Bezlotoxumab (MK-6072) Versus Placebo in Children With Clostridium Difficile Infection (CDI) (MK-6072-001) (MODIFY III)

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of a Single Infusion of Bezlotoxumab (MK-6072, Human Monoclonal Antibody to C. Difficile Toxin B) in Children Aged 1 to <18 Years Receiving Antibacterial Drug Treatment for C. Difficile Infection (MODIFY III)

The primary objectives of this study are to evaluate the pharmacokinetics (PK), safety, and tolerability of bezlotoxumab (MK-6072) in children aged 1 to <18 years of age with a confirmed diagnosis of Clostridium difficile infection (CDI) who are receiving antibacterial drug treatment. The primary hypothesis is that the area under the concentration-time curve from 0 to infinity (AUC0-inf) of bezlotoxumab after treatment of pediatric participants with bezlotoxumab is similar when compared to the AUