Conditions: Moderate-severe Pain
Keywords: Pediatric pain indication controlled release morphine
Enrollment: 19
Healthy volunteers: no

Brief summary:
Safety and pharmacokinetics of an abuse-deterrent, extended-release formulation of morphine sulfate with a sequestered naltrexone core in children 7-17 with moderate-severe pain.

Detailed description:
Subjects, once stabilized to Embeda, need only complete a minimum of 2 of the 6 week study duration to satisfy the PK endpoint. A safety follow-up visit is required at 1 week post-last dose.

Arms:
arm 1: One arm, open label, active

Interventions: intervention 1: Ages 7-11 intervention 2: ages 12-17
Intervention descriptions: intervention 1: Oral/Capsule, once per day or twice per day dosing; Treatment duration consists of a 1 to 4 week Conversion/Titration Phase leading to a 2 to 6 week Maintenance Treatment duration. intervention 2: Oral/Capsule, once per day or twice per day dosing; Treatment duration consists of a 1 to 4 week Conversion/Titration Phase leading to a 2 to 6 week Maintenance Treatment duration.

Protocol document:
Prot_000.pdf: 
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CLINICAL PROTOCOL
AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND 
PHARMACOKINETICS OF PF-06412528 IN CHILDREN 7-17 YEARS FOR THE 
TREATMENT OF MODERATE-TO-SEVERE PAIN
Compound:
PF-06412528
Compound Name:
EMBEDA® (morphine sulfate and naltrexone 
hydrochloride) Extended Release Capsules
European Clinical Trial Database 
(EudraCT) Number:
N/A
Protocol Number:
B4541006
Phase:
4
CCI


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Document History
Document
Version Date
Summary of Changes
Amendment 2
26 May 2015
A substantial change will be preceded by (SC). All other 
changes are administrative changes as required by the latest 
protocol template. 
Title 
Removed the word “chronic” from the title and throughout the 
protocol, to improve recruitment by expanding the subject 
population to subjects with moderate-to-severe post-surgical 
pain requiring around-the-clock opioid therapy based on 
investigators feedback.
Protocol Summary
Endpoints
Primary

(SC) Pharmacokinetics: volume of 
distribution (Vd/F) deleted and changed to
“average concentration at steady-state
(Css, av),” the low fluctuation in plasma 
concentration-time profile of morphine and 
the sparse PK Sampling schedule do not 
support an estimation of Vd/F analysis.
Study Design
Added

Safety Assessment

Pharmacokinetic Assessment

Safety Analysis

Pharmacokinetic Analysis 
(SC) Pharmacokinetics: Vd/F added here 
data permitting.
Sections 3.3 and 6.3: (SC) Added PK collections to 
Visit 6/ET, to accommodate PK sample at early withdrawal if 
not obtained at Visit 4, which was not provided in 
Amendment 1.
Section 4.1 Inclusion Criteria
2. (SC) “…confirmed moderate-to-severe chronic
pain (of cancerous or non-cancerous origin) requiring 
around-the-clock treatment with an opioid analgesic 
for an extended period of time.” changed to
“confirmed moderate-to-severe pain requiring 
around the-clock treatment with an opioid analgesic, 
”to remove “chronic and allow for the recruitment of 
post-surgery subjects.”
3.  (SC) “…5 consecutive days” changed to
“3 consecutive days” to expand the subject population 
and to align with the post-surgical days requirement. 


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Most post-surgery subjects will be switched to an 
extended release opioid within 48 to 72 hours if
around-the-clock treatment with an opioid analgesic is 
required.
Section 4.2 Exclusion Criteria
8. (SC) “Undergone major surgery within past 
30 days…” changed to “…past 3 days….,” based on 
feedback from Embeda investigators, subjects are not 
likely to be treated with ER opioids for 30 days.
11.  (SC) Clarified “subject endorses a 4 or 5 on the 
Columbia Suicide Severity Rating Scale,” to be 
consistent throughout the protocol.
12. (SC) Added “History of sleep apnea with the past 
year…, additional safety measure.
13. (SC) Added ALT and AST 3 x upper limit of 
normal.., additional safety measure.
14. (SC) Added “Epidural opioid <2 hours prior to 
the first dose of study drug,” additional safety 
measure to prevent respiratory depression.
15. (SC) Added “Planned surgery during the course 
of the study,” additional safety measure.
Section 4.3 Life Style Changes wording is modified, to adjust 
the pregnancy wording for the age group of the subjects.
Section 5.2 Subject Compliance wording is modified, to set 
guidelines to aid the investigator.
Section 5.6 Study Drug Accountability is modified, to set 
guidelines to aid the investigator.
Section 5.7 (SC) Concomitant medications modified, to clarify 
allowed and prohibited medications.
Section 6.2 Treatment Periods description is modified, to 
simplify the protocol. 
Section 6.3 Addition and description of Early Termination Visit 
and Procedures, to ensure final safety assessments are performed 
and PK sample for subjects who withdraw if not done are 
obtained.
Section 6.4 Combined Post Treatment Visit 7 and End of Study 
Visit 8, to reduce the duration from 21 days to 7 days post the 
Last Treatment Visit.
Section 6.5 Subject Withdrawal is modified, to provide more 
details to aid investigator in handling subjects who withdraw.
Section 6.6 Lost to Follow-Up is modified, to provide more 
details to aid investigator.
Section 8.4 Medication Errors is modified and moved, to 
provide more clarity.
Section 8.11 Occupational Exposure is added, to provide 


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guidance for possible AE.
Section 9 Data Analysis/Statistical Methods
(SC) Deleted “Unless otherwise indicated, any 
statistical tests performed will be 2-sided and 
differences resulting in a p-value 0.05 will be 
considered statistically significant,” as there are no 
statistical analyses performed in the study.
Appendix 1: Abbreviation table added per new template.
Appendix 2: Becomes Conversion Guide.
Appendix 3: Becomes C-SSRS Children’s Lifetime/Recent.
Appendix 4: Becomes C-SSRS Baseline/Screening.
Appendix 5: (SC) C-SSRS Baseline replaced with
Baseline/Screening. Baseline instrument was inserted in error.
Appendix 6: Becomes C-SSRS Since Last Visit.
Amendment 1
05 November 2013
Substantial changes reflect 2 points of advice from FDA (letter 
dated 08/28/2013) from the Division of Anesthesia, Analgesia, 
and Addiction Products.  They are: 1) a minimum requirement 
of 100 subjects exposed to a minimum of two weeks of 
PF-06412528 in the Maintenance Phase and 2) Perform the 
suicidality assessment (ie, C-SSRS) at every scheduled visit.  
To comply with FDA, Pfizer has modified the Maintenance 
Phase to 6 weeks, which includes the FDA 2-week minimum 
as described in the Statistical Analysis Plan and no more than 
6 weeks to facilitate recruitment.  A substantial change will be 
preceded by (SC).
Administrative changes include any grammatical/syntax and 
minor clarifying changes pertinent to FDA advice.  An 
administrative non-significant change will be preceded by 
(NSC).
Protocol Summary
-Study Design

Completers defined as subjects completing at least 
2 weeks of maintenance treatment for this 6-week study.
--Sample Size Determination

(SC) Reference to “100 subjects enrolled” changed to
“140 subjects” to account for a 40% discontinuation rate.

(SC) “An approximately similar number of subjects will 
be enrolled in each of the two age groups (7-11 years old 
and 12-17 years old)” changed to “…at least 100 subjects 
completing at least 2 weeks of the Maintenance Phase with 
neither age group exceeding a 3:1 margin compared to the 
other age group (7-11 years old and 12-17 years old).”

(SC) “N=50 subjects per age group” changed to


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“100 subjects”
--Safety Analysis

(NSC) Figure 1 modified to accommodate FDA advice on 
shorter study duration.

(SC) Reference to “100 subjects enrolled” changed to
“140 subjects” to account for a 40% discontinuation rate.

(NSC) Internal Review Committee replaces Data 
Monitoring Board.
Schedule of Activities

(NSC) Table modified to accommodate FDA advice on 
shortening study.
Section 3. Study Design

(NSC) References to study durations (and table) modified 
to accommodate shortened study.

(NSC) Figure 2 deleted due to complexity in 
understanding. Schedule of Activities will act in its place.

(SC) Reference to “100 subjects enrolled” changed to
“140 subjects” to account for a 40% discontinuation rate.
Section 3.2. Treatment Period

(SC) Stable dose definition refined by adding a time 
element (5 to 7 days).

(NSC) References to treatment durations changed from
12 weeks to 10 weeks.
Section 3.2.1. Conversion/Titration Phase

(SC) Time element (5 to 7 days) added to stable dose 
definition.
Section 3.2.2. Maintenance Phase (Visit 4-7 a-c)

(NSC) “(Visit 4-7 a-c)” in section header changed to
“(Visit 4-6)”. 

(NSC) The Maintenance Phase of the study will begin as 
subjects reach a stable dose of PF-06412528 without the 
need for immediate-release morphine as rescue and will 
continue an additional 8 to 11 weeks to ensure that 
subjects are exposed to a total of 12 weeks of 
PF-06412528 treatment” changed to “The Maintenance 
Phase of the study will begin as subjects reach a stable 
dose of PF-06412528 without the need for 
immediate-release morphine as rescue and will continue 
an additional 6 weeks to ensure that subjects completed 
the Treatment Period.”

(SC) “To ensure that subjects receive a total of 12 weeks 


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of treatment, subjects who reach stable dose at Visit 3a, 
3b, 3c or 3d will continue in the study until Visits 7c, 7b, 
7b, or 7a, respectively” changed to “To ensure that 
subjects receive a total of 6 weeks of treatment, subjects 
who reach stable dose at Visit 3a, 3b, 3c or 3d will 
continue in the study until Visit 6 is completed.”

(SC)” During the Maintenance Phase visits are separated 
by 14 2 days, except for subjects who reach a stable dose 
at Visit 3a, where the interval between Visit 7b and 7c will 
be only 7 days 2 days and subjects who reach a stable 
dose at Visit 3c, where the interval between Visit 7a and 
7b will be only 7 days 2 days.” changed to During the 
Maintenance Phase visits are separated by 14 2 days.” 
due to visits no longer needed.

(NSC) Unscheduled visits at “Visit 5” changed to
“Visit 7.”

(NSC) “8-11 weeks” changed to “6 weeks.” to 
accommodate shortened study.

(NSC) “At the final Maintenance Phase visit (Visit 7a, 7b, 
or 7c; Day 84 2 days), which is contingent on when a 
subject achieved a stable dose, the investigator will 
discontinue the subject’s PF-06412528 therapy and 
convert the subject back to their standard of care of opioid 
therapy.  A Post-Treatment visit will be scheduled in 
7 2 days (Visit 8) and a health status telephone contact 
(End of Study) will be made 28 2 days (Visit 9) 
following last dose” changed to “At the final Maintenance 
Phase visit (Visit 6), which is contingent on when a 
subject achieved a stable dose, the investigator will 
discontinue the subject’s PF-06412528 therapy and 
convert the subject back to their standard of care of opioid 
therapy.  A Post-Treatment visit will be scheduled in 
7 2 days (Visit 7) and a health status in-clinic or 
telephone contact (End of Study) will be made 28 2 days 
(Visit 8) following last dose.”
Section 3.3 Post-Treatment Period

(NSC) Visit 8 changed to Visit 7.
Section 3.4 End of Treatment Period

(NSC) Header changed to “End of Study Period”.

(NSC) “Visit 9” changed to “Visit 8”.
Section 4.1. Inclusion Criteria

(SC) #3: “Be an experienced opioid user, defined as any 
subject who has been on around-the-clock opioid therapy, 
equivalent to 20 mg per day of morphine, for a period of 
at least 2 weeks immediately prior to Screening” changed 
to “Be an experienced opioid user, defined as any subject 


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who has been on around-the-clock opioid therapy, 
equivalent to 20 mg per day of morphine, for a period of 
5 consecutive days immediately prior to Screening.”
Section 4.6 Rater Qualifications

(SC) New section added for C-SSRS assessments.
Section 5.3.3. Administration

(NSC) Reference to DAI manual for instructions on how 
to administer study drug via apple sauce.
Section 5.5.2. Prohibited Medications and Therapies

(SC)  Added the exception that the use of IR morphine in 
the Maintenance Phase would be acceptable.  Rationale: 
any exacerbation of pain where IR morphine would be 
needed will not be a reason to discontinue subject.
Section 6 Study Procedures

Subjects/caregivers will be asked to complete a diary each 
day in the evening before going to bed during the 
Conversion/Titration Phase of the study changed to
subjects/caregivers will be asked to complete a diary each 
day during the Treatment and Post-Treatment Phases of 
the study.  Rationale: No time element for completing the 
diary.  Only the pain NRS was required to be recorded at 
bedtime in the diary.
Section 6.1. Screening Period (Day -14 to -1)

(SC) The phrase of “Suicidality Assessment” changed to
“Suicide Ideation and Behavior (SIB)” Assessment.

Added C-SSRS Children’s Lifetime/Recent”.

Added C-SSRS Screening version (for 12-17 years).
Section 6.2.1 Conversion/Titration Phase

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS) -(Section 7.4.1):

Children’s Since Last Visit (Ages 7-11) 
(Version 6/23/10)-(Appendix 4).

Baseline (Ages 12-17) (Version 
1/14/09)-(Appendix 5).
Visit 3a (Day 7 2 Days)

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS) -(Section 7.4.1):

Children’s Since Last Visit (Ages 7-11) 


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(Version 6/23/10)-(Appendix 4).

Since Last Visit (Ages 12-17) 
(Version 1/14/09)-(Appendix 6).
Visit 3b (Day 14 2 Days)

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS) -(Section 7.4.1): 

Children’s Since Last Visit (Ages 7-11) 
(Version 6/23/10)-(Appendix 4).

Since Last Visit (Ages 12-17) 
(Version 1/14/09)-(Appendix 6).

(NSC) Section for Converted Subjects: “Visit 4 (Day 21)” 
changed to “Day 28”.
Visit 3c (Day 21 2 Days)

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS) -(Section 7.4.1):

Children’s Since Last Visit (Ages 7-11) 
(Version 6/23/10)-(Appendix 4).

Since Last Visit (Ages 12-17) 
(Version 1/14/09)-(Appendix 6).

(NSC) Section for Converted Subjects: “Visit 4 (Day 21)” 
changed to “Day 35”.
Visit 3d (Day 28 2 Days)

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS) -(Section 7.4.1):

Children’s Since Last Visit (Ages 7-11) 
(Version 6/23/10)-(Appendix 4).

Since Last Visit (Ages 12-17) 
(Version 1/14/09)-(Appendix 6).

(NSC) Section for Converted Subjects: “Visit 4 (Day 21)” 
changed to “Day 42”.
Section 6.3. Maintenance Phase
Visit 4 (Day 21 2 days, Day 28 2 days, Day 35 2 days, or 
Day 42 2 days

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS) -(Section 7.4.1):

Children’s Since Last Visit (Ages 7-11) 


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(Version 6/23/10)-(Appendix 4).

Since Last Visit (Ages 12-17) 
(Version 1/14/09)-(Appendix 6).
Visit 5 (Day 352 days, 422 days, 492 days, or 562 days)

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS)-(Section 7.4.1).

Children’s Since Last Visit (Ages 7-11) 
(Version 6/23/10)-(Appendix 4).

Since Last Visit (Ages 12-17) 
(Version 1/14/09)-(Appendix 6).
Visit 6 (Day 492 days, 562 days, 632 days, or 702 days)

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS)-(Section 7.4.1).

Children’s Since Last Visit (Ages 7-11) 
(Version 6/23/10)-(Appendix 4).

Since Last Visit (Ages 12-17) 
(Version 1/14/09)-(Appendix 6).
(SC) Due to FDA advice on shortening the study Visits 7a, 
7b, 7c were deleted. Visit 7 is now included under 
Section 6.4 Post-Treatment period.
Section 6.4 Post-Treatment Period

(NSC) Visit 8 change to Visit 7 (562 days, 632 days, 
702 days, or 772 days).

(SC) Deleted 12-lead ECG. Rationale: Will insert into 
protocol “for-cause” only.

(SC) Deleted Urine Drug Test as it has no value at this 
time point.

(SC) Added “Suicide Ideation and Behavior (SIB) 
Assessment”: Columbia-Suicide Severity Rating Scale 
(C-SSRS) -(Section 7.4.1):

Children’s Since Last Visit (Ages 7-11) 
(Version 6/23/10)-(Appendix 4).

Since Last Visit (Ages 12-17) 
(Version 1/14/09)-(Appendix 6).

(SC) added “in-clinic” pain intensity score.

(NSC) Added “Assess Treatment Response” to match 
Schedule of Activities.


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Section 6.5. End of Study Period

(NSC) Visit 9 (Day 1122 days or 282 Days After Last 
Dose) changed to Visit 8 ((Day 772 days, 842 days, 
912 days or 982 days.
Section 6.6. Subject Withdrawal

(SC) Added protocol-specific language for suicide 
ideation/behavior.
Section 7.1.1. Pain Intensity

(NSC) Appendix 3 changed to Appendix 7 due to addition 
of C-SSRS.
Section 7.1.2. Rescue Medication Use

(SC) Added that rescue medication will be recorded in 
Maintenance Phase as well.
Section 7.2.4. Electrocardiogram

(SC) Added new wording for how to perform the ECG.
Section 7.2.5. Clinical Opiate Withdrawal Scale (COWS)

(NSC) Appendix 4 changed to Appendix 8.
Section 7.2.7. Urine Drug Test

(SC) Added that an opioid finding at the Screen and 
Baseline visits is an expected results due to a subject still 
taking their SOC medication.  An illicit drug finding is a 
reason to screen fail a subject. 
Section 7.3. Pregnancy Testing

(SC) Urine pregnancy test at Visits 2-7 changed to
Visits 2-6 due to shortened study.
Section 7.4.1. Columbia-Suicide Severity Rating Scale 
(C-SSRS)-Lifetime

(SC) Entire section replaced with revised section due to 
FDA advice.
Section 7.5.1. Blood Sample Collection and Handling

(SC) Second bulleted paragraph devoted to collection 
procedures and storage temperatures deleted due to the 
procedures not validated for morphine.  Reader is referred 
to the central laboratory procedure manual for mixing and 
storage information.
Section 9.1. Sample Size Determination

“The study plans to enroll 100 pediatric subjects for the 
purpose of establishing a safety database, with as many 


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subjects as possible being exposed to 12 weeks of therapy 
with PF-06412528 and an approximately similar number 
of subjects enrolled in each of the two age groups 
(7-11 years old and 12-17 years old)” changed to “The 
study plans to enroll approximately 140 subjects for the 
purpose of establishing a safety database, with at least 
100 subjects completing at least 2 weeks of the 
Maintenance Phase with neither age group exceeding a 
3:1 margin compared to the other age group (7-11 years 
old and 12-17 years old)”.
Section 9.6. Data Management Committee

(SC)All references to Data Monitoring Committee or 
DMC change to Internal Review Committee or IRC, 
respectively.
Appendices

All reordered due to addition of C-SSRS instruments.
Original Protocol
11 April 2013
N/A


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PROTOCOL SUMMARY
Background and Rationale:
PF-06412528 capsules consist of controlled-release pellets containing morphine sulfate and 
naltrexone hydrochloride.  The pellets are designed to release morphine in an 
extended-release manner over time while retaining naltrexone, a mu-opioid antagonist, in the 
inner core unless the inner core is disrupted.  Upon crushing or chewing the pellets, 
naltrexone is released along with the morphine thereby attenuating the liking and euphoric 
effects of the opioid.  
 
