Clostridium Difficile InfectionPhase 3MODIFY IINCT01513239

A Study of MK-6072 and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-002)

A Phase 3 study testing MK-6072, MK-3415A and SOC in people with Clostridium Difficile Infection, run by Merck Sharp & Dohme LLC.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

MK-3415A is the combination of monoclonal antibodies to Clostridium (C.) difficile toxin A (MK-3415) and toxin B (MK-6072). This study will investigate whether: 1) treatment with MK-6072 or MK-3415A in addition to standard of care (SOC) antibiotic therapy will decrease Clostridium Difficile Infection (CDI) recurrence… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Clostridium Difficile Infection
What is being tested?: MK-6072, MK-3415A and SOC
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 1,203 participants
Where: No sites listed yet
Study dates: 1 Feb 2012to 22 May 2015
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Participant has a diagnosis of CDI defined as: a) presence of diarrhea (passage of 3 or more loose stools in 24 or fewer hours); and b) positive test for toxigenic C. difficile from a stool collected no more than 7 days before study infusion.
Participant is receiving SOC therapy (i.e., oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole) for CDI.
Participant is highly unlikely to become pregnant or to impregnate a partner by meeting at least one of the following criteria: a) females not of reproductive potential (i.e., one who has either (1) reached natural menopause, defined as 6 months of spontaneous amenorrhea with serum follicle stimulating hormone [FSH] levels in the postmenopausal range, or 12 months of spontaneous amenorrhea not including cases with an underlying disease, such as anorexia nervosa, that causes amenorrhea; (2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or (3) bilateral tubal ligation); or b) participants of reproductive potential who agree to remain abstinent or use (or have their partner use) two acceptable methods of birth control (i.e., intrauterine device [IUD], diaphragm with spermicide; contraceptive sponge, condom, vasectomy and any registered and marketed hormonal contraceptives that contain an estrogen and/or progestational agent including oral, subcutaneous, intrauterine, or intramuscular agents) starting at enrollment and throughout the 12-week study.

Who cannot join

Participant with an uncontrolled chronic diarrheal illness such that their normal 24-hour bowel movement habit is 3 or more loose stools.
Participant with planned surgery for CDI within 24 hours.
Female participant with a positive pregnancy test in the 48 hours before infusion and pre-menopausal females who are not sterilized and therefore have the potential to bear a child who are unwilling to undergo pregnancy testing.
Female participant breast feeding or planning to breast feed before completion of the 12-week study.
Female participant planning to donate ova before completion of the 12-week study and male participants planning to impregnate or donate sperm before completion of the 12-week study.
Participant has previously participated in this study, has previously received MK-3415 or MK-6072 (either alone or in combination), has received a C. difficile vaccine, or has received another experimental monoclonal antibody against C. difficile toxin A or B.

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Participant plans to donate blood and/or blood products within 6 months after infusion.
Participant has received immune globulin within 6 months before infusion or is planning to receive immune globulin before completion of the 12-week study.
Treatment with SOC therapy is planned for longer than 14 days.
Participant has received more than a 24-hour regimen of cholestyramine, colestimide, rifaximin, or nitazoxanide within 14 days before infusion or plans to receive these medication before completion of the 12-week study period.
Participant plans to take medications that are given to decrease gastrointestinal peristalsis, such as loperamide (Imodium™) or diphenoxylate hydrochloride/atropine sulfate (Lomotil™) any time during the 14 days after infusion. Participants receiving opioid medications at the onset of diarrhea may be included if they are on a stable dose or if there is anticipation of a dose decrease or cessation of use.
Participant plans to take the probiotic Saccaromyces boulardii or plans to receive fecal transplantation therapy, or any other therapies that have been demonstrated to decrease CDI recurrence at any time after infusion (Day 1) and through completion of the 12-week study period.
Participant has received another investigational study agent within the past 30 days or is currently participating in or scheduled to participate in any other clinical study with an investigational agent during the 12-week study.
Participant is not expected to survive for 72 hours.
Participant has any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of the participant, would make it unlikely for the participant to complete the study, or would confound the results of the study.

