SUMMIT-LTS: Long-Term Safety and Tolerability Study of NKTR-181 in Subjects With Chronic Low Back Pain or Chronic Non-Cancer Pain

• Sponsor: Nektar Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02367820
• Collaborator: (none)
• Enrollment: 638
• Locations: 56
• Arm: 1
• Actual Duration (Months): 32.6
• Patients Per Site: 11.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Low Back Pain; Chronic Pain	Drug: NKTR-181 BID tablets	Phase 3

Detailed Description

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

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 638 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Multicenter, Open-Label, 52-Week Study To Evaluate the Long-Term Safety and Tolerability of NKTR-181 in Subjects With Moderate to Severe Chronic Low Back Pain or Chronic Non-Cancer Pain
• Actual Study Start Date: Apr 14, 2015
• Actual Primary Completion Date: Dec 1, 2017
• Actual Study Completion Date: Jan 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NKTR-181 NKTR-181 twice daily (BID) tablets	Drug: NKTR-181 BID tablets; NKTR-181 tablets 100-600 mg twice daily (BID)

Outcome Measures

Primary Outcome Measures

1. Number of Participants Reporting Adverse Events [Screening baseline through end of study, an average of 57 weeks]

   Count of subjects reporting treatment emergent adverse events

Secondary Outcome Measures

1. Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 [Baseline, monthly change from baseline till the end of study]

   A self-reported scale measuring severity of pain on function. The mean of the 4 intensity items (3-6) is calculated and used as a measure of pain severity. If there were missing items when the pain severity score was calculated, the mean of the completed items in one dimension (dimensions include pain severity and pain interference) were imputed to substitute the missing item, provided that more than 50% of the items in one dimension were completed (Halling, 1999). The range of pain intensity and interference for each question is from 0 to 10. The range of possible scores is from 0 to 70. Higher score indicates relatively worse pain severity and greater interference that pain causes in day to day activities.

2. Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 [Baseline, monthly change from baseline till the end of study]

   A self-reported scale measuring interference of pain on function. The mean of the 7 interference items was calculated and used as a measure of Pain interference. If there were missing items when the pain interference score was calculated, the mean of the completed items in one dimension (dimensions include pain severity and pain interference) were imputed to substitute the missing item, provided that more than 50% of the items in one dimension were completed (Halling, 1999). The range of pain interference is from 0 to 10. Higher score indicates relatively worse pain problem.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or non-pregnant, non-nursing female aged 18 to 75 years old

• Clinical diagnosis of moderate to severe, chronic low back or non-cancer pain for at least three months

• Not experiencing adequate pain relief or have failed previous treatment with non-opioid analgesics

• Opioid analgesia is necessary

• Currently taking no less than 10 mg but no more than 60 mg of morphine sulfate equivalents (MSE) per day of opioid analgesics for at least 7 days prior to entry

• Females of child bearing potential must be using a highly effective form of birth control. All subjects must agree to use double-barrier contraception during participation in this study and for at least 2 months after the last dose of the study drug.

• Willing and able to provide informed consent

Exclusion Criteria:

• History of hypersensitivity, intolerance, or allergy to opioids

• Surgical procedures in the last 4 weeks or plans to undergo surgical procedures during the study period