 The drug was developed with 
the potential to decrease the misuse, abuse, and diversion of prescription opioids, a public 
health problem among many age groups including adolescents. 
One of the major challenges facing clinicians who wish to prescribe pain medications to 
children is the paucity of information in the pediatric population about the proper choice of 
pain medication, dosage guidelines, and expectations with regard to efficacy and untoward 
effects.  Efforts to address this challenge include the Best Pharmaceuticals for Children Act 
(BPCA) and the Pediatric Research Equity Act (PREA).
The use of morphine to treat pain in pediatric patients with cancer is well recognized.  
However, the increasing use of morphine in children to treat other forms of moderate to 
severe pain (eg, neurological pain) has become apparent only during the past decade.  During 
that same period, new extended-release opioid dosage forms have found their way to the 
market with only limited information about their use in pediatric patients.  Therefore, in 
addition to meeting regulatory requirements, there is an unmet therapeutic need to research 
the safe and effective use of all extended-release opioid products in children.  The present 
study is intended to evaluate the safety and characterize the pharmacokinetics (PK) of
PF-06412528 in children 7 to 17 years of age who require opioid analgesia for 
moderate-to-severe pain. 
Objectives:
Primary
•
To demonstrate the safety of PF-06412528 in children 7 to 17 years of age treated 
with PF-06412528 for moderate-to-severe pain.
•
To characterize the PK of morphine in children 7 to 17 years of age treated with 
PF-06412528 for moderate-to-severe pain.
Secondary
•
To determine the exposures of naltrexone and 6-β-naltrexol in children 7 to 17 years 
of age treated with PF-06412528 for moderate-to-severe pain.
CCI


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Endpoints:
Primary

Safety: incidence, intensity, relationship, and seriousness of adverse events (including 
symptoms of opioid toxicity or withdrawal) during treatment with PF-06412528.

Pharmacokinetics: population PK of morphine apparent clearance (CL/F) and 
average concentration at steady-state (Css, av) following treatment with PF-06412528.
Secondary

Safety: changes in vital signs (pulse rate, blood pressure, respiratory rate), clinical 
chemistry, and hematology laboratory values.

Pharmacokinetics: morphine apparent volume of distribution (Vz/F, data permitting)
and systemic exposure levels of the metabolites of morphine (morphine-3-glucuronide 
[M3G] and morphine-6-glucuronide [M6G]), naltrexone, and 6--naltrexol,  
following multiple-dose treatment with PF-06412528.
Other

Analgesic Effect: pain intensity scores (Appendix 7); actual and percentage change 
from baseline) and rescue medication or additional analgesic medication use over 
time. 

Pharmacokinetics: graphical representations and regression analyses may be used to 
characterize the dose-exposure relationships for morphine, naltrexone, and 
6--naltrexol data permitting.
Study Design:
This is a multicenter, 6-week, open-label, single-arm study to demonstrate the safety and 
characterize the PK of PF-06412528 in children 7 to 17 years of age, with 
moderate-to-severe pain. The study will enroll approximately 140 children to obtain at least
100 subjects exposed to study treatment for at least 2 weeks in the Maintenance Phase.  
Plasma samples will be collected during the Maintenance Phase at 2 time points under 
steady-state conditions to characterize the PK of morphine and determine the systemic 
exposures of naltrexone and 6--naltrexol.
Assessments:
Safety Assessments
Before admission to the study, subjects will undergo a physical examination and a round of 
testing procedures/measurements including 12-lead electrocardiogram (ECG), blood 
pressure, pulse rate, respiratory rate, and clinical and laboratory testing.  During the study,


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the investigator will pay close attention to monitoring for adverse events including, but not 
limited to, opioid overdose (toxicity) and/or signs and symptoms of opioid withdrawal.
Pharmacokinetic Assessments
Once the subjects have achieved a stable dose of PF-06412528, two blood samples will be 
taken at two time points post-dose at least two hours apart during Visit 4 to characterize the 
PK of morphine and its metabolites and determine the exposure levels of naltrexone and 
6-β-naltrexol.
Statistical Method:
Sample Size Determination
The study plans to enroll approximately 140 subjects for the purpose of establishing a safety 
database, with at least 100 subjects exposed to study drug for at least 2 weeks in the 
Maintenance Phase with neither age group exceeding a 3:1 margin compared to the other age 
group (7-11 years old and 12-17 years old).  Likewise, the study plans to evaluate the PK of 
morphine in all subjects that provide plasma samples.
 
 
 
  
Pharmacokinetic Analysis
Given the very low fluctuation in steady-state morphine concentrations following 
PF-06412528 BID dosing, the concentrations observed during the Maintenance Phase will be 
used as an estimate of Css,av of morphine and its metabolites (data permitting) in pediatric
subjects. The CL/F of morphine will be estimated using a ratio of the daily dosing rate of 
PF-06412528 and the estimates of morphine Css,av in the Maintenance Phase. The 
concentration-time dataset will be analyzed to obtain estimates for Vz/F of morphine in 
pediatric subjects, data permitting. Covariates of interest (PF-06412528 dosage, age, body 
weight, gender, concomitant medications etc) will be assessed for their ability to account for 
the observed variability in morphine Css,av. 
The observational data will be summarized using descriptive statistics (mean, standard 
deviation, median, minimum, and maximum) for the study group as a whole. Data 
permitting, graphical representations and regression analyses may be used to characterize the 
dose-exposure relationships for morphine, naltrexone, and 6-β-naltrexol.
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Safety Analysis
No formal hypothesis testing of safety data will be performed.  The safety population 
comprises all subjects in the Treatment Period who receive at least one dose of PF-06412528.
Results from the safety assessments and any adverse events will be presented in tabular 
and/or graphic form adhering to current Pfizer Data Standards.
Pfizer Data Standards will be used to provide safety summaries on treatment emergent 
adverse events (AE).  In addition, demographics and other safety endpoints (labs, ECG, and 
vital signs) will be summarized using the following descriptive statistics: N, mean, median, 
standard deviation, and minimum and maximum for continuous variables, and subject counts 
and percentages for categorical variables.  In particular, presentations for the assessments of 
objective signs and symptoms of opioid withdrawal [Clinical Opiate Withdrawal Scale
(COWS); Appendix 8] will be presented in tabular and/or graphic form adhering to current 
Pfizer Data Standards. 
An Internal Review Committee (IRC) will be established for the purpose of reviewing safety 
information on an ongoing basis in accordance with Standard Operating Procedures. The 
IRC will be responsible for ongoing monitoring of the safety of subjects in the study 
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to titrate study 
drug or conduct evaluations/assessments required to protect the wellbeing of the subject.
Periods
Screening
(2 Wks)
Treatment
Post-Treatment
Follow Up/ /EOS
(Clinic)
(1 Wk)
Conversion/Titration Phase
(1 to 4 Wks)
Maintenance Phase
(2-6 Wks)
Scheduled Visits
Visit
Day ±Allowable Window
1
2
3a 1
3b 2
3c 2
3d 2
4
5
6/ET
7
-14 to -1
1
72
NR
NR
NR
212
352
492
562
142
NR
NR
282
422
562
632
212
NR
352
492
632
702
282
422
562
702
772
Activities
Informed Consent/Assent 3
X
Inclusion/Exclusion Criteria (Sections 4.1 and 4.2)
X
Demographics
X
Medical History
X
Opioid Therapy Review 
X4
X5
Safety
Physical Examination (Section 7.2.6)
X
X
Clinical Laboratory Tests (Section 7.2.3)
X
X
Pregnancy Test (Section 7.3)
X6
<---------------------------------X7---------------------------------------->
X6
Urine Drug Test (Section 7.2.7)
X
Single, 12–lead ECG 8 (Section 7.2.4)
X
Vital Signs (Section 7.2.2)
X
X
X
X
X
X
X
X
X
Suicide Ideation and Behavior (SIB) 
X
X
X
X
X
X
X
X
X
X


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Periods
Screening
(2 Wks)
Treatment
Post-Treatment
Follow Up/ /EOS
(Clinic)
(1 Wk)
Conversion/Titration Phase
(1 to 4 Wks)
Maintenance Phase
(2-6 Wks)
Scheduled Visits
Visit
Day ±Allowable Window
1
2
3a 1
3b 2
3c 2
3d 2
4
5
6/ET
7
-14 to -1
1
72
NR
NR
NR
212
352
492
562
142
NR
NR
282
422
562
632
212
NR
352
492
632
702
282
422
562
702
772
Activities
Assessment9 (Section 7.4.1)
COWS (Section 7.2.5)
X
X
X
X
X
X
X
X
X
Concomitant Medication (Section 5.7)
X
X
X
X
X
X
X
X
X
Adverse Events10 (Section 7.2.1)
X
X
X
X
X
X
X
X
X
X
Treatment Response
Pain Intensity (In-Clinic) (Section 7.1.1)
X
X
X
X
X
X
X
X
Review Diary Information11
X
X
X
X
X
X
X
Pain Intensity (Diary Review) 
X
X
X
X
X
X
X
Rescue Medication (Diary Review)
X
X
X
X
X
X
X
Concomitant Medication (Diary Review)
X
X
X
X
X
X
X
Study Drug Use (Diary Review)
X
X
X
X
X
X
X
Adverse Events (Diary review)
X
X
X
X
X
X
X
Plasma Sample (Section 7.5.2)12
X
X13
Caregiver Training and Subject Instruction
X
Dose Conversion Calculation13
X
Dispense Study Drug
X
X
X
X
X
X
X
Prescribe Rescue Medication (as necessary)
X
X
X
X
X
X
X
X
Dose Titration (as needed)
X
X
X
X
Drug Accountability
X
X
X
X
X
X
Early Withdrawal Subjects13,15
X
Weekly Telephone call16
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Min = Minimum; Max = Maximum; NR = Not Required; EOS = End of Study; ECG = Electrocardiogram; ET = Early Termination; COWS = Clinical Opiate Withdrawal 
Scale; PK = Pharmacokinetics, Wks= Weeks
1.
Visit 3a is a mandatory visit. 
2.
Visits 3b, 3c, and 3d are required only if further dose titrations are required to reach a stable dose.  Subjects must reach a stable dose of PF-06412528 on or 
before Visit 3d to be eligible to start the 6-week Maintenance Phase.  Unscheduled visits during the Treatment Period for purposes of dose adjustment will, 
at a minimum, require a NRS pain scale and a COWS score on subjects. An unscheduled visit for an AE will require performing the Visit 6 procedures. 
3.
Informed consent must be provided by the subject’s caregiver (parent or legal guardian). Subjects are required to provide their assent.
4.
Review the subject’s pre-study standard of care (SOC) therapy and record on the appropriate case reporting form. 
5.
SOC therapy is required to stop on this visit. Record these changes on the appropriate case reporting form.
6.
Serum pregnancy test for a qualified female of childbearing potential (Section 7.3).
7.
Urine pregnancy test for a qualified female of childbearing potential (Section 7.3).
8.
ECGs performed post-baseline are acceptable when performed “for-cause”. 
9.
Refer to Section 7.4.1 for the correct Columbia-Suicide Severity Rating Scale to apply for a given age group.
10. Record serious adverse events from the signing of the informed consent. Non-serious AEs are recorded from first dose of study drug. Review and transcribe 
Caregiver adverse findings from the Daily Diary to the appropriate case reporting form. Follow up on all SAEs through and including 28 calendar days post 
the last dose of study drug (Section 8.2). Follow up requirements for non-serious AEs (Section 8.1).
11. Review all sections of the Daily Diary as part of the Caregiver Training and Subject Instruction. Issue a new diary at each scheduled visit. Weekly phone 
contact between visits to review diary entries.  Call must be documented in source.
12. Two plasma samples for PK analysis will be collected at least 2 hours apart.   
13. Request PK samples (Section 7.5.1) of early termination subjects if not acquired at Visit 4.
14. Consult Appendix 2 of the protocol for the PF-06412528 Conversion Guide.  The investigator must figure the conversion to PF-06412528 by Visit 2.
15. Subjects prematurely withdrawing from the Treatment Period regardless of reason (eg, failure to achieve a stable dose, lack of efficacy, AE) are requested to 
fulfill the Visit 6 procedures and activities.  Early withdrawal subjects will be converted back to their pre-study SOC medication or alternate pain therapy, at 
the discretion of the investigator.
16. Weekly telephone contact with the caregiver must be documented in source. 


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................23
LIST OF FIGURES .................................................................................................................23
APPENDICES .........................................................................................................................23
1. INTRODUCTION ...............................................................................................................24
1.1. Mechanism of Action/Indication.............................................................................24
1.2. Background .............................................................................................................24
1.3. Morphine .................................................................................................................24
1.4. Naltrexone ...............................................................................................................25
1.5. Additional Information............................................................................................26
1.6. Study Rationale .......................................................................................................26
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................27
2.1. Objectives................................................................................................................27
2.1.1. Primary .......................................................................................................27
2.1.2. Secondary ...................................................................................................27
2.2. Endpoints.................................................................................................................27
2.2.1. Primary .......................................................................................................27
2.2.2. Secondary ...................................................................................................28
3. STUDY DESIGN.................................................................................................................28
3.1. Screening Period .....................................................................................................29
3.2. Treatment Period.....................................................................................................29
3.2.1. Conversion/Titration Phase (Visits 2-3d)...................................................30
3.2.2. Maintenance Phase (Visit 4 – 6).................................................................30
3.2.3. Early Termination Visit..............................................................................31
3.3. Post-Treatment Period/End of Study Period ...........................................................31
4. SUBJECT SELECTION......................................................................................................31
4.1. Inclusion Criteria.....................................................................................................31
4.2. Exclusion Criteria....................................................................................................32
4.3. Life Style Guidelines...............................................................................................33
4.4. Caregiver(s).............................................................................................................34
4.5. Sponsor’s Qualified Medical Personnel..................................................................35
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4.6. Rater Qualifications.................................................................................................35
5. STUDY TREATMENTS.....................................................................................................36
5.1. Allocation to Treatment ..........................................................................................36
5.1.1. Opioid Toxicity and Withdrawal................................................................36
5.1.2. Signs and Symptoms of Opioid Toxicity....................................................36
5.1.3. Management of Opioid Toxicity ................................................................36
5.1.4. Signs and Symptoms of Opioid Withdrawal ..............................................37
5.1.5. Management of Opioid Withdrawal...........................................................37
5.2. Subject Compliance.................................................................................................37
5.3. Study Drug Supplies................................................................................................37
5.3.1. Dosage Form(s) and Packaging..................................................................37
5.3.2. Preparation and Dispensing........................................................................38
5.4. Administration.........................................................................................................38
5.5. Study Drug Storage .................................................................................................39
5.6. Study Drug Accountability......................................................................................40
5.6.1. Destruction of Study Drug Supplies...........................................................41
5.7. Concomitant Medication(s).....................................................................................41
5.7.1. Permitted Medications and Therapies ........................................................41
5.7.2. Prohibited Medications and Therapies .......................................................41
5.8. Rescue Medication ..................................................................................................42
6. STUDY PROCEDURES .....................................................................................................42
6.1. Screening Visit (Days -14 to -1) .............................................................................42
6.2. Treatment Period.....................................................................................................43
6.2.1. Conversion/Titration Phase ........................................................................43
6.2.2. Maintenance Phase .....................................................................................47
6.3. Early Termination Visit...........................................................................................48
6.4. Post Treatment/End of Study (EOS) Visit 7 ...........................................................48
6.5. Subject Withdrawal.................................................................................................48
6.6. Lost to Follow-Up (LTFU) .....................................................................................50
6.7. Unscheduled Visits for Pain, Adverse Events.........................................................50
7. ASSESSMENTS..................................................................................................................51
7.1. Analgesic Effect Assessments.................................................................................51


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7.1.1. Pain Intensity ..............................................................................................51
7.1.2. Rescue Medication Use ..............................................................................51
7.2. Safety Assessments .................................................................................................52
7.2.1. Adverse Events...........................................................................................52
7.2.1.1. Recording of Adverse Events by Investigator...........................52
7.2.1.2. Recording of Adverse Events Using a Home Diary .................52
7.2.2. Vital Signs ..................................................................................................52
7.2.3. Clinical Laboratory Tests ...........................................................................52
7.2.4. Electrocardiogram.......................................................................................53
7.2.5. Clinical Opiate Withdrawal Scale (COWS) ...............................................53
7.2.6. Physical Examination .................................................................................53
7.2.7. Urine Drug Test ..........................................................................................54
7.3. Pregnancy Testing...................................................................................................54
7.4. Assessment of Suicidal Ideation and Behavior.......................................................54
7.4.1. Columbia- Suicide Severity Rating Scale (C-SSRS)..................................54
7.5. Pharmacokinetic Evaluation....................................................................................56
7.5.1. Blood Sample Collection and Handling .....................................................56
7.5.2. Plasma Sample Shipment to Bioanalytical Laboratory ..............................56
7.6. Blood Volume .........................................................................................................56
8. ADVERSE EVENT REPORTING......................................................................................56
8.1. Adverse Events........................................................................................................56
8.2. Reporting Period .....................................................................................................57
8.3. Definition of an Adverse Event...............................................................................57
8.4. Medication Errors....................................................................................................58
8.5. Abnormal Test Findings..........................................................................................58
8.6. Serious Adverse Events...........................................................................................59
8.6.1. Potential Cases of Drug-Induced Liver Injury............................................59
8.7. Hospitalization ........................................................................................................60
8.8. Severity Assessment................................................................................................62
8.9. Causality Assessment..............................................................................................62
8.10. Exposure During Pregnancy..................................................................................62
8.11. Occupational Exposure .........................................................................................64


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8.12. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal)...............................................................................................................64
8.13. Eliciting Adverse Event Information ....................................................................64
8.14. Reporting Requirements........................................................................................64
8.14.1. Serious Adverse Event Reporting Requirements .....................................64
8.14.2. Non-serious Adverse Event Reporting Requirements..............................65
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities ...................65
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................65
9.1. Sample Size Determination.....................................................................................65
9.2. Efficacy Analysis ....................................................................................................66
9.3. Pharmacokinetic Analysis.......................................................................................66
9.3.1. Pharmacokinetic Analysis Datasets............................................................66
9.3.2. Pharmacokinetic Endpoints ........................................................................66
9.3.3. Pharmacokinetic Analysis ..........................................................................66
9.4. Safety Analysis........................................................................................................67
9.4.1. Adverse Events...........................................................................................67
9.4.2. Clinical Laboratory Values.........................................................................67
9.4.3. Electrocardiogram.......................................................................................67
9.4.4. Vital Signs ..................................................................................................67
9.4.5. Opiate Withdrawal......................................................................................67
9.4.6. Dosing and Compliance..............................................................................68
9.5. Interim Analysis ......................................................................................................68
9.6. Data Monitoring Committee ...................................................................................68
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................68
11. DATA HANDLING AND RECORD KEEPING .............................................................69
11.1. Case Report Forms/Electronic Data Record .........................................................69
11.2. Record Retention...................................................................................................69
12. ETHICS..............................................................................................................................70
12.1. Institutional Review Board/Ethics Committee......................................................70
12.2. Ethical Conduct of the Study ................................................................................70
12.3. Subject Information and Consent..........................................................................70
12.4. Subject Recruitment ..............................................................................................72


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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................72
13. DEFINITION OF END OF TRIAL...................................................................................72
13.1. End of Trial in all Participating Countries ............................................................72
14. SPONSOR DISCONTINUATION CRITERIA ................................................................72
15. PUBLICATION OF STUDY RESULTS..........................................................................72
15.1. Communication of Results by Pfizer ....................................................................72
15.2. Publications by Investigators ................................................................................73
16. REFERENCES ..................................................................................................................75
LIST OF TABLES
Table 1.
Clinical Laboratory Tests .....................................................................................52
LIST OF FIGURES
Figure 1.
Overall Study Design............................................................................................29
APPENDICES
Appendix 1. Abbreviations......................................................................................................77
Appendix 2. Conversion Guide................................................................................................79
Appendix 3. Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Lifetime/Recent (Version 6/23/10)-Age 7-11 ......................................................90
Appendix 4. Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
(Version 1/14/09)-Age12-17 ................................................................................93
Appendix 5. Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s Since Last 
Visit (Version 6/23/10)-Age 7-11.........................................................................96
Appendix 6. Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
(Version 1/14/09)-Age 12-17 ...............................................................................99
Appendix 7. Pain Numeric Rating Scale (NRS-Pain) ...........................................................102
Appendix 8. Clinical Opiate Withdrawal Scale (COWS)......................................................103


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06412528 (morphine sulfate and naltrexone hydrochloride) is a combination 
opioid/antagonist controlled-release product indicated for the management of pain severe 
enough to require daily, around-the-clock, long-term opioid treatment and for which 
alternative treatment options are inadequate.  Currently, the product is approved for adult use 
only.
PF-06412528 is not intended to be used for acute pain, as an as needed (prn) analgesic, or for 
pain that is mild or does not persist for an extended period of time.
1.2. Background
Moderate to severe pain associated with an underlying disease is a common complaint 
among children, affecting upwards of 15% to 20% of the pediatric population at one time or 
another.1,2 Unfortunately, for many children, pain may be untreated or undertreated, 
resulting too often in prolongation of suffering, disruption of the family routine, and 
continuation of long-term disability.2 For the clinician, the management of pain can 
represent a greater challenge than the treatment of the primary disease itself.  Surveys 
evaluating the pain experience in pediatric patients have shown children and adolescents can 
reliably communicate their pain experience by documenting the intensity, duration, and 
locations of the experience.  Consequently, one outcome of better understanding the pain 
experience in children and adolescents is physician recognition of the need to adequately 
treat pain in pediatric patients based on the patient’s response as is often done in adult 
patients experiencing moderate to severe pain.2,3,4,5,6,7
PF-06412528 capsules consist of controlled-release pellets containing morphine sulfate and 
naltrexone hydrochloride.  The pellets are designed to release morphine in an 
extended-release manner over time while retaining naltrexone, a mu-opioid antagonist, in the 
inner core unless the inner core is disrupted.  Upon crushing or chewing the pellets,
naltrexone is released along with the morphine thereby attenuating the liking and euphoric 
effects of the opioid.  
 
The study is being conducted as a Phase 4 post-marketing requirement by the Food and Drug 
Administration (FDA) consistent with ICH E11 guidelines for “Clinical Investigation of 
Medicinal Products in the Pediatric Population.”  
1.3. Morphine
The pharmacokinetics of morphine in PF-06412528 are characterized by a relatively slow 
absorption phase and prolonged pharmacokinetic disposition phase compared with an 
immediate-release (IR) formulation (oral morphine solution).8 Approximately 20 to 40% of 
an oral dose reaches the systemic circulation within 30 minutes following administration of 
an oral solution, compared with 8 hours following administration of an equivalent dose of 
PF-06412528.  Once absorbed, morphine is distributed to major organ systems throughout
the body including the brain.  However, while the central nervous system (CNS) represents 
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the primary site of action for the drug, only small quantities of morphine cross the blood 
brain barrier.  Morphine is extensively metabolized, primarily via glucuronidation, to 
multiple metabolites including morphine-3-glucuronide, M3G (approximately 50%) and 
morphine-6-glucuronide, M6G (approximately 5 to 15%), which are then largely excreted in 
the urine.  In adults, the mean plasma clearance of morphine is approximately 20 to 
30 mL/min/kg.8 The half-life of morphine is reportedly 2 hours following intravenous 
administration but significantly more prolonged following oral administration of a 
controlled-release product. 
 
  
 
  
 
 
 
 
In pediatric patients, the PK of morphine have been characterized in infants, pre-term infants, 
and neonates, usually following parenteral administration of morphine.9,10 In older children,
the PK of morphine have been characterized following oral therapy with morphine for cancer 
pain.11 The latter PK study was conducted in 40 children whose median age was 11.4 years 
(range 1.7 to 18.7 years).  Morphine sulfate was administered orally as either an IR liquid or 
sustained-release tablets at an average daily dose of 35 mg (1.4 mg/kg/day).  For the pediatric 
group as a whole, the population PK estimates of morphine apparent clearance and volume of 
distribution were 23.1 mL/min/kg and 5.2 L/kg, respectively.  Of interest, the apparent 
clearance of morphine was on average 1.7-fold higher in the group of children <11 years of 
age (n=18; mean age 6.3 years, range 1.7 to 9 years) compared with the children >11 years 
(n=22; mean age 13.8 years, range 11 to 18.7 years) making up the older group 
(37.4 mL/min/kg versus 21.9 mL/min/kg).  The average half-life of morphine for the 
pediatric group as a whole was 2.3 hours.  The analgesic properties of morphine in children 
and dosing guidelines for oral and parenteral administration have also been described in the 
literature.3,12
1.4. Naltrexone
Naltrexone is a mu opioid antagonist.  While absorbed orally, the drug is subject to 
significant first-pass metabolism, with absolute bioavailability estimates ranging from 5 to 
40%.  Both parent drug and active metabolite (6-β–naltrexol) contribute to the mu-opioid 
antagonistic activity of naltrexone.  Likewise, both parent drug and active metabolite are 
excreted in the urine (53% to 79% of the dose).  The elimination half-life of naltrexone is 
approximately 4 hours.
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Under normal dosing conditions with PF-06412528, clinical studies have shown that there is 
minimal systemic exposure of naltrexone when taken as directed.  In adult patients titrated up 
to 120 to 160 mg of PF-06412528 per day, naltrexone levels in the range of 4 to 26 pg/mL 
were detected under steady-state conditions.8 In a long term study, with PF-06412528 doses 
up to 860 mg administered twice daily, approximately 11% of blood samples taken pre-dose 
at steady state had detectable concentrations of naltrexone in plasma from 4 to 145 pg/mL. 
There were no adverse events associated with these clinically insignificant concentrations 
among the population of opioid-dependent patients with chronic pain. However, under 
conditions in which PF-06412528 is chewed or crushed, up to 100% of the sequestered 
naltrexone dose could be released from the formulation, with a naltrexone exposure level 
comparable to that of an IR oral solution of the same dose.
1.5. Additional Information
PF-06412528 was developed with the potential to decrease misuse, abuse, and diversion; a 
recently increasing public health problem among many age groups including adolescents.  
Non-medical use of opioids has often been associated with legitimate prescriptions.  The 
adolescent group, in particular, has been identified as a population at risk of misuse.13
Theoretically, PF-06412528 will deliver morphine as effectively as other long-acting 
morphine preparations while also deterring misuse and abuse because of the presence of the 
opioid antagonist sequestered in the formulation.
Complete information for PF-06412528 may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure.
1.6. Study Rationale
One of the major challenges facing clinicians who wish to prescribe pain medications to 
children is the paucity of information in the pediatric population about the proper choice of 
pain medication, dosage guidelines, and expectations with regard to efficacy and untoward 
effects.  This has led to documented cases of overdosing and under dosing pain medications 
in pediatric patients.1 Efforts to address this challenge include the Best Pharmaceuticals for 
Children Act (BPCA) and the Pediatric Research Equity Act (PREA), which were enacted by 
Congress “to promote drug development in children because of the inadequacy of pediatric 
use information for the majority of drug products approved in the United States”.14
While the use of morphine to treat pain in pediatric patients with cancer is well recognized, 
its use to treat other forms of moderate-to-severe pain (eg, arthritis, neuropathic pain) has 
become apparent only during the past decade.  During that same period, new 
extended-release opioid dosage forms have found their way to the market, but with only 
limited utility.  According to a published Food and Drug Administration (FDA) Workshop on 
pediatric analgesic trial design, “comparatively few children receive round-the-clock opioids 
for severe pain for time periods more than 4 weeks.”6 An in-house analysis of Truven 
(formerly MarketScan) Commercial claims and Encounters database supplied by Truven 
Health Analytics from October 2011 through September 2012 included an evaluation of 
14 million children from 59.4 million Truven enrollees of which 3,000 (0.02%) received an 
ER opioid prescription.  Of those children receiving an ER opioid prescription, 179 (5.8%) 


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were in the 0-2 years age range, 80 (2.6%) were in the 3-6 years age range, 283 (9.2%) were 
in the 7-11 years age range, and 2,537 (82.4%) were adolescents in the 12-17 years age 
range.  This study is a post-marketing commitment required by the FDA that will 
characterize the PK and establish a safety database of PF-06412528 in 100 pediatric pain 
subjects. 
Moreover, the results of this in-house analysis also revealed that very few children (6.1%) 
treated with opioids take them chronically and even fewer (2.1%) are treated with a 
long-acting opioid. Therefore, this study will establish a safety database and characterize the 
pharmacokinetics of PF-06412528 in 100 children with moderate-to-severe pain, as required.
Although chronic opioid use is not common in children, this study is meant to provide 
valuable safety and PK data on this new formulation of morphine with possible 
abuse-deterrent properties as a benefit to patients and the community in hopefully achieving 
an incremental advance in addressing abuse, misuse, and diversion. The benefit of having 
additional PK, safety, and dosing data for children with this new formulation is also a critical 
reason for obtaining these data. The risk to the children is estimated to be the same as with 
other formulations of morphine to which these patients would already be exposed as they are 
opioid-dependent. The additional risk could be precipitation of opioid withdrawal. This risk 
is very low in view of the documented experience in adults showing no definitive withdrawal 
if the formulation is taken as directed. Withdrawal can be immediately treated with good 
outcome as described in Section 5.1.5.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary

To demonstrate the safety of PF-06412528 in children 7 to 17 years of age treated 
with PF-06412528 for moderate-to-severe pain.

To characterize the pharmacokinetics of morphine in children 7 to 17 years of age 
treated with PF-06412528 for moderate-to-severe pain.
2.1.2. Secondary

To determine the systematic exposures of naltrexone and 6--naltrexol in children 
7 to 17 years of age treated with PF-06412528 for moderate-to-severe pain.
2.2. Endpoints
2.2.1. Primary

Safety: incidence, intensity, relationship, and seriousness of adverse events (including 
symptoms of opioid toxicity or withdrawal) during treatment with PF-06412528.

Pharmacokinetics: population pharmacokinetic estimates of morphine apparent 
clearance (CL/F) and average steady-state concentration (Css,av) following treatment 
with PF-06412528.


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2.2.2. Secondary 
•
Safety: changes in vital signs (pulse rate, blood pressure, and respiratory rate), clinical 
chemistry, and hematology laboratory values.
•
Pharmacokinetics: apparent volume of distribution (Vz/F) of morphine, data 
permitting; and systemic exposure levels of the metabolites of morphine 
(morphine-3-glucuronide [M3G] and morphine-6-glucuronide [M6G]), naltrexone, 
and 6-β-naltrexol.
 
 
 
 
 
3. STUDY DESIGN
This is a multicenter, 6-week, open-label, single-arm study to demonstrate the safety and 
characterize the PK of PF-06412528 in children 7 to 17 years of age, with 
moderate-to-severe pain.
Subjects must be taking opioids prior to entry into the study.  Initial PF-06412528 dosage 
will be determined by the subject’s pre-study opioid treatment prior to the 
Conversion/Titration Period.  
The study consists of 3 study periods (Figure 1) including:
•
Screening Period (Visit 1) lasting up to 2 weeks.
•
Treatment Period (Visits 2-6) lasting up to 10 weeks.
•
Post-Treatment Period/End of Study Period (Visit 7) lasting 1 week.
CCI


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Figure 1.
Overall Study Design
The study will enroll approximately 140 children between the ages of 7 and 17 years with at 
least 100 subjects exposed to study treatment for at least 2 weeks in the Maintenance Phase.  
Plasma samples will be collected at 2 time points under steady-state conditions from each 
subject in the two age groups (7-11 years and 12-17 years) to characterize the 
pharmacokinetics of morphine and determine the systemic exposures of M3G, M6G, 
naltrexone and 6--naltrexol.
Opioid naïve subjects will not be enrolled in the study.  
3.1. Screening Period
The Screening Period occurs up to 2 weeks.  This period includes one scheduled study center 
visit.  The purpose of the Screening Period is:
1. To assess a subject’s initial eligibility for study entry;
2. To assess caregiver(s) willingness and initial eligibility to meet their requirements of
the study; and
3. To ascertain a subject’s total daily opioid dose (including maintenance opioid and 
intermittent opioid usage) to guide the conversion from a subject’s current opioid 
therapy to PF-06412528 treatment.
3.2. Treatment Period
The Treatment Period will be conducted using an open-label, non-randomized, single-arm 
study design to demonstrate the safety and characterize the pharmacokinetics of 
PF-06412528 under multiple dose conditions.  
The Treatment Period duration is 7 to 10 weeks and consists of two phases of variable 
lengths depending on when a subject achieves a stable dose of PF-06412528; a 
Conversion/Titration Phase lasting up to 4 weeks and a Maintenance Phase lasting up to
6 weeks. The purpose of the Conversion/Titration Phase is to convert subjects from their 
current opioid therapy to PF-06412528 using a standardized conversion guide (see 
(2 Weeks)
Visit 1
Conversion/ 
Titration 
Phase 
(1-4 Weeks)
Visits 2-3a-d
Maintenance 
Phase
(2-6 Weeks)
Visits 4-6
(1 Week)
Visit 7
Treatment Period
Screening 
Period
Post-Treatment 
Period/End of 
Study


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Appendix 2), and individualize subjects’ pain management by titrating with PF-06412528.  
The purpose of the Maintenance Phase is to maintain the subject on a stable dose of 
PF-06412528 up to an additional 6 weeks, if possible, such that a subject could potentially be
exposed to up to 10 weeks of treatment with PF-06412528. 
During the Treatment Period, safety, pain intensity and pharmacokinetics will be assessed.
3.2.1. Conversion/Titration Phase (Visits 2-3d)
Subjects and their caregiver(s) will report for weekly visits during this 1-4 week period to 
convert their current standard of care opioid therapy for pain management to PF-06412528.  
The goals of the Conversion/Titration Phase are to convert subjects from their pre-study 
standard of care opioid analgesic to PF-06412528 and to individualize pain management by 
titrating PF-06412528 (Visits 2-3d; see Schedule of Activities) to achieve a stable dose.  A 
stable dose is characterized as a dose that provides adequate analgesia and minimizes adverse 
reactions for 5 to 7 days. During Visit 2 the subject’s study eligibility will be verified, the 
subject’s current standard of care opioid therapy will be discontinued and PF-06412528 will 
be initiated at a dose determined using the PF-06412528 Conversion Guide (Appendix 2).  
Four weekly scheduled study visits (Visits 3a-3d) are planned to provide enough time to 
individualize pain management with PF-06412528. Visit 3a is mandatory for all subjects and 
Visits 3b, 3c, and 3d are optional, if additional dose titration is needed. Visits 3b or 3c or 3d 
can be skipped if a subject reaches a stable dose at a prior visit.  When a stable dose is 
achieved, the subject advances to the Maintenance Phase at the next visit (Visit 4). More 
frequent consultation with the investigator as well as additional unscheduled clinic visits are
permitted, as needed (eg, to titrate study drug).  All information about the dosing of 
PF-06412528 (ie, dosage strength, frequency of dosing, and daily schedule) will be obtained 
and recorded at each scheduled/unscheduled visit.
The Conversion/Titration Phase will end once a PF-06412528 dose that provides adequate 
analgesia and minimizes adverse reactions is achieved (ie, stable dose) with infrequent need 
for IR morphine as rescue as determined by the investigator. Subjects who do not reach a 
stable dose without the need for IR morphine as rescue by Visit 3d, will be removed from 
treatment and converted back to their previous opioid therapy or another therapy at the 
discretion of the investigator.
The start of the Maintenance Phase will begin once a subject has achieved a stable dose of 
PF-06412528 and the next study visit (Visit 4) will be scheduled in two weeks’ time.  
3.2.2. Maintenance Phase (Visit 4 – 6)
The goal of the Maintenance Phase is to characterize the PK under steady-state study 
conditions as well as demonstrate the safety of PF-06412528 over a 2-6 week period.  If at 
Visit 4 subjects require additional pain relief in the opinion of the investigator, they will 
continue in the study for an additional 2-4 weeks (Visit 5 and/or Visit 6) up to 6 weeks total.  


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Daily Diary and in-clinic pain intensity and safety will be assessed at each visit to determine 
if any dose adjustments are required. Rescue medication (acetaminophen and/or NSAID’s) 
is permitted during this phase.  IR morphine for rescue is discouraged during the 
Maintenance Phase.
Blood samples will be collected for PK analysis at Visit 4 for those subjects that achieve a 
stable dose between Visits 3a-d.  Two blood samples will be taken at least two-hours apart at 
Visit 4.  If for any reason PK samples are not obtained at Visit 4, the subject should return to 
enable them to be obtained at an unscheduled visit.
At the final Maintenance Phase visit (Visit 4 or 5 or 6), the investigator will discontinue the 
subject’s PF-06412528 therapy and convert the subject back to their standard of care of 
opioid therapy. Blood samples will be collected for PK analysis if not already obtained. A
Post-Treatment/End of Study visit will be scheduled in 7 2 days (Visit 7).
3.2.3. Early Termination Visit
Subjects who do not reach a stable dose at Visits 3a-3d will proceed to the Early Termination 
Visit.  Subjects who do not complete 2-weeks of PF-06412528 treatment at their maintenance 
dose for any reason will proceed to the Early Termination Visit.  
All subjects who discontinue early from the study will complete the procedures specified for 
Visit 6/Early Termination (Section 6.3).
3.3. Post-Treatment Period/End of Study Period
The purpose of the Post-Treatment Period/End of Study (Visit 7) is to perform safety 
assessments 7 2 days after the last dose of PF-06412528 at Visit 6.  
Subjects who discontinue early from the study as well as subjects who complete 2 weeks of 
PF-06412528 during the Maintenance Phase and have their last dose of PF-06412528 at 
Visit 4 will complete the Visit 6/Early Termination procedures without the need to return for 
the Post Treatment/End of Study Visit.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subject and caregiver eligibility should be reviewed and documented by an appropriately 
qualified member of the investigator’s study team before subjects and caregivers are included 
in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:


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1. Subjects between the ages of 7 and 17 years, inclusive, at the time of enrollment.
2. Having confirmed moderate-to-severe pain requiring around-the-clock treatment with 
an opioid analgesic.
3. Be an experienced opioid user, defined as any subject treated with opioid therapy, 
equivalent to 20 mg per day of morphine, for a period of 3 consecutive days
immediately prior to first day of dosing with PF-06412528. 
4. Have parental/guardian (or adult caregiver) capable of providing informed consent, 
supervising the storage and administration of study drug, and complying with 
scheduled visits, treatment plan, and all other study procedures (see Section 4.4).
5. Evidence of a personally signed and dated informed consent document indicating that 
the subject’s parent or legal/parental/guardian (eg, caregiver) has been informed of all 
pertinent aspects of the study.  Subjects will be required to provide assent in 
compliance with local regulations and Institutional Review Board (IRB)
requirements.
6. Male subjects able to father children and female subjects of childbearing potential
who are sexually active and at risk for pregnancy must agree to use a highly effective 
method of contraception throughout the study and for at least 28-days after the last 
dose of PF-06412528.  
7. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. A life-expectancy (assessed by investigator) of less than 6 months or is no longer 
capable of taking medication orally.
2. Pregnant female subjects; breastfeeding female subjects; or male subjects with 
partners currently pregnant.
3. History of known hypersensitivity to morphine, naltrexone, or opioid products in 
general.
4. Participation in other studies involving investigational drugs within 30 days prior to 
study entry and/or study participation.
5. Significant respiratory depression and/or severe bronchial asthma. 
6. Known or suspected of having paralytic ileus or has any other medical condition that, 
in the opinion of the investigator, would pose a safety risk to taking PF-06412528.


