a CMH test stratified by index ER opioid using 
row mean scores, as is appropriate for ordered categories. 
9.3.6. 
EuroQOL 5 Dimensions (5 Levels of Response) Instrument 
The EQ-5D-5L measures quality of life in 5 dimensions: 
Mobility 
Self-care 
Usual activities 
Pain/discomfort 
Anxiety/depression 
Each is rated in 5 levels from no problems/pain/anxiety to being unable/extreme 
pain/extreme anxiety. The responses for each category will be summarized by 
treatment and visit with frequencies and percentages reporting each level. 
In addition, a visual analog scale (VAS) rates the subject's health on a 0-100 scale from 
the worst imaginable health state to the best imaginable health state. The VAS values 
and changes from baseline to each visit will be summarized with descriptive statistics. 
9.4. 
Exploratory Efficacy Analyses 
Exploratory analyses are: 
• 
Change in sensitivity to thermal stimuli on QST (subjects participating in the 
substudy). This will be reported in a separate report of the substudy. 
• 
Univariate and multivariate regression analyses with each subject characteristic 
as an independent variable to determine the subjects’ characteristics that 
predict suboptimal or optimal response to structured discontinuation of opioid 
therapy 
• 
Changes from baseline in endocrine function and sexual function as 
characterized in the male and female questionnaires; relationship of changes in 
endocrine function to changes in PI; relationship of changes in endocrine 
function to changes in male and female sexual function; and relationship of 
baseline endocrine status to efficacy of opioid discontinuation  
• 
Changes from baseline in neurocognitive function as characterized by the 
number of correct responses from the DSST  
 
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9.4.1. 
Subject Characteristics Predictive of Response  
The baseline characteristics listed in Section 8.3 will be used as covariates and factors 
in regression or ANCOVA models against the change from baseline to Week 12 in mean 
Average PI. Each baseline characteristic will be fit individually into the model including 
terms for treatment and treatment-by-baseline characteristic interaction and the terms 
tested for significance. A forward-stepwise regression approach will also be used to fit 
the best predictive model. Only suboptimal responders in the ITT Set with a Week 12 
mean Average PI will be used in these analyses. 
MMRM models using observed data for subjects in the discontinuation arms (without 
multiple imputation), including Week as a factor will also be used to assess the 
predictive ability of each baseline characteristic. 
9.4.2. 
Digit Symbol Substitution Test 
The DSST assesses overall neuropsychological function. The test is sensitive to brain 
damage, dementia, age, and depression, and is a widely used instrument for measuring 
the neuropsychological effects of opioid therapy. The digits (1-9) are paired with 
symbols, and the test consists of matching the symbol for a series of digits as fast as 
possible. The measure is the number of correct symbols in 90 seconds, which will be 
analyzed using ANCOVA with model terms of baseline score, stratification parameters, 
and treatment group using observed data (without multiple imputation) 
9.4.3. 
Changes in Endocrine and Sexual Function 
Endocrine function will be assessed at Screening, Week 12, and Week 24. 
The endocrine endpoints will be: 
• 
HPG axis: Total testosterone, free testosterone (assayed using the equilibrium 
dialysis method), FSH, LH, and, in women estradiol 
• 
HPA axis: ACTH, cortisol, dehydroepiandrosterone sulfate (DHEAS) 
• 
Growth hormone axis: IGF-1 
 
Questionnaires regarding sexual function (International Index of Erectile Function [IIEF] 
in males and Female Sexual Function Index [FSFI] in females) will be obtained at the 
same time point that endocrine blood samples are drawn. 
The IIEF is a 15-item questionnaire which encompasses 5 domains of sexual function in 
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males: Erectile Function, Orgasmic Function, Sexual Desire, Intercourse Satisfaction, 
and Overall Satisfaction. Each question is scored on a scale of 0 to 5 or 1 to 5. Missing 
responses are scored as 0. The score for each domain is obtained by summing the scores 
for each domain as follows: 
Domain 
Items 
Maximum Score 
Erectile Function 
1, 2, 3, 4, 5, 15 
30 
Orgasmic Function 
9, 10 
10 
Sexual Desire 
11, 12 
10 
Intercourse Satisfaction 
6, 7, 8 
15 
Overall Satisfaction 
13, 14 
10 
 
