Assessment of efficacy and safety in patients with non-cancer-related pain and opioid-induced constipation

Study identifier:D3820C00005

ClinicalTrials.gov identifier:N/A

EudraCT identifier:2011-001986-41

CTIS identifier:N/A

Study Complete

Official Title

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of NKTR-118 in Patients with Non-Cancer-Related Pain and Opioid-Induced Constipation (OIC)

Medical condition

Opioid-Induced Constipation (OIC)

Phase

Phase 3

Healthy volunteers

Study drug

NKTR-118, Placebo

Sex

All

Actual Enrollment

744

Study type

Interventional

Age

18 Years - 84 Years

Date

Study Start Date: 01 Mar 2011

Primary Completion Date: 01 Sept 2012

Study Completion Date: 01 Sept 2012

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Oct 2014 by AstraZeneca Pharmaceuticals

Collaborators

Inclusion and exclusion criteria

Location

Research Site

ALMERIA, Spain

Location

Research Site

ANDERSON, SC, United States

Location

Research Site

ANTWERPEN, Belgium

Location

Research Site

AUSTIN, TX, United States

Location

Research Site

AYRSHIRE, AYR, United Kingdom

Location

Research Site

BAJA, Hungary

Location

Research Site

BALTIMORE, MD, United States

Location

Research Site

BARCELONA, CATALUNA, Spain

Arms	Assigned Interventions
Experimental: 1 Oral treatment	Drug: NKTR-118 12.5 mg oral tablet once daily
Experimental: 2 Oral treatment	Drug: NKTR-118 25 mg oral tablet once daily
Placebo Comparator: 3 Oral treatment	Drug: Placebo Placebo to NKTR-118

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
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

Participant Flow: Overall Study

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
STARTED	233	234	233
COMPLETED	178	174	188
NOT COMPLETED	55	60	45
Other	3	2	1
Lost to Follow-up	11	9	9
Study-Specific Withdrawal Criteria	0	3	3
Lack of Efficacy	3	0	3
Adverse Event	11	24	12
Eligibility Criteria Not Fulfilled	0	0	1
Withdrawal by Subject	23	20	13
Did Not Receive Treatment	2	0	1
Severe non-compliance with protocol	2	2	2

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

A total of 4 patients (2 patients in the NKTR-118 25 mg and 1 patient each in the NKTR-118 12.5 mg and placebo groups) had been previously randomized within the NKTR-118 program at a different study center. These patients were excluded from the ITT and Safety analysis sets. Baseline characteristics are summarized based on the ITT analysis set.

Reporting Groups

	Description
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

Baseline Measures

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo	Total
Number of Participants [units: Participants]	232	232	232	696
Age Continuous [units: Years] Mean ± Standard Deviation	52.0 ± 11.02	51.9 ± 12.11	52.3 ± 11.62	52.1 ± 11.58
Gender, Male/Female [units: Participants]
Female	149	147	145	441
Male	83	85	87	255
Race/Ethnicity, Customized [units: Participants]
American Indian or Alaska Native	1	1	2	4
Asian	1	0	0	1
Native Hawaiian or Other Pacific Islander	0	1	0	1
Black or African American	41	40	44	125
White	187	189	183	559
Other	2	1	3	6
Baseline laxative response status ^[1] [units: Participants]
Laxative Inadequate Response (LIR)	125	124	121	370
Laxative Adequate Response (LAR)	5	5	4	14
Laxative Unknown Response (LUR)	102	103	107	312

Outcome Measures

1. Primary Outcome Measure: Response (responder/non-responder) to study drug during Weeks 1 to 12 [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Primary
Measure Name	Response (responder/non-responder) to study drug during Weeks 1 to 12
Measure Description	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.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	232	232	232
Response (responder/non-responder) to study drug during Weeks 1 to 12 [units: Number of patients]	81	92	68

Statistical Analysis 1 for Response (responder/non-responder) to study drug during Weeks 1 to 12

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Cochran-Mantel-Haenszel
P-Value^[4]	0.202
Risk Ratio (RR)^[5]	1.188
95% Confidence Interval	( 0.911 to 1.548 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via Cochran Mantel-Haenszel test stratified by response to laxatives at baseline (LIR, LAR, LUR).
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Response (responder/non-responder) to study drug during Weeks 1 to 12