About this study

Official title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of a Single Infusion of MK-6072 (Human Monoclonal Antibody to Clostridium Difficile Toxin B), and MK-3415A (Human Monoclonal Antibodies to Clostridium Difficile Toxin A and B) in Patients Receiving Antibiotic Therapy for Clostridium Difficile Infection (MODIFY II)

Read the detailed description

An extended 9-month follow-up to assess for CDI recurrence through Month 12 will be conducted in a subset of participants.

Conditions: Clostridium Difficile Infection
Being tested: MK-6072, MK-3415A, Placebo, SOC
Keywords: Clostridium difficile, Clostridium difficile infection (CDI), recurrent Clostridium difficile, vancomycin, metronidazole, monoclonal antibody
Medical subject headings: Clostridium Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

MK-6072Biological
Single IV infusion of MK-6072 (10 mg/kg of monoclonal antibody to C. difficile Toxin B)
MK-3415ABiological
Single IV infusion of MK-3415A (10 mg/kg of monoclonal antibody to C. difficile Toxin A and 10 mg/kg of monoclonal antibody to C. difficile Toxin B)
PlaceboBiological
Single IV infusion of normal saline (0.9% sodium chloride)
SOCDrug
SOC for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.

Study groups in NCT01513239
Study group	Role	What they receive
MK-6072 + SOC	Experimental	Single intravenous (IV) infusion of 10 mg/kg MK-6072 + Standard of Care (SOC) for CDI Receives: Biological: MK-6072; Drug: SOC
MK-3415A + SOC	Experimental	Single IV infusion of 10 mg/kg MK-3415A + SOC for CDI Receives: Biological: MK-3415A; Drug: SOC
Placebo + SOC	Placebo comparator	Normal saline IV infusion (0.9% sodium chloride) + SOC for CDI Receives: Biological: Placebo; Drug: SOC

What is being measured

The primary outcome is the main question the study is designed to answer.

Percentage of Participants With CDI Recurrence
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile after clinical cure of the initial CDI episode. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Measured: 12 weeks
Percentage of Participants With One or More Adverse Events During 4 Weeks Following Infusion Treatment
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.
Measured: Up to 4 weeks
Percentage of Participants With One or More Drug-related Adverse Events During 4 Weeks Following Infusion Treatment
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. A drug-related adverse event is determined by the investigator to be related to the drug.
Measured: Up to 4 weeks
Percentage of Participants With One or More Serious Drug-related Adverse Events During 4 Weeks Following Infusion Treatment
A serious adverse event (SAE) is any AE occurring at any dose or during any use of the medicinal product that results in death; or is life threatening; or results in a persistent or significant disability/incapacity; or results in or prolongs an existing inpatient hospitalization; or is a congenital anomaly/birth defect; or other important medical events. A serious drug-related adverse event is determined by the investigator to be related to the drug.
Measured: Up to 4 weeks
Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event During 4 Weeks Following Infusion Treatment
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.
Measured: Up to 4 weeks
Percentage of Participants With One or More Infusion-specific Adverse Events on the Day of Infusion or the Day After Infusion
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.
Measured: Up to 24 hours

Secondary outcomes (8)

Percentage of Participants With Global Cure
Global cure is defined as the clinical cure of the initial CDI episode with no CDI recurrence through Week 12. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Measured: 12 weeks
Percentage of Participants With CDI Recurrence in Those With Clinical Cure of the Initial CDI Episode
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Measured: 12 weeks
Percentage of Participants With CDI Recurrence in Those With a History of CDI in the 6 Months Prior to Enrollment
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Measured: 12 weeks
Percentage of Participants With CDI Recurrence in Those With the 027 Ribotype
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. The 027 ribotype is a more virulent, epidemic strain responsible for several outbreaks of disease associated with an increased risk of severity and mortality.
Measured: 12 weeks
Percentage of Participants With CDI Recurrence in Those With an Epidemic Strain
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. An epidemic strain includes ribotypes 027, 014, 002, 001, 106 or 020.
Measured: 12 weeks
Percentage of Participants With CDI Recurrence in Those With Clinically Severe CDI
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. Participants with clinically severe CDI have a Zar Score greater than or equal to 2 points based on the presence of 1 or more of the following: 1) age >60 years old (1 point); 2) body temperature >38.3°C (>100°F) (1 point); 3) albumin level ˂2.5 mg/dl (1 point); 4) peripheral white blood cell count >15,000 cells/mm^3 within 48 hours (1 point); 5) endoscopic evidence of pseudomembranous colitis (2 points); and 6) treatment in Intensive Care Unit (2 points).
Measured: 12 weeks
Percentage of Participants With CDI Recurrence in Those 65 Years and Older
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Measured: 12 weeks
Percentage of Participants With CDI Recurrence in Those With Compromised Immunity
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen. Compromised immunity is an active hematological malignancy (including leukemia, lymphoma, multiple myeloma), an active malignancy requiring recent cytotoxic chemotherapy, receipt of a prior hematopoietic stem cell transplant, receipt of a prior solid organ transplant, asplenia, or neutropenia/pancytopenia due to other conditions.
Measured: 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Feb 201222 May 2015