The FSFI is a 19-item questionnaire which encompasses 6 domains of sexual function in 
females: Desire, Arousal, Lubrication, Orgasm, Satisfaction, and Pain. A full scale score 
is obtained by summing the scores for each domain. Each question is scored on a scale 
of 0 to 5 or 1 to 5. Missing responses are scored as 0, which also indicates no reported 
sexual activity. The score for each domain has a maximum of 6 and is obtained by 
summing the scores for each domain and multiplying by a factor as follows: 
Domain 
Items 
Factor 
Desire 
1, 2 
0.6 
Arousal 
3, 4, 5, 6 
0.3 
Lubrication 
7, 8, 9, 10 
0.3 
Orgasm 
11, 12, 13 
0.4 
Satisfaction 
14, 15, 16 
0.4 
Pain 
17, 18, 19 
0.4 
ANCOVA models for change from baseline in mean Average PI will be fit with terms for 
treatment and for each individual change from baseline endocrine endpoint along with 
interaction terms with treatment. Significance of terms will be reported. 
For males and females separately, Pearson and Spearman correlations for changes in 
baseline to Week 12 and Week 24 in each endocrine function endpoint against each 
change from baseline to the corresponding time point in sexual function domain will be 
tabulated. 
ANCOVA models for change from baseline to Week 12 and for change from baseline to 
Week 24 in mean Average PI will be fit with terms for treatment and each endocrine 
endpoint baseline as a covariate and its interaction with treatment in separate models. 
Significance of terms will be assessed. 
Only observed data will be used in these analyses without imputation of missing values. 
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10. 
ANALYSIS OF PHARMACOKINETICS 
Not applicable. 
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11. 
ANALYSIS OF PHARMACODYNAMICS 
Not applicable. 
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12. 
SAFETY 
Safety during the BSODP will be assessed using the Safety Set Post-Randomization by 
actual treatment received. Safety will be assessed based on occurrence of AEs, 
occurrence of abuse-related AEs, occurrence of withdrawal AEs, occurrence of opioid-
specific side effects, changes in vital signs (heart rate, blood pressure, and respiratory 
rate only), changes in physical examination findings, changes in clinical laboratory 
parameters, occurrence of abnormal UDT findings, occurrence of C-SSRS findings, and 
severity of opioid withdrawal effects as measured by COWS and SOWS. 
AEs, serious adverse events (SAEs), and vital signs will also be summarized for each of 
the Safety Sets Pre-Randomization for each Responder type. 
12.1. 
Extent of Exposure 
Extent of exposure to study medication will be evaluated as exposure duration and 
average daily dose for the index ER opioids and the IR opioids. Extent of exposure 
measures will only be assessed during the BSODP.  
Exposure duration will be calculated in days as (last dose date – first dose date (i.e., 
randomization date) + 1), regardless of missed doses. 
Average daily dose in mg will also be summed from dosing records as follows:  
Total daily dose of index ER opioid at every dose level will be multiplied by the number 
of days on that dose during the BSODP and summed across all doses.  Total daily dose of 
IR opioid during the BSODP will be summed for each day that such medication was 
taken.  Those sums will then be divided by the total number of days of participation in 
the BSODP to calculate an average daily dose of index ER opioid and IR opioid. 
Extent of exposure (duration) and average daily dose will be summarized with 
descriptive statistics for quantitative assessments by treatment group within each 
cohort (SR and OR) for each type of formulation (ER/CR and IR). 
12.2. 
Treatment Compliance 
Compliance with treatment will be calculated for the index ER opioids only as a 
percentage based on doses received and expected during the BSODP. 
Compliance will be calculated from randomization up to the last dose date (early 
discontinuation or 24 weeks) in the BSODP by dividing the number of doses of ER opioids 
taken by the subject by the number of doses required by the protocol and multiplying 
by 100 to determine the percentage of compliance. 
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The compliance percentage will be summarized with descriptive statistics for 
quantitative assessments. The compliance percentage will also be summarized with 
frequencies and percentages of subjects with compliance in the following categories: 
<80% 
80-120% 
>120% 
12.3. 
Adverse Events 
Adverse events (AEs) will be coded using MedDRA. Incidence of AEs will be summarized 
by primary system organ class (SOC) and by preferred term (PT) within primary SOC. 
Treatment emergence within each Pre-Randomization period covered by the Safety Sets 
and during the BSODP is defined in Section 7.2.3. Each AE will be classified into the 
given period for which it was treatment emergent according to its start date and time 
relative to the start and end dates and times of each period. In general, if an AE has an 
unknown start time but the start date is the same as the start date of a Pre-
Randomization period or the BSODP, the AE will be assumed to have started after the 
start time of the period and therefore will be considered a TEAE in that period. If the 
AE start time is present and the AE start date is the same as the start date of a period, 
then the AE will be considered as being a TEAE in the previous period only if the AE 
start time is before the start time of the period that starts on the same day. 
AEs that start outside of these periods will be listed with all AEs. Only TEAEs will be 
summarized in tables. 
For purposes of determining treatment emergence only, partial and missing AE start 
dates will be imputed according to the rules described here. The partial dates will be 
displayed in listings. Missing AE start times will not be imputed. But, as stated above, an 
AE with a missing start time will be considered to be a TEAE in a period which shares 
the same start date as the start date of the AE. This will also hold true for start dates 
imputed according to the rules below. 
The general strategy for the imputation of dates will be to use the first of the month for 
a missing day and the first of the year for a missing day and month. If the month or year 
coincides with the start date of a period, the date will be set to the start date of the 
latest period the subject entered which shares the same date. If an AE start date is 
completely missing, the date will be set to the start date of the latest period which the 
subject entered. Treatment emergence will then be determined according to the rules 
already given. 
Incomplete start dates for AEs will be estimated as follows: 
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• 
If the day is missing, then the first day of the month will be used. If the months 
and years are the same as one or more Pre-Randomization periods or the BSODP, 
then the start date of the latest period with the same month and year will be 
used. 
• 
If the day and month are missing, then the first day of the year will be used.  If 
the year is the same as one or more Pre-Randomization periods or the BSODP, 
then the start date of the latest period with the same year will be used. 
• 
If the date is completely missing, it will be set to the first dose date of double-
blind treatment. If a subject does not enter the Post-Randomization Period, then 
the date will be set to the date that starts the latest period into which the 
subject entered (i.e., for Suboptimal Responders, the first date of taking the 
standardized regimen Pre-Randomization; for Optimal Responders, the latest of 
the first date defining the Pre-Randomization Observation, Taper, and Titration 
Periods) 
• 
If the estimated AE onset date is after the AE stop date, then the AE stop date 
will be used as the start date. 
An overall summary of TEAEs within the BSODP will show the frequency and percentage 
of subjects with any TEAE of the specified type within the period: 
• 
Any TEAE 
• 
TEAEs related to study medication 
• 
Fatal TEAEs 
• 
Serious TEAEs 
• 
Serious TEAEs related to study medication 
• 
Any Abuse-related TEAEs  
• 
TEAEs associated with opioid use 
• 
TEAEs associated with withdrawal from opioids 
 
Total counts of each type of TEAE will also be included in the summary without 
percentages. 
Related TEAEs in the overall summary will be those that are assessed by the investigator 
to be either possibly or probably related. Any TEAE with missing relationship will be 
considered related. 
Potential abuse-related events will be tracked using the Misuse Abuse Diversion Drug 
Event Reporting System (MADDERS®), which is a clinician-based assessment to identify 
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and classify such events based on selected AEs and drug accountability discrepancies. A 
listing of abuse-related TEAEs will include the MADDERS® classification. 
TEAEs associated with opioid use are shown in the following table. 
Adverse Events Associated with Opioid Use by MedDRA SOC and PT 
SOC 
PTs 
Gastrointestinal Disorders 
constipation, nausea, vomiting, dry mouth 
Nervous System Disorders 
somnolence, dizziness, memory impairment, 
disturbance in attention 
General Disorders and 
Administrative Site Conditions 
fatigue, decreased appetite 
Investigations 
weight increased 
Psychiatric Disorders 
sleep disorders 
Skin and Subcutaneous Tissues 
Disorders 
pruritus, hyperhydrosis 
 
