Trial Outcomes & Findings for Efficacy and Safety Study of NKTR-181 in Opioid-Naive Subjects With Low Back Pain (NCT NCT02362672)

NCT ID: NCT02362672

Last Updated: 2020-09-16

Results Overview

The daily pain intensity is an 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1189 participants
• Primary outcome timeframe: 12 Weeks of randomized double blinded period
• Results posted on: 2020-09-16

Participant Flow

First subject screened: 11Mar2015; Last subject out: 28 Dec 2016. The study was conducted at 55 medical/research sites in the United States.

The titration phase of the study was designed to titrate patients to a dose of NKTR-181 that provided adequate analgesia and acceptable side effects.

Participant milestones

Measure	NKTR-181 (Open-label Titration Phase) NKTR-181 100-400 mg twice daily tablets	NKTR-181 (Double-blind Treatment Phase) NKTR-181: 100-400 mg twice daily tablets	Placebo (Double-blind Treatment Phase) Placebo: Placebo, twice daily tablets
Titration Phase STARTED	1189	0	0
Titration Phase COMPLETED	610	0	0
Titration Phase NOT COMPLETED	579	0	0
Double-blind Maintenance Phase STARTED	0	309	301
Double-blind Maintenance Phase COMPLETED	0	249	242
Double-blind Maintenance Phase NOT COMPLETED	0	60	59

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Efficacy and Safety Study of NKTR-181 in Opioid-Naive Subjects With Low Back Pain

Baseline characteristics by cohort

Measure	NKTR-181 n=309 Participants NKTR-181 (Double-blind Treatment Phase)	Placebo n=301 Participants Placebo (Double-blind Treatment Phase)	Total n=610 Participants Total of all reporting groups
Age, Continuous	52.0 years STANDARD_DEVIATION 12.7 • n=5 Participants	50.7 years STANDARD_DEVIATION 12.5 • n=7 Participants	51.4 years STANDARD_DEVIATION 12.6 • n=5 Participants
Sex: Female, Male Female	187 Participants n=5 Participants	170 Participants n=7 Participants	357 Participants n=5 Participants
Sex: Female, Male Male	122 Participants n=5 Participants	131 Participants n=7 Participants	253 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Black or African American	95 Participants n=5 Participants	93 Participants n=7 Participants	188 Participants n=5 Participants
Race (NIH/OMB) White	205 Participants n=5 Participants	196 Participants n=7 Participants	401 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Screening Baseline Pain Intensity in Numeric Rating Scale (NRS)	6.7 units on a scale STANDARD_DEVIATION 0.9 • n=5 Participants	6.8 units on a scale STANDARD_DEVIATION 0.9 • n=7 Participants	6.73 units on a scale STANDARD_DEVIATION 0.9 • n=5 Participants

PRIMARY outcome

Timeframe: 12 Weeks of randomized double blinded period

Population: The analysis set (N=610) is the intention-to-treat population, which was defined as all randomized subjects

The daily pain intensity is an 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain).

Outcome measures

Measure	NKTR-181 n=309 Participants NKTR-181 (Double-blind Treatment Phase)	Placebo n=301 Participants Placebo (Double-blind Treatment Phase)
The Change in Weekly (ie, 7-day Average) Pain Score at the End of Double-blind, Randomized Treatment Period, Relative to the Weekly Score at the End of Titration (Double-blind Baseline)	0.9 units on a scale Standard Error 0.11	1.5 units on a scale Standard Error 0.11

SECONDARY outcome

Timeframe: Screening Baseline through Week 12

A responder is defined by the Sponsor as a randomized subject who completes the double-blind Randomized Treatment Period and experiences improvement in the Week 12 Weekly Pain Score from Screening Pain Score. This includes the proportion of responders with at least 30% and at least 50% reduction in pain intensity.

