SUMMIT-07: Efficacy and Safety Study of NKTR-181 in Opioid-Naive Subjects With Low Back Pain

• Sponsor: Nektar Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02362672
• Collaborator: (none)
• Enrollment: 1,189
• Locations: 54
• Arms: 2
• Actual Duration (Months): 22.8
• Patients Per Site: 22
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether a new opioid molecule, NKTR-181, is effective for the relief of moderate to severe chronic low back pain as compared to a placebo.

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

Detailed Description

This is an enriched enrollment, randomized withdrawal study with an open label, dose-titration period followed by a randomized, double-blind, placebo-control treatment of twelve weeks. During the double-blind treatment period, this study will evaluate the analgesic effect of NKTR-181 versus placebo in patients with moderate to severe chronic low back pain.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1189 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, and Tolerability of NKTR-181 in Opioid-Naive Subjects With Moderate to Severe Chronic Low Back Pain
• Actual Study Start Date: Mar 11, 2015
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NKTR-181 NKTR-181 twice daily (BID) tablets	Drug: NKTR-181 BID tablets; NKTR-181 tablets 100-400 mg twice daily (BID)
Placebo Comparator: Placebo Placebo to match NKTR-181 twice daily (BID) tablets	Drug: Placebo to match NKTR-181 BID tablets; Placebo to match NKTR-181 tablets 100-400 mg twice daily (BID)

Outcome Measures

Primary Outcome Measures

1. 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) [12 Weeks of randomized double blinded period]

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

Secondary Outcome Measures

1. Responder Analysis Based on Percent Reduction in Pain Intensity [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.

2. Patient Global Impression of Change (PGIC): Number of Responders [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.

3. Change in Sleep Quality in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R) [Screening Baseline through Week 12]

   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.

4. Change in Sleep Quantity Measure in Hours in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R) [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.

5. Change in Roland Morris Disability Questionnaire (RMDQ) [Screening Baseline through Week 12]

   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.

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 non-neuropathic low back pain for at least six months

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

• Opioid analgesia is necessary

• Currently taking no more than 10 mg morphine sulfate equivalents per day of short acting opioids for 14 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:

• Taking extended release or long-acting opioids within 6 months

• History of hypersensitivity, intolerance, or allergy to opioids

• Compression of spinal nerve root; spinal fracture, tumor, or abscess

• Surgical procedures on the low back in the last 12 months or facet nerve root block or radiofrequency ablation in the last 3 months

• Untreated moderate to severe sleep apnea

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

Sponsors and Collaborators

• Nektar Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Nektar Therapeutics
• ClinicalTrials.gov Identifier: NCT02362672
• Other Study ID Numbers: 14-181-07
• First Posted: Feb 13, 2015
• Last Update Posted: Sep 16, 2020
• Last Verified: Sep 1, 2020

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

Study Results

Participant Flow

Recruitment Details	First subject screened: 11Mar2015; Last subject out: 28 Dec 2016. The study was conducted at 55 medical/research sites 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 (Open-label Titration Phase)	NKTR-181 (Double-blind Treatment Phase)	Placebo (Double-blind Treatment Phase)
Arm/Group Description	NKTR-181 100-400 mg twice daily tablets	NKTR-181: 100-400 mg twice daily tablets	Placebo: Placebo, twice daily tablets
Period Title: Titration Phase
STARTED	1189	0	0
COMPLETED	610	0	0
NOT COMPLETED	579	0	0
Period Title: Titration Phase
STARTED	0	309	301
COMPLETED	0	249	242
NOT COMPLETED	0	60	59

Baseline Characteristics

Arm/Group Title	NKTR-181	Placebo	Total
Arm/Group Description	NKTR-181 (Double-blind Treatment Phase)	Placebo (Double-blind Treatment Phase)	Total of all reporting groups
Overall Participants	309	301	610
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.0 (12.7)	50.7 (12.5)	51.4 (12.6)
Sex: Female, Male (Count of Participants)
Female	187 60.5%	170 56.5%	357 58.5%
Male	122 39.5%	131 43.5%	253 41.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 1%	3 1%	6 1%
Asian	4 1.3%	2 0.7%	6 1%
Native Hawaiian or Other Pacific Islander	0 0%	2 0.7%	2 0.3%
Black or African American	95 30.7%	93 30.9%	188 30.8%
White	205 66.3%	196 65.1%	401 65.7%
More than one race	0 0%	1 0.3%	1 0.2%
Unknown or Not Reported	2 0.6%	4 1.3%	6 1%
Screening Baseline Pain Intensity in Numeric Rating Scale (NRS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.7 (0.9)	6.8 (0.9)	6.73 (0.9)

Outcome Measures

1. Primary Outcome

Title	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)
Description	The daily pain intensity is an 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain).
Time Frame	12 Weeks of randomized double blinded period

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	NKTR-181	Placebo
Arm/Group Description	NKTR-181 (Double-blind Treatment Phase)	Placebo (Double-blind Treatment Phase)
Measure Participants	309	301
Mean (Standard Error) [units on a scale]	0.9 (0.11)	1.5 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NKTR-181, Placebo
	Comments	NKTR-181 (Double-blind Treatment Phase), Placebo (Double-blind Treatment Phase)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	z-test
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Responder Analysis Based on Percent Reduction in Pain Intensity
Description	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.
Time Frame	Screening Baseline through Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NKTR-181	Placebo
Arm/Group Description	NKTR-181 (Double-blind Treatment Phase)	Placebo (Double-blind Treatment Phase)
Measure Participants	309	301
Subjects with 30% improvement	220 71.2%	172 57.1%
Subjects with 50% improvement	158 51.1%	114 37.9%