TEAEs associated with opioid withdrawal will be identified from the following table, 
where any 3 of the TEAEs occur with start dates within 3 days of each other and 
encompass at least 2 SOCs. A listing of subjects with TEAEs satisfying the condition will 
be produced including the details of the TEAEs. 
Adverse Events Associated with Opioid Withdrawal by MedDRA SOC and PT 
SOC 
PTs 
Psychiatric disorders 
agitation, anxiety, insomnia, restlessness 
Eye disorders 
lacrimation increased 
Respiratory, thoracic and 
mediastinal disorders 
rhinorrhea, yawning 
Skin and subcutaneous tissues 
disorders 
piloerection, hyperhidrosis 
Nervous system disorders 
tremor 
General disorders and 
administration site conditions 
hot flush, chills 
Musculoskeletal and connective 
tissue disorders 
bone pain, myalgia, muscle twitching 
Gastrointestinal disorders 
nausea, vomiting, diarrhoea, abdominal pain 
upper 
 
 
Summaries of TEAEs within the BSODP will be presented by SOC and by PT within SOC, 
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showing the frequency and percentage of subjects with TEAEs in each SOC and PT. 
Should a subject have more than one TEAE in a given SOC or PT, the subject will be 
counted only once. Tables will be ordered by SOC and PT within SOC according to 
descending frequencies in the discontinuation arm. The summaries to be produced are 
listed below: 
• 
All TEAEs by primary SOC and PT 
• 
All serious TEAEs by primary SOC and PT 
• 
All TEAEs by maximum relationship to study medication, primary SOC and PT 
• 
All serious TEAEs by maximum relationship to study medication by primary SOC 
and PT 
• 
All TEAEs leading to discontinuation of study medication by primary SOC and PT 
• 
All TEAEs by maximum severity, primary SOC, and PT 
• 
Common TEAEs (≥5% in any treatment group) by PT 
• 
Abuse-related TEAEs by primary SOC and PT 
• 
TEAEs associated with opioid use by primary SOC and PT 
 
TEAEs with missing relationship will be counted in the summary of TEAEs by maximum 
relationship as probably related to study medication. For the summary by maximum 
severity (mild, moderate, severe), TEAEs with missing severity will be tabulated as a 
severe TEAE. 
Additional summaries of the potential abuse-related TEAEs identified by MADDERS® will 
be provided. The MADDERS® classifies such events as abuse, misuse, suicide-related, 
therapeutic error, none of the above, and unknown. The summaries will show the 
frequencies and percentages of subjects in each Safety Set Pre- and Post-Randomization 
with at least one TEAE in each classification followed by the TEAEs summarized with 
frequencies and percentages by MedDRA SOC and PT. The items on the MADDERS® 
questionnaire will be listed without summary. 
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In addition to the data listing of AEs, the following subject listings will also be produced 
for Section 14 of the CSR: 
• 
AE preferred terms and associated investigator’s terms (not by subject) 
• 
SAEs 
• 
TEAEs causing discontinuation of study medication 
• 
Fatal TEAEs 
• 
Abuse-related TEAEs from MADDERS® 
 
Listings of all TEAEs for subjects with any potentially clinically significant (PCS) 
abnormal laboratory value, as defined in Section 12.4, will be produced. Likewise, 
listings of all TEAEs for subjects with any PCS vital sign value, as defined in Section 
12.5. 
For the pre-randomization period(s), only a summary of TEAEs and of Serious TEAEs by 
primary SOC and PT will be produced. 
12.4. 
Laboratory Evaluations 
Laboratory evaluations include serum chemistry, hematology, and urinalysis. All 
chemistry and hematology assessments are numeric, as well as a few urinalysis 
assessments, and will be classified as low, normal, or high relative to reference ranges. 
Numeric laboratory values and changes from baseline will be summarized with 
descriptive statistics for quantitative assessments. Before summary, the results will be 
standardized to the International System of Units (SI), or other appropriate common 
units. If values for a particular assessment cannot be standardized, then results will be 
summarized separately for each unit. 
Qualitative urinalysis results will be summarized with frequencies and percentages of 
subjects with each recorded value at baseline and at each post baseline visit. 
Denominators for percentages will be the counts of subjects with a urinalysis value at 
the visit. Due to the variety of results reported from urinalysis, no shifts or changes 
from baseline will be summarized. 
For quantitative laboratory assessments, shift tables for transitions from baseline to 
each post baseline visit will be produced for each lab test with baseline low, normal, 
high, missing, and total across the columns, and likewise down the rows for each visit. 
The total/total cell will contain the denominator for percentages in the shift tables. 
Potentially clinically significant (PCS) high laboratory values will be those that are >2.0 
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times the upper limit of normal at a post-randomization visit. The frequencies and 
percentages of subjects with PCS high values will be summarized for subjects with a 
normal or low value at baseline for the laboratory test. 
PCS low laboratory values will be those that are <0.5 times the lower limit of normal at 
a post-randomization visit. The frequencies and percentages of subjects with PCS low 
values will be summarized for subjects with a normal or high value at baseline for the 
laboratory test. 
Adverse events associated with PCS high and low laboratory results will be listed as 
mentioned in Section 12.3. 
12.5. 
Vital Signs 
Vital signs collected at each visit in this study are systolic and diastolic blood pressures, 
heart rate, and respiratory rate. 
Vital signs values and changes from baseline will be summarized by visit in the BSODP 
with descriptive statistics. Vital signs will be classified as PCS low and PCS high relative 
to the ranges given in the table below. 
Measurement 
PCS Low Reference Value 
PCS High Reference Value 
Systolic blood pressure 
90 mmHg 
180 mmHg 
Diastolic blood pressure 
50 mmHg 
100 mmHg 
Heart rate 
50 beats per minute 
110 beats per minute 
 