Outcome measures

Measure	NKTR-181 n=309 Participants NKTR-181 (Double-blind Treatment Phase)	Placebo n=301 Participants Placebo (Double-blind Treatment Phase)
Responder Analysis Based on Percent Reduction in Pain Intensity Subjects with 30% improvement	220 Participants	172 Participants
Responder Analysis Based on Percent Reduction in Pain Intensity Subjects with 50% improvement	158 Participants	114 Participants

SECONDARY outcome

Timeframe: Screening Baseline through Week 12

The PGIC assesses the change in overall status relative to the initiation of the treatment. The scale measures global change of overall status on a 7-point scale (1 = No change (or condition has got worse), 2 = Almost the same, 3 = A little better, 4 = Somewhat better, 5 = Moderately better, 6 = Better, 7 = A great deal better). The proportion of subjects responding " A great deal better " and "better" was summarized by treatment group.

Outcome measures

Measure	NKTR-181 n=309 Participants NKTR-181 (Double-blind Treatment Phase)	Placebo n=301 Participants Placebo (Double-blind Treatment Phase)
Patient Global Impression of Change (PGIC): Number of Responders	159 Participants	100 Participants

SECONDARY outcome

Timeframe: Screening Baseline through Week 12

Population: The MOS Sleep-R was analyzed and presented as a change from Screening Baseline to Week 12 in double blinded treatment period. Subjects who discontinued from treatment early were not included in this analysis.

The MOS Sleep Scale measure sleep parameters contains 12 items. Eleven of them scored using a 5-point response scale and across 5 dimensions of sleep, including disturbance (4 items), sleep problems index (9 items), somnolence (3 items), adequacy (2 items), and respiratory impairments (2 items). The original survey items are converted to a 0 to 100 range (by Converting 1 to 0, 2 to 25, 3 to 50, 4 to 75, and 5 to 100). Items in each dimension (disturbance, sleep problems index, somnolence, adequacy, respiratory impairments) of sleep are averaged together to create the score for the scale. The range of each sleep dimension is from 0 to 100. Higher score of sleep disturbance, somnolence, sleep indices, and respiratory impairments indicates relatively worse sleep problem, whereas lower scores for sleep adequacy indicate worse sleep problems.

Outcome measures

Measure	NKTR-181 n=254 Participants NKTR-181 (Double-blind Treatment Phase)	Placebo n=253 Participants Placebo (Double-blind Treatment Phase)
Change in Sleep Quality in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R) Sleep Disturbance	-16.7 units on a scale Standard Deviation 23.9	-9.5 units on a scale Standard Deviation 22.8
Change in Sleep Quality in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R) Sleep Problems Index	-11.6 units on a scale Standard Deviation 18.9	-6.9 units on a scale Standard Deviation 18.4
Change in Sleep Quality in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R) Respiratory Impairments	-3.5 units on a scale Standard Deviation 18.9	-2.2 units on a scale Standard Deviation 18.6
Change in Sleep Quality in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R) Sleep Adequacy	9.1 units on a scale Standard Deviation 26.1	4.0 units on a scale Standard Deviation 25.6
Change in Sleep Quality in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R) Somnolence	-6.1 units on a scale Standard Deviation 21.0	-7.4 units on a scale Standard Deviation 21.8

SECONDARY outcome

Timeframe: Screening Baseline through Week 12

The 12 items of the MOS Sleep Scale measure sleep parameters across 6 dimensions of sleep, including disturbance (4 items), sleep problems index (9 items), quantity (1 item), somnolence (3 items), adequacy (2 items), and respiratory impairments (2 items). One of the 12 items, Sleep quantity, records the actual number of hours slept. Reported here is the sleep quantity.

Outcome measures

Measure	NKTR-181 n=254 Participants NKTR-181 (Double-blind Treatment Phase)	Placebo n=253 Participants Placebo (Double-blind Treatment Phase)
Change in Sleep Quantity Measure in Hours in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R)	0.3 hours Standard Deviation 1.1	0.2 hours Standard Deviation 1.2

SECONDARY outcome

Timeframe: Screening Baseline through Week 12

Population: The RMDQ was analyzed and presented as a change from Screening Baseline to Week 12 in double blinded treatment period. Subjects who discontinued from treatment early were not included in this analysis.

The RMDQ contains 24 items that is used to quantify the impact of low back pain on subject's ability to perform daily activities, mood and sleep. The questionnaire consists of 24 statements derived from the Sickness Impact Profile, with the addition of the phrase "because of my back." The questionnaire covers the areas of mobility, self-care, and sleeping.

The RMDQ score is the total number of items checked which is from a minimum of 0 to a maximum of 24; the greater the score the grater the physical disability due to lower back pain.