• Untreated moderate to severe sleep apnea

• Chronic migraines as the primary pain condition

• Cancer related pain

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigator Site - Saraland	Saraland	Alabama	United States	36571
2	Investigator Site - Phoenix	Phoenix	Arizona	United States	85023
3	Investigator Site - Tempe	Tempe	Arizona	United States	85283
4	Investigator Site - Little Rock	Little Rock	Arkansas	United States	72211
5	Investigator Site - Stamford	Stamford	Connecticut	United States	06905
6	Investigator Site - Clearwater	Clearwater	Florida	United States	33765
7	Investigator Site - Fort Lauderdale	Fort Lauderdale	Florida	United States	33312
8	Investigator Site - Fort Myers	Fort Myers	Florida	United States	33912
9	Investigator Site - Jacksonville	Jacksonville	Florida	United States	32257
10	Investigator Site - Orlando	Orlando	Florida	United States	32806
11	Investigator Site - Ormond Beach	Ormond Beach	Florida	United States	32174
12	Investigator Site - Plantation	Plantation	Florida	United States	33324
13	Investigator Site - Tampa	Tampa	Florida	United States	33603
14	Investigator Site - West Palm Beach	West Palm Beach	Florida	United States	33409
15	Investigator Site - Atlanta	Atlanta	Georgia	United States	30338
16	Investigator Site - Blue Ridge	Blue Ridge	Georgia	United States	30513
17	Investigator Site - Marietta	Marietta	Georgia	United States	30060
18	Investigator Site - Norcross	Norcross	Georgia	United States	30092
19	Investigator Site - Gurnee	Gurnee	Illinois	United States	60031
20	Investigator Site - West Des Moines	West Des Moines	Iowa	United States	50265
21	Investigator Site - Wichita	Wichita	Kansas	United States	67207
22	Investigator Site - Louisville	Louisville	Kentucky	United States	40213
23	Investigator Site - Bossier	Bossier City	Louisiana	United States	71111
24	Investigator Site - New Orleans	New Orleans	Louisiana	United States	70115
25	Investigator Site - Shreveport	Shreveport	Louisiana	United States	71105
26	Investigator Site - Bay City	Bay City	Michigan	United States	48706
27	Investigator Site - Pinconning	Pinconning	Michigan	United States	48706
28	Investigator Site - Biloxi	Biloxi	Mississippi	United States	39531
29	Investigator Site - Saint Louis 1	Saint Louis	Missouri	United States	63141
30	Investigator Site - Saint Louis 2	Saint Louis	Missouri	United States	63141
31	Investigator Site - Omaha	Omaha	Nebraska	United States	68134
32	Investigator Site - Las Vegas 2	Las Vegas	Nevada	United States	89102
33	Investigator Site - Las Vegas 1	Las Vegas	Nevada	United States	89119
34	Investigator Site - Rochester	Rochester	New York	United States	14642
35	Investigator Site - Williamsville	Williamsville	New York	United States	14221
36	Investigator Site - Greensboro	Greensboro	North Carolina	United States	27410
37	Investigator Site - Winston Salem	Winston-Salem	North Carolina	United States	27103
38	Investigator Site - Fargo	Fargo	North Dakota	United States	58104
39	Investigator Site - Beavercreek	Beavercreek	Ohio	United States	45432
40	Investigator Site - Cincinnati 1	Cincinnati	Ohio	United States	45219
41	Investigator Site - Cincinnati 2	Cincinnati	Ohio	United States	45246
42	Investigator Site - Columbus	Columbus	Ohio	United States	43235
43	Investigator Site - Duncansville	Duncansville	Pennsylvania	United States	16635
44	Investigator Site - Jenkintown	Jenkintown	Pennsylvania	United States	19046
45	Investigator Site - Dakota Dunes	Dakota Dunes	South Dakota	United States	57047
46	Investigator Site - Rapid City	Rapid City	South Dakota	United States	57702
47	Investigator Site - Memphis	Memphis	Tennessee	United States	38119
48	Investigator Site - Arlington	Arlington	Texas	United States	76012
49	Investigator Site - Austin	Austin	Texas	United States	78731
50	Investigator Site - Killeen	Killeen	Texas	United States	76543
51	Investigator Site - San Antonio	San Antonio	Texas	United States	78229
52	Investigator Site - Salt Lake City	Salt Lake City	Utah	United States	84124
53	Investigator Site - West Jordan	West Jordan	Utah	United States	84088
54	Investigator Site - Midlothian	Midlothian	Virginia	United States	23114
55	Investigator Site - Norfolk	Norfolk	Virginia	United States	23507
56	Investigator Site - Kenosha	Kenosha	Wisconsin	United States	53142

Sponsors and Collaborators

• Nektar Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jan 15, 2016
• Statistical Analysis Plan - Oct 3, 2017

More Information

Additional Information:

