An Open-label Study To Evaluate The Pharmacokinetics And Safety Of Alo-02 (Oxycodone Hydrochloride And Naltrexone Hydrochloride) Extended-release Capsules In Children And Adolescents 7-17 Years Of Age Who Require Opioid Analgesia
Phase: PHASE4
Conditions: Moderate-severe Pain
Sponsor: Pfizer

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CLINICAL PROTOCOL
AN OPEN-LABEL STUDY TO EVALUATE THE PHARMACOKINETICS AND 
SAFETY OF ALO-02 (OXYCODONE HYDROCHLORIDE AND NALTREXONE 
HYDROCHLORIDE) EXTENDED-RELEASE CAPSULES IN CHILDREN AND 
ADOLESCENTS 7-17 YEARS OF AGE WHO REQUIRE OPIOID ANALGESIA
Compound:
ALO-02 (PF-06412527)
Compound Name:
oxycodone hydrochloride and naltrexone 
hydrochloride extended-release capsules
United States (US) Investigational New 
Drug (IND) Number:
107,037
European Clinical Trials Database 
(EudraCT) Number:
Not applicable
Protocol Number:
B4531015
Phase:
4
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Document History
Document
Version Date
Summary of Changes
Amendment 1
06 July 2016
A substantial change will be preceded by (SC). All other 
changes are administrative changes as required by the latest 
protocol template. 
SC Table 3 ALO-02 Total Daily Dose and Dosing Schedule
now has lower doses of 3 mg, 5 mg and 15 mg of oxycodone
with naltrexone.
Appendix 6 was deleted because it was redundant
Columbia-Suicide Rating Scale (C-SSRS) Baseline Age 
12-17 years is Appendix 4.
Visit 5 was clarified from Visit 5/Early Termination to 
Visit 5/Early Termination/End-of-Study Visit.
Visit 6 was clarified from Follow-Up/End-of-Study to 
Visit 6/Follow-Up/Post-Treatment Period.
Visit 6 was clarified that it can be an office visit or a 
telephone call at the discretion of the investigator.
Diary was changed from eDiary to Diary since an electronic 
diary is not being used in this study.
Schedule of Activities telephone calls added a call at Visit 2. 
Added footnote 19 which states, “The Follow UP? Post 
Treatment Visit, this may be done over the telephone at the 
Investigator’s discretion.”  Added Footnote 20 which states, 
“The investigator or his/her designee will discuss with the 
subject/caregiver the need to use highly effective 
contraception consistenly and correctly according to the 
Schedule of Activities and document such conversations in 
the subject’s chart.”
Added Contraception Check to remind to check with the 
subject/caregiver.
Added Emergency Card so the site is aware when to give the 
emergency card to the subject.
Appendix 2 added dosing chart for drug conversion
guidelines at the dose level for ease of conversion at the sites 
and to be consistent with the Embeda protocol. 
Original protocol
02 April 2015
Not Applicable (N/A)
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES................................................................................................13
1. INTRODUCTION ...............................................................................................................16
1.1. Mechanism of Action/Indication.............................................................................16
1.2. Background .............................................................................................................16
1.3. Oxycodone ..............................................................................................................16
1.4. Naltrexone ...............................................................................................................17
1.5. Study Rationale .......................................................................................................18
1.6. Dose Rationale ........................................................................................................19
1.7. Additional Information............................................................................................19
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................20
2.1. Objectives................................................................................................................20
2.1.1. Primary .......................................................................................................20
2.1.2. Secondary ...................................................................................................20
2.2. Endpoints.................................................................................................................20
2.2.1. Primary .......................................................................................................20
2.2.2. Secondary ...................................................................................................20
2.2.3. Other ...........................................................................................................20
3. STUDY DESIGN.................................................................................................................21
3.1. Screening Period .....................................................................................................22
3.2. Treatment Period.....................................................................................................22
3.2.1. Conversion/Titration Phase (Visits 2 through 3d)......................................22
3.2.2. Maintenance Phase (Visit 4 and Visit 5) ....................................................22
3.2.3. Early Termination Visit..............................................................................23
3.3. Follow Up/Post Treatment Visit .............................................................................23
4. SUBJECT SELECTION......................................................................................................23
4.1. Inclusion Criteria.....................................................................................................24
4.2. Exclusion Criteria....................................................................................................24
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4.3. Lifestyle Guidelines ................................................................................................26
4.4. Caregiver(s).............................................................................................................27
4.5. Sponsor’s Qualified Medical Personnel..................................................................27
4.6. Rater Qualifications for Columbia-Suicide Severity Rating Scale (C-SSRS) ........28
5. STUDY TREATMENTS.....................................................................................................28
5.1. Allocation to Treatment ..........................................................................................28
5.2. Subject Compliance.................................................................................................28
5.3. Opioid Withdrawal and Overdose...........................................................................28
5.3.1. Signs and Symptoms of Opioid Withdrawal ..............................................28
5.3.2. Management of Opioid Withdrawal...........................................................29
5.3.3. Signs and Symptoms of Opioid Overdose..................................................29
5.3.4. Management of Opioid Overdose...............................................................29
5.4. Investigational Product Supplies.............................................................................30
5.4.1. Dosage Form(s) and Packaging..................................................................30
5.4.2. Preparation and Dispensing........................................................................30
5.4.3. Administration............................................................................................31
5.5. Investigational Product Storage ..............................................................................32
5.6. Investigational Product Accountability...................................................................33
5.6.1. Destruction of Investigational Product Supplies ........................................33
5.7. Concomitant Treatments(s).....................................................................................33
5.7.1. Permitted Medications and Therapies ........................................................33
5.7.2. Prohibited Medications and Therapies .......................................................34
5.8. Rescue Medications.................................................................................................34
6. STUDY PROCEDURES .....................................................................................................34
6.1. Screening Visit (Days -14 to -1) .............................................................................34
6.2. Treatment Period.....................................................................................................36
6.2.1. Conversion/Titration Phase ........................................................................36
6.2.2. Maintenance Phase .....................................................................................39
6.3. Early Termination Visit...........................................................................................42
6.4. Visit 6 Follow Up/Post Treatment Visit..................................................................42
6.5. Subject Withdrawal.................................................................................................42
6.6. Lost to Follow-Up (LTFU) .....................................................................................43
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6.7. Unscheduled Visits..................................................................................................44
7. ASSESSMENTS..................................................................................................................44
7.1. Analgesic Effect Assessments.................................................................................44
7.1.1. Pain Intensity ..............................................................................................44
7.1.2. Rescue Medication Use ..............................................................................45
7.2. Safety Assessments .................................................................................................45
7.2.1. Adverse Events...........................................................................................45
7.2.1.1. Recording of Adverse Events Using a Diary ............................45
7.2.2. Vital Signs ..................................................................................................45
7.2.3. Clinical Laboratory Tests ...........................................................................46
7.2.4. Electrocardiogram.......................................................................................46
7.2.5. Clinical Opiate Withdrawal Scale (COWS) ...............................................46
7.2.6. Physical Examination .................................................................................46
7.2.7. Urine Drug Test ..........................................................................................47
7.3. Pregnancy Testing...................................................................................................47
7.4. Contraception Check...............................................................................................48
7.5. Suicidality Assessment............................................................................................48
7.5.1. Columbia-Suicide Severity Rating Scale (C-SSRS)...................................48
7.6. Pharmacokinetic Evaluation....................................................................................49
7.6.1. Blood Sample Collection and Handling .....................................................49
7.6.2. Plasma Sample Shipment to Bioanalytical Laboratory ..............................49
7.7. Blood Volume .........................................................................................................49
8. ADVERSE EVENT REPORTING......................................................................................50
8.1. Adverse Events........................................................................................................50
8.2. Reporting Period .....................................................................................................50
8.3. Definition of an Adverse Event...............................................................................51
8.4. Medication Errors....................................................................................................51
8.5. Abnormal Test Findings..........................................................................................52
8.6. Serious Adverse Events...........................................................................................52
8.6.1. Protocol-Specified Serious Adverse Events...............................................53
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................53
8.7. Hospitalization ........................................................................................................54
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8.8. Severity Assessment................................................................................................55
8.9. Causality Assessment..............................................................................................55
8.10. Exposure During Pregnancy..................................................................................56
8.11. Occupational Exposure .........................................................................................57
8.12. Withdrawal Due to Adverse Events (See Also Section 6.5 on Subject 
Withdrawal)...............................................................................................................57
8.13. Eliciting Adverse Event Information ....................................................................58
8.14. Reporting Requirements........................................................................................58
8.14.1. Serious Adverse Event Reporting Requirements .....................................58
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................58
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................59
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................59
9.1. Sample Size Determination.....................................................................................59
9.2. Efficacy Analysis ....................................................................................................59
9.3. Pharmacokinetic Analysis.......................................................................................60
9.3.1. Pharmacokinetic Analysis Datasets............................................................60
9.3.2. Pharmacokinetic Endpoints ........................................................................60
9.3.3. Pharmacokinetic Analysis ..........................................................................60
9.4. Safety Analysis........................................................................................................60
9.4.1. Adverse Events ...........................................................................................61
9.4.2. Clinical Laboratory Values.........................................................................61
9.4.3. Electrocardiogram.......................................................................................61
9.4.4. Vital Signs ..................................................................................................61
9.4.5. Opiate Withdrawal......................................................................................61
9.4.6. Dosing and Compliance..............................................................................61
9.5. Interim Analysis ......................................................................................................62
9.6. Data Monitoring Committee ...................................................................................62
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................62
11. DATA HANDLING AND RECORD KEEPING .............................................................62
11.1. Case Report Forms/Electronic Data Record .........................................................62
11.2. Record Retention...................................................................................................63
12. ETHICS..............................................................................................................................64
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12.1. Institutional Review Board/Ethics Committee......................................................64
12.2. Ethical Conduct of the Study ................................................................................64
12.3. Subject Information and Consent/Assent..............................................................64
12.4. Subject Recruitment ..............................................................................................66
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................66
13. DEFINITION OF END OF TRIAL...................................................................................66
13.1. End of Trial ...........................................................................................................66
14. SPONSOR DISCONTINUATION CRITERIA ................................................................66
15. PUBLICATION OF STUDY RESULTS..........................................................................66
15.1. Communication of Results by Pfizer ....................................................................66
15.2. Publications by Investigators ................................................................................67
16. REFERENCES ..................................................................................................................69
LIST OF TABLES
Table 1.
Schedule of Activities...........................................................................................13
Table 2.
Pharmacokinetic Parameters of Oxycodone after IV Bolus Administration 
in Children 2-10 Years of Age and Healthy Adults .............................................17
Table 3.
ALO-02 Total Daily Dose and Dosing Schedule .................................................30
Table 4.
Clinical Laboratory Tests .....................................................................................46
Table 5.
Blood Volume.......................................................................................................50
Table 6.
Conversion Factors to ALO-021...........................................................................75
LIST OF FIGURES
Figure 1.
Overall Study Design............................................................................................21
Figure 2.
Daily Pain Numerical Rating Scale (NRS-Pain) ..................................................45
APPENDICES
Appendix 1. Abbreviations......................................................................................................73
Appendix 2. ALO-02 Conversion Guide.................................................................................75
Appendix 3. Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s 
Lifetime/Recent (Version 6/23/10):  Age 7-11.....................................................86
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Appendix 4. Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
Version (Version 1/14/09):  Age 12-17................................................................89
Appendix 5. Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s Since Last 
Visit (Version 6/23/10):  Age 7-11.......................................................................92
Appendix 6. Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
(Version 1/14/09): Age 12-17...............................................................................95
Appendix 7. Pain Numerical Rating Scale (NRS-Pain)...........................................................98
Appendix 8. Clinical Opiate Withdrawal Scale (COWS)........................................................99
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PROTOCOL SUMMARY 
Background and Rationale:
ALO-02 (PF-06412527) is a combination opioid agonist/opioid antagonist 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.
ALO-02 capsules consist of controlled-release pellets containing oxycodone hydrochloride 
(HCl) and naltrexone HCl. The pellet formulation is designed to release oxycodone in an 
extended-release (ER) manner over time while retaining naltrexone HCl in the inner core 
unless the inner core is disrupted.  Upon crushing or chewing the pellets, naltrexone is 
released along with the oxycodone, thereby, attenuating the liking and euphoric effects of the
opioid.  Naltrexone HCl is formulated in a 12% (w/w) ratio in combination with oxycodone 
HCl across all dosage strengths.  ALO-02 was developed with the goal of decreasing misuse, 
abuse, and diversion of opioids; an increasing public health problem among many age 
groups, including adolescents.
One of the major challenges facing clinicians who wish to prescribe pain medications to 
children and adolescents 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)1 and the Pediatric Research Equity Act (PREA).2  The study is being 
conducted as a Phase 4 post-marketing requirement to the Food and Drug Administration 
(FDA) consistent with ICH E11 guidelines for “Clinical Investigation of Medicinal Products 
in the Pediatric Population”. 
The proposed study is intended to characterize the pharmacokinetics (PK) of ALO-02 and 
evaluate the safety of ALO-02 in children and adolescents 7 to 17 years of age who require 
opioid analgesia for moderate-to-severe pain.
Objectives:
Primary

To characterize the PK of oxycodone in children and adolescents 7 to 17 years of age 
treated with ALO-02. 