First posted20 Jan 2012 (estimated)
Study start1 Feb 2012
Primary completion22 May 2015
Study completion22 May 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (17)Papers the sponsor has linked to this study.
Other trials for Clostridium Difficile InfectionStudies of the same condition, open and under way.
More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Care provider, Investigator
Enrolment: 1,203 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01513239
Sponsor's protocol ID: 3415A-002
Other IDs: 132231, 2011-004994-94
Acronym: MODIFY II
Status last verified: Aug 2018
First submitted: 16 Jan 2012
Last updated: 5 Sep 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
Individual data sharing: Yes: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Publications

de Almeida C, Wong M, Kleijn HJ, Wrishko RE. Predicted Bezlotoxumab Exposure in Patients Who Have Received a Hematopoietic Stem Cell Transplant. Clin Ther. 2023 Apr;45(4):356-362. doi: 10.1016/j.clinthera.2023.02.006. Epub 2023 Mar 9.
PubMed 36906440
Zhang H, Mehrotra DV, Shen J. AWOT and CWOT for genotype and genotype-by-treatment interaction joint analysis in pharmacogenetics GWAS. Bioinformatics. 2023 Jan 1;39(1):btac834. doi: 10.1093/bioinformatics/btac834.
PubMed 36661328
Bouza E, Cornely OA, Ramos-Martinez A, Plesniak R, Ellison MC, Hanson ME, Dorr MB. Analysis of C. difficile infection-related outcomes in European participants in the bezlotoxumab MODIFY I and II trials. Eur J Clin Microbiol Infect Dis. 2020 Oct;39(10):1933-1939. doi: 10.1007/s10096-020-03935-3. Epub 2020 Jun 6.
PubMed 32504314
Shen J, Mehrotra DV, Dorr MB, Zeng Z, Li J, Xu X, Nickle D, Holzinger ER, Chhibber A, Wilcox MH, Blanchard RL, Shaw PM. Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment. mSphere. 2020 May 6;5(3):e00232-20. doi: 10.1128/mSphere.00232-20.
PubMed 32376702
Zhang H, Zhao N, Mehrotra DV, Shen J. Composite Kernel Association Test (CKAT) for SNP-set joint assessment of genotype and genotype-by-treatment interaction in Pharmacogenetics studies. Bioinformatics. 2020 May 1;36(10):3162-3168. doi: 10.1093/bioinformatics/btaa125.
PubMed 32101275
Cornely OA, Mullane KM, Birch T, Hazan-Steinberg S, Nathan R, Bouza E, Calfee DP, Ellison MC, Wong MT, Dorr MB. Exploratory Evaluation of Bezlotoxumab on Outcomes Associated With Clostridioides difficile Infection in MODIFY I/II Participants With Cancer. Open Forum Infect Dis. 2020 Jan 31;7(2):ofaa038. doi: 10.1093/ofid/ofaa038. eCollection 2020 Feb.
PubMed 32099847
Goldstein EJC, Citron DM, Gerding DN, Wilcox MH, Gabryelski L, Pedley A, Zeng Z, Dorr MB. Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: 12-Month Observational Data From the Randomized Phase III Trial, MODIFY II. Clin Infect Dis. 2020 Aug 14;71(4):1102-1105. doi: 10.1093/cid/ciz1151.
PubMed 31883370
Zeng Z, Zhao H, Dorr MB, Shen J, Wilcox MH, Poxton IR, Guris D, Li J, Shaw PM. Bezlotoxumab for prevention of Clostridium difficile infection recurrence: Distinguishing relapse from reinfection with whole genome sequencing. Anaerobe. 2020 Feb;61:102137. doi: 10.1016/j.anaerobe.2019.102137. Epub 2019 Dec 14.