Frequencies and percentages of subjects with PCS low values will be summarized 
relative to the frequency of subjects with a value above the PCS low reference value at 
baseline. Likewise, subjects with PCS high values will be summarized relative to the 
frequency of subjects with a value below the PCS high reference value at baseline. 
Vital signs and changes from Screening will also be summarized with descriptive 
statistics for the pre-randomization periods using the Safety Sets Pre-Randomization 
described for each responder type. 
For Suboptimal Responders, the vital signs at Screening, at the end of the Run-in Period 
(SR1), and at the Randomization Visit (SR2) will be summarized with changes from 
Screening to SR1 and to SR2 using the Safety Set Pre-Randomization. 
For Optimal Responders, the vital signs at Screening and at the end of the Observation 
Period (OR1) will be summarized with changes from Screening to OR1 for the Safety Set 
Pre-Randomization (Observation Period). Vital signs at Screening, and visits OR2 1 week 
into the Taper Period and OR3 at the end of the Taper Period will be summarized with 
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changes from Screening to OR2 and OR3 using the Safety Set Pre-Randomization (Taper 
Period). Finally, the vital signs at Screening and at the Randomization Visit (OR4) will be 
summarized with changes from Screening to OR4 using the Safety Set Pre-Randomization 
(Titration Period). 
No PCS tables for abnormal vital signs during the pre-randomization periods will be 
produced. Adverse events associated with PCS vital sign values will be listed as 
mentioned in Section 12.3. 
12.6. 
Physical Examination 
For each body system, PE results will be summarized with frequencies and percentages 
of subjects with a shift from normal or missing at baseline to abnormal at a post-
randomization visit within the BSODP. The denominator for percentages will be the 
number of subjects with a normal or missing assessment at baseline for the body system 
and who have a post-baseline PE. A listing of PE data will also be provided. 
12.7. 
Urine Drug Testing 
UDT is done at Screening and at Weeks 4, 12, and 24 of the BSODP. Abnormal results 
will be listed and summarized by treatment group at each visit. The summary will show 
the frequencies and percentages of subjects with at least one abnormal result and the 
frequencies and percentages of subjects with each type of drug detected at the visit. 
12.8. 
Subjective Opiate Withdrawal Scale 
The SOWS consists of a series of 16 statements describing how a subject may feel. The 
subject is supposed to answer on a scale of 0 = not at all to 4 = extremely. The score is 
the sum of the items and ranges from 0 to 64. 
Values and changes from baseline to each visit where collected in the BSODP will be 
summarized with descriptive statistics. 
12.9. 
Clinical Opiate Withdrawal Scale 
The COWS presents a set of symptoms possibly associated with opiate withdrawal. The 
presence of or severity level of the symptoms are rated as categories which translate to 
scores for each symptom. The total score is the sum of the individual symptom scores 
and ranges from 0-44. Scores in the 0-4 range indicate no particular evidence of 
withdrawal effects. Otherwise, the scores can be interpreted as follows: 
5-12 = mild 
13-24 = moderate 
25-36 = moderately severe 
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>36 = severe withdrawal 
Values and changes from baseline to each visit where collected in the BSODP will be 
summarized with descriptive statistics. 
Shift tables showing changes from baseline to each visit in the categories above also will 
be presented. 
12.10. 
Columbia-Suicide Severity Rating Scale 
Suicidality assessment by the C-SSRS is done at Screening and at Weeks 6 and 24 during 
the BSODP. The screening assessment period is defined as lifetime. The assessment 
period for the BSODP visits is the time since the last visit. Summarization will be done 
at each visit as well as over the entire BSODP. 
12.10.1. 
Suicidal Behavior 
Four types of suicidal behavior are defined in the C-SSRS (actual, interrupted, and 
aborted attempts, and preparatory acts or behavior), as well as an overall suicidal 
behavior assessment. For each behavior type, the frequency and percentage of subjects 
with a yes response to each behavior type will be reported at each visit. The 
denominator for percentages will be the number of subjects with a C-SSRS assessment 
at the visit. Subjects with a yes response at any BSODP visit will be given a yes response 
for the behavior type over the full treatment period, which will also be summarized. 
The number of actual suicide attempts per subject will be summarized with frequencies 
and percentages of subjects. The highest lethality per subject will be similarly 
summarized. Lethalities for all suicide attempts will be summarized with frequencies 
and percentages of all attempts. 
For subjects for whom no suicidal behavior of any kind was indicated at the screening 
assessments, the frequency and percentage of subjects who demonstrated any type of 
suicidal behavior as assessed during the treatment period will be reported by treatment 
group. 
12.10.2. 
Suicidal Ideation 
Five types of increasing suicidal ideation are defined in the C-SSRS: (1) death wish, 
(2) active thoughts, (3) active ideation without intention to act, (4) active ideation with 
some intent to act without a plan, and (5) active ideation with a specific plan and 
intent. The incidence of each type of suicidal ideation and of any type of suicidal 
ideation will be summarized by treatment group at each visit with frequencies and 
percentages of subjects with an assessment at the visit. The suicidal ideation severity 
rating will take the numeric value of the most intense ideation type observed (1-5) or 
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else 0 if no ideation is observed. Baseline suicidal ideation severity rating will be the 
rating observed at Screening. The rating at baseline and the rating with change from 
baseline at each visit will be summarized by treatment group with descriptive statistics. 
The worst rating observed during treatment and change from baseline will also be 
summarized. 
A scale for the intensity of suicidal ideation will be calculated as a sum of the 5 
intensity items. A subject with no suicidal ideation during a period will be assigned a 
score of 0, so an intensity scale of 0 to 25 results. Suicidal ideation intensity and 
changes from baseline will be summarized by treatment groups similarly to suicidal 
ideation severity. 
For the subjects for whom no suicidal ideation of any kind was identified at the 
Screening assessment, the frequency and percentage of subjects who demonstrated any 
type of suicidal ideation and also any type of serious ideation as assessed during the 
BSODP will be reported by treatment group. Serious suicidal ideation will be defined as 
an ideation severity rating of 4 or 5 at any time post-randomization. 
A subject will be defined to have worsening of suicidal ideation if the greatest severity 
rating at any post-randomization visit is more severe than the ideation severity rating 
taken at screening. The frequency and percentage of subjects with worsening ideation 
will be reported. 
12.10.3. 
Suicidality 
The frequency and percentage of subjects reporting any type of behavior or ideation at 
any time during the BSODP will be reported by treatment group. 
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13. 
INTERIM ANALYSES 
Not applicable. 
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14. 
END OF STUDY STATISTICAL ANALYSIS PLAN 
MODIFICATIONS 
 The study was ended earlier than planned. As a result, some of the planned analyses 
could not be completed due to insufficient sample size. The following is a list of 
changes for the respective section in the analysis plan. Section 6.4, the analysis 
population of the per-protocol set will not be used. 
Section 6.5, for protocol deviations, summaries will not be provided. Only a listing will 
be provided. 
Section 7.5, for the primary efficacy analysis, analyses by the subgroups sex and age 
will not be provided. 
Section 8.1, for disposition a flow chart showing the number of subjects entering each 
period and moving onto the next will not be provided. The early discontinuation 
assessment tool will be listed only. No summaries will be provided.  
Section 8.2, the demographic summaries will be provided for the Safety Set Post-
Randomization only. Summaries for other populations will not be provided. 
Section 8.3, the summary of the baseline characteristics will be provided for the Safety 
Set Post-Randomization only. Summaries for other populations will not be provided. 
Section 8.5, prior medication summaries will be provided for suboptimal responders at 
pre-randomization and for optimal responders at pre-randomization (observation 
period). Concomitant medications will be provided at post-randomization for suboptimal 
and optimal responders. 
Section 9, the planned efficacy analyses will not be provided. Summary statistics will be 
provided for the average PI score and change from baseline at each visit for suboptimal 
and optimal responders. Summary statistics will also be provided for the average PID 
cumulative response for percent improvement in suboptimal responders and percent 
worsening in optimal responders at Weeks 12 and 24. Summary statistics will be 
provided for observed values and changes from baseline for the MOS Sleep Scale, PHQ-8, 
EuroQOL 5 Dimensions, Digit Symbol Substitution Test, and the sexual function for 
suboptimal and optimal responders at each visit. Frequencies and percentages will be 
provided for the Patient Global Impression of Change at each visit for suboptimal and 
optimal responders. A listing will be provided for the quantitative sensory testing.  
Section 12.3, the following adverse event summaries will be provided for suboptimal 
responders: 
• 
Overall summary of TEAEs at pre-randomization 
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• 
Overall summary of TEAEs at post-randomization 
• 
TEAEs by system organ class and preferred term at pre-randomization 
• 
TEAEs by system organ class and preferred term at post-randomization 
• 
TEAEs by maximum relationship, system organ class, and preferred term at post-
randomization 
• 
TEAEs by maximum severity, system organ class, and preferred term at post-
randomization 
• 
TEAEs associated with opioid withdrawal by preferred term at post-
randomization 
• 
Potential abuse-related TEAEs by MADDERS Classification at post-randomization 
The following adverse event summaries will be provided for optimal responders: 
• Overall summary of TEAEs at pre-randomization (observation period)  
• Overall summary of TEAEs at pre-randomization (taper period) 
• Overall summary of TEAEs at pre-randomization (titration period) 
• Overall summary of TEAEs at post-randomization 
• TEAEs by system organ class and preferred term at pre-randomization 
(observation period) 
• TEAEs by system organ class and preferred term at pre-randomization 
(taper period) 
• TEAEs by system organ class and preferred term at pre-randomization 
(titration period) 
• TEAEs by system organ class and preferred term at post-randomization 
•  TEAEs by maximum relationship, system organ class, and preferred term at 
post-randomization 
• 
TEAEs by maximum severity, system organ class, and preferred term at post-
randomization 
• 
TEAEs associated with opioid withdrawal by preferred term at post-
randomization 
• 
Potential abuse-related TEAEs by MADDERS Classification at post-randomization 
AE listings will be provided for: 
• All adverse events 
• Abuse-related events 
• Abuse-related adverse events from MADDERS 
• Serious adverse events 
• Adverse events leading to study discontinuation 
• Adverse events with potentially clinically significant abnormal laboratory 
values 
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• Adverse events with potentially clinically significant abnormal vital sign 
values 
 