To evaluate the safety of ALO-02 in children and adolescents 7 to 17 years of age. 
Secondary

To determine the systemic exposures of naltrexone and 6--naltrexol in children and 
adolescents 7 to 17 years of age treated with ALO-02.
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Endpoints:
Primary

Pharmacokinetics: estimates of oxycodone average steady-state concentration (Css,av)
and apparent oral clearance (CL/F).

Safety: incidence, intensity, relationship, and seriousness of adverse events (including 
symptoms of opioid withdrawal or overdose).
Secondary

Pharmacokinetics: apparent volume of distribution (Vz/F) of oxycodone, data 
permitting; and systemic exposure levels of the metabolites of oxycodone 
(oxymorphone and noroxycodone), naltrexone, and 6-β-naltrexol.

Safety: changes in vital signs (blood pressure, heart rate, respiratory rate), clinical 
chemistry, and hematology laboratory values.
Other

Analgesic effect: pain intensity scores (actual and % 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 oxycodone, naltrexone, and 
6--naltrexol.
Study Design:
This is a multicenter, open-label, single-arm study designed to characterize the PK and 
evaluate the safety of ALO-02 in opioid experienced children and adolescents with 
moderate-to-severe pain.  The study will enroll approximately 140 children and adolescents
to achieve at least 100 subjects exposed to at least 2 weeks of treatment with ALO-02 in the 
Maintenance Phase.  Plasma samples will be collected during the Maintenance Phase under 
steady-state conditions to characterize the pharmacokinetics of oxycodone and determine the 
systemic exposures of oxymorphone, noroxycodone, naltrexone, and 6--naltrexol.
The study consists of 4 study periods including occurring over a period of up to 9 weeks:

Screening Period (Visit 1) lasting up to 2 weeks.

Treatment Period (Visits 2-5) lasting up to 6-8 weeks.

Follow-Up/Post-Treatment Period (Visit 6) lasting 1 week.
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All subjects will be treated with ALO-02 capsules for oral use for up to 8 weeks in this 
single-arm, open-label study.  Subjects must be taking opioids prior to entry into the study.  
Initial ALO-02 dose will be determined by the subject’s pre-study opioid treatment prior to 
the Conversion/Titration Period.  The Treatment Period duration is 6 to 8 weeks and consists 
of two phases of variable lengths depending on when a subject achieves a stable dose of 
ALO-02 and how long opioid analgesia is required. 
Assessments:
Safety Assessments
After signing the consent/assent and before admission to the study, subjects will undergo a 
physical examination and testing procedures/measurements including 12-lead 
electrocardiogram (ECG), blood pressure, heart rate, and clinical and laboratory testing.  
During the study, the investigator will closely monitor adverse events including, but not 
limited to, opioid overdose and/or signs and symptoms of opioid withdrawal.
Pharmacokinetic Assessments
Once a subject has achieved a stable dose of ALO-02, two 6 mL (2×6 mL) blood samples 
will be collected on the same day at least 2 hours apart for the purpose of quantifying 
concentrations of oxycodone, noroxycodone, oxymorphone, naltrexone, and 6--naltrexol in 
plasma. 
Statistical Method:
Approximately 140 subjects will need to be enrolled in order to ensure that 100 subjects are 
exposed to at least 2 weeks of treatment with ALO-02 in the Maintenance Phase for the 
purpose of establishing a safety database.  
 
 
 
