Trial Outcomes & Findings for Assessment of Efficacy and Safety in Patients With Non-cancer-related Pain and Opioid-induced Constipation (NCT NCT01323790)

Last Updated: 2015-06-02

Results Overview

Responder was defined as having at least 3 spontaneous bowel movements (SBMs)/week with at least 1 SBM/week increase over baseline for at least 9 out of the 12 treatment weeks and 3 out of the last 4 treatment weeks during the double-blind treatment period. An SBM is a bowel movement occurring 24 hours or more since the last use of rescue medication.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

700 participants

Primary outcome timeframe

Baseline (Week 1) to end of treatment (Week 12)

Results posted on

2015-06-02

Participant Flow

This multicenter study was conducted in Belgium, Croatia, Czech Republic, Hungary, Spain, Sweden, United Kingdom, and the United States between 28 March 2011 and 20 September 2012.

The study duration was up to 18 weeks, consisting of an initial screening period lasting up to 2 weeks, a 2-week OIC confirmation period, during which the diagnosis of OIC and stability of the opioid regimen were confirmed, a 12-week treatment period, and a follow-up visit 2 weeks after the last dose of study drug.

Participant milestones

Participant milestones
Measure	NKTR-118 12.5 mg NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg NKTR-118 25 mg QD, oral treatment	Placebo Placebo QD, oral treatment
Overall Study STARTED	233	234	233
Overall Study COMPLETED	178	174	188
Overall Study NOT COMPLETED	55	60	45

Reasons for withdrawal

Reasons for withdrawal
Measure	NKTR-118 12.5 mg NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg NKTR-118 25 mg QD, oral treatment	Placebo Placebo QD, oral treatment
Overall Study Other	3	2	1
Overall Study Lost to Follow-up	11	9	9
Overall Study Study-Specific Withdrawal Criteria	0	3	3
Overall Study Lack of Efficacy	3	0	3
Overall Study Adverse Event	11	24	12
Overall Study Eligibility Criteria Not Fulfilled	0	0	1
Overall Study Withdrawal by Subject	23	20	13
Overall Study Did Not Receive Treatment	2	0	1
Overall Study Severe non-compliance with protocol	2	2	2

Baseline Characteristics

Assessment of Efficacy and Safety in Patients With Non-cancer-related Pain and Opioid-induced Constipation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	NKTR-118 12.5 mg n=232 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=232 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=232 Participants Placebo QD, oral treatment	Total n=696 Participants Total of all reporting groups
Age, Continuous	52.0 Years STANDARD_DEVIATION 11.02 • n=5 Participants	51.9 Years STANDARD_DEVIATION 12.11 • n=7 Participants	52.3 Years STANDARD_DEVIATION 11.62 • n=5 Participants	52.1 Years STANDARD_DEVIATION 11.58 • n=4 Participants
Sex: Female, Male Female	149 Participants n=5 Participants	147 Participants n=7 Participants	145 Participants n=5 Participants	441 Participants n=4 Participants
Sex: Female, Male Male	83 Participants n=5 Participants	85 Participants n=7 Participants	87 Participants n=5 Participants	255 Participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Black or African American	41 Participants n=5 Participants	40 Participants n=7 Participants	44 Participants n=5 Participants	125 Participants n=4 Participants
Race/Ethnicity, Customized White	187 Participants n=5 Participants	189 Participants n=7 Participants	183 Participants n=5 Participants	559 Participants n=4 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants
Baseline laxative response status Laxative Inadequate Response (LIR)	125 Participants n=5 Participants	124 Participants n=7 Participants	121 Participants n=5 Participants	370 Participants n=4 Participants
Baseline laxative response status Laxative Adequate Response (LAR)	5 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	14 Participants n=4 Participants
Baseline laxative response status Laxative Unknown Response (LUR)	102 Participants n=5 Participants	103 Participants n=7 Participants	107 Participants n=5 Participants	312 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

Population: The ITT analysis set included all randomized patients, with the exception of patients who were found to have randomized multiple times within the program at different centers.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=232 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=232 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=232 Participants Placebo QD, oral treatment
Response (Responder/Non-responder) to Study Drug During Weeks 1 to 12	81 Number of patients	92 Number of patients	68 Number of patients

SECONDARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

Population: The ITT analysis set included all randomized patients, with the exception of patients who were found to have randomized multiple times within the program at different centers. The LIR subgroup used 1 or more laxative classes for at least 4 days in the 2 weeks prior to entry and reported moderate to very severe symptoms.