• Related Info

Publications

• Gudin J, Rauck R, Argoff C, Agaiby E, Gimbel J, Katz N, Doberstein SK, Tagliaferri M, Tagliaferri M, Potts J, Wild J, Lu L, Siddhanti S, Hale M, Markman J. Long-term Safety and Tolerability of NKTR-181 in Patients with Moderate to Severe Chronic Low Back Pain or Chronic Noncancer Pain: A Phase 3 Multicenter, Open-Label, 52-Week Study (SUMMIT-08 LTS). Pain Med. 2020 Nov 7;21(7):1347-1356. doi: 10.1093/pm/pnz169.

• Responsible Party: Nektar Therapeutics
• ClinicalTrials.gov Identifier: NCT02367820
• Other Study ID Numbers: 14-181-08
• First Posted: Feb 20, 2015
• Last Update Posted: Jun 22, 2021
• Last Verified: Jun 1, 2021

• Additional relevant MeSH terms: Back Pain; Low Back Pain; Chronic Pain

Study Results

Participant Flow

Recruitment Details	First subject screened 14 April 2015. Last subject out: 24 January 2018. The study was conducted at 55 medical/research centers in the United States.
Pre-assignment Detail	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.

Arm/Group Title	NKTR-181
Arm/Group Description	NKTR-181 tablets at 100-600 mg orally twice daily
Period Title: Overall Study
STARTED	638
COMPLETED	402
NOT COMPLETED	236

Baseline Characteristics

Arm/Group Title	Rollover NKTR-181	Rollover PBO	De Novo Naive	De Novo Opioid Experienced	Total
Arm/Group Description	Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Subjects administered placebo in preceding phase 3 efficacy/safety study	Newly enrolled opioid naïve subjects	Newly enrolled opioid experienced subjects	Total of all reporting groups
Overall Participants	214	217	73	134	638
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.7 (12.01)	51.4 (12.31)	51.9 (10.44)	55.6 (11.12)	52.4 (11.85)
Sex: Female, Male (Count of Participants)
Female	123 57.5%	126 58.1%	44 60.3%	82 61.2%	375 58.8%
Male	91 42.5%	91 41.9%	29 39.7%	52 38.8%	263 41.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1.4%	2 0.9%	0 0%	1 0.7%	6 0.9%
Asian	2 0.9%	2 0.9%	1 1.4%	0 0%	5 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.5%	0 0%	0 0%	1 0.2%
Black or African American	71 33.2%	70 32.3%	19 26%	24 17.9%	184 28.8%
White	136 63.6%	138 63.6%	51 69.9%	106 79.1%	431 67.6%
More than one race	0 0%	1 0.5%	1 1.4%	1 0.7%	3 0.5%
Unknown or Not Reported	2 0.9%	3 1.4%	1 1.4%	2 1.5%	8 1.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Reporting Adverse Events
Description	Count of subjects reporting treatment emergent adverse events
Time Frame	Screening baseline through end of study, an average of 57 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rollover NKTR-181	Rollover PBO	De Novo Opioid Experienced	De Novo Naive
Arm/Group Description	Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Subjects administered placebo in preceding phase 3 efficacy/safety study	Newly enrolled opioid experienced subjects	Newly enrolled opioid naïve subjects
Measure Participants	214	217	134	73
Count of Participants [Participants]	138 64.5%	151 69.6%	110 150.7%	62 46.3%

2. Secondary Outcome

Title	Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52
Description	A self-reported scale measuring severity of pain on function. The mean of the 4 intensity items (3-6) is calculated and used as a measure of pain severity. If there were missing items when the pain severity score was calculated, the mean of the completed items in one dimension (dimensions include pain severity and pain interference) were imputed to substitute the missing item, provided that more than 50% of the items in one dimension were completed (Halling, 1999). The range of pain intensity and interference for each question is from 0 to 10. The range of possible scores is from 0 to 70. Higher score indicates relatively worse pain severity and greater interference that pain causes in day to day activities.
Time Frame	Baseline, monthly change from baseline till the end of study

Outcome Measure Data

Analysis Population Description

Safety Analysis Set is defined as all enrolled subjects who received at least 1 dose of study drug.