 
Pharmacokinetic Analysis
Given the expected low fluctuation in steady-state oxycodone concentrations following 
ALO-02 BID dosing in children and adolescents based on the ALO-02 study B4531006 in 
adults, the concentrations observed during the Maintenance Phase will be used as an estimate 
of Css,av of oxycodone and its metabolites (data permitting) in subjects. The CL/F of 
oxycodone will be estimated using a ratio of the daily dosing rate of ALO-02 and the 
estimates of oxycodone Css,av in the Maintenance Phase.  The concentration-time dataset will 
be analyzed to obtain estimates for Vz/F of oxycodone, data permitting. Covariates of 
interest (ALO-02 dosage, age, body weight, gender, concomitant medications, etc.) will be 
evaluated in order to explain the observed between-subject variability in oxycodone Css,av. 
CCI
CCI
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Graphical representations and regression analyses may be used to characterize the 
dose-exposure relationships for oxycodone, naltrexone, and 6--naltrexol (data permitting).
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 ALO-02.  
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.  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; 
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 
according to the Charter. 
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the Study Procedures and 
Assessments sections of the protocol (Section 6 and 7) for detailed information on each procedure and assessment required for 
compliance with the protocol. 
The investigator may schedule visits (unscheduled visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
Table 1.
Schedule of Activities
SCREENING 
TREATMENT PERIOD
FOLLOW UP/
POST 
TREATMENT19
Conversion/Titration Phase (up to 4 Weeks)
Maintenance Phase (2-4 Weeks)
Visit Identifier
1
(Days -14 to -1)
2
(Day 1)
3a1
(Day 7 )
3b2
(Day 14)
3c2
(Day 21)
3d2
(Day 28)
4
(Day 21, 28, 35 or 42)
5/Early 
Termination/
End of Study18
(Day 35, 42, 49 or 56)
6
(Day 28,42,49,56 or 63)
Visit window
2
2
2
2
2
2
2
Study Entry & Safety Procedures
Informed Consent/Assent3
X
Inclusion & Exclusion Criteria
X
Demographics
X
Medical history
X
Physical examination
X
X
Vital signs
X
X
X
X
X
X
X
X
Clinical laboratory tests
(serum chemistry and hematology)
X
X
Urinalysis (dip stick)
X
X
Serum pregnancy test4
X
X
Urine pregnancy test5
X
X
X
X
X
X
Contraception Check20
X
X
X
X
X
X
X
Urine drug test (UDT)
X
Single, 12-lead ECG6
X
Suicide ideation and behavior 
assessment (C-SSRS)7
X
X
X
X
X
X
X
X
X
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SCREENING 
TREATMENT PERIOD
FOLLOW UP/
POST 
TREATMENT19
Conversion/Titration Phase (up to 4 Weeks)
Maintenance Phase (2-4 Weeks)
Visit Identifier
1
(Days -14 to -1)
2
(Day 1)
3a1
(Day 7 )
3b2
(Day 14)
3c2
(Day 21)
3d2
(Day 28)
4
(Day 21, 28, 35 or 42)
5/Early 
Termination/
End of Study18
(Day 35, 42, 49 or 56)
6
(Day 28,42,49,56 or 63)
Visit window
2
2
2
2
2
2
2
COWS assessment
X
X
X
X
X
X
X
X
AE assessment8
X
X
X
X
X
X
X
X
X
Opioid analgesic review and 
conversion to ALO-029
X10
X11
Concomitant treatments
X
X
X
X
X
X
X
X
Subject instruction and 
caregiver training
X
Dispense ALO-02
X
X
X
X
X
X12
Prescribe rescue medication if 
necessary
X
X
X
X
X
X
X
ALO-02 titration visits 
(as needed)2
X
X
X
X
NRS-Pain scale (in-clinic)
X
X
X
X
X
X
X
Diary Review13
       Pain intensity
X
X
X
X
X
X
       Rescue medication
X
X
X
X
X
X
       Concomitant medication
X
X
X
X
X
X
       Compliance to ALO-02
X
X
X
X
X
X
       AE review
X
X
X
X
X
X
Pharmacokinetic Assessment
Plasma samples for PK 
analyses14
X
X15
Other Assessments
ALO-02 accountability
X
X
X
X
X
X
X
Early Termination15, 16
X
Weekly telephone call17
X
--------------------------------------------------------------------------------------------------------------
Emergency Card
X
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Abbreviations:  AE = adverse event; COWS = Clinical Opiate Withdrawal Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; CRF = case report form; 
ECG = electrocardiogram; NRS = Numerical Rating Scale – Pain; PK = pharmacokinetics; UDT = urine drug test
1.
Visit 3a is a mandatory visit.
2.
Visits 3b-3d are required only if further dose titrations are required to reach a stable dose. Once a stable dose is achieved the patient is to advance to Visit 4. Subjects must 
reach a stable dose of ALO-02 on or before Visit 3 to be eligible to start the 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 [legally acceptable representative/parent(s)/legal guardian].  Subjects are required to provide their assent in 
compliance with local regulations and IRB requirements.
4.
Serum pregnancy test for females of childbearing potential (Section 7.3).
5.
Urine pregnancy test for females of childbearing potential (Section 7.3).
6.
ECGs performed post-screening are acceptable when performed “for-cause”. 
7.
Refer to Section 7.5.1 for the correct version of Columbia-Suicide Severity Rating Scale (C-SSRS) to administer for a given age group.
8.
Report serious adverse events from the signing of the informed consent.  AEs are recorded from first dose of ALO-02.  Review and transcribe Caregiver adverse findings 
from the daily Diary to the appropriate CRF.
9.
Refer to Appendix 2 of the protocol for the ALO-02 Conversion Guide.  The Investigator must calculate the conversion to ALO-02 by Visit 2.
10. Review the subject’s pre-study standard of care opioid therapy and record on the appropriate CRF. 
11. Pre-study standard of care opioid analgesic is to be discontinued at this visit.  Record these changes on the appropriate CRF.
12. Only if at Visit 4 the subject needs an additional 2 weeks of treatment with ALO-02.
13. Review all sections of the daily Diary as part of the Caregiver Training and Subject Instruction.  Weekly phone contact between visits to review diary entries.  Telephone call 
must be documented in source documents.
14. Two blood samples for PK analysis will be collected on the same day at least 2 hours apart.
15. PK samples will be collected at Visit 4 or at Early Termination if they are not collected at Visit 4 (Section 7.6.1).
16. All subjects including subjects who discontinue early from the study during the Treatment Period regardless of reason (eg, failure to achieve a stable dose, lack of efficacy, 
AE) are requested to fulfill the Early Termination procedures and activities (Section 6.2.2). 
17. Weekly telephone contact with the caregiver (ie, parent/legal guardian) must be documented in source documents. 
18. Subjects who discontinue early from the study as well as subjects who complete 2 weeks of ALO-02 during the Maintenance Phase and have their last dose of ALO-02 at 
Visit 4 will complete the Visit 5/Early Termination/End-of-Study Visit procedures.
19. The Follow Up/Post Treatment Visit, this may be done over the telephone at the investigator’s discretion.
20. The investigator or his/her designee will discuss with the subject/caregiver 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.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
ALO-02 (PF-06412527) is a combination opioid agonist/opioid antagonist 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. 
ALO-02 capsules consist of controlled-release pellets containing oxycodone hydrochloride 
(HCl) and naltrexone HCl.  Naltrexone HCl is formulated in a 12% (w/w) ratio in 
combination with oxycodone HCl across all dosage strengths.  This abuse deterrent 
formulation (ADF) uses a proprietary sequestered opioid antagonist platform which is 
comprised of a sequestered naltrexone core with an outer layer of extended-release (ER)
opioid. The first ADF approved in the United States with this technology is EMBEDA,
which consists of morphine sulfate and naltrexone HCl in an ER capsule.3  The pellet 
formulation is designed to release oxycodone in an ER manner while retaining naltrexone 
HCl in the inner core unless the inner core is disrupted.  Upon crushing or chewing the 
pellets, naltrexone is released along with the oxycodone thereby attenuating the liking and 
euphoric effects of the opioid. 
1.2. Background 
Moderate-to-severe pain associated with an underlying disease is a common condition among 
children and adolescents, affecting upwards of 15% to 20% of the pediatric population at one 
time or another.4,5  For many children and adolescents, the pain may be untreated or 
undertreated, resulting too often in prolongation of suffering, disruption of the family routine, 
and continuation of long-term disability.5  For the clinician, the management of pain can 
represent a challenge greater than the treatment of the primary disease itself.  Surveys 
evaluating the pain experience in pediatric patients have shown that 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.5,6,7,8,9,10
1.3. Oxycodone 
Oxycodone is a pure opioid agonist available in both immediate release (IR) and ER
formulations.  Following oral administration of ALO-02 capsules, time to maximum 
observed oxycodone concentration (Tmax) is delayed to approximately 12 hours post-dose.
Area under the concentration-time curve (AUC) is equivalent and maximum oxycodone 
plasma concentration (Cmax) is reduced by approximately 67% when compared with IR 
oxycodone tablets.11  When ALO-02 capsules are administered in the fasted state or after a 
high-fat meal, or when the contents of ALO-02 capsules are sprinkled on applesauce and 
administered in the fasted state, oxycodone PK are unaffected, yielding similar AUC, Cmax, 
and Tmax values.12  An analysis of pharmacokinetic results from Phase 1 studies with 
ALO-02 capsule strengths 20 mg/2.4 mg up to 80 mg/9.6 mg showed that oxycodone AUC 
and Cmax increased in a dose proportional manner.13
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Following intravenous administration, the volume of distribution (Vz) for oxycodone is 
2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 is about 45%. 
Oxycodone has been found to be excreted in breast milk.14
In humans, oxycodone HCl is extensively metabolized to noroxycodone, oxymorphone, and 
their glucuronides.11  CYP3A-mediated N-demethylation to an inactive metabolite form 
noroxycodone is the principal metabolic pathway of oxycodone in humans. 
CYP2D6-mediated O-demethylation to an active metabolite oxymorphone is a minor 
metabolic pathway. Oxymorphone is present in the plasma only in low concentrations.
The total clearance of oxycodone is 0.8 L/min and the apparent elimination half-life (t½)
following the administration of IR oxycodone is 3.5 to 4 hours.  Following oral 
administration of ALO-02 capsules, the t½ of oxycodone is approximately 7.2 hours8 and 
steady-state is reached within 48 hours upon twice daily dosing approximately 12 hours 
apart.15  Oxycodone and its metabolites are excreted primarily via the kidney.11  The urinary 
recovery of total oxycodone (free and conjugated) and its metabolites is approximately 
72% of the dose within 48 hours after oral administration.16
The PK profiles of oxycodone have been described in adults17 and in children.18  Marked 
differences in PK parameters were observed in infants up to 6 months of age versus adults,
and there are some differences in PK parameters in children 2-10 years of age (see 
Table 2).14,15,19,20  However, in children and adolescents 7 to 17 years old, no PK differences 
in oxycodone PK are expected compared to adults.16
Table 2.
Pharmacokinetic Parameters of Oxycodone after IV Bolus Administration 
in Children 2-10 Years of Age and Healthy Adults
t½
Vss
CL
Children 2-10 years a
1.80.4 h
2.10.8 L/kg
15.24.2 mL/min/kg
Adults
3.72.3 h b
2.60.52 L/kg b
780330 mL/min b,c
Abbreviations:  CL = renal clearance; IV = intravenous; t½ = elimination half-life; Vss = volume of distribution at steady 
state
a.  Olkkola et al. 1994
b.  Poyhia et al. 1991
c.  mean body weight 7711 kg
1.4. Naltrexone
Naltrexone is a synthetic congener of oxymorphone with no opioid agonist activity, but with 
significant opioid antagonist properties.21 When ALO-02 capsules are administered in the
fasted state or after a high-fat meal, or when the contents of ALO-02 capsules are sprinkled 
on applesauce and administered in the fasted state, naltrexone plasma concentrations remain 
undetectable, suggesting that administration of ALO-02 capsules with food or sprinkling of 
pellets on applesauce does not affect sequestration of naltrexone.9
Following oral administration of naltrexone IR tablets, naltrexone undergoes rapid and nearly 
complete absorption with approximately 96% of the dose absorbed from the gastrointestinal 
tract. Peak plasma levels of both naltrexone and its major metabolite, 6--naltrexol occur 
within one hour of dosing.22  The rate and extent of absorption (Cmax and AUC, respectively) 
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of naltrexone IR tablets have been shown to increase in a dose proportional manner following 
oral administration of naltrexone 50 mg tablets as 50 mg, 100 mg and 200 mg doses. 
The volume of distribution for naltrexone following intravenous administration is estimated 
to be 1350 liters.21 In vitro tests with human plasma show naltrexone to be 21% bound to 
plasma proteins over the therapeutic dose range.  The systemic clearance (after intravenous 
administration) of naltrexone is ~3.5 L/min, which exceeds liver blood flow (~1.2 L/min).  
This suggests both that naltrexone is a highly extracted drug (>98% metabolized) and that 
extrahepatic sites of drug metabolism exist. The major metabolite of naltrexone is 
6--naltrexol. Two other minor metabolites are 2-hydroxy-3-methoxy-6--naltrexol and 
2-hydroxy-3-methyl-naltrexone.  The activity of naltrexone is believed to be due to both 
parent and the 6--naltrexol metabolite.23
In humans, naltrexone is excreted primarily in the urine as conjugates of naltrexone and 
6--naltrexol. The renal clearance for naltrexone ranges from 30 to 127 mL/min and 
suggests that renal elimination is primarily by glomerular filtration. In comparison, the renal 
clearance for 6--naltrexol ranges from 230 to 369 mL/min, suggesting an additional renal 
tubular secretory mechanism. The urinary excretion of unchanged naltrexone accounts for 
less than 2% of an oral dose; urinary excretion of unchanged and conjugated 6--naltrexol 
accounts for 43% of an oral dose. The pharmacokinetic profile of naltrexone suggests that 
naltrexone and its metabolites may undergo enterohepatic recycling. The mean t½ of 
naltrexone and 6--naltrexol are 4 hours and 13 hours, respectively.21
1.5. Study Rationale
One of the major challenges facing clinicians who wish to prescribe pain medications to 
children and adolescents 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.4  This has led to documented cases of overdosing and under-dosing of
pain medications in pediatric patients.  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”.24
According to a published Food and Drug Administration (FDA) Workshop on pediatric 
analgesic trial design “comparatively few children receive around-the-clock opioids for 
severe pain for time periods of more than 4 weeks”.9 During the past decade, new ER opioid 
dosage forms have found their way to the market, but with only limited utility and are only
infrequently used to manage pain in children and adolescents.  An in-house analysis of the 
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%) 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
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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 ALO-02 in 100 pediatric pain 
subjects.
The risk to children and adolescents of being on ALO-02 is estimated to be the same as with
any other formulations of oxycodone to which patients would already be exposed.  Because 
of the presence of naltrexone in the formulation, a risk could be precipitation of opioid 
withdrawal if it is released and absorbed.  This risk is very low in view of the documented 
experience in adults showing no definitive withdrawal since, if the formulation is taken as 
directed, naltrexone absorption is negligible.  Analysis from the two Phase 3 studies showed 
that there was no apparent relationship between naltrexone and 6--naltrexol exposure and 
withdrawal as measured on the Clinical Opiate Withdrawal Scale (COWS).  Opiate 
withdrawal can be immediately treated with good outcome as described in Section 5.3.2.
1.6. Dose Rationale
The dosing recommendation for initiating ALO-02 is based on the dosage guidelines for 
opioid analgesics in children and adolescents25,26,27,28 and the growth charts published by the 
Centers for Disease Control and Prevention (CDC).29 For example, the recommended 
starting oral dose of ER oxycodone formulations for opioid-nȁive children and adolescents in 
the World Health Organization (WHO) Guidelines28 is 5 mg every 12 hours for children 
>8 years of age. Furthermore, the WHO advises that high strength modified-release 
oxycodone formulations should only be used in patients who are opioid tolerant, as 
administration of these strengths to non-opioid tolerant patients may cause fatal respiratory 
depression.28
For the IR oxycodone formulation, the WHO recommends starting doses of 0.05-0.125 
mg/kg/dose every 4 hours and 0.125-0.2 mg/kg/dose (maximum 5 mg) every 4 hours for 
opioid-nȁive and younger children of 1-12 months and 1-12 years of age, respectively.28  For 
children 7 years of age, the 3rd percentile of weight distribution is approximately 18 kg.29
Using a more conservative dosing approach for ALO-02 in pediatric patients the dose in this 
study should be calculated using 0.05-0.10 mg/kg/dose every 4 hours as a starting dose of 
oxycodone in children 7 years of age weighing 18 kg. This results in a 5.4 to 10.8 mg total 
daily dose (TDD) of oxycodone.30
For purposes of this study, ALO-02 3 mg oxycodone/0.36 mg naltrexone capsule, 5 mg
oxycodone/0.60 mg naltrexone capsule and 15 mg oxycodone/1.8 mg naltrexone capsule will 
be developed to meet the therapeutic needs of younger and lower weight children.31 The 
lower dosing strengths of ALO-02 will allow for the inclusion of opioid experienced as well 
as opioid naïve children who require around-the-clock treatment with an opioid for 
moderate-to-severe pain.
1.7. Additional Information
ALO-02 was developed with the goal of decreasing misuse, abuse, and diversion of opioid; 
an increasing public health problem among many age groups, including adolescents.  
Non-medical use of opioids has often been associated with prescriptions intended for 
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legitimate pain patients that are often diverted to unintended users.  Approximately 70% of 
non-medical users of prescription opioids obtain them from friends or relatives.32 The 
adolescent group, in particular, has been identified as a population at risk of misuse.33  
ALO-02 will deliver oxycodone as effectively as other long-acting oxycodone preparations 
while also deterring misuse and abuse because of the presence of the opioid antagonist 
sequestered in the formulation.
Complete information for ALO-02 may be found in the single reference safety document
(SRSD), which for this study is the Investigator’s Brochure (IB).
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary 

To characterize the PK of oxycodone in children and adolescents 7 to 17 years of age 
treated with ALO-02. 

To evaluate the safety of ALO-02 in children and adolescents 7 to 17 years of age.
2.1.2. Secondary

To determine the systemic exposures of naltrexone and 6--naltrexol in children and 
adolescents 7 to 17 years of age treated with ALO-02.
2.2. Endpoints
2.2.1. Primary

Pharmacokinetics: estimates of oxycodone average steady-state concentration (Css,av)
and apparent oral clearance (CL/F).

Safety: incidence, intensity, relationship, and seriousness of adverse events (including 
symptoms of opioid withdrawal or overdose).
2.2.2. Secondary

Pharmacokinetics: apparent volume of distribution (Vz/F) of oxycodone, data 
permitting; and systemic exposure levels of the metabolites of oxycodone 
(oxymorphone and noroxycodone), naltrexone, and 6--naltrexol.

Safety: changes in vital signs (blood pressure, heart rate, respiratory rate), clinical 
chemistry, and hematology laboratory values.
2.2.3. Other

Analgesic effect: pain intensity scores (actual and % change from baseline) and rescue 
medication or additional analgesic medication use over time.
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
Pharmacokinetics: graphical representations and regression analyses may be used to 
characterize the dose-exposure relationships for oxycodone, naltrexone, and 
6--naltrexol.
3. STUDY DESIGN
This is a multicenter, open-label, single-arm study designed to characterize the PK and to 
evaluate the safety of ALO-02 in children and adolescents 7 to 17 years of age who require 
opioid analgesia for moderate-to-severe pain.  The study consists of 4 study periods
occurring over a period of up to 9 weeks (Figure 1) including:

Screening Period (Visit 1) lasting up to 2 weeks.

Treatment Period (Visits 2-5) lasting up to 6-8 weeks.