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Cochran-Mantel-Haenszel
P-Value^[4]	0.021
Risk Ratio (RR)^[5]	1.348
95% Confidence Interval	( 1.045 to 1.739 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via Cochran Mantel-Haenszel test stratified by response to laxatives at baseline (LIR, LAR, LUR).
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Response (responder/non-responder) to study drug in the LIR subgroup during Weeks 1 to 12 [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Secondary
Measure Name	Response (responder/non-responder) to study drug in the LIR subgroup during Weeks 1 to 12
Measure Description	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.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	125	124	121
Response (responder/non-responder) to study drug in the LIR subgroup during Weeks 1 to 12 [units: Number of patients]	53	58	38

Statistical Analysis 1 for Response (responder/non-responder) to study drug in the LIR subgroup during Weeks 1 to 12

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Cochran-Mantel-Haenszel
P-Value^[4]	0.074
Risk Ratio (RR)^[5]	1.350
95% Confidence Interval	( 0.967 to 1.884 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Response rate over Weeks 1 to 12 in the LIR subgroup is a key secondary endpoint included in the multiple testing procedure.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Response (responder/non-responder) to study drug in the LIR subgroup during Weeks 1 to 12

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Cochran-Mantel-Haenszel
P-Value^[4]	0.014
Risk Ratio (RR)^[5]	1.489
95% Confidence Interval	( 1.078 to 2.058 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Response rate over Weeks 1 to 12 in the LIR subgroup is a key secondary endpoint included in the multiple testing procedure.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Time (in hours) to first post-dose laxation without the use of rescue laxatives within the previous 24 hours [ Time Frame: 12 weeks ]

Measure Type	Secondary
Measure Name	Time (in hours) to first post-dose laxation without the use of rescue laxatives within the previous 24 hours
Measure Description
Time Frame	12 weeks
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	232	232	232
Time (in hours) to first post-dose laxation without the use of rescue laxatives within the previous 24 hours [units: Hours] Median (95% Confidence Interval)	19.3 (9.4 to 22.3)	12.0 (7.0 to 21.5)	37.2 (30.0 to 46.9)

No statistical analysis provided for Time (in hours) to first post-dose laxation without the use of rescue laxatives within the previous 24 hours

4. Secondary Outcome Measure: Change from baseline in mean number of days per week with at least 1 SBM during Weeks 1 to 12 [ Time Frame: 12 weeks ]

Measure Type	Secondary
Measure Name	Change from baseline in mean number of days per week with at least 1 SBM during Weeks 1 to 12
Measure Description
Time Frame	12 weeks
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	228	226	231
Change from baseline in mean number of days per week with at least 1 SBM during Weeks 1 to 12 [units: Number of Days] Least Squares Mean (Standard Error)	2.12 (0.12)	2.41 (0.13)	1.73 (0.12)

Statistical Analysis 1 for Change from baseline in mean number of days per week with at least 1 SBM during Weeks 1 to 12

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.010
Other^[5]	0.39
95% Confidence Interval	( 0.09 to 0.69 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via Mixed Model Repeated Measures (MMRM) with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in mean number of days per week with at least 1 SBM during Weeks 1 to 12

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	0.68
95% Confidence Interval	( 0.37 to 0.98 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Change from baseline in degree of straining [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Secondary
Measure Name	Change from baseline in degree of straining
Measure Description	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.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	228	226	231
Change from baseline in degree of straining [units: units on a scale] Least Squares Mean (Standard Error)	-0.67 (0.06)	-0.80 (0.06)	-0.48 (0.06)

Statistical Analysis 1 for Change from baseline in degree of straining

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.005
Other^[5]	-0.19
95% Confidence Interval	( -0.32 to -0.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in degree of straining

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	-0.32
95% Confidence Interval	( -0.45 to -0.18 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Change from baseline in stool consistency (Bristol stool scale) [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Secondary
Measure Name	Change from baseline in stool consistency (Bristol stool scale)
Measure Description	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.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	228	226	231
Change from baseline in stool consistency (Bristol stool scale) [units: units on a scale] Least Squares Mean (Standard Error)	0.54 (0.07)	0.71 (0.07)	0.26 (0.06)

Statistical Analysis 1 for Change from baseline in stool consistency (Bristol stool scale)

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.001
Other^[5]	0.28
95% Confidence Interval	( 0.12 to 0.45 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in stool consistency (Bristol stool scale)

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	0.45
95% Confidence Interval	( 0.29 to 0.62 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Change from baseline in percent numbers of days with a CSBM (complete spontaneous bowel movement) [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Secondary
Measure Name	Change from baseline in percent numbers of days with a CSBM (complete spontaneous bowel movement)
Measure Description	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.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	228	226	231
Change from baseline in percent numbers of days with a CSBM (complete spontaneous bowel movement) [units: units on a scale] Least Squares Mean (Standard Error)	23.48 (1.88)	27.20 (1.93)	16.76 (1.86)