Arm/Group Title	Rollover NKTR-181	Rollover PBO	De Novo Opioid Experienced	De Novo Naive
Arm/Group Description	Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Subjects administered placebo in preceding phase 3 efficacy/safety study	Newly enrolled opioid experienced subjects	Newly enrolled opioid naïve subjects
Measure Participants	185	188	129	72
Pain Intensity: Baseline	3.57 (1.968)	4.11 (2.112)	5.91 (1.749)	6.18 (1.459)
Pain Intensity: Change from Baseline to Day 1	-1.22 (2.109)	-1.71 (2.212)	-2.19 (2.009)	-2.66 (1.808)
Pain Intensity: Change from Baseline to Day 30	-1.02 (2.233)	-1.40 (2.314)	-2.26 (2.134)	-2.26 (2.068)
Pain Intensity: Change from Baseline to Day 60	-1.28 (2.037)	-1.58 (2.172)	-2.01 (2.000)	-2.49 (1.966)
Pain Intensity: Change from Baseline to Day 90	-1.31 (2.142)	-1.48 (2.278)	-2.06 (1.932)	-2.38 (2.115)
Pain Intensity: Change from Baseline to Day 120	-1.24 (2.269)	-1.44 (2.267)	-2.04 (1.933)	-2.58 (1.874)
Pain Intensity: Change from Baseline to Day 150	-1.28 (2.116)	-1.54 (2.319)	-2.09 (2.016)	-2.44 (2.323)
Pain Intensity: Change from Baseline to Day 180	-1.37 (2.103)	-1.49 (2.425)	-1.87 (2.053)	-2.80 (2.173)
Pain Intensity: Change from Baseline to Day 210	-1.28 (2.131)	-1.58 (2.220)	-2.06 (1.944)	-3.01 (2.258)
Pain Intensity: Change from Baseline to Day 240	-1.15 (1.837)	-1.82 (2.190)	-2.21 (1.908)	-2.84 (2.289)
Pain Intensity: Change from Baseline to Day 270	-1.45 (2.154)	-1.62 (2.366)	-1.83 (1.915)	-2.65 (1.933)
Pain Intensity: Change from Baseline to Day 300	-1.09 (2.149)	-1.48 (2.303)	-2.08 (2.144)	-2.31 (2.043)
Pain Intensity: Change from Baseline to Day 364	-0.78 (2.175)	-1.31 (2.520)	-1.20 (2.102)	-2.15 (2.055)

3. Secondary Outcome

Title	Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52
Description	A self-reported scale measuring interference of pain on function. The mean of the 7 interference items was calculated and used as a measure of Pain interference. If there were missing items when the pain interference score was calculated, the mean of the completed items in one dimension (dimensions include pain severity and pain interference) were imputed to substitute the missing item, provided that more than 50% of the items in one dimension were completed (Halling, 1999). The range of pain interference is from 0 to 10. Higher score indicates relatively worse pain problem.
Time Frame	Baseline, monthly change from baseline till the end of study

Outcome Measure Data

Analysis Population Description

Safety Analysis Set is defined as all enrolled subjects who received at least 1 dose of study drug.