Responder is defined as having at least 3 SBMs/week, with at least 1 SBM/week increase over baseline for at least 9 out of 12 weeks and at least 3 out of the last 4 weeks.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=125 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=124 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=121 Participants Placebo QD, oral treatment
Response (Responder/Non-responder) to Study Drug in the LIR Subgroup During Weeks 1 to 12	53 Number of patients	58 Number of patients	38 Number of patients

SECONDARY outcome

Timeframe: 12 weeks

Population: The ITT analysis set included all randomized patients, with the exception of patients who were found to have randomized multiple times within the program at different centers.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=232 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=232 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=232 Participants Placebo QD, oral treatment
Time (in Hours) to First Post-dose Laxation Without the Use of Rescue Laxatives Within the Previous 24 Hours	19.3 Hours Interval 9.4 to 22.3	12.0 Hours Interval 7.0 to 21.5	37.2 Hours Interval 30.0 to 46.9

SECONDARY outcome

Timeframe: 12 weeks

Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who were found to have randomized multiple times within the program at different centers.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=228 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=226 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=231 Participants Placebo QD, oral treatment
Change From Baseline in Mean Number of Days Per Week With at Least 1 SBM During Weeks 1 to 12	2.12 Number of Days Standard Error 0.12	2.41 Number of Days Standard Error 0.13	1.73 Number of Days Standard Error 0.12

SECONDARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

A single-item straining question was asked via the eDiary: "How much did you strain during your bowel movement?" Patients responded on a 5 point Likert scale: 1=Not at all; 2=A little bit; 3=A moderate amount; 4=A great deal; 5=An extreme amount. A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=228 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=226 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=231 Participants Placebo QD, oral treatment
Change From Baseline in Degree of Straining	-0.67 units on a scale Standard Error 0.06	-0.80 units on a scale Standard Error 0.06	-0.48 units on a scale Standard Error 0.06

SECONDARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

Patients rated stool consistency through completion of the BSS after each BM. The 7 stool types are: 1. Separate hard lumps, like nuts (hard to pass); 2. Sausage-shaped, but lumpy; 3. Like sausage, but with cracks on its surface; 4. Like a sausage or snake, smooth and soft; 5. Soft blobs with clear cut edges (passed easily); 6. Fluffy pieces with ragged edges, a mushy stool; 7. Watery, no solid pieces. A positive change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=228 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=226 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=231 Participants Placebo QD, oral treatment
Change From Baseline in Stool Consistency (Bristol Stool Scale)	0.54 units on a scale Standard Error 0.07	0.71 units on a scale Standard Error 0.07	0.26 units on a scale Standard Error 0.06

SECONDARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

A single-item question on the completeness of evacuation, developed and validated through 1:1 interviews with OIC patients, was asked via the eDiary: "Did you feel like your bowels were completely empty after the bowel movement?" Patients provided a yes or a no response. A positive change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=228 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=226 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=231 Participants Placebo QD, oral treatment
Change From Baseline in Percent Numbers of Days With a CSBM (Complete Spontaneous Bowel Movement)	23.48 Percent days/week Standard Error 1.88	27.20 Percent days/week Standard Error 1.93	16.76 Percent days/week Standard Error 1.86

SECONDARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

The number of spontaneous bowel movements/week was determined from the patient's eDiary.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=228 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=226 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=231 Participants Placebo QD, oral treatment
Change From Baseline in Mean Spontaneous Bowel Movements/Week	2.62 Number of SBMs/week Standard Error 0.18	3.14 Number of SBMs/week Standard Error 0.19	2.10 Number of SBMs/week Standard Error 0.18

SECONDARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

Population: The ITT analysis set included all randomized patients, with the exception of patients who were found to have randomized multiple times within the program at different centers.

Time to first post-dose laxation without the use of rescue laxatives within the last 24 hours was calculated in hours as: Date/Time of first post-dose laxation without rescue - First dose date/time.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=125 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=124 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=121 Participants Placebo QD, oral treatment
Time (in Hours) to First Post-dose Laxation Without the Use of Rescue Laxatives Within the Previous 24 Hours in the Laxative Inadequate Response (LIR) Subgroup	12.8 hours Interval 6.4 to 21.9	18.1 hours Interval 6.5 to 22.8	38.2 hours Interval 28.9 to 57.4

SECONDARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

Population: The ITT analysis set included all randomized patients who had evaluable data at baseline and post-baseline, with the exception of patients who randomized multiple times at different centers. MMRM analysis includes all patients with baseline and at least 1 post-baseline assessment, while the Ns at Week 12 reflect patients providing data at Week 12.