Outcome measures

Measure	NKTR-181 n=254 Participants NKTR-181 (Double-blind Treatment Phase)	Placebo n=253 Participants Placebo (Double-blind Treatment Phase)
Change in Roland Morris Disability Questionnaire (RMDQ)	-4.0 units on a scale Standard Deviation 5.7	-3.5 units on a scale Standard Deviation 5.6

Adverse Events

NKTR-181 (Titration Phase)

Serious events: 9 serious events

Other events: 803 other events

Deaths: 0 deaths

NKTR-181 (Double-blind Treatment Phase)

Serious events: 5 serious events

Other events: 111 other events

Deaths: 0 deaths

Placebo (Double-blind Treatment Phase)

Serious events: 6 serious events

Other events: 66 other events

Deaths: 0 deaths

Serious adverse events

Measure	NKTR-181 (Titration Phase) n=1189 participants at risk NKTR-181 100-400 mg twice daily tablets	NKTR-181 (Double-blind Treatment Phase) n=309 participants at risk NKTR-181 100-400 mg twice daily tablets	Placebo (Double-blind Treatment Phase) n=301 participants at risk Placebo, twice daily tablets
Cardiac disorders Atrial Fibrillation	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Eye disorders Blindness transient	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Gastrointestinal disorders Large intestine perforation	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Gastrointestinal disorders Diverticulum intestinal	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
General disorders Chest Pain	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.32% 1/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Infections and infestations Cellulitis	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Infections and infestations Gastrointestinal infection	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Infections and infestations Herpes virus infection	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Infections and infestations Infective exacerbation of chronic obstructive airways	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Infections and infestations Pneumonia	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Infections and infestations Diverticulitis	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.32% 1/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Infections and infestations Bacterial infection	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Infections and infestations Gastroenteritis	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Injury, poisoning and procedural complications Rib fracture	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.32% 1/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Injury, poisoning and procedural complications Skin abrasions	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Nervous system disorders Cerebrovascular accident	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Dysarthria	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Respiratory, thoracic and mediastinal disorders Pulmonary Embolism	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Renal and urinary disorders Renal failure	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.32% 1/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Skin and subcutaneous tissue disorders Angiodema	0.08% 1/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Vascular disorders Hypertension	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.32% 1/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Vascular disorders Malignant hypertension	0.00% 0/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.00% 0/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.

Other adverse events

Measure	NKTR-181 (Titration Phase) n=1189 participants at risk NKTR-181 100-400 mg twice daily tablets	NKTR-181 (Double-blind Treatment Phase) n=309 participants at risk NKTR-181 100-400 mg twice daily tablets	Placebo (Double-blind Treatment Phase) n=301 participants at risk Placebo, twice daily tablets
Gastrointestinal disorders Constipation	35.7% 425/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	8.7% 27/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	3.0% 9/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Gastrointestinal disorders Nausea	14.8% 176/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	10.4% 32/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	6.0% 18/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Gastrointestinal disorders Vomiting	5.6% 67/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	4.9% 15/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	1.7% 5/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Gastrointestinal disorders Dry mouth	5.6% 66/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	2.3% 7/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Gastrointestinal disorders Diarrhoea	2.9% 35/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	2.6% 8/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	5.6% 17/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
General disorders Fatigue	5.1% 61/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	1.3% 4/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Nervous system disorders Somnolence	9.0% 107/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	2.6% 8/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	0.33% 1/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.
Nervous system disorders Headache	7.0% 83/1189 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	3.2% 10/309 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.	4.7% 14/301 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which is approximately 20 to 25 weeks for each subject. Adverse events were collected after the subject provided written informed consent till the end of study through spontaneous reports or were observed during other assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up is no longer possible.

Additional Information

Medical Affairs

Nektar Therapeutics

Email: StudyInquiry@nektar.com

Results disclosure agreements

• Principal investigator is a sponsor employee If a joint manuscript has not been submitted for publication within twelve (12) months of completion or termination of the study, the PI is free to publish separately, upon provision of any proposed publication or manuscript to the Sponsor at least sixty (60) days before it is submitted or otherwise disclosed.
• Publication restrictions are in place

Restriction type: OTHER