Clinical trial NCT02367820
Conditions: Low Back Pain Chronic Pain
Sponsor: Nektar Therapeutics
Start date: 2015-04-14; Completion date: 2018-01-01
Enrollment: 638 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this 52-week open label study is to determine the long-term safety of a new opioid molecule, NKTR-181, in patients with moderate to severe chronic low back pain or chronic non-cancer pain.

Detailed description:
This is an open-label safety and tolerability study in which approximately 600 subjects will receive NKTR-181 for up to 52 weeks. Subjects may include newly enrolled subjects and subjects who have recently completed SUMMIT-07 study.

This study will also investigate the pharmacokinetics of NKTR-181 in patients with chronic low back pain or chronic non-cancer pain.

Arms: arm 1: NKTR-181 twice daily (BID) tablets
Interventions: intervention 1: NKTR-181 BID tablets
Intervention descriptions: intervention 1: NKTR-181 tablets 100-600 mg twice daily (BID)

Protocol documents:
Prot_002.pdf: 
Protocol No.:14-181-08 Amendment 2.0 
 
NKTR-181 
Nektar Therapeutics 
 
Page 1 of 59 
Confidential and Proprietary 
 
15 Jan 2016 
 
Nektar Therapeutics 
CLINICAL STUDY PROTOCOL 
A PHASE 3 MULTICENTER, OPEN-LABEL, 52-WEEK STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND TOLERABILITY OF NKTR-181 IN SUBJECTS WITH 
MODERATE TO SEVERE CHRONIC LOW BACK PAIN OR CHRONIC 
NONCANCER PAIN 
Protocol Number: 14-181-08 
Protocol Version Amendment 2.0 
Protocol Amendment Date 15 January 2016 
Supersedes: Protocol amendment 1.0 dated 22 May 2015 
Original Protocol dated15 January 2015 
IND Number: 109,963 
Sponsor: Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
Sponsor’s Contact
 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The confidential information in this document is provided to you as an Investigator or consultant for review by you, 
your staff, and the applicable Institutional Review Board/Independent Ethics Committee and applicable Regulatory 
Authorities. Your acceptance of this document constitutes agreement that you will not disclose the information 
herein to others without written authorization from Nektar Therapeutics, except to the extent necessary to obtain 
informed consent from persons who participate as subjects in this study. 


Protocol No.:14-181-08 Amendment 2.0 
 
NKTR-181 
Nektar Therapeutics 
 
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INVESTIGATOR SIGNATURE PAGE 
Nektar Therapeutics 
TITLE: 
A Phase 3 Multicenter, Open-Label, 52-Week Study to Evaluate 
the Long-Term Safety and Tolerability of NKTR-181 in Subjects 
with Moderate to Severe Chronic Low Back Pain or Chronic 
Noncancer Pain 
PROTOCOL NUMBER: 
14-181-08 
PHASE OF STUDY: 
3 
PROTOCOL 
AMENDMENT DATE: 
15 Jan 2016 
STUDY SPONSOR: 
Nektar Therapeutics 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 USA 
 
PRINCIPAL INVESTIGATOR COMMITMENT: 
I, the undersigned Principal Investigator, submit this statement of commitment as evidence that I 
understand my responsibilities pursuant to Federal Regulations (21 CFR § 312) and ICH E6 
Good Clinical Practice guidelines, as well as with any and all applicable federal, state and/or 
local laws and regulations, and agree to conduct the study in accordance with the protocol 
referenced herein. 
 






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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE......................................................................................2 
PRINCIPAL INVESTIGATOR COMMITMENT: ...................................................................2 
PROTOCOL APPROVAL PAGE ...............................................................................................3 
LIST OF STUDY CONTACTS ....................................................................................................4 
TABLE OF CONTENTS ..............................................................................................................5 
LIST OF TABLES .........................................................................................................................8 
ABBREVIATIONS ........................................................................................................................9 
1.0 
STUDY SYNOPSIS .........................................................................................................11 
1.1 
Study Schematic.....................................................................................................13 
1.2 
Schedule of Assessments .......................................................................................14 
2.0 
INTRODUCTION............................................................................................................17 
2.1 
Background ............................................................................................................17 
2.2 
NKTR-181 .............................................................................................................17 
2.3 
Study and Dose Rationale ......................................................................................17 
3.0 
STUDY OBJECTIVES ....................................................................................................19 
3.1 
Primary Objective ..................................................................................................19 
3.2 
Secondary Objective ..............................................................................................19 
4.0 
STUDY DESIGN ..............................................................................................................20 
4.1 
Summary of Study Design .....................................................................................20 
5.0 
SELECTION OF STUDY POPULATION ...................................................................21 
5.1 
Inclusion Criteria ...................................................................................................21 
5.1.1 
Rollover Subjects ..................................................................................21 
5.1.2 
De Novo Subjects ..................................................................................22 
5.2 
Exclusion Criteria for ALL Subjects .....................................................................22 
5.3 
Removal of Subjects from Study Therapy or Assessment .....................................24 
6.0 
TREATMENT PLAN ......................................................................................................25 
6.1 
Screening Period (Visits 1-2) .................................................................................25 
6.1.1 
Rollover Subjects ..................................................................................25 
6.1.2 
De Novo Subjects ..................................................................................25 
6.2 
Treatment Period (Visits 3-20) ..............................................................................26 
6.2.1 
Pharmacokinetic Substudy ....................................................................27 
6.3 
Safety Follow-Up Period (Visits 23-24) ................................................................28 


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6.4 
Rescue Medication .................................................................................................28 
6.5 
Monitoring of Hepatic Transaminases ...................................................................28 
6.6 
Prior and Concomitant Medications ......................................................................29 
6.6.1 
Prohibited and Restricted Medications .................................................29 
6.6.2 
Permitted Medications ..........................................................................30 
6.7 
Assigning Subject Numbers ...................................................................................30 
7.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS ..............................................32 
7.1 
Description and Formulation .................................................................................32 
7.1.1 
Study Drug Description ........................................................................32 
7.1.2 
Rescue Medication ................................................................................32 
7.2 
Study Drug Packaging and Labeling .....................................................................32 
7.3 
Study Drug Storage ................................................................................................33 
7.4 
Accountability and Reconciliation .........................................................................33 
8.0 
PHARMACOKINETIC MEASUREMENTS ...............................................................34 
8.1 
Pharmacokinetic Blood Sample Collection ...........................................................34 
8.2 
Pharmacokinetic Analysis of Samples ...................................................................35 
9.0 
EFFICACY ASSESSMENTS .........................................................................................36 
9.1 
Modified Brief Pain Inventory-Short Form (mBPI-SF) ........................................36 
10.0 
ASSESSMENT OF SAFETY ..........................................................................................37 
10.1 
Adverse Events and Serious Adverse Events ........................................................37 
10.1.1 
Adverse Events Definition and Assessment .........................................37 
10.1.2 
Monitoring Adverse Events ..................................................................37 
10.1.3 
Grading of Adverse Events ...................................................................38 
10.1.4 
Causality Relationship of Adverse Events ............................................39 
10.1.5 
Adverse Event Reporting and Follow-up ..............................................39 
10.1.6 
Serious Adverse Event Definition .........................................................40 
10.1.7 
Serious Adverse Event Reporting .........................................................40 
10.1.8 
Serious Adverse Event Follow-up ........................................................41 
10.1.9 
Expedited Reporting of Serious Adverse Events ..................................42 
10.2 
Special Reporting Situations ..................................................................................42 
10.2.1 
Misuse or Abuse ....................................................................................42 
10.2.2 
Pregnancy ..............................................................................................43 
10.3 
Clinical Laboratory Tests .......................................................................................43 


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10.4 
Vital Signs ..............................................................................................................44 
10.5 
Twelve-Lead Electrocardiograms ..........................................................................44 
10.6 
Medical History .....................................................................................................45 
10.7 
Pregnancy Tests .....................................................................................................45 
10.8 
Drug and Alcohol Screening ..................................................................................45 
10.9 
Suicidality Assessment ..........................................................................................46 
10.10 Opioid Withdrawal .................................................................................................46 
10.10.1 
Clinical Opiate Withdrawal Scale (COWS) ..........................................46 
10.10.2 
Subjective Opiate Withdrawal Scale (SOWS) ......................................47 
11.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE ......................................................................48 
11.1 
General Considerations ..........................................................................................48 
11.2 
Determination of Sample Size ...............................................................................48 
11.3 
Analysis Sets ..........................................................................................................48 
11.4 
Subject Disposition ................................................................................................49 
11.5 
Demographic and Baseline Disease Characteristics ..............................................49 
11.6 
Prior and Concomitant Medications ......................................................................49 
11.7 
Study Drug Exposure .............................................................................................49 
11.8 
Rescue Medication .................................................................................................49 
11.9 
Safety Analyses ......................................................................................................49 
11.9.1 
Time to Discontinuation ........................................................................49 
11.9.2 
Incidence of Aberrant Drug Behavior as Measured Using 
MADDERSTM .......................................................................................49 
11.9.3 
Adverse Events .....................................................................................50 
11.9.4 
Clinical Laboratory Results ..................................................................50 
11.9.5 
Twelve-Lead Electrocardiogram Measurements ..................................50 
11.9.6 
Vital Signs .............................................................................................50 
11.9.7 
Clinical and Subjective Opiate Withdrawal Scales ...............................50 
11.10 Efficacy Analyses ..................................................................................................51 
11.10.1 
Modified Brief Pain Inventory–Short Form ..........................................51 
11.10.2 
Time to Stabilization of Pain Scores During the Study ........................51 
11.11 Missing Data ..........................................................................................................51 
11.12 Pharmacokinetics ...................................................................................................51 
12.0 
STUDY OR STUDY SITE TERMINATION ................................................................52 


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13.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................53 
13.1 
Changes to the Protocol .........................................................................................53 
13.2 
Monitoring .............................................................................................................53 
13.3 
Direct Access to Source Data/Documents for Audits and Inspections ..................54 
14.0 
ETHICS ............................................................................................................................55 
14.1 
Institutional Review Board/Independent Ethics Committee Approval .................55 
14.2 
Written Informed Consent .....................................................................................55 
15.0 
DATA HANDLING AND RECORD KEEPING ..........................................................56 
15.1 
Data Collection Instruments and Source Documents ............................................56 
15.1.1 
Study Records .......................................................................................56 
15.1.2 
Data Collection Instruments (DCIs)......................................................56 
15.2 
Retention of Essential Documents .........................................................................56 
16.0 
PUBLICATION POLICY ...............................................................................................57 
17.0 
REFERENCES .................................................................................................................58 
18.0 
APPENDICES ..................................................................................................................59 
  
LIST OF TABLES 
Table 1: 
Recommended Procedures for Subjects with Elevated Aminotransferase 
Test Results ......................................................................................................29 
Table 2: 
Pharmacokinetic Sample Collection Times in the PK Substudy .....................34 
Table 3: 
Clinical Laboratory Tests .................................................................................44 
  


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NKTR-181 
Nektar Therapeutics 
 
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ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
adverse event 
ALT  
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST  
aspartate aminotransferase 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
mBPI-SF 
Modified Brief Pain Inventory-Short Form 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
COX-2 
cyclooxygenase-2 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
%CV 
percent coefficient of variation 
CYP3A 
cytochrome P450 enzyme isoform 3A 
DCI 
data collection instruments 
ECG 
Electrocardiogram 
eCOA 
electronic clinical outcome assessments 
eCRF 
electronic case report form 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


Protocol No.:14-181-08 Amendment 2.0 
 
NKTR-181 
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Abbreviation or Term 
Definition 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice and Web Response System 
MAD 
multiple ascending dose 
MADDERSTM 
Misuse, Abuse, and Divergent Drug Event Reporting System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSE 
morphine sulfate equivalent 
NME 
new molecular entity 
NSAID 
non-steroidal anti-inflammatory drug 
PAMORA 
peripherally acting mu-opioid receptor antagonist 
PD 
Pharmacodynamic 
PHQ-8 
Personal Health Questionnaire Depression Scale 
PK 
Pharmacokinetic 
q12h 
every 12 hours 
QTcF 
corrected QT interval (Fredericia) 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOP 
standard operating procedure 
SOWS 
Subjective Opiate Withdrawal Scale 
SUSAR 
suspected unexpected serious adverse reactions 
T 
temperature  
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
 


Protocol No.:14-181-08 Amendment 2.0 
 
NKTR-181 
Nektar Therapeutics 
 
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1.0 
STUDY SYNOPSIS 
Name of Sponsor:  
Nektar Therapeutics 
Name of Finished Product: NKTR-181 tablets 
Name of Active Ingredient: NKTR-181 
Title of Study: 
A Phase 3 Multicenter, Open-Label, 52-Week Study to Evaluate the Long-Term 
Safety and Tolerability of NKTR-181 in Subjects with Moderate to Severe Chronic 
Low Back Pain or Chronic Noncancer Pain 
Duration of Study:  
Approximately 57 weeks for each subject 
Phase of Development: 
3 
Objectives: 
Primary: 
• To evaluate the long-term safety and tolerability of NKTR-181 in subjects with 
moderate to severe chronic low back pain or chronic noncancer pain.  
Secondary: 
• To evaluate the efficacy of NKTR-181 as measured by the modified Brief Pain 
Inventory-Short Form (mBPI-SF). 
Study Population 
Opioid non-tolerant adults 18-75 years of age, inclusive, with moderate to severe 
chronic low back painor chronic noncancer pain. 
Number of Subjects 
(planned):  
Approximately 600 subjects are expected to be enrolled. This number may increase 
or decrease to meet the International Conference on Harmonisation (ICH) regulatory 
exposure requirements for NKTR-181 of at least 300 subjects who complete 
26 weeks of NKTR-181 treatment and at least 100 subjects who complete 52 weeks 
of NKTR-181 treatment. The subjects will comprise those qualifying to rollover from 
completing Study 14-181-07 and Study 14-181-12 as well as newly enrolled (“De 
Novo”) subjects qualifying for this study. Approximately 250 De Novo Subjects will 
be enrolled in the trial. 
Number of Study Sites: 
Approximately 100  
Countries: 
USA 
Key Inclusion Criteria:  
1. 
Clinical diagnosis of moderate to severe chronic low back pain for > 3 months 
before signing the informed consent form (ICF). 
2. 
Newly enrolled subjects (“De Novo Subjects”) who are treating their chronic 
low back pain with no less than 10 mg but no more than 60 mg of morphine 
sulfate equivalents/day for at least the 7 days prior to signing the ICF.. 
3. 
Subjects who have completed Study 14-181-07 or Study 14-181-12 and meet 
entry criteria are eligible (“Rollover Subjects”). 
Study Design: 
Open-label, multicenter, safety and tolerability study of NKTR-181 in the treatment 
of moderate to severe chronic low back pain or chronic noncancer pain.  
The study will be divided into the following 3 periods: 
• Screening: Up to 21 days 
• Treatment: Up to 52 weeks (inclusive of a 1-week taper) 
• Follow-up: Approximately 14 days after last dose of study drug 


Protocol No.:14-181-08 Amendment 2.0 
 
NKTR-181 
Nektar Therapeutics 
 
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Test Product, Dose and 
Mode of Administration:  
Name: NKTR-181 tablet(s)  
Dose, Route, and Frequency: NKTR-181 100-mg and 200-mg tablets will be 
administered orally twice daily (BID) as doses of 100 mg, 200 mg, 300 mg,  400 mg, 
500 mg and 600 mg BID. Each dose will consist of tablets as follows: 
100-mg dose = 1 x 100-mg tablet 
200-mg dose = 1 x 200-mg tablet  
300-mg dose = 1 x 200-mg tablet + 1 x 100-mg tablet  
400-mg dose = 2 x 200-mg tablets 
500–mg dose = 2 x 200-mg tablet + 1x 100-mg tablet 
600-mg dose = 3 x 200 mg tablet 
Subjects should take NKTR-181 BID at approximately 8 AM and 8 PM. 
Safety: 
Key Safety Endpoints: 
Safety and tolerability will be evaluated based on the following: 
• Incidence, type, seriousness, and severity of adverse events (AEs) reported 
• Clinical laboratory evaluations 
• Electrocardiograms (ECGs) 
• Vital signs (respiratory rate, pulse, heart rate, blood pressure, and temperature) 
• Drug withdrawal as measured by the Clinical Opiate Withdrawal Scale (COWS) 
and the Subjective Opiate Withdrawal Scale (SOWS) 
• Incidence of aberrant drug behavior according to MADDERSTM assessment 
• Suicidality assessment (Columbia-Suicide Severity Rating Scale [C-SSRS]) 
Efficacy: 
Efficacy Endpoint: 
• Efficacy will be evaluated based on the mBPI-SF administered at clinic visits. 
Pharmacokinetics: 
Plasma concentrations of NKTR-181 and selected metabolites will be tabulated by 
time and subject and assessed for relationship to dose during the treatment phase. 
These data will be pooled with those from other studies during population PK 
analyses and investigation of exposure-response relationships for efficacy and safety.
Statistical Methods: 
Summaries for the assessment of long-term safety will be presented by De Novo and 
Rollover Subjects separately and for all subjects combined. The frequency and 
percentage of subjects experiencing treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), and AEs leading to withdrawal from the study drug 
will be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system 
organ class, preferred term, severity, and relationship to the study drug. Laboratory 
test results, vital signs, ECGs, SOWS, COWS, and change from baseline will be 
summarized using descriptive statistics. The relationship between duration of 
exposure and the frequency and severity of AEs will be examined. Time-to-event 
endpoints will be estimated using the Kaplan-Meier method. Change over time from 
baseline in each question and metric of the mBPI-SF will be summarized using 
descriptive statistics. 
 