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7. Have other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
treatment administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the subject inappropriate for entry 
into this study.  This may include, but not be limited to, a clinically significant 
medical condition (eg, cardiovascular, neurological, renal, hepatic, pulmonary, 
gastrointestinal [including dysphagia], endocrine, hematological, immunological, 
rheumatological, metabolic, psychiatric) or physical examination, vital signs, ECG, 
clinical laboratory test abnormalities during Screening that, in the judgment of the 
investigator, would impact the safety of the subject during study participation.
8. Undergone surgery within 3 days prior to the first day of dosing.  
9. Positive urine drug test (UDT) at Screening for any illicit or scheduled drug not 
prescribed for the subject.
10. Subjects who are children of or related to, investigational site staff members directly 
involved in the conduct of the study site staff members otherwise supervised by the 
investigator, or Pfizer employees directly involved in the conduct of the study.
11. Subject endorses a 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) 
ideation section or reports any suicidal behavior. (Section 7.4.1).
12. History of sleep apnea within the past year that would compromise the safety of the 
subject in the judgment of the investigator.
13. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater 
than 3 times the upper limit of normal at the Screening Visit.  
14. Epidural opioid <2 hours prior to the first dose of study drug.
15. Any planned surgery during the course of the study, with the exception of the 
placement of central or peripheral venous access devices.
4.3. Life Style Guidelines
All male subjects who are able to father children and female subjects who are of childbearing 
potential and are sexually active and at risk for pregnancy must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the active 
treatment period and for 28 days after the last dose of study drug.  The investigator or his or
her designee, in consultation with the subject, will confirm an appropriate method of 
contraception for the individual subject from the permitted list of contraception methods (see 
below) and instruct the subject in its consistent and correct use.  Subjects need to affirm that 
they meet the criteria for correct use of at least 1 of the selected methods of contraception.  
The investigator or his/her designee will discuss with the subject the need to use highly 
effective contraception consistently and correctly according to the schedule of activities and 
document such conversation in the subject’s chart.  In addition, the investigator or his or her 


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designee will instruct the subject to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the subject or the subject’s partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:

Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the subject plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.

Correctly placed copper containing intrauterine device (IUD).

Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).

Pre-pubertal females belonging to Stage 1 on the Tanner scale.
All sexually active male subjects must agree to prevent potential transfer of and exposure 
to drug through semen to their partners by using a condom consistently and correctly, 
beginning with the first dose of study drug and continuing for at least 28 days after the 
last dose.
4.4. Caregiver(s)
The parent or legal guardian of the subject will actively participate as caregiver in this study.  
As caregiver, the parent or legal guardian will not only provide informed consent, but also 
actively participate in the study procedures including the handling, storage, and 
administration of study drug.  The caregiver must be available to be contacted by the study 
center at least once a week.  The role of the caregiver will include monitoring for signs and 
symptoms of opioid toxicity or opioid withdrawal and communicating safety information to 
the investigator or designee as appropriate.  The investigational site will be responsible for 
training the caregiver and subject, when appropriate, to recognize the signs and symptoms of 
opioid toxicity and opioid withdrawal (see Section 5.1.1) and to complete a diary on a daily 
basis during the Treatment and Post-Treatment Periods of the study.  The caregiver/subject
will be instructed to seek immediate medical attention if signs or symptoms of opioid toxicity 
or withdrawal occur.
A subject’s caregiver(s) must meet all of the following criteria for the subject to be eligible 
for enrollment into the study:

Is 18 years of age and has demonstrated responsibility as a caregiver through 
training to:

Recognize the signs and symptoms of opioid toxicity and withdrawal and 
recognize the need for immediate medical attention;


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
Administer study drug as directed and record time of each dose of study drug;

Monitor the subject and record observations of adverse events in the diary.

Is available to accompany the subject to clinic visits.

Can follow printed instructions in English or Spanish.

Is willing and able to give written informed consent for the subject.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the coordinator’s manual or team 
SharePoint site.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact number in 
the event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems, however it should only be 
used in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace 
the established communication pathways between the investigational site and study team or 
advice on medical questions or problems that may arise during the study. The contact
number is not intended for use by the subject directly and if a subject calls that number, he or 
she will be directed back to the investigational site.
4.6. Rater Qualifications
Clinic staff administering the assessments and directing the caregiver in the completion of
the Columbia-Suicide Severity Rating Scale (C-SSRS) must be trained.  The risk assessment 
for the C-SSRS must be done by a clinically qualified child and adolescent Mental Health 
Provider (MHP).  In the United States, in addition to Child and Adolescent Psychiatrists 
(board certified or board eligible), clinically qualified MHPs include the following: 
(1) general psychiatrists, (2) Psy. D. or Ph. D. level Clinical Psychologists, (3) licensed 
Master’s level Clinical Social Workers, or (4) licensed psychiatric Nurse Practitioners who 
have training and experience in the diagnosis and treatment of children and adolescents with 
psychiatric disorders.


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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference On Harmonization (ICH) 
guidelines investigational drug is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
All subjects will be treated with PF-06412528 (morphine sulfate and naltrexone 
hydrochloride) extended-release capsules for oral use in this single-arm, open-label study.
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
5.1.1. Opioid Toxicity and Withdrawal
5.1.2. Signs and Symptoms of Opioid Toxicity
Acute over dosage with morphine is manifested by respiratory depression (a decrease in 
respiratory rate and/or tidal volume, irregular respiration, cyanosis), somnolence progressing 
to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils and, 
sometimes, shock, convulsions, non-cardiogenic pulmonary edema, pulmonary edema, 
hypotension, cardiac arrest, and death.15,16,17,18  Marked mydriasis rather than miosis may be 
seen due to severe hypoxia in some overdose situations.19
5.1.3. Management of Opioid Toxicity
To treat opioid overdose, primary attention should be given to re-establishment of a patent 
and protected airway and institution of assisted or controlled ventilation if needed.  Other 
supportive measures (including oxygen, vasopressors) should be employed in the 
management of circulatory shock and pulmonary edema accompanying overdose as 
indicated.  Cardiac arrest or arrhythmias will require advanced life support techniques. 
The pure opioid antagonist, naloxone is a specific antidote to respiratory depression resulting 
from opioid overdose. If needed, the appropriate intravenous dose of naloxone HCl should 
be administered simultaneously with efforts at respiratory resuscitation at doses of 
0.01 mg/kg in pediatric subjects weighing less than 20 kg (or younger than 5 years) and 
0.01-0.02 mg/kg for those weighing more than 20 kg (or older than 5 years) up to a total dose 
of 10 mg.15,19
Since the duration of reversal would be expected to be less than the duration of action of 
morphine in PF-06412528, the subject must be carefully monitored until spontaneous 
respiration is readily re-established.  PF-06412528 will continue to release and add to the 
morphine load for up to 24 hours after administration and the management of overdose 
should be monitored accordingly.  If the response to opioid antagonists is suboptimal or not 
sustained, additional naloxone should be given as directed by the manufacturer of the 
product.


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Opioid antagonists should not be administered in the absence of clinically significant 
respiratory or circulatory depression secondary to morphine overdose.  Such agents should be 
administered cautiously to persons who are known or suspected to be physically dependent 
on an opioid.  In such cases, an abrupt or complete reversal of opioid effects may precipitate 
an acute withdrawal syndrome.
The sequestered naltrexone in PF-06412528 has no role in the treatment of opioid overdose. 
5.1.4. Signs and Symptoms of Opioid Withdrawal
Opioid withdrawal is characterized by varying degrees of some or all of the following signs 
and symptoms in children:  increased muscle tone, myoclonus, ataxia, abnormal movements, 
pupil dilatation (>4 mm), high pitched crying, restlessness, vomiting, poor feeding, diarrhea, 
tachypnea, yawning, sneezing, hypertension, and mottling.20
5.1.5. Management of Opioid Withdrawal
In general, if significant opioid withdrawal occurs, the subject’s symptoms may be medically 
managed with pediatric doses of midazolam for anxiety and restlessness (250 mcg/kg not to 
exceed 20 mg),21 with supplemental doses of morphine sulfate for opioid replacement if 
necessary, and with pediatric oral doses of ondansetron (4 mg every 8 hours as needed)22 to 
control nausea and vomiting.  Otherwise, the subject’s symptoms can be treated with careful 
observation and supportive medical care.
5.2. Subject Compliance
Dosing will be recorded in the Daily Diary, transcribed to a case report form (CRF), and 
discussed at scheduled visits with the caregiver/subject. If a subject’s overall compliance 
falls to <70% in any given period between visits, the investigator or his/her designee will 
counsel the caregiver/subject on the importance of good compliance and document efforts to 
improve the subject’s compliance.  If the subject’s compliance does not improve after 
repeated efforts, the investigator should consider discontinuing the subject from the study
after confirming the decision with Pfizer.
5.3. Study Drug Supplies
5.3.1. Dosage Form(s) and Packaging
PF-06412528 (morphine sulfate and naltrexone hydrochloride extended release capsules) is a 
Schedule II (CII) oral dosage form available in the following strengths:  20 mg/0.8 mg, 
30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, and 100 mg/4 mg.  For purposes 
of this study, both a 10 mg/0.4 mg capsule and a 15 mg/0.6 mg capsule will be developed to 
meet the therapeutic needs of younger (lower weight) children.  All PF-06412528 study drug, 
including the newly developed 10 mg/0.4 mg and 15 mg/0.6 mg capsule strengths, will be 
supplied by the Sponsor.
PF-06412528 study drug will be packaged and provided for use according to the total daily 
dose requirements of a subject as listed below:


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Morphine 
Sulfate
Total Daily Dose
Dosing 
Schedule
Capsule (dosage 
form)
Conversion/ 
Titration Phase 
Bottle Fill count 
(capsules/bottle)
Maintenance Phase 
Bottle Fill count 
(capsules/bottle)
10 mg
10 mg QD
10
20
15 mg
15 mg QD
10
18
20 mg
10 mg BID
20
36
30 mg
15 mg BID
20
36
40 mg
20 mg BID
20
36
60 mg
30 mg BID
20
36
80 mg
2x20 mg BID 
40
72
100 mg
50 mg BID
20
36
120 mg
60 mg BID
20
36
160 mg
80 mg BID
20
36
200 mg
100 mg BID
20
36
No other medications, including rescue medications, will be supplied by the Sponsor. 
5.3.2. Preparation and Dispensing
Study drug will be shipped to the study center only after receipt of required documents in 
accordance with applicable regulatory requirements and Sponsor procedures.
Study drug must be dispensed and administered according to the procedures described in the 
protocol.  Only subjects enrolled in the study may receive study drug in accordance with all 
applicable regulatory requirements.  Only authorized study center personnel and the 
caregiver may supply or administer study drug.  Authorized site personnel will be the 
investigator (or his/her designee), in accordance with all applicable regulatory requirements.
An Interactive Response Technology (IRT) system will monitor study drug inventory at the 
study centers and will enact resupply of study drug shipments as necessary.
5.4. Administration
PF-06412528 is to be administered with or without food, as per the investigator’s Brochure.  
The bottle label will direct the subject to take either QD or BID depending on the total daily 
dose requirement for that subject (eg, children of low weight may be assessed to start with 
the 10 or 15 mg dose QD.  Those labels will indicate QD dosing.  Dosing strengths greater 
than 15 mg will indicate BID dosing).  When given BID, one dose must be administered in 
the morning and the second dose is to be administered approximately 12 hours later.  
Morning doses should be encouraged to be administered daily between 6:00-10:00 AM
throughout the study.  As a general rule, the initial calculated daily dosage of 
PF-06412528 should be reduced by 50% and then titrated to achieve a stable dose.  When 
converting to PF-06412528, the investigator should consider the potency, route of 
administration, and total daily dose of the discontinued opioid(s), the medical status of the 
subject, the subject’s degree of opioid experience and tolerance, the type and severity of 
chronic pain, and the use of concomitant rescue medications to control the pain.  Because 
CCI


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steady-state plasma concentrations are approximated within 24 to 36 hours, PF-06412528 
dosage adjustments may be done as frequently as every 1 to 2 days. Study drug will be 
dispensed to the subject’s caregiver only.
When PF-06412528 extended-release capsules are administered whole, the naltrexone 
remains intact and does not affect the analgesic potential of morphine.  However, if the 
capsule is crushed, chewed or dissolved, the naltrexone component is released, competitively 
binds at the mu-opioid receptors, thus inhibits the effects of the opioid.
Therefore, PF-06412528 extended-release capsules are to be swallowed whole.  The pellets 
in the capsules are not to be crushed, chewed, or dissolved prior to swallowing.
The co-ingestion of PF-06412528 with alcohol could result in an increase in morphine 
plasma levels and potentially fatal overdose of morphine.  Subjects should not consume 
alcoholic beverages or use prescription or non-prescription products containing alcohol while 
on PF-06412528 therapy.
Misuse of the formulation by tampering (eg, crushing, chewing, or dissolving the contents) 
may result in the rapid release of both morphine and naltrexone, which may lead to fatal 
respiratory depression (particularly in opioid naïve individuals) or symptoms of significant 
opioid withdrawal in opioid-tolerant individuals.
As an alternative to taking the capsules whole, and only at the discretion of the investigator, 
PF-06412528 capsules (pellets) may be sprinkled over applesauce and then swallowed.  This 
method of drug administration is only appropriate for children unable to swallow capsules, 
but able to reliably swallow the applesauce without chewing it. Capsule shells containing 
sugar spheres will be provided to assess a subject’s swallowing ability on an as needed basis.  
The investigator also may use the capsule shells to assess a subject’s reliability to swallow 
the applesauce without chewing it in the clinic.  When using this method, the caregiver 
should sprinkle the pellets onto a small amount of applesauce (ie, a teaspoonful) and have the 
child consume the applesauce without chewing it.  The child’s mouth should then be rinsed 
(swish and swallow) to ensure that all the pellets have been swallowed. Instructions and 
training of administering the applesauce will be provided at the clinical site as per the 
instructions in Pfizer’s Drug Administration and Instruction (DAI) guideline.
5.5. Study Drug Storage
According to the investigator’s Brochure, all study drug (PF-06412528) should be stored 
within the range of 59-77F.
The investigator, or an approved representative, eg, pharmacist, will ensure that all study 
drugs are stored in a secured area with controlled access under required storage conditions 
and in accordance with applicable regulatory requirements.
Study drug should be stored in its original container and in accordance with the label.  See 
the label for storage conditions of the product.


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Storage conditions stated in the SRSD (eg, Investigator’s Brochure) will be superseded by 
the storage conditions stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations.  This 
should be captured from the time of study drug receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit, as applicable, should be regularly inspected to ensure it is maintained in 
working order.  
Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  Once an 
excursion is identified, the study drug must be quarantined and not used until the sponsor 
provides documentation of permission to use the study drug.  It will not be considered a 
protocol deviation if the sponsor approves the use of the study drug after the temperature 
excursion.  Use of the study drug prior to sponsor approval will be considered a protocol 
deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
Site staff will instruct subjects on the proper storage requirements for take home study drugs.
5.6. Study Drug Accountability
Study drug and bottles must be returned to the investigator at each visit.  The investigator is 
responsible for study drug accountability, reconciliation, and record maintenance.  In 
accordance with all applicable regulatory requirements, the investigator or designated study 
center personnel must maintain study drug accountability records throughout the study.  The 
investigator will return all unused study drug to the sponsor or sponsor’s designee.
Study drug accountability forms maintained during the study will be used to support subject 
dosing data.  Study center personnel are responsible for reconciling and resolving 
discrepancies in study drug accountability.  It is the responsibility of the Sponsor study 
monitor (or designee) to periodically review study drug accountability records to ensure that 
FDA regulations and guidelines concerning study drug accountability are being adhered to.
Periodic inventories of study drug during the study and at the end of the study will be 
performed by the Sponsor study monitor (or designee) and the investigator (or designee).  
Missing study drug must be recorded on the study drug accountability/return forms along
with an explanation of the discrepancy.  Missing medication stock must be reported to the 
Sponsor immediately when discovered.  It is essential that all study drug be accounted for.  
All unused study drug and bottles will be returned to Pfizer or designee, after the proper 
completion of Drug Enforcement Agency (DEA) 222 forms.


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5.6.1. Destruction of Study Drug Supplies
The sponsor or designee will provide guidance on the destruction of unused study drug (eg, 
at the site).  If destruction is authorized to take place at the study site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer, and all 
destruction must be adequately documented.
5.7. Concomitant Medication(s)
5.7.1. Permitted Medications and Therapies
Permitted medications and therapies during this study will include:

Acetaminophen and/or NSAID’s (as a rescue medication) anytime during the 
Treatment and Post-Treatment Periods.

IR morphine as a single ingredient product at usual doses as rescue medication during 
the Conversion/Titration Phase until a stable dose is achieved.  IR morphine for 
rescue is discouraged during the Maintenance Phase.

Non-opioid adjunctive analgesics, bowel regimens, and anti-emetics are permitted.

For any other medications and therapies not listed (eg but not limited to CNS 
depressants including sedatives, hypnotics, and other tranquilizer-type drugs 
(eg, benzodiazepines, phenothiazines) the investigator will consult with Pfizer’s 
clinical team because of the risk of hypotension, respiratory depression, and profound 
sedation or coma.  

Other non-scheduled prescribed medications for treatment of concomitant medical 
conditions (eg, cancer, arthritis, diabetes).

Any drug deemed necessary to either treat opioid toxicity (eg, vasopressors, 
naloxone) or control signs and symptoms of opioid withdrawal (eg, midazolam, 
ondansetron).

Stable regimen of prescribed physical therapy, including heat application (at the same 
intensity and frequency as at study entry).
5.7.2. Prohibited Medications and Therapies

Opioid analgesics (including tramadol, tapentadol, buprenorphine), except IR
morphine as rescue medication during the Conversion/Titration and Maintenance 
Phases.  This includes mixed agonist/antagonist opioid analgesics (eg, pentazocine, 
butorphanol).

Monoamine oxidase inhibitors.

Ethanol in the form of alcoholic beverages (includes medications containing alcohol).


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5.8. Rescue Medication
Subjects/caregivers will be required to record use of rescue medication in the diary during the 
Treatment Period and Post-Treatment Period.
Acetaminophen and/or NSAID medications (eg, ibuprofen) as allowed by label for 
children/adolescents is permitted as rescue medication, at the discretion of the investigator, at 
any time in conjunction with PF-06412528 to provide pain relief.  The use of IR morphine as 
a rescue medication is permitted during the Conversion/Titration Phase, at the discretion of 
the investigator, to aid in the conversion.
6. STUDY PROCEDURES
Subjects/caregivers will be asked to complete a diary each day during the Treatment and 
Post-Treatment Periods of the study.
The investigator (and designee) is responsible for ensuring that the specified training for 
completion of the diary is followed for all subjects/caregivers.  Training materials will be 
provided for site staff and caregiver/subjects.  During the study, the investigator will review 
the subject’s progress at the time of a subject’s study visit.
6.1. Screening Visit (Days -14 to -1)
During the Screening Visit subjects and caregiver(s) will be assessed for study eligibility.  
This period may last up to 14 days before entering the Treatment Period; however, subjects 
are encouraged to be screened as soon as conveniently possible to expedite the 
conversion/titration process.  During this visit, the following assessments and procedures will 
be performed:

Informed Consent/Assent: Subject’s parent or legal guardian must sign the informed 
consent document (ICD).  A subject will be required to provide assent in compliance 
with local regulations and IRB requirements.

Inclusion/Exclusion Criteria: Assess subject against inclusion and exclusion criteria
in Sections 4.1 and 4.2, respectively.

Demographics: Information such as date of birth, race, gender, height, and weight 
will be collected.

Medical History: Review any significant medical/surgical histories and concurrent 
illnesses that required or are requiring specialist consultation or treatment.

Review Pre-study Opioid Therapy: Review standard of care opioid therapy and 
document name, dose, and dosing frequency on the appropriate CRF.

Concomitant Medications: Record all previous (within last 30 days) and concurrent 
medications (Over-The-Counter or prescribed): Section 5.7.


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
Physical Examination: See Section 7.2.6.

Clinical Laboratory Testing: Hematology, blood chemistry, and urinalysis 
(Section 7.2.3).

Pregnancy Test: Conduct serum pregnancy test for all females of childbearing 
potential (See Section 7.3).

Urine Drug Test: See Section 7.2.7.

Electrocardiogram: See Section 7.2.4.

Vital Signs: Resting blood pressure, pulse rate, and respiration (See Section 7.2.2).

Suicide Ideation and Behavior (SIB) Assessment: C-SSRS (Section 7.4.1):

Children’s Lifetime/Recent (Ages 7-11) (Version 6/23/10) -Appendix 3.

Baseline/Screening (Ages 12-17) (Version 1/14/09) -Appendix 4.

COWS: See Section 7.2.5.

Adverse Events: Reporting of serious adverse events (See Section 7.2.1).