3. Secondary Outcome

Title	Patient Global Impression of Change (PGIC): Number of Responders
Description	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.
Time Frame	Screening Baseline through Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NKTR-181	Placebo
Arm/Group Description	NKTR-181 (Double-blind treatment phase)	Placebo (Double-blind treatment phase)
Measure Participants	309	301
Count of Participants [Participants]	159 51.5%	100 33.2%

4. Secondary Outcome

Title	Change in Sleep Quality in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R)
Description	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.
Time Frame	Screening Baseline through Week 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NKTR-181	Placebo
Arm/Group Description	NKTR-181 (Double-blind Treatment Phase)	Placebo (Double-blind Treatment Phase)
Measure Participants	254	253
Sleep Disturbance	-16.7 (23.9)	-9.5 (22.8)
Sleep Problems Index	-11.6 (18.9)	-6.9 (18.4)
Respiratory Impairments	-3.5 (18.9)	-2.2 (18.6)
Sleep Adequacy	9.1 (26.1)	4.0 (25.6)
Somnolence	-6.1 (21.0)	-7.4 (21.8)

5. Secondary Outcome

Title	Change in Sleep Quantity Measure in Hours in the Medical Outcome Study Sleep Scale - Revised (MOS Sleep-R)
Description	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.
Time Frame	Screening Baseline through Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NKTR-181	Placebo
Arm/Group Description	NKTR-181 (Double-blind Treatment Phase)	Placebo (Double-blind Treatment Phase)
Measure Participants	254	253
Mean (Standard Deviation) [hours]	0.3 (1.1)	0.2 (1.2)

6. Secondary Outcome

Title	Change in Roland Morris Disability Questionnaire (RMDQ)
Description	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.
Time Frame	Screening Baseline through Week 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	NKTR-181	Placebo
Arm/Group Description	NKTR-181 (Double-blind Treatment Phase)	Placebo (Double-blind Treatment Phase)
Measure Participants	254	253
Mean (Standard Deviation) [units on a scale]	-4.0 (5.7)	-3.5 (5.6)

Adverse Events

Time Frame	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 Event Reporting Description	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.
Arm/Group Title	NKTR-181 (Titration Phase)		NKTR-181 (Double-blind Treatment Phase)		Placebo (Double-blind Treatment Phase)
Arm/Group Description	NKTR-181 100-400 mg twice daily tablets		NKTR-181 100-400 mg twice daily tablets		Placebo, twice daily tablets
All Cause Mortality
	NKTR-181 (Titration Phase)		NKTR-181 (Double-blind Treatment Phase)		Placebo (Double-blind Treatment Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	NKTR-181 (Titration Phase)		NKTR-181 (Double-blind Treatment Phase)		Placebo (Double-blind Treatment Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/1189 (0.8%)		5/309 (1.6%)		6/301 (2%)
Cardiac disorders
Atrial Fibrillation	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Eye disorders
Blindness transient	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Gastrointestinal disorders
Large intestine perforation	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Diverticulum intestinal	0/1189 (0%)		0/309 (0%)		1/301 (0.3%)
General disorders
Chest Pain	0/1189 (0%)		1/309 (0.3%)		0/301 (0%)
Infections and infestations
Cellulitis	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Gastrointestinal infection	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Herpes virus infection	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Infective exacerbation of chronic obstructive airways	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Pneumonia	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Diverticulitis	0/1189 (0%)		1/309 (0.3%)		0/301 (0%)
Bacterial infection	0/1189 (0%)		0/309 (0%)		1/301 (0.3%)
Gastroenteritis	0/1189 (0%)		0/309 (0%)		1/301 (0.3%)
Injury, poisoning and procedural complications
Rib fracture	0/1189 (0%)		1/309 (0.3%)		0/301 (0%)
Skin abrasions	0/1189 (0%)		0/309 (0%)		1/301 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/1189 (0%)		0/309 (0%)		1/301 (0.3%)
Dysarthria	0/1189 (0%)		0/309 (0%)		1/301 (0.3%)
Nervous system disorders
Cerebrovascular accident	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Renal and urinary disorders
Renal failure	0/1189 (0%)		1/309 (0.3%)		0/301 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Skin and subcutaneous tissue disorders
Angiodema	1/1189 (0.1%)		0/309 (0%)		0/301 (0%)
Vascular disorders
Hypertension	0/1189 (0%)		1/309 (0.3%)		0/301 (0%)
Malignant hypertension	0/1189 (0%)		0/309 (0%)		1/301 (0.3%)
Other (Not Including Serious) Adverse Events
	NKTR-181 (Titration Phase)		NKTR-181 (Double-blind Treatment Phase)		Placebo (Double-blind Treatment Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	803/1189 (67.5%)		111/309 (35.9%)		66/301 (21.9%)
Gastrointestinal disorders
Constipation	425/1189 (35.7%)		27/309 (8.7%)		9/301 (3%)
Nausea	176/1189 (14.8%)		32/309 (10.4%)		18/301 (6%)
Vomiting	67/1189 (5.6%)		15/309 (4.9%)		5/301 (1.7%)
Dry mouth	66/1189 (5.6%)		7/309 (2.3%)		1/301 (0.3%)
Diarrhoea	35/1189 (2.9%)		8/309 (2.6%)		17/301 (5.6%)
General disorders
Fatigue	61/1189 (5.1%)		4/309 (1.3%)		1/301 (0.3%)
Nervous system disorders
Somnolence	107/1189 (9%)		8/309 (2.6%)		1/301 (0.3%)
Headache	83/1189 (7%)		10/309 (3.2%)		14/301 (4.7%)

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.