Section 12.4, for laboratory summaries, summary and shift tables will be 
provided for hematology and chemistry results. No summaries will be provided 
for urinalysis results. In addition frequencies of potentially clinically significant 
results and a listing of treatment-emergent abnormal laboratory results will be 
presented.  
 
Section 12.5, for vital signs actual results, changes from baseline, and 
potentially clinically significant abnormalities will be summarized at post-
randomization only. 
 
Section 12.6, abnormal physical examination results will be listed. No other 
summaries will be provided. 
 
Section 12.9, for the COWS only summary tables for observed values and changes 
from baseline will be presented. Shift tables will not be provided.  
 
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15. 
REFERENCE LIST 
Little RJA, Rubin DB. Statistical analysis with missing data (2nd ed.). Hoboken, NJ: John 
Wiley & Sons, Inc., 2002. 
Spritzer KL, Hays RD. MOS Sleep Scale: A Manual for Use and Scoring, Version 1.0. Los 
Angeles, CA: November 2003. 
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16. 
PROGRAMMING CONSIDERATIONS 
All tables and listings will be generated using SAS® for Windows, Release 9.3 or higher 
(SAS® Institute Inc., Cary, NC, USA). Computer-generated table and listing output will 
adhere to the following specifications. 
16.1. 
General Considerations 
• 
A separate SAS program will be created for each output. 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in RTF format. 
• 
Numbering of tables and listings will follow International Conference on 
Harmonization (ICH) E3 guidance. 
 
16.2. 
Table and Listing Format 
16.2.1. 
General 
• 
All tables and listings will be produced in landscape format. 
• 
All tables and listings will be produced using the Courier New font, size 9. 
• 
The data displays for all tables and listings will have minimum 1-inch margins. 
• 
Tables and listings will be in black and white (no color), unless otherwise 
specified. 
• 
Specialized text styles, such as bolding, italics, borders, shading, superscripted 
and subscripted text, will not be used in the tables and listings unless otherwise 
specified. On some occasions, superscripts 1, 2, and 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the tables and listings. Special 
characters, such as non-printable control characters, printer-specific, or font-
specific characters, will not be used. Hexadecimal-derived characters will be use 
if they are appropriate to help display math symbols. Certain superscripts and 
subscripts (e.g., kg/m2) will be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, and column headers, as 
appropriate. 
 
16.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
Opioid PMR Consortium 
Protocol No. 2065-5 
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• 
All output should have Page n of N at the top right corner of each page. Tables 
and listings should be internally paginated in relation to the total length (i.e., 
the page number should appear sequentially as page n of N, where N is the total 
number of pages in the table). 
• 
The date (date output was generated) should appear along with the program 
name in the footer on each page. 
 
16.2.3. 
Display Titles 
• 
ICH E3 numbering will be used. A decimal system (x.y and x.y.z) will be used to 
identify tables and listings with related contents. The title will be centered. The 
analysis set will be identified on the line immediately following the title. The 
title and table designation are single spaced. A solid line spanning the margins 
will separate the display titles from the column headers. There will be 1 blank 
line between the last title and the solid line. 
 
Table x.y.z 
First Line of Title 
Second Line of Title if needed 
Analysis Set 
16.2.4. 
Column Headers 
• 
Column headings should be immediately below the solid line described above. 
• 
For numeric variables, include “unit” in the column or row heading when 
appropriate. 
• 
Analysis set sizes for each treatment will be presented in the column heading as 
N=xxx (or row heading where appropriate). This is distinct from the ‘n’ used for 
the descriptive statistics, where n represents the number of subjects with non-
missing data.  
 