PubMed 31846705
Kelly CP, Poxton IR, Shen J, Wilcox MH, Gerding DN, Zhao X, Laterza OF, Railkar R, Guris D, Dorr MB. Effect of Endogenous Clostridioides difficile Toxin Antibodies on Recurrence of C. difficile Infection. Clin Infect Dis. 2020 Jun 24;71(1):81-86. doi: 10.1093/cid/ciz809.
PubMed 31628838
Montgomery DL, Matthews RP, Yee KL, Tobias LM, Dorr MB, Wrishko RE. Assessment of Bezlotoxumab Immunogenicity. Clin Pharmacol Drug Dev. 2020 Apr;9(3):330-340. doi: 10.1002/cpdd.729. Epub 2019 Aug 14.
PubMed 31411386
Basu A, Prabhu VS, Dorr MB, Golan Y, Dubberke ER, Cornely OA, Heimann SM, Pedley A, Xu R, Hanson ME, Marcella S. Bezlotoxumab Is Associated With a Reduction in Cumulative Inpatient-Days: Analysis of the Hospitalization Data From the MODIFY I and II Clinical Trials. Open Forum Infect Dis. 2018 Nov 15;5(11):ofy218. doi: 10.1093/ofid/ofy218. eCollection 2018 Nov.
PubMed 30460321
Yee KL, Kleijn HJ, Kerbusch T, Matthews RP, Dorr MB, Garey KW, Wrishko RE. Population Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Clostridium difficile Infection. Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01971-18. doi: 10.1128/AAC.01971-18. Print 2019 Feb.
PubMed 30455246
Kelly CP, Wilcox MH, Glerup H, Aboo N, Ellison MC, Eves K, Dorr MB. Bezlotoxumab for Clostridium difficile Infection Complicating Inflammatory Bowel Disease. Gastroenterology. 2018 Oct;155(4):1270-1271. doi: 10.1053/j.gastro.2018.06.080. Epub 2018 Sep 15. No abstract available.
PubMed 30227108
Prabhu VS, Cornely OA, Golan Y, Dubberke ER, Heimann SM, Hanson ME, Liao J, Pedley A, Dorr MB, Marcella S. Thirty-Day Readmissions in Hospitalized Patients Who Received Bezlotoxumab With Antibacterial Drug Treatment for Clostridium difficile Infection. Clin Infect Dis. 2017 Oct 1;65(7):1218-1221. doi: 10.1093/cid/cix523.
PubMed 30060024
Birch T, Golan Y, Rizzardini G, Jensen E, Gabryelski L, Guris D, Dorr MB. Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection. J Antimicrob Chemother. 2018 Sep 1;73(9):2524-2528. doi: 10.1093/jac/dky182.
PubMed 29788418

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

Official record

Not yet recruitingObservational study
Epidemiology of Clostridioides Difficile Infection (CDI) in Long-term Care Facilities, Assessment of Professional Practices Related to CDI Risk Prevention, and Strategies for Improving Care.
Clostridioides Difficile Infection
Active, not recruitingPhase 2
Autologous Fecal Microbiota Transplantation (Auto-FMT) for Prophylaxis of Clostridium Difficile Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation
Allogeneic Hematopoietic Stem Cell
Active, not recruitingObservational study
C. Difficile Toxin Levels in Stool From Healthy Individuals Following Standard of Care Antibiotic Treatment for CDI.
Clostridioides Difficile Infection Recurrence
RecruitingPhase 3
VE303 for Prevention of Recurrent Clostridioides Difficile Infection
Clostridium Difficile, Clostridium Difficile Infections
RecruitingEarly Phase 1
Prevention of Recurrence of Clostridioides Difficile Colitis With Ursodeoxycholic Acid (UCDA) as a Supplement to Standard Therapy
Clostridioides Difficile Infection

