Safety of Subcutaneous Methylnaltrexone for Opioid-Induced Constipation in Patients With Advanced Illness

• Sponsor: Bausch Health Americas, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00672139
• Collaborator: Progenics Pharmaceuticals, Inc. (Industry)
• Enrollment: 156
• Locations: 46
• Arm: 1
• Duration (Months): 58
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an open-label, multicenter extension of study 3200K1-4000-WW that will evaluate the safety of methylnaltrexone. This drug will be administered by subcutaneous injection and will be tested in late stage, advanced illness patients who have constipation caused by opioid pain relievers. This study will last 3 months.

Condition or Disease	Intervention/Treatment	Phase
Opioid-Induced Constipation	Drug: Methylnaltrexone bromide	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-Label Extension Study To Assess The Safety Of A Fixed Dose Of Subcutaneous Methylnaltrexone In Subjects With Advanced Illness And Opioid-Induced Constipation
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Methylnaltrexone bromide Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; or 0.4 mL (8 mg) every other day if weight between 38 and <62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.

Drug: Methylnaltrexone bromide; Other Names: Relistor

Outcome Measures

Primary Outcome Measures

1. Number of Laxations Per Subject Within 24 Hours of Dosing Per Week. [10 weeks]

   This was defined as the total number of days with a laxation (ie, a bowel movement) within 24 hours after dosing in each 7-day interval after the start of dosing. Results shown are the ranges (lowest and highest weekly values) of mean (± standard deviation) numbers of laxations within 24 hours of dosing per week during the 10-week treatment period for each group.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Has completed study 3200K1-4000-WW, including 2 weeks of therapy and completion of all post baseline efficacy, safety, and health outcomes assessments.

• Is receiving opioids on a regular schedule, not just as needed to control pain.

• Likely to continue to need treatment of OIC for the duration of participation in the study.

Exclusion Criteria:

• Has a suspected mechanical gastrointestinal obstruction, fecal impaction, or clinically important active diverticular disease as determined by the investigator.

• Currently using an opioid antagonist or partial antagonist.

• Has any other clinically important abnormalities such that risk to patient of participation outweighs the potential benefit of therapy as determined by the investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Salix Investigational Site	Mobile	Alabama	United States	36604
2	Salix Investigational Site	Laguna Hills	California	United States	92637
3	Salix Investigational Site	Lancaster	California	United States	93534
4	Salix Investigational Site	Aurora	Colorado	United States	80045
5	Salix Investigational Site	Auburndale	Florida	United States	33823
6	Salix Investigational Site	Hudson	Florida	United States	34667
7	Salix Investigational Site	Lakeland	Florida	United States	33805
8	Salix Investigational Site	Lakeland	Florida	United States	33815
9	Salix Investigational Site	Miami Springs	Florida	United States	33166
10	Salix Investigational Site	Ruskin	Florida	United States	33573
11	Salix Investigational Site	Sebring	Florida	United States	33870
12	Salix Investigational Site	Tampa	Florida	United States	33609
13	Salix Investigational Site	Tampa	Florida	United States	33612-9416
14	Salix Investigational Site	Tampa	Florida	United States	33619
15	Salix Investigational Site	Temple Terrace	Florida	United States	33617
16	Salix Investigational Site	Orange	New Jersey	United States	07018
17	Salix Investigational Site	Flat Rock	North Carolina	United States	28731
18	Salix Investigational Site	Winston-Salem	North Carolina	United States	27103-5766
19	Salix Investigational Site	Cleveland	Ohio	United States	44119
20	Salix Investigational Site	Philadelphia	Pennsylvania	United States	19111
21	Salix Investigational Site	Austin	Texas	United States	78757
22	Salix Investigational Site	Houston	Texas	United States	77030
23	Salix Investigational Site	American Fork	Utah	United States	84003
24	Salix Investigational Site	Orem	Utah	United States	84058
25	Salix Investigational Site	Provo	Utah	United States	84604
26	Salix Investigational Site	Madison	Wisconsin	United States	53792
27	Salix Investigational Site	Coburg	Victoria	Australia	3058
28	Salix Investigational Site	East Melbourne	Victoria	Australia	3002
29	Salix Investigational Site	Adelaide		Australia	5000
30	Salix Investigational Site	Leuven		Belgium	B-3000
31	Salix Investigational Site	Edmonton	Alberta	Canada	T6G 1Z2
32	Salix Investigational Site	Edmonton	Alberta	Canada	T6L 5X8
33	Salix Investigational Site	Hamilton	Ontario	Canada	L8M 1W9
34	Salix Investigational Site	London	Ontario	Canada	N6A 4L6
35	Salix Investigational Site	Montreal	Quebec	Canada	H3A 1A1
36	Salix Investigational Site	Quebec		Canada	G1R 3S1
37	Salix Investigational Site	Montpellier		France	34295
38	Salix Investigational Site	Berlin		Germany	14089
39	Salix Investigational Site	L'Aquila		Italy	67100
40	Salix Investigational Site	Milano		Italy	20133
41	Salix Investigational Site	Milan		Italy	20020
42	Salix Investigational Site	Roma		Italy	00144
43	Pfizer Investigational Site	Mexico City DF		Mexico	03600
44	Salix Investigational Site	Almada		Portugal	2801-951
45	Salix Investigational Site	Porto		Portugal	4200-072
46	Salix Investigational Site	Cheltenham	Gloucestershire	United Kingdom	GL53 0QJ

