A Study of CB-183,315 in Participants With Clostridium Difficile Associated Diarrhea (MK-4261-006)

• Sponsor: Cubist Pharmaceuticals LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01598311
• Collaborator: (none)
• Enrollment: 608
• Arms: 2
• Actual Duration (Months): 39.3

Study Details

Study Description

Brief Summary

A total of 608 participants with Clostridium Difficile Associated Diarrhea (CDAD) will participate in this study; participants will receive either oral vancomycin or CB-183,315 in a blinded fashion. Treatment will last for 10 days and participants will be followed up for at least 40 days and a maximum of 100 days. The purpose of this study is to evaluate how well CB-183,315 treats CDAD as compared to vancomycin.

Condition or Disease	Intervention/Treatment	Phase
Clostridium Difficile Infection	Drug: CB-183,315; Drug: Vancomycin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 608 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blinded, Active-Controlled Study of CB-183,315 in Patients With Clostridium Difficile Associated Diarrhea
• Actual Study Start Date: May 16, 2012
• Actual Primary Completion Date: Jul 26, 2015
• Actual Study Completion Date: Aug 25, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CB-183,315 Participants took CB-183,315 250 mg twice daily (b.i.d.) and placebo capsules b.i.d. by mouth for 10 days.	Drug: CB-183,315; CB-183,315 250 mg white coated tablet over-encapsulated in a size 00 opaque hard gelatin capsule.; Other Names: Surotomycin ; Drug: Placebo; Placebo size 00 opaque hard gelatin capsules.
Active Comparator: Vancomycin Participants took vancomycin 125 mg four times daily (q.i.d.) by mouth for 10 days.	Drug: Vancomycin; Vancomycin hydrochloride 125 mg capsule over-encapsulated in size 00 opaque hard gelatin capsule.

Outcome Measures

Primary Outcome Measures

1. Adjusted Percentage of Participants Meeting Clinical Response Criteria for Cure at End of Treatment (EOT) [Up to 3 days after EOT (up to Day 13)]

   The percentage of participants considered "cured" (i.e., ≤2 loose stools per 24 hour period for at least 2 consecutive days and no need for additional antibiotics during the 3 days following EOT) was determined in the mMITT population. A CDAD diagnosis was defined as: 1) diarrhea with a minimum of 3 unformed bowel movements (UBM) or >200 mL volume of stool for participants with a collection device (e.g., rectal tube or colostomy bag) over 24 hours; and 2) a positive result for Clostridium difficile toxin by enzyme immunoassay (EIA), polymerase chain reaction (PCR), or a cell culture cytotoxin neutralization assay. Percentages were first stratified according to age (<75 or ≥75 years) and number of previous CDAD episodes (0 or ≥1) and constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights, and the weighted averages were then derived across strata in order to calculate the adjusted percentage.

2. Percentage of Participants Experiencing an Adverse Event (AE) [Up to 30 days after EOT (up to Day 40)]

   An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.

3. Percentage of Participants Discontinuing From Study Treatment Due to an AE [Up to EOT (up to Day 10)]

   An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.

Secondary Outcome Measures

1. Number of Clinical Failure Events up to Day 40 [Up to 30 days after EOT (up to Day 40)]

   The total number of clinical failure events, which included treatment failure, CDAD recurrence, death, or being lost to follow-up, occurring during each time period was determined in each arm.

2. Adjusted Percentage of Participants With Sustained Clinical Response at End of Study [Up to 40 days after EOT (up to Day 50)]

   The percentage of participants with sustained clinical response was determined for each arm. Sustained clinical response was declared when participants had a clinical outcome of cure at EOT, did not experience any CDAD recurrence, did not die, were not lost to follow-up, and did not have the end of study visit prior to Day 40. Percentages were first stratified according to age (<75 or ≥75 years) and number of previous CDAD episodes (0 or ≥1) and constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights, and the weighted averages were then derived across strata in order to calculate the adjusted percentage.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 89 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Is able to read and sign a consent form;

• Is from ≥18 to <90 years of age;

• Has diarrhea, at least 3 times during one day, or 200 mL or liquid stool if using a rectal device;

• Tests positive for Clostridium difficile;

• If female, must not be pregnant or nursing and take appropriate measures to not get pregnant during the study.