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NKTR-181 
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1.2 
Schedule of Assessments 
Assessment Period 
Screening 
Up to 21 days 
Treatment* 
52 weeks 
Follow-Up 
14 days 
Unscheduled 
Visit 
Visit 
1 
21 
3 
4, 5, 6, 7, 8, 9 
(Flexible) 
10, 13, 17, 
& 20 
11 &12 
14-16 & 
18-19 
21/ET2 
22/EOT 
23 
24/EOS 
 
Dayse 
≤ 21 days prior to  Visit 3 
1 
Every 4-10 Days 
after previous visit 
Every 30
(- 3) 
Every 30 
(- 3) 
Every 30
(- 3) 
D357 
(+ 3) 
D364
(+ 3) 
72 hours 
14 
(± 2) 
 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics3 
X 
 
 
 
 
 
 
 
 
 
 
 
PHQ-84 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history5 
X 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test6 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination7 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs8 
X 
 
X 
X 
X 
 
 
 
X 
X 
 
X 
12-lead electrocardiogram9 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Clinical laboratory tests10 
X 
 
X 
X 
X 
X
 
X 
X 
X 
X 
X 
Pregnancy test11 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
Urine drug screen12 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
eC-SSRS13 
X 
 
X 
 
X 
 
 
X 
X 
 
 
 
Taper opioid analgesics14 
 
X 
 
 
 
 
 
 
 
 
 
 
Dose titration assessment 
 
 
 
X 
 
 
 
 
 
 
 
 
mBPI-SF15 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
COWS 
 
X16 
X16
 
 
 
 
X 
X 
X 
X 
X 
SOWS17 
 
X 
 
 
 
 
 
X 
X 
X 
X 
 
PK blood sample collection 
 
 
X18
X19
X 
X 
 
X 
X 
 
 
X 
Discontinue current analgesics 
 
 
X 
 
 
 
 
 
 
 
 
 
Dispense/review/collect/instruct 
study drug 
 
 
X 
X 
X 
X 
X 
X20 
X21 
 
 
X 
Opioid side effect training 
 
 
X 
 
 
 
 
 
 
 
 
 
Abuse & diversion assessment 
 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
Concomitant medications22 
 
 
 
X 
Adverse events22 
 
 
 
X 


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Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index, COWS, Clinical Opiate Withdrawal 
Scale; eC-SSRS, electronic Columbia–Suicide Severity Rating Scale; ECG, electrocardiogram, EOS, end of study; EOT, end of treatment; ET, early termination; mBPI-
SF, modified Brief Pain Index-Short Form; MSE, morphine sulfate equivalent; NRS numerical rating scale;, PHQ-8, Personal Health Questionnaire Depression Scale PK, 
pharmacokinetic; SOWS, Subjective Opiate Withdrawal Scale; TBL, total bilirubin. 
* 
If at any time a subject does not tolerate study drug between protocol-mandated visits in the Treatment Period, per Investigator discretion, an unscheduled visit should 
occur. 
FOOTNOTES: 
1. There is no Visit 2 for Rollover Subjects. 
2. If a subject was dosed with study drug and discontinues from the study before completing all of the scheduled assessments, then assessments for Visit 21/ET and all 
safety follow-up procedures should be completed for this subject. 
3. Demographics include birth date, race/ethnicity, smoking status, height, weight, BMI, and sex at birth. For Rollover Subjects, all demographic information (except 
weight and BMI) will be carried forward from Study 14-181-07 or Study 14-181-12. 
4. The Personal Health Questionnaire Depression Scale (PHQ-8) is a self-administered (i.e., the subject completes the scale) version of the Primary Care Evaluation of 
Mental Disorders for mood.. Subjects who score 10 or greater are not eligible to participate in this study. 
5. Medical history includes medication history, history of substance or opioid abuse, medical/surgical history and concurrent illnesses and will be collected for all 
subjects and noted as to whether the condition is active. All relevant medical history will be collected and carried forward for Rollover Subjects. Ongoing adverse 
events that occurred in Study 14-181-07 and Study 14-181-12 will continue to be followed for Rollover Subjects. 
6. Subjects who have a positive alcohol breath test will not be eligible for participation in this study. 
7. Physical examination, including all major organ systems (general, head, eyes, ears, mouth/throat, neck, heart, lungs, abdomen, lymph nodes, joints, extremities, 
integumentary, neurologic, and psychiatric) will be performed for all De Novo Subjects. Physical examinations will not be conducted on Rollover Subjects. 
8. Vital signs (respiratory rate, blood pressure, pulse, and temperature) will be measured after subjects have been resting for at least 5 minutes. 
9. Subjects must be resting quietly in the supine position for > 5 minutes prior to collection of 12-lead ECG. During the treatment period, if an ECG is obtained and 
reveals that the subject’s QTcF interval is > 500 msec or has an increase of ≥ 60 msec compared to baseline QTcF and confirmed with a second ECG within 30 
minutes, treatment with study medication should be interrupted. In the event this occurs, the investigator should contact the Medical Monitor as soon as possible to 
discuss if the subject can continue on treatment or if the subject should stop study medication. Subjects who are discontinued will be required to complete the ET 
Visit and all safety follow-up procedures.  
10. Clinical laboratory tests will include hematology, chemistry, and urinalysis at Visits 1, 10, 13, 17, 20, 21, and 22. Clinical laboratory tests will include only ALT, 
AST, ALP, and TBL at all other visits indicated. Clinical laboratory tests will be collected at Visits 23 and 24 only if results from previous visits were abnormal and 
clinically significant. Conjugated bilirubin is required only at Visit 1. 
11. Pregnancy tests are required only for females of childbearing potential. Serum pregnancy test is required at Visit 1 (sent to central laboratory). Urine pregnancy test is 
required for subsequent visits. A negative pregnancy test result must be obtained before the administration of the study drug. 


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12. Urine dipstick drug test to screen for amphetamines, cannabinoids, cocaine, and opioids. Urine drug screen at visits 1 and 3 is done for De Novo subjects only. Urine 
drug screen at visit 4 is done for Rollover subjects only. No urine drug sceen will be conducted at visits 5, 6,7,8 and 9. Rollover Subjects will have urine collected for 
testing at central lab rather than being tested onsite. Opioids will not be tested for Rollover Subjects at Visits 1 and 3. De Novo Subjects on non-opioid analgesics at 
the time of Visit 1 must have a negative urine drug screen at Visit 1 and Visit 3. De Novo subjects on opioid analgesics at the time of Visit 1 must have a negative 
urine drug screen for all drugs except opioids. Dipstick urine drug screen tests will be provided by the sponsor. 
13. The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) is a subject self-report rating scale (i.e., the subject completes the scale) to lifetime and study-
defined suicidal ideation and to assess suicidal ideation and behaviors since the time of the last visit. Subjects who answered YES to Question 4 or Question 5 within 
the past 12 months of the Baseline/Screening version of the eC-SSRS (Visit 1) are not eligible to participate in this study 
14. De Novo subjects taking opioid analgesics will begin to taper their opioids over the next 7-14 days. Subjects must be on ≤ 30 morphine sulfate equivalents (MSE)/day 
for at least 3 days before proceeding to Visit 3. 
15. The modified Brief Pain Inventory-Short Form (mBPI-SF) is a subject self-report rating (i.e., the subject completes the rating inventory) of pain and the impact of that 
pain on daily function. 
16. De Novo Subject undergoing opioid taper will have COWS administered at Visit 2. All subjects will be administered COWS at Visit 3. COWS score must be ≤ 12 to 
enter the Treatment Period. 
17. De Novo Subjects taking opioid analgesics at Visit 2 will complete a SOWS assessment daily while tapering their opioids over the next 7-14 days. All subjects will 
complete the SOWS on the two days prior to Visit 21 and daily between Visits 21 and 22. Subjects will then complete the SOWS twice daily for three days following 
the last dose of study drug (i.e., following Visit 22), then daily for the remainder for the study (i.e., through Visit 24). 
18. A PK sample will be collected on all subjects at Visit 3. PK sample at Visit 3 must be collected prior to the subject taking the first dose of study medication for De 
Novo Subjects. 
19. For subjects participating in the PK substudy, the dosing period PK collection may be completed when a stable dose has been identified. This may occur as early as 
the second visit following the start of a dose level. Subjects will be reminded to not take their AM dose on the planned dosing period PK collection visit. A predose 
sample will be obtained and the subject will take their AM dose in the clinic. PK samples will be obtained 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose. 
20. Dispense taper study drug only for subjects completing study. Taper study drugs are not dispensed at Early Termination. 
21. Study drug is not dispensed at Visit 22/EOT. Final study drug and rescue medication reconciliation conducted at Visit 22/EOT. 
22. Collection of concomitant medications and adverse events will start after the signing of the ICF through study completion. 


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2.0 
INTRODUCTION 
2.1 
Background 
The Centers for Disease Control and Prevention estimates that over 100 million people in the 
United States (US) currently live with chronic pain, negatively impacting their quality of life and 
ability to function.  Opioid analgesics are effective agents for the relief of moderate to severe 
pain; however, their clinical utility is limited by central nervous system (CNS)-related adverse 
effects, such as sedation, cognitive impairment, and respiratory depression.  In addition, the 
issues of abuse and overdose-related death are significant public health problems.  Although 
abuse-deterrent opioid formulations are currently available, the mechanisms built into these 
drugs can be subverted.  An opioid analgesic with clinically meaningful analgesia, reduced CNS 
side effects, and reduced potential for abuse when taken orally may fill an important unmet 
medical need.   
2.2 
NKTR-181 
NKTR-181 is a new molecular entity (NME) opioid analgesic that has been engineered using 
Nektar’s advanced polymer conjugation technology platform.  NKTR-181 is not a prodrug or a 
reformulation of a marketed opioid.  The unique physiochemical properties of NKTR-181 impart 
its reduced rate of entry into the CNS and reduced opioid-related CNS adverse effects, including 
measures of abuse liability.   
According to the Controlled Substances Act, NKTR-181 is currently designated as a Schedule II 
drug.   
Please refer to the NKTR-181 Investigator’s Brochure for detailed preclinical and clinical study 
data.   
2.3 
Study and Dose Rationale  
This study is designed to provide adequate safety data in subjects with chronic low back pain or 
chronic noncancer pain in order to fulfill ICH requirements for new chemical entities.  The dose 
range to be utilized is 100-mg NKTR-181 twice daily (BID) to 600-mg NKTR-181 BID.  This 
dose range has been established based upon safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) data from three Phase 1 studies and the findings of a completed Phase 2 
study in opioid-naïve subjects with moderate to severe chronic pain due to osteoarthritis of the 
knee.  Phase 1 multiple ascending dose (MAD) studies established a dose that was not tolerated 
in opioid-naïve, healthy subjects (500-mg NKTR-181 every 12 hours [q12h]) and demonstrated 
400-mg NKTR-181 q12h to be a safe and well-tolerated dose. In both studies, pupillometry 


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demonstrated robust CNS mu-opioid agonist effects consistent with known, approved 
extended-release/long-acting (ER/LA) opioids.   
Evidence supporting the minimum dose of 100-mg NKTR-181 BID comes from the Phase 1 
clinical program and a completed Phase 2, enriched-enrollment, randomized withdrawal design 
study in approximately 200 subjects with moderate to severe chronic pain due to osteoarthritis of 
the knee.  In this Phase 2 study, 49% of subjects were randomized at 100-mg NKTR-181 BID 
and an average 40% reduction in average daily pain scores was demonstrated during the 
open-label titration period, consistent with known, approved opioid analgesics.   
Recently, over 330 opioid-naïve subjects gradually titrated to a dose of 400mg q12h in the 
ongoing Phase 3 study (14-181-07) have shown a good safety and tolerability profile.  In 
addition, the current long term safety study (14-181-08) and the second efficacy study 
(14-181-12) both allow inclusion of opioid-experienced subjects who are expected to tolerate 
higher doses of NKTR-181.  Thus, titration to a maximum dose of 600mg q12h will be allowed 
in a measured step-wise approach starting at the lowest dose available so as to ensure tolerability 
while managing chronic pain.   


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3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
• To evaluate the long-term safety and tolerability of NKTR-181 in subjects with moderate to 
severe chronic low back pain or chronic noncancer pain.   
3.2 
Secondary Objective 
• To evaluate the effectiveness of NKTR-181 as measured by the modified Brief Pain 
Inventory-Short Form (mBPI-SF).   


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4.0 
STUDY DESIGN 
4.1 
Summary of Study Design 
This is a multicenter, Phase 3, open-label safety and tolerability study in which approximately 
600 subjects will receive open-label NKTR-181 for up to 12 months (52 weeks) from 
approximately 100 sites.  Subjects may include newly enrolled subjects (approximately 250 De 
Novo Subjects) and subjects who have recently completed Study 14-181-07 or Study 14-181-12 
(Rollover Subjects).   
The study comprises 3 periods: 
• Screening: Up to 21 days; Visits 1-2  
• Treatment: 52 weeks; Visits 3-22 
• Safety Follow-Up: Approximately 14 days after the last dose of study drug; Visits 23-24  
This study will also investigate the PK of NKTR-181 in patients with chronic low back pain or 
chronic noncancer pain.  Blood samples for PK analyses will be collected from all subjects 
according the Schedule of Assessments (Section 1.2), and during a complete 12-hour dosing 
interval in a substudy of approximately 100 subjects at selected sites.   
A schematic of the study design is presented in Section 1.1, and the Schedule of Assessments is 
presented in Section 1.2.   


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5.0 
SELECTION OF STUDY POPULATION 
5.1 
Inclusion Criteria  
Each subject must meet the following criteria to be enrolled in this study: 
1. Willing and able to provide written informed consent.   
2. Willing and able to understand and comply with all study procedures, including 
swallowing oral medications.   
3. Females or males, age 18 to 75 years of age at time of signing the informed consent form 
(ICF) (either for this study, Study 14-181-07, or Study 14-181-12), inclusive.   
4. Body mass index (BMI) of 18-45 kg/m2, inclusive.   
5. In good general health as determined by medical history and physical examination; 
clinical laboratory tests and vital signs are not indicative of ongoing medical illness.   
6. Women must be either surgically sterile (by means of hysterectomy or bilateral 
oophorectomy) or be post-menopausal (defined as spontaneous cessation of menses for at 
least 1 year.  Women of childbearing potential must commit to use 2 highly effective 
forms of contraception such as a barrier contraception (e.g., condom or occlusive cap 
[diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository) 
through the duration of the study in addition to either an intrauterine device or hormonal 
contraception and continued until 2 weeks following the last dose of study drug.   
Males with female partners of child-bearing potential must agree to use a barrier 
contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository) 
throughout the duration of the study until 2 weeks following the last dose of study drug; 
in addition to their female partner using either an intrauterine device or hormonal 
contraception and continued until 2 weeks following the last dose of study drug.  This 
criterion may be waived for male subjects who have had a vasectomy > 6 months before 
signing the ICF.   
5.1.1 
Rollover Subjects 
Rollover Subjects must also meet the following criteria in order to be eligible for the study: 
1. Must fully complete through the End of Treatment Visit of Study 14-181-07 or 
Study 14-181-12 prior to receiving study drug.   


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2. Have no break in treatment with study drug. 
5.1.2 
De Novo Subjects 
De Novo Subjects must also meet the following criteria in order to be eligible for the study: 
1. Are not eligible for Study 14-181-07 or Study 14-181-12. 
2. Have a clinical diagnosis of moderate to severe chronic low back pain for > 3 months. 
3. Be non-tolerant to opioid analgesics (i.e., currently taking no less than 10 mg but no more 
than 60 mg of morphine sulfate equivalents [MSE]/day for at least the 7 days prior to 
signing the ICF). 
4. Negative urine drug screen (except opioids) and/or alcohol breathalyzer test during 
screening. 
5. Not currently participating or have previously participated in another drug or biologic 
study within 30 days before signing the ICF. 
6. Approximately 250 De Novo subjects will be enrolled. 
5.2 
Exclusion Criteria for ALL Subjects 
Subjects who meet any of the following criteria will not be permitted entry into the study: 
1. Females who are pregnant or breastfeeding. 
2. Known history of hypersensitivity, intolerance, or allergy to opioids or acetaminophen. 
3. Any history within the past year or current evidence of substance, alcohol, or opioid 
abuse. 
4. Have not received any prior treatment for chronic pain. 
5. Untreated moderate to severe sleep apnea. 
6. Have chronic migraines as the primary pain condition. 
7. Any history of seizures (with the exception of pediatric febrile seizures). 
8. Diagnosed as having current cancer-related pain or having been diagnosed with or treated 
for cancer (excluding superficial basal cell carcinoma) within the past 5 years. 


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9. Currently have any pending application(s) for any disability/worker’s compensation 
related to their pain.   
10. Score of 10 or greater on the Personal Health Questionnaire Depression Scale (PHQ-8; 
Kroenke, 2009) at Visit 1.   
11. Answered YES to Question 4 or Question 5 within the past 12 months of the 
Baseline/Screening version of the electronic Columbia-Suicide Severity Rating Scale 
(eC-SSRS) at Visit 1.   
12. Score of  > 12 on the Clinical Opiate Withdrawal Scale (COWS) at Visit 3.   
13. Clinically significant abnormalities in vital signs or clinical laboratory results (including 
hematology, chemistry, or urinalysis; total bilirubin [TBL] > 1.5 X upper limit of normal 
[ULN]; alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 2.0 X 
ULN; or creatinine clearance (calculated by Cockcroft-Gault) (< 60 mL/min.) 
14. Have undergone surgical procedures within the 4 weeks prior to ICF or plans to have 
surgical procedure on source of pain during the time of participation in the study.   
15. QTcF interval > 450 msec for males and > 470 msec for females, or any clinically 
significant abnormality on a 12-lead ECG per central read.   
16. Any history of malignancy likely to result in significant disability or likely to require 
significant medical or surgical intervention within the next 3 months. This does not 
include minor surgical procedures for localized cancer (e.g., basal cell carcinoma).   
17. History of unstable or deteriorating cardiac disease within the previous 12 months of 
screening including but not limited to the following: 
• 
Unstable angina pectoris or myocardial infarction 
• 
Congestive heart failure requiring hospitalization 
• 
Uncontrolled clinically significant arrhythmias 
18. Any condition including medical, emotional, psychiatric, or logistical that, in the opinion 
of the Investigator, would preclude the subject from adhering to the protocol. 


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5.3 
Removal of Subjects from Study Therapy or Assessment 
Subjects may choose to discontinue the study at any time, for any reason, and without prejudice 
to further treatment.   
Subjects may stop participating in or be withdrawn from the study for any of the following 
reasons but are to be followed for safety until resolution or for 14 days after the subject’s last 
study visit, whichever comes first (see Section 10.1.5): 
• Lack of efficacy 
• Occurrence of an unacceptable AE 
• Opioid withdrawal  
• Noncompliance of the subject with protocol-mandated procedures 
• Continued participation is no longer in the subject’s best interest in the opinion of the 
Investigator 
• The subject is lost to follow-up. Before a subject is considered “lost to follow-up,” study 
personnel must contact the subject at least twice by phone and once by mail with documented 
receipt(s) 
• Death 
• The study is terminated by the sponsor 
During the treatment period, if an ECG is obtained and reveals that the subject’s QTcF interval is 
> 500 msec or has an increase of ≥ 60 msec compared to baseline QTcF and confirmed with a 
second ECG within 30 minutes, treatment with study medication should be interrupted. In the 
event this occurs, the investigator should contact the Medical Monitor as soon as possible to 
discuss if the subject can continue on treatment or if the subject should stop study medication.   
In the event of a subject’s withdrawal, the Investigator will promptly notify the sponsor and 
make every effort to complete the ET assessments specified in the Schedule of Assessments 
(Section 1.2). 