Arm/Group Title	Rollover NKTR-181	Rollover PBO	De Novo Opioid Experienced	De Novo Naive
Arm/Group Description	Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Subjects administered placebo in preceding phase 3 efficacy/safety study	Newly enrolled opioid experienced subjects	Newly enrolled opioid naïve subjects
Measure Participants	185	188	129	72
Pain Interference: Baseline	2.91 (2.205)	3.25 (2.281)	5.41 (2.298)	5.44 (1.957)
Pain Interference: Change from Baseline to Day 1	-1.23 (2.301)	-1.52 (2.163)	-2.34 (2.175)	-2.71 (2.169)
Pain Interference: Change from Baseline to Day 30	-1.07 (2.070)	-1.29 (2.340)	-2.51 (2.583)	-2.17 (2.679)
Pain Interference: Change from Baseline to Day 60	-1.17 (2.070)	-1.32 (2.104)	-2.18 (2.350)	-2.38 (2.277)
Pain Interference: Change from Baseline to Day 90	-1.24 (2.344)	-1.34 (2.222)	-2.15 (2.447)	-2.11 (2.179)
Pain Interference: Change from Baseline to Day 120	-1.31 (2.389)	-1.36 (2.309)	-2.33 (2.299)	-2.48 (2.173)
Pain Interference: Change from Baseline to Day 150	-1.12 (2.329)	-1.22 (2.500)	-2.26 (2.372)	-2.16 (2.290)
Pain Interference: Change from Baseline to Day 180	-1.31 (2.247)	-1.33 (2.507)	-2.09 (2.551)	-2.27 (2.404)
Pain Interference: Change from Baseline to Day 210	-0.95 (2.325)	-1.29 (2.215)	-2.43 (2.365)	-2.38 (2.611)
Pain Interference: Change from Baseline to Day 240	-0.95 (2.119)	-1.55 (2.197)	-2.49 (2.503)	-2.27 (2.240)
Pain Interference: Change from Baseline to Day 270	-1.21 (2.339)	-1.37 (2.329)	-2.02 (2.374)	-2.01 (2.193)
Pain Interference: Change from Baseline to Day 300	-0.90 (2.307)	-1.38 (2.137)	-2.07 (2.280)	-1.94 (2.357)
Pain Interference: Change from Baseline to Day 364	-0.69 (2.258)	-1.14 (2.493)	-1.33 (2.396)	-2.08 (2.504)