Advise the caregiver that the next visit (Visit 2) is the first dose visit with 
PF-06412528 and request their child refrain from taking their standard of care opioid 
on the day of Visit 2.  In the event the standard of care opioid has been taken, 
reschedule the visit for the next day.  A telephone call is encouraged the day before 
Visit 2 to remind the caregiver.
6.2. Treatment Period
The Treatment Period will consist of two phases, the Conversion/Titration Phase and the 
Maintenance Phase.  The procedures for each phase are described below.
6.2.1. Conversion/Titration Phase
Pre-Dose Visit 2 (Day 1)
During this visit (Study Day 1) the following procedures will be followed before the 
administration of study medication:

Review any results from laboratory samples (hematology, chemistry, urinalysis, 
pregnancy tests) that may exclude a subject from participating.

Pregnancy Test: Take a urine sample from all females of childbearing potential.

Vital Signs.


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
SIB Assessment: C-SSRS (Section 7.4.1):

Children’s Since Last Visit (Ages 7-11) (Version 6/23/10)-(Appendix 5).

Since Last Visit (Ages 12-17) (Version 1/14/09)-(Appendix 6).

COWS assessment.

Opioid Therapy Review: Review standard of care opioid therapy and document 
name of all opioids, dose, and dosing frequency.

Concomitant medications: Review and document concomitant medication use 
(name, dose, and frequency).

Adverse Event Assessment with focus on serious: Only pre-dose serious adverse 
events will be documented. 

Pain Intensity: In-clinic assessment.

Discontinue previous standard of care opioid therapy as part of dose conversion.

Prescribe Rescue Medication (if needed): Prescribe rescue medication 
(acetaminophen and/or NSAID’s) to be used during conversion and titration.  IR
morphine may also be prescribed for rescue, with the intent to limit its use until a 
stable dose is achieved.

Dispense Study Drug: Dispense appropriate dose of PF-06412528 based on the 
Conversion Guide (as described in Appendix 2).

Caregiver(s) Training and Subject Instruction: Train the caregiver(s) and instruct 
the subject on study medication administration and recording of drug accountability, 
including recording the date/clock time of study drug administration, rescue 
medication use, analgesia assessments and adverse events between visits in the diary.

Schedule the Visit 3a (Day 72 days) visit.
Visit 3a (Day 7 2 Days)
All subjects will have this Day 7 visit, which is designated Visit 3a on the Schedule of 
Activities. 
During this visit, the investigator will review the subject’s Daily Diary to assess the subject’s 
pain management to determine whether a stable dose of PF-06412528 has been achieved; 
ie, a dose that provides adequate analgesia, minimal adverse reactions.


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During this visit the following procedures will be followed: 

Assess Treatment Response:

Pain intensity (Diary Review and in-clinic assessment);

Rescue Medication (Diary Review);

Concomitant Medication (Diary Review);

Study Drug Use (Diary Review);

Adverse Events (Diary Review).

COWS Assessment.

Concomitant Medication Assessment.

Adverse Event Assessment.

Pregnancy Test: Take a urine sample from all females of childbearing potential.

Vital Signs: Record blood pressure, pulse rate, and respiration.

SIB Assessment: C-SSRS (Section 7.4.1):

Children’s Since Last Visit (Ages 7-11) (Version 6/23/10)-(Appendix 5).

Since Last Visit (Ages 12-17) (Version 1/14/09)-(Appendix 6).

Drug Accountability: See Section 5.6.

Dose Titration: Adjust PF-06412528 dosage as needed to optimize pain therapy.

Prescribe Rescue Medication (if needed): Prescribe rescue medication 
(acetaminophen and/or NSAID’s) to be used during conversion and titration.

Dispense Study Drug (PF-06412528) to caregiver.
For Converted Subjects: If, at this visit, the subject has been fully discontinued from the 
standard of care opiate therapy and successfully titrated to a stable dose of PF-06412528 and 
with infrequent use of IR morphine for rescue the subject may be scheduled for the next visit, 
which will be Visit 4 (Schedule of Activities).  It is at this visit (Visit 3a) the subject enters
the Maintenance Phase of the Treatment Period.
For Non-Converted Subjects: If, at this visit, the subject has not achieved a stable dose of 
PF-06412528, this subject will remain in the Conversion/Titration Phase, therefore:


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ADDITIONAL TITRATION VISITS IF NEEDED
Visit 3b (Day 14 2 days)

Follow the same procedures and assessments as described at Visit 3a.
For Converted Subjects: If, at this visit, the subject has been fully discontinued from the 
standard of care opiate therapy and successfully titrated to a stable dose of PF-06412528 and 
with infrequent use of IR morphine for rescue the subject may be scheduled for the next visit, 
which will be Visit 4 (Schedule of Activities). It is at this visit (Visit 3b) the subject enters
the Maintenance Phase of the Treatment Period.
For Non-Converted Subjects: If, at this visit, the subject has not achieved a stable dose of 
PF-06412528, this subject will remain in the Conversion/Titration Phase, therefore:

Schedule the Visit 3c (Day 21 2) visit.
Visit 3c (Day 21 2 days)

Follow the same procedures and assessments as described at Visit 3a.
For Converted Subjects: If, at this visit, the subject has been fully discontinued from the 
standard of care opiate therapy and successfully titrated to a stable dose of PF-06412528 and 
with infrequent use of IR morphine for rescue the subject may be scheduled for the next visit, 
which will be Visit 4 (Schedule of Activities). It is at this visit (Visit 3c) subject enters the 
Maintenance Phase of the Treatment Period.
For Non-Converted Subjects: If, at this visit, the subject has not achieved a stable dose of 
PF-06412528, the subject will remain in the Conversion/Titration Phase, therefore:

Schedule the Visit 3d (Day 28 2 days) visit.
Visit 3d (Day 28 2 days)

Follow the same procedures and assessments as described at Visit 3a.
For Converted Subjects: If, at this visit, the subject has been fully discontinued from the 
standard of care opiate therapy and successfully titrated to a stable dose of PF-06412528 and 
with infrequent use of IR morphine for rescue the subject may be scheduled for the next visit, 
which will be Visit 4 (Schedule of Activities). It is at this visit (Visit 3d) subject enters the 
Maintenance Phase of the Treatment Period.
For Non-Converted Subjects: If, at this visit, the subject has not achieved a stable dose of 
PF-06412528, the subject will be discontinued from treatment.  PF-06412528 will be 
discontinued and if needed, converted to a standard of care analgesic therapy at the 
investigator’s discretion.


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
Schedule the Visit 6/Early Termination Visit: See Section 6.3.

Schedule the Post Treatment/End of Study (Visit 7): See Section 6.4.
6.2.2. Maintenance Phase
Once the investigator has determined that the subject has achieved a stable dose of 
PF-06412528, the subject will enter the Maintenance Phase of the Treatment Period and 
scheduled to return in two weeks for Visit 4. In the event a subject prematurely withdraws 
before Visit 4, perform the Visit 6/ET procedures a soon as possible.
Visit 4 
Perform the following assessments:

Follow the same procedures and assessments as described at Visit 3a.

Obtain Plasma Samples: Obtain 2 separate 6 mL blood samples for measurement of 
the concentration of morphine and metabolites in plasma and naltrexone and 
6--naltrexone in plasma, with at least 2 hours separating the 1st and 2nd samples. 
Record the following items on the appropriate CRF:

The exact dosing date and clock times of the morning dose and previous 
3 doses of PF-06412528, and

The exact clock time of the blood draw for the 2 samples.
Visit 5

Follow the same procedures and assessments as described at Visit 3a.
Visit 6/Early Termination
During this visit the following procedures will be followed for all subjects:

Physical examination.

Serum pregnancy test.

Clinical Laboratory Test (Hematology, blood chemistry and urinalysis): See 
Section 7.2.3.

Follow the same procedures and assessments as described at Visit 3a, (except do not 
perform the urine pregnancy test, instead a serum pregnancy test should be performed
at this visit): See Schedule of Activity and Section 7.3.


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
Obtain plasma samples for PK analysis (only if not acquired at Visit 4): Record the 
following items on the appropriate CRF:

The exact dosing date and clock time for the morning and previous 3 doses of 
PF-06412528, and

The exact clock time of the blood draw for the 2 samples.

Subjects who discontinue early from the study as well as subjects who complete 
2 weeks of PF-06412528 during the Maintenance Phase and have their last dose of 
PF-06412528 at Visit 4 will complete the Visit 6/Early Termination procedures 
without the need to return for the Post Treatment/End of Study Visit.

Schedule Post Treatment/End of Study Visit, if required.
6.3. Early Termination Visit
Subjects who do not reach a stable dose at Visits 3a-3d will proceed to the Early Termination 
Visit.  Subjects who do not complete 2-weeks of the PF-06412528 treatment at their 
maintenance dose for any reason will proceed to the Early Termination Visit.
All subjects including subjects who discontinue early from the study will complete the 
procedures specified for Visit 6/Early Termination (see Section 6.2.2).
6.4. Post Treatment/End of Study (EOS) Visit 7
Approximately 1 week after discontinuing PF-06412528 and initiating dose conversion back 
to the subject’s standard of care therapy, subjects will undergo the Post-Treatment/End of 
Study procedures, which will consist of an assessment of any AEs since the previous visit 
and the suicidality assessment.  
The following procedures will include:

SIB Assessment: C-SSRS (Section 7.4).

AE assessment.
6.5. Subject Withdrawal
Withdrawal of consent: caregivers/subjects who request to discontinue study treatment will 
remain in the study and must continue to be followed for protocol specified follow-up 
procedures.  The only exception to this is when the caregiver/subject specifically withdraws 
consent for any further contact with him or her or persons previously authorized by the 
subject to provide this information. Caregiver/subjects should notify the investigator in 
writing of the decision to withdraw consent from future follow-up, whenever possible.  The 
withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is only from further receipt of study drug or also 
from study procedures and/or post treatment study follow-up, and entered on the appropriate 


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CRF page.  In the event that vital status (whether the subject is alive or dead) is being 
measured, publicly available information should be used to determine vital status only as 
appropriately directed in accordance with local law.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site.  
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request that the 
subject return all unused study drug, request the subject to return for a final visit, if 
applicable, and follow-up with the subject regarding any unresolved AEs.  The clinical staff 
will make every effort to contact subjects 28 days following their last dose to ascertain health 
status (ie, AE/suicidality).
Subjects who do not reach a stable dose by Visit 4 (Day 28) will be discontinued from the 
study.  Subjects who have illicit substances at Screening on the UDT will be discontinued 
from the study, unless supported by prescription for medicinal use. Those subjects who 
discontinue the study early and do not complete 2 weeks of the Maintenance Phase should 
return to the study center as soon as possible for PK sampling and Early Termination 
procedures.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
In the event of clinically important treatment-emergent suicidal ideation or suicidal behavior, 
the subject will be withdrawn from the study and will receive the appropriate medical care, 
which may include medication.  The investigator will follow up until the subject’s condition 
has stabilized.  Additionally, a risk assessment or evaluation of suicide risk will be completed 
by a child and adolescent mental health provider as part of the psychiatric evaluation and 
assessment of subject safety.  Refer to Section 7, Assessments.  Clinically important 
suicidality includes but is not limited to:
1. Suicidal behavior (with or without intent of suicide or serious self-harm).
2. Determination of 'yes' on question 4 (Active Suicidal Ideation with Some Intent or 
Act, Without Specific Plan) for the Suicidal Ideation section of the C-SSRS.
3. Determination of 'yes' on question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) for the Suicidal Ideation section of the C-SSRS.


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4. Determination of 'yes' on the question of Actual Attempt, Interrupted Attempt, 
Aborted Attempt, or Preparatory Acts or Behavior for Suicidal Behavior section of 
C-SSRS.
5. Acute suicidality to such a degree that precaution against suicide must be exercised.
6.6. Lost to Follow-Up (LTFU)
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter.  All attempts should be documented in the subject’s medical records.  If it is 
determined that the subject has died, the site will use permissible local methods to obtain the 
date and cause of death.  If the investigator’s use of a third-party representative to assist in 
the follow-up portion of the study has been included in the subject’s informed consent, then 
the investigator may use a sponsor-retained third-party representative to assist site staff with 
obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
A subject will be considered LTFU when one or more Treatment Period visits are missed 
AND attempts to contact the subject have been unsuccessful leading to an outcome of a 
missed Visit 6 visit.  The following attempts must be made in the order listed below:
1. 3 documented* attempts via telephone; then
2. 1 documented* trip by study center personnel to a subject’s last known address; then
3. 1 certified, receipted postal letter.
* Receipts, dates and times must be documented in source documents.
Note: A subject who does not return to study but does eventually respond to a site’s attempts and is known to 
be in general good health will be considered as “no longer willing to participate in the study”.
6.7. Unscheduled Visits for Pain, Adverse Events
If at any time pain increases during the Treatment Period, rescue medication therapy is 
preferred, which includes IR morphine as necessary. For unscheduled visits due to an 
increase in pain where up-titration is necessary, record at a minimum, the Numeric Rating
Scale (NRS) pain and COWS scores on the appropriate CRF in addition to any related CRF 
(eg, concomitant medications, dosing log).  An unscheduled visit for any other reason (most 
typically an AE) will require the Visit 6/ET procedures to be performed (Schedule of 


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Activities).  An unscheduled visit due to a combination of an AE and an increase in pain 
requires the Visit 6 procedures.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.
The study team will be informed of these incidents in a timely fashion.
7.1. Analgesic Effect Assessments
7.1.1. Pain Intensity
Daily average NRS-Pain scores will be assessed with an 11-point NRS ranging from zero (no 
pain) to 10 (worst possible pain) captured on the diary (Appendix 7). A subject will rate their
average pain intensity during the past 24 hours by choosing the appropriate number from 0 to 
10 as shown below.  The subject will conduct the self-assessment daily with the caregiver(s) 
in the evening prior to bedtime and recorded in the diary during the Treatment and 
Post-Treatment Periods. These diary assessments will be reviewed by the investigator at the 
in-clinic visits for the purpose of assessing the need for titrating study drug and will not be 
documented.  Pain Intensity will also be completed at the in-clinic visits during the 
Treatment and Post-Treatment Periods.  Only the in-clinic visit pain assessments will be 
documented for analysis.
Select the number that best describes your average pain in the past 24 hours.  (Select one 
number only).
7.1.2. Rescue Medication Use
The use of Rescue Medication will be recorded in the diary during the Treatment and
Post-Treatment Periods.  
The administration of acetaminophen and/or NSAID’s administered during the study is 
recorded by the caregiver(s), but is not to be more than required by label and at the direction 
of the investigator.


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7.2. Safety Assessments
7.2.1. Adverse Events
7.2.1.1. Recording of Adverse Events by Investigator
The investigator is responsible for the detection and documentation of all events meeting the 
definition of an AE or serious adverse event (SAE).  All AEs and SAEs will be recorded in 
the source documents.  All AEs will be entered on the appropriate CRF page from the time of 
dosing until completion of the End of Study requirements.  All SAEs will be recorded on the 
CRF from the time written informed consent is given until 28 days after the last dose of study 
drug is administered.  Information collected will include the nature of the event, as well as its 
date and time of onset, intensity, duration, causality, and outcome.  Even if the investigator 
regards the AE as not reasonably attributable to study drug, the event must be recorded in the 
source documentation including the CRF.
7.2.1.2. Recording of Adverse Events Using a Home Diary
The study caregiver (parent or legal guardian) will be instructed on the use of a diary, which 
the caregiver will record dosing information, concomitant medications, and AEs between 
visits to the clinic.  The caregiver will be instructed on the signs and symptoms of opioid 
overexposure (eg, toxicity), opioid withdrawal, as well as other signs and symptoms 
commonly associated with opioid AEs (eg, nausea, headache, constipation). 
The Clinical Site will contact the caregiver (ie, at least on a weekly basis) to ensure that the 
caregiver is monitoring for opioid AEs and is recording all relevant AE information in the 
home diary.  All AEs will be brought to the attention of the investigator.
7.2.2. Vital Signs
Vital signs, including resting systolic and diastolic blood pressure, pulse, and respiratory rate, 
are performed at designated study visits as outlined in the Schedule of Activities.
7.2.3. Clinical Laboratory Tests
The hematology, clinical chemistry, and urinalysis tests presented in Table 1 are performed 
at designated study visits as outlined in the Schedule of Activities.
Table 1.
Clinical Laboratory Tests
Serum Chemistry
Alanine aminotransferase (ALT; serum glutamate 
pyruvate transaminase) 
Chloride
Albumin
Serum creatinine
Alkaline phosphatase
Creatine phosphokinase
Aspartate aminotransferase (AST; serum glutamic 
oxaloacetic transaminase)
Glucose
Bicarbonate
Phosphorus
Bilirubin (total)
Potassium
Blood urea nitrogen
Protein (total)
Calcium
Sodium


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Serum Chemistry
Cholesterol (total)
Hematology
Hematocrit
Red blood cell count
Hemoglobin
White blood cell count
Platelet count
White blood cell differential count (lymphocytes, 
monocytes, neutrophils, eosinophils, and basophils)
Other
Routine urinalysis (dip-stick unless otherwise indicated)
7.2.4. Electrocardiogram
A single, 12-lead ECG will be performed at Screening for determination of ECG-related 
eligibility.  The ECG should be recorded after subjects have been resting at least 5 minutes in 
the supine position in a quiet environment. An abnormal, clinically significant finding at 
screen will be cause to not enroll the subject. Post-Screening ECGs may be collected if 
needed (for-cause), at the discretion of the investigator.  In the event a clinically significant 
ECG abnormality is observed on a for-cause ECG, the investigator should consider 
evaluation of the subject by a cardiologist. 
7.2.5. Clinical Opiate Withdrawal Scale (COWS)
Clinical opiate withdrawal is assessed by a clinician-administered instrument, the COWS, at 
designated study visits as outlined in the Schedule of Activities. 
The COWS (Appendix 8) contains 11 common opiate withdrawal signs or symptoms rated 
by the clinician.  The summed score of the 11 items is used to assess a subject’s level of 
opiate withdrawal.23
A subject experiencing a COWS score 13 is treated for opiate withdrawal signs and
symptoms according to the investigator’s medical judgment.
7.2.6. Physical Examination
A physical examination is performed at designated study visits as outlined in the Schedule of 
Activities.  Physical examinations may be conducted by a physician, trained physician's 
assistant, or nurse practitioner as acceptable according to local regulation.  A complete 
physical examination will include head, ears, eyes, nose, mouth, skin, heart and lung 
examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface.  Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight.  
Height and weight is measured only at Visit 1 of the Screening Period.


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7.2.7. Urine Drug Test
A urine drug sample is collected at Screening, as outlined in the Schedule of Activities, for 
the purpose of mainly detecting illicit drug substances. Certain positive test results may be 
acceptable providing documentation is confirmed by the investigator. An opioid finding at 
the Screening visit is an expected result due to a subject’s standard of care therapy not being 
discontinued at Screen or washed out by the Baseline visit. Illicit drugs found during these 
tests will disqualify the subject from entering the study.
Specifically, the following drugs will be screened for by immunoassay by a central 
laboratory:

Opioids ( ie, codeine, morphine, hydrocodone, hydromorphone, dihydromorphone, 
oxycodone);

Amphetamines (including methamphetamine and ecstasy);

Phencyclidine;

Cocaine;

Tetrahydrocannabinol (marijuana);

Methadone.
7.3. Pregnancy Testing
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at the Screening and Visit 6/ET, and a urine pregnancy 
test, with sensitivity of at least 25 mIU/mL, will be performed at all other study visits 
(ie, Visits 2-5), including unscheduled visits.  A negative pregnancy result is required before 
the subject may receive the study drug.  Pregnancy tests will also be done whenever one 
menstrual cycle is missed during the treatment period (or when potential pregnancy is 
otherwise suspected) and at the end of the study to confirm the subject has not become 
pregnant during the study.  In the case of a positive human chorionic gonadotropin test, the 
subject will be withdrawn from study medication but may remain in the study.  Pregnancy 
tests may also be repeated as per request of IRB/Ethics Committees (EC) or if required by 
local regulations.
7.4. Assessment of Suicidal Ideation and Behavior
7.4.1. Columbia- Suicide Severity Rating Scale (C-SSRS) 
Suicide ideation and behaviors will be evaluated at all scheduled visits from Screening 
(Visit 1) through End of Study (Visit 7).  The age-appropriate scale must be utilized based 
upon the subject’s age at the Screen (Visit 1) visit.  