All Clostridium Difficile Infection trials

Study at a glance

From the registry record, last updated by the sponsor on 5 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of a Single Infusion of MK-6072 (Human Monoclonal Antibody to Clostridium Difficile Toxin B), and MK-3415A (Human Monoclonal Antibodies to Clostridium Difficile Toxin A and B) in Patients Receiving Antibiotic Therapy for Clostridium Difficile Infection (MODIFY II)
ClinicalTrials.gov ID: NCT01513239
Acronym / sponsor ID: MODIFY II / 3415A-002
Conditions: Clostridium Difficile Infection
Keywords: Clostridium difficile, Clostridium difficile infection (CDI), recurrent Clostridium difficile, vancomycin, metronidazole, monoclonal antibody
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 1,203 participants (actual)
Lead sponsor: Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
Study start: 1 Feb 2012 (actual)
Primary completion: 22 May 2015 (actual)
Study completion: 22 May 2015 (actual)
First posted: 20 Jan 2012 (estimated)
Results: Posted 15 Dec 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

An extended 9-month follow-up to assess for CDI recurrence through Month 12 will be conducted in a subset of participants.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, care provider, investigator)
Number of arms: 3

Arm	Type	Receives
MK-6072 + SOC	Experimental	Biological: MK-6072, Drug: SOCSingle intravenous (IV) infusion of 10 mg/kg MK-6072 + Standard of Care (SOC) for CDI
MK-3415A + SOC	Experimental	Biological: MK-3415A, Drug: SOCSingle IV infusion of 10 mg/kg MK-3415A + SOC for CDI
Placebo + SOC	Placebo comparator	Biological: Placebo, Drug: SOCNormal saline IV infusion (0.9% sodium chloride) + SOC for CDI

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Participant has a diagnosis of CDI defined as: a) presence of diarrhea (passage of 3 or more loose stools in 24 or fewer hours); and b) positive test for toxigenic C. difficile from a stool collected no more than 7 days before study infusion.
Participant is receiving SOC therapy (i.e., oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole) for CDI.
Participant is highly unlikely to become pregnant or to impregnate a partner by meeting at least one of the following criteria: a) females not of reproductive potential (i.e., one who has either (1) reached natural menopause, defined as 6 months of spontaneous amenorrhea with serum follicle stimulating hormone [FSH] levels in the postmenopausal range, or 12 months of spontaneous amenorrhea not including cases with an underlying disease, such as anorexia nervosa, that causes amenorrhea; (2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or (3) bilateral tubal ligation); or b) participants of reproductive potential who agree to remain abstinent or use (or have their partner use) two acceptable methods of birth control (i.e., intrauterine device [IUD], diaphragm with spermicide; contraceptive sponge, condom, vasectomy and any registered and marketed hormonal contraceptives that contain an estrogen and/or progestational agent including oral, subcutaneous, intrauterine, or intramuscular agents) starting at enrollment and throughout the 12-week study.

Key exclusion criteria (15 listed)

Participant with an uncontrolled chronic diarrheal illness such that their normal 24-hour bowel movement habit is 3 or more loose stools.
Participant with planned surgery for CDI within 24 hours.
Female participant with a positive pregnancy test in the 48 hours before infusion and pre-menopausal females who are not sterilized and therefore have the potential to bear a child who are unwilling to undergo pregnancy testing.
Female participant breast feeding or planning to breast feed before completion of the 12-week study.
Female participant planning to donate ova before completion of the 12-week study and male participants planning to impregnate or donate sperm before completion of the 12-week study.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
MK-6072Single IV infusion of MK-6072 (10 mg/kg of monoclonal antibody to C. difficile Toxin B)	Biological	MK-6072 + SOC
MK-3415ASingle IV infusion of MK-3415A (10 mg/kg of monoclonal antibody to C. difficile Toxin A and 10 mg/kg of monoclonal antibody to C. difficile Toxin B)	Biological	MK-3415A + SOC
PlaceboSingle IV infusion of normal saline (0.9% sodium chloride)	Biological	Placebo + SOC
SOCSOC for CDI will be prescribed for 10 to 14 days and can begin on the day of study drug infusion; but the first dose must have been administered prior to or within a few hours following study drug infusion. SOC is defined as the receipt of oral metronidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.	Drug	MK-3415A + SOC, MK-6072 + SOC, Placebo + SOC