Follow-Up/Post-Treatment Period (Visit 6) lasting 1 week.
Figure 1.
Overall Study Design
The study will enroll approximately 140 children and adolescents between the ages of 7 and 
17 years, with at least 100 subjects being exposed to ALO-02 for at least 2 weeks of the
Maintenance Phase.34  Plasma samples will be collected at 2 time points at least 2 hours apart
under steady-state conditions from each subject in the two age groups (7-11 years and 
12-17 years) to characterize the PK of oxycodone and determine any systemic exposures of 
naltrexone and 6--naltrexol.
Screening
Period
(2 Weeks)
Visit 1
Conversion/ 
Titration Phase 
(Up to 4 Weeks)
Visits 2-3a-3d
Maintenance 
Phase 
(2-4 Weeks)
Visits 4 and 5
Follow Up 
/Post 
Treatment 
Visit
(1 Week)
Visit 6
Treatment Period
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3.1. Screening Period
The Screening will occur up to 2 weeks before Visit 2.  This period includes one scheduled 
visit to the study center.  The purpose of the Screening Visit is to:
1. Assess a subject’s eligibility for study entry;
2. Assess caregiver’s willingness and eligibility to meet requirements of the study; and
3. 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 ALO-02 treatment.
3.2. Treatment Period
The Treatment Period duration is 6 to 8 weeks and consists of two phases of variable lengths 
depending on when a subject achieves a stable dose of ALO-02 and how long opioid 
analgesia is required.
3.2.1. Conversion/Titration Phase (Visits 2 through 3d)
The goals of the Conversion/Titration Phase are to convert subjects from their pre-study 
standard of care opioid analgesic to ALO-02 and to individualize pain management by 
titrating ALO-02 (Visits 2-3d; see Schedule of Activities) to achieve a stable dose.  Subjects 
and their caregiver will report for up to 4 visits during this period.  During Visit 2 the 
subject’s study eligibility will be verified, the subject’s current standard of care opioid 
therapy will be discontinued and ALO-02 will be initiated at a dose determined using the 
ALO-02 Conversion Guide (Appendix 2). 
The Conversion/Titration Phase will end once an ALO-02 dose that provides adequate 
analgesia with minimal adverse reactions is achieved (ie, stable dose) and minimal use of IR 
oxycodone as rescue, as determined by the investigator.  Visit 3a is mandatory for all 
subjects, while Visits 3b, 3c, and 3d are optional and should be used 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).  Subjects who do not reach a stable dose without the need for IR 
oxycodone as rescue by Visit 3d, will be withdrawn from the study and, if needed, converted
to standard of care opioid therapy at the discretion of the investigator. 
3.2.2. Maintenance Phase (Visit 4 and Visit 5)
The goal of the Maintenance Phase is to characterize the PK of oxycodone under steady-state 
conditions, as well as demonstrate the safety of ALO-02 over a 2-week or 4-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 weeks and then proceed to Visit 5 (up to 4 weeks 
total).
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During the Maintenance Phase visits are separated by 14 2 days.  Unscheduled visits are 
permitted at any time during the Maintenance Phase, as needed, and will follow the 
procedures outlined in Section 6.7.
Daily Diary and in-clinic pain intensity scores and safety will be assessed at each visit to 
determine if any dose adjustments are required.  Rescue medications (acetaminophen or 
NSAIDs) are permitted during this phase.  IR oxycodone HCl for rescue is discouraged 
during the Maintenance Phase.
Blood samples will be collected for PK analysis at Visit 4 for those subjects who achieve a 
stable dose between Visits 3a-3d.  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 
for an unscheduled visit or no later than Visit 5/Early Termination/End-of-Study Visit.
At Visit 4 or Visit 5, the investigator will discontinue the subject’s ALO-02 therapy and, if 
needed, convert the subject back to standard of care opioid therapy.  Blood samples will be 
collected for PK analysis if not already obtained.
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 ALO-02 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 5/Early Termination/End-of-Study Visit (see Section 6.2.2).
3.3. Follow Up/Post Treatment Visit
The purpose of the Follow Up/Post Treatment Visit (Visit 6) is to perform final adverse event 
safety assessments 72 days after the last dose of ALO-02 at Visit 5/Early 
termination/End-of-Study Visit for all subjects and not just for subjects completing Visit 5.  
The Follow Up/Post Treatment Visit can be done over the telephone at the investigator’s 
discretion. 
Subjects who discontinue early from the study as well as subjects who complete 2 weeks of 
ALO-02 during the Maintenance Phase and have their last dose of ALO-02 at Visit 4 will 
complete the Visit 5/Early Termination/End-of-Study Visit procedures without the need to 
return to the clinic for the Follow Up/ Post Treatment 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 participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
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4.1. Inclusion Criteria
Subject and caregiver eligibility should be reviewed and documented by an appropriate 
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:
1. Male and female subjects aged 7 to 17 years, inclusive.
2. Expected to require (based on the investigator’s judgment) continuous
around-the-clock opioid treatment equivalent to at least 6 mg total daily dose of 
oxycodone for the management of moderate-to-severe pain. 
3. Treated with opioids for at least 3 consecutive days immediately prior to first day of 
dosing with at least 6 mg daily dose of oxycodone (or the equivalent if converted 
from a different opioid the conversion to oxycodone should include a 25-50% dose 
reduction).
4. Evidence of a personally signed and dated informed consent document indicating that 
the subject’s legally acceptable representative/parent(s)/legal guardian (eg, caregiver) 
have 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.
5. Have legally acceptable representative/parent(s)/legal guardian (or adult caregiver) 
capable of supervising the storage and administration of study drug, and complying 
with scheduled visits, treatment plan, laboratory tests, and all other study procedures
(see Section 4.4).
6. Male subjects able to father children and female subjects of childbearing potential 
who are sexually active and at risk of 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 ALO-02.  Note: this excludes pre-pubertal females (see Section 4.3). 
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 the subject is no 
longer capable of taking medication orally.
2. History of known hypersensitivity to oxycodone, naltrexone, or opioid products in 
general.  This criterion does not include subjects who have experienced common 
opioid side effects (eg, nausea, vomiting, and constipation).
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3. Respiratory depression and/or unstable, severe bronchial asthma.
4. History of sleep apnea within the past year that would compromise the safety of the 
subject in the judgment of the investigator.
5. Known or suspected paralytic ileus or any other medical condition that, in the opinion 
of the investigator, would pose a safety risk to taking ALO-02.
6. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product 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.
7. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater 
than 3 times the upper limit of normal at the Screening Visit. 
8. Surgery within 3 days prior to first day of dosing. 
9. Epidural opioid <2 hours prior to the first dose of study drug.
10. Any planned surgery during the course of the study, with the exception of the 
placement of central or peripheral venous access devices. 
11. Subject endorses 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) 
ideation section or reports any suicidal behavior (Section 7.5.1).
12. Positive urine drug test (UDT) at Screening for any illicit substances or controlled 
substance medications that have not been prescribed to the subject.  An exception to 
the exclusion for positive opioids, amphetamine, or tetrahydrocannabinol (THC) if 
written evidence of a valid, current prescription is presented and documented in the 
source.
13. Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant; male subjects able to father children and female subjects of 
childbearing potential who are sexually active and are unwilling or unable to use a 
highly effective method of contraception as outlined in this protocol for the duration 
of the study and for at least 28 days after last dose of investigational product or longer 
based upon the compound’s half-life characteristics.
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14. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation.
15. Subjects who are children of, or related to, investigational site staff members, site 
staff members otherwise supervised by the investigator, or Pfizer employees directly 
involved in the conduct of the study.
4.3. Lifestyle 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 at least 28 days after the last dose of ALO-02.  The investigator or 
his or her designee, in consultation with the subject/caregiver, will confirm that the subject 
has selected an appropriate method of contraception for the individual subject and his or her 
partner 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/caregiver 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 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 the following:
1. 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.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. 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 investigational product and continuing for at least 28 days after the last 
dose.
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4.4. Caregiver(s)
The legally acceptable representative/parent(s)/legal guardian of the subject will actively 
participate as a caregiver in this study.  The caregiver will provide informed consent and 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 also include monitoring for signs 
and symptoms of opioid withdrawal or opioid toxicity and communicating safety information 
to the investigator (or designee) as appropriate.  The investigational site will be responsible 
for training the caregiver to recognize the signs and symptoms of opioid withdrawal and 
opioid overdose (see Section 5.2) and to complete a diary on a daily basis during the 
Treatment and Post-Treatment Periods of the study.  The caregiver will be instructed to seek 
immediate medical attention if signs or symptoms of opioid withdrawal or toxicity 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 withdrawal and overdose and 
recognize the need for immediate medical attention;

Administer study drug as directed and record time of each dose of study drug
in the diary;

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 
study is documented in the study contact list located in the study coordinator’s manual or 
B4531015 study team SharePoint site. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects/caregivers 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 
center 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 
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should be used only 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 
the study team for 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 for Columbia-Suicide Severity Rating Scale (C-SSRS) 
Clinic staff administering the assessments and directing the Caregiver in the completion of 
the Columbia-Suicide Severity Rating Scale (C-SSRS) must be appropriately trained.  The 
risk assessment for the C-SSRS must be done by a clinically qualified child and adolescent 
mental health professional (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) licensed 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.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH)
guidelines investigational product 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 ALO-02 capsules for oral use in this single-arm, open-label 
study. 
5.2. Subject Compliance
Subject compliance with ALO-02 will include study drug accountability utilizing capsule 
count.  Dosing will be recorded in the Daily Diary, and discussed at scheduled visits with the 
caregiver/subject. If a subject’s overall medication 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 the investigator should consider 
discontinuing the subject from the study after confirming the decision with Pfizer.
5.3. Opioid Withdrawal and Overdose
5.3.1. 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, 
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pupil dilation (>4 mm), high pitched crying, restlessness, vomiting, poor feeding, diarrhea, 
tachypnea, yawning, sneezing, hypertension, and mottling.35
5.3.2. Management of Opioid Withdrawal
In general, if significant opioid withdrawal occurs, the subject’s symptoms may be medically 
managed with pediatric oral doses of midazolam HCl for anxiety and restlessness 
(0.25-0.5 mg/kg/dose not to exceed 20 mg/dose),36 with supplemental doses of IR oxycodone 
HCl for opioid replacement if necessary, and with oral doses of ondansetron HCl 4 mg every 
8 hours as needed36 to control nausea and vomiting.  Otherwise, the subject’s symptoms can 
be treated with careful observation and supportive medical care.
5.3.3. Signs and Symptoms of Opioid Overdose
Acute overdose with oxycodone 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.37,38 Marked mydriasis rather than miosis may be seen 
due to severe hypoxia in some overdose situations.38
5.3.4. Management of Opioid Overdose
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 initial dose of 
0.01 mg/kg in pediatric subjects weighing less than 20 kg (or younger than 5 years) followed 
by 0.1 mg/kg if desired clinical response has not been achieved, and 0.01 mg/kg for those 
weighing more than 20 kg (or older than 5 years) followed by 0.1 mg/kg if desired clinical 
response has not been achieved up to a total dose of 0.4 mg to 2 mg.39
Since the duration of reversal would be expected to be less than the duration of action of 
oxycodone in ALO-02, the subject must be carefully monitored until spontaneous respiration 
is readily re-established.  ALO-02 will continue to release and add to the oxycodone 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.
Opioid antagonists should not be administered in the absence of clinically significant 
respiratory or circulatory depression secondary to oxycodone overdose.  Such agents should 
be administered cautiously to persons who are known or suspected to be physically 
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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 ALO-02 has no role in the treatment of opioid overdose.  
Investigators may write a prescription for subjects with take-home naloxone auto-injector
(Evzio)40 for intramuscular/subcutaneous use that the subject and parents/legal guardians 
can have close by in case an opioid overdose occurs.  Evzio is not a substitute for emergency 
medical care. 
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
PF-06412527/ALO-02 (oxycodone HCl and naltrexone HCl) capsules are Schedule II (C-II) 
oral dosage form available in the following strengths: 3 mg/0.36 mg, 5 mg/0.60 mg, 
10 mg/1.2 mg, 15 mg/1.8 mg, 20 mg/2.4 mg, 30 mg/3.6 mg, 40 mg/4.8 mg, 60 mg/7.2 mg, 
and 80 mg/9.6 mg.  All ALO-02 will be supplied by the sponsor.
ALO-02 will be packaged and provided for use according to the total daily dose requirement 
as listed in Table 3.  No other medications, including rescue medications, will be supplied by 
the sponsor.
Table 3.
ALO-02 Total Daily Dose and Dosing Schedule
Oxycodone HCl 
Total Daily Dose
ALO-02 Capsule Strength 
and Dosing Schedule
Conversion/Titration 
Phase Bottle Pill Count 
(capsules/bottle)
Maintenance Phase 
Bottle Pill Count 
(capsules/bottle)
6 mg
3 mg/0.36 mg BID
20
34
10 mg
5 mg/0.60  mg BID
20
34
20 mg
10 mg/1.2 mg BID
20
34
30 mg
15 mg/1.8 mg BID
20
34
40 mg
20 mg/2.4 mg BID
20
34
60 mg
30 mg/3.6 mg BID
20
34
80 mg
40 mg/4.8 mg BID
20
34
100 mg
20 mg/2.4 mg + 30 mg/3.6 mg 
BID
40
(blister pack)
72
(blister pack)
120 mg
60 mg/7.2 mg BID
20
34
140 mg
30 mg/3.6 mg + 40 mg/4.8 mg 
BID
40
(blister pack)
72
(blister pack)
160 mg
80 mg/9.6 mg BID
20
34
5.4.2. Preparation and Dispensing
ALO-02 will be shipped to the study center only after receipt of required documents in 
accordance with applicable regulatory requirements and sponsor procedures.
ALO-02 must be dispensed and administered according to the procedures described in the 
protocol.  Only subjects enrolled in the study may receive ALO-02 in accordance with all 
applicable regulatory requirements.  Only authorized study center personnel and the 
caregiver may supply or administer ALO-02.  Authorized site personnel will be the 
investigator (or his/her designee), in accordance with all applicable regulatory requirements.
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An Interactive Response Technology (IRT) system will monitor ALO-02 inventory at the 
study centers and will enact resupply of ALO-02 shipments as necessary.
5.4.3. Administration
ALO-02 is to be administered orally with or without food as per the IB.  The bottle label will 
direct the subject to take 1 capsule orally BID approximately 12 hours apart.  Morning doses 
should be administered between 6:00-10:00 AM every day throughout the study.
When ALO-02 capsules are administered whole, naltrexone HCl remains intact and does not 
affect the analgesic potential of oxycodone.  However, if the capsule is crushed, chewed or 
dissolved, the naltrexone HCl component is released, competitively binds at the -opioid 
receptors and thus inhibits the effects of the opioid. Therefore, ALO-02 capsules are to be 
swallowed whole.  The pellets in the capsules are not to be crushed, chewed, or dissolved.
As an alternative to taking the capsules whole, and only at the discretion of the investigator, 
the contents of the ALO-02 capsules (pellets) may be sprinkled over applesauce and then 
swallowed immediately without chewing.  This method of drug administration is only 
appropriate for children and adolescents unable to swallow capsules, but able to reliably 
swallow the applesauce without chewing it.  The investigator can assess in the clinic, the 
subject’s reliability in swallowing the applesauce without chewing it.  Placebo capsules filled 
with pellets containing sugar spheres and no oxycodone will be provided to the site for this 
purpose.  When using this method, the caregiver should sprinkle the pellets onto a small 
amount of applesauce (eg, 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 Investigational Product 
Manual.
The co-ingestion of ALO-02 with alcohol could result in an increase in oxycodone plasma 
levels and potentially fatal overdose of oxycodone.  Subjects should not consume alcoholic 
beverages or use prescription or non-prescription products containing alcohol while on 
ALO-02 therapy.
Misuse of the formulation by tampering (eg, crushing, chewing, or dissolving the contents) 
may result in the rapid release of both oxycodone and naltrexone, which may lead to fatal 
respiratory depression or symptoms of significant opioid withdrawal in opioid-tolerant 
individuals.
Medication errors are reportable irrespective of the presence of an associated adverse event 
(AE)/serious adverse event (SAE) including:

Medication errors involving subject exposure to the product.