Statistical Analysis 1 for Change from baseline in percent numbers of days with a CSBM (complete spontaneous bowel movement)

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.002
Other^[5]	6.72
95% Confidence Interval	( 2.37 to 11.06 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in percent numbers of days with a CSBM (complete spontaneous bowel movement)

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	10.43
95% Confidence Interval	( 6.03 to 14.84 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

8. Secondary Outcome Measure: Change from baseline in mean spontaneous bowel movements/week [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Secondary
Measure Name	Change from baseline in mean spontaneous bowel movements/week
Measure Description	The number of spontaneous bowel movements/week was determined from the patient's eDiary.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	228	226	231
Change from baseline in mean spontaneous bowel movements/week [units: units on a scale] Least Squares Mean (Standard Error)	2.62 (0.18)	3.14 (0.19)	2.10 (0.18)

Statistical Analysis 1 for Change from baseline in mean spontaneous bowel movements/week

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.028
Other^[5]	0.52
95% Confidence Interval	( 0.06 to 0.98 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in mean spontaneous bowel movements/week

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	1.04
95% Confidence Interval	( 0.58 to 1.51 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response (LIR, non-LIR), treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

9. Secondary Outcome Measure: 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 [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Secondary
Measure Name	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
Measure Description	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.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	125	124	121
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 [units: hours] Median (95% Confidence Interval)	12.8 (6.4 to 21.9)	18.1 (6.5 to 22.8)	38.2 (28.9 to 57.4)

No statistical analysis provided for 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

10. Secondary Outcome Measure: Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM) [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Secondary
Measure Name	Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)
Measure Description	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. A negative change from baseline indicates improvement.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	173	165	184
Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM) [units: units on a scale] Least Squares Mean (Standard Error)
Total score	-0.75 (0.05)	-0.81 (0.05)	-0.63 (0.05)
Abdominal symptoms subscore	-0.67 (0.06)	-0.62 (0.06)	-0.72 (0.06)
Rectal symptoms subscore	-0.59 (0.05)	-0.71 (0.05)	-0.47 (0.05)
Stool symptoms subscore	-0.93 (0.07)	-1.04 (0.07)	-0.66 (0.07)

Statistical Analysis 1 for Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.080
Other^[5]	-0.12
95% Confidence Interval	( -0.26 to 0.01 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Analysis for change in PAC-SYM total score from baseline (Week 1) to end of treatment (Week 12)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.011
Other^[5]	-0.18
95% Confidence Interval	( -0.32 to -0.04 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Analysis for change in PAC-SYM total score from baseline (Week 1) to end of treatment (Week 12)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.552
Slope^[5]	0.05
95% Confidence Interval	( -0.11 to 0.20 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Analysis for change in PAC-SYM abdominal symptoms subscore from baseline (Week 1) to end of treatment (Week 12)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.236
Other^[5]	0.09
95% Confidence Interval	( -0.06 to 0.25 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Analysis for change in PAC-SYM abdominal symptoms subscore from baseline (Week 1) to end of treatment (Week 12)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.095
Other^[5]	-0.11
95% Confidence Interval	( -0.24 to 0.02 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Analysis for change in PAC-SYM rectal symptoms subscore from baseline (Week 1) to end of treatment (Week 12)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	-0.24
95% Confidence Interval	( -0.37 to -0.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Analysis for change in PAC-SYM rectal symptoms subscore from baseline (Week 1) to end of treatment (Week 12)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 7 for Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.002
Other^[5]	-0.27
95% Confidence Interval	( -0.44 to -0.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Analysis for change in PAC-SYM stool symptoms subscore from baseline (Week 1) to end of treatment (Week 12)
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 8 for Change from baseline in Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM)

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	-0.38
95% Confidence Interval	( -0.56 to -0.21 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Analysis for change in PAC-SYM stool symptoms subscore from baseline (Week 1) to end of treatment (Week 12)
[5]	Other relevant estimation information:
	No text entered.