Primary outcome

Percentage of Participants With CDI Recurrence
Time frame: 12 weeks
CDI recurrence is defined as the development of a new episode of diarrhea (3 or more loose stools in 24 or fewer hours) and a positive lab stool test (local or central) for toxigenic C. difficile after clinical cure of the initial CDI episode. Clinical cure is defined as no diarrhea [2 or fewer loose stools per 24 hours] for 2 consecutive days following completion of SOC therapy for the initial CDI episode in participants who received =< 14 day regimen.
Percentage of Participants With One or More Adverse Events During 4 Weeks Following Infusion Treatment
Time frame: Up to 4 weeks
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.
Percentage of Participants With One or More Drug-related Adverse Events During 4 Weeks Following Infusion Treatment
Time frame: Up to 4 weeks
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event. A drug-related adverse event is determined by the investigator to be related to the drug.
Percentage of Participants With One or More Serious Drug-related Adverse Events During 4 Weeks Following Infusion Treatment
Time frame: Up to 4 weeks
A serious adverse event (SAE) is any AE occurring at any dose or during any use of the medicinal product that results in death; or is life threatening; or results in a persistent or significant disability/incapacity; or results in or prolongs an existing inpatient hospitalization; or is a congenital anomaly/birth defect; or other important medical events. A serious drug-related adverse event is determined by the investigator to be related to the drug.
Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event During 4 Weeks Following Infusion Treatment
Time frame: Up to 4 weeks
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.
Percentage of Participants With One or More Infusion-specific Adverse Events on the Day of Infusion or the Day After Infusion
Time frame: Up to 24 hours
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an adverse event.

8 secondary outcomes

Percentage of Participants With Global Cure
Time frame: 12 weeks
Percentage of Participants With CDI Recurrence in Those With Clinical Cure of the Initial CDI Episode
Time frame: 12 weeks
Percentage of Participants With CDI Recurrence in Those With a History of CDI in the 6 Months Prior to Enrollment
Time frame: 12 weeks
Percentage of Participants With CDI Recurrence in Those With the 027 Ribotype
Time frame: 12 weeks
Percentage of Participants With CDI Recurrence in Those With an Epidemic Strain
Time frame: 12 weeks
Percentage of Participants With CDI Recurrence in Those With Clinically Severe CDI
Time frame: 12 weeks
Percentage of Participants With CDI Recurrence in Those 65 Years and Older
Time frame: 12 weeks
Percentage of Participants With CDI Recurrence in Those With Compromised Immunity
Time frame: 12 weeks

Results and safety

Results posted to the registry on 15 Dec 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
MK-3415A + SOC	397	322
MK-6072 + SOC	407	337
Placebo + SOC	399	311
MK-3415A + SOC 9-ME	0	0
MK-6072 + SOC 9-ME	0	0
Placebo + SOC 9-ME	0	0

Primary outcome: Percentage of Participants With CDI Recurrence

Time frame: 12 weeks. Number. Unit: Percentage of participants

Measure	MK-3415A + SOC n = 390	MK-6072 + SOC n = 395	Placebo + SOC n = 378
Value	14.9	15.7	25.7

MK-3415A + SOC vs Placebo + SOC: Adjusted Difference: -10.7 (95% CI -16.4 to -5.1), p <0.0001, Miettinen and Nurminen
MK-6072 + SOC vs Placebo + SOC: Adjusted Difference: -9.9 (95% CI -15.5 to -4.3), p = 0.0003, Miettinen and Nurminen
MK-3415A + SOC vs MK-6072 + SOC: Adjusted Difference: -0.8 (95% CI -5.9 to 4.2), p = 0.3718, Miettinen and Nurminen

Population analysed: The (Full Analysis Set) FAS population consisting of all randomized participants with participants excluded for the failure to receive infusion of study medication; for lack of a positive local stool test for toxigenic C. difficile; or for failure to receive protocol defined standard of care therapy within a 1 day window of the infusion.