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6.0 
TREATMENT PLAN 
6.1 
Screening Period (Visits 1-2) 
Subjects will provide written informed consent to participate in the study before completing any 
protocol-specified procedures or evaluations.  Subjects will be eligible to enter the Screening 
Period in 2 ways:  
• If they are currently enrolled in and expected to complete Study 14-181-07 or 
Study 14-181-12 through the End of Treatment Visit.; these subjects (either on NKTR-181 or 
placebo) may be eligible to enroll in this study as a Rollover Subject 
• If they have a clinical diagnosis of moderate to severe chronic low back pain for 
> 3 months,and are non-tolerant to opioid analgesics (i.e., currently taking no less than 10 mg 
but no more than 60 mg MSE/day for at least the 7 days prior to signing the ICF); such 
subjects may be eligible to enroll in this study as a De Novo Subject 
6.1.1 
Rollover Subjects 
Rollover Subjects should have no break in treatment with study drug. Visit 1 (Screening) will 
take place concurrently with a scheduled, on treatment clinic visit, during Study 14-181-07 and 
Study 14-181-12.   
The End of Treatment Visit in Study 14-181-07 and Study 14-181-12, where the subject has 
completed tapering to the 100-mg NKTR-181 BID starting dose for this study, will be the first 
visit of the Treatment Period (Visit 3).  There is no Visit 2 for Rollover Subjects.   
6.1.2 
De Novo Subjects 
As of this protocol amendment, de-novo subjects with chronic low back pain and taking opioid 
containing medications are eligible to enroll.  At Visit 2, De Novo Subjects will have their 
eligibility re-confirmed and concomitant medication and AEs will be assessed.  At Visit 2, De 
Novo Subjects who remain eligible will begin to taper current opioid analgesics.  De Novo 
Subjects who have been taking opioid-containing medications prior to study start (currently 
taking no less than 10 mg but no more than 60 mg MSE/day for at least the 7 days prior to 
signing the ICF) will decrease their opioid dose to no more than 30 mg MSE/day over the 
7-14 days following Visit 2.  De Novo Subjects must be taking no more than 30 mg MSE/day 
for the 3 days prior to entry into the Treatment Period, in order to reduce the potential for 
opioid withdrawal when transitioning onto NKTR-181.  Subjects who experience 
breakthrough pain will be allowed rescue medication, as outlined in Section 6.4 


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De Novo Subjects will record the Subjective Opiate Withdrawal Scale (SOWS) score daily and 
COWS at each clinic visit.  Subjects experiencing opioid withdrawal will be treated 
appropriately according to the Investigator’s clinical practice.   
6.2 
Treatment Period (Visits 3-20) 
At Visit 3, subjects will be evaluated for entry into the Treatment Period.  The Investigator or 
qualified sub-Investigator will complete the COWS (Wesson, 2003).  The subject must score 
≤ 12 to continue in the Treatment Period.  Subjects who score greater than 12 will complete their 
Screening Period and end study participation and will be treated appropriately for withdrawal 
according to the investigators clinical practice.  A Rollover Subject’s last COWS assessment 
during Study 14-181-07 or Study 14-181-12 will satisfy this requirement.  De Novo Subjects will 
discontinue all current analgesics including their prior opioid medication.   
All subjects will begin dosing with 100-mg NKTR-181 BID with dose escalation in stepwise 
increments of 100-mg (e.g., from 200-mg BID to 300-mg BID) up to a maximum dose of 
600-mg BID.  All dose escalations will occur prior to visit 10.  The dose of NKTR-181 will not 
exceed 600 mg BID in this study.  Subjects will be instructed to take study drug BID, preferably 
at 8 AM and 8 PM.  Subjects will also receive training on the recognition and management of 
constipation and other opioid related side effects.  Side effects should be managed according to 
standard of care practices.   
If a subject cannot tolerate 100-mg NKTR-181 BID, the subject will be discontinued from the 
study; these subjects will be required to complete the Early Termination (ET) visit (Visit 21/ET) 
and safety follow-up requirements.  Refer to the Schedule of Assessments (Section 1.2) for 
complete information regarding all assessments to be completed at the ET Visit and safety 
follow-up requirements.   
Within 4-10 days after receiving the first dose of NKTR-181, subjects will return to the clinic at 
which time the Investigator will assess for tolerability and effectiveness.  Tolerability and 
effectiveness will be assessed based on Investigator (or qualified sub-Investigator) clinical 
judgment.  The Investigator (or qualified sub-Investigator) will determine whether the subject 
should remain at the current dose or titrate to the next dose level.   
Subjects will return to the clinic for assessments of tolerability and effectiveness every 4 
to10 days for up to 6 more times over a 5-week period until a stable dose is achieved.  A stable 
dose is a dose that is effective and tolerated on two sequential visits (i.e., after at least 8 days of 
continuous treatment).  Subjects who continue to tolerate study drug but do not have adequate 
relief of pain, based on the Investigator’s clinical judgment, will continue dose escalations of 
100-mg BID increments until the maximum dose of 600-mg NKTR-181 BID is reached.   


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Subjects who do not achieve adequate pain control at 600-mg NKTR-181 BID will be classified 
as non-responders and will be discontinued from further participation in the study.  
Non-responders will be required to complete the ET Visit (Visit 21/ET) and safety follow-up 
requirements.   
Subjects will begin a monthly clinic visit schedule after a tolerable, effective and stable dose is 
achieved.  Doses of NKTR-181 may be adjusted upwards (up to a maximum dose of 600-mg 
NKTR-181 BID) or downwards as needed during the Treatment Period, based on the 
Investigator’s (or qualified sub-Investigator’s) assessment of effectiveness and tolerability.   
If at any time a subject cannot tolerate study drug between protocol-mandated visits, per 
Investigator discretion, an unscheduled visit should occur.  For subjects with tolerability issues, 
the dose of NKTR-181 may be adjusted downwards, as necessary, based on the Investigator’s 
clinical judgment in a stepwise 100-mg changes (e.g., 300-mg BID may be lowered to 200-mg 
BID).  Dose adjustments may occur at unscheduled visits, however, an unscheduled visit will not 
replace a regularly scheduled visit, and the subject should be seen at all regularly scheduled 
visits.   
Throughout the Treatment Period, subjects who experience breakthrough pain will be allowed 
rescue medication, as outlined in Section 6.4.  Note: If subject is off of study drug for 3 days or 
more, sponsor must be consulted prior to restarting study drug.   
Subjects will report their pain experience at each visit using the mBPI-SF.  At quarterly intervals, 
subjects will be assessed for vital signs, 12-lead electrocardiogram (ECG), and clinical 
laboratory testing.   
Following 51 weeks of NKTR-181 treatment, subjects will begin a 1-week taper from study 
drug.  The NKTR-181 dose will be decreased over the 1-week period until all subjects are 
receiving 100-mg BID for at least 2 days.  Subjects will return to the site for their End of 
Treatment visit (Visit 22/EOT).  Following completion of Visit 22/EOT or completion of an ET 
Visit at any time after receiving study drug, subjects will proceed to the Safety Follow-Up 
Period.   
The COWS and SOWS will be administered according to the Schedule of Assessments (Section 
1.2) to monitor for opioid withdrawal.  Subjects experiencing opioid withdrawal will be treated 
appropriately according to the Investigator’s clinical practice.   
6.2.1 
Pharmacokinetic Substudy 
Blood samples for PK analysis will be collected from all subjects as described in the Schedule of 
Assessments (Section 1.2).  In addition, serial blood samples will be collected predose through 


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12 hours postdose in a subset of approximately 100 subjects at sites participating in the PK 
substudy.   
At sites that agree to participate in the sub-study for PK analysis, all subjects will complete the 
dosing period PK collection when a stable dose has been identified.  This visit may occur as 
early as the second visit following the start of a dose level.  During the visit, subjects will 
complete all regular study procedures according to the Schedule of Assessments (Section 1.2).   
The PK collection visit will be scheduled to start in the morning, prior to the subject taking their 
morning dose of NKTR-181.  Subjects should be reminded in advance of the visit to hold their 
morning dose of study drug and to bring their study drug supply to the clinic with them.  
Subjects will take their morning dose of NKTR-181 in the clinic after a predose PK sample is 
drawn.   
To facilitate sample collection, a peripheral saline lock may be inserted for this visit.  Refer to 
Section 8.1 for sample collection instructions.   
6.3 
Safety Follow-Up Period (Visits 23-24) 
To capture evidence of withdrawal following discontinuation of study drug, all subjects 
(including ET subjects) will record SOWS measurements and be administered COWS 
assessments as described in the Schedule of Assessments (Section 1.2).   
During the Safety Follow-Up Period, clinical laboratory samples will be collected only if a prior 
laboratory result was considered abnormal and clinically significant.   
6.4 
Rescue Medication 
Nektar will provide over-the-counter analgesics, including aspirin, acetaminophen, ibuprofen, 
and naproxen, for subjects who experience breakthrough pain.  The subject, in consultation with 
the Investigator, will be allowed to choose which rescue medication(s) they will use.  Subjects 
may use their selected rescue medications up to the maximum daily dose indicated on the label, 
at any time during the study.   
6.5 
Monitoring of Hepatic Transaminases 
Hepatic function testing (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase [ALP], and total bilirubin [TBL]) will be performed according to the 
Schedule of Assessments (Section 1.2).  In the event that an elevation of ALT or AST 
> 3 X ULN is observed in an individual study subject, the subject should be contacted 
immediately and the procedures in Table 1 should be followed.  The Medical Monitor or 


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designee may be contacted for further discussion as needed.  If a subject’s study drug is 
interrupted for 3 days or more due to elevated hepatic transaminase levels, sponsor must be 
consulted prior to restarting study drug.   
Table 1: 
Recommended Procedures for Subjects with Elevated Aminotransferase 
Test Results 
Magnitude of Elevation in ALT or AST 
Recommendation 
> 3 to ≤ 8 X ULN 
The subject should be seen for an unscheduled visit as 
soon as possible. At the unscheduled visit, the subject 
will be examined for clinical signs and/or symptoms of 
hepatic dysfunction [fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (> 5%)]. Repeat hepatic function tests 
should be performed. Review the subject’s current list of 
concomitant medications to assess for confounding 
medications that could cause elevations in AST and/or 
ALT. The subject should return every 48 to 72 hours for 
examination and repeat hepatic function testing until all 
test values are ≤ 2.0 X ULN or return to baseline. 
> 3 X ULN and hyperbilirubinemia (> 1.5 X ULN) 
Study medication should be permanently discontinued. 
> 3 X ULN with ongoing, unresolved symptoms such as 
fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia (> 5%) 
Study medication should be permanently discontinued. 
> 5 X ULN for ≥ 2 weeks  
Study medication should be permanently discontinued. 
> 8 X ULN 
Study medication should be permanently discontinued. 
 
6.6 
Prior and Concomitant Medications 
Commencing with signing the ICF, all medications (both prescription and over-the-counter), 
vitamin and/or mineral supplements, and/or herbs the subjects take through the End of Study 
(EOS) (or ET) will be documented on the concomitant medication electronic case report forms 
(eCRFs).  Documentation will include start and stop date, dose and route of administration, 
dosing frequency, and indication.   
6.6.1 
Prohibited and Restricted Medications 
Subjects must not take any medication for chronic pain during the study (through the end of the 
Treatment Period) that was not provided by the sponsor (including rescue medication) and 
should be reminded of such at each study visit.  Use of moderate to strong cytochrome P450 3A4 
(CYP3A4) inhibitors and inducers is prohibited throughout the study.   


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Subjects who have been taking opioid-containing medications prior to study start (no less than 
10 mg MSE/day and no more than 60 mg MSE/day) will be eligible to participate.  However, the 
opioid must be tapered to no more than 30 mg MSE/day for at least 3 days prior to Visit 3, then 
completely discontinued prior to starting NKTR-181.  Concomitant use of opioids with 
NKTR-181 is prohibited.  Use of these medications will be documented on the concomitant 
medication eCRFs and will include start and stop date, dose and route of administration, dosing 
frequency, and indication.   
6.6.2 
Permitted Medications 
Subjects may use the following medications while participating in this study: 
• Medications for stable diseases (e.g., metformin for diabetes. Note that NKTR-181 may 
increase the exposure of metformin; serum glucose levels should be monitored closely) 
• Hypnotics or barbiturates if stable for at least 21 days prior to screening 
• Adjuvant analgesics (e.g., antiepileptics, muscle relaxants for muscle spasms, triptans for 
migraine [no opioid treatment for migraine will be allowed]) 
• Aspirin (≤ 325 mg) for cardiovascular prophylaxis 
• Antiemetics for nausea and vomiting 
• Psyllium husks, stool softeners, laxatives, enemas, and peripherally acting mu-opioid receptor 
antagonists (PAMORAs; e.g., MOVANTIKTM) for opioid-induced constipation 
• Medications to treat AEs or exacerbation of existing medical conditions 
• Hormonal birth control 
• Injected, topical, optical, or inhaled/nasal corticosteroids 
Allowed rescue medication is described in Section 6.4 
6.7 
Assigning Subject Numbers 
Each subject will be assigned a unique subject number at Visit 1 of the Screening Period after 
signing the ICF.  This unique subject number will be used on all subjects’ study information.  
Subject numbers assigned to those subjects who fail the Screening Period or who withdraw from 
the Treatment Period will not be reassigned.  Rollover Subjects will retain their subject ID from 
Study 14-181-07 or Study 14-181-12.  For De Novo Subject, the first 4 digits will be the unique 


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site number (XXXX) followed by another 4-digit subject ID (YYYY), which together will be the 
unique subject number (e.g., XXXX-YYYY).  The second set of 4 digits (YYYY) will be 
sequential within sites, starting with 8001 (indicating that the subject is a De Novo Subject).   


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7.0 
INVESTIGATIONAL PRODUCT(S)/STUDY DRUGS 
7.1 
Description and Formulation 
7.1.1 
Study Drug Description  
NKTR-181 (referred to as the study drug) will be administered orally in tablet form.  Study drug 
tablets are white-coated and are available in dosing strengths of 100 mg and 200 mg.   
NKTR-181 dosage strengths to be evaluated are 100 mg, 200 mg, 300 mg, and 400 mg BID.  
Each dose of study drug will consist of matching tablets as follows: 
• 100-mg dose = 1 × 100-mg NKTR-181 tablet 
• 200-mg dose = 1 × 200-mg NKTR-181 tablet 
• 300-mg dose = 1 x 200-mg NKTR-181 tablet + 1 x 100-mg NKTR-181 tablet  
• 400-mg dose = 2 × 200-mg NKTR-181 tablets  
• 500-mg dose = 2 × 200-mg tablets + 1 × 100-mg NKTR-181 tablet 
• 600-mg dose = 3 × 200-mg NKTR-181 tablets 
7.1.2 
Rescue Medication 
For subjects who are experiencing breakthrough pain, the sponsor will provide aspirin, 
acetaminophen, ibuprofen, and naproxen for use as rescue medication.  Aspirin will be provided 
in 325-mg tablets for oral use.  Acetaminophen will be provided in 500-mg tablets for oral use.  
Ibuprofen will be provided in 200-mg tablets for oral use.  Naproxen will be provided in 220-mg 
tablets for oral use, as directed on label.   
7.2 
Study Drug Packaging and Labeling 
NKTR-181 tablets are packaged in cold-sealed blister packs that are inserted into wallets and 
contained in a metalized pouch with a desiccant.  Sufficient drug to provide up to 10 days of 
dosing will be packaged in a wallet.  Pouches and wallets are minimally labeled to be compliant 
with US Food and Drug Administration (FDA).   


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7.3 
Study Drug Storage 
Study drug must be stored at controlled room temperature in a secure area.  NKTR-181 is 
designated a Schedule II drug and must be handled, stored, and accounted for in accordance with 
all federal, state, and local regulations for a Schedule II drug.   
7.4 
Accountability and Reconciliation 
The Investigator is responsible for ensuring accountability of all study medications supplied and 
appropriate storage and allocation of these supplies.   
The Investigator is responsible for ensuring that all study drugs and rescue medications received 
at the site are inventoried and accountability performed and that dispensed study drug is recorded 
in both the eCRF and the study drug accountability logs.  The Investigator or designee will verify 
study drug accountability with subjects during site visits.  Any discrepancies should be 
investigated.  The Investigator will not supply study drug or rescue medication to any person 
except those who are subjects in this study and will not dispense study drug or rescue medication 
from any site other than those listed on Form FDA 1572.  Study medication and rescue 
medication may not be relabeled or reassigned for use by other subjects.   
All unused or damaged study drug or rescue medication will be returned and unit counts will be 
performed whenever medication is returned.  The site must account for all medication received.  
The site will retain and store all study drug and rescue medication until inventoried by the study 
monitor.  All returned, unused, and damaged study drug and rescue medication will be returned 
to the sponsor or designee for destruction.   


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8.0 
PHARMACOKINETIC MEASUREMENTS 
This study will investigate the PK of NKTR-181 in patients with chronic low back pain or 
chronic noncancer pain.   
8.1 
Pharmacokinetic Blood Sample Collection 
Blood samples for PK analysis will be collected from all subjects according to the Schedule of 
Assessments (Section 1.2).  Each participating site will be provided instructions for specimen 
collection, processing, storage, packaging, and shipment.  The first PK blood sample must be 
collected from all subjects prior to receiving the first dose of study drug (Visit 3).   
In a PK substudy of approximately 100 subjects at selected sites, serial blood samples will also 
be collected during a complete 12-hour dosing interval as shown in Table 2.   
Table 2: 
Pharmacokinetic Sample Collection Times in the PK Substudy 
Time (hours) 
Eventa 
Sample Name 
Actual Time 
(example) 
Predose 
Cryovial Preparation 
 
Approximately 15 - 30 min 
Predose 
Sample collection 
Predose 
Within 15 mins  prior to dosing 
0:00 
NKTR-181 dosing 
 
9:00 AM 
0:30 
Sample collection 
0.5 hour postdose 
9:30 AM 
1:00 
Sample collection 
1.0 hour postdose 
10:00 AM 
2:00 
Sample collection 
2.0 hours postdose 
11:00 AM 
3:00 
Sample collection 
3.0 hours postdose 
12:00 PM 
4:00 
Sample collection 
4.0 hours postdose 
1:00 PM 
5:00 
Sample collection 
5.0 hours postdose 
2:00 PM 
6:00 
Sample collection 
6.0 hours postdose 
3:00 PM 
8:00 
Sample collection 
8.0 hours postdose 
5:00 PM 
12:00 
Sample collection 
12.0 hours postdose 
9:00 PM 
a Cryovials for PK sample collection must be prepared in advance of the first sample collection time on the day of 
collection and must undergo processing steps following sample collection according to the instructions provided in 
the Laboratory Manual.  


