Clostridium Difficile InfectionPhase 3MODIFY INCT01241552

A Study of MK-3415, MK-6072, and MK-3415A in Participants Receiving Antibiotic Therapy for Clostridium Difficile Infection (MK-3415A-001)

A Phase 3 study testing MK-3415, MK-6072 and MK-3415A 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

Who is it for?: Ages 18 years and older
Conditions the study is for: Clostridium Difficile Infection
What is being tested?: MK-3415, MK-6072 and MK-3415A
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: 1,452 participants
Where: No sites listed yet
Study dates: 10 Oct 2011to 9 Dec 2014
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 confirmed diagnosis of CDI as defined by: a. diarrhea, as defined by passage of 3 or more loose stools in 24 or fewer hours, AND b. A positive test for toxigenic C. difficile from a stool collected no more than 7 days before study infusion.
participant must be receiving SOC therapy for CDI. SOC therapy 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.
participant is highly unlikely to become pregnant or to impregnate a partner since they meet at least one of the following criteria: a. A female participant who is not of reproductive potential is eligible without requiring the use of contraception. A female participant who is not of reproductive potential is defined as: 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 as determined by the local laboratory, or 12 months of spontaneous amenorrhea); (2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or (3) bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g. anorexia nervosa). b. A participant who is of reproductive potential agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control starting at enrollment and through the 12 Week study period. Acceptable methods of birth control are: intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, vasectomy and any registered and marketed hormonal contraceptives that contain an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents)
participant or legal representative must have voluntarily agreed to participate by providing written informed consent after the nature of the study has been fully explained.

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 a planned surgery for CDI within 24 hours.
participant has a positive pregnancy test in the 48 hours before the infusion or is unwilling to undergo pregnancy testing if a pre-menopausal female who is not sterilized and therefore has the potential to bear a child.
participant is breast-feeding or plans to breast-feed prior to the completion of the 12-week study period.
A female participant who plans to donate ova prior to the completion of the 12-week study period, or a male participant who is planning to impregnate or provide sperm donation prior to the completion of the 12-week study period.
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.

Show all 15Show fewer

participant plans to donate blood and/or blood products within 6 months following the infusion.
participant has received immune globulin within 6 months prior to receipt of the infusion or is planning to receive immune globulin prior to the completion of the 12-week study period.
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 prior to receipt of the infusion or is planning to receive these medications prior to the 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™), at any time during the 14 days following 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 Saccharomyces boulardii or receive fecal transplant therapy, or any other therapies that have been demonstrated to decrease CDI recurrences at any time following infusion (Day 1) and through the completion of the 12-week study period.
participant has received another investigational study agent within the previous 30 days, or is currently participating in or scheduled to participate in any other clinical trial with an investigational agent during the 12-week study period.
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 participating in the study, 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, Adaptive Design Study of the Efficacy, Safety, and Tolerability of a Single Infusion of MK-3415 (Human Monoclonal Antibody to Clostridium Difficile Toxin A), MK-6072 (Human Monoclonal Antibody to Clostridium Difficile Toxin B), and MK-3415A (Human Monoclonal Antibodies to Clostridium Difficile Toxin A and Toxin B) in Patients Receiving Antibiotic Therapy for Clostridium Difficile Infection (MODIFY I)

This study will investigate whether: 1) treatment with MK-3415A in addition to standard of care (SOC) antibiotic therapy will decrease Clostridium difficile infection (CDI) recurrence as compared to treatment with MK-6072 or MK-3415, 2) treatment with MK-3415A, MK-6072, or MK-3415, in addition to SOC antibiotic therapy will decrease CDI recurrence as compared to placebo, and 3) MK-3415A, MK-6072, and MK-3415 will be generally well tolerated in participants receiving SOC therapy for CDI as compared to placebo.

Conditions: Clostridium Difficile Infection
Being tested: MK-3415, MK-6072, MK-3415A, Placebo, SOC
Keywords: Clostridium difficile, recurrent Clostridium difficile, vancomycin, metronidazole, monoclonal antibody, Clostridium difficile infection (CDI)
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-3415Biological
A single IV infusion of MK-3415 (10 mg/kg of monoclonal antibody to Clostridium difficile Toxin A)
MK-6072Biological
A single infusion of MK-6072 (10 mg/kg of monoclonal antibody to Clostridium difficile Toxin B)
MK-3415ABiological
A single IV infusion of MK-3415A (10 mg/kg of monoclonal antibody to Clostridium difficile Toxin A and 10mg/kg of monoclonal antibody to Clostridium difficile Toxin B)
PlaceboBiological
A single IV infusion of normal saline (0.9% sodium chloride)
SOCDrug
Standard of care (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 metranidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.