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For subjects who will be ages 7-11:

The Children’s Lifetime/Recent (Version 6/23/10) (Appendix 3) of the C-SSRS 
should be completed at the Screening Visit (Visit 1).  Please note the Lifetime/Recent 
scale refers to the subject’s lifetime experience.  At all study visits following the 
Screening Visit, the Children’s Since Last Visit (Version 6/23/10) (Appendix 5) of 
the C-SSRS should be utilized, even if the child has their 12th birthday during the 
study.  The Since Last Visit version refers to the subject’s experience since their last 
visit.
For subjects who will be ages 12-17:

The Baseline/Screening (Version 1/14/09) (Appendix 4) of the C-SSRS should be 
completed at the Screening Visit (Visit 1).  Please note the Screening scale refers to 
the subject’s lifetime experience.  At all study visits following Visit 1, the Since Last 
Visit (Version 1/14/09) (Appendix 6) of the C-SSRS should be utilized.  The Since 
Last Visit version refers to the subject’s experience since their last visit. 
At screening, if the subject endorses a 4 or 5 on the C-SSRS ideation section or reports any 
suicidal behavior, then the subject is not eligible for study participation and an evaluation of 
suicide risk (risk assessment) must be completed.  Refer to Section 7, Assessments for details 
on Risk Assessment.
At every on-site study visit after screening, if the subject endorses a 4 or 5 on the C-SSRS 
ideation section or reports any suicidal behavior, then the subject must be discontinued as 
outlined in Section 6.5, Subject Withdrawal and an evaluation of suicide risk (risk 
assessment) must be completed.  Refer to Section 7, Assessments for details on Risk 
Assessment.
Risk Assessment: In the event that a subject endorses a 4 or 5 on the C-SSRS ideation 
section or reports any suicidal behavior, an evaluation of suicide risk (risk assessment) 
completed as part of the psychiatric evaluation and assessment of subject safety to participate 
will be done by the following child and adolescent mental health provider (MHP): In the 
United States: 1) Child and Adolescent Psychiatrists (board certified or board eligible), 2) 
psychiatrists who have training and experience in the diagnosis and treatment of psychiatric 
disorders in the pediatric population, or 3) Psy.D. or Ph.D. level Clinical Psychologists, 
licensed Master’s level Clinical Social Workers (MSW), or licensed psychiatric Nurse 
Practitioners (PNP) who have training and experience in the diagnosis and treatment of 
psychiatric disorders in the pediatric population.
Written documentation of the risk assessment should be included in the subject’s source 
documentation, and the risk assessment CRF will be completed. The risk assessment CRF 
serves as further verification that the psychiatric evaluation and assessment of subject safety 
has been completed for all subjects endorsing items 4 or 5 on the C-SSRS ideation section or
reporting any suicidal behavior. Note: Per protocol, subjects endorsing items 4 or 5 on the 
C-SSRS ideation section or reporting suicidal behavior at screening are ineligible for study 


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participation. Subjects endorsing items 4 or 5 on the C-SSRS ideation section or reporting 
any suicidal behavior following the Screening visit must be withdrawn from the study and 
will receive the appropriate medical care.  Refer to Section 6.5, Subject Withdrawal.
7.5. Pharmacokinetic Evaluation
7.5.1. Blood Sample Collection and Handling
During Visit 4, a total of two 6 mL (2×6 mL) PK samples of blood will be taken at least two 
hours apart for the purpose of quantifying the concentrations of morphine, M3G, M6G, 
naltrexone, and 6--naltrexol in plasma. PK samples will be collected at Visit 6 or at Early 
Termination if they are not collected at Visit 4. The clock time of the first PK sample will be 
documented (and noted relative to the clock time of the morning dose of PF-06412528) on 
the CRF.  The second PK sample will be drawn at least 2-hours after the first sample and the 
clock time recorded.  Note: The exact dosing date and time for the previous 3 doses are also 
to be recorded on the appropriate CRF.
Plasma samples received by the bioanalytical laboratory will be assayed for either morphine
and morphine metabolites (MG3, MG6) or naltrexone and 6--naltrexol using a validated 
analytical method that conforms with Pfizer’s standard operating procedures.  All samples 
collected during the study will be assayed and retained in accordance with local regulations 
and, if not used (or reused) within this timeframe, will be destroyed. Please refer to the 
central laboratory procedures manual for collection and storage information.
7.5.2. Plasma Sample Shipment to Bioanalytical Laboratory
The shipping procedures and address of the bioanalytical laboratory will be provided under 
separate cover.
7.6. Blood Volume
Total blood sampling volume for the individual subjects is approximately 36 mL.  
Blood Volume
Sample Type
Sample 
Volume (mL)
Number of Sampling Times
Total Volume 
(mL)
Screening
Treatment  Period
End of Study
Safety Labs
6
1
1
12
Pregnancy*
6
1
1
12
PK
6
6 mLX 2
12
TOTAL
36
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed catheters.  
* Includes only females of child-bearing age who are sexually active.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the study drug(s) will be reported as described in the following sections. 


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For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
trial. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving study drug, through and including 28 calendar days after the last administration of 
the study drug.  Serious adverse events occurring to a subject after the active reporting period 
has ended should be reported to the Sponsor if the investigator becomes aware of them; at a 
minimum, all serious adverse events that the investigator believes have at least a reasonable 
possibility of being related to study drug are to be reported to the Sponsor.

AEs (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of study treatment through last subject visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.


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Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the medication error 
CRF which is a specific version of the AE page, and on the SAE form when appropriate.  In 
the event of medication dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the study drug;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms, and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or withdrawal from the study, significant 
additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) levels 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events. 


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The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin 2 X ULN with no evidence of hemolysis 
and an alkaline phosphatase 2 X ULN or not available.

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).
Concurrent with

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least 1 X ULN or if 
the value reaches 3 X ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment. 
In addition to repeating AST and ALT, laboratory tests should include albumin, creatine 
kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin 
time (PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced subject, surgery, blood transfusion, history of 
liver or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for liver function test (LFT) abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 


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wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.


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8.8. Severity Assessment
If required on the AE case report forms (CRFs), the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the AE.  For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the study drug caused or contributed to an AE; generally 
the facts (evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the study drug caused the event, then the event 
will be handled as “related to study drug” for reporting purposes, as defined by the Sponsor 
(see the section on Reporting Requirements).  If the investigator's causality assessment is 
"unknown but not related to study drug", this should be clearly documented on study records. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For investigational products study treatment and for marketed products, an exposure during 
pregnancy (EDP) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or being
exposed (eg, because of treatment or environmental exposure) to the study drug; or
the female becomes, or is found to be pregnant after discontinuing and/or being
exposed to the study drug.
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).


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2. A male has been exposed (eg, because of treatment or environmental exposure) to 
the study drug prior to or around the time of conception and/or is exposed during his 
partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the study drug, the investigator must submit this information 
to the Pfizer Drug Safety Unit on a SAE report form and EDP supplemental form, regardless 
of whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure. The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to study drug.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to safety within 24 hours of investigator’s awareness, 
using the SAE Report form, regardless of whether there is an associated AE/SAE.  Since the 
information does not pertain to a subject enrolled in the study, the information is not reported 
on a CRF, however a copy of the completed SAE Report form is maintained in the study 
master file.
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a subject withdraws due to an SAE, the SAE must be reported in accordance with the 
reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent/legal guardian.  In addition, each study subject/parent/legal guardian
will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy and exposure via 
breastfeeding and occupational exposure cases.
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 


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may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative.
8.14.2. Non-serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol for secondary 
endpoints; any major modifications of the primary endpoint definition and/or its analysis will 
be reflected in a protocol amendment.
Additional unplanned analyses may be required after all planned analyses have been 
completed.  Any unplanned analyses will be clearly identified in the final clinical study 
report. 
Descriptive summaries for variables measured on a continuous scale will include the mean, 
standard deviation, median, minimum, and maximum values.  Descriptive summaries for 
variables measured on a categorical scale will include the number and percentage of subjects 
who presented each value.
9.1. Sample Size Determination
The study plans to enroll approximately 140 subjects for the purpose of establishing a safety 
database, with at least 100 subjects exposed to at least 2 weeks of the Maintenance Phase
with neither age group exceeding a 3:1 margin compared to the other age group (7-11 years 
old and 12-17 years old).  
 
CCI


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9.2. Efficacy Analysis
Analgesic effect analyses will be performed using all available in-clinic pain intensity data 
from the safety population (see Section 9.4).  The baseline pain intensity score will be the 
score from the in-clinic assessment at Visit 2.
Pain intensity scores will be summarized descriptively by study week and phase of the 
Treatment Period (Conversion/Titration Phase and Maintenance Phase).  Actual scores and 
the change and percentage change from baseline will be calculated.
Rescue medication or additional analgesic medication use over time will be summarized 
descriptively.
9.3. Pharmacokinetic Analysis
9.3.1. Pharmacokinetic Analysis Datasets
The PK concentration population will be defined as all subjects with at least 1 plasma 
concentration measurement in this study.  The PK analysis population will be defined as all 
pediatric subjects who have usable PK data (ie, data for which the relationship between the 
time of dose time of sampling can be determined) and are included in the estimates of the 
primary pharmacokinetic parameters of interest. 
9.3.2. Pharmacokinetic Endpoints
Primary PK endpoints will include estimates of morphine Css,av and CL/F.  Secondary PK 
endpoints will include Vz/F of morphine, data permitting. The exposure levels of the 
metabolites of morphine M3G and M6G, naltrexone, 6-β-naltrexol following multiple dose 
treatment with PF-06412528.  Graphical representations and regression analyses may be used 
to characterize the dose-exposure relationships for morphine, naltrexone, and 6-β-naltrexol
(data permitting).
9.3.3. Pharmacokinetic Analysis
Given the expected very low fluctuation in steady-state morphine concentrations following 
PF-06412528 BID dosing in children based on PF-06412528 study ALO-KNT-202 in adults,
the concentrations observed during the maintenance phase will be used as an estimate of 
Css,av of morphine and its metabolites (data permitting) in pediatric subjects. The CL/F of 
morphine will be estimated using a ratio of the daily dosing rate of PF-06412528 and the 
estimates of morphine Css,av in the Maintenance Phase. The concentration-time dataset will 
be analyzed to obtain estimates for Vz/F of morphine in pediatric subjects, data permitting. 
Covariates of interest (PF-06412528 dosage, age, body weight, gender, concomitant 
medications etc) will be assessed for their ability to account for the observed variability in 
morphine Css,av.
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The observational data will be summarized using descriptive statistics (mean, standard 
deviation, median, minimum, and maximum) for the study group as a whole. Data 
permitting, graphical representations and regression analyses may be used to characterize the 
dose-exposure relationships for morphine, naltrexone, and 6--naltrexol.
9.4. Safety Analysis
One safety population is planned consisting of all subjects who participate in the Treatment 
Period and receive at least one dose of PF-06412528.
Safety data will be summarized for the Safety population. 
9.4.1. Adverse Events
All AEs will be coded to System Organ Class and Preferred Term (using MedDRA).  
Treatment-emergent AEs will be defined as AEs that commence on or after the start of 
PF-06412528 administration.  Subjects who have multiple events in the same System Organ 
Class and Preferred Term in a period will be counted only once at each level of summation 
(overall, by System Organ Class, and by Preferred Term).
Treatment-emergent AEs will be summarized separately for the Conversion/Titration Phase
and the Maintenance Phase (including up to End of Study) by System Organ Class, Preferred 
Term, maximum intensity, and highest relationship to study drug.
Serious AEs and those leading to study withdrawal will be summarized.
9.4.2. Clinical Laboratory Values
Clinical laboratory data (hematology, chemistry and urinalysis) including changes from 
Screening will be summarized descriptively by study visit, as applicable.
9.4.3. Electrocardiogram
Electrocardiogram data including changes from Screening will be summarized descriptively 
by study visit, as applicable.
9.4.4. Vital Signs
Vital signs data including changes from Baseline will be summarized descriptively by study 
visit, as applicable. 
9.4.5. Opiate Withdrawal
COWS scores will be summarized descriptively by study visit, as applicable.  Additionally, 
for COWS, the proportion of subjects with mild (COWS Score 5-12), moderate 
(COWS Score 13-24), moderately severe (COWS Score 25-36), or severe withdrawal 
(COWS Score >36) will be presented.


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9.4.6. Dosing and Compliance
Study drug administration will be summarized descriptively by each subject’s mean and 
median total daily dose and duration of exposure, separately for the Conversion/Titration 
Phase and Maintenance Phase.
9.5. Interim Analysis
No interim analysis is planned for this study. 
9.6. Data Monitoring Committee 
This study will use an IRC. The IRC will be responsible for ongoing monitoring of the 
safety of subjects in the study according to the Charter. The recommendations made by the 
IRC to alter the conduct of the study will be forwarded to the Clinical Lead or delegate for 
final decision.  Pfizer will forward such decisions, which may include summaries of 
aggregate analyses of endpoint events and of safety data that are not endpoints, to regulatory 
authorities, as appropriate.  
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or
discontinuation of the study or for longer if required by applicable local regulations.


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP [International Committee on Harmonization (ICH)]
1996), and the Declaration of Helsinki (World Medical Association 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where
required by laws.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify the study subjects.  The study 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.


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The investigator must ensure that each study subject, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation. 
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 
signer’s relationship to the study subject (eg, parent, spouse), and that the subject’s assent 
was obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.
In determining which potential subjects are capable of providing assent, the investigator 
and/or IRB/EC should take into account the age, maturity, and psychological state of the 
potential subjects.  (The American Academy of Pediatrics advises that assent usually should 
be obtained from all subjects with an intellectual age of 7 years or more.)  If a child or 
adolescent is legally unable to provide informed consent to participate in the clinical trials, 
informed consent must be obtained instead from the legally acceptable representative of the 
child or adolescent, usually their parent(s) or legal guardian, before the child can participate 
in the study. 
Assent is not required if the investigator and/or the IRB/EC determine that the capability of 
the child or adolescent subject is so limited that they cannot provide assent, or if the 
intervention or procedure involved in the research holds out a prospect of direct benefit that 
is important to the health or well-being of the potential subjects and is available only in the 
context of the research.  In addition, in certain circumstances full informed consent from 
“emancipated minors” is both necessary and sufficient, rather than assent plus the consent of 
a legally acceptable representative.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legal representative before any study-specific 
activity is performed. The investigator will retain the original of each subject's signed 
consent document.


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12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures. 
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the study
treatment, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as Last Subject Last Visit and meeting all 
of the End of Study requirements.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of PF-06412528 at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 5 days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in subjects that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual subjects has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.


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For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
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Goodman JE, McGrath PJ.  The epidemiology of pain in children and adolescents: a 
review.  Pain. 1991 Sep;46(3):247–64.
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American Pain Society, Research Education Treatment Advocacy.  Principles of 
analgesic use in the treatment of acute pain and cancer pain.  6th ed.  Glenview, IL:  
American Pain Society; 2008.
3.
Berde CB, Sethna NF.  Analgesics for the treatment of pain in children.  N Engl J Med. 
2002;347(14):1094-103.
4.
Chambliss CR, Heggen J, Copelan DN, Pettignano R.  The assessment and management 
of chronic pain in children.  Pediatr Drugs. 2002;4(11):737-46.
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McCulloch R, Collins JJ.  Pain in children who have life-limiting conditions.  Child 
Adolesc Psychiatr Clin N Am. 2006;15(3):657-82.
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Berde CB, Walco GA, Krane EJ, et al., Pediatric analgesic trials designs, measures, and 
extrapolation: report of an FDA scientific workshop.  Pediatrics 2012;129(2):354-64.
7.
McGrath PJ, Walco GA, Turk DC, Dworkin RH, Brown MT, Davidson K, et al.  Core 
outcome domains and measures for pediatric acute and chronic/recurrent pain clinical 
trials: PedIMMPACT recommendations.  J Pain. 2008;9(9):771-83.
8.
EMBEDA(morphine sulfate and naltrexone hydrochloride exteneded-release 
capsules) prescribing information.  King Pharmaceuticals, Inc., Bristol, TN.  June 2009. 
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Choonara A, McKay P, Hain R, Rane A.  Morphine metabolism in children.  Br. J. Clin. 
Pharmac. 1989;28:599-604.
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Bhat R, Chari G, Gulati A, Aldana O, Velamati R, and Bhargava H.  Pharmacokinetics 
of a single dose of morphine in preterm infants during the first week of life.  J 
Pediatrics.  1990:117;477-81.
11.
Hunt A, Simon J, Dick G, Goldman MB.  Population pharmacokinetics of oral 
morphine and its glucuronides in children receiving morphine as immediate-release 
liquid or sustained-release tablets for cancer pain.  J of Pediatrics.  1999:135(1);47-55.
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Berde CB, Beyer JE, Bournaki MC, Levin CR, Sethna NF.  Comparison of morphine 
and methadone for prevention of postoperative pain in 3- to 7-year old children.  J 
Pediatrics.  1991:119;136-41.
13.
Compton WM, Volkow ND.  Major increases in opioid analgesic abuse in the United 
States: concerns and strategies.  Drug Alcohol Depend. 2006 Feb 1;81(2):103-7.
14.
Sandra Lynn Kweder, M.D., Deputy Director, Office of New Drugs, CDER testimony 
before the House Subcommittee on Health, May 22, 2007.


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15.
Yaksh TL and Wallace MS. Chapter 18. Opioids, Analgesia, and Pain Management. 
Treatment of Acute Opioid Toxicity. Section on “treatment of acute opioid toxicity: 
symptoms and diagnosis”, page 39 of 46 pages. In: Brunton LL, Chabner BA, 
Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 
12th ed. New York: McGraw-Hill; 2011. 
http://www.accessmedicine.com/content.aspx?aID=16663974. Accessed December 2, 
2011.
16.
American Heart Association Guidelines for Cardiopulmonary Resuscitation and 
Emergency Cardiovascular Care. Management of Cardiac Arrest. Circulation 2005; 
112:IV-58-IV-66. http://www.circulationaha.org.
17.
Stephens E, Louden M, VanDeVoort JT, et al. Toxicity, Opioids Treatment and 
Management: Emergency Department Care. Medscape 2010. 
http://emedicine.medscape.com/article/815784-overview.
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Plum F. and Posner J. “Chapter One, The Pathologic Physiology of Signs and 
Symptoms of Coma”. The Diagnosis of Stupor and Coma. Third Edition. Philadelphia: 
FA Davis Company, 1980.
19.
Stephens E, Louden M, VanDeVoort JT, et al. Toxicity, Opioids Treatment and 
Management: Emergency Department Care. Medscape 2010. 
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20.
Ista E, van Dijk M, Gamel C, Tibboel D, de Hooh M,  Withdrawal symptoms in 
children after long-term administration of sedatives and/or analgesics: a literature
review. “ Assessment remains troublesome”. Intensive care Medicine. 2007; 33: 
1396-1406. 
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Wesson D, Ling W.  The Clinical Opiate Withdrawal Scale (COWS).  J Psychoactive
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Pharmacol.  2012;52:1601-1606.