Sponsors and Collaborators

• Bausch Health Americas, Inc.
• Progenics Pharmaceuticals, Inc.

Investigators

• Study Director: Enoch Bortey, Bausch Health Americas, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bausch Health Americas, Inc.
• ClinicalTrials.gov Identifier: NCT00672139
• Other Study ID Numbers: 3200K1-4001; B2541006
• First Posted: May 6, 2008
• Last Update Posted: Mar 7, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Bausch Health Americas, Inc.: Opioid-Induced Constipation
• Additional relevant MeSH terms: Constipation; Opioid-Induced Constipation; Bromides; Methylnaltrexone

Study Results

Participant Flow

Recruitment Details	Patients participated in this study at sites in Australia, Belgium, Brazil, Canada, France, Germany, Italy, Mexico, Spain, Sweden, the United Kingdom, and the United States.
Pre-assignment Detail	The main eligibility criteria for this study were completion of 2 weeks of therapy and all post-baseline efficacy, safety, and health outcomes assessments in lead-in study MNTX4000 and an anticipated continued need for treatment of opioid-induced constipation.

Arm/Group Title	Methylnaltrexone Bromide 8 mg	Methylnaltrexone Bromide 12 mg
Arm/Group Description	Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and <62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.
Period Title: Overall Study
STARTED	57	92
COMPLETED	27	47
NOT COMPLETED	30	45

Baseline Characteristics

Arm/Group Title	Methylnaltrexone Bromide 8 mg	Methylnaltrexone Bromide 12 mg	Total
Arm/Group Description	Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and <62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Total of all reporting groups
Overall Participants	57	92	149
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	24 42.1%	46 50%	70 47%
>=65 years	33 57.9%	46 50%	79 53%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.07 (14.29)	64.59 (11.98)	65.92 (12.98)
Sex: Female, Male (Count of Participants)
Female	44 77.2%	33 35.9%	77 51.7%
Male	13 22.8%	59 64.1%	72 48.3%
Underlying Advanced Illness (Number) [Number]
Cancer	36 63.2%	49 53.3%	85 57%
Pulmonary disease	7 12.3%	18 19.6%	25 16.8%
Cardiovascular disease	4 7%	15 16.3%	19 12.8%
Neurologic disease	3 5.3%	3 3.3%	6 4%
Other	7 12.3%	7 7.6%	14 9.4%
Weight (participants) [Number]
38 to < 62 kg	54 94.7%	0 0%	54 36.2%
≥ 62 kg	3 5.3%	92 100%	95 63.8%
Glomerular filtration rate (participants) [Number]
< 30 mL/min/1.73 m^2	2 3.5%	0 0%	2 1.3%
≥ 30 mL/min/1.73 m^2	54 94.7%	89 96.7%	143 96%
Missing	1 1.8%	3 3.3%	4 2.7%