Exclusion Criteria:

• Has toxic megacolon and/or known small bowel ileus;

• Has received treatment with intravenous immune globulin (IVIG) within the past 30 days;

• Has received treatment with a fecal transplant within 7 days, and/or if the doctor anticipates to give the participant a fecal transplant during the study;

• Has received a certain amount of antibacterial therapy specific for current CDAD, unless it is not working;

• Has received an investigational vaccine against Clostridium difficile;

• Has received an investigational product containing monoclonal antibodies against toxin A or B within 180 days;

• Has more than 2 episodes of CDAD within 90 days;

• Has had major gastrointestinal (GI) surgery (i.e. significant bowel resection) within 3 months (this does not include appendectomy or cholecystectomy);

• Has a history of prior inflammatory bowel disease: ulcerative colitis, Crohn's disease, or microscopic colitis;

• Is unable to discontinue loperamide, diphenoxylate/atropine, or cholestyramine during the duration of the study;

• Is unable to discontinue opiate treatment unless on a stable dose;

• Has known positive stool cultures for other enteropathogens including but not limited to Salmonella, Shigella, and Campylobacter;

• Has had stool studies positive for pathogenic ova and/or parasites;

• Has an intolerance or hypersensitivity to daptomycin and/or vancomycin;

• Has a life-threatening illness at the time of enrollment;

• Has poor concurrent medical risks that in the opinion of the Investigator the participant should not enroll;

• Has received an investigational drug or participated in any experimental procedure within 1 month;

• Has human immunodeficiency virus (HIV), a cluster of differentiation (CD) 4 count <200 cells/mm^3 within 6 months of start of study therapy;

• Anticipates that certain antibacterial therapy for a non-CDAD infection will be required for >7 days;

• Is unable to discontinue Saccharomyces or similar probiotic;

• Is on a concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy;

• Is unable to comply with the protocol requirements;

• Has any condition that, in the opinion of the Investigator, might interfere;

• Is not expected to live for less than 8 weeks.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Cubist Pharmaceuticals LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cubist Pharmaceuticals LLC
• ClinicalTrials.gov Identifier: NCT01598311
• Other Study ID Numbers: 4261-006; LCD-CDAD-11-06; MK-4261-006; 2012-000252-34
• First Posted: May 15, 2012
• Last Update Posted: Aug 22, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Cubist Pharmaceuticals LLC: CDAD; Clostridium difficile Associated Diarrhea; CDI; Clostridium difficile Infection; Diarrhea
• Additional relevant MeSH terms: Clostridium Infections; Diarrhea; Vancomycin

Study Results

Participant Flow

Recruitment Details	This study enrolled adult participants with Clostridium Difficile associated diarrhea (CDAD) at 104 study centers in North America, Asia-Pacific, and South America.

Arm/Group Title	CB-183,315	Vancomycin
Arm/Group Description	Participants took CB-183,315 250 mg twice daily (b.i.d.) and placebo b.i.d. by mouth for 10 days.	Participants took vancomycin 125 mg four times daily (q.i.d.) by mouth for 10 days.
Period Title: Overall Study
STARTED	303	305
Treated	294	301
Treated and Confirmed CDAD	285	292
COMPLETED	256	244
NOT COMPLETED	47	61

Baseline Characteristics

Arm/Group Title	CB-183,315	Vancomycin	Total
Arm/Group Description	Participants took CB-183,315 250 mg b.i.d. and placebo b.i.d. by mouth for 10 days.	Participants took vancomycin 125 mg q.i.d. by mouth for 10 days.	Total of all reporting groups
Overall Participants	285	292	577
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	57.6 (18.3)	56.5 (18.3)	57.1 (18.3)
Sex: Female, Male (Count of Participants)
Female	173 60.7%	194 66.4%	367 63.6%
Male	112 39.3%	98 33.6%	210 36.4%