Primary outcome: Percentage of Participants With One or More Adverse Events During 4 Weeks Following Infusion Treatment

Time frame: Up to 4 weeks. Number. Unit: Percentage of participants

Measure	MK-3415A + SOC n = 390	MK-6072 + SOC n = 396	Placebo + SOC n = 381
Value	57.4	58.1	60.4

MK-3415A + SOC vs Placebo + SOC: Difference in Percentages: -2.9 (95% CI -9.8 to 4.0), p = 0.408, Miettinen and Nurminen
MK-6072 + SOC vs Placebo + SOC: Difference in Percentages: -2.3 (95% CI -9.2 to 4.6), p = 0.517, Miettinen and Nurminen

Population analysed: All Participants as Treated (APaT), based on the treatment actually received. One participant randomized to the MK- 3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.

Primary outcome: Percentage of Participants With One or More Drug-related Adverse Events During 4 Weeks Following Infusion Treatment

Time frame: Up to 4 weeks. Number. Unit: Percentage of participants

Measure	MK-3415A + SOC n = 390	MK-6072 + SOC n = 396	Placebo + SOC n = 381
Value	6.7	6.8	6.8

MK-3415A + SOC vs Placebo + SOC: Difference in Percentages: -0.2 (95% CI -3.8 to 3.5), p = 0.931, Miettinen and Nurminen
MK-6072 + SOC vs Placebo + SOC: Difference in Percentages: 0.0 (95% CI -3.7 to 3.6), p = 0.997, Miettinen and Nurminen

Population analysed: APaT based on the treatment actually received. One participant randomized to the MK-3415A + SOC arm who was treated with MK-3415, but was not treated with MK-6072, was not analyzed.

Primary outcome: Percentage of Participants With One or More Serious Drug-related Adverse Events During 4 Weeks Following Infusion Treatment

Time frame: Up to 4 weeks. Number. Unit: Percentage of participants

Measure	MK-3415A + SOC n = 390	MK-6072 + SOC n = 396	Placebo + SOC n = 381
Value	0.8	0.0	0.3

MK-3415A + SOC vs Placebo + SOC: Difference in Percentages: 0.5 (95% CI -0.8 to 2.0), p = 0.328, Miettinen and Nurminen
MK-6072 + SOC vs Placebo + SOC: Difference in Percentages: -0.3 (95% CI -1.5 to 0.7), p = 0.308, Miettinen and Nurminen

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: Non-serious adverse events up to Day 28; serious adverse events up to Day 90. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
MK-3415A + SOC	118 of 390 (30.3%)	37 of 390 (9.5%)	31 of 390
MK-6072 + SOC	111 of 396 (28%)	44 of 396 (11.1%)	25 of 396
Placebo + SOC	129 of 381 (33.9%)	37 of 381 (9.7%)	33 of 381
MK-3415 + SOC	1 of 1 (100%)	1 of 1 (100%)	1 of 1
MK-3415A + SOC 9-ME	6 of 112 (5.4%)	0 of 112 (0%)	2 of 112
MK-6072 + SOC 9-ME	7 of 100 (7%)	0 of 100 (0%)	5 of 100
Placebo + SOC 9-ME	3 of 83 (3.6%)	0 of 83 (0%)	2 of 83