The PAC-SYM questionnaire is a 12-item questionnaire that evaluates the severity of symptoms of constipation in 3 domains (stool, rectal, and abdominal symptoms) on a 5-point Likert scale ranging from 0 (absent) to 4 (very severe) in the 2 weeks (14 days) prior to assessment. Each domain score is the mean of the non-missing items for that domain. The total score is the mean of all non-missing items (ie, symptoms). The range of the domain or total score is 0 (response is 'absent' for each item) to 4 (response is 'very severe' for each item). A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=173 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=165 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=184 Participants Placebo QD, oral treatment
Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) Total score	-0.75 units on a scale Standard Error 0.05	-0.81 units on a scale Standard Error 0.05	-0.63 units on a scale Standard Error 0.05
Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) Abdominal symptoms subscore	-0.67 units on a scale Standard Error 0.06	-0.62 units on a scale Standard Error 0.06	-0.72 units on a scale Standard Error 0.06
Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) Rectal symptoms subscore	-0.59 units on a scale Standard Error 0.05	-0.71 units on a scale Standard Error 0.05	-0.47 units on a scale Standard Error 0.05
Change From Baseline in Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM) Stool symptoms subscore	-0.93 units on a scale Standard Error 0.07	-1.04 units on a scale Standard Error 0.07	-0.66 units on a scale Standard Error 0.07

SECONDARY outcome

Timeframe: Baseline (Week 1) to end of treatment (Week 12)

The PAC-QOL scale is a 28-item self-report instrument designed to evaluate the burden of constipation on patients' everyday functioning and well-being in the 2 weeks (14 days) prior to assessment. Each item is rated on a 5-point Likert scale ranging from 0 (not at all) to 4 (extremely). The instrument can be used to generate an overall score, but is also reported to assess 4 specific constipation-related domains including: 1) Worries and concerns (11 items), 2) Physical discomfort (4 items), 3) Psychosocial discomfort (8 items), and 4) Satisfaction (5 items). Each domain score is the mean of the non-missing items for that domain. The total score is the mean of all non-missing items. The range of the domain or total score is 0 (response is 'not at all' for each item) to 4 (response is 'extremely' for each item). A negative change from baseline indicates improvement.

Outcome measures

Outcome measures
Measure	NKTR-118 12.5 mg n=168 Participants NKTR-118 12.5 QD, oral treatment	NKTR-118 25 mg n=167 Participants NKTR-118 25 mg QD, oral treatment	Placebo n=185 Participants Placebo QD, oral treatment
Change From Baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain	-1.12 units on a scale Standard Error 0.09	-1.30 units on a scale Standard Error 0.09	-0.81 units on a scale Standard Error 0.09

Adverse Events

NKTR-118 12.5 mg

Serious events: 14 serious events

Other events: 90 other events

Deaths: 0 deaths

NKTR-118 25 mg

Serious events: 8 serious events

Other events: 112 other events

Deaths: 0 deaths

Placebo

Serious events: 12 serious events

Other events: 73 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Mark Sostek

AstraZeneca

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	NKTR-118 12.5 mg n=230 participants at risk	NKTR-118 25 mg n=232 participants at risk	Placebo n=231 participants at risk
Cardiac disorders ACUTE MYOCARDIAL INFARCTION	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Cardiac disorders ANGINA PECTORIS	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Ear and labyrinth disorders VERTIGO	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders ABDOMINAL PAIN	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders DIARRHOEA	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders PANCREATITIS	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders RECTAL HAEMORRHAGE	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Infections and infestations PNEUMONIA	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Infections and infestations POSTOPERATIVE WOUND INFECTION	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Infections and infestations SEPSIS	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Infections and infestations URINARY TRACT INFECTION	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Infections and infestations WOUND INFECTION STAPHYLOCOCCAL	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Injury, poisoning and procedural complications ACCIDENTAL OVERDOSE	0.87% 2/230 • Number of events 2 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Injury, poisoning and procedural complications BRAIN CONTUSION	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Injury, poisoning and procedural complications POST LAMINECTOMY SYNDROME	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Injury, poisoning and procedural complications SUBDURAL HAEMORRHAGE	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Investigations CHEST X-RAY ABNORMAL	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Investigations CSF CULTURE POSITIVE	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Metabolism and nutrition disorders DEHYDRATION	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Musculoskeletal and connective tissue disorders INTERVERTEBRAL DISC DEGENERATION	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Musculoskeletal and connective tissue disorders OSTEOARTHRITIS	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Musculoskeletal and connective tissue disorders OSTEONECROSIS	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Nervous system disorders APHASIA	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Nervous system disorders GRAND MAL CONVULSION	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Nervous system disorders MIGRAINE	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Nervous system disorders PARAESTHESIA	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Nervous system disorders SYNCOPE	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Psychiatric disorders ALCOHOL ABUSE	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Psychiatric disorders ANXIETY	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Psychiatric disorders DEPRESSION	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Psychiatric disorders MAJOR DEPRESSION	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Psychiatric disorders MENTAL STATUS CHANGES	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Renal and urinary disorders NEPHROLITHIASIS	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Renal and urinary disorders RENAL FAILURE ACUTE	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders CHRONIC OBSTRUCTIVE PULMONARY DISEASE	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders PULMONARY EMBOLISM	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Respiratory, thoracic and mediastinal disorders RESPIRATORY FAILURE	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Vascular disorders ACCELERATED HYPERTENSION	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Vascular disorders HYPERTENSION	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Vascular disorders MALIGNANT HYPERTENSION	0.00% 0/230 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.