Outcome Measures

1. Primary Outcome

Title	Number of Laxations Per Subject Within 24 Hours of Dosing Per Week.
Description	This was defined as the total number of days with a laxation (ie, a bowel movement) within 24 hours after dosing in each 7-day interval after the start of dosing. Results shown are the ranges (lowest and highest weekly values) of mean (± standard deviation) numbers of laxations within 24 hours of dosing per week during the 10-week treatment period for each group.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

The analysis population included subjects who received study drug and had laxation data and drug administration data. Two subjects in the 12 mg/day group had no drug administration data and were not included in efficacy analyses (but they were included in baseline characteristics and safety analyses).

Arm/Group Title	Methylnaltrexone Bromide 8 mg	Methylnaltrexone Bromide 12 mg
Arm/Group Description	Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and <62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.	Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.
Measure Participants	57	90
Lowest weekly average # laxations/week	1.7 (1.5)	2.4 (2.3)
Highest weekly average # laxations/week	2.6 (2.4)	3.4 (3.4)

Adverse Events

Time Frame	Adverse events were collected over the 10-week treatment period.
Adverse Event Reporting Description	Adverse events were collected by non-systematic (patient reports) and systematic methods (investigator examinations and lab tests). For both adverse events tables, a subject reporting more than one adverse event for a particular MedDRA preferred term or system organ class was counted only once for that MedDRA preferred term or system organ class.
Arm/Group Title	Methylnaltrexone Bromide 8 mg		Methylnaltrexone Bromide 12 mg
Arm/Group Description	Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.4 mL (8 mg) every other day if weight between 38 and <62 kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.		Methylnaltrexone subcutaneously as needed no more than 1 dose in a 24-hour period for a maximum of 10 weeks in this study. Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg. Subjects with impaired kidney function received reduced doses according to instructions in the Relistor prescribing information.
All Cause Mortality
	Methylnaltrexone Bromide 8 mg		Methylnaltrexone Bromide 12 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Methylnaltrexone Bromide 8 mg		Methylnaltrexone Bromide 12 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/57 (38.6%)		37/92 (40.2%)
Blood and lymphatic system disorders
Anemia	3/57 (5.3%)		1/92 (1.1%)
Thrombocytopenia	1/57 (1.8%)		0/92 (0%)
Cardiac disorders
Arrhythmia	0/57 (0%)		1/92 (1.1%)
Cardiac failure congestive	1/57 (1.8%)		1/92 (1.1%)
Myocardial infarction	1/57 (1.8%)		0/92 (0%)
Gastrointestinal disorders
Constipation	1/57 (1.8%)		3/92 (3.3%)
Diarrhea	0/57 (0%)		1/92 (1.1%)
Dysphagia	0/57 (0%)		1/92 (1.1%)
Intestinal obstruction	0/57 (0%)		1/92 (1.1%)
Vomiting	0/57 (0%)		1/92 (1.1%)
General disorders
Asthenia	0/57 (0%)		1/92 (1.1%)
Disease progression	15/57 (26.3%)		22/92 (23.9%)