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 5 Sep 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 36906440de Almeida C, Wong M, Kleijn HJ, Wrishko RE. Predicted Bezlotoxumab Exposure in Patients Who Have Received a Hematopoietic Stem Cell Transplant. Clin Ther. 2023 Apr;45(4):356-362. doi: 10.1016/j.clinthera.2023.02.006. Epub 2023 Mar 9.
Derived from this study: PubMed 36661328Zhang H, Mehrotra DV, Shen J. AWOT and CWOT for genotype and genotype-by-treatment interaction joint analysis in pharmacogenetics GWAS. Bioinformatics. 2023 Jan 1;39(1):btac834. doi: 10.1093/bioinformatics/btac834.
Derived from this study: PubMed 32504314Bouza E, Cornely OA, Ramos-Martinez A, Plesniak R, Ellison MC, Hanson ME, Dorr MB. Analysis of C. difficile infection-related outcomes in European participants in the bezlotoxumab MODIFY I and II trials. Eur J Clin Microbiol Infect Dis. 2020 Oct;39(10):1933-1939. doi: 10.1007/s10096-020-03935-3. Epub 2020 Jun 6.
Derived from this study: PubMed 32376702Shen J, Mehrotra DV, Dorr MB, Zeng Z, Li J, Xu X, Nickle D, Holzinger ER, Chhibber A, Wilcox MH, Blanchard RL, Shaw PM. Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment. mSphere. 2020 May 6;5(3):e00232-20. doi: 10.1128/mSphere.00232-20.
Derived from this study: PubMed 32101275Zhang H, Zhao N, Mehrotra DV, Shen J. Composite Kernel Association Test (CKAT) for SNP-set joint assessment of genotype and genotype-by-treatment interaction in Pharmacogenetics studies. Bioinformatics. 2020 May 1;36(10):3162-3168. doi: 10.1093/bioinformatics/btaa125.
Derived from this study: PubMed 32099847Cornely OA, Mullane KM, Birch T, Hazan-Steinberg S, Nathan R, Bouza E, Calfee DP, Ellison MC, Wong MT, Dorr MB. Exploratory Evaluation of Bezlotoxumab on Outcomes Associated With Clostridioides difficile Infection in MODIFY I/II Participants With Cancer. Open Forum Infect Dis. 2020 Jan 31;7(2):ofaa038. doi: 10.1093/ofid/ofaa038. eCollection 2020 Feb.
Derived from this study: PubMed 31883370Goldstein EJC, Citron DM, Gerding DN, Wilcox MH, Gabryelski L, Pedley A, Zeng Z, Dorr MB. Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: 12-Month Observational Data From the Randomized Phase III Trial, MODIFY II. Clin Infect Dis. 2020 Aug 14;71(4):1102-1105. doi: 10.1093/cid/ciz1151.
Derived from this study: PubMed 31846705Zeng Z, Zhao H, Dorr MB, Shen J, Wilcox MH, Poxton IR, Guris D, Li J, Shaw PM. Bezlotoxumab for prevention of Clostridium difficile infection recurrence: Distinguishing relapse from reinfection with whole genome sequencing. Anaerobe. 2020 Feb;61:102137. doi: 10.1016/j.anaerobe.2019.102137. Epub 2019 Dec 14.
Derived from this study: PubMed 31628838Kelly CP, Poxton IR, Shen J, Wilcox MH, Gerding DN, Zhao X, Laterza OF, Railkar R, Guris D, Dorr MB. Effect of Endogenous Clostridioides difficile Toxin Antibodies on Recurrence of C. difficile Infection. Clin Infect Dis. 2020 Jun 24;71(1):81-86. doi: 10.1093/cid/ciz809.
Derived from this study: PubMed 31411386Montgomery DL, Matthews RP, Yee KL, Tobias LM, Dorr MB, Wrishko RE. Assessment of Bezlotoxumab Immunogenicity. Clin Pharmacol Drug Dev. 2020 Apr;9(3):330-340. doi: 10.1002/cpdd.729. Epub 2019 Aug 14.
Derived from this study: PubMed 30460321Basu A, Prabhu VS, Dorr MB, Golan Y, Dubberke ER, Cornely OA, Heimann SM, Pedley A, Xu R, Hanson ME, Marcella S. Bezlotoxumab Is Associated With a Reduction in Cumulative Inpatient-Days: Analysis of the Hospitalization Data From the MODIFY I and II Clinical Trials. Open Forum Infect Dis. 2018 Nov 15;5(11):ofy218. doi: 10.1093/ofid/ofy218. eCollection 2018 Nov.
Derived from this study: PubMed 30455246Yee KL, Kleijn HJ, Kerbusch T, Matthews RP, Dorr MB, Garey KW, Wrishko RE. Population Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Clostridium difficile Infection. Antimicrob Agents Chemother. 2019 Jan 29;63(2):e01971-18. doi: 10.1128/AAC.01971-18. Print 2019 Feb.
Individual participant dataSharing planned: Yes. https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Merck Sharp & Dohme LLC

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing MK-6072, MK-3415A and SOC in people with Clostridium Difficile Infection, run by Merck Sharp & Dohme LLC.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Dec 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With CDI Recurrence (time frame: 12 weeks). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01513239, which also lists 17 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Sep 2018.