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8.2 
Pharmacokinetic Analysis of Samples 
Plasma concentrations of NKTR-181 and selected metabolites will be tabulated by time and 
subject and inspected for relationship to dose during the treatment phase.  These data will be 
pooled with those from other studies during Population PK analyses and investigation of 
exposure-response relationships for efficacy and safety that will be specified in a population PK 
Analysis Plan.   


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9.0 
EFFICACY ASSESSMENTS 
9.1 
Modified Brief Pain Inventory-Short Form (mBPI-SF) 
The mBPI-SF (Mendoza, 2006) was developed to provide information on pain intensity and the 
degree to which pain interferes with patient functioning.  Using a 0 to 10 numerical rating scale 
(NRS), subjects rate their pain at the time of responding to the questionnaire (Pain Now), and 
also at its worst, least, and average over the previous 24 hours.  With 0 being "no interference" 
and 10 being "interferes completely," the mBPI-SF asks for ratings of the degree to which pain 
interferes with mood, walking and other physical activity, work, social activity, relations with 
others, and sleep.   


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10.0 
ASSESSMENT OF SAFETY  
10.1 
Adverse Events and Serious Adverse Events 
10.1.1 
Adverse Events Definition and Assessment 
An AE is defined as any untoward medical occurrence in a subject who is administered a 
medicinal product and that does not necessarily have a causal relationship with this treatment.   
An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, regardless of whether or not it is considered 
related to the medicinal product. An AE can also arise from any use of the drug and from any 
route of administration, formulation, or dose.  This definition includes intercurrent illnesses or 
injuries, and exacerbation of preexisting conditions as well as events attributed to protocol-
mandated procedures.  Clinical laboratory abnormalities will only be reported as AEs if they are 
deemed clinically significant by the Investigator and/or are associated with signs and symptoms, 
require treatment, or require follow-up.   
An AE does not include the following: 
• A medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or transfusion); an 
AE is the underlying condition that leads to the procedure.   
• Preexisting diseases or conditions present or detected before the start of study drug 
administration that do not worsen or increase in severity or frequency after the administration 
of study drug.   
• Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery for a condition that has not worsened on study, social and/or convenience 
admissions to grant families a respite in caring for a subject).   
• Adverse events that start in Study 14-181-07 and Study 14-181-12 and are ongoing during this 
study will continue to be followed for Rollover Subjects.   
10.1.2 
Monitoring Adverse Events 
All AEs will be assessed by the Investigator and recorded on the eCRF, including but not limited 
to the following: the event term, the date of onset and resolution, seriousness, severity, 
relationship to study drug, outcome, treatment of the event, and action taken with the study drug.  
Adverse events will be reported starting immediately after the subject has provided written 
informed consent through the EOS Visit (Visit 24/EOS).   


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Any AE attributed to a protocol-mandated procedure occurring after the subject has provided 
informed consent but prior to the first dose of study drug should be recorded on the eCRF as an 
AE.   
Adverse events that are not attributed to protocol-mandated procedures occurring after signing of 
the informed consent but before the first dose of study drug will be reported as medical history.   
Example 1: 
Thrombophlebitis associated with a blood draw for assessments required prior to dosing per 
protocol is an event that is related to protocol-mandated procedures. In this scenario, the event 
of “thrombophlebitis” will be captured as an AE on the eCRF page, and it will be documented 
as being “unrelated” to study drug as applicable.   
Example 2: 
An ankle sprain following an unexpected fall from a flight of stairs while at home, after the 
subject has provided informed consent, but before the first dose of study drug, is clearly 
unrelated to any protocol-mandated procedures and would therefore be captured as medical 
history in the medical history section of the eCRF. 
10.1.3 
Grading of Adverse Events 
The severity of an event and the seriousness are not to be considered synonymous.  The severity 
is grading the intensity of an event.  The seriousness of an event is based on the subject/event 
outcome (Section 10.1.6).  All AEs will be assessed for severity by the Investigator using the 
following criteria:   
• Mild: The event results in mild or transient discomfort, not requiring or needing only minimal 
intervention or treatment; does not limit or interfere with daily activities (e.g., insomnia, mild 
headache);  
• Moderate: The event is sufficiently discomforting so as to limit or interfere with daily 
activities; may require interventional treatment (e.g., fever requiring antipyretic medication); 
and  
• Severe: The event results in significant symptoms that prevent normal daily activities; may 
require hospitalization or invasive intervention. 


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10.1.4 
Causality Relationship of Adverse Events 
The relationship of each AE to the study drug will be evaluated by the Investigator using the 
following definitions: 
• Not related: The AE is clearly not related to the study drug(s). The AE can be explained to be 
likely related to other factors such as concomitant medications or the subject’s clinical state;  
• Unlikely related: The AE is doubtfully related to the study drug(s).  The current knowledge or 
information about the AE indicates that a relationship to the study drug is unlikely;  
• Possibly related: The AE may be related to the study drug(s).  A plausible temporal sequence 
exists between the time of administration of the study drug and the development of the AE, 
and it follows a known response pattern to the study drug.  The AE is unlikely explained by 
the known characteristics of the subject’s clinical state or other concomitant therapies or 
interventions administered to the subject; and    
• Related: The AE is clearly related to the study drug(s).  A plausible temporal sequence exists 
between the time of administration of the study drug and the development of the AE, and it 
follows a known response pattern to the study drug.  The AE cannot be reasonably explained 
by the known characteristics of the subject’s clinical state or other concomitant therapies or 
interventions administered to the subject.  Additionally, the occurrence of this AE can be 
confirmed with a positive re-challenge test or supporting laboratory data.   
The causality criteria of “related” and “possibly related” will be considered related to the study 
drug as applicable for regulatory reporting requirements.   
10.1.5 
Adverse Event Reporting and Follow-up 
All ongoing AEs must be followed until resolution or for 14 days after the subject’s last study 
visit, whichever comes first.  If the AE has not completely resolved by the Visit 24/EOS, the 
final outcome of these ongoing AEs will be captured as “Not Recovered/Not Resolved” or 
“Recovering/Resolving”, whichever is applicable.   
For specific instructions on identifying, reporting, and following serious adverse events (SAEs), 
see Sections 10.1.7 and 10.1.8.   


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10.1.6 
Serious Adverse Event Definition 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life-threatening, i.e., in the opinion of the Investigator or sponsor, the AE places the subject 
at immediate risk of death from the event as it occurred; it does not include a reaction that, had 
it occurred in a more severe form, might have caused death; 
• Requires inpatient hospitalization or prolongation of an existing hospitalization that occurs 
during the course of a subject’s participation in a clinical study, except for those that occur 
due to any of the following: 
o A surgery or procedure that was planned or anticipated before the subject entered the 
study and that is part of the planned study procedure; or  
o Nonmedical reasons, in the absence of an AE; 
• Results in persistent or significant disability or incapacity;  
• Is a congenital anomaly or birth defect; or 
• Is an important medical event that, based upon appropriate medical judgment, may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the other 
outcomes listed above.   
Death is an outcome of an AE, and not an AE in itself.  All fatal events regardless of causality 
must be reported.  “Life-threatening” means that the subject was at immediate risk of death from 
the event as it occurred.  This does not include an event that might have led to death, if it had 
occurred with greater severity.  “Inpatient hospitalization” means that the subject has been 
admitted to a hospital for medical reasons for any length of time.  The Investigator should 
attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information.  In such cases, the diagnosis should be documented as the AE and/or SAE and not 
the individual signs/symptoms.   
10.1.7 
Serious Adverse Event Reporting 
All SAEs regardless of causality attribution occurring during the conduct of the study should be 
reported to Nektar Therapeutics Drug Safety or its designee within 24 hours of when the site 
becomes aware of the event.   


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SAEs assessed by the Investigator as related to study drug and occurring after a subject’s final 
study visit but within 14 days after the subject’s last dose of study drug will also be reported to 
Nektar Therapeutics Drug Safety or its designee within 24 hours of when the site becomes 
aware of the event.   
Follow-up reports and any additional records (such as hospital records, consultant reports, and 
autopsy findings) should be emailed or faxed to Nektar Therapeutics Drug Safety or designee 
within 24 hours of when the site becomes aware of the additional information.  All SAEs and 
subsequent follow-up information must be reported to Nektar Therapeutics Drug Safety or its 
designee via: 
• 
 
 
 
 
 
The Investigator must complete the SAE form, assess the causality relationship to the study drug, 
as applicable, and send the completed SAE form via email or fax to Nektar Therapeutics Drug 
Safety or designee.   
Any medication or other therapeutic measures used to treat the event will be recorded.   
All SAEs will be followed as described in Section 10.1.8.   
Reporting of SAEs to the Institutional Review Board (IRB) will be done in accordance with the 
standard operating procedures (SOPs) and policies of the IRB.  Adequate documentation must be 
provided to the sponsor, showing that the IRB was properly notified.  Serious AEs will be 
reported by the sponsor or designee to the regulatory authorities, per local regulations.   
10.1.8 
Serious Adverse Event Follow-up 
All SAEs will be followed until resolution, stabilization of condition, return to baseline, or until 
follow-up is no longer possible.   
Any SAE occurring after the end of the study for a subject but within 14 days of the subject’s 
last dose of study drug will be captured only if assessed by the Investigator as related to study 
drug.   


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10.1.9 
Expedited Reporting of Serious Adverse Events 
A suspected unexpected serious adverse reaction (SUSAR) is an SAE that is considered 
“unexpected” and is assessed by the Investigator or the sponsor as related to the study drug.  All 
SAEs deemed related to the study drug and not expected based on the most current NKTR-181 
Investigator’s Brochure are subject to expedited reporting to the applicable regulatory authorities 
by the sponsor.  Therefore, the Investigator or site personnel must report all SAEs to Nektar 
Therapeutics Drug Safety or its designee within 24 hours of first becoming aware of the event.   
Fatal or life-threatening SUSARs will be reported to the regulatory authorities by the sponsor as 
soon as possible but no later than 7 calendar days after the sponsor or its designee has first 
knowledge of the minimum criteria for expedited reporting, with a full written report within 
8 calendar days later. Nonfatal or nonlife-threatening SUSARs will be reported to the regulatory 
authorities, IRBs, and Investigators as soon as possible but no later than 15 calendar days after 
the sponsor or its designee has first knowledge of the SUSAR.   
Reporting of SUSARs to all applicable regulatory authorities will be made by Nektar 
Therapeutics Drug Safety or its designee as per local country and regional regulations.   
Notification of SUSARs to the central IRBs will be made by Nektar Therapeutics Clinical 
Operations or its designee in accordance with the SOPs and policies of the IRBs.  Reporting to 
local IRBs will be made by the applicable study site personnel per their institutional guidelines.  
Adequate documentation must be provided to Nektar Therapeutics Clinical Operations or its 
designee showing that the local IRB was properly notified.   
Reporting of SUSARs to all participating clinical Investigators will be done by Nektar 
Therapeutics Clinical Operations or its designee per local regulations.   
10.2 
Special Reporting Situations 
10.2.1 
Misuse or Abuse 
Potentially aberrant drug behavior will be identified, assessed, and quantified using the Misuse, 
Abuse, and Diversion Drug Event Reporting System (MADDERSTM) with every study drug 
reconciliation and at the EOT Visit or ET Visit.  The MADDERS™ consists of a set of forms 
completed by Investigators or qualified sub-Investigators when potentially abuse-related events 
are identified and upon the completion of each subject in the study (Smith, 2013).   


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10.2.2 
Pregnancy 
Pregnancy tests will be conducted according to the Schedule of Assessments (Section 1.2).  The 
sponsor must be notified within 24 hours of the initial report and any follow-up reports of a male 
subject’s female partner or a female subject becoming pregnant during the course of the study 
and for 2 months after the last dose of the study drug.  Pregnancy, although reportable, is not 
considered an AE/SAE unless a female subject or male subject’s female partner experiences 
signs or symptoms of pregnancy complications; however, the contact information for pregnancy 
reporting is the same as for SAE reporting and listed in Section 10.1.7.  Females who become 
pregnant will be followed every trimester until the outcome of the pregnancy is known.  
Pregnancy follow-up should describe the outcome of the pregnancy, including any voluntary or 
spontaneous termination, details of the birth, and the presence or absence of any congenital 
abnormalities or birth defects in the offspring.   
10.3 
Clinical Laboratory Tests 
Clinical laboratory tests will be conducted according to the Schedule of Assessments (Section 
1.2).  Clinical laboratory tests will be performed by a designated central laboratory. Each site 
will be provided instructions for specimen collection, processing, storage, packaging and 
shipment.  Results of laboratory tests will be provided to the site.   
Clinical laboratory test data will be reviewed by the Investigator or qualified sub-Investigator.  
Additional clinical laboratory tests may be ordered at the Investigator’s or qualified 
sub-Investigator’s discretion.  All additional testing will be performed by the designated central 
laboratory.   
The Investigator or qualified sub-Investigator will review all lab results for clinical significance.  
Any laboratory result deemed clinically significant will be recorded as an AE as described in 
Section 10.1.   
Clinical laboratory tests that will be conducted for this study are listed in Table 3.   


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Table 3: 
Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
• Hemoglobin 
• Hematocrit 
• Red blood cells 
• White blood cells 
• Platelet count 
• Neutrophils (absolute) 
• Lymphocytes (absolute) 
• Monocytes (absolute) 
• Eosinophils (absolute) 
• Basophils (absolute) 
• Mean corpuscular volume 
• Mean corpuscular hemoglobin 
• Mean corpuscular hemoglobin 
concentration 
• AST 
• ALT 
• ALP 
• Gamma-glutamyl transferase 
(GGT) 
• Albumin 
• Creatinine 
• Glucose 
• Total protein 
• TBL 
• Conjugated bilirubin  
• Sodium 
• Potassium 
• Chloride 
• CO2 content or bicarbonate 
• Blood urea nitrogen 
• Specific gravity 
• pH 
• Glucose 
• Protein 
• Bilirubin 
• Ketones 
• Leukocytes 
• Blood 
For positive protein, white blood cell 
or blood, a microscopic examination 
will include the following: 
• Red blood cells 
• White blood cells 
• Epithelial cells 
• Bacteria 
• Crystals 
• Casts 
Abbreviations: AST; alanine aminotransferase; ALT, aspartate aminotransferase; ALP, alkaline phosphatase; CO2, 
carbon dioxide; TBL, total bilirubin. 
 
10.4 
Vital Signs 
Vital sign measurement will be recorded according to the Schedule of Assessments (Section 1.2).  
Vital signs include pulse rate, respiratory rate, systolic and diastolic blood pressure (BP), and 
temperature.  Pulse and BP measurements will be taken after the subject has been resting for at 
least 5 minutes.   
10.5 
Twelve-Lead Electrocardiograms 
Twelve-lead electrocardiograms (ECGs) will be performed on a calibrated 12-lead machine 
according to the Schedule of Assessments (Section 1.2).  Subjects must be resting quietly in the 
supine position for at least 5 minutes before the 12-lead ECG.  Interpretation of 12-lead ECGs 
and interval duration measurements will be performed by a designated ECG laboratory.  
Interpretation of ECGs and interval duration measurements will be provided to the site.   


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The Investigator or qualified sub-Investigator will review all ECG interpretations and interval 
duration measurements for clinical significance.  During the treatment period, if an ECG is 
obtained and reveals that the subject’s QTcF interval is > 500 msec or has an increase of 
≥ 60 msec compared to baseline QTcF and confirmed with a second ECG within 30 minutes, 
treatment with study medication should be interrupted.  In the event this occurs, the investigator 
should contact the Medical Monitor as soon as possible to discuss if the subject can continue on 
treatment or if the subject should stop study medication.  Subjects who are discontinued will be 
required to complete the ET Visit and all safety follow-up procedures.  Any ECG interpretation 
deemed to be clinically significant will be reported as an AE as described in Section 10.1.   
10.6 
Medical History 
Relevant and significant medication history, including history of substance or opioid abuse, 
medical/surgical history, and concurrent illnesses will be collected for all subjects and noted as 
to whether the condition is active.  All relevant medical history will be collected and carried 
forward for Rollover Subjects..  Ongoing adverse events that occurred in Study 14-181-07 and 
Study 14-181-12 will continue to be followed for Rollover Subjects.   
10.7 
Pregnancy Tests 
Serum pregnancy tests will be performed on women of childbearing potential at Visit 1 via the 
designated central laboratory.  Women of childbearing potential must have a negative pregnancy 
test at Visit 1 in order to continue in the study.  Urine pregnancy tests will be performed at the 
site on women of childbearing potential according to the Schedule of Assessments (Section 1.2).  
Urine pregnancy tests will be provided by the sponsor.  A negative pregnancy test result must be 
obtained before the administration of the study drug.   
A pregnancy test does not need to be performed on women who are postmenopausal for at least 
1 year or surgically sterile for at least 3 months before signing the ICF (Section 10.2.2).   
If a female subject or a male subject’s female partner becomes pregnant, administration of the 
study drug must be discontinued immediately, and the sponsor notified within 24 hours of the 
initial report of the pregnancy.   
10.8 
Drug and Alcohol Screening 
Subjects will undergo an alcohol breath test at the first visit during the Screening Period 
(Visit 1).  Subjects who have a positive alcohol breath test will not be eligible for participation in 
this study.  Disposable, individual use alcohol breathalyzers will be provided by the sponsor.   


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Urine samples will be collected for drug screening at Visits 1 and 3 and according to the 
Schedule of Assessments (Section 1.2).  Samples will be screened for amphetamines, 
cannabinoids, cocaine, and opioids.  Urine drug screen at visits 1 and 3 is done for De Novo 
subjects only.  Urine drug screen at visit 4 is done for Rollover subjects only.  No urine drug 
screen will be conducted at visits 5, 6, 7, 8 and 9.  Rollover Subjects will have urine collected for 
testing at central lab rather than being tested onsite.  Opioids will not be tested for Rollover 
Subjects at Visits 1 and 3.  De Novo subject on non-opioid analgesics at the time of Visit 1 
must have a negative urine drug screen at Visit 1 and Visit 3.  De Novo subjects on opioid 
analgesics at the time of Visit 1 must have a negative urine drug screen for all drugs except 
opioids.  Dipstick urine drug screen tests will be provided by the sponsor.   
10.9 
Suicidality Assessment 
The C-SSRS is a validated suicidality assessment instrument administered to prospectively 
assess the severity and frequency of suicidal ideation and behaviors.  The C-SSRS identifies the 
full range of suicidal ideation and behavior and monitors change from visit to visit (Posner, 2011
).  For this study, the electronic version (validated eC-SSRS) will be used.  The eC-SSRS is a 
fully structured, patient self-report clinical interview designed and developed for computer 
administration (Mundt, 2010; Mundt, 2013).  The eC-SSRS will administer the 
“Baseline/Screening” version of the scale at Visit 1.  It assesses suicidal ideation and behavior 
over the lifetime and over the past 12 months.  The eC-SSRS will administer the “Since Last 
Visit” version of the scale at all the other required visits according to the Schedule of 
Assessments (Section 1.2).  The “Since Last Visit” version asks about any suicidal thought or 
behaviors the subject may have had since the last time the scale was administered.   
10.10 Opioid Withdrawal 
10.10.1 
Clinical Opiate Withdrawal Scale (COWS) 
Opiate withdrawal will be assessed using the COWS (Wesson, 2003).  The scale consists of 
11 evaluations of physical components of withdrawal and is based on clinician observations and 
questions.   
The COWS will be administered by the Investigator or qualified sub-Investigator at Visit 3 prior 
to any other study assessments.  The COWS must be ≤ 12 in order for the subject to continue 
participation in the study.  Subjects who score greater than 12 will complete their Screening 
Period, end study participation, and be treated appropriately for withdrawal according to the 
Investigator’s clinical practice. A COWS assessment will be administered by the Investigator or 
qualified sub-Investigator at Visits 3, 21, and 22/EOT (or ET Visit), and during the Safety 
Follow-Up Period at Visits 23 and 24/EOS.  Subjects experiencing opioid withdrawal will be 
treated appropriately according to the Investigator’s clinical practice.   