Adverse Events

Time Frame	Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject.
Adverse Event Reporting Description	Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study 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 was no longer possible.
Arm/Group Title	Rollover NKTR-181		Rollover PBO		De Novo Opioid Experienced		De Novo Naive
Arm/Group Description	Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study		Subjects administered placebo in preceding phase 3 efficacy/safety study		Newly enrolled opioid experienced subjects		Newly enrolled opioid naïve subjects
All Cause Mortality
	Rollover NKTR-181		Rollover PBO		De Novo Opioid Experienced		De Novo Naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/214 (0%)		0/217 (0%)		0/134 (0%)		0/73 (0%)
Serious Adverse Events
	Rollover NKTR-181		Rollover PBO		De Novo Opioid Experienced		De Novo Naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/214 (4.7%)		8/217 (3.7%)		8/134 (6%)		4/73 (5.5%)
Cardiac disorders
Myocardial Infarction	0/214 (0%)	0	1/217 (0.5%)	1	0/134 (0%)	0	0/73 (0%)	0
Endocrine disorders
Goitre	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Gastrointestinal disorders
abdominal pain	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Diarrhoea	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Duodenal ulcer	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Duodenitis	0/214 (0%)	0	0/217 (0%)	0	0/134 (0%)	0	1/73 (1.4%)	1
Gastric ulcer	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Pancreatitis	0/214 (0%)	0	0/217 (0%)	0	0/134 (0%)	0	1/73 (1.4%)	1
Rectal haemorrhage	0/214 (0%)	0	1/217 (0.5%)	1	0/134 (0%)	0	0/73 (0%)	0
General disorders
Generalized Oedema	0/214 (0%)	0	0/217 (0%)	0	0/134 (0%)	0	1/73 (1.4%)	1
Infections and infestations
Gastroenteritis	1/214 (0.5%)	1	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Pneumonia	0/214 (0%)	0	1/217 (0.5%)	1	1/134 (0.7%)	1	0/73 (0%)	0
Cellulitis	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Diverticulitis	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Hisoplasmosis	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Urinary Tract Infection	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Injury, poisoning and procedural complications
Head injury	0/214 (0%)	0	1/217 (0.5%)	1	0/134 (0%)	0	0/73 (0%)	0
Road traffic accident	0/214 (0%)	0	1/217 (0.5%)	1	0/134 (0%)	0	0/73 (0%)	0
Subdural haematoma	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Musculoskeletal and connective tissue disorders
Back Pain	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Osteoarthritis	0/214 (0%)	0	0/217 (0%)	0	0/134 (0%)	0	1/73 (1.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Follicular thyroid cancer	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Lung adenocarcinoma	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Nervous system disorders
Cerebral Infarction	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Cerebrovascular accident	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Convulsion	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Syncope	0/214 (0%)	0	1/217 (0.5%)	1	0/134 (0%)	0	0/73 (0%)	0
Renal and urinary disorders
Renal Mass	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Reproductive system and breast disorders
Uterine Cyst	1/214 (0.5%)	1	0/217 (0%)	0	0/134 (0%)	0	0/73 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	0/214 (0%)	0	0/217 (0%)	0	0/134 (0%)	0	1/73 (1.4%)	1
Pulmonary fibrosis	0/214 (0%)	0	1/217 (0.5%)	1	0/134 (0%)	0	0/73 (0%)	0
Skin and subcutaneous tissue disorders
Decubitus Ulcer	0/214 (0%)	0	1/217 (0.5%)	1	0/134 (0%)	0	0/73 (0%)	0
Vascular disorders
Deep Vein Thrombosis	0/214 (0%)	0	0/217 (0%)	0	1/134 (0.7%)	1	0/73 (0%)	0
Malignant hypertension	0/214 (0%)	0	1/217 (0.5%)	1	0/134 (0%)	0	0/73 (0%)	0
Other (Not Including Serious) Adverse Events
	Rollover NKTR-181		Rollover PBO		De Novo Opioid Experienced		De Novo Naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	136/214 (63.6%)		151/217 (69.6%)		110/134 (82.1%)		62/73 (84.9%)
Gastrointestinal disorders
Constipation	28/214 (13.1%)	28	41/217 (18.9%)	41	56/134 (41.8%)	56	41/73 (56.2%)	41
Nausea	17/214 (7.9%)	17	21/217 (9.7%)	21	17/134 (12.7%)	17	21/73 (28.8%)	21
Diarrhoea	6/214 (2.8%)	6	11/217 (5.1%)	11	4/134 (3%)	4	8/73 (11%)	8
Vomiting	13/214 (6.1%)	13	10/217 (4.6%)	10	3/134 (2.2%)	3	9/73 (12.3%)	9
General disorders
Drug withdrawal	10/214 (4.7%)	10	16/217 (7.4%)	16	10/134 (7.5%)	10	2/73 (2.7%)	2
Fatigue	1/214 (0.5%)	1	4/217 (1.8%)	4	4/134 (3%)	4	4/73 (5.5%)	4
Infections and infestations
Upper respiratory tract infection	12/214 (5.6%)	12	19/217 (8.8%)	19	10/134 (7.5%)	10	7/73 (9.6%)	7
Urinary tract infection	10/214 (4.7%)	10	14/217 (6.5%)	14	5/134 (3.7%)	5	6/73 (8.2%)	6
Influenza	5/214 (2.3%)	5	10/217 (4.6%)	10	4/134 (3%)	4	5/73 (6.8%)	5
Musculoskeletal and connective tissue disorders
Arthralgia	6/214 (2.8%)	6	7/217 (3.2%)	7	7/134 (5.2%)	7	3/73 (4.1%)	3
Nervous system disorders
Headache	9/214 (4.2%)	9	21/217 (9.7%)	21	21/134 (15.7%)	21	6/73 (8.2%)	6
Somnolence	6/214 (2.8%)	6	13/217 (6%)	13	9/134 (6.7%)	9	3/73 (4.1%)	3
Dizziness	5/214 (2.3%)	5	3/217 (1.4%)	3	6/134 (4.5%)	6	5/73 (6.8%)	5
Psychiatric disorders
Insomnia	4/214 (1.9%)	4	4/217 (1.8%)	4	5/134 (3.7%)	5	4/73 (5.5%)	4
Skin and subcutaneous tissue disorders
Pruritis	4/214 (1.9%)	4	5/217 (2.3%)	5	6/134 (4.5%)	6	6/73 (8.2%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.