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Appendix 1. Abbreviations
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC 
area under the curve
BID
twice-a-day
BPCA
Best Pharmaceuticals for Children Act
CL/F
apparent oral clearance
Cmax
peak concentration
CNS
Central Nervous System
COWS
Clinical Opiate Withdrawal Scale
CRF
case report form
CSA
clinical study agreement
Css, av
average concentration at steady-state
Css, min
minimum concentration at steady-state
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
coefficient of variation
DAI
dosage and administration instructions
DEA
Drug Enforcement Agency
EC
ethics committee
ECG
electrocardiogram
EDP
exposure during pregnancy
ET
early termination
FDA
Food and Drug Administration (United States)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HCl
hydrochloride
ICH
International Conference on Harmonisation
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IVR
interactive voice response
LFT
liver function test
M3G
morphine 3 glucuronide
M6G
morphine 6 glucuronide
medDRA
Medical Dictionary and Regulatory Activities
MHP
mental health provider
mL
milliliter
NRS
Numeric Rating Scale


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Abbreviation
Term
NSAID
non-steroidal anti-inflammatory drug
PASS
Post-Authorization Safety Study
PK
pharmacokinetic
PREA
Pediatric Research Equity Act
QD
once-a-day
SAE
serious adverse event
SIB
suicidal ideation and behavior
SOC
standard of care
SRSD
single reference safety document
UDT
urine drug test
ULN
upper limit of normal
US
United States
Vz/F
apparent volume of distribution


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Appendix 2. Conversion Guide
PF-06412528 CONVERSION GUIDE
This conversion guide summarizes published relative potency data to help healthcare 
professionals convert treatment regimens for subjects with moderate to severe chronic pain to 
an approximate daily equianalgesic dose of PF-06412528.  The conversion ratios in this 
guide are for converting from other opioids to PF-06412528 only.  Only oral and transdermal 
(not rectal) conversion information is provided.  These conversion ratios are only 
approximate and are not to be used in the reverse.
The tables included in this booklet should be considered for guidance only, and the actual 
dose of any opioid product should be based on clinical judgment and adjusted on an 
individual basis.
IMPORTANT INFORMATION ABOUT THIS GUIDE:
Due to incomplete cross-tolerance when converting from a non-morphine analgesic to 
PF-06412528, the following equianalgesic conversion tables should be used with some 
degree of caution.  For this reason, it is better to underestimate the subject’s 24-hour oral 
morphine requirement and provide rescue medication rather than to overestimate and manage 
an adverse event.1
TRANSDERMAL FENTANYL PRODUCTS:

Duragesic(fentanyl transdermal system) 12.5 mcg/h, 25 mcg/h, 50 mcg/h, 
75 mcg/h, 100 mcg/h.

Generic equivalent.
HOW TO CONVERT FROM TRANSDERMAL FENTANYL TO PF-06412528:
1. Determine the total daily dose of transdermal fentanyl.
Note that fentanyl is approximately 50 to 150 times more potent than morphine.2
2. Calculate the conversion of the total daily dose of the current transdermal fentanyl 
therapy into the equianalgesic dose of morphine, using the appropriate ratio (based on 
an approximate equianalgesic ratio of 10:1 for a 10 mcg fentanyl to 1 mg morphine 
comparison).3
3. Refer to the analgesic table below to find the equianalgesic dose of PF-06412528.  In 
general, it is safest to give half of the estimated daily morphine demand as the initial 
dose and to manage inadequate analgesia by supplementation with rescue medication.


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4. Administer the calculated dose in the most convenient dosing strength of 
PF-06412528, either as a single dose q24h or in 2 divided doses q12h.  PF-06412528 
should not be given more frequently than every 12 hours.
CONVERTING FROM TRANSDERMAL FENTANYL TO PF-06412528:2,3,4,5,6
Transdermal
fentanyl daily dosea
Equianalgesic 
morphine daily 
dose
(mg)
Suggested 
equianalgesic dose of
PF-06412528 
administered q24h or 
in 2 divided doses 
q12h
(mg)
Suggested starting dose of 
PF-06412528 at ≈50% 
reduction based on existing 
capsule strengths
(mg) b
12.5 mcg/h=300 mcg/day
30
30
15 QD
25 mcg/h=600 mcg/day
60
60
15 BID
50 mcg/h=1200 mcg/day
120
120
30 BID
75 mcg/h=1800 mcg/day
180
180
2X20 BID
100 mcg/h=2400 mcg/day
240
240
60 BID
a Calculate the total daily dose of transdermal fentanyl.
b It is likely that rescue medication may be needed for breakthrough pain until the dose of PF-06412528 can 
be titrated to the effective daily dose, thus ensuring a smooth transition.  After patch removal, 17 or more 
hours are required for a 50% decrease in serum fentanyl concentration in healthy individuals.3
There is a lack of systematic evidence bearing on these types of analgesic substitutions.  
Therefore, specific recommendations are not possible.  Healthcare professionals are advised 
to refer to published relative potency data, keeping in mind that such ratios are only 
approximate.
In general, it is safest to give half of the estimated daily morphine demand as the initial dose 
and to manage inadequate analgesia by supplementation with rescue medication.
HYDROCODONE PRODUCTS:

Lorcet(hydrocodone bitartrate and acetaminophen tablets USP 10 mg/650 mg); 
LorcetPlus (hydrocodone bitartrate and acetaminophen tablets USP 
7.5 mg/650 mg).

Lortab(hydrocodone bitartrate and acetaminophen tablets, USP) 5 mg/500 mg, 
7.5 mg/500 mg, 10 mg/500 mg; Lortab Elixir (hydrocodone bitartrate and 
acetaminophen oral solution) 7.5 mg/500 mg per 15 mL.

Maxidone(hydrocodone bitartrate and acetaminophen tablets) 10 mg/750 mg.

Norco(hydrocodone bitartrate and acetaminophen tablets USP) 5 mg/325 mg, 
7.5 mg/325 mg, 10 mg/325 mg.

Vicodin(hydrocodone bitartrate and acetaminophen tablets, USP) 5 mg/500 mg; 
Vicodin ES(hydrocodone bitartate and acetaminophen tablets, USP) 


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7.5 mg/750 mg; Vicodin HP(hydrocodone bitartate and acetaminophen tablets, 
USP) 10 mg/660 mg.

Vicoprofen(hydrocodone bitartrate and ibuprofen tablets) 7.5 mg/200 mg.

Zydone(hydrocodone bitartrate and acetaminophen tablets, USP) 5 mg/400 mg, 
7.5 mg/400 mg, 10 mg/400 mg.

Generic equivalent and other immediate-release (IR) products.
HOW TO CONVERT HYDROCODONE TO PF-06412528:
1. Determine the total daily dose of hydrocodone. 
2. Calculate the conversion of the total daily dose of the current hydrocodone therapy 
into the equianalgesic dose of morphine using the appropriate ratio (based on an 
approximate equianalgesic ratio of 1:1).7
3. Refer to the analgesic table below to find the equianalgesic dose of PF-06412528.  In 
general, it is safest to give half of the estimated daily morphine demand as the initial 
dose and to manage inadequate analgesia by supplementation with rescue medication. 
4. Administer the calculated dose in the most convenient dosing strength of 
PF-06412528, either as a single dose q24h or in 2 divided doses q12h.  PF-06412528 
should not be given more frequently than every 12 hours. 
CONVERTING FROM HYDROCODONE TO PF-06412528:
Hydrocodone
daily dose
(mg)a
Equianalgesic 
morphine daily dose 
(mg)
Suggested 
equianalgesic dose 
of PF-06412528 
administered q24h 
or in 2 divided doses 
q12h
(mg)
Suggested starting 
dose of PF-06412528 
at ≈50% reduction 
based on existing 
capsule strengths
(mg) b
20
20
20
10 QD
30
30
30
15 QD
40
40
40
10 BID
60
60
60
15 BID
80
80
80
20 BID
a Calculate the total daily dose of hydrocodone.  At lower doses of hydrocodone, it may be necessary to start 
with the lowest strength of PF-06412528.
There is a lack of systematic evidence bearing on these types of analgesic substitutions.  Therefore, specific 
recommendations are not possible.  Healthcare professionals are advised to refer to published relative 
potency data, keeping in mind that such ratios are only approximate.
b It is likely that rescue medication may be needed for breakthrough pain until the dose of PF-06412528 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.


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In general, it is safest to give half of the estimated daily morphine demand as the initial dose 
and to manage inadequate analgesia by supplementation with rescue medication.
HYDROMORPHONE PRODUCTS:

Dilaudid(hydromorphone hydrochloride) Tablets, 2 mg, 4 mg, 8 mg; Dilaudid Oral 
Liquid, (5 mg/5 mL).

Generic equivalent and other immediate-release (IR) products.
HOW TO CONVERT FROM HYDROMORPHONE TO PF-06412528:
1. Determine the total daily dose of hydromorphone. 
2. Calculate the conversion of the total daily dose of the current hydromorphone therapy 
into the equianalgesic dose of morphine, using the appropriate ratio (based on an 
approximate equianalgesic ratio of 1:4).7
3. Refer to the analgesic table below to find the equianalgesic dose of PF-06412528.  In 
general, it is safest to give half of the estimated daily morphine demand as the initial 
dose and to manage inadequate analgesia by supplementation with rescue medication. 
4. Administer the calculated dose in the most convenient dosing strength of 
PF-06412528, either as a single dose q24h or in 2 divided doses q12h.  PF-06412528 
should not be given more frequently than every 12 hours. 
CONVERTING FROM HYDROMORPHONE TO PF-064125287-9:
Hydromorphone daily 
dose
(mg)a
Equianalgesic 
morphine dose
(mg)
Suggested 
equianalgesic dose 
of PF-06412528 
administered q24h 
or in 2 divided doses 
q12h
(mg)
Suggested starting 
dose of PF-06412528 
at ≈50% reduction 
based on existing 
capsule strengths
(mg) b
6
24
20
10 QD
8
32
30
15 QD
12
48
50
10 BID
16
64
60
15 BID
20
80
80
20 BID
24
96
100
30 BID
a Calculate the total daily dose of hydromorphone. 
There is a lack of systematic evidence bearing on these types of analgesic substitutions.  Therefore, specific 
recommendations are not possible.  Healthcare professionals are advised to refer to published relative 
potency data, keeping in mind that such ratios are only approximate.
b It is likely that rescue medication may be needed for breakthrough pain until the dose of PF-06412528 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.


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In general, it is safest to give half of the estimated daily morphine demand as the initial dose 
and to manage inadequate analgesia by supplementation with rescue medication.
METHADONE PRODUCTS:

DolophineHydrochloride (methadone hydrochloride tablets, USP) 5 mg, 10 mg.

MethadoseDispersible Tablets, 40 mg (methadone hydrochloride tablets for oral 
suspension USP) and Methadone Hydrochloride Tablets USP, 40 mg (dispersible, 
orange flavored) (methadone hydrochloride tablets for oral suspension USP); 
Methadose Oral Concentrate (methadone hydrochloride oral concentrate USP) 
10 mg/mL; Methadose Sugar-Free Oral Concentrate (methadone hydrochloride oral 
concentrate USP) dye-free, sugar-free, unflavored, 10 mg/mL.

Generic equivalent and other immediate-release (IR) products.
HOW TO CONVERT METHADONE TO PF-06412528:
1. Determine the total daily dose of methadone. 
2. Calculate the conversion of the total daily dose of the current methadone therapy into 
the equianalgesic dose of morphine, using the appropriate ratio (based on an 
approximate equianalgesic ratio of 1:3-15).9,10
3. Refer to the analgesic table below to find the equianalgesic dose of PF-06412528.  In 
general, it is safest to give half of the estimated daily morphine demand as the initial 
dose and to manage inadequate analgesia by supplementation with rescue medication. 
4. Administer the calculated dose in the most convenient dosing strength of 
PF-06412528, either as a single dose q24h or in 2 divided doses q12h.  PF-06412528 
should not be given more frequently than every 12 hours. 
CONVERTING FROM METHADONE TO PF-06412528:2,9,10,11,12
Methadone
daily dose
(mg)a
Equianalgesic 
morphine dose
(mg)
Suggested 
equianalgesic dose 
of PF-06412528 
administered q24h 
or in 2 divided doses 
q12h
(mg)
Suggested starting dose 
of PF-06412528 at 
≈50% reduction based 
on existing capsule 
strengths
(mg) b
20
60
60
15 BID
30
90
90
20 BID
40
120
120
30 BID
50
150
150
2X20 BID
60
180
180
50 BID
80
240
240
60 BID
100
300
300
80 BID
a.
Calculate the total daily dose of methadone.


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There is a lack of systematic evidence bearing on these types of analgesic substitutions.  Therefore, specific 
recommendations are not possible.  Healthcare professionals are advised to refer to published relative 
potency data, keeping in mind that such ratios are only approximate.
b.
It is likely that rescue medication may be needed for breakthrough pain until the dose of PF-06412528 can 
be titrated to the effective daily dose, thus ensuring a smooth transition.
Data on the equianalgesic dose of methadone compared with morphine are inconclusive.  
Conversion ratios in many commonly used equianalgesic dosing tables do not apply in the 
setting of repeated methadone dosing.  Although with single-dose administration, the onset 
and duration of analgesic action as well as the analgesic potency of methadone and morphine 
are similar, methadone’s potency increases over time with repeated dosing.2,9
In general, it is safest to give half of the estimated daily morphine demand as the initial dose 
and to manage inadequate analgesia by supplementation with rescue medication.
OTHER MORPHINE PRODUCTS:

Avinza(morphine sulfate extended-release capsules) 30 mg, 45 mg, 60 mg, 75 mg, 
90 mg, 120 mg. 

Kadian(morphine sulfate extended-release) Capsules, 10 mg, 20 mg, 30 mg, 50 mg, 
60 mg, 80 mg, 100 mg, 200 mg. 

MS Contin(morphine sulfate controlled-release) Tablets, 15 mg, 30 mg, 60 mg, 
100 mg, 200 mg. 

OramorphSR (morphine sulfate) sustained release tablets, 15 mg, 30 mg, 60 mg, 
100 mg. 

Generic equivalent and other immediate-release (IR) products.
HOW TO CONVERT FROM OTHER MORPHINE PRODUCTS TO PF-06412528:
1. Determine the total daily dose of the current opioid therapy being used. 
2. Calculate the conversion of the total oral daily dose of the current morphine therapy 
into the equianalgesic dose of morphine, using the appropriate ratio (1:1). 
3. Refer to the specific analgesic table below to find an equianalgesic dose of 
PF-06412528. 
4. Administer the calculated dose in the most convenient dosing strength of 
PF-06412528, either as a single dose q24h or in 2 divided doses q12h.  PF-06412528 
should not be given more frequently than every 12 hours. 


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CONVERTING FROM OTHER MORPHINE PRODUCTS TO PF-06412528:
Morphine
daily oral dose
(mg)a
Equianalgesic
morphine oral dose
(mg)
Suggested 
equianalgesic dose of 
PF-06412528 
administered q24h or 
in 2 divided doses 
q12h
(mg)
Suggested starting 
dose of PF-06412528 
at ≈50% reduction 
based on existing 
capsule strengths
(mg) b
30
30
30
15 QD
60
60
60
15 BID
90
90
90
20 BID
100
100
100
30 BID
200
200
200
50 BID
a Calculate the total daily morphine dose.  This amount can be given as PF-06412528 in a single daily q24h 
dose or in 2 divided doses q12h.
b Consider giving the subject rescue medication to make up the difference (if the starting dose is less than an 
equianalgesic dose) until the dose of PF-06412528 is titrated to the effective daily dose.
To convert from parenteral morphine, a dose of oral morphine 3 times the daily parenteral 
morphine requirement may be sufficient in chronic use settings. 
OXYCODONE PRODUCTS:

Combunox(oxycodone HCl and ibuprofen) Tablets, 5 mg/400 mg.

OxyContin(oxycodone HCl controlled-release) Tablets, 10 mg, 15 mg, 20 mg, 
30 mg, 40 mg, 60 mg, 80 mg, 160 mg.

OxyFast(oxycodone hydrochloride) Oral Concentrate Solution, 20 mg/1 mL.

OxyIR(oxycodone hydrochloride) Immediate-Release Oral Capsules, 5 mg.

Percocet(oxycodone and acetaminophen tablets, USP) 2.5 mg/325 mg, 
5 mg/325 mg, 7.5 mg/325 mg, 10 mg/325 mg, 10 mg/650 mg.

Percodan(oxycodone and aspirin tablets, USP) 4.8355 mg/325 mg.

Tylox(oxycodone and acetaminophen capsules USP) 5 mg/500 mg.

Generic equivalent and other immediate-release (IR) products.
HOW TO CONVERT OXYCODONE TO PF-06412528:
1. Determine the total daily dose of oxycodone. 
2. Calculate the conversion of the total daily dose of the current oxycodone therapy into 
the equianalgesic dose of morphine, using the appropriate ratio (based on an 
approximate equianalgesic ratio of 1:1.5).7


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3. Refer to the analgesic table below to find the equianalgesic dose of PF-06412528.  In 
general, it is safest to give half of the estimated daily morphine demand as the initial 
dose and to manage inadequate analgesia by supplementation with rescue medication. 
4. Administer the calculated dose in the most convenient dosing strength of 
PF-06412528, either as a single dose q24h or in 2 divided doses q12h.  PF-06412528 
should not be given more frequently than every 12 hours. 
CONVERTING FROM OXYCODONE TO PF-06412528:7,13
Oxycodone
daily dose
(mg)a
Equianalgesic daily 
morphine dose
(mg)
Suggested 
equianalgesic dose of 
PF-06412528 
administered q24h or 
in 2 divided doses 
q12h
(mg)
Suggested starting dose 
of PF-06412528 at ≈50% 
reduction based on 
existing capsule strengths
(mg) b
20
30
30
15 QD
30
45
40
10 BID
40
60
60
15 BID
60
90
90
20 BID
80
120
120
30 BID
100
150
150
2X20 BID
a Calculate the total daily dose of oxycodone.
There is a lack of systematic evidence bearing on these types of analgesic substitutions.  Therefore, specific 
recommendations are not possible.  Healthcare professionals are advised to refer to published relative 
potency data, keeping in mind that such ratios are only approximate.
b It is likely that some rescue medication may be needed for breakthrough pain until the dose of PF-06412528 
can be titrated to the effective daily dose, thus ensuring a smooth transition.
In general, it is safest to give half of the estimated daily morphine demand as the initial dose 
and to manage inadequate analgesia by supplementation with IR morphine.
OXYMORPHONE PRODUCTS:

Opana(oxymorphone hydrochloride) Tablets, 5 mg, 10 mg; Opana ER 
(oxymorphone hydrochloride) Extended-Release Tablets, 5 mg, 7.5 mg, 10 mg, 
15 mg, 20 mg, 30 mg, 40 mg.
HOW TO CONVERT FROM OXYMORPHONE TO PF-06412528:
1. Determine the total daily dose of oxymorphone. 
2. Calculate the conversion of the total daily dose of the current oxymorphone therapy 
into the equianalgesic dose of morphine, using the appropriate ratio (based on an 
approximate equianalgesic ratio of 1:2-10).9,14,15
3. Refer to the analgesic table below to find the equianalgesic dose of PF-06412528.  In 
general, it is safest to give half of the estimated daily morphine demand as the initial 
dose and to manage inadequate analgesia by supplementation with rescue medication. 


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4. Administer the calculated dose in the most convenient dosing strength of 
PF-06412528, either as a single dose q24h or in 2 divided doses q12h.  PF-06412528 
should not be given more frequently than every 12 hours. 
CONVERTING FROM OXYMORPHONE TO PF-06412528:9,14,15
Oxymorphone
daily dose
(mg)a
Equianalgesic 
morphine dose
(mg)
Suggested 
equianalgesic dose of 
PF-06412528 
administered q24h or 
in 2 divided doses 
q12h
(mg)b
Suggested starting 
dose of PF-06412528 
at ≈50% reduction 
based on existing 
capsule strengths
(mg) b
10
20
20
10 QD
20
40
40
10 BID
40
80
80
20 BID
a Calculate the daily dose of oxymorphone.
There is a lack of systematic evidence bearing on these types of analgesic substitutions.  Therefore, specific 
recommendations are not possible.  Healthcare professionals are advised to refer to published relative 
potency data, keeping in mind that such ratios are only approximate.
b It is likely that rescue medication may be needed for breakthrough pain until the dose of PF-06412528 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.
In general, it is safest to give half of the estimated daily morphine demand as the initial dose 
and to manage inadequate analgesia by supplementation with rescue medication.


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REFERENCES:

PF-06412528 Investigator’s Brochure.

Gordon DB, Stevenson KK, Griffie J, Muchka S, Rapp C, Ford-Roberts K. Opioid 
equianalgesic calculations. J Palliat Med. 1999;2(2):209-218. 

Duragesic [package insert]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals Inc; 
February 2008. 