Outcome Measures

1. Primary Outcome

Title	Adjusted Percentage of Participants Meeting Clinical Response Criteria for Cure at End of Treatment (EOT)
Description	The percentage of participants considered "cured" (i.e., ≤2 loose stools per 24 hour period for at least 2 consecutive days and no need for additional antibiotics during the 3 days following EOT) was determined in the mMITT population. A CDAD diagnosis was defined as: 1) diarrhea with a minimum of 3 unformed bowel movements (UBM) or >200 mL volume of stool for participants with a collection device (e.g., rectal tube or colostomy bag) over 24 hours; and 2) a positive result for Clostridium difficile toxin by enzyme immunoassay (EIA), polymerase chain reaction (PCR), or a cell culture cytotoxin neutralization assay. Percentages were first stratified according to age (<75 or ≥75 years) and number of previous CDAD episodes (0 or ≥1) and constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights, and the weighted averages were then derived across strata in order to calculate the adjusted percentage.
Time Frame	Up to 3 days after EOT (up to Day 13)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized and treated participants with a confirmed CDAD diagnosis (mMITT population).

Arm/Group Title	CB-183,315	Vancomycin
Arm/Group Description	Participants took CB-183,315 250 mg b.i.d. and placebo b.i.d. by mouth for 10 days.	Participants took vancomycin 125 mg q.i.d. by mouth for 10 days.
Measure Participants	285	292
Number (95% Confidence Interval) [Adjusted percentage of participants]	83.4 29.3%	82.1 28.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CB-183,315, Vancomycin
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was declared when the lower bound of the 95% CI for the difference in adjusted percentage of cured subjects was > -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -4.9 to 7.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Clinical Failure Events up to Day 40
Description	The total number of clinical failure events, which included treatment failure, CDAD recurrence, death, or being lost to follow-up, occurring during each time period was determined in each arm.
Time Frame	Up to 30 days after EOT (up to Day 40)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized and treated participants with a confirmed CDAD diagnosis (mMITT population).

Arm/Group Title	CB-183,315	Vancomycin
Arm/Group Description	Participants took CB-183,315 250 mg b.i.d. and placebo b.i.d. by mouth for 10 days.	Participants took vancomycin 125 mg q.i.d. by mouth for 10 days.
Measure Participants	285	292
Day 0 to Day 13	48	54
Day 14 to Day 24	42	49
Day 25 to Day 35	11	11
Day 36 to Day 40	2	2

3. Secondary Outcome

Title	Adjusted Percentage of Participants With Sustained Clinical Response at End of Study
Description	The percentage of participants with sustained clinical response was determined for each arm. Sustained clinical response was declared when participants had a clinical outcome of cure at EOT, did not experience any CDAD recurrence, did not die, were not lost to follow-up, and did not have the end of study visit prior to Day 40. Percentages were first stratified according to age (<75 or ≥75 years) and number of previous CDAD episodes (0 or ≥1) and constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights, and the weighted averages were then derived across strata in order to calculate the adjusted percentage.
Time Frame	Up to 40 days after EOT (up to Day 50)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized and treated participants with a confirmed CDAD diagnosis (mMITT population).

Arm/Group Title	CB-183,315	Vancomycin
Arm/Group Description	Participants took CB-183,315 250 mg b.i.d. and placebo b.i.d. by mouth for 10 days.	Participants took vancomycin 125 mg q.i.d. by mouth for 10 days.
Measure Participants	285	292
Number (95% Confidence Interval) [Adjusted percentage of participants]	63.3 22.2%	59.0 20.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CB-183,315, Vancomycin
	Comments
	Type of Statistical Test	Superiority
	Comments	Superiority was declared if the lower bound of the 95% CI of the adjusted difference in sustained response was > 0.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 95%; -3.6 to 12.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Percentage of Participants Experiencing an Adverse Event (AE)
Description	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.
Time Frame	Up to 30 days after EOT (up to Day 40)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized and treated participants (Safety Population).