16.2.5. 
Body of Data Display 
16.2.5.1. 
General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left justified; 
• 
whole numbers (e.g., counts) are right justified; and 
• 
numbers containing fractional portions are decimal aligned. 
 
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16.2.5.2. 
Table Conventions 
• 
Units will be included where available.  
• 
If the categories of a parameter are ordered, then all categories between the 
minimum and the maximum category should be presented in the table, even if 
n=0 for a given category. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
n 
severe 
0 
moderate 
8 
mild 
3 
• 
Unless otherwise specified, the mean, median, first quartile, and third quartile 
for a set of values will be printed out to 1 more significant digit than the original 
values, and standard deviations should be printed out to 2 more significant digits 
than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure:  
n 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Q1 
XXX.X 
Median 
XXX.X 
Q3 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value 
rounded to 3 decimal places. Any p-value less than 0.001 will be presented as < 
0.001. If the p-value is returned is greater than 0.999, then the value will be 
presented as >0.999. 
• 
Percentage values will be printed to one decimal place in parentheses. 
Percentages for zero counts will not be displayed. Percentages equal to 100% 
will be displayed as (100).  
• 
The percentage of subjects will normally be calculated as a proportion of the 
number of subjects in the analysis set, unless otherwise specified in the 
footnote. 
• 
For categorical summaries (number and percentage of subjects) where a subject 
can be included in more than one category, a footnote or programming note will 
describe if the subject should be included in the summary statistics for all 
relevant categories or just 1 category and the criteria for selecting the category. 
• 
Where a category with a subheading (such as system organ class) has to be split 
over more than one page, the output heading followed by “(cont)” will be 
displayed at the top of each subsequent page. The overall summary statistics for 
the subheading should only be output on the first relevant page. 
 
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16.2.5.3. 
Listing Conventions 
• 
Listings will be sorted for presentation in order treatment, subject number, 
visit/collection date, and visit/collection time. 
• 
Dates should be printed in SAS® DATE9 format (ddmonyyyy or 01JUL2000). 
Missing portions of dates will be represented on subject listings as dashes (--
JUL2000),  
• 
All observed time values will be presented using a 24-hour clock format (HH:MM 
or HH:MM:SS). Time will only be reported if it was measured as part of the 
study.  
• 
Units will be included where available. 
 
16.2.5.4. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from 
the footnotes. All footnotes will be left justified with single-line spacing 
immediately below the solid line underneath the data display. 
• 
Footnotes will begin with “Note:” if it is an informational footnote or a, b, c, 
etc. if it is a reference footnote. Each footnote will start on a new line, where 
possible. 
• 
Footnotes will be used sparingly and must add value to the table or listing. If 
more than six lines of footnotes are planned, then a cover page may be used to 
display the footnotes, and only those essential to the comprehension of the data 
will be repeated on each page. 
• 
The last lines of the footnote will be a standard source line that indicates the 
name of the program used to produce the data display, the date and time the 
program was run and the source (either listing or eCRF page). 
 