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated AEs are captured on an 
AE CRF page (refer to ADVERSE EVENT REPORTING section for further details).
5.5. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all ALO-02 
capsules are stored in a secured area with controlled access under required storage conditions 
and in accordance with applicable regulatory requirements.
ALO-02 is a scheduled, controlled II substance. Study drug is to be stored at 15-25°C and 
must be secured in a locked cabinet in compliance with all applicable regulatory guidelines 
for the handling of Schedule II controlled substances.  Access must be limited to authorized 
study personnel only. 
Storage conditions stated in the SRSD (eg, IB) will be superseded by the storage conditions 
stated in the labeling.
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 (or designee). 
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 (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of ALO-02 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 (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order.
Once a deviation is identified, ALO-02 must be quarantined and not used until the sponsor 
provides documentation of permission to use ALO-02. It will not be considered a protocol 
deviation if the sponsor approves the use of the investigational product after the temperature 
excursion.  Use of ALO-02 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. 
Study drug, bottles and or blister card 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 study drug to the sponsor (or designee).
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5.6. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the ALO-02 supplies. 
Investigational product 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 ALO-02 accountability.  It is the responsibility of the sponsor 
study monitor (or designee) to review ALO-02 accountability records to ensure that FDA 
regulations and guidelines concerning investigational product accountability are being 
adhered to.
Periodic inventories of ALO-02 during and at the end of the study will be performed by the 
sponsor study monitor (or designee) and the investigator (or designee).  Missing ALO-02
must be recorded on the investigational product accountability/return forms along with an 
explanation of the discrepancy.  Missing medication stock must be reported to the sponsor 
immediately whenever discovered.  It is essential that all ALO-02 capsules are accounted for.  
All unused ALO-02 and bottles will be returned to the sponsor (or designee) after the proper 
completion of Drug Enforcement Agency (DEA) 222 Form(s).
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused ALO-02.
5.7. Concomitant Treatments(s)
5.7.1. Permitted Medications and Therapies
Permitted medications and therapies during the study are listed below. 

Acetaminophen and/or NSAIDs as a rescue medication anytime during the Treatment 
and Post-Treatment Periods at the discretion of the investigator.

During the Treatment Period, the use of acetaminophen or non-steroidal 
anti-inflammatory (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 ALO-02 to provide pain relief. 

IR oxycodone HCl as a single-entity ingredient (eg, Roxicodone) as rescue 
medication at doses prescribed by the investigator during the Conversion/Titration 
Phase until a stable dose of ALO-02 is achieved.  The use of IR oxycodone HCl is 
discouraged during the Maintenance Phase.

The use of IR oxycodone HCl as rescue medication is permitted during the 
Conversion/Titration Phase at the discretion of the investigator.  However, IR 
oxycodone HCl should be discontinued at the time a stable dose of ALO-02 is 
determined during the Conversion/Titration Phase.

Non-opioid adjunct analgesics, bowel regimens, anti-emetics are permitted.
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
For any other medications and therapies not listed (eg but not limited to central 
nervous system (CNS) depressants including sedatives, hypnotics, and other 
tranquilizer-type drugs) the investigator will consult with Pfizer’s clinical team.
5.7.2. Prohibited Medications and Therapies

Opioid analgesics (including tramadol, tapentadol, buprenorphine) except 
IR oxycodone HCl used as a rescue medication.

Mixed opioid agonist-antagonists such as pentazocine, nalbuphine, and butorphanol.

Monoamine oxidase inhibitors.

Ethanol in the form of alcoholic beverages (includes medications containing alcohol).
5.8. Rescue Medications
Acetaminophen and/or NSAID medications (eg, ibuprofen) as allowed by label for 
children/adolescents are permitted as rescue medication, at the discretion of the investigator, 
at any time in conjunction with ALO-02 to provide pain relief.  The dose of acetaminophen 
in children weighing less than 60 kg is 10-15 mg/kg/dose orally every 4-6 hours as needed or 
4000 mg/day, while the dose in adolescents weighing 60 kg or greater is 650 mg to 1000 mg 
every 4-6 hours as needed not to exceed 4000 mg/day.41  The dose of ibuprofen in children 
up to 12 years old is 5-10 mg/kg/dose orally every 6-8 hours as needed with maximum of 
4 doses/day, while the dose in subjects 12 years and older is 200 -400 mg orally every 
4-6 hours as needed with a maximum of 1200 mg/day.42  The use of IR oxycodone HCl as a 
rescue medication is permitted during the Conversion/Titration Phase, at the discretion of the 
investigator, to aid in the conversion.  The use of IR oxycodone HCl is discouraged during 
the Maintenance Phase.  Subjects/caregivers will be required to record use of rescue 
medication in the diary.
6. STUDY PROCEDURES 
Subjects/Caregivers will be asked to complete a diary each day during the Treatment Period
of the study.
The investigator and designees are 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 
should be screened as soon as conveniently possible to expedite the Conversion/Titration 
process.  During this visit, the following assessments and procedures will be performed:  
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
Informed Consent/Assent:  Subject’s legally acceptable representative/parent/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 Section 4.1 and Section 4.2, respectively.

Demographics: Information such as date of birth, race, gender, weight, and height 
will be collected.

Medical history: Review any significant medical/surgical histories and concurrent 
illnesses that required or require specialist consultation or treatment.

Review of pre-study opioid therapy: review the subject’s opioid therapy and 
document name of all opioids, dose, and dosing frequency.

Concomitant Treatments:  Record all previous medications taken within the last 
30 days before screening and concomitant medications (over-the-counter or 
prescribed. However, if there is a large volume of medications taken in an inpatient 
setting (such as burn or oncology patients), the requirements for electronic data 
capture (EDC) entry will be reduced. For subjects that are inpatients at the time of 
the Screening Visit and prior to enrollment, only opioids, medications for chronic 
pain, and medications indicated for chronic preexisting conditions will be transcribed 
onto the respective electronic Case Reprot Form (eCRF). See Section 5.7.

Physical examination: See Section 7.2.6.

Vital signs: Resting blood pressure, heart rate, and respiratory rate.

Clinical laboratory testing: Hematology, blood chemistry, and urinalysis (see
Section 7.2.3).

Serum pregnancy test: For all females of childbearing potential (see Section 7.3).

Contraception Check.

Urine drug screen: See Section 7.2.7.

Electrocardiogram: See Section 7.2.4.

Suicide Ideation and Behavior Assessment: Columbia-Suicide Severity Rating 
Scale (C-SSRS) – Section 7.5.1:

Children’s Lifetime/Recent (ages 7-11), version 23 Jun 2010 – Appendix 3.

Screening (ages 12-17), version 14 Jan 2009 – Appendix 4.
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
COWS: See Section 7.2.5.

Adverse events: See Section 7.2.1 for reporting of SAEs. 

Advise the caregiver that the next visit (Visit 2) is the day when the first dose of 
ALO-02 will be administered and request that the subject refrains from taking their 
pre-study opioid on the day of Visit 2.  In the event that the opioid has been taken, the 
visit should be rescheduled for the next day.  A telephone call is encouraged the day 
before Visit 2 to remind the caregiver.  Whenever possible, Visit 2 should be 
scheduled during morning hours. 

Subjects/caregivers are provided with an emergency contact card.
Procedures required by this protocol that were otherwise performed within the last 14 days 
prior to administration of ALO-02 may be utilized for this study.
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
Visit 2 (Day 1)
During this visit (Study Day 1) the following procedures will be performed before the 
administration of ALO-02: 

Vital Signs.

Review any results from laboratory samples that may exclude a subject from 
participating.

Urine Pregnancy Test: For all females of childbearing potential. 

Suicide Ideation and Behavior Assessment:  C-SSRS – see Section 7.5.1
Children’s Since Last Visit (ages 7-11), version 23 Jun 2010 – Appendix 5.

Since Last Visit (ages 12-17), version 14 Jan 2009 – Appendix 6.

Contraception Check.

COWS assessment.

Pain Numeric Rating Scale (NRS -Pain): in-clinic assessment.

AE assessment:  only pre-dose SAEs will be documented.

Review of opioid therapy:  review the subject’s opioid therapy and document name 
of all opioids, dose, and dosing frequency on the appropriate CRF.
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
Concomitant Treatments:  review and document all concomitant medications 
including dose and frequency. 

Discontinue pre-study opioid therapy as part of dose conversion.

Dispense ALO-02:  dispense appropriate dose of ALO-02 based on the Conversion 
Guide as described in Appendix 2.
The following procedures will be performed after dispensing of ALO-02 and after 
completion of all pre-dose procedures at Visit 2 described above:

Subject Instruction and Caregiver Training: Train the caregiver(s) and instruct the 
subject on ALO-02 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.  Administer the 
first dose of ALO-02 in-clinic and only after the above mentioned procedures are 
completed.

Prescribe Rescue Medication (if needed):  prescribe acetaminophen and/or an 
NSAID to be used during the Conversion/Titration Phase.  IR oxycodone HCL may 
also be prescribed for rescue with the intent to limit its use until a stable dose of 
ALO-02 is achieved.

Schedule the Visit 3a.

Weekly telephone calls to contact the caregiver.
Visit 3a (Day 72 days)
All subjects must come to clinic for this visit. 
During this visit, the investigator will review the subject’s daily diary to assess the subject’s 
pain to determine whether a stable dose of ALO-02 has been achieved (ie, a dose that 
provides adequate analgesia and minimal adverse reactions).
During this visit the following procedures will be followed:

Assess Treatment Response:

Pain intensity (diary review and in-clinic assessment);

Rescue medication (diary review);

Compliance with ALO-02 (diary review);

Concomitant medications (diary review);

AEs (diary review).
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
COWS assessment.

NRS-Pain Scale:  in-clinic assessment.

Concomitant treatments.

AE assessment.

Vital signs.

Urine pregnancy test: For all females of childbearing potential.

Contraception Check.

Suicide Ideation and Behavior Assessment:  C-SSRS – see Section 7.5.1.

ALO-02 Accountability: see Section 5.5.

Dose Titration: adjust ALO-02 total daily dose as needed to optimize pain therapy.

Prescribe Rescue Medication (if needed): prescribe acetaminophen and/or an 
NSAID to be used during the Conversion/Titration Phase.

Dispense ALO-02 to caregiver. 