11. Secondary Outcome Measure: Change from baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain [ Time Frame: Baseline (Week 1) to end of treatment (Week 12) ]

Measure Type	Secondary
Measure Name	Change from baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain
Measure Description	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). A negative change from baseline indicates improvement.
Time Frame	Baseline (Week 1) to end of treatment (Week 12)
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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

Measured Values

	NKTR-118 12.5 mg	NKTR-118 25 mg	Placebo
Number of Participants Analyzed [units:participants]	168	167	185
Change from baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain [units: units on a scale] Least Squares Mean (Standard Error)	-1.12 (0.09)	-1.30 (0.09)	-0.81 (0.09)

Statistical Analysis 1 for Change from baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain

Groups^[1]	NKTR-118 12.5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	0.011
Other^[5]	-0.31
95% Confidence Interval	( -0.54 to -0.07 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Change from baseline in Patient Assessment of Constipation Quality of Life (PAC-QOL) Satisfaction Domain

Groups^[1]	NKTR-118 25 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.001
Other^[5]	-0.49
95% Confidence Interval	( -0.73 to -0.25 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis via MMRM with fixed effects for baseline, baseline laxative response, treatment and treatment time interaction. Study pooled center is included as a random effect.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Reporting Groups

	Description
NKTR-118 12.5 mg	No text entered.
NKTR-118 25 mg	No text entered.
Placebo	No text entered.

Serious Adverse Events

NKTR-118 12.5 mg

NKTR-118 25 mg

Placebo

Total, serious adverse events

# participants affected / at risk

14/230 (6.09%)

8/232 (3.45%)

12/231 (5.19%)

CARDIAC DISORDERS

ACUTE MYOCARDIAL INFARCTION¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

CARDIAC DISORDERS

ANGINA PECTORIS¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

EAR AND LABYRINTH DISORDERS

VERTIGO¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

GASTROINTESTINAL DISORDERS

ABDOMINAL PAIN¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

GASTROINTESTINAL DISORDERS

DIARRHOEA¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

GASTROINTESTINAL DISORDERS

PANCREATITIS¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

GASTROINTESTINAL DISORDERS

RECTAL HAEMORRHAGE¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

INFECTIONS AND INFESTATIONS

PNEUMONIA¹,^†

# participants affected / at risk

1/230 (0.43%)

1/232 (0.43%)

0/231 (0.00%)

# events

INFECTIONS AND INFESTATIONS

POSTOPERATIVE WOUND INFECTION¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

INFECTIONS AND INFESTATIONS

SEPSIS¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

INFECTIONS AND INFESTATIONS

URINARY TRACT INFECTION¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

INFECTIONS AND INFESTATIONS

WOUND INFECTION STAPHYLOCOCCAL¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

ACCIDENTAL OVERDOSE¹,^†

# participants affected / at risk

2/230 (0.87%)

0/232 (0.00%)

0/231 (0.00%)

# events

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

BRAIN CONTUSION¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

POST LAMINECTOMY SYNDROME¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

SUBDURAL HAEMORRHAGE¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

INVESTIGATIONS

CHEST X-RAY ABNORMAL¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

INVESTIGATIONS

CSF CULTURE POSITIVE¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

METABOLISM AND NUTRITION DISORDERS

DEHYDRATION¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

INTERVERTEBRAL DISC DEGENERATION¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

1/231 (0.43%)

# events

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

OSTEOARTHRITIS¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

OSTEONECROSIS¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

NERVOUS SYSTEM DISORDERS

APHASIA¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

NERVOUS SYSTEM DISORDERS

GRAND MAL CONVULSION¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

NERVOUS SYSTEM DISORDERS

MIGRAINE¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

NERVOUS SYSTEM DISORDERS

PARAESTHESIA¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

NERVOUS SYSTEM DISORDERS

SYNCOPE¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

PSYCHIATRIC DISORDERS

ALCOHOL ABUSE¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

PSYCHIATRIC DISORDERS

ANXIETY¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

PSYCHIATRIC DISORDERS

DEPRESSION¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

1/231 (0.43%)

# events

PSYCHIATRIC DISORDERS

MAJOR DEPRESSION¹,^†

# participants affected / at risk

0/230 (0.00%)

0/232 (0.00%)

1/231 (0.43%)

# events

PSYCHIATRIC DISORDERS

MENTAL STATUS CHANGES¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

RENAL AND URINARY DISORDERS

NEPHROLITHIASIS¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

RENAL AND URINARY DISORDERS

RENAL FAILURE ACUTE¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

CHRONIC OBSTRUCTIVE PULMONARY DISEASE¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

PULMONARY EMBOLISM¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

RESPIRATORY FAILURE¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

VASCULAR DISORDERS

ACCELERATED HYPERTENSION¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

VASCULAR DISORDERS

HYPERTENSION¹,^†

# participants affected / at risk

1/230 (0.43%)

0/232 (0.00%)

0/231 (0.00%)

# events

VASCULAR DISORDERS

MALIGNANT HYPERTENSION¹,^†

# participants affected / at risk

0/230 (0.00%)

1/232 (0.43%)

0/231 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 15.0

Other Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	2%

Reporting Groups

	Description
NKTR-118 12.5 mg	No text entered.
NKTR-118 25 mg	No text entered.
Placebo	No text entered.