Levy MH. Pharmacologic treatment of cancer pain. N Engl J Med. 
1996;335(15):1124-1132.

Baumann TJ, Strickland J. Pain management. In: DiPiro JT, Talbert RL, Yee GC, 
Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic 
Approach. 7th ed. New York, NY: McGraw-Hill Medical. 2008:989-1003. 

Smith AP, Lee NM, Loh HH. Opioid analgesics and antagonists. In: Munson PL, 
Mueller RA, Breese GR, eds. Principles of Pharmacology: Basic Concepts & Clinical 
Applications. New York, NY: Chapman & Hall; 1995:399-416. 

McCaffery M, Pasero C. Pain: Clinical Manual. 2nd ed. St. Louis, MO: Mosby; 
1999:241-243. 

Dilaudid [package insert]. Stamford, CT: Purdue Pharma LP; 2008.

American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and 
Cancer Pain. 5th ed. Glenview, IL: American Pain Society; 2003. 

Dolophine hydrochloride [package insert]. Columbus, OH: Roxane Laboratories Inc; 
2009. 

Twycross RG. Opioids. In: Wall PD, Melzack R, eds. Textbook of Pain. London, 
England: Churchill Livingstone; 1994:943-962. 

Hanks G, Cherny NI, Fallon M. Opioid analgesic therapy. In: Doyle D, Hanks G, 
Cherny NI, Calman K. Oxford Textbook of Palliative Medicine. 3rd ed. New York, NY: 
Oxford University Press; 2004:316-341. 

OxyContin [package insert]. Stamford, CT: Purdue Pharma LP; 2007. 

Opana ER [package insert]. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2008. 

Sloan P, Slatkin N, Ahdieh H. Effectiveness and safety of oral extended- release 
oxymorphone for the treatment of cancer pain: a pilot study. Support Care Cancer. 
2005;13(1):57-65.


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
CSR ALO-KNT-202.  A Phase II Multi-dose, Double-blind, Crossover Study to Assess 
the Safety, Efficacy, and Pharmacokinetics of Kadian NT (Morphine Sulfate Plus 
Naltrexone Hydrochloride Extended-release Capsules) in Subjects with Chronic Pain 
Due to Osteoarthritis of the Hip or Knee.  06 March 2007.


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Appendix 3. Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Lifetime/Recent (Version 6/23/10)-Age 7-11


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Appendix 4. Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
(Version 1/14/09)-Age12-17 


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Appendix 5. Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s Since Last 
Visit (Version 6/23/10)-Age 7-11


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Appendix 6. Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
(Version 1/14/09)-Age 12-17


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Appendix 7. Pain Numeric Rating Scale (NRS-Pain)
Question:
Select the number that best describes your average pain in the past 24 hours.  (Select one 
number only)
0
1
2
3
4
5
6
7
8
9
10
No
Pain
Worst 
Possible 
Pain


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Appendix 8. Clinical Opiate Withdrawal Scale (COWS)
For each item, check the number that best describes the subject’s signs or symptom.  Rate on 
just the apparent relationship to opiate withdrawal.  For example, if heart rate is increased 
because the subject was jogging just prior to assessment, the increased pulse rate would not 
add to the score.
Resting Pulse Rate: _________beats/minute
Measured after subject 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
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
Sweating: Over past ½ hour not accounted 
for by room temperature or subject 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
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
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
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


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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
Anxiety or Irritability
0 none
1 subject reports increasing irritability or 
anxiousness
2 subject obviously irritable or anxious
4 subject so irritable or anxious that 
participation in the assessment is 
difficult
Bone or Joint Aches: If subject was having 
pain previously, only the additional 
component attributed to opiates withdrawal 
is scored
0
not present
1
mild diffuse discomfort
2
subject reports severe diffuse aching 
of joints/ muscles
4
subject is rubbing joints or muscles 
and is unable to sit still because of 
discomfort
Gooseflesh Skin
0 skin is smooth
3 piloerrection of skin can be felt or hairs 
standing up on arms
5 prominent piloerection
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
Total Score ________
The total score is the sum of all 11 items
Initials of person completing
Assessment: _______
Score: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe; more than 36 = severe 
withdrawal.

SAP_001.pdf: 
B4541006:  SAP V1.0
Final
Page 1 of 12
Protocol B4541006
AN OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND 
PHARMACOKINETICS OF PF-06412528 IN CHILDREN 7-17 YEARS FOR THE 
TREATMENT OF MODERATE-TO-SEVERE CHRONIC PAIN
Statistical Analysis Plan
(SAP)
Version: 1.0
Author:   
 (
, 
 – NY, NY)
 (
, 
 – Durham, NC)
Date:       13 December 2013
PPD
PPD
PPD
PPD


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Distribution list of reviewers for this document prior to final sign-off.
Functional Zone Name
Reviewer’s Name
Study Clinician
Medical Monitor
Clinical Pharmacology
Clinical Pharmacology Statistics
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................6
2.2.1. Primary Objectives .......................................................................................6
2.2.2. Secondary Objectives ...................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Safety Analysis Set....................................................................................................7
5.2. Pharmacokinetic (PK) Analysis Set ..........................................................................7
5.3. Treatment Misallocations..........................................................................................7
5.4. Protocol Deviations...................................................................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Safety Endpoints .......................................................................................................8
6.1.1. Primary .........................................................................................................8
6.1.2. Secondary .....................................................................................................8
6.2. Pharmacokinetics/Pharmacodynamics Endpoints.....................................................8
6.2.1. PK Endpoints................................................................................................8
6.2.1.1. Primary........................................................................................8
6.2.1.2. Secondary....................................................................................8
6.2.2. PD Endpoints................................................................................................9
6.3. Efficacy Endpoints ....................................................................................................9
6.4. Covariates..................................................................................................................9
7. HANDLING OF MISSING VALUES ..................................................................................9
7.1. Concentrations Below the Limit of Quantification...................................................9
7.2. Deviations, Missing Concentrations and Anomalous Values ...................................9
7.3. Pharmacokinetic parameters .....................................................................................9
8. STATISTICAL  METHODOLOGY AND STATISTICAL ANALYSES .........................10


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8.1. Safety Analysis........................................................................................................10
8.1.1. Treatment and Disposition of Subjects.......................................................10
8.1.2. Demographic and Clinical Examination Data............................................10
8.1.3. Discontinuation(s).......................................................................................10
8.1.4. Adverse Events...........................................................................................10
8.1.5. Laboratory Data..........................................................................................10
8.1.6. Electrocardiogram.......................................................................................10
8.1.7. Vital Signs ..................................................................................................10
8.1.8. Opiate Withdrawal......................................................................................11
8.1.9. Columbia-Suicide Severity Rating Scale....................................................11
8.1.10. Dosing and Compliance............................................................................11
8.1.11. Concomitant Treatments...........................................................................11
8.1.12. Screening and Other Special Purpose Data ..............................................11
8.2. PK/PD Analysis.......................................................................................................11
8.2.1. Pharmacodynamic Analysis........................................................................11
8.2.2. Pharmacokinetic Analysis ..........................................................................11
8.3. Efficacy Analysis ....................................................................................................12
9. REFERENCES ....................................................................................................................12


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1. AMENDMENTS FROM PREVIOUS VERSION(S)
None.
2. INTRODUCTION
PF-06412528 capsules consist of controlled-release pellets containing morphine sulfate and 
naltrexone hydrochloride.  The pellets are designed to release morphine in an 
extended-release manner over time while retaining naltrexone, a mu-opioid antagonist, in 
the inner core unless the inner core is disrupted… The drug was developed with the potential 
to decrease the misuse, abuse, and diversion of prescription opioids, a public health problem 
among many age groups including adolescents.
The use of morphine to treat pain in pediatric patients with cancer is well recognized.  
However, the increasing use of morphine in children to treat other forms of moderate to 
severe pain (eg, neurological pain) has become apparent only during the past decade…  The 
present study is intended to establish safety and pharmacokinetic information on 
PF-06412528 in children with chronic moderate-to-severe pain. 
2.1. Study Design
This is a multicenter, 6-week, open-label, single-arm study to demonstrate the safety and 
characterize the pharmacokinetics of PF-06412528 in children 7 to 17 years of age, with 
moderate-to-severe chronic pain requiring continuous around-the-clock therapy with an 
opioid analgesic for an extended period of time.  The study consists of 4 study periods 
(Figure 1) including:

Screening Period (Visit 1) lasting up to 2 weeks.

Treatment Period (Visits 2-6) lasting up to 10 weeks.

Post-Treatment Period (Visit 7) lasting 1 week.

End of Study Period (Visit 8) lasting 3 weeks.
Figure 1.
Overall Study Design
Screening 
Period
(2 Weeks)
Visit 1
Conversion/ 
Titration Phase 
(1-4 Weeks)
Visits 2-3a-d
Maintenance 
Phase
(6 Weeks)
Visits 4-6
Post-
Treatment 
Period
(1 Week)
Visit 7
Treatment Period
End of Study 
Period
(3 Weeks)
Visit 8


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The study will enroll approximately 140 children between the ages of 7 and 17 years with at 
least 100 subjects completing the Maintenance Phase.  Plasma samples will be collected at 
2 time points under steady-state conditions from each subject in the two age groups 
(7-11 years and 12-17 years) to characterize the pharmacokinetics of morphine and 
determine the systemic exposures of naltrexone and 6-β-naltrexol.
The Screening Period occurs up to 2 weeks.  This period includes one scheduled study center 
visit.  
The Treatment Period of the study will be conducted using an open-label, non-randomized, 
single-arm study design to demonstrate the safety and characterize the pharmacokinetics of 
PF-06412528 under multiple dose conditions.  The Treatment Period occurs over 10 weeks 
and consists of two phases of variable lengths depending on when a subject achieves a stable 
dose of PF-06412528; a Conversion/Titration Phase lasting 1-4 weeks and a Maintenance 
Phase lasting 6 weeks.  A stable dose is characterized as a dose that provides adequate 
analgesia and minimizes adverse reactions over a 5 to 7-day period.  The purpose of the 
Conversion/Titration Phase is to convert subjects from their current opioid therapy to 
PF-06412528 using a standardized conversion guide…, and individualize subjects’ pain 
management by titrating with PF-06412528.  The purpose of the Maintenance Phase is to 
maintain the subject on a stable dose of PF-06412528 for an additional 6 weeks, such that a
subject could potentially be exposed to up to 10 weeks of treatment with PF-06412528. 
Blood samples will be collected for pharmacokinetic analysis at Visit 4 only for those 
subjects that achieve a stable dose between Visits 3a-d. Two blood samples will be taken two-
hours apart at Visit 4. Subjects will be assigned 1:1 with respect to beginning the 
pharmacokinetic sampling within either 0-to-5 hours or >5 to ≤9 hours after the morning 
dose of PF-06412528. Only the first of the two pharmacokinetic samples must be collected 
within the designated time window; the other sample should be collected approximately two 
hours after the first sample.
The purpose of the Post-Treatment Period (Visit 7) is to perform safety assessments 
7 2 days after the last dose of PF-06412528.  All treated subjects will be required to attend 
Visit 7, including those who discontinued early.
The purpose of the End of Study Period (Visit 8) is to perform final safety assessments
28 2 days after the last dose of PF-06412528 for all treated subjects.  This visit may be 
performed as an in-clinic visit or by telephone.
2.2. Study Objectives
2.2.1. Primary Objectives

To demonstrate the safety of PF-06412528 in children 7 to 17 years of age treated 
with PF-06412528 for chronic, moderate-to-severe pain.

To characterize the pharmacokinetics of morphine in children 7 to 17 years of age 
treated with PF-06412528 for chronic, moderate-to-severe pain.


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2.2.2. Secondary Objectives

To determine the exposures of naltrexone and 6--naltrexol in children 7 to 17 years 
of age treated with PF-06412528 for chronic, moderate-to-severe pain.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis is planned.  Final analysis will follow the official database release.  Since 
this is an open label single-arm study, unblinding is not applicable.
With respect to pharmacokinetics, it is estimated that a sample size of N=50 per treatment 
group would provide adequate (>80%) power to estimate CL/F and Vd/F, taking into 
consideration the sample size estimates for various levels of PK variability as described by 
Wang, et al. However, since the study is expected to enroll slowly over time, modeling and 
simulation will be performed - beginning with adult population PK model and adding 
pediatric data from each age group as it becomes available – to verify that the sample size 
and the sampling scheme proposed for the present study are adequate to estimate CL/F and 
Vd/F with 80% power to establish the 95% CI within 60 to 140% of the geometric mean 
value for each PK parameter.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
Since this is open label single arm study, no statistical hypothesis is proposed.
4.2. Statistical Decision Rules
Not Applicable.
5. ANALYSIS SETS
5.1. Safety Analysis Set
One safety population is planned consisting of all subjects who participate in the Treatment 
Period and receive at least one dose of PF-06412528.
5.2. Pharmacokinetic (PK) Analysis Set
The pharmacokinetic concentration population will be defined as all subjects who have 
undergone at least 1 plasma concentration measurement in this study.  The pharmacokinetic 
analysis population will be defined as all pediatric subjects who have usable 
pharmacokinetic data (ie, data for which the relationship between the time of dose time of 
sampling can be determined) and are included in the estimates of the primary 
pharmacokinetic parameters of interest. 
5.3. Treatment Misallocations
All analyses will be performed on an “as-treated” basis. Subjects receiving a treatment that is 
not consistent with the treatment they are intended to receive will be reported under the 
treatment that they actually received for all safety and PK analyses, where applicable.


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5.4. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg, lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the 
pharmacokineticist/clinical pharmacologist, a concentration value may also be excluded if 
the last dose time prior to PK sampling is not recorded or if the concentration is anomalous 
for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
6. ENDPOINTS AND COVARIATES
6.1. Safety Endpoints
6.1.1. Primary
Incidence, intensity, relationship, and seriousness of adverse events (including symptoms of 
opioid toxicity or withdrawal) during treatment with PF-06412528.
6.1.2. Secondary
Changes in vital signs (pulse rate, blood pressure, respiratory rate), clinical chemistry, and 
hematology laboratory values.
Additional safety data includes:

Electrocardiogram

Clinical opiate withdrawal scale (COWS)

Physical examination

Urine drug test

Columbia- Suicide Severity Rating Scale (C-SSRS)
6.2. Pharmacokinetics/Pharmacodynamics Endpoints
6.2.1. PK Endpoints
6.2.1.1. Primary
population pharmacokinetic estimates of morphine apparent clearance (CL/F) and volume of 
distribution (Vd/F) following treatment with PF-06412528
6.2.1.2. Secondary
exposure levels of the metabolites of morphine (morphine-3-glucuronide [M3G] and 
morphine-6-glucuronide [M6G]), naltrexone, and 6-β-naltrexol following multiple-dose 
treatment with PF-06412528.


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6.2.2. PD Endpoints
Not applicable
6.3. Efficacy Endpoints
•
Pain intensity scores
•
Rescue medication or additional analgesic medication use
6.4. Covariates
Covariate testing will be done by adding continuous (age, body weight) and categorical 
(gender) variables to the structural PK model to improve fit and reduce variability.  
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
7.3. Pharmacokinetic parameters
Actual PK sampling times will be used in the population PK analysis.
If an individual subject has a known biased estimate in PK concentrations (due for example 
to an unexpected event such as vomiting before all the drug is absorbed in the body), this will 
be footnoted in summary tables and will not be included in population PK analyses.
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8. STATISTICAL  METHODOLOGY AND STATISTICAL ANALYSES
8.1. Safety Analysis
For the analysis of safety endpoints, the sponsor data standard rules for reporting will be 
applied.
8.1.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics and safety (adverse events and laboratory data).  
Frequency counts will be supplied for subject discontinuation(s) by phase.
8.1.2. Demographic and Clinical Examination Data
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.1.3. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized.
8.1.4. Adverse Events
All AEs will be coded to System Organ Class and Preferred Term (using MedDRA).  
Treatment-emergent AEs will be defined as AEs that commence on or after the start of 
PF-06412528 administration.  Subjects who have multiple events in the same System Organ 
Class and Preferred Term in a period will be counted only once at each level of summation 
(overall, by System Organ Class, and by Preferred Term).
Treatment-emergent AEs will be summarized separately for the Conversion/Titration Phase 
and the Maintenance Phase (including up to End of Study) by System Organ Class, Preferred 
Term, maximum intensity, and highest relationship to study drug.
Serious AEs and those leading to study discontinuation will be summarized. 
8.1.5. Laboratory Data
Clinical laboratory data (hematology, chemistry and urinalysis) including changes from 
Screening will be summarized descriptively by study visit, as applicable.
8.1.6. Electrocardiogram
Electrocardiogram data including changes from Screening will be summarized descriptively 
by study visit, as applicable.
8.1.7. Vital Signs
Vital signs data including changes from Baseline will be summarized descriptively by study 
visit, as applicable. 


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8.1.8. Opiate Withdrawal
COWS scores will be summarized descriptively by study visit, as applicable.  Additionally, 
for COWS, the proportion of subjects with mild (COWS Score 5-12), moderate (COWS Score 
13-24), moderately severe (COWS Score 25-36), or severe withdrawal (COWS Score >36) 
will be presented. 
8.1.9. Columbia-Suicide Severity Rating Scale
Responses to the C-SSRS will be summarized descriptively.
8.1.10. Dosing and Compliance
Study drug administration will be summarized descriptively by each subject’s mean and 
median total daily dose and duration of exposure, separately for the Conversion/Titration 
Phase and Maintenance Phase.
8.1.11. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.1.12. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, urine drug screen, 
serum or urine B-hCG for all females of childbearing potential will be obtained at Screening.
These data will be provided in the listings. 
8.2. PK/PD Analysis
8.2.1. Pharmacodynamic Analysis
Not applicable.
8.2.2. Pharmacokinetic Analysis
The pharmacokinetics of morphine and its metabolites (data permitting) will be 
characterized using nonlinear mixed-effects modeling with the population pharmacokinetic 
software program (NONMEM).  For modeling building purposes, a one-compartment model 
with first-order absorption and elimination will be evaluated as the initial structural model.  
During model building, the sparse concentration data from the PK analysis population in 
this study may be enriched with full concentration data from previously conducted 
PF-06412528 studies in adults, or the PK absorption parameters (ka and Tlag) may be fixed 
based on modeling with full concentration data.  
Covariate testing will be done by adding continuous (age, body weight) and categorical 
(gender) variables to the structural model to improve fit and reduce variability.  Goodness of 
fit will be evaluated based on the minimization of the objective function, precision of PK 
parameter estimates, randomness of scatter in appropriate plots, and reduction in the 
intersubject variability and residual error. 


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.
An analysis describing the details of model building, covariate assessment, and model 
validated will be provided in a separate document.
In addition to population pharmacokinetic modeling, the highest exposure level and observed 
exposure levels over time will be reported from the Maintenance Treatment Phase for 
morphine, naltrexone, and 6-β-naltrexol.  The observational data will be summarized using 
descriptive statistics (mean, standard deviation, median, minimum, and maximum) for the 
study group as a whole.  Data permitting, graphical representations and regression analyses 
may be used to characterize the dose-exposure relationships for morphine, naltrexone, and 
6-β-naltrexol. 
8.3. Efficacy Analysis
Analgesic effect analyses will be performed using all available in-clinic pain intensity data 
from the safety population… The baseline pain intensity score will be the score from the in-
clinic assessment at Visit 2.
Pain intensity scores will be summarized descriptively by study week and phase of the 
Treatment Period (Conversion/Titration Phase and Maintenance Phase).  Actual scores and 
the change and percentage change from baseline will be calculated.
Rescue medication or additional analgesic medication use over time will be summarized 
descriptively.
9. REFERENCES
“Modern Robust Statistical Methods,” David M Erceg-Hurn, Vikki M. Mirosevich, American 
Psychologist, October 2008, Vol. 63, No. 7, 591-601.
Wang Y, Jadhav PR, Mallika L, and Gobburu JV. Clarification on Precision Criteria to
Derive Sample Size When Designing Pediatric Pharmacokinetic Studies. J Clin Pharmacol. 
2012;52:1601-1606.
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