Study groups in NCT01241552
Study group	Role	What they receive
MK-3415 + SOC	Experimental	Single intravenous (IV) infusion of 10 mg/kg MK-3415 + Standard of Care for CDI Receives: Biological: MK-3415; Drug: SOC
MK-6072 + SOC	Experimental	Single IV infusion of 10 mg/kg MK-6072 + Standard of Care for CDI Receives: Biological: MK-6072; Drug: SOC
MK-3415A + SOC	Experimental	Single IV infusion of 10 mg/kg MK-3415A + Standard of Care for CDI Receives: Biological: MK-3415A; Drug: SOC
Placebo + SOC	Placebo comparator	Normal saline infusion (0.9% sodium chloride) + Standard of Care 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 Clostridium Difficile Infection (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 local or central lab stool test for toxigenic Clostridium (C.) difficile following clinical cure of the initial CDI episode
Measured: Up to 12 weeks
Percentage of Participants With One or More Adverse Events (AEs) During 4 Weeks Following Infusion
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended signs (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specific procedure, whether or not considered related to the medicinal product or protocol specific procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Measured: Up to 28 days
Percentage of Participants With Any Drug-related AE During 4 Weeks Following Infusion
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended signs (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specific procedure, whether or not considered related to the medicinal product or protocol specific procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. A drug-related AE was an AE determined by the investigator to be related to the drug.
Measured: Up to 28 days
Percentage of Participants With Any Serious Adverse Events (SAEs) During 4 Weeks Following Infusion
A SAE is any AE occurring at any dose or during any use of Sponsor's 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 is a cancer, or is associated with an overdose (whether accidental or intentional); or is other important medical events.
Measured: Up to 28 days
Percentage of Participants With Any Serious Drug-related Adverse Events During 4 Weeks Following Infusion
A SAE is any AE occurring at any dose or during any use of Sponsor's 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 is a cancer, or is associated with an overdose (whether accidental or intentional); or is other important medical events. A serious drug-related AE was a SAE determined by the investigator to be related to the drug.
Measured: Up to 28 days
Percentage of Participants Who Discontinued Study Medication Due to an AE During 4 Weeks Following Infusion
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended signs (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specific procedure, whether or not considered related to the medicinal product or protocol-specific procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Measured: Up to 28 days
Percentage of Participants With Infusion-specific AEs
Infusion-specific AEs included local infusion site AEs; and systemic AEs which include nausea, vomiting, chills, fatigue, feeling hot, infusion site conditions (bruising, coldness, erythema, extravasation, pain, phlebitis, pruritus), pyrexia, arthralgia, musculoskeletal pain, myalgia, dizziness, headache, dysphonia, nasal congestion, pruritus, rash, pruritic rash, urticaria, flushing, hot flush, hypertension, and hypotension.
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 and no CDI recurrence through Week 12. Clinical cure is defined as participants who received ≤ 14 day regimen of SOC therapy and have no diarrhea (≤2 loose stools per 24 hours) for two consecutive days following completion of SOC therapy for the initial CDI episode.
Measured: Up to 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 local or central lab stool test for toxigenic C. difficile following clinical cure of the initial CDI episode. Clinical cure is defined as participants who received ≤ 14 day regimen of SOC therapy and have no diarrhea (≤2 loose stools per 24 hours) for two consecutive days following completion of SOC therapy for the baseline CDI episode.
Measured: Up to 12 weeks
Percentage of Participants ≥ 65 Years of Age at Study Entry 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 local or central lab stool test for toxigenic C. difficile following clinical cure of the initial CDI episode.
Measured: Up to 12 weeks
Percentage of Participants With a History of CDI in the 6 Months Prior to Enrollment 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 local or central lab stool test for toxigenic C. difficile following clinical cure of the initial CDI episode.
Measured: Up to 12 weeks
Percentage of Participants With Clinically Severe CDI at Study Entry 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 local or central lab stool test for toxigenic C. difficile following clinical cure of the initial CDI episode. Clinically severe CDI is defined as a Zar Score ≥ 2 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: Up to 12 weeks
Percentage of Participants With the B1/NAP1/027 Strain of C. Difficile at Study Entry 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 local or central lab stool test for toxigenic C. difficile following clinical cure of the initial CDI episode.
Measured: Up to 12 weeks
Percentage of Participants With an Epidemic Strain of C. Difficile (Ribotypes 027, 014, 002, 001, 106, and 020) at Study Entry 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 local or central lab stool test for toxigenic C. difficile following clinical cure of the initial CDI episode.
Measured: Up to 12 weeks
Percentage of Participants With Compromised Immunity at Study Entry 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 local or central lab stool test for toxigenic C. difficile following clinical cure of the initial CDI episode. Compromised immunity is defined as follows: 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: Up to 12 weeks