Arm/Group Title	CB-183,315	Vancomycin
Arm/Group Description	Participants took CB-183,315 250 mg b.i.d. and placebo b.i.d. by mouth for 10 days.	Participants took vancomycin 125 mg q.i.d. by mouth for 10 days.
Measure Participants	294	301
Number [Percentage of Participants]	52.4 18.4%	60.1 20.6%

5. Primary Outcome

Title	Percentage of Participants Discontinuing From Study Treatment Due to an AE
Description	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.
Time Frame	Up to EOT (up to Day 10)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized and treated participants (Safety Population).

Arm/Group Title	CB-183,315	Vancomycin
Arm/Group Description	Participants took CB-183,315 250 mg b.i.d. and placebo b.i.d. by mouth for 10 days.	Participants took vancomycin 125 mg q.i.d. by mouth for 10 days.
Measure Participants	294	301
Number [Percentage of Participants]	3.7 1.3%	3.0 1%

Adverse Events

Time Frame	All AEs were collected up to Day 13; only serious AEs (SAEs) and drug-related AEs were collected up to Day 50.
Adverse Event Reporting Description	The analysis population consists of all randomized participants who received ≥1 dose of study drug.
Arm/Group Title	CB-183,315		Vancomycin
Arm/Group Description	Participants took CB-183,315 250 mg b.i.d. and placebo b.i.d. by mouth for 10 days.		Participants took vancomycin 125 mg q.i.d. by mouth for 10 days.
All Cause Mortality
	CB-183,315		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/294 (3.1%)		11/301 (3.7%)
Serious Adverse Events
	CB-183,315		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/294 (11.2%)		39/301 (13%)
Blood and lymphatic system disorders
Anaemia	0/294 (0%)	0	1/301 (0.3%)	1
Autoimmune haemolytic anaemia	1/294 (0.3%)	1	0/301 (0%)	0
Leukopenia	1/294 (0.3%)	1	0/301 (0%)	0
Thrombocytopenia	1/294 (0.3%)	1	0/301 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/294 (0%)	0	1/301 (0.3%)	1
Angina pectoris	0/294 (0%)	0	1/301 (0.3%)	1
Cardiac arrest	1/294 (0.3%)	1	2/301 (0.7%)	2
Cardiac failure	1/294 (0.3%)	1	0/301 (0%)	0
Cardiac failure congestive	4/294 (1.4%)	4	2/301 (0.7%)	2
Cardio-respiratory arrest	0/294 (0%)	0	1/301 (0.3%)	1
Left ventricular failure	0/294 (0%)	0	1/301 (0.3%)	1
Myocardial infarction	0/294 (0%)	0	2/301 (0.7%)	2
Pericarditis	0/294 (0%)	0	1/301 (0.3%)	1
Ventricular tachycardia	1/294 (0.3%)	1	0/301 (0%)	0
Congenital, familial and genetic disorders
Sickle cell anaemia with crisis	0/294 (0%)	0	1/301 (0.3%)	1
Endocrine disorders
Adrenal insufficiency	1/294 (0.3%)	1	0/301 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/294 (0.3%)	1	4/301 (1.3%)	4
Diarrhoea	1/294 (0.3%)	1	1/301 (0.3%)	1
Enteritis	0/294 (0%)	0	1/301 (0.3%)	1
Enterovesical fistula	1/294 (0.3%)	1	0/301 (0%)	0
Gastrooesophageal reflux disease	1/294 (0.3%)	1	0/301 (0%)	0
Ileus	0/294 (0%)	0	1/301 (0.3%)	1