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10.10.2 
Subjective Opiate Withdrawal Scale (SOWS) 
Opiate withdrawal will be further assessed using the SOWS (Handelsman, 1987).  The SOWS is 
a self-administered scale for grading opiate withdrawal symptoms.  It contains 16 symptoms that 
the subject rates for intensity on a scale of 0 (not at all) to 4 (extremely).  The SOWS will be 
completed by the subject according to the Schedule of Assessments (Section 1.2).  The SOWS 
may be completed in the clinic or at home depending on the requirements of the Schedule of 
Assessments.   
Subjects will complete the SOWS at Visit 2 (De Novo Subjects only), 21, and 22/EOT (or ET 
Visit) in the clinic.  Subjects will complete the SOWS daily between Visits 21 and 22/EOT. 
Subjects will complete the SOWS BID for 3 days following the last dose of study drug (from 
Visit 22/EOT or Early Termination) and then once daily throughout the remainder of the Safety 
Follow-Up Period (i.e., through Visit 24).  Subjects experiencing opioid withdrawal will be 
treated appropriately according to the Investigator’s clinical practice.   


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11.0 
STATISTICAL METHODS PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE 
11.1 
General Considerations 
Statistical analyses of this study will be the responsibility of Nektar or its designee.  Data 
collected from eCRFs, Interactive Voice and Web Response System (IXRS), or clinical 
laboratory evaluations will be listed by subject identification.   
Generally, if not specified, continuous data will be summarized by descriptive statistics, 
including sample size, mean, standard deviation, median, and range.  Categorical data will be 
summarized by the number and percentage of subjects.  Data analysis will be performed using 
SAS® version 9.2 or greater.   
Summaries for the assessment of long-term safety will be presented by De Novo Subjects and 
Rollover Subjects separately and for all subjects combined.   
All analyses will be conducted on the Safety Analysis Set as defined in Section 11.3.   
Additional exploratory analyses of the data may be conducted as deemed appropriate.  A detailed 
Statistical Analysis Plan (SAP) describing the statistical methodologies will be developed by the 
sponsor or its designee.   
11.2 
Determination of Sample Size 
Approximately 600 subjects are expected to be enrolled (dosed).  This number may increase or 
decrease to meet the International Conference on Harmonisation (ICH) regulatory exposure 
requirements for NKTR-181.   
No formal sample size calculation will be performed for this long-term safety study.  The sample 
size determination is based on the regulatory exposure requirement (ICH E1 A [1995]) that at 
least 300 subjects must complete 6 months (26 weeks) of NKTR-181 treatment and at least 
100 subjects must complete 12 months (52 weeks) of NKTR-181 treatment.   
11.3 
Analysis Sets 
Safety Analysis Set: The Safety Analysis Set includes all subjects who received at least 1 dose of 
study drug. Analyses of safety will be summarized for this analysis set.   
Pharmacokinetic (PK) Analysis Set: The PK Analysis Set consists of all subjects who received at 
least 1 dose of NKTR-181 and have at least 1 PK data available.   


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11.4 
Subject Disposition 
Frequency counts and percentages of all subjects who are enrolled, receive study drug, and 
complete the study or discontinue early will be presented.  Reasons for discontinuing the study 
will be summarized.   
11.5 
Demographic and Baseline Disease Characteristics 
Demographic and baseline characteristics will be summarized descriptively for overall subjects.   
11.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be reported at each visit and coded to Anatomical, 
Therapeutic, or Chemical (ATC) level and preferred drug name according to the World Health 
Organization Drug Dictionary.  Prior and concomitant medications will be summarized by 
treatment group, ATC classification, and preferred drug name.   
11.7 
Study Drug Exposure 
The duration of study drug exposure will be summarized descriptively.   
11.8 
Rescue Medication 
Rescue medication use over time will be summarized descriptively.   
11.9 
Safety Analyses 
Safety assessments are important endpoints of this study. All safety analyses will be based on the 
Safety Analysis Set and will be presented by subject group (De Novo Subjects or Rollover 
Subjects) and for all subjects combined.  Safety data such as AE reports, clinical laboratory test 
results, vital signs, and ECGs will be descriptively summarized.  Suicidality assessments 
(C-SSRS) will also be tabulated.   
11.9.1 
Time to Discontinuation 
The time to discontinuation from study drug due to AEs and time to discontinuation due to any 
reason will be summarized using Kaplan-Meier estimates.   
11.9.2 
Incidence of Aberrant Drug Behavior as Measured Using MADDERSTM 
The incidence of aberrant drug behavior as measured using MADDERSTM will be presented in a 
data listing.   


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11.9.3 
Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 17.1 or later.  The incidence of 
treatment emergent adverse events (TEAEs) will be presented by severity and relationship to 
study drug as perceived by the Investigator.   
Adverse events, serious adverse events (SAEs), AEs by intensity, AEs by causality, AEs leading 
to death, and AEs leading to study discontinuation will be tabulated by System Organ Class and 
Preferred Term.   
The event rate (per 100 patient years) of TEAEs by preferred term will be calculated and 
summarized descriptively.  The relationship between drug exposure and the frequency and 
severity of AEs will be examined.   
11.9.4 
Clinical Laboratory Results 
All clinical laboratory results and change from baseline will be summarized descriptively. 
Individual results that are outside of normal range will be summarized by shift tables and flagged 
in data listings.  Observed values and change from baseline will be summarized over time.   
11.9.5 
Twelve-Lead Electrocardiogram Measurements 
Electrocardiogram measurements will be tabulated and summarized.  Observed values and 
changes from baseline in ECG parameters will be summarized descriptively.  The proportions of 
subjects with potentially clinically significant values at post-baseline will be tabulated.   
11.9.6 
Vital Signs 
Vital signs will be tabulated and summarized. Observed values and changes from baseline in 
vital signs will be summarized descriptively.  The changes from baseline to each visit and to 
endpoint will be summarized.  The proportions of subjects with potentially clinically significant 
values post-baseline will be tabulated.   
11.9.7 
Clinical and Subjective Opiate Withdrawal Scales 
Individual item and total score from the COWS and the SOWS will be summarized over time.   


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11.10 Efficacy Analyses 
11.10.1 
Modified Brief Pain Inventory–Short Form 
The mBPI-SF will be assessed at each visit during the study.  The change from baseline and 
value at each visit will be summarized descriptively over time.   
11.10.2 
Time to Stabilization of Pain Scores During the Study 
The time to stabilization of pain scores since the first dose during the study will be estimated 
using the Kaplan-Meier method.   
11.11 Missing Data 
Missing data will not be imputed.  Final statistical considerations and methodology for handling 
missing data will be detailed in a separate document (SAP).   
11.12 Pharmacokinetics 
Individual subject PK concentration-time data, as well as summary statistics for each treatment 
(e.g., mean, median, standard deviation and/or standard error, and percent coefficient of variation 
[% CV]), will be tabulated.  In addition, summaries for each treatment by sex will also be 
provided.  Results from this study will be pooled with those from other Phase 3 studies for 
population PK analyses and to allow exploration of possible exposure-response relationships for 
efficacy and safety.   


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12.0 
STUDY OR STUDY SITE TERMINATION 
The sponsor has the right to suspend or terminate the study at any time.  The study may be 
suspended or terminated for any reason.   


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13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor will implement and maintain quality control and quality assurance procedures with 
written SOPs to ensure that the study is conducted and data are generated, documented, and 
reported in compliance with the protocol, Good Clinical Practice (GCP), and applicable 
regulatory requirements.   
All protocol deviations and the reasons for such deviations are to be documented in the source 
documents and reported to the sponsor.   
13.1 
Changes to the Protocol 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IRB/independent ethics committee (IEC), 
except when necessary to eliminate immediate hazards to the subject.  Any deviation may result 
in the subject having to be withdrawn from the study and rendering that subject nonevaluable.   
13.2 
Monitoring 
In accordance with Code of Federal Regulations 21 CFR 312.56, ICH GCP and local regulations, 
the clinical monitor will periodically inspect all eCRFs, study documents, research facilities, and 
clinical laboratory facilities associated with this study at mutually convenient times during and 
after completion of the study.  As required by 21 CFR 312 Subpart D (Responsibilities of 
Sponsors and Investigators), ICH GCP, and local regulations, the monitoring visits provide the 
sponsor with the opportunity to evaluate the progress of the study; verify the accuracy and 
completeness of eCRFs; ensure that all protocol requirements, applicable FDA, ICH GCP, and 
local regulations, and Investigator’s obligations are being fulfilled; and resolve any 
inconsistencies in the study records.  This includes inspection of all documents and records that 
are required to be maintained by the Investigator, including but not limited to medical records 
(office, clinic, or hospital) for the subjects in this study.  The names and identities of all research 
subjects will be kept in strict confidence and will not appear on eCRFs or other records provided 
to or retained by the sponsor.  The Investigational New Drug Application (IND) regulations also 
require the Investigator to allow authorized representatives of the sponsor, IRB/IEC, and FDA to 
inspect and make copies of the same records.  The names and identities of the subjects need not 
be divulged to the sponsor; however, the records must nevertheless be inspected.  This can be 
accomplished by blacking out the subject’s name and replacing the name with the subject’s study 
identification number.  If these requirements are in conflict with local regulatory restrictions or 
institutional requirements, the Investigator must inform the sponsor of these restrictions before 
initiation of the study.   


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13.3 
Direct Access to Source Data/Documents for Audits and Inspections 
Members of the sponsor’s GCP Quality Assurance Department or designees may conduct an 
audit of a clinical site at any time during or after completion of the study.  The Investigator will 
be informed if an audit is to take place and advised as to the scope of the audit.  Inspections and 
audits are typically carried out during the clinical and reporting phases of this study to ensure 
that the study is conducted and data are generated, documented, and reported in compliance with 
the protocol, GCP, written SOPs and applicable laws, rules, and regulations.   
Representatives of the FDA or other regulatory agencies, including IRB/IEC representatives may 
also conduct an audit of the study.  If informed of such an inspection, the Investigator should 
notify the sponsor immediately.  The Investigator will ensure that the auditors have access to the 
clinical supplies, study site facilities, laboratory and that all data (including original source 
documentation) and all study files are available, if requested.   


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14.0 
ETHICS 
This study will be conducted to be consistent with the principles that have their origin in the 
Declaration of Helsinki and in accordance with FDA regulations (21 CFR § 11, 50, 54, 56, 
and 312), with the ICH GCP guidelines (ICH E6), as well as with any and all applicable federal, 
state and/or local laws and regulations.   
14.1 
Institutional Review Board/Independent Ethics Committee Approval 
Before enrollment of subjects into the study, as required by federal regulations (21 CFR § 56), 
ICH GCP and local regulations, the current protocol and ICF will be reviewed and approved by 
an appropriate IRB or IEC.  A letter documenting the IRB or IEC approval must be received by 
the sponsor before the initiation of the study at a clinical site.  Amendments to the protocol will 
be subject to the same requirements as the original protocol.   
The Investigator will submit a progress report at least once yearly to the IRB or IEC.  However, 
the frequency of these reports will depend on IRB or IEC requirements.  As soon as possible 
after completion or termination of the study, the Investigator will submit a final report to the IRB 
or IEC per the IRB or IEC requirements, and in compliance with FDA regulations and ICH 
GCPs.   
The Investigator, the sponsor, or designee shall promptly notify the IRB or IEC of any SAEs, or 
any other information that may affect the safe use of the study drug during the course of the 
study, per the IRB or IEC local requirements, and in compliance with FDA regulations and ICH 
GCPs.   
14.2 
Written Informed Consent 
Written informed consent must be obtained from each subject or subject’s legal representative 
before entering the study.  Subjects/legal representatives will be informed of the nature of the 
study, and the ICF must be presented to each subject/legal representative in the language in 
which the subject/legal representative is fluent.   
Informed consent will be obtained and documented by each subject or subject’s legal 
representative prior to any protocol-specific procedures.  Signed ICFs will be retained by the 
Investigator with the study records.  Each subject/legal representative will be given a copy of the 
signed and dated ICF.   


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15.0 
DATA HANDLING AND RECORD KEEPING 
15.1 
Data Collection Instruments and Source Documents 
15.1.1 
Study Records 
During the study, the Investigator will maintain adequate records for the study, including a 
record of potential subjects screened and medical records, and records detailing the progress of 
the study for each enrolled subject, laboratory reports, eCRFs, signed ICFs, drug accountability 
records, correspondence with the IRB or IEC and regulatory agencies’ AE reports, and 
information regarding subject discontinuation and completion of the study.   
15.1.2 
Data Collection Instruments (DCIs) 
Data collection instruments (DCIs) (e.g., eCRFs, eCOA, paper forms) will be used in this study.  
These instruments are used to transmit the information collected during the performance of this 
study to the sponsor or sponsor’s designee and regulatory authorities.  The Investigator must 
review the DCIs for completeness and accuracy and must approve all data, including any 
changes made.  Furthermore, the Investigator retains full responsibility for the appropriateness 
and accuracy of all data collected in the DCIs.   
15.2 
Retention of Essential Documents 
All records and documents pertaining to the study including, but not limited to, those outlined 
above (see Section 15.1.1) will be maintained by the Investigator for a period of at least 2 years 
after FDA approval of the drug or at least 2 years after withdrawal of the IND under which this 
study was conducted, whichever is longer.  To avoid any possible errors, the Investigator will 
contact the sponsor before transferring or destroying any study records.  The Investigator will 
also promptly notify the sponsor in the event of accidental loss or destruction of any study 
records.   


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16.0 
PUBLICATION POLICY 
All data are the property of the sponsor. However, it is intended that the results of the study will 
be published and/or presented at scientific meetings.  Any formal presentation or publication of 
data from this study will be considered as a joint publication by the Investigator(s) and 
appropriate sponsor personnel.  Authorship will be determined by mutual agreement.   
The sponsor must receive copies of any intended communication in advance of submission for 
publication (at least 14 days for an abstract or oral presentation and 30 days for a journal 
submission).  The sponsor will review the communications for accuracy (thus avoiding potential 
discrepancies with submissions to health authorities), verify that confidential information is not 
being inadvertently divulged, and provide any relevant supplementary information.   
The Investigator may be required to sign the clinical study report if it is to be used in a 
registration submission to the health authorities of some countries.   


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17.0 
REFERENCES 
1. 
Foley KM. The treatment of cancer pain. N Engl J Med 1985;313(2):84-95. 
2. 
Handelsman L, Cochrane KJ, Aronson MJ, et al. Two new rating scales for opiate 
withdrawal. Am J Drug Alcohol Abuse 1987;13(3):293-308. 
3. 
Kroenke K, Strine TW, Spitzer RL, et al. The PHQ-8 as a measure of current depression 
in the general population. J Affect Disord. 2009;114(1-3):163-173. 
4. 
Mendoza T, Mayne T, Rublee D, et al. Reliability and validity of a modified Brief Pain 
Inventory short form in patients with osteoarthritis. Eur J Pain. 2006;10(4):353-361. 
5. 
Mundt JC, Greist JH, Gelenberg AJ, et al. Feasibility and validation of a 
computer-automated Columbia-Suicide Severity Rating Scale using interactive voice 
response technology. J Psychiatr Res. 2010;44(16):1224-1228.  
6. 
Mundt JC, Greist JH, Jefferson JW, et al. Prediction of suicidal behavior in clinical 
research by lifetime suicidal ideation and behavior ascertained by the electronic 
Columbia-Suicide Severity Rating Scale. J Clin Psychiatry. 2013;74(9):887-893. 
7. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277.  
8. 
Smith SM, Dart RC, Katz NP, et al. Classification and definition of misuse, abuse, and 
related events in clinical trials: ACTTION systematic review and recommendations. Pain. 
2013;154(11):2287-2296. 
9. 
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs 2003; 35(2):253-259. 


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18.0 
APPENDICES 
Not applicable.  