General physical health deterioration	1/57 (1.8%)		0/92 (0%)
Pain	1/57 (1.8%)		0/92 (0%)
Infections and infestations
Campylobacter infection	0/57 (0%)		1/92 (1.1%)
Cellulitis	0/57 (0%)		1/92 (1.1%)
Pneumonia	0/57 (0%)		1/92 (1.1%)
Sepsis	1/57 (1.8%)		0/92 (0%)
Septic shock	0/57 (0%)		1/92 (1.1%)
Urinary tract infection	1/57 (1.8%)		0/92 (0%)
Urosepsis	0/57 (0%)		1/92 (1.1%)
Injury, poisoning and procedural complications
Fall	0/57 (0%)		1/92 (1.1%)
Femoral neck fracture	1/57 (1.8%)		0/92 (0%)
Hip fracture	1/57 (1.8%)		0/92 (0%)
Wound	0/57 (0%)		1/92 (1.1%)
Metabolism and nutrition disorders
Dehydration	1/57 (1.8%)		0/92 (0%)
Hypoglycemia	0/57 (0%)		1/92 (1.1%)
Musculoskeletal and connective tissue disorders
Back pain	0/57 (0%)		1/92 (1.1%)
Pathological fracture	0/57 (0%)		1/92 (1.1%)
Nervous system disorders
Cerebrovascular accident	1/57 (1.8%)		0/92 (0%)
Psychiatric disorders
Confusional state	0/57 (0%)		1/92 (1.1%)
Delirium	0/57 (0%)		2/92 (2.2%)
Suicidal ideation	0/57 (0%)		2/92 (2.2%)
Renal and urinary disorders
Hematuria	0/57 (0%)		1/92 (1.1%)
Renal failure	1/57 (1.8%)		0/92 (0%)
Urinary retention	0/57 (0%)		1/92 (1.1%)
Renal failure acute	0/57 (0%)		1/92 (1.1%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/57 (0%)		1/92 (1.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/57 (0%)		2/92 (2.2%)
Pleuritic pain	0/57 (0%)		1/92 (1.1%)
Pneumonia aspiration	1/57 (1.8%)		0/92 (0%)
Pulmonary embolism	1/57 (1.8%)		0/92 (0%)
Respiratory failure	0/57 (0%)		1/92 (1.1%)
Vascular disorders
Hypotension	0/57 (0%)		1/92 (1.1%)
Other (Not Including Serious) Adverse Events
	Methylnaltrexone Bromide 8 mg		Methylnaltrexone Bromide 12 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/57 (78.9%)		60/92 (65.2%)
Gastrointestinal disorders
Abdominal pain	13/57 (22.8%)		21/92 (22.8%)
Diarrhea	11/57 (19.3%)		12/92 (13%)
Dysphagia	3/57 (5.3%)		3/92 (3.3%)
Flatulence	3/57 (5.3%)		1/92 (1.1%)
Nausea	5/57 (8.8%)		14/92 (15.2%)
Vomiting	4/57 (7%)		5/92 (5.4%)
General disorders
Asthenia	10/57 (17.5%)		8/92 (8.7%)
Chest pain	1/57 (1.8%)		5/92 (5.4%)
Disease progression	4/57 (7%)		4/92 (4.3%)
Fatigue	3/57 (5.3%)		3/92 (3.3%)
Oedema peripheral	10/57 (17.5%)		13/92 (14.1%)
Pyrexia	1/57 (1.8%)		10/92 (10.9%)
Infections and infestations
Urinary tract infection	6/57 (10.5%)		7/92 (7.6%)
Injury, poisoning and procedural complications
Contusion	7/57 (12.3%)		1/92 (1.1%)
Fall	8/57 (14%)		12/92 (13%)
Laceration	3/57 (5.3%)		2/92 (2.2%)
Metabolism and nutrition disorders
Decreased appetite	4/57 (7%)		5/92 (5.4%)
Dehydration	4/57 (7%)		2/92 (2.2%)
Musculoskeletal and connective tissue disorders
Back pain	3/57 (5.3%)		1/92 (1.1%)
Pain in extremity	0/57 (0%)		5/92 (5.4%)
Nervous system disorders
Dizziness	4/57 (7%)		6/92 (6.5%)
Lethargy	4/57 (7%)		3/92 (3.3%)
Psychiatric disorders
Agitation	5/57 (8.8%)		7/92 (7.6%)
Anxiety	4/57 (7%)		7/92 (7.6%)
Confusional state	9/57 (15.8%)		11/92 (12%)
Restlessness	3/57 (5.3%)		3/92 (3.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/57 (5.3%)		5/92 (5.4%)
Dyspnoea	7/57 (12.3%)		9/92 (9.8%)
Rales	4/57 (7%)		0/92 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/57 (0%)		5/92 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.