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17. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 
03.010.00 and 03.013.00 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009.00 describes the quality control procedures that are 
performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs 
produce the proper clinical trial output by checking for their logic, efficiency and 
commenting and by review of the produced output. 
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18. 
INDEX OF TABLES 
Number 
Name 
Table 14.1.1.1 
Subject Disposition for Suboptimal and Optimal Responders – All Subjects 
Table 14.1.1.1.1 
Subject Disposition by Period – Pre-randomization – Suboptimal 
Responders 
Table 14.1.1.1.2 
Subject Disposition by Period – Pre-randomization – Optimal Responders 
Table 14.1.1.2.1 
Subject Disposition – Post-randomization – Suboptimal Responders 
Table 14.1.1.2.2 
Subject Disposition – Follow-up Period – Suboptimal Responders 
Table 14.1.1.3.1 
Subject Disposition – Post-randomization – Optimal Responders 
Table 14.1.1.3.2 
Subject Disposition – Follow-up Period – Optimal Responders 
Table 14.1.2.1 
Demographics and Baseline Characteristics – Safety Set Post-
Randomization – Suboptimal Responders 
Table 14.1.2.2 
Demographics and Baseline Characteristics – Safety Set Post-
Randomization – Optimal Responders 
Table 14.1.3.1 
Baseline Disease Characteristics – Safety Set Post-Randomization – 
Suboptimal Responders 
Table 14.1.3.2 
Baseline Disease Characteristics – Safety Set Post-Randomization – Optimal 
Responders 
Table 14.1.4.1 
Summary of  Medical History – Safety Set Post-Randomization – Suboptimal 
Responders 
Table 14.1.4.2 
Summary of Medical History – Safety Set Post-Randomization – Optimal 
Responders 
Table 14.1.5.1.1 
Summary of Prior Medications Prior to Enrollment – Safety Set Pre-
Randomization – Suboptimal Responders 
Table 14.1.5.1.2 
Summary of Concomitant Medications Post-Randomization – Safety Set 
Post-Randomization – Suboptimal Responders 
Table 14.1.5.2.1 
Summary of Prior Medication Prior to Enrollment – Safety Set Pre-
Randomization (Observation Period) – Optimal Responders 
Table 14.1.5.2.2 
Summary of Concomitant Medications Post-Randomization – Safety Set 
Post-Randomization – Optimal Responders 
Table 14.1.6.1 
Extent of Exposure and Treatment Compliance – Safety Set Post-
Randomization – Suboptimal Responders 
Table 14.1.6.2 
Extent of Exposure and Treatment Compliance – Safety Set Post-
Randomization – Optimal Responders 
Table 14.2.1.1.1 
Mean Average PI Score: Actual and Change from Baseline Descriptive 
Summary – Observed Data – Intent-to-Treat Set – Suboptimal Responders 
Table 14.2.1.1.2 
Mean Average PID: Cumulative Response in Percent Improvement at 
Weeks 12 and 24 – Observed Data – Intent-to-Treat Set – Suboptimal 
Responders 
Table 14.2.1.2.1 
Mean Average PI Score: Actual and Change from Baseline Descriptive 
Summary – Observed Data – Intent-to-Treat Set – Optimal Responders 
Table 14.2.1.2.2 
Mean Average PID: Cumulative Response in Percent Improvement at 
Weeks 12 and 24 – Observed Data – Intent-to-Treat Set – Optimal 
Responders 
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Clinical Study Report version: Final
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Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
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Number 
Name 
Table 14.2.2.1 
Medical Outcomes Study Sleep Scale: Change from Baseline Descriptive 
Summary – Intent-to-Treat Set – Suboptimal Responders 
Table 14.2.2.2 
Medical Outcomes Study Sleep Scale: Change from Baseline Descriptive 
Summary – Intent-to-Treat Set – Optimal Responders 
Table 14.2.3.1 
Patient Health Questionnaire Depression Scale (PHQ-8): Actual and 
Change from Baseline Descriptive Summary - Intent-to-Treat Set – 
Suboptimal Responders 
Table 14.2.3.2 
Patient Health Questionnaire Depression Scale: Actual and Change from 
Baseline Descriptive Summary - Intent-to-Treat Set – Optimal Responders 
Table 14.2.4.1 
EuroQOL 5 Dimensions Instrument: Descriptive Summary – Intent-to-Treat 
Set – Suboptimal Responders 
Table 14.2.4.2 
EuroQOL 5 Dimensions Instrument: Descriptive Summary – Intent-to-Treat 
Set – Optimal Responders 
Table 14.2.5.1 
Patient Global Impression of Change: Frequencies and Percentages of 
Subjects – Intent-to-Treat Set – Suboptimal Responders 
Table 14.2.5.2 
Patient Global Impression of Change: Frequencies and Percentages of 
Subjects – Intent-to-Treat Set – Optimal Responders 
Table 14.2.6.1 
Digit Symbol Substitution Test: Actual and Change from Baseline 
Descriptive Summary – Intent-to-Treat Set – Suboptimal Responders 
Table 14.2.6.2 
Digit Symbol Substitution Test: Actual and Change from Baseline 
Descriptive Summary – Intent-to-Treat Set – Optimal Responders 
Table 14.2.7.1 
Sexual Function: Actual and Change from Baseline Descriptive Summary – 
Intent-to-Treat Set – Suboptimal Responders 
Table 14.2.7.2 
Sexual Function: Actual and Change from Baseline Descriptive Summary – 
Intent-to-Treat Set – Optimal Responders 
Table 14.3.1.1.1 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) – Safety 
Set Pre-Randomization – Suboptimal Responders 
Table 14.3.1.1.2 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) – Safety 
Set Post-Randomization – Suboptimal Responders 
Table 14.3.1.1.3 
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term – Safety Set Pre-Randomization – Suboptimal Responders 
Table 14.3.1.1.4 
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term – Safety Set Post-Randomization – Suboptimal Responders 
Table 14.3.1.1.5 
Treatment-Emergent Adverse Events (TEAEs) by Maximum Relationship, 
System Organ Class and Preferred Term – Safety Set Post-Randomization – 
Suboptimal Responders 
Table 14.3.1.1.6 
Treatment-Emergent Adverse Events (TEAEs) by Maximum Severity, 
System Organ Class and Preferred Term – Safety Set Post-Randomization – 
Suboptimal Responders 
Table 14.3.1.1.7 
Treatment-Emergent Adverse Events (TEAEs) Associated with Opioid 
Withdrawal – Safety Set Post-Randomization – Suboptimal Responders 
Table 14.3.1.1.8 
Potential Abuse-related Treatment-Emergent Adverse Events (TEAEs) by 
MADDERS Classification – Safety Set Post-Randomization – Suboptimal 
Responders 
Table 14.3.1.2.1 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) – Safety 
Set Pre-Randomization (Observation Period) – Optimal Responders 
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Clinical Study Report version: Final
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Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
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Number 
Name 
Table 14.3.1.2.2 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) – Safety 
Set Pre-Randomization (Taper Period) – Optimal Responders 
Table 14.3.1.2.3 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) – Safety 
Set Pre-Randomization (Titration Period) – Optimal Responders 
Table 14.3.1.2.4 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs) – Safety 
Set Post-Randomization – Optimal Responders 
Table 14.3.1.2.5 
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term – Safety Set Pre-Randomization (Observation Period) – 
Optimal Responders 
Table 14.3.1.2.6 
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term – Safety Set Pre-Randomization (Taper Period) – Optimal 
Responders 
Table 14.3.1.2.7 
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term – Safety Set Pre-Randomization (Titration Period) – 
Optimal Responders 
Table 14.3.1.2.8 
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term – Safety Set Post-Randomization – Optimal Responders 
Table 14.3.1.2.9 
Treatment-Emergent Adverse Events (TEAEs) by Maximum Relationship, 
System Organ Class and Preferred Term – Safety Set Post-Randomization – 
Optimal Responders 
Table 14.3.1.2.10 
Treatment-Emergent Adverse Events (TEAEs) by Maximum Severity, 
System Organ Class and Preferred Term – Safety Set Post-Randomization – 
Optimal Responders 
Table 14.3.1.2.11 
Treatment-Emergent Adverse Events (TEAEs) Associated with Opioid 
Withdrawal – Safety Set Post-Randomization – Optimal Responders 
Table 14.3.1.2.12 
Potential Abuse-related Treatment-Emergent Adverse Events (TEAEs) by 
MADDERS Classification – Safety Set Post-Randomization – Optimal 
Responders 
Table 14.3.4.1.1 
Laboratory Test: Chemistry – Actual and Change from Baseline – Safety Set 
Post-Randomization – Suboptimal Responders 
Table 14.3.4.1.2 
Laboratory Test: Chemistry – Shift from Baseline – Safety Set Post-
Randomization – Suboptimal Responders 
Table 14.3.4.1.3 
Laboratory Test: Hematology – Actual and Change from Baseline – Safety 
Set Post-Randomization – Suboptimal Responders 
Table 14.3.4.1.4 
Laboratory Test: Hematology – Shift from Baseline – Safety Set Post-
Randomization – Suboptimal Responders 
Table 14.3.4.1.5 
Laboratory Test: Frequencies and Percentages of Potentially Clinically 
Significant Results – Safety Set Post-Randomization – Suboptimal 
Responders  
Table 14.3.4.1.6 
Listing of Treatment-Emergent Abnormal Laboratory Results – Safety Set 
Post-Randomization – Suboptimal Responders 
Table 14.3.4.2.1 
Laboratory Test: Chemistry – Actual and Change from Baseline – Safety Set 
Post-Randomization – Optimal Responders 
Table 14.3.4.2.2 
Laboratory Test: Chemistry – Shift from Baseline – Safety Set Post-
Randomization – Optimal Responders 
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Clinical Study Report version: Final
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Protocol: 2065-5 
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Statistical Analysis Plan 
 