Other Adverse Events

NKTR-118 12.5 mg

NKTR-118 25 mg

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

90/230 (39.13%)

112/232 (48.28%)

73/231 (31.60%)

GASTROINTESTINAL DISORDERS

ABDOMINAL DISTENSION¹,^†

# participants affected / at risk

4/230 (1.74%)

6/232 (2.59%)

5/231 (2.16%)

# events

GASTROINTESTINAL DISORDERS

ABDOMINAL PAIN¹,^†

# participants affected / at risk

27/230 (11.74%)

44/232 (18.97%)

18/231 (7.79%)

# events

GASTROINTESTINAL DISORDERS

ABDOMINAL PAIN UPPER¹,^†

# participants affected / at risk

5/230 (2.17%)

6/232 (2.59%)

3/231 (1.30%)

# events

GASTROINTESTINAL DISORDERS

DIARRHOEA¹,^†

# participants affected / at risk

19/230 (8.26%)

21/232 (9.05%)

10/231 (4.33%)

# events

GASTROINTESTINAL DISORDERS

FLATULENCE¹,^†

# participants affected / at risk

4/230 (1.74%)

14/232 (6.03%)

7/231 (3.03%)

# events

GASTROINTESTINAL DISORDERS

NAUSEA¹,^†

# participants affected / at risk

16/230 (6.96%)

20/232 (8.62%)

11/231 (4.76%)

# events

GASTROINTESTINAL DISORDERS

VOMITING¹,^†

# participants affected / at risk

8/230 (3.48%)

16/232 (6.90%)

9/231 (3.90%)

# events

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

FATIGUE¹,^†

# participants affected / at risk

3/230 (1.30%)

6/232 (2.59%)

3/231 (1.30%)

# events

INFECTIONS AND INFESTATIONS

NASOPHARYNGITIS¹,^†

# participants affected / at risk

3/230 (1.30%)

7/232 (3.02%)

1/231 (0.43%)

# events

INFECTIONS AND INFESTATIONS

SINUSITIS¹,^†

# participants affected / at risk

3/230 (1.30%)

7/232 (3.02%)

4/231 (1.73%)

# events

INFECTIONS AND INFESTATIONS

UPPER RESPIRATORY TRACT INFECTION¹,^†

# participants affected / at risk

4/230 (1.74%)

6/232 (2.59%)

6/231 (2.60%)

# events

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

FALL¹,^†

# participants affected / at risk

6/230 (2.61%)

1/232 (0.43%)

3/231 (1.30%)

# events

INVESTIGATIONS

BLOOD THYROID STIMULATING HORMONE INCREASED¹,^†

# participants affected / at risk

6/230 (2.61%)

0/232 (0.00%)

0/231 (0.00%)

# events

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

ARTHRALGIA¹,^†

# participants affected / at risk

3/230 (1.30%)

5/232 (2.16%)

2/231 (0.87%)

# events

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

BACK PAIN¹,^†

# participants affected / at risk

12/230 (5.22%)

12/232 (5.17%)

4/231 (1.73%)

# events

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

PAIN IN EXTREMITY¹,^†

# participants affected / at risk

5/230 (2.17%)

7/232 (3.02%)

1/231 (0.43%)

# events

NERVOUS SYSTEM DISORDERS

DIZZINESS¹,^†

# participants affected / at risk

8/230 (3.48%)

3/232 (1.29%)

6/231 (2.60%)

# events

NERVOUS SYSTEM DISORDERS

HEADACHE¹,^†

# participants affected / at risk

12/230 (5.22%)

12/232 (5.17%)

8/231 (3.46%)

# events

PSYCHIATRIC DISORDERS

ANXIETY¹,^†

# participants affected / at risk

5/230 (2.17%)

3/232 (1.29%)

4/231 (1.73%)

# events

VASCULAR DISORDERS

HYPERTENSION¹,^†

# participants affected / at risk

1/230 (0.43%)

8/232 (3.45%)

3/231 (1.30%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 15.0

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact

Name/Title:	Mark Sostek
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

Clinical Study Protocol
Download
Clinical_Study_Report_Synopsis_D3820C00005
Download
Trial Results Summaries
Available here

Contacts

Contact

Quintiles Worldwide

+1 877 503 8895

clinical.studies.ns@quintiles.com

Investigators

Principal Investigator

Mark Sostek

AstraZeneca Pharmaceuticals

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Clinical Study Protocol

Clinical_Study_Report_Synopsis_D3820C00005

Trial Results Summaries