Intestinal obstruction	1/294 (0.3%)	1	0/301 (0%)	0
Irritable bowel syndrome	0/294 (0%)	0	1/301 (0.3%)	1
Lower gastrointestinal haemorrhage	1/294 (0.3%)	1	0/301 (0%)	0
Nausea	1/294 (0.3%)	1	0/301 (0%)	0
Pancreatitis	1/294 (0.3%)	1	1/301 (0.3%)	1
Pancreatitis acute	1/294 (0.3%)	1	0/301 (0%)	0
Vomiting	1/294 (0.3%)	1	1/301 (0.3%)	1
General disorders
Impaired healing	1/294 (0.3%)	1	0/301 (0%)	0
Systemic inflammatory response syndrome	0/294 (0%)	0	1/301 (0.3%)	1
Hepatobiliary disorders
Cholecystitis acute	1/294 (0.3%)	1	0/301 (0%)	0
Immune system disorders
Heart transplant rejection	1/294 (0.3%)	1	0/301 (0%)	0
Infections and infestations
Abscess limb	1/294 (0.3%)	1	1/301 (0.3%)	1
Cellulitis	2/294 (0.7%)	2	0/301 (0%)	0
Infective exacerbation of chronic obstructive airways disease	0/294 (0%)	0	1/301 (0.3%)	1
Klebsiella bacteraemia	0/294 (0%)	0	1/301 (0.3%)	1
Lobar pneumonia	1/294 (0.3%)	1	1/301 (0.3%)	1
Pneumonia	3/294 (1%)	3	1/301 (0.3%)	1
Septic shock	0/294 (0%)	0	2/301 (0.7%)	2
Serratia sepsis	1/294 (0.3%)	1	0/301 (0%)	0
Staphylococcal sepsis	1/294 (0.3%)	1	0/301 (0%)	0
Injury, poisoning and procedural complications
Alcohol poisoning	0/294 (0%)	0	1/301 (0.3%)	1
Facial bones fracture	0/294 (0%)	0	1/301 (0.3%)	1
Head injury	0/294 (0%)	0	1/301 (0.3%)	1
Hip fracture	0/294 (0%)	0	1/301 (0.3%)	1
Metabolism and nutrition disorders
Cachexia	0/294 (0%)	0	1/301 (0.3%)	1
Diabetic ketoacidosis	1/294 (0.3%)	1	0/301 (0%)	0
Hypercalcaemia	1/294 (0.3%)	1	0/301 (0%)	0
Hypoglycaemia	1/294 (0.3%)	1	1/301 (0.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/294 (0.3%)	1	0/301 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile duct cancer	0/294 (0%)	0	1/301 (0.3%)	1
Cancer pain	0/294 (0%)	0	1/301 (0.3%)	1
Oesophageal carcinoma	1/294 (0.3%)	1	0/301 (0%)	0
Nervous system disorders
Aphasia	0/294 (0%)	0	1/301 (0.3%)	1
Convulsion	0/294 (0%)	0	1/301 (0.3%)	1
Hepatic encephalopathy	1/294 (0.3%)	1	0/301 (0%)	0
Psychiatric disorders
Depression	1/294 (0.3%)	1	0/301 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/294 (0%)	0	1/301 (0.3%)	1
Dyspnoea	0/294 (0%)	0	1/301 (0.3%)	1
Pleural effusion	1/294 (0.3%)	1	0/301 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	0/294 (0%)	0	1/301 (0.3%)	1
Vascular disorders
Aortic aneurysm rupture	0/294 (0%)	0	1/301 (0.3%)	1
Femoral artery embolism	1/294 (0.3%)	1	0/301 (0%)	0
Hypertensive crisis	0/294 (0%)	0	1/301 (0.3%)	1
Hypovolaemic shock	1/294 (0.3%)	1	1/301 (0.3%)	1
Other (Not Including Serious) Adverse Events
	CB-183,315		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/294 (18%)		72/301 (23.9%)
Gastrointestinal disorders
Diarrhoea	8/294 (2.7%)	9	22/301 (7.3%)	23
Nausea	25/294 (8.5%)	25	23/301 (7.6%)	23
Nervous system disorders
Headache	31/294 (10.5%)	33	36/301 (12%)	38

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.