SAP_003.pdf: 


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TABLE OF CONTENTS 
LIST OF TABLES .......................................................................................................................3 
ABBREVIATIONS .......................................................................................................................4 
1.0 
ADMINISTRATIVE STRUCTURE .............................................................................6 
2.0 
INTRODUCTION ............................................................................................................6 
3.0 
STUDY OBJECTIVES ....................................................................................................6 
3.1 
Primary Objective ..................................................................................................6 
3.2 
Secondary Objectives ..............................................................................................6 
4.0 
STUDY DESIGN ...............................................................................................................6 
4.1 
Method of Randomization ...................................................................................7 
5.0 
STUDY ENDPOINTS ......................................................................................................7 
6.0 
ASSESSMENTS ...............................................................................................................8 
6.1 
Efficacy Assessments .............................................................................................8 
6.1.1 
Modified Brief Pain Inventory-Short Form  (mBPI-SF) .................8 
6.2 
Safety Assessments ................................................................................................8 
7.0 
STATISTICAL CONSIDERATIONS .......................................................................8 
7.1 
General Considerations .......................................................................................8 
7.2 
Study Day ...............................................................................................................9 
7.3 
Analysis Sets ..........................................................................................................9 
7.4 
Definition of Visit Window ..................................................................................9 
8.0 
STATISTICAL ANALYSES .......................................................................................11 
8.1 
Subject  Disposition ..............................................................................................11 
8.2 
Protocol Deviations ..............................................................................................11 
8.3 
Demographic and Baseline Disease Characteristics .........................................11 
8.4 
Prior and Concomitant Medication .................................................................12 
8.5 
Study Drug Exposure and Drug Compliance ...................................................13 
8.6 
Efficacy Endpoint .................................................................................................14 
8.6.1 
Responder Rates Based on mBPI Pain Intensity ..............................14 
8.6.2 
Time to Dose Level increase after  the Titration Period ...................15 
8.6.3 
Time to Discontinuation ......................................................................15 
8.6.4 
Rescue Medication ...............................................................................15 
8.7 
Safety Endpoints .................................................................................................16 
8.7.1 
Adverse events .....................................................................................16 
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8.7.2 
Clinical and Subjective Opiate Withdrawal Scales ...........................17 
8.7.3 
C-SSRS .................................................................................................18 
8.7.4 
MADDERS™ ......................................................................................19 
8.7.5 
Clinical Laboratory Evaluations .......................................................20 
8.7.6 
Vital Signs and ECGs ..........................................................................20 
8.8 
Pharmacokinetics and Pharmacodynamics .......................................................20 
8.9 
Handling of Multiplicity ......................................................................................21 
8.10 
Handling Missing Values .....................................................................................21 
9.0 
CHANGES OF ANALYSIS FROM PROTOCOL ..................................................21 
10.0 
REFERENCES ...............................................................................................................22 
 
LIST OF TABLES 
Table 1: 
Windowed Visits for Summary .................................................................10 
 
LIST OF APPENDIX TABLES 
Appendix 1 
Reference for Vital Sign and ECG Ranges ................................................23 
Appendix 2 
Abuse related adverse events of interest (MedDRA 18.0) ........................24 
Appendix 3 
Abuse potential adverse event terms of interest characterized as 
psychotomimetic in nature .........................................................................25 
Appendix 4 
Drug Withdrawal- Related Adverse Events Occurring Following 
Drug Discontinuation (Preferred Terms; MedDRA 18.0) .........................28 
 
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ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATC 
anatomical, therapeutic, or chemical 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
mBPI-SF 
Modified Brief Pain Inventory-Short Form 
CI 
confidence interval 
CLBP 
chronic low back pain 
COWS 
Clinical Opiate Withdrawal Scale 
CRO 
clinical research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP3A 
cytochrome P 450 enzyme isoform 3A 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
ET 
early termination 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GSP 
Good Statistical Practice 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IXRS 
Interactive Voice and Web Response System 
MADDERS™ 
Misuse, Abuse, and Divergent Drug Event Reporting System 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Abbreviation or Term 
Definition 
MMRM 
mixed model repeated measures 
NSAID 
non-steroidal anti-inflammatory drug 
NRS 
Numeric Rating Scale 
PHQ-8 
Personal Health Questionnaire Depression Scale 
PK 
pharmacokinetic 
QTcF 
corrected QT interval, Fridericia's correction 
RR 
respiratory rate 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOWS 
Subjective Opiate Withdrawal  Scale 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
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1.0 
ADMINISTRATIVE STRUCTURE 
This study is being conducted under the sponsorship ofNektar Therapeutics.  Statistical analyses 
will be performed by the Biometrics Department at Nektar Therapeutics and a contract research 
organization (CRO).  Pharmacokinetic (PK) concentrations will be analyzed by Nektar India. 
Central clinical laboratories and central electrocardiograms (ECGs) are used for processing of 
laboratory safety specimens and ECG data.  The Interactive Voice and Web Response System 
(IXRS) provider will manage the study drug distribution and inventory management. 
2.0 
INTRODUCTION 
This document is a description of the planned statistical analyses of the data captured according 
to Nektar Therapeutics Protocol14-l8l-08, “A Phase 3 Multicenter, Open-Label, 52-Week Study 
to Evaluate the Long-Term Safety and Tolerability ofNKTR-181 in Subjects with Moderate to 
Severe Chronic Low Back Pain or Chronic Noncancer Pain”. 
This Phase 3 study will be conducted in accordance with the protocol, Good Clinical Practice 
(GCP), Good Statistical Practice (GSP), and all applicable regulatory requirements.  
Analyses of pharmacokinetics will be addressed in a separate analysis plan. 
3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
NKTR-181 in subjects with moderate to severe chronic low back pain or chronic noncancer pain. 
3.2 
Secondary Objectives 
The secondary objective is to evaluate the effectiveness ofNKTR-181 as measured by the 
modified Brief Pain Inventory-Short Form (mBPI-SF). 
4.0 
STUDY DESIGN 
This is a multicenter, Phase 3, open-label safety and tolerability study in which approximately 
600 subjects will receive open-label NKTR-181 for up to 12 months (52 weeks) from 
approximately 100 sites. Subjects may include newly enrolled subjects (approximately 250 De 
Novo Subjects) and subjects who have recently completed Study 14-181-07 or Study 14-181-12 
(Rollover Subjects). 
The study comprises 3 periods: 
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• Screening: Up to 21 days; Visits 1-2 
• Treatment: 52 weeks; Visits 3-22 
• Safety Follow-Up: Approximately 14 days after the last dose of study drug; Visits 23-24 
This study will also investigate the PK ofNKTR-181 in patients with chronic low back pain or 
chronic noncancer pain. Blood samples for PK analyses will be collected from all subjects 
according the Schedule of Assessments (Section 1.2 of protocol), and during a complete 12-hour 
dosing interval in a substudy of approximately  100 subjects at selected sites. 
The three study periods are described in further detail in Study Protocol 14-181-08, Sections 6.1 
to 6.3.  A schematic of the study design is presented in Section 1.1, and the Schedule of 
Assessments is presented in Section 1.2 of the protocol. 
4.1 
Method of Randomization 
Randomization is not applicable to this study. 
5.0 
STUDY ENDPOINTS 
Key Safety Endpoint: 
• Incidence, type, seriousness, and severity of adverse events (AEs) reported 
• Clinical laboratory evaluations 
• Electrocardiograms (ECGs) 
• Vital signs (respiratory rate, pulse, heart rate, blood pressure, and temperature) 
• Drug withdrawal as measured by the Clinical Opiate Withdrawal Scale (COWS) and the 
Subjective Opiate Withdrawal Scale (SOWS) 
• Incidence of aberrant drug behavior according to MADDERS™ assessment 
• Suicidality assessment (Columbia-Suicide Severity Rating Scale [C-SSRS]). 
Efficacy Endpoints: 
• • 
The mBPI-SF assessed at clinic visits. 
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6.0 
ASSESSMENTS 
6.1 
Efficacy Assessments 
6.1.1 
Modified Brief Pain Inventory-Short Form  (mBPI-SF) 
The mBPI-SF (Mendoza, 2006) was developed to provide information on pain intensity and the 
degree to which pain interferes with patient functioning. Using a 0 to 10 numerical rating scale 
(NRS), subjects rate their pain at the time of responding to the questionnaire (Pain Now), and 
also at its worst, least, and average over the previous 24 hours. With 0 being "no interference" 
and 10 being "interferes completely," the mBPI-SF asks for ratings of the degree to which pain 
interferes with mood, walking and other physical activity, work, social activity, relations with 
others, and sleep. 
6.2 
Safety Assessments 
Safety assessments include adverse events and serious adverse events, clinical laboratory tests, 
vital signs, twelve-lead ECGs, relevant and significant medication history (including history of 
substance or opioid abuse, medical/surgical history, and concurrent illnesses), pregnancy tests, 
drug and alcohol screening, Columbia-Suicide Severity Rating Scale (C-SSRS) suicidality 
assessment, Clinical Opiate Withdrawal Scale (COWS; Wesson, 2003), Subjective Opiate 
Withdrawal Scale (SOWS; Handelsman, 1987), and Misuse, Abuse, and Divergent Drug Event 
Reporting System (MADDERS™). 
7.0 
STATISTICAL CONSIDERATIONS 
Statistical analysis of this study will be the responsibility of Nektar Therapeutics or its designee 
using the SAS® software version 9.4 or greater.  Other analyses than those stated in the 
statistical analysis plan might be performed to gain information needed for the planning and 
analyses of future studies. 
7.1 
General Considerations 
Generally, if not specified, continuous data will be summarized by descriptive statistics (n, mean, 
standard deviation, median, minimum, maximum).  Categorical data will be summarized by the 
number and percentage of subjects.  All assessments, if necessary, will be summarized by 
Denovo naive, Denovo opioid experienced, Rollover by treatment received in feeder study.  All 
statistical tests, as deemed necessary, will be 2-sided with a significance level of 5%. 
 
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7.2 
Study Day 
• The day of the titration start (Visit 3 date) will be called Titration Day 1.  Visit 10 is the end 
of titration, the dose at visit 10 is defined as stable dose.  The day of the stable dose (Visit 10 
date) wil1 be called Day I . Study day will be calculated from the Day 1. 
• Baseline is defined as the last non-missing observation prior to or on Titration Day 1. Change 
from baseline variables will be calculated as the post-baseline  value minus baseline value. 
 
7.3 
Analysis Sets 
Denovo opioid experienced subjects are defined as de novo subjects who are currently taking no 
less than 10 mg but no more than 60 mg MSE/day for at least the 7 days prior to signing the ICF 
Denovo naive patients are defined as de novo subjects who are not opioid experienced subjects. 
Safety Analysis Set: The Safety Analysis Set includes all subjects who received at least 1 dose 
of study drug.  Analyses of safety will be summarized for this population. 
Completers Analysis Set: All subjects in the Safety Analysis Set who complete 52-week 
exposure to NKTR-181. 
Pharmacokinetic (PK) Analysis Set: The PK Analysis Set consists of all subjects who received 
at least 1 dose ofNKTR-181 and have at least 1 PK data point available. 
7.4 
Definition of Visit Window 
Deviations are to be expected between subjects in the actual number of study days from Day 1 to 
when planned visits are carried out.  To handle this for tables, figures, listings, and analyses 
where data are to be grouped by visit, visit numbers will be defined according to Table 1. 
The following windows will apply only for summaries for value and change value by visit and 
summaries for abnormalities. If multiple assessments were performed within the visit window, 
the following will be applied: 
• If there are multiple records in the same visit window, the measurement closest to the 
scheduled visit day will be used. 
• If two visits are equidistant from the scheduled day, the later will be assigned to the visit. 
• In the summaries for abnormalities, the worst case will be summarized for that visit 
regardless of how close to the scheduled visit it is. 
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Table 1: 
Windowed Visits for Summary 
Visit 
Scheduled 
Study Day 
Windowed 
Visits for Labs 
Windowed 
Visits for Vital 
Signs 
Windowed 
Visits for 
ECG 
Windowed  
Visits for  
CSSRS 
Windowed 
Visits for 
mBPI 
Windowed
Visits for
COWS 
Baseline 
First dose 
<=first dose 
date 
<=first dose 
date 
<=first dose 
date 
<=first dose date
<=first dose 
date 
<=first dose 
date 
The 
Titration 
visits 
 
go with the 
actual visit 
go with the 
actual visit 
NA 
NA 
go with the 
actual visit 
NA 
Visit 10 - 
Stable Dose 
1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
NA 
Visit 11 
30 
Day2 to 45 
NA 
NA 
NA 
Day2 to 45 
NA 
Visit 12 
60 
Day46 to 75 
NA 
NA 
NA 
Day46to 75 
NA 
Visit 13 
90 
Day76 to 105 
Day2 to 105 
Day2 to 105 
Day2 to 105 
Day76 to 105 
NA 
Visit 14 
120 
NA 
NA 
NA 
NA 
Day106 to 135 
NA 
Visit 15 
150 
NA 
NA 
NA 
NA 
Day136 to 165 
NA 
Visit 16 
180 
NA 
NA 
NA 
NA 
Day165 to 195 
NA 
Visit 17 
210 
Day106 to 225 Day106 to 225 Day106 to 225 Day106 to 225 Day196 to 225 
NA 
Visit 18 
240 
NA 
NA 
NA 
NA 
Day226 to 255 
NA 
Visit 19 
270 
NA 
NA 
NA 
NA 
Day256 to 285 
NA 
Visit 20 
300 
Day226 to one 
day before visit 
21 
Day226 to one 
day before visit
21 
Day226 to one 
day before 
visit 21 
Day226 to one 
day before visit
21 
Day286 to one 
day before visit 
21 
NA 
Visit 21 
357 from 
Titration 
Day 1 
go with the 
actual visit 
NA 
NA 
go with the 
actual visit 
go with the 
actual visit 
go with the 
actual visit 
Visit 22 
364 from 
Titration 
Day 1 
go with the 
actual visit 
go with the 
actual visit 
go with the 
actual visit 
go with the 
actual visit 
go with the 
actual visit 
go with the 
actual visit 
3-day Safety 
Follow-up 
3 days after 
ET visit 
3 to 6 days after 
ET visit 
3 to 6 days after
ET visit 
NA 
NA 
NA 
3 to 6 days 
after ET visit
14-day 
Safety 
Follow-up 
14 days 
after ET 
visit 
>=7 days after 
ET visit 
NA 
NA 
NA 
NA 
>=7 days 
after 
ET visit 
Abbreviations:  C-SSRS, Columbia-Suicide Severity Rating Scale; NA, not applicable. 
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8.0 
STATISTICAL ANALYSES 
8.1 
Subject  Disposition 
Frequency counts and percentages will be tabulated for all subjects who complete or early 
discontinue from the study drug.  Reasons for early discontinuation from study drug will be 
summarized by the highest titrated dose level. 
8.2 
Protocol Deviations 
Subjects with major protocol deviations and violations will be listed and summarized by the 
highest dose level which a subject was titrated to and for each study site and for overall subjects. 
Major protocol deviations or violations may include but not limited to the followings: 
Subjects who entered the study even though they did not satisfy the entry criteria; 
1. Subjects who developed withdrawal criteria during the study but were not withdrawn from 
study medication; 
2. Subjects who received prohibited medication. 
Subjects with one or more protocol deviations or violations in the same category/type will be 
counted once for that category. 
Protocol deviations and violations will be will be captured by searching relevant data fields 
reported in the clinical database using computer algorithms and site monitoring by clinical 
research associates.  All deviations and violations will be reviewed by medical monitors.  Final 
determination of major deviations and violations will be reviewed by the study team at regular 
intervals throughout the trial (including the clinical study manager, the Medical Monitor, and the 
statistician). 
Subjects who have protocol deviation/violation will also be presented in a data listing. 
8.3 
Demographic and Baseline Disease Characteristics 
Demographic and baseline characteristics  including age (years) sex, race, ethnicity, smoking 
history, height (cm), weight (kg), body mass index (BMI; kg/m2), and time since diagnosis of 
chronic noncancer pain will be summarized descriptively  by highest titration dose level. 
General medical history including past or present clinically significant medical conditions 
collected at screening will be summarized and presented in a data listing.  Medical history of 
noncancer pain onset will be summarized. 
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Age will be calculated as follows: 
 
 
rounded down to the integer value in years. 
 
 
 
BMI will be calculated as follows: 
 
 
BMI = (weight in kilograms)/ (height in meters)2 
 
 
Time to noncancer pain onset will be calculated as follows: 
 
 
 
rounded off to one decimal place in  
 
year. 
Partial dates for date of onset in the calculation will be imputed.  If year and month in the initial 
diagnosis are presented and day is missing, the first day of the month will be imputed. If year is 
presented but month/day is missing, missing day and month will be imputed as January 1. No 
imputation will be done if the year is missing. 
8.4 
Prior and Concomitant Medication 
Prior and concomitant medications are recorded on the electronic case report form (eCRF) and 
coded to anatomical, therapeutic, or chemical code and preferred drug name using the World 
Health Organization (WHO) Dictionary (Version WHODRUG2014MAR01 WHO Drug 
Dictionary Enhanced [DDE]). 
Prior medications are defined as medications taken before or on the date of first dose of 
NKTR-181 in 14-181-08 (Visit 3), including medications continued during treatment. 
Concomitant medications are defined as medications taken on or after the date of first dose of 
NKTR-181 in 14-181-08 (Visit 3) including medications initiated prior to the date of first dose 
and continued during treatment, and medications initiated on or after the date of first dose. 
Prior and concomitant medications will be tabulated separately for the Safety Population by 
WHO DDE ATC level 2 classifications, preferred term.  The number and percent of subjects 
taking medication will be calculated. If the ATC level 2 classification is missing, the next non- 
missing level of classification will be used (level 1). If a subject reports the same ATC level 2 
classification multiple times, the ATC level 2 classification will be incremented by one.  As with 
ATC level 2 classification, if a subject reported multiple medications within the same preferred 
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term, the preferred term increments by one.  Percentages will be calculated using the total 
number  of subjects in the corresponding dose level in the Safety Population. 
Prior and concomitant medications will be presented in a data listing. 
8.5 
Study Drug Exposure and Drug Compliance 
Duration  of exposure to study  drug, cumulative dose of the study drug, and compliance of the 
study drug will be summarized for NKTR-181 on the Safety Analysis Set for the overall study 
period  based on the Safety Analysis Set.  The exposure duration  of the study drug will be also 
summarized by time interval (e.g., ≥ 1 month, ≥ 2 months, ..., ≥ 12 months, and > 13 months). 
The exposure duration (days) will be calculated as the number  of days exposed  to study drug: 
date of last dose - the date of first dose + 1. 
The cumulative dose (mg) will be calculated as the sum of the number  of tablets taken times the 
dosage per tablets at each dosage  level. A subject's compliance of the study drug will be 
calculated according to the following: 
 