Timeline

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

10 Oct 20119 Dec 2014

First posted16 Nov 2010 (estimated)
Study start10 Oct 2011
Primary completion9 Dec 2014
Study completion9 Dec 2014

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 (14)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: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 1,452 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01241552
Sponsor's protocol ID: 3415A-001
Acronym: MODIFY I
Status last verified: Aug 2018
First submitted: 12 Nov 2010
Last updated: 5 Sep 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
Individual data sharing: Yes: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Publications

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
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
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
Gerding DN, Kelly CP, Rahav G, Lee C, Dubberke ER, Kumar PN, Yacyshyn B, Kao D, Eves K, Ellison MC, Hanson ME, Guris D, Dorr MB. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence. Clin Infect Dis. 2018 Aug 16;67(5):649-656. doi: 10.1093/cid/ciy171.
PubMed 29538686
Wilcox MH, Gerding DN, Poxton IR, Kelly C, Nathan R, Birch T, Cornely OA, Rahav G, Bouza E, Lee C, Jenkin G, Jensen W, Kim YS, Yoshida J, Gabryelski L, Pedley A, Eves K, Tipping R, Guris D, Kartsonis N, Dorr MB; MODIFY I and MODIFY II Investigators. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. N Engl J Med. 2017 Jan 26;376(4):305-317. doi: 10.1056/NEJMoa1602615.
PubMed 28121498
Desai K, Gupta SB, Dubberke ER, Prabhu VS, Browne C, Mast TC. Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach. BMC Infect Dis. 2016 Jun 18;16:303. doi: 10.1186/s12879-016-1610-3.
PubMed 27316794

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, Adaptive Design Study of the Efficacy, Safety, and Tolerability of a Single Infusion of MK-3415 (Human Monoclonal Antibody to Clostridium Difficile Toxin A), MK-6072 (Human Monoclonal Antibody to Clostridium Difficile Toxin B), and MK-3415A (Human Monoclonal Antibodies to Clostridium Difficile Toxin A and Toxin B) in Patients Receiving Antibiotic Therapy for Clostridium Difficile Infection (MODIFY I)
ClinicalTrials.gov ID: NCT01241552
Acronym / sponsor ID: MODIFY I / 3415A-001
Conditions: Clostridium Difficile Infection
Keywords: Clostridium difficile, recurrent Clostridium difficile, vancomycin, metronidazole, monoclonal antibody, Clostridium difficile infection (CDI)
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 1,452 participants (actual)
Lead sponsor: Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
Study start: 10 Oct 2011 (actual)
Primary completion: 9 Dec 2014 (actual)
Study completion: 9 Dec 2014 (actual)
First posted: 16 Nov 2010 (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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4

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

Who may qualify

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

Key inclusion criteria (4 listed)

participant has a confirmed diagnosis of CDI as defined by: a. diarrhea, as defined by passage of 3 or more loose stools in 24 or fewer hours, AND b. A positive test for toxigenic C. difficile from a stool collected no more than 7 days before study infusion.
participant must be receiving SOC therapy for CDI. SOC therapy 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.
participant is highly unlikely to become pregnant or to impregnate a partner since they meet at least one of the following criteria: a. A female participant who is not of reproductive potential is eligible without requiring the use of contraception. A female participant who is not of reproductive potential is defined as: 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 as determined by the local laboratory, or 12 months of spontaneous amenorrhea); (2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or (3) bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g. anorexia nervosa). b. A participant who is of reproductive potential agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control starting at enrollment and through the 12 Week study period. Acceptable methods of birth control are: intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, vasectomy and any registered and marketed hormonal contraceptives that contain an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents)
participant or legal representative must have voluntarily agreed to participate by providing written informed consent after the nature of the study has been fully explained.

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 a planned surgery for CDI within 24 hours.
participant has a positive pregnancy test in the 48 hours before the infusion or is unwilling to undergo pregnancy testing if a pre-menopausal female who is not sterilized and therefore has the potential to bear a child.
participant is breast-feeding or plans to breast-feed prior to the completion of the 12-week study period.
A female participant who plans to donate ova prior to the completion of the 12-week study period, or a male participant who is planning to impregnate or provide sperm donation prior to the completion of the 12-week study period.