Weekly telephone calls to contact the caregiver.
For Converted Subjects: If at Visit 3a the subject has been successfully titrated to a stable 
dose of ALO-02 and with minimal use of IR oxycodone HCl for rescue, the subject may be 
scheduled for Visit 4 (see Schedule of Activities and Section 6.2.2).  It is at this visit, 
Visit 3a, that the subject enters the Maintenance Phase of the Treatment Period.
For Non-Converted Subjects: If at Visit 3a the subject has not achieved a stable dose of 
ALO-02, this subject will remain in the Conversion/Titration Phase; therefore, the next visit 
should be scheduled as described further in the protocol.
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 Visit 3b the subject has been successfully titrated to a stable 
dose of ALO-02 and with minimal use of IR oxycodone HCl for rescue the subject may be 
scheduled for Visit 4 (see Schedule of Activities and Section 6.2.2).  It is at this visit, 
Visit 3b, that the subject enters the Maintenance Phase of the Treatment Period.
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For Non-Converted Subjects: If at Visit 3b the subject has not achieved a stable dose of 
ALO-02, this subject will remain in the Conversion/Titration Phase; therefore, the next visit 
should be scheduled as described further in the protocol.
Visit 3c (Day 212 days)

Follow the same procedures and assessments as described at Visit 3a.
For Converted Subjects: If at Visit 3c the subject has been successfully titrated to a stable 
dose of ALO-02 and with minimal use of IR oxycodone HCl for rescue the subject may be 
scheduled for Visit 4 (see Schedule of Activities and Section 6.2.2).  It is at this visit, 
Visit 3c, that the subject enters the Maintenance Phase of the Treatment Period.
For Non-Converted Subjects: If at Visit 3c the subject has not achieved a stable dose of 
ALO-02, this subject will remain in the Conversion/Titration Phase; therefore, the next visit 
should be scheduled as described further in the protocol.
Visit 3d (Day 282 days)

Follow the same procedures and assessments as described at Visit 3a.
For Converted Subjects: If at Visit 3d the subject has been successfully titrated to a stable 
dose of ALO-02 and with minimal use of IR oxycodone HCl for rescue the subject will be 
scheduled for the next visit, which will be Visit 4 (see Schedule of Activities).  It is at this 
visit, Visit 3d, that the subject enters the Maintenance Phase of the Treatment Period.
For Non-Converted Subjects: If at Visit 3d the subject has not achieved a stable dose of 
ALO-02 the subject will be discontinued from the study and will complete the procedures 
specified for Visit 5/Early Termination/End-of-Study Visit. The Follow-up/Post Treatment 
(Visit 6) will be scheduled in one week.  ALO-02 will be discontinued, and if needed, 
converted to a standard of care opioid therapy at the investigator’s discretion.

Schedule the Follow Up/Post Treatment Visit (Visit 6): see Section 6.3.

The Follow-Up/Post Treatment Visit (Visit 6) may be done in the clinic or over the 
telephone at the discretion of the investigator.
6.2.2. Maintenance Phase
Once the investigator has determined that the subject has achieved a stable dose of ALO-02, 
the subject will enter the Maintenance Phase of the Treatment Period and be scheduled to 
return to the study center for Visit 4 two weeks after the last Conversion/Titration Phase visit.
Visit 4
Perform the following assessments:

Assess Treatment Response:
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
Pain intensity (diary review and in-clinic assessment);

Rescue medication (diary review);

Compliance with ALO-02 (diary review);

Concomitant medication (diary review);

AEs (diary review).

COWS assessment.

NRS-Pain Scale: in-clinic assessment.

Concomitant treatments.

AE assessment.

Vital signs.

Urine pregnancy test:  For all females of childbearing potential.

Contraception Check.

Suicide Ideation and Behavior Assessment:  C-SSRS – see Section 7.5.1.

ALO-02 accountability.

Prescribe rescue medication (if needed):  prescribe acetaminophen and/or an 
NSAID to be used during the Maintenance Phase.

Obtain plasma samples for PK analysis: Record the following items on the 
appropriate CRF:

The exact dosing date and clock times of the previous 4 doses of ALO-02, and

The exact clock time of the blood draw for the 2 samples.

Dispense ALO-02 to caregiver if the subject needs additional 2 weeks of treatment 
with ALO-02 and schedule Visit 5/Early Termination/End-of-Study Visit.

Weekly telephone calls to contact the caregiver.
Visit 5/Early Termination/End-of-Study Visit
Subjects who discontinue early from the study as well as subjects who complete 2 weeks of 
ALO-02 during the Maintenance Phase and have their last dose of ALO-02 at Visit 4 will 
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complete the Visit 5/Early Termination/End-of-Study Visit procedures without the need to 
return for the Follow Up/Post Treatment Visit. 
During this visit the following procedures will be followed for all subjects:

Physical examination.

Vital signs.

Clinical laboratory testing.

Serum pregnancy test:  for all females of childbearing potential.

Contraception Check.

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 times of the previous 4 doses of ALO-02, and

The exact clock time of the blood draw for the 2 samples.

Assess Treatment Response:

Pain intensity (diary review and in-clinic assessment);

Rescue medication (diary review);

Compliance with ALO-02 (diary review);

Concomitant medication (diary review);

AEs (diary review).

COWS assessment.

NRS-Pain Scale: in-clinic assessment.

Concomitant treatments.

AE assessment.

Suicide Ideation and Behavior Assessment: C-SSRS – see Section 7.5.1.

ALO-02 accountability.
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
Prescribe rescue medication (if needed):  prescribe acetaminophen and/or an 
NSAID.

Review and document rescue medication use (name, dose, and frequency).

Weekly telephone calls to contact the caregiver.
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 ALO-02 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 5/Early Termination/End-of-Study Visit (see Section 6.2.2).
6.4. Visit 6 Follow Up/Post Treatment Visit
The purpose of the Follow Up/Post Treatment Visit (Visit 6) is to perform final adverse event 
safety assessments.  Visit 6 will occur approximately 1 week (7 2 days) after discontinuing 
ALO-02 at Visit 5/Early termination/ End-of-Study Visit for all subjects and not just for 
subjects completing Visit 5. The Follow Up/Post Treatment Visit can be done over the 
telephone at the investigator’s discretion.
The following procedures are as follows:

Suicide Ideation and Behavior Assessment:  C-SSRS – see Section 7.5.1.

AE assessment.
6.5. Subject Withdrawal 
Caregivers may withdraw the subject from the study at any time at their own request, or the 
subject may be withdrawn at any time at the discretion of the investigator or sponsor for 
safety, including pregnancy, 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. 
Subjects who withdraw early from the study during the Treatment Period regardless of 
reason (eg, failure to achieve a stable dose, lack of efficacy, AE) are requested to fulfill the 
Early Termination procedures and activities.  Should any invasive procedures or new 
therapies be initiated during the study (eg, nerve block, implanted spinal cord stimulator) the 
subject may continue at the discretion of the investigator.
Subjects who do not reach a stable ALO-02 dose by Visit 4 (Day 28) will be discontinued 
from the study.  Subjects who test positive for illicit substances on UDT at Screening will be 
discontinued from the study, unless supported by prescription for medicinal use (eg, ADHD 
medications or medical marijuana).  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.
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If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject/caregiver.  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/caregiver to return all unused investigational product(s), request that 
the subject/caregiver return for the Early Termination visit, if applicable, and follow-up with 
the subject/caregiver 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).
In the event of clinically important treatment-emergent suicidal ideation or suicidal behavior, 
the subject will be discontinued from the study and will receive the appropriate medical care.  
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 
MHP as part of the psychiatric evaluation and assessment of subject safety.  Refer to
Section 7.5, 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.
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)
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 5/Early Termination/End-of-Study visit.  The following attempts must be made 
in the order listed below:
1. 3 documented* attempts via telephone; then
2. If feasible, 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”.
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6.7. Unscheduled Visits
A subject/caregiver is to contact the study center if the subject is experiencing inadequate 
analgesia or intolerable opioid or other effects before a scheduled study center visit.  If at any 
time pain worsens despite the use of rescue medication therapy, including IR oxycodone 
HCl, an unscheduled visit may be needed to adjust the dose of ALO-02.  For unscheduled 
visits due to an increase in pain where titration is necessary, record at a minimum, the Daily 
Pain Numerical Rating Scale (NRS-Pain) pain and COWS scores on the 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 5/Early termination/End-of-Study 
Visit procedures to be performed (see Schedule of Activities).  An unscheduled visit due to a 
combination of an AE and an increase in pain requires the Visit 5/Early termination/End-of 
Study Visit 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 that 
he or 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 Numerical Rating Scale 
ranging from zero (no pain) to 10 (worst possible pain) captured in the diary (Appendix 7).  
A subject will rate their average pain in the past 24 hours by selecting one number as shown 
below.  The subject will conduct the self-assessment daily with the caregiver(s) in the 
evening prior to bedtime and record 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.  Pain intensity will also be 
completed at the in-clinic visits during the Treatment Periods.  Only the in-clinic visit pain 
assessments will be documented on the CRF and used for analysis.
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Figure 2.
Daily Pain Numerical Rating Scale (NRS-Pain)
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 during the Treatment Period will be recorded in the diary. 
The administration of acetaminophen and/or an NSAID during the study is recorded by the 
caregiver, but is not to be more than labelled and directed by the investigator.
7.2. Safety Assessments
7.2.1. Adverse Events
7.2.1.1. Recording of Adverse Events Using a Diary
The study caregiver (parent or legal guardian) will be instructed on the use of a diary, in 
which the caregiver will record dosing information, concomitant treatments, and AEs 
between visits to the clinic.  The caregiver will be instructed and details will be provided in 
written format to the caregiver on the signs and symptoms of opioid overdose (eg, toxicity), 
opioid withdrawal, as well as other signs and symptoms commonly associated with opioid 
AEs (eg, nausea, headache, and 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. The investigator or 
designee will review and transcribe Caregiver adverse findings for the daily Diary to the 
appropriate CRF.  Weekly telephone contact with the caregiver (ie, parent/legal guardian) 
must be documented in source documents.
7.2.2. Vital Signs
Vital signs including resting systolic and diastolic blood pressure, heart rate, and respiratory 
rate are performed at designated study visits as outlined in the Schedule of Activities. 
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7.2.3. Clinical Laboratory Tests
The hematology, blood chemistry, and urinalysis tests presented in Table are performed at 
designated study visits as outlined in the Schedule of Activities.
Table 4.
Clinical Laboratory Tests
Serum Chemistry
Alanine aminotransferase (ALT)
Chloride
Albumin
Serum creatinine
Alkaline phosphatase
Creatine phosphokinase
Aspartate aminotransferase (AST)
Glucose
Bicarbonate
Phosphorus
Bilirubin (total)
Potassium
Blood urea nitrogen
Protein (total)
Calcium
Sodium
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)
Urinalysis
Routine dip-stick unless otherwise indicated
Pregnancy
Serum and urine hCG
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.  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 
withdrawal.43  
A subject assessed with a COWS score 13 will be 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 
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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.
Height and weight is measured only at screening (Visit 1).
7.2.7. Urine Drug Test
A urine drug sample is collected at the Screening Visit, as outlined in the Schedule of 
Activities, for the purpose of detecting illicit drug substances and/or prohibited analgesic 
medications (notably opioid analgesics).  Certain positive test results may be acceptable 
providing documentation of a valid prescription is confirmed by the investigator. A positive 
UDT for cocaine, phencyclidine (PCP), metamphetamine, and ecstasy will disqualify the 
subject from the study.
Specifically, the following drugs will be screened for by immunoassay by a central 
laboratory:

Opioids (codeine, morphine, hydrocodone, hydromorphone, dihydromorphone);

Oxycodone;

Methadone;

Amphetamines (including metamphetamine and ecstasy);

Phencyclidine (PCP);

Cocaine;

THC (marijuana).
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 Visit and End-of-Study Visit, and a 
urine pregnancy test, with the same sensitivity of at least 25 mIU/mL, will be performed at 
all other study visits (ie, Visits 2-5).  A negative pregnancy result is required before the 
subject may receive the investigational product.  Pregnancy tests will also be done whenever 
one menstrual cycle is missed during the treatment period (or when potential pregnancy is 
otherwise suspected) and repeated at the end of the study to confirm the subject has not 
become pregnant during the study.  In the case of a positive confirmed pregnancy, the subject
will be withdrawn from administration of ALO-02 but may remain in the study.  Pregnancy 
tests may also be repeated as per request of IRB/Ethics Committees (ECs) or if required by 
local regulations.
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7.4. Contraception Check
The investigator or his/her designee will discuss with the subject/caregiver 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.
7.5. Suicidality Assessment
7.5.1. Columbia-Suicide Severity Rating Scale (C-SSRS)
Suicide ideations and behaviors will be evaluated during all scheduled visits (Visits 1 
through 6).  The age-appropriate scale must be utilized based upon the subject’s age at 
screening (Visit 1). 
For subjects who are between ages 7 and 11:

The Children’s Lifetime/Recent (Version 23 Jun 2010) of the C-SSRS (Appendix 3) 
should be completed at screening (Visit 1).  The Children’s Lifetime/Recent scale 
refers to the subject’s lifetime experience.  At all study visits after the screening visit, 
the Children’s Since Last Visit (Version 23 Jun 2010) of the C-SSRS (Appendix 5) 
should be utilized, even if the child has his/her 12th birthday during the study.  The 
Children’s Since Last Visit version refers to the subject’s experience since the last 
visit.
For subjects who are between ages 12 and 17:

The Baseline/Screening (Version 14 Jan 2009) of the C-SSRS (Appendix 4) should 
be completed at screening (Visit 1).  The Baseline/Screening scale refers to the 
subject’s lifetime experience.  At all study visits after the screening visit, the Since 
Last Visit (Version 14 Jan 2009) of the C-SSRS (Appendix 6) should be utilized.  The 
Since Last Visit version refers to the subject’s experience since the 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 withdrawn from 
the study 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 one of the following child and adolescent MHP.  In the United States, in 
addition to child and adolescent psychiatrists (board certified or board eligible), clinically 
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qualified MHPs include the following: (1) general psychiatrists, (2) licensed 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.
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 
participation. Subjects endorsing items 4 or 5 on the C-SSRS ideation section or reporting 
any suicidal behavior following the Screening visit must be discontinued from the study and 
will receive the appropriate medical care.  Refer to Section 6.5, Subject Withdrawal.
7.6. Pharmacokinetic Evaluation 
7.6.1. Blood Sample Collection and Handling
A total of two 6 mL (2×6 mL) blood samples will be taken for the purpose of quantifying the 
concentrations of oxycodone, noroxycodone, oxymorphone, naltrexone, and 6--naltrexol in 
plasma.  PK samples will be collected at Visit 5 or at Early Termination/End-of-Study Visit
if they are not collected at Visit 4. The clock time of the first pharmacokinetic sample will 
be documented (and noted relative to the clock time of the morning dose of ALO-02) on the 
CRF.  The second pharmacokinetic 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 
4 doses of ALO-02 are also to be recorded on the appropriate CRF.
Plasma samples received by the bioanalytical laboratory will be assayed for oxycodone,
noroxycodone, oxymorphone, naltrexone, and 6--naltrexol using validated analytical 
methods 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.
7.6.2. Plasma Sample Shipment to Bioanalytical Laboratory
The shipping procedures and address of the bioanalytical laboratory will be provided under 
separate cover.
7.7. Blood Volume
Total blood sampling volume for the individual subject is approximately 36 mL.  The actual 
times of blood sampling may change. 
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Table 5.
Blood Volume
Sample Type
Blood volume 
(mL)
Number of Sampling Times
Total volume 
(mL)
Screening
Treatment Period
End-of-Study
Safety labs
6
1
--
1
12
Pregnancya
6
1
--
1
12
PK
6
2
--
12
TOTAL
--
--
--
--
36b
a.  Applies to females of child-bearing age who are sexually active.
b.  Total volume does not include discarded blood from pre-draws used to remove fluid from flushed catheters.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
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 a
serious adverse event (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 nonserious AE 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 
study. 
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 investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs 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 SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.

AEs (serious and nonserious) should be recorded on the CRF from the time the 
subject has taken at least 1 dose of investigational product through the subject’s last
visit.
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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.
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 product, 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.
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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

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 AEs 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

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation 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
A serious adverse event 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;

Lack of efficacy should be reported as an AE when it is associated with an SAE.
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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. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements). 
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level 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. 
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 values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal
range: AST or ALT values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1 × ULN or if the 
value reaches 3 × ULN (whichever is smaller).
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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 measurements of 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 person, 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 of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
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: 
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
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 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

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;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive 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.
8.8. Severity Assessment
If required on the AE 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 
the 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 
nonserious); 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 investigational product caused or contributed to an 
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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 investigational product caused 
the event, then the event will be handled as “related to investigational product” 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 investigational product,”
this should be clearly documented on study records. 
In addition, if the investigator determines that 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 both unapproved/unlicensed products 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 having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
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).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product 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 investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an 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
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terminated fetus should be assessed by gross visual inspection (unless preprocedure 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 baby, 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 the investigational product.
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.
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 the drug safety unit within 24 hours of the 
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 investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also Section 6.5 on Subject Withdrawal)
Withdrawal due to AEs 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 because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
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8.13. Eliciting Adverse Event Information
The caregiver will be questioned about AEs at each visit.  The investigator will review the 
observation log form the diary, and use judgment which observations need to be entered as 
AEs.  The investigator is to report all directly observed AEs and all AEs spontaneously 
reported by the study subject/parent(s)/legal guardian/legally acceptable representative.  See
Section 7.2.1.1 on recording of AEs using Diary.
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 time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, 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 
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. Nonserious 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.
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8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE 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.
Approximately 140 pediatric subjects will be enrolled in order to achieve that at least 
100 children and adolescents are exposed to at least 2 weeks of treatment with ALO-02 in the 
Maintenance Phase for the purpose of establishing a safety database.  At least 25% of 
children and adolescents will be enrolled in each of the two age groups (7-11 years old and 
12-17 years old). 
9.2. Efficacy Analysis
Analgesic effect analyses will be performed using all available in-clinic pain intensity data 
from the safety population in 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.
CCI
CCI
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9.3. Pharmacokinetic Analysis
9.3.1. Pharmacokinetic Analysis Datasets
The PK concentration population is defined as all subjects with at least 1 plasma 
concentration measurement in this study.  The PK analysis population will be defined as all 
subjects who have usable PK data (ie, concentration data can be associated with the dose 
level, time of dosing, and time of PK sampling) and are included in the estimates of the 
primary PK parameters of interest.
9.3.2. Pharmacokinetic Endpoints
Primary PK endpoints will include estimates of oxycodone average steady-state plasma 
concentration (Css,av) and apparent clearance (CL/F) following treatment with ALO-02.  
Secondary PK endpoints will include apparent volume of distribution (Vz/F) of oxycodone
(data permitting).  Endpoints will also include the exposure levels of the metabolites of 
oxycodone (oxymorphone and noroxycodone), naltrexone, and 6--naltrexol following 
multiple dose treatment with ALO-02.  Graphical representations and regression analyses 
may be used to characterize the dose-exposure relationships for oxycodone, naltrexone, and 
6--naltrexol (data permitting). 
9.3.3. Pharmacokinetic Analysis
Given the expected low fluctuation in steady-state oxycodone concentrations following 
ALO-02 BID dosing in children and adolescents based on the ALO-02 study B4531006 in 
adults, the concentrations observed during the Maintenance Phase will be used as an estimate 
of Css,av of oxycodone and its metabolites (data permitting) in subjects. The CL/F of 
oxycodone will be estimated using a ratio of the daily dosing rate of ALO-02 and the 
estimates of oxycodone Css,av in the Maintenance Phase. The concentration-time dataset will 
be analyzed to obtain estimates for Vz/F of oxycodone in subjects, data permitting.
Covariates of interest (ALO-02 dosage, age, body weight, gender, concomitant medications 
etc.) will be evaluated in order to explain the observed between-subject variability in 
oxycodone 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. Graphical 
representations and regression analyses may be used to characterize the dose-exposure 
relationships for oxycodone, naltrexone, and 6-β-naltrexol (data permitting).
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 ALO-02.
Safety data will be summarized for the Safety population.
Results from the safety assessments and any adverse events will be presented in tabular 
and/or graphic form adhering to current Pfizer Data Standards.
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Pfizer Data Standards will be used to provide safety summaries on treatment emergent 
adverse events.  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; 
Appendix 8) will be presented in tabular and/or graphic form adhering to current Pfizer Data 
Standards.
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 
ALO-02 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. 
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 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. 
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. There is a permissible 4 hour window within which study 
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drug can be taken if a drug dose is missed.  If later than 4 hours, the subject should be given 
rescue medication to treat breakthrough pain until the next scheduled dosing time.
9.5. Interim Analysis
No interim analysis is planned for this study. 
9.6. Data Monitoring Committee 
This study will use an Internal Review Committee (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 are 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 institutional review board (IRB)/ethics committee (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.
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.
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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 are true. Any corrections to entries made in the CRFs or 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 investigative 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/assent 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, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to 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 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.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
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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/assent 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/EC 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 (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/Assent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
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 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 subject’s personal data consistent 
with applicable privacy laws.
The informed consent/assent documents 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 or her legally acceptable
representative, or parent(s) or legal guardian if a minor, 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 legally acceptable representative, parents(s) or 
legal guardian and the subject’s assent, when applicable before any study-specific activity is 
performed.  The investigator will retain the original of each subject's signed consent/assent
document.
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12.4. Subject Recruitment
Advertisements approved by IRBs/ECs 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 that might influence the evaluation of the benefits and risks of the investigational 
product, 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 
End of Trial is defined as Last Subject Last Visit and meeting all of the Post-Treatment 
Period requirements. 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer. In addition, Pfizer retains the right to discontinue development of 
ALO-02 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), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, 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 patients 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.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU 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.
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.
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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.
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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mg With Sequestered Naltrexone 4.8 mg.  08 Jun 2012.
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and methadone for prevention of postoperative pain in 3- to 7-year old children.  J 
Pediatrics.  1991:119;136-41.
50.
EMBEDA(morphine sulfate and naltrexone hydrochloride exteneded-release 
capsules) prescribing information.  King Pharmaceuticals, Inc., Bristol, TN.  June 2009. 
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Appendix 1. Abbreviations
Abbreviation
Term
ADHD
attention deficit hyperactivity disorder
AE
adverse event
ALO-02
oxycodone hydrochloride and naltrexone hydrochloride 
extended-release capsules
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BID
twice daily
BPCA
Best Pharmaceuticals for Children Act
CDC
Centers for Disease Control and Prevention
Cmax
maximum (peak) observed drug concentration
Css
steady state plasma drug concentration
Css,av
average steady state plasma drug concentration
CNS
central nervous system
COWS
Clinical Opiate Withdrawal Scale
CRF
case report form
CSA
clinical study agreement
C-SSRS
Columbia-Suicide Severity Rating Scale
DAI
Drug Administration and Instructions
DEA
Drug Enforcement Agency
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
ER
extended-release
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
HRQL
health-related quality of life
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
IR
immediate-release
IRB
Institutional Review Board
IRC
internal review committee
IRT
interactive response technology
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Abbreviation
Term
IUD
intrauterine device
IVR
interactive voice response
IWR
interactive web response
LFT
liver function test
LPD
local product document
LSLV
last subject last visit 
N/A
not applicable
MHP
mental health professional
NRS-Pain
pain numeric rating scale
PCD
primary completion date
PCP
phencyclidine
PREA
Pediatric Research Equity Act
SAE
serious adverse event
SAP
statistical analysis plan
SCL
Supply Chain Lead
SIB
suicidal ideation and behavior
SOP
standard operating procedure
SPC
summary of product characteristics
SRSD
single reference safety document
t½
elimination half-life
Tmax
time to Cmax
THC
tetrahydrocannabinol
QD
once daily
ULN
upper limit of normal
US
United States
USPI
United States package insert
Vz/F
apparent volume of distribution 
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Appendix 2. ALO-02 Conversion Guide
While there are useful tables of opioid equivalents readily available, there is substantial 
inter-patient variation in the relative potency of different opioid drugs and products.  As such, 
it is safer to underestimate a patient's 24 hour oral oxycodone requirement and provide rescue 
medication (eg, IR oxycodone) than to overestimate the 24-hour oxycodone requirements 
which could result in adverse reactions.
Investigators should consider the following when using the information in Table 6:

This is not a table of equianalgesic doses

The conversion factors in this table are only for the conversion from one of the listed oral 
opioid analgesics to ALO-02.

The table cannot be used to convert from ALO-02 to another opioid. Doing so will 
result in an overestimation of the dose of the new opioid and may result in fatal overdose.