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Number 
Name 
Table 14.3.4.2.3 
Laboratory Test: Hematology – Actual and Change from Baseline – Safety 
Set Post-Randomization – Optimal Responders 
Table 14.3.4.2.4 
Laboratory Test: Hematology – Shift from Baseline – Safety Set Post-
Randomization – Optimal Responders 
Table 14.3.4.2.5 
Laboratory Test: Frequencies and Percentages of Potentially Clinically 
Significant Results – Safety Set Post-Randomization – Optimal Responders  
Table 14.3.4.2.6 
Listing of Treatment-Emergent Abnormal Laboratory Results – Safety Set 
Post-Randomization – Optimal Responders 
Table 14.3.4.3.1 
Urine Drug Testing – Summary of Abnormalities – Safety Set Post-
Randomization – Suboptimal Responders 
Table 14.3.4.3.2 
Urine Drug Testing – Summary of Abnormalities – Safety Set Post-
Randomization – Optimal Responders 
Table 14.3.4.4.1.1 
Vital Signs – Actual and Change from Baseline – Safety Set Post-
Randomization – Suboptimal Responders 
Table 14.3.4.4.1.2 
Vital Signs: Potentially Clinically Significant Abnormalities – Safety Set 
Post-Randomization – Suboptimal Responders 
Table 14.3.4.4.2.1 
Vital Signs – Actual and Change from Baseline – Safety Set Post-
Randomization – Optimal Responders 
Table 14.3.4.4.2.2 
Vital Signs: Potentially Clinically Significant Abnormalities – Safety Set 
Post-Randomization – Optimal Responders 
Table 14.3.4.5.1 
Subjective Opiate Withdrawal Scale (SOWS) – Actual and Change from 
Baseline – Safety Set Post-Randomization – Suboptimal Responders 
Table 14.3.4.5.2 
Subjective Opiate Withdrawal Scale (SOWS) – Actual and Change from 
Baseline – Safety Set Post-Randomization – Optimal Responders 
Table 14.3.4.6.1 
Clinical Opiate Withdrawal Scale (COWS): Actual and Change from 
Baseline – Safety Set Post-Randomization – Suboptimal Responders  
Table 14.3.4.6.2 
Clinical Opiate Withdrawal Scale (COWS): Actual and Change from 
Baseline – Safety Set Post-Randomization – Optimal Responders  
Table 14.3.4.7.1.1 
Columbia-Suicide Severity Rating Scale: Suicidal Behavior Descriptive 
Summary – Safety Set Post-Randomization – Suboptimal Responders 
Table 14.3.4.7.1.2 
Columbia-Suicide Severity Rating Scale: Suicidal Ideation and Suicidality 
Descriptive Summary – Safety Set Post-Randomization – Suboptimal 
Responders 
Table 14.3.4.7.2.1 
Columbia-Suicide Severity Rating Scale: Suicidal Behavior Descriptive 
Summary – Safety Set Post-Randomization – Optimal Responders 
Table 14.3.4.7.2.2 
Columbia-Suicide Severity Rating Scale: Suicidal Ideation and Suicidality 
Descriptive Summary – Safety Set Post-Randomization – Optimal 
Responders 
 
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OPC, 2065-5
Clinical Study Report version: Final
Page 72 of 73


1004904A 
 
 
Opioid PMR Consortium 
Protocol: 2065-5 
SAP v1.3 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.01     
  INC Research © LLC 
Page 72 of 72 
19. 
INDEX OF LISTINGS 
Number 
Name 
Listing 16.2.1 
Subject Disposition 
Listing 16.2.2 
Protocol Deviations 
Listing 16.2.3 
Eligibility Criteria 
Listing 16.2.4.1 
Demographic and Baseline Characteristics 
Listing 16.2.4.2 
Medical History 
Listing 16.2.4.3 
Pre-Enrollment Prior Opioid Medications 
Listing 16.2.4.4 
Pre-Enrollment Prior Non-opioid Medications  
Listing 16.2.4.5 
Prior and Concomitant Medications 
Listing 16.2.4.6 
Prior and Concomitant Medications ATC Level and Associated Verbatim 
Terms 
Listing 16.2.5.1 
Study Drug Administration 
Listing 16.2.5.2 
MADDERS Supplemental Drug Accountability 
Listing 16.2.6.1 
Pain Intensity on NRS 
Listing 16.2.6.2 
Endocrine Laboratory Tests and Sexual Function Questionnaire 
Listing 16.2.6.3 
Quantitative Sensory Testing (QST) 
Listing 16.2.6.4 
Early Discontinuation Assessment Tool 
Listing 16.2.7.1 
Adverse Events 
Listing 16.2.7.2 
Abuse-related Events 
Listing 16.2.7.3 
Abuse-related Events from MADDERS Supplemental 
Listing 16.2.7.4 
Serious Adverse Events 
Listing 16.2.7.5 
Adverse Events Leading to Study Discontinuation 
Listing 16.2.7.6 
Adverse Events for Subjects with Potentially Clinically Significant (PCS) 
Abnormal Laboratory Values 
Listing 16.2.7.7 
Adverse Events for Subjects with Potentially Clinically Significant (PCS) 
Abnormal Vital Sign Values 
Listing 16.2.7.8 
Adverse Events Preferred Terms and Associated Verbatim Terms 
Listing 16.2.8.1 
Laboratory Test – Chemistry 
Listing 16.2.8.2 
Laboratory Test – Hematology 
Listing 16.2.8.3 
Laboratory Test – Urinalysis 
Listing 16.2.8.4 
Laboratory Test – Urine drug testing (UDT) 
Listing 16.2.8.5 
Laboratory Test – Pregnancy Test 
Listing 16.2.8.6 
Vital Signs 
Listing 16.2.8.7 
Subjective Opioid Withdrawal Scale (SOWS) 
Listing 16.2.8.8 
Clinical Opioid Withdrawal Scale (COWS) 
Listing 16.2.8.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Listing 16.2.8.10 
12-Lead ECG 
Listing 16.2.8.11 
Abnormal Physical Examination Results 
 
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Clinical Study Report version: Final
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