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-3415A single IV infusion of MK-3415 (10 mg/kg of monoclonal antibody to Clostridium difficile Toxin A)	Biological	MK-3415 + SOC
MK-6072A single infusion of MK-6072 (10 mg/kg of monoclonal antibody to Clostridium difficile Toxin B)	Biological	MK-6072 + SOC
MK-3415AA single IV infusion of MK-3415A (10 mg/kg of monoclonal antibody to Clostridium difficile Toxin A and 10mg/kg of monoclonal antibody to Clostridium difficile Toxin B)	Biological	MK-3415A + SOC
PlaceboA single IV infusion of normal saline (0.9% sodium chloride)	Biological	Placebo + SOC
SOCStandard of care (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 metranidazole, oral vancomycin, IV metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.	Drug	MK-3415 + SOC, MK-3415A + SOC, MK-6072 + SOC, Placebo + SOC

Primary outcome

Percentage of Participants With Clostridium Difficile Infection (CDI) Recurrence
Time frame: Up to 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 local or central lab stool test for toxigenic Clostridium (C.) difficile following clinical cure of the initial CDI episode
Percentage of Participants With One or More Adverse Events (AEs) During 4 Weeks Following Infusion
Time frame: Up to 28 days
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended signs (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specific procedure, whether or not considered related to the medicinal product or protocol specific procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Percentage of Participants With Any Drug-related AE During 4 Weeks Following Infusion
Time frame: Up to 28 days
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended signs (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specific procedure, whether or not considered related to the medicinal product or protocol specific procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. A drug-related AE was an AE determined by the investigator to be related to the drug.
Percentage of Participants With Any Serious Adverse Events (SAEs) During 4 Weeks Following Infusion
Time frame: Up to 28 days
A SAE is any AE occurring at any dose or during any use of Sponsor's 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 is a cancer, or is associated with an overdose (whether accidental or intentional); or is other important medical events.
Percentage of Participants With Any Serious Drug-related Adverse Events During 4 Weeks Following Infusion
Time frame: Up to 28 days
A SAE is any AE occurring at any dose or during any use of Sponsor's 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 is a cancer, or is associated with an overdose (whether accidental or intentional); or is other important medical events. A serious drug-related AE was a SAE determined by the investigator to be related to the drug.
Percentage of Participants Who Discontinued Study Medication Due to an AE During 4 Weeks Following Infusion
Time frame: Up to 28 days
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended signs (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specific procedure, whether or not considered related to the medicinal product or protocol-specific procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Percentage of Participants With Infusion-specific AEs
Time frame: Up to 24 hours
Infusion-specific AEs included local infusion site AEs; and systemic AEs which include nausea, vomiting, chills, fatigue, feeling hot, infusion site conditions (bruising, coldness, erythema, extravasation, pain, phlebitis, pruritus), pyrexia, arthralgia, musculoskeletal pain, myalgia, dizziness, headache, dysphonia, nasal congestion, pruritus, rash, pruritic rash, urticaria, flushing, hot flush, hypertension, and hypotension.

8 secondary outcomes

Percentage of Participants With Global Cure
Time frame: Up to 12 weeks
Percentage of Participants With CDI Recurrence in Those With Clinical Cure of the Initial CDI Episode
Time frame: Up to 12 weeks
Percentage of Participants ≥ 65 Years of Age at Study Entry With CDI Recurrence
Time frame: Up to 12 weeks
Percentage of Participants With a History of CDI in the 6 Months Prior to Enrollment With CDI Recurrence
Time frame: Up to 12 weeks
Percentage of Participants With Clinically Severe CDI at Study Entry With CDI Recurrence
Time frame: Up to 12 weeks
Percentage of Participants With the B1/NAP1/027 Strain of C. Difficile at Study Entry With CDI Recurrence
Time frame: Up to 12 weeks
Percentage of Participants With an Epidemic Strain of C. Difficile (Ribotypes 027, 014, 002, 001, 106, and 020) at Study Entry With CDI Recurrence
Time frame: Up to 12 weeks
Percentage of Participants With Compromised Immunity at Study Entry With CDI Recurrence
Time frame: Up to 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-3415 + SOC	242	201
MK-6072 + SOC	403	340
MK-3415A + SOC	403	343
Placebo + SOC	404	340

Primary outcome: Percentage of Participants With Clostridium Difficile Infection (CDI) Recurrence

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

Measure	MK-3415 + SOC n = 232	MK-6072 + SOC n = 386	MK-3415A + SOC n = 383	Placebo + SOC n = 395
Value	25.9	17.4	15.9	27.6

MK-3415 + SOC vs Placebo + SOC: Adjusted Difference: -1.7 (95% CI -8.6 to 5.5), p = 0.3182, Miettinen and Nurminen
MK-6072 + SOC vs Placebo + SOC: Adjusted Difference: -10.1 (95% CI -15.9 to -4.3), p = 0.0003, Miettinen and Nurminen
MK-3415A + SOC vs Placebo + SOC: Adjusted Difference: -11.6 (95% CI -17.4 to -5.9), p < 0.0001, Miettinen and Nurminen

Population analysed: Participants who received infusion of study medication; had a positive local stool test for toxigenic C. difficile; received protocol defined standard of care therapy within 1 day window of the infusion; and complied with Good Clinical Practice.