Compliance will be calculated based on the drug administration recorded in the CRFs.   The 
number of tablets taken will be calculated as the total number of tablets dispensed minus the total 
number of tablets returned.  If the number of returned tablets is missing  due to any reason, it will 
be assumed that the subject took all dispensed tablets during that period.  For those subjects who 
are lost to follow-up, it will be assumed that they took the number of dispensed tablets up until 
the last day of contact. 
The number of tablets planned will be calculated as the prescribed number  of tablets per day 
multiplied by the number  of days potentially exposed  to the study drug: 
 
where  n is related  to the dose level.  n is 2 for 100mg and 200mg, n is 4 for 300mg and 400mg, 
and n is 6 for 500mg and 600mg. The number  of tablets planned  will be adjusted for the first 
dose and the last dose time of the study drug. 
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8.6 
Efficacy Endpoint 
The mBPI-SF will be assessed at each visit during the study.  The mean of the 4 intensity items 
(3-6) will be calculated and used as a measure of pain severity.  The mean of the 7 interference 
items (9A-9G) will be calculated and used as a measure of Pain interference.  Change from 
baseline to each month (visit) will be calculated for the Pain severity, Pain interference, and each 
individual score, if applicable. 
If there are missing items when the pain severity score and pain interference score are calculated, 
the mean of the completed items in one dimension (dimensions include pain severity and pain 
interference) will be imputed to substitute the missing item, provided that more than 50% of the 
items in one dimension are completed (Halling, 1999). 
The change from baseline and value for mBPI-SF dimentions and individual scores at each visit 
will be summarized descriptively over time. 
In addition, an exploratory analysis will be performed on mBPI.  The change from baseline to the 
end of the long term safety study will be analyzed.  Baseline will be considered as last non- 
missing assessment on or prior to the first dose in this long term safety study (visit 3).  The 
change from baseline will be analyzed using Mixed Model Repeated Measure (MMRM) 
analysis.  The model will include change from baseline as dependent variable, baseline score as a 
covariate, subject's status (De Novo or Rollover with NKTR-181 or Rollover with Placebo), 
time, subject's status and time interaction as fixed effects.  Point estimates on the Least Squared 
means over time will be calculated with corresponding 95% confidence intervals different dose 
levels. These analysis will be applied to both pain intensity and interference based on mBPI. The 
pain intensity means and LSmeans over time will be present graphically. 
8.6.1 
Responder Rates Based on mBPI Pain Intensity 
Pain intensity score reduction based on the mBPI Pain Intensity subscale for each visit will be 
used to classify responder where: 
Pain intensity score reduction = (mBPI Pain Intensity change from visit 3/visit 3 mBPI Pain 
Intensity)*100. 
Three responder rates will be calculated at each time point, where responders are defined as 
subjects with: 
• Pain intensity score reduced by 30% from visit 3 mBPI Pain Intensity, 
• Pain intensity score reduced by 50% from visit 3 mBPI Pain Intensity, 
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• Pain intensity score reduced according to multiple cut-offs of 10% increments from the visit 
3 mBPI Pain Intensity. 
Responder rate = (no. of responders / total no. of subjects)*100, where total no. of subjects is the 
number of all the subjects in the analysis set. Subjects, who discontinue prior to the time point or 
have a missing pain score at that time point, will be counted as non-responders. 
The number and percentage of responders in each dose level for pain intensity score reduction 
according to multiple cut-offs of 10% increments from baseline will be presented. 
8.6.2 
Time to Dose Level increase after  the Titration Period 
Time to dose level increase after the titration period will be calculated for all subjects.  Dose 
level increase is defined as the first dose level increased from the stable dose to a stable higher 
dose level. The stable higher dose is defined as an increased dose taken by the subject for at least 
2 weeks. The first time when the subject reached the stable higher dose is defined as the date of 
the dose level increase. The time to dose level increase is calculated as follows: 
Date of dose level increase – the stable dose date+ 1. 
The visit 10 date in the long term safety will be used as the stable dose date.  The time to 
discontinuation will be estimated using the Kaplan-Meier method. If a subject completed the 
treatment per the protocol without dose increase (increase to a stable level) will be censored at 
the date of last dose of treatment. 
8.6.3 
Time to Discontinuation 
Time to treatment discontinuation due to any reason will be calculated for all subjects.  The time 
to discontinuation is calculated as follows: 
Date of last dose – date of first dose + 1. 
The first dose date is the first titration dose in the long term safety study.  The time to 
discontinuation will be estimated using the Kaplan-Meier method. If a subject completed the 
treatment per the protocol, the subject will be censored at the date of last dose of treatment. 
Time to treatment discontinuation due to AE, lack of efficacy, and time to treatment 
discontinuation due to any reason will be summarized separately. 
8.6.4 
Rescue Medication 
A subject's rescue medication use will be calculated based on drug accountability recorded in 
CRF.  The mean number of occasions rescue medication per day will be presented by dose level 
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using descriptive statistics. The mean number of occasions rescue medication per day will be 
derived for each visit, if appropriate, as well as overall.  The frequency of subjects using any 
rescue medication in terms of mean number of occasions rescue medication per day will be 
summarized by dose level by visit as well as overall. 
The mean number of occasions rescue medication per day will be calculated as follows:  
(sum of number of occasions of rescue medication) / 
(exposure duration of study drug in days). 
The number of rescue medication taken based on drug administration will be calculated as the 
total number of tablets dispensed minus the total number of tablets returned.  If the number of 
returned tablets is missing, it will be assumed that the subject took the dispensed all tablets 
during that visit.  For those subjects who are lost to follow-up, it will be assumed that they took 
the number of prescribed tablets up until the last day of contact. 
8.7 
Safety Endpoints 
Safety analysis will be performed on the Safety Analysis Set. 
8.7.1 
Adverse events 
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred or 
worsened in severity after the first administration of study drug (Visit 3) but on or prior to the 
end of study.  Adverse events will be mapped to system organ class (SOC) and preferred term 
using MedDRA, version 17.1 or later. 
The number and percent of subjects who had TEAEs, serious TEAEs, AEs with death outcome, 
AEs that led to study drug withdrawal, and AE of interest will be summarized.  AE of interest is 
AEs which may indicate potential abuse.   The list of abuse related AE of interest is in 
Appendix 2 to Appendix 4.  For withdrawal symptoms (Error! Reference source not found.), 
only the preferred terms occurred after last dose of treatment will be considered as withdrawal. 
Adverse events will also be summarized by SOC and preferred term and presented by maximum 
reported intensity and by Investigator's causality assessment.  Corresponding data listings will be 
presented as well. 
An AE that was present at treatment initiation, but resolved and then reappeared while the 
subject was on treatment, is a TEAE (regardless of the intensity of the AE when the treatment 
was initiated).  If the start date of an AE is incomplete and cannot be categorized as occurring 
before or after the first dose, then the AE will be considered as TEAE.  If the start time of AE is 
provided then the AE start date and time will be used to classify the AE as TEAE or not.  If the 
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start time is not provided and the AE occurs on the same day of first study drug administration 
then the AE will be classified as TEAE. 
The duration of AEs will be calculated, partial dates for AE start, will be imputed as follows:  If 
AE start date is missing, the missing day will be imputed as the first day of the month if the 
month of AE occurrence is after the month of first dose date.  If the month of AE occurrence is 
the same month as first dose then the missing day will be imputed as the same day as the first 
dose date.  If the month of AE occurrence is not the same as the month of first dose date then the 
missing day will be imputed as the first day of the month.  If AE start month is missing and AE 
start year is the same as the year of the first dose, the missing month will be imputed as the 
month of the first dose date.  If AE start year is not the same as the first dose year, the missing 
month and day of AE occurrence will be imputed as January 1 of the year.  If AE start year is 
missing, no imputation will be done.  If there is insufficient data for AE start date to make this 
comparison, the AE will be considered as treatment-emergent. 
Partial dates for AE stop date will be imputed as follows: if the day and month are both missing, 
the missing date will be imputed as the treatment termination date or 14 days after last dose of 
study drug whichever is later.  If only the day is missing but month and year are present, the 
missing day will be imputed as the last day of the month.  No imputation will be done if the year 
is missing.  For unresolved/resolving/unknown AEs with a completely missing stop date, there 
will be no imputation. 
8.7.2 
Clinical and Subjective Opiate Withdrawal Scales 
The COWS consists of 11 items to provide a description of the symptoms of withdrawal that can 
be directly observed by a physician interviewer: increased resting pulse rate, gastrointestinal 
upset, sweating, tremor, restlessness, yawning, pupil size, anxiety or irritability, arthralgias, 
piloerection of skin, and runny nose or tearing. 
The total score of the COWS is the sum of the responses to the 11 items, which can range from 0 
to 48, with higher scores indicating greater withdrawal severity.  If there are missing items when 
the total score is calculated, the total score will be set to missing.  Total score between 5 and 12 
inclusive indicates mild withdrawal; between 13 and 24 inclusive indicates moderate withdrawal; 
between 25 and 36 inclusive indicates moderately severe withdrawal; and total score greater than 
36 indicates severe withdrawal. 
The SOWS is a self-rating scale which has been shown to be a reliable and valid measure of the 
opiate withdrawal syndrome.  It contains 16 symptoms whose intensity the subject rates on a 5- 
point scale of 0 = not at all, 1 = a little, 2 = moderately, 3 = quite a bit, 4 = extremely. The total 
 
 
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score is a sum of item ratings, and ranges from 0 to 64.  If there are missing items when the total 
score is calculated, the total score will be set to missing. 
The total score for COWS and SOWS will be calculated at all scheduled assessment time points.  
The COWS and SOWS total scores will be summarized descriptively.  The total score of COWS 
will be summarized categorically by dose level. 
8.7.3 
C-SSRS 
The C-SSRS is a suicidality assessment instrument administered to prospectively assess the 
severity and frequency of suicidal ideation and behaviors.  The C-SSRS identifies the full range 
of suicidal ideation and behavior and monitors change from visit to visit.  The C-SSRS will be 
administered the "Baseline/Screening" version of the scale at Visit 1.  It assesses suicidal 
ideation and behavior over the lifetime and over the past 12 months.  The C-SSRS will be 
administered the "Since Last Visit" version of the scale at all the other required visits according 
to the scheduled assessments. The "Since Last Visit" version asks about any suicidal thought or 
behaviors the subject may have had since the last time the scale was administered. 
Suicidal Ideation Score: The maximum suicidal ideation category (1-5 on the CSSRS) present at 
the assessment. Assign a score of 0 if no ideation is present.  Suicidal ideation is a "yes" answer 
at any time during treatment to any one of the five suicidal ideation questions on the C-SSRS. 
Suicidal behavior: A "yes" answer at any time during treatment to any one of the five suicidal 
behavior questions (Categories 6-10) on the C-SSRS. 
Suicidal ideation or behavior: A "yes" answer at any time during treatment to any one of the ten 
suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
The score at each assessment for each patient will be used for determining treatment emergence.  
Treatment-emergent suicidal ideation: An increase in the maximum suicidal ideation score 
during treatment from baseline (excludes "lifetime" scores from the Baseline C-SSRS scale or 
Baseline/Screening C-SSRS scale). 
Treatment-emergent serious suicidal ideation: An increase in the maximum suicidal ideation 
score to 4 or 5 on the C-SSRS during treatment from not having serious suicidal ideation (scores 
of 0-3) at baseline (excludes "lifetime" scores from the Baseline C-SSRS scale or 
Baseline/Screening C-SSRS scale). 
 
 
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Emergence of serious suicidal ideation: An increase in the maximum suicidal ideation score to 4 
or 5 on the C-SSRS during treatment from no suicidal ideation (scores of 0) at baseline (excludes 
"lifetime" scores from the Baseline C-SSRS scale or Baseline/Screening C-SSRS scale). 
An improvement in suicidal ideation at a time point is considered as a decrease in suicidal 
ideation score at the time point of interest (e.g., the last measurement during treatment) from the 
baseline measurement. 
Emergence of suicidal behavior compared to all prior history: The occurrence of suicidal 
behavior (Categories 6-10) during treatment from not having suicidal behavior (Categories 6-10) 
prior to treatment. 
Number of subjects with Suicidal Ideation and Suicidal Behavior during treatment will be 
summarized in a table.  Number of subjects with suicide-related Treatment-Emergent events and 
shift-table of changes in C-SSRS Categories from baseline during Treatment will be summarized 
as well. 
8.7.4 
MADDERS™ 
Abuse-related events, also called misuse- and abuse-related events, consists of a related group of 
phenomena that include actual abuse (i.e., use intended to produce a euphoric effect), misuse 
(use outside of prescribing instructions to produce a therapeutic effect), suicide-related events, 
therapeutic error, overdose, diversion, addiction, withdrawal, tampering, and diversion 
(Smith, 2013).  Until recently, these terms were used inconsistently, and consensus definitions of 
these terms for the purpose of clinical trials were not available, making it impossible to reliably 
quantify the rate of these events in studies. 
Investigators are trained to identify any potentially abuse-related event, and at the time of 
identifying the event complete a Supplemental Adverse Event Form.  In addition, a 
Supplemental Drug Accountability Form is completed for any subjects who have drug 
accountability discrepancies identified at any visit.  Each time either of these events is 
completed, a Classification Form is completed by the investigator indicating the investigator's 
classification of the event in question.  Finally, all subjects complete an interview-based 
assessment at the final visit of the study to identify any undetected abuse-related events that may 
have occurred during the study.  Any events that have led to the completion of a Classification 
Form are provided to an Adjudication Committee for review and final classification. 
Incidence of aberrant drug behavior according to MADDERS™ assessment will be summarized. 
Incidence per person-month will be summarized if applicable. 
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8.7.5 
Clinical Laboratory Evaluations 
All clinical laboratory results and change from baseline values will be summarized descriptively 
by treatment arm. Change from baseline via -categorical variable indicating whether the 
individual values are inside or outside the lab normal ranges will be tabulated using shift tables. 
In addition to change from baseline summaries, hepatic function results (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and 
total bilirubin [TBL]) will be summarized by treatment arm for an elevation of ALT or AST >1 
to ≤ 3 X ULN;  > 3 to ≤ 5 X ULN, and > 5 to ≤ 8 X ULN. 
Individual results that are outside of normal range will be flagged in data listings. 
8.7.6 
Vital Signs and ECGs 
The following variables will be derived for systolic and diastolic supine blood pressure and 
supine pulse rate and/or ECG parameters: 
• Change from baseline. 
• Treatment-emergent change from baseline, see Appendix 1 (treatment-emergent 
decrease/increase). 
• Categorical variable indicates whether the individual values are inside or outside the 
predefined clinical relevant ranges. 
• Overall interpretation of ECGs as normal or abnormal will be recorded at the visits as 
specified in the assessment schedule. 
Descriptive statistics will be presented for scheduled visits on observed data.  In addition to the 
descriptive statistics, treatment-emergent abnormal value and shifts from baseline to post-
baseline result will be presented.  All the summaries mentioned above will be performed by the 
dose level in which subjects were titrated. 
Data listings with flagging for values outside normal ranges will be presented. 
8.8 
Pharmacokinetics and Pharmacodynamics 
Pharmacokinetics/pharmacodynamics will be analyzed on PK Analysis Set.  The Nektar 
Therapeutics Pharmacology group will estimate PK parameters and analyze PK/PD data.  
Detailed descriptions of PK analysis will be included in a PK analysis plan developed separately. 
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8.9 
Handling of Multiplicity 
No corrections for multiplicity will be made. 
8.10 
Handling Missing Values 
No other missing data imputation will be performed unless otherwise stated in this document. 
9.0 
CHANGES OF ANALYSIS FROM PROTOCOL 
Not applicable. 
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10.0 
REFERENCES 
1. 
Handelsman L, Cochrane KJ, Aronson MJ, et al. Two new rating scales for opiate 
withdrawal. Am J Drug Alcohol Abuse. 1987;13(3):293-308. 
2. 
Halling J., Langstrom G., Wiklund I. Handling missing data in Quality of Life 
questionnaires: experiences from clinical trials.  6th Annual Conference of the 
International Society for Quality of Life Research, Barcelona, Spain, Nov 3-6, 1999. 
3. 
Mendoza T, Mayne T, Rublee D, et al. Reliability and validity of a modified Brief Pain 
Inventory short form in patients with osteoarthritis. Eur J Pain. 2006;10(4):353-361. 
4. 
Smith SM, Dart RC, Katz NP, et al. Classification and definition of misuse, abuse, and 
related events in clinical trials: ACTTION systematic review and recommendations.  
Pain.  2013;154(11):2287-2296. 
5. 
Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive 
Drugs. 2003;35(2):253-259. 
 
 
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Reference for Vital Sign and ECG Ranges 
Extended Reference Ranges for Vital Signs Used in the Statistical Analyses 
Variable 
Type 
Variable 
SI Unit 
Outside lower limit 
if 
Outside 
upper 
limit if 
Treatment 
emergent 
decrease if 
Treatment 
emergent 
increase if 
SBU 
SBP supine/standing 
mmHg 
<90 
>160 
<-30 
>30 
DBU 
DBP supine/standing 
mmHg 
<50 
>100 
<-15 
>15 
PLU 
Pulse rate supine 
beats/min 
<40 
>100 
<-20 
>20 
SBD 
Standing-supine 
change in SBP 
mmHg 
<-25 at least once at
2 or 5 min 
NA 
NA 
NA 
DBD 
Standing-supine 
change in DBP 
mmHg 
<-15 at least once at
2 or 5 min 
NA 
NA 
NA 
Abbreviation: NA, not applicable 
 
 
Reference Ranges for ECG Variables 
Interval 
Unit 
Outside lower 
limit if 
Outside upper limit 
if 
Treatment 
emergent 
decrease if 
Treatment 
emergent increase 
if 
RR 
ms 
<400 and <500 
>1333 and >2000 
NA 
NA 
PR interval 
ms 
<100 
>240 
NA 
>40 and >60 
QRS 
ms 
<70 
>120 
NA 
>15 and >30 
QTc 
ms 
<300 
>450, >480 and 
>500 
NA 
>30 and >60 
Abbreviation: NA, not applicable 
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 Abuse related adverse events of interest (MedDRA 18.0) 
System Organ Class 
Higher Level GT 
Higher Level Term 
Preferred term 
Nervous system disorders 
 
 
Dizziness 
Psychiatric disorders 
Mood disorders and 
disturbances NEC 
Emotional and mood 
disturbances NEC 
Euphoric Mood 
Mood altered 
Elevated mood 
Affect alterations 
Inappropriate affect 
General disorders and 
administration site conditions 
General system disorders 
NEC 
Feelings and sensations 
NEC 
Feeling drunk 
Feeling abnormal 
Feeling of relaxation 
Nervous system disorder 
Neurological disorders 
NEC 
Disturbances in 
consciousness NEC 
Sedation 
General disorders and 
administration site conditions 
General system disorders 
NEC 
Asthenic conditions 
Sluggishness 
Nervous system disorder 
Neurological disorders 
NEC 
Disturbances in 
consciousness NEC 
Somnolence 
 
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Abuse potential adverse event terms of interest characterized as psychotomimetic in nature 
System Organ Class 
Higher Level GT 
Higher Level Term 
Preferred term 
Psychiatric disorders 
Psychiatric and behavioural 
symptoms NECPsychiatric 
disorders 
Abnormal behaviour NEC 
Abnormal behaviour 
Nervous system 
disorders 
Sleep disturbances (incl 
subtypes) 
Abnormal sleep-related events Abnormal dreams 
Psychiatric disorders 
Schizophrenia and other 
psychotic disorders 
Psychotic disorder NEC 
Acute psychosis 
Mood disorders and 
disturbances NEC 
Emotional and mood 
disturbances NEC 
Anger 
Anxiety disorders and 
symptoms 
Anxiety symptoms 
Agitation 
Deliria (incl confusion) 
Confusion and disorientation 
Confusional state 
Communication disorders and 
disturbances 
Communications disorders 
Communication disorder
Deliria (incl confusion) 
Deliria 
Delirium 
Disturbances in thinking and 
perception 
Delusional symptoms 
Delusion 
Schizophrenia and other 
psychotic disorders 
Delusional disorders 
Delusional disorder, 
unspecified type 
Dissociative disorders 
Dissociative states 
Depersonalisation 
Disturbances in thinking and 
perception 
Perception disturbances 
Derealisation 
Deliria (incl confusion) 
Confusion and disorientation 
Disorientation 
Dissociative disorders 
Dissociative states 
Dissociation 
 