Follow your established hospital guidelines to convert from intravenous (IV), pain 
controlled analgesia (PCA) and/or epidural treatment with opioid analgesics before using 
the oral conversion guidelines in this Appendix. 
Table 6.
Conversion Factors to ALO-021
Prior Oral Opioid
Approximate Oral Conversion Factor
Codeine (including combination drugs)
0.1
Hydrocodone (including combination drugs)
0.67
Hydromorphone
2.67
Methadone
2 
(see note on conversion below)
Morphine
0.67
Oxycodone (including combination drugs)
1
Tramadol
See note on conversion below
Transdermal fentanyl
See note on conversion below
1.  Use this formula to calculate total daily dose of ALO-02:  
mg/day prior opioid x conversion factor = mg/day ALO-02
Option 1.
To calculate the estimated ALO-02 dose using Table 6:
For subjects on a single opioid, sum the current total daily dose of the opioid and then 
multiply the total daily dose by the conversion factor listed in Table 6 to calculate the 
approximate oral oxycodone daily dose.
For subjects on a regimen of more than one opioid, calculate the approximate oral oxycodone 
dose for each opioid and sum the totals to obtain the approximate total oxycodone daily dose. 
For subjects on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the 
opioid component of these products in the conversion table.
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For subjects on around-the-clock opioid who are not on oxycodone, reduce the estimated 
equianalgesic oxycodone total daily dose by 25-50%.
Always round the dose down, if necessary, to the appropriate ALO-02 strength(s) available.
Example conversion from a single opioid to ALO-02:
Step 1:Sum the total daily dose of the prior opioid (for example: extended-release 
hydrocodone) 30 mg hydrocodone twice daily = 60 mg total daily dose of hydrocodone.
Step 2:Calculate the equivalent dose of oral oxycodone based on the total daily dose of the 
current opioid using Table 6. In this example, a patient receiving 60 mg total daily dose of 
hydrocodone × 0.67 (conversion factor) = 40.2 mg of oral oxycodone daily. The total daily 
dose (40 mg) should then be divided in 2 equal doses; 20 mg twice daily.
Step 3:Reduce the dose by 25-50%. By applying the dose reduction factor of 50% to the 
above example, the final dosing regimen would be 10 mg/1.2 mg twice daily.
Close observation and frequent titration are warranted until pain management is stable on the 
new opioid.  Monitor subjects for signs and symptoms of opioid withdrawal or for signs of 
oversedation/toxicity after converting subjects to ALO-02.
Option 2.
Product Specific Conversion Guide:
IMPORTANT INFORMATION ABOUT THIS GUIDE:
Due to incomplete cross-tolerance when converting from a non-oxycodone analgesic to 
ALO-02, 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 oxycodone
requirement and provide rescue medication rather than to overestimate and manage an 
adverse event.1
Conversion from Other Oxycodone Products to ALO-02
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.
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
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 FROM OTHER OXYCODONE PRODUCTS TO ALO-02:
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 oxycodone therapy 
into the equianalgesic dose of oxycodone, using the appropriate ratio (1:1). 
3. Refer to the specific analgesic table below to find an equianalgesic dose of ALO-02. 
4. Administer the calculated dose in the most convenient dosing strength of ALO-02 in 
2 divided doses q12h.  ALO-02 should not be given more frequently than every 
12 hours. 
CONVERTING FROM OTHER OXYCODONE TO ALO-0210
Oxycodone
daily dose (mg)a
Equianalgesic daily 
morphine dose
(mg)
Suggested 
equianalgesic dose of 
ALO-02 
administered in 
2 divided doses q12h
(mg)
Suggested starting dose 
of ALO-02 based on 
existing capsule strengths
(mg)b
5
7.5
5
3 BID
10
15
10
3 BID
15
20
15
5 BID
20
30
20
5 BID
30
45
30
5 BID
40
60
40
10 BID
60
90
60
15 BID
80
120
80
40 BID
100
150
100
50 BID
a.
Calculate the total daily dose of oxycodone.  It may be necessary to start with the lower strength of 
ALO-02.
b.
It is likely that some rescue medication may be needed for breakthrough pain until the dose of ALO-02 can 
be titrated to the effective daily dose, thus ensuring a smooth transition.
c.
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.
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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.
Conversion From Transdermal Fentanyl To ALO-02
Eighteen hours following the removal of the transdermal fentanyl patch, ALO-02 treatment 
can be initiated. Although, there has been no systemic assessment of such conversion, a 
conservative ALO-02 dose, approximately 10 mg/1.2 mg twice daily of ALO-02 should be 
initially substituted for each 25 mcg/hr fentanyl transdermal patch. Follow the patient 
closely during conversion from transdermal fentanyl to ALO-02, as there is limited 
documented experience with this conversion.
HOW TO CONVERT FROM TRANSDERMAL FENTANYL TO ALO-02
1. Determine the total daily dose of transdermal fentanyl.
Note that fentanyl is approximately 50 to 150 times more potent than morphine.5
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).6
3. Refer to the analgesic table below to find the equianalgesic dose of ALO-02.  In 
general, it is safest to give half of the estimated daily ALO-02 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 ALO-02, in 
2 divided doses q12h.  ALO-02 should not be given more frequently than every 
12 hours.
CONVERTING FROM TRANSDERMAL FENTANYL TO ALO-025,6,7,8,9
Transdermal
fentanyl daily dosea
Equianalgesic 
morphine daily 
dose
(mg)
Equianalgesic dose of
ALO-02 total daily 
dose
(mg)
Suggested starting dose of 
ALO-02 at ≈50% reduction 
based on existing capsule 
strengths(mg)b 
12.5 mcg/h=300 mcg/day
30
20
5 BID
25 mcg/h=600 mcg/day
60
40
10 BID
50 mcg/h=1200 mcg/day
120
80
20 BID
75 mcg/h=1800 mcg/day
180
120
30 BID
100 mcg/h=2400 mcg/day
240
160
40 BID
a.
Calculate the total daily dose of transdermal fentanyl. It may be necessary to start with the lower strength 
of ALO-02. 
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b.
It is likely that rescue medication may be needed for breakthrough pain until the dose of ALO-02 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.
c.
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.
Conversion from Transdermal Buprenorphine to ALO-02
There has been no systematic assessment of conversion from transdermal buprenorphine to 
other opioids. Therefore, subjects taking transdermal buprenorphine should be started on 
ALO-02 dose, 10 mg/1.2 mg twice daily.  It is likely that rescue medication may be needed 
for breakthrough pain until the dose of ALO-02 can be titrated to the effective daily dose, 
thus ensuring a smooth transition.
Conversion from Tramadol to ALO-02
Because tramadol is not a pure opioid, there has been limited systematic assessment of 
conversion from tramadol to other opioids.
TRAMODOL PRODUCTS

Ultram(tramadol is available in 50 mg, 100 mg, 200 mg and 300 mg strengths). 

Ultram ER(extended release formulations is available in 100, 200 and 300 mg 
strengths).

Ultracet(tramadol 37.5 mg and acetaminophen 325 mg).

Generic equivalent and other immediate release (IR) products.
HOW TO CONVERSION FROM TRAMADOL TO ALO-02
1. Determine the total daily dose of tramadol dose.
Note that morphine is 10-20 times more potent than tramadol.45
2. Calculate the conversion of the total daily dose of the current tramadol therapy into 
the equianalgesic dose of morphine, using the appropriate ratio (based on an 
approximate oral equianalgesic ratio of 1:10-20).45
3. Refer to the analgesic table below to find the equianalgesic dose of ALO-02.  In 
general, it is safest to give half of the estimated daily ALO-02 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 ALO-02, in 
2 divided doses q12h.  ALO-02 should not be given more frequently than every 
12 hours.
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CONVERTING FROM TRAMADOL TO ALO-02
Tramadol
daily dose
(mg)a
Equianalgesic 
morphine dose
(mg)
Suggested 
equianalgesic dose 
of ALO-02
(mg)
Suggested starting dose 
of ALO-02 at ≈50% 
reduction based on 
existing capsule 
strengths (mg)b
150
15
10
3 BID
200
20
12
3 BID
300
30
20
5 BID
400
40
25
5 BID
a.
Calculate the total daily dose of transdermal fentanyl. It may be necessary to start with the lower strength 
of ALO-02. 
b.
It is likely that rescue medication may be needed for breakthrough pain until the dose of ALO-02 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.
c.
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.
Conversion from Methadone to ALO-02
Close monitoring is of particular importance when converting from methadone to other 
opioid agonists. The ratio between methadone and other opioid agonists may vary widely as 
a function of previous dose exposure. Methadone has a long half-life and can accumulate in 
the plasma.
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 ALO-02
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).46,47  Calculate the conversion of the total 
daily dose of the current methadone therapy into the equianalgesic dose of ALO-02, 
using the appropriate ratio (based on an approximate equianalgesic ratio of 1:2). 
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3. Refer to the analgesic table below to find the equianalgesic dose of ALO-02.  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 ALO-02.
CONVERTING FROM METHADONE TO ALO-025,46,47,48,49
Methadone
daily dose
(mg)a
Equianalgesic 
morphine dose
(mg)
Suggested 
equianalgesic dose 
of ALO-02
(mg)
Suggested starting dose 
of ALO-02 at ≈50% 
reduction based on 
existing capsule 
strengths (mg)b
10
30
20
5 BID
20
60
40
10 BID
30
90
60
15 BID
40
120
80
20 BID
50
150
100
30 BID
60
180
120
30 BID
80
240
160
40 BID
a.
Calculate the total daily dose of methadone.  It may be necessary to start with the lower strength of 
ALO-02. 
b.
It is likely that rescue medication may be needed for breakthrough pain until the dose of ALO-02 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.
c.
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.
Conversion from Hydrocodone to ALO-02
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) 
7.5 mg/750 mg; Vicodin HP(hydrocodone bitartate and acetaminophen tablets, 
USP) 10 mg/660 mg.
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
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 FROM HYDROCODONE TO ALO-02:
1. Determine the total daily dose of hydrocodone.
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 1:1).10 Calculate the conversion of the total 
daily dose of the current hydrocodone therapy into the equianalgesic dose of ALO-02, 
using the appropriate ratio (based on an approximate equianalgesic ratio of 1:0.67).
3. Refer to the analgesic table below to find the equianalgesic dose of ALO-02.  In 
general, it is safest to give half of the estimated daily ALO-02 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 ALO-02, in 
2 divided doses q12h.  ALO-02 should not be given more frequently than every 
12 hours.
CONVERTING FROM HYDROCODONE TO ALO-02:
Hydrocodone
daily dose
(mg)a
Equianalgesic 
morphine daily dose 
(mg)
Equianalgesic dose 
of
ALO-02 total daily 
dose
(mg)
Suggested starting 
dose of ALO-02 at 
≈50% reduction 
based on existing 
capsule strengths
(mg) b
20
20
13
3 BID
30
30
20
5 BID
40
40
30
10 BID
60
60
40
10 BID
80
80
60
15 BID
a.
Calculate the total daily dose of hydrocodone. It may be necessary to start with the lowest strength of 
ALO-02.
b.
It is likely that rescue medication may be needed for breakthrough pain until the dose of ALO-02 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.
c.
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.
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Conversion from Hydromorphone to ALO-02
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 ALO-02:
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).10  Calculate the conversion of the total daily 
dose of the current hydromorphone therapy into the equianalgesic dose of ALO-02, 
using the appropriate ratio (based on an approximate equianalgesic ratio of 1:2.67). 
3.
Refer to the analgesic table below to find the equianalgesic dose of ALO-02.  In 
general, it is safest to give half of the estimated daily ALO-02 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 ALO-02, in 
2 divided doses q12h.  ALO-02 should not be given more frequently than every 
12 hours.
CONVERTING FROM HYDROMORPHONE TO ALO-02:10,46,50
Hydromorphone daily 
dose
(mg)a
Equianalgesic 
morphine dose
(mg)
Suggested 
equianalgesic dose 
of ALO-02
(mg)
Suggested starting 
dose of ALO-02at 
≈50% reduction based 
on existing capsule 
strengths (mg) b
6
24
20
5 BID
8
32
20
5 BID
12
48
30
5 BID
16
64
40
10 BID
20
80
40
15 BID
24
96
60
15 BID
a. Calculate the total daily dose of hydromorphone. It may be necessary to start with the lowest strength of 
ALO-02.
b. It is likely that rescue medication may be needed for breakthrough pain until the dose of ALO-02 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.
c.
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.
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Conversion from Morphine to ALO-02
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 MORPHINE PRODUCTS TO ALO-02:
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 to oxycodone, using the appropriate ratio 
(1:1.5).1 Calculate the conversion of the total oral daily dose of the current morphine 
therapy into the equianalgesic dose of ALO-02, using the appropriate ratio (1:0.67). 
3. Refer to the specific analgesic table below to find an equianalgesic dose of ALO-02. 
4. Administer the calculated dose in the most convenient dosing strength of ALO-02 in 
2 divided doses q12h.  ALO-02 should not be given more frequently than every 
12 hours.
CONVERTING FROM MORPHINE PRODUCTS TO ALO-02:10
Morphine
daily oral dose
(mg)a
Equianalgesic
morphine oral dose
(mg)
Suggested 
equianalgesic dose of 
ALO-02
(mg)
Suggested starting 
dose of ALO-02 at 
≈50% reduction based 
on existing capsule 
strengths (mg) b
15
15
10
3 BID
30
30
20
5BID
60
60
40
10 BID
90
90
60
15 BID
100
100
60
15 BID
200
200
120
30 BID
a. Calculate the total daily morphine dose. It may be necessary to start with the lowest strength of ALO-02.
b. It is likely that rescue medication may be needed for breakthrough pain until the dose of ALO-02 can be 
titrated to the effective daily dose, thus ensuring a smooth transition.
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c.
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.
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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 (Version 1/14/09):  Age 12-17
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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 Numerical Rating Scale (NRS-Pain)
Question:  
Select the number that best described your pain in the past 24 hours.  (Select one number 
only)
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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.
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