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

Time frame: Up to 28 days. Number. Unit: Percentage of participants

Measure	MK-3415 + SOC n = 235	MK-6072 + SOC n = 390	MK-3415A + SOC n = 387	Placebo + SOC n = 400
Value	67.2	65.4	59.7	62.0

MK-3415 + SOC vs Placebo + SOC: Percentage Difference: 5.2 (95% CI -2.5 to 12.8), p = 0.185, Miettinen and Nurminen
MK-6072 + SOC vs Placebo + SOC: Percentage Difference: 3.4 (95% CI -3.3 to 10.1), p = 0.323, Miettinen and Nurminen
MK-3415A + SOC vs Placebo + SOC: Percentage Difference: -2.3 (95% CI -9.1 to 4.5), p = 0.507, Miettinen and Nurminen

Population analysed: All randomized participants who received infusion of study medication, based on the treatment actually received. One participant randomized to receive MK-3415A, and two participants randomized to receive MK-6072 actually received placebo instead.

Primary outcome: Percentage of Participants With Any Drug-related AE During 4 Weeks Following Infusion

Time frame: Up to 28 days. Number. Unit: Percentage of participants

Measure	MK-3415 + SOC n = 235	MK-6072 + SOC n = 390	MK-3415A + SOC n = 387	Placebo + SOC n = 400
Value	7.2	8.2	6.2	5.0

MK-3415 + SOC vs Placebo + SOC: Percentage Difference: 2.2 (95% CI -1.5 to 6.7), p = 0.246, Miettinen and Nurminen
MK-6072 + SOC vs Placebo + SOC: Percentage Difference: 3.2 (95% CI -0.3 to 6.8), p = 0.069, Miettinen and Nurminen
MK-3415A + SOC vs Placebo + SOC: Percentage Difference: 1.2 (95% CI -2.1 to 4.6), p = 0.464, Miettinen and Nurminen

Primary outcome: Percentage of Participants With Any Serious Adverse Events (SAEs) During 4 Weeks Following Infusion

Time frame: Up to 28 days. Number. Unit: Percentage of participants

Measure	MK-3415 + SOC n = 235	MK-6072 + SOC n = 390	MK-3415A + SOC n = 387	Placebo + SOC n = 400
Value	27.7	21.5	14.7	20.0

MK-3415 + SOC vs Placebo + SOC: Percentage Difference: 7.7 (95% CI 0.9 to 14.7), p = 0.027, Miettinen and Nurminen
MK-6072 + SOC vs Placebo + SOC: Percentage Difference: 1.5 (95% CI -4.1 to 7.2), p = 0.594, Miettinen and Nurminen
MK-3415A + SOC vs Placebo + SOC: Percentage Difference: -5.3 (95% CI -10.6 to 0.0), p = 0.051, Miettinen and Nurminen

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to 90 days. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
MK-3415 + SOC	104 of 235 (44.3%)	84 of 235 (35.7%)	Not reported
MK-6072 + SOC	120 of 390 (30.8%)	116 of 390 (29.7%)	Not reported
MK-3415A + SOC	94 of 387 (24.3%)	110 of 387 (28.4%)	Not reported
Placebo + SOC	126 of 400 (31.5%)	103 of 400 (25.8%)	Not reported

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 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 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 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.
Derived from this study: PubMed 30227108Kelly 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.
Derived from this study: PubMed 30060024Prabhu 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.
Derived from this study: PubMed 29788418Birch 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.
Derived from this study: PubMed 29538686Gerding DN, Kelly CP, Rahav G, Lee C, Dubberke ER, Kumar PN, Yacyshyn B, Kao D, Eves K, Ellison MC, Hanson ME, Guris D, Dorr MB. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection in Patients at Increased Risk for Recurrence. Clin Infect Dis. 2018 Aug 16;67(5):649-656. doi: 10.1093/cid/ciy171.
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-3415, MK-6072 and MK-3415A 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 4 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 Clostridium Difficile Infection (CDI) Recurrence (time frame: Up to 12 weeks). The study lists 7 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 NCT01241552, which also lists 14 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.