 
Dissociative disorder 
Cognitive and attention 
disorders and disturbances 
Cognitive and attention 
disorders and disturbances 
NEC 
Disturbance in attention 
Nervous system 
disorders 
Dissociative disorders 
Dissociative states 
Dysarthria 
Psychiatric disorders 
Mood disorders and 
disturbances NEC 
Emotional and mood 
disturbances NEC 
Emotional disorder 
Psychiatric disorders 
Anxiety disorders and 
symptoms 
Fear symptoms and phobic 
disorders (incl social phobia) 
Fear 
 
Perception disturbances 
Flashback 
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System Organ  Class 
Higher Level GT 
Higher Level Term 
Preferred term 
 
Disturbances in thinking and 
perception 
Thinking disturbances 
Flight of ideas 
Perception disturbances 
Hallucination 
Hallucination, auditory 
Hallucinations, mixed 
Hallucination, olfactory 
Hallucination, 
synaesthetic 
Hallucination, tactile 
Hallucination, visual 
Personality disorders and 
disturbances in behaviour 
Behaviour and socialisation 
disturbances 
Hostility 
Nervous system 
disorders 
Neurological disorders NEC 
Paraesthesias and 
dysaesthesias 
Hypoaesthesia 
Psychiatric disorders 
Disturbances in thinking and 
perception 
Perception disturbances 
Illusion 
Personality disorders and 
disturbances in behaviour 
Behaviour and socialisation 
disturbances 
Indifference 
Mood disorders and 
disturbances NEC 
Emotional and mood 
disturbances NEC 
Irritability 
Dementia and amnestic 
conditions 
Amnestic symptoms 
Memory impairment 
Cognitive and attention 
disorders and disturbances 
Cognitive and attention 
disorders and disturbances 
NEC 
Mental impairment 
Mood disorders and 
disturbances NEC 
Fluctuating mood symptoms 
Mood swings 
Musculoskeletal  and 
connective tissue 
disorders 
Muscle disorders 
Muscle tone abnormalities 
Muscle rigidity 
Psychiatric disorders 
Sleep disorders and 
disturbances 
Parasomnias 
Nightmare 
Nervous system 
disorders 
Neurological disorders NEC 
Paraesthesias and  
dysaesthesias 
Paraesthesia 
Psychiatric disorders 
Personality disorders and 
disturbances in behaviour 
Behaviour and socialisation 
disturbances 
Paranoia 
 
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System Organ Class 
Higher Level GT 
Higher Level Term 
Preferred term 
 
Schizophrenia  and other 
psychotic disorders 
Psychotic disorder NEC 
Psychotic disorder 
Nervous system 
disorders 
Neurological disorders NEC 
Sensory abnormalities NEC 
Sensory disturbance 
Psychiatric disorders 
Disturbances in thinking and 
perception 
Delusional symptoms 
Somatic delusion 
Perception disturbances 
Somatic hallucination 
Psychiatric and behavioural 
symptoms NEC 
Abnormal behaviour NEC 
Staring 
Sleep disorders and 
disturbances 
Dyssomnias 
Stupor 
Disturbances in thinking and 
perception 
Thinking disturbances 
Thinking abnormal 
Thought blocking 
Schizophrenia and other 
psychotic disorders 
Brief psychotic disorder 
Transient psychosis 
 
 
 
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Drug Withdrawal- Related Adverse Events Occurring Following Drug Discontinuation 
(Preferred Terms; MedDRA 18.0) 
System Organ Class 
Preferred term 
Cardiac disorders 
Syncope 
Gastrointestinal  disorders 
Vomiting 
Diarrhoea 
Nausea 
General disorders and administration 
site conditions 
Hyperhidrosis 
Pain 
Musculoskeletal and connective tissue 
disorders 
Chills 
Nervous system disorders 
Headache 
Agitation 
Dyssomnia 
Insomnia 
Poor quality sleep 
Syncope 
Terminal insomnia (lower level term of interest:  early morning awakening) 
Tremor 
Psychiatric disorders 
Agitation 
Anhedonia 
Anxiety 
Dysphoria 
Dyssomnia 
Dysthymic disorder 
Feeling of despair 
Insomnia 
Morose 
Negative thoughts 
Nervousness 
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System Organ Class 
Preferred term 
 
Obsessive thoughts 
Terminal insomnia (lower level term of interest: early morning awakening) 
Depressed mood 
Depression 
Poor quality sleep 
Skin and subcutaneous tissue disorders Hyperhidrosis 
Vascular disorders 
Syncope 
 
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Protocol No.: 14-181-08 Pharmacokinetic Analysis Plan 
 
NKTR-181 
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Nektar Therapeutics 
 
PHARMACOKINETIC ANALYSIS PLAN 
 
A PHASE 3 MULTICENTER, OPEN-LABEL, 52-WEEK STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND TOLERABILITY OF NKTR-181 IN SUBJECTS WITH 
MODERATE TO SEVERE CHRONIC LOW BACK PAIN OR CHRONIC 
NONCANCER PAIN   
 
Protocol Number: 14-181-08 
 
 
  
 
NEKTAR Therapeutics 
Clinical Pharmacology 
455 Mission Bay Boulevard South 
San Francisco, CA 94158 
United States 
Protocol Version Amendment 2.0 15 Jan 2016 
 
Version: 
1.0 Final 
 
Date: 
17 October 2017 
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Protocol No.: 14-181-08 Pharmacokinetic Analysis Plan 
 
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LIST OF ABBREVIATIONS 
°C 
Degrees Centigrade 
AUC(0-last) 
Area under the plasma drug concentration-time curve (from time=0 hr to the last measurable 
concentration) 
AUC(0-inf) 
Area under the plasma drug concentration-time curve (from time=0 hr to infinity) 
BLQ  
Below the limit of quantification 
Cmax 
Maximum observed plasma drug concentration 
cm 
Centimeter 
g 
Gram 
hr 
Hour 
kg 
Kilogram 
L 
Liter 
mg 
Milligram 
mL 
Milliliter 
N 
Sample Size, Number of Subjects 
PK 
Pharmacokinetic/Pharmacokinetics 
SD 
Standard Deviation 
T 
Time 
Tmax 
Time at which Cmax is observed 
t1/2 
Terminal half-life 
 
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Protocol No.: 14-181-08 Pharmacokinetic Analysis Plan 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ......................................................................................................................2 
LIST OF ABBREVIATIONS .......................................................................................................3 
1.0 
INTRODUCTION..............................................................................................................5 
2.0 
STUDY OBJECTIVES ......................................................................................................6 
2.1 
Primary Objective ....................................................................................................6 
2.2 
Secondary Objectives ...............................................................................................6 
2.3 
Objective of the Pharmacokinetic Analysis .............................................................6 
3.0 
STUDY DESIGN ................................................................................................................7 
3.1 
General Description .................................................................................................7 
3.2 
Pharmacokinetic Assessment ...................................................................................7 
4.0 
PHARMACOKINETIC ENDPOINTS ............................................................................8 
4.1 
Pharmacokinetic Endpoints for the PK Sub-study ...................................................8 
4.2 
Pharmacokinetic Evaluation based on Sparse Sampling Data .................................9 
5.0 
PK ANALYSIS POPULATION .....................................................................................10 
5.1 
PK Sub-Study Population ......................................................................................10 
5.2 
Sparse Sampling PK Population ............................................................................10 
6.0 
PHARMACOKINETIC DATA EVALUATION ..........................................................11 
6.1 
Bioanalysis of Plasma Samples .............................................................................11 
6.2 
Calculation of Plasma Drug Pharmacokinetic Parameters ....................................11 
6.3 
Presentation of Individual and Mean Plasma Drug Concentrations and PK 
Paramters................................................................................................................11 
6.3.1 
Listings and Tables ...............................................................................11 
6.3.2 
Plots .......................................................................................................12 
6.4 
Reporting Conventions ..........................................................................................12 
7.0 
REFERENCES .................................................................................................................13 
 
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1.0 
INTRODUCTION 
NKTR-181 is a new molecular entity (NME) opioid analgesic designed with the intent of 
preserving opioid analgesic effectiveness, while reducing the rate and extent of entry of the 
molecule into the CNS, and thereby reducing CNS-related side effects.   
The intent of this document is to provide guidance for the PK analysis of data captured according 
to protocol number 14-181-08, “A Phase 3 Multicenter, Open-Label, 52-Week Study to Evaluate 
the Long-Term Safety and Tolerability of NKTR-181 in Subjects with Moderate to Severe 
Chronic Low Back Pain or Chronic Non-cancer Pain”.  This PK analysis plan (PKAP) describes 
the planned analysis of the PK data and the description of the tables, listings, and figures (TLFs) 
to be presented in the Clinical Study Report (CSR).  A separate statistical analysis plan provides 
the description of the planned statistical analyses to support the primary and secondary 
objectives of the study.   
This PKAP extends and supersedes the descriptions of PK analyses provided in the protocol; any 
substantially different analysis will be identified in the CSR.  Should additional analyses beyond 
those described in the PKAP be required, they may be performed and will be identified in the 
appropriate section of the CSR.  Deviations from this PKAP, both substantial and non-
substantial, will be documented in the CSR.   
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2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of 
NKTR-181 in subjects with moderate to severe chronic low back pain or chronic non-cancer 
pain.  
2.2 
Secondary Objectives 
The secondary objective of the study is to evaluate the effectiveness of NKTR-181 as measured 
by the modified Brief Pain Inventory-Short Form (mBPI-SF). 
2.3 
Objective of the Pharmacokinetic Analysis 
To characterize the pharmacokinetics of NKTR-181 and its metabolites oxycodol and oxycodone 
in subjects enrolled in the PK sub-study using noncompartmental analysis. 
To evaluate NKTR-181 pharmacokinetics using sparse samples collected in subjects enrolled in 
the study. 
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3.0 
STUDY DESIGN 
3.1 
General Description 
This is a multicenter, Phase 3, open-label safety and tolerability study in which approximately 
600 subjects will receive open-label NKTR-181 for up to 12 months (52 weeks) from 
approximately 100 sites. Study may include newly enrolled subjects (approximately 250 De 
Novo Subjects) and subjects who have recently completed Study 14-181-07 (Rollover Subjects). 
The study comprises 3 periods: 
Screening: Up to 21 days; Visits 1-2 
Treatment: 52 weeks; Visits 3-22 
Safety Follow-Up: Approximately 14 days after the last dose of study drug; Visits 23-24 
The three study periods are described in further detail in Study Protocol 14-181-08, Sections 6.1 
to 6.3.  A schematic of the study design is presented in Section 1.1, and the Schedule of 
Assessments is presented in Section 1.2 of the protocol. 
3.2 
Pharmacokinetic Assessment 
This study will investigate the PK of NKTR-181 in patients with chronic low back pain or 
chronic non-cancer pain. Sparse blood samples for PK analysis will be collected from all 
subjects at  follows:  Visits 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17, 20, 21, 22, Unscheduled visits, 
end of treatment, and Early Termination visits.   
In addition, a subset of approximately 100 subjects will be participating in the PK sub-study.  
The PK sub-study commences after a stable dose has been identified. This may occur as early as 
the second visit following the start of the Treatment phase.  The PK collection visit will be 
scheduled to start in the morning, prior to the subject taking their morning dose of NKTR-181.  
Subjects should be reminded in advance of the visit to hold their morning dose of study drug and 
to bring their study drug supply to the clinic with them.  Subjects will take their morning dose of 
NKTR-181 in the clinic after a predose PK sample is drawn.  PK samples will be obtained 0.5, 1, 
2, 3, 4, 5, 6, 8, and 12 hours postdoc.   
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4.0 
PHARMACOKINETIC ENDPOINTS 
4.1 
Pharmacokinetic Endpoints for the PK Sub-study 
The endpoints for PK analyses include non-compartmental PK parameters derived from plasma 
NKTR-181, oxycoldol, and oxycodone concentration data.   
Where possible, the following plasma PK parameters will be calculated for all three analytes: 
Cmax: Maximum observed plasma concentration expressed in units of ng/mL.   
Tmax: Time that Cmax was observed expressed in units of hr.   
AUC(0-last):  Area under the plasma concentration-time curve from time =0 to the time of the last 
measureable concentration.  AUC(0-last) will be expressed in units of ng.hr/mL.  
AUC(0-12):  Area under the plasma concentration-time curve from time =0 to the time of the last 
time-point (12 hour post morning dose).  AUC(0-12) will be expressed in units of ng.hr/mL.   
Dose normalized Cmax: Dose normalized maximum observed plasma concentration expressed in 
units of ng/mL/mg.   
Dose normalized AUC(0-last): Dose normalized area under the plasma concentration-time curve 
expressed in units of ng.hr/mL/mg.   
Metabolite to parent ratio for AUC(0-last) (M/PAUC(0-last)) calculated as: 
(AUC(0-last)metab*MWparent) / (AUC(0-last)parent*MWmetab) 
Metabolite to parent ratio for Cmax (M/PCmax) calculated as:  
(Cmax metab*MWparent) / (Cmax parent*MWmetab) 
Molecular Weight (MW) Table: 
Analyte 
Molecular Weight (g/mol) 
NKTR-181 (parent) 
595.72 
Oxycodol (metabolite) 
317.38 
Oxycodone (metabolite) 
315.36 
 
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4.2 
Pharmacokinetic Evaluation based on Sparse Sampling Data 
NKTR-181 concentration-time data at each dose level and study visit during Treatment period 
will be pooled from all subjects and described by descriptive statistics to evaluate trends in drug 
concentrations with dose and study visits. No formal statistical tests will be conducted. 
Furthermore, visual inspection of drug concentrations at each dose level and study visit will be 
performed. Only patients on a stable dose level will be included in the graphical analysis.   
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5.0 
PK ANALYSIS POPULATION 
5.1 
PK Sub-Study Population  
The PK sub-study population included all subjects in the PK subgroup who received NKTR-181 
and had relatively complete individual analyte concentration-time profiles that allow 
computation of meaningful PK parameter values.  Subjects with pre-dose BLQ levels in the PK 
sub-study population will be excluded from the descriptive summary tables.  The number and % 
of subjects with pre-dose BLQ samples will be tabulated by dose level and overall. 
5.2 
Sparse Sampling PK Population  
Subjects who received at least one dose of NKTR-181 and had at least one plasma sample will 
be included in the sparse sampling PK population. The PK analysis data set will include all 
plasma samples from all subjects with the following exceptions: Subjects with only pre-first dose 
NKTR-181 concentration available for the entire duration of the study and post-dose samples 
with BLQ concentrations. 
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6.0 
PHARMACOKINETIC DATA EVALUATION 
6.1 
Bioanalysis of Plasma Samples 
Concentrations of NKTR-181, oxycoldol, and oxycodone in plasma samples will be assayed 
using validated methods.  NKTR-181 levels will be analyzed for both spare samples and PK 
subgroup samples. Oxycodol and oxycodone levels will be analyzed for the PK subgroup 
samples only. 
For the purpose of the PK analysis, plasma concentration values reported as below the limit of 
quantification (BLQ) will be treated as zero for pre-dose samples.  Plasma concentrations values 
reported as BLQ at all other times will be considered as missing.  Concentration values in any 
sample matrix reported as NR (not received) or NA (not analyzed) will be treated as missing 
values.   
Unreliable results, such as those arising from procedural errors during conduct of the study or 
analytical errors will not be used.   
6.2 
Calculation of Plasma Drug Pharmacokinetic Parameters 
All parameter values listed in Section 4.0 will be determined by non-compartmental analysis.  
PK parameter calculations will be based on the actual sampling times.  Calculation of AUC will 
be performed using linear trapezoidal rule.   
  
6.3 
Presentation of Individual and Mean Plasma Drug Concentrations and PK 
Paramters 
6.3.1 
Listings and Tables 
Listings for blood collection dates and times will be generated by subject, and treatment.  
Sampling time deviations will be computed as differences between scheduled (nominal) and 
actual sampling times and expressed in minutes and as a percentage of the nominal time.   
Plasma analyte concentrations at each nominal PK sampling time will be tabulated by treatment 
using descriptive statistics, including the number of observations (n), n listed as BLQ, arithmetic 
mean, geometric mean, standard deviation, standard error of the mean (SEM), CV%, median, 
minimum and maximum.  Missing and BLQ concentration values will be treated using the 
criteria provided in Section 6.1.  Missing concentration values will not be included in the 
descriptive statistics.   
For the PK sub-study, plasma PK parameters will be listed by subjects and summarized by dose 
level using descriptive statistics, including, n, geometric mean, mean, standard deviation, CV%, 
median, minimum and maximum.   
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For sparse PK sampling, number of subjects and samples at each dose level and study visit will 
be tabulated and summarized using descriptive statistics, including, n, median,  and range.  
6.3.2 
Plots 
The following plots will be generated for the PK sub-study population: 
Plots of individual plasma NKTR-181, oxycoldol, and oxycodone concentration versus 
actual time on linear and semi-log scales for each subject by treatment.   
Overlay plots of mean ( SEM) plasma NKTR-181, oxycoldol, and oxycodone 
concentrations in each treatment versus nominal time on linear and semi-log scales. 
Overlay plots of mean ( SEM) concentration versus nominal time for all treatments by 
analyte on linear and semi-log scales 
Spaghetti plots of individual plasma concentration versus nominal time for all subjects by 
treatment by analyte on linear and semi-log scales   
The following plots will be generated for the sparse PK population: 
Plots of plasma NKTR-181 concentrations by dose and study visit for subjects who enter 
the Stable dose Treatment Period.  
6.4 
Reporting Conventions 
Rounding for the reporting of PK parameters will be 3 significant figures except Cmax and AUC 
for NKTR-181 oxycodol, and oxycodone which will be rounded to 4 significant figures.  The 
same convention will be followed for descriptive statistics, except for n, which will be rounded 
to the whole value.  Descriptive statistics will not be performed if n3 and summary tables will 
only include median, minimum, and maximum.  .  Percentages presented in tables will be 
rounded to one decimal place.  If “%” is part of the column heading, do not repeat the “%” sign 
in the body of the table.   
16.1.9 Documentation of Statistical Methods
Confidential and Proprietary
Clinical Study Report 14-181-08
NKTR-181
Nektar Therapeutics
30 April 2018
Page 41 of 42


Protocol No.: 14-181-08 Pharmacokinetic Analysis Plan 
 
NKTR-181 
Nektar Therapeutics 
 
Page 13 of 13 
Confidential and Proprietary 
 
17 October 2017 
7.0 
REFERENCES 
1. 
Clinical Study Protocol Number 14-181-08.   
16.1.9 Documentation of Statistical Methods
Confidential and Proprietary
Clinical Study Report 14-181-08
NKTR-181
Nektar Therapeutics
30 April 2018
Page 42 of 42