Measure	NKTR-118 12.5 mg n=230 participants at risk	NKTR-118 25 mg n=232 participants at risk	Placebo n=231 participants at risk
Gastrointestinal disorders ABDOMINAL DISTENSION	1.7% 4/230 • Number of events 4 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	2.6% 6/232 • Number of events 6 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	2.2% 5/231 • Number of events 5 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders ABDOMINAL PAIN	11.7% 27/230 • Number of events 27 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	19.0% 44/232 • Number of events 44 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	7.8% 18/231 • Number of events 18 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders ABDOMINAL PAIN UPPER	2.2% 5/230 • Number of events 5 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	2.6% 6/232 • Number of events 6 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.3% 3/231 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders DIARRHOEA	8.3% 19/230 • Number of events 19 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	9.1% 21/232 • Number of events 21 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	4.3% 10/231 • Number of events 10 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders FLATULENCE	1.7% 4/230 • Number of events 4 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	6.0% 14/232 • Number of events 14 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	3.0% 7/231 • Number of events 7 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders NAUSEA	7.0% 16/230 • Number of events 16 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	8.6% 20/232 • Number of events 20 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	4.8% 11/231 • Number of events 11 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Gastrointestinal disorders VOMITING	3.5% 8/230 • Number of events 8 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	6.9% 16/232 • Number of events 16 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	3.9% 9/231 • Number of events 9 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
General disorders FATIGUE	1.3% 3/230 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	2.6% 6/232 • Number of events 6 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.3% 3/231 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Infections and infestations NASOPHARYNGITIS	1.3% 3/230 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	3.0% 7/232 • Number of events 7 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Infections and infestations SINUSITIS	1.3% 3/230 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	3.0% 7/232 • Number of events 7 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.7% 4/231 • Number of events 4 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	1.7% 4/230 • Number of events 4 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	2.6% 6/232 • Number of events 6 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	2.6% 6/231 • Number of events 6 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Injury, poisoning and procedural complications FALL	2.6% 6/230 • Number of events 6 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/232 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.3% 3/231 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Investigations BLOOD THYROID STIMULATING HORMONE INCREASED	2.6% 6/230 • Number of events 6 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/232 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.00% 0/231 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Musculoskeletal and connective tissue disorders ARTHRALGIA	1.3% 3/230 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	2.2% 5/232 • Number of events 5 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.87% 2/231 • Number of events 2 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Musculoskeletal and connective tissue disorders BACK PAIN	5.2% 12/230 • Number of events 12 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	5.2% 12/232 • Number of events 12 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.7% 4/231 • Number of events 4 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Musculoskeletal and connective tissue disorders PAIN IN EXTREMITY	2.2% 5/230 • Number of events 5 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	3.0% 7/232 • Number of events 7 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	0.43% 1/231 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Nervous system disorders DIZZINESS	3.5% 8/230 • Number of events 8 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.3% 3/232 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	2.6% 6/231 • Number of events 6 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Nervous system disorders HEADACHE	5.2% 12/230 • Number of events 12 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	5.2% 12/232 • Number of events 12 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	3.5% 8/231 • Number of events 8 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Psychiatric disorders ANXIETY	2.2% 5/230 • Number of events 5 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.3% 3/232 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.7% 4/231 • Number of events 4 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.
Vascular disorders HYPERTENSION	0.43% 1/230 • Number of events 1 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	3.4% 8/232 • Number of events 8 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.	1.3% 3/231 • Number of events 3 Adverse Events are reported for those subjects who were randomized and receieved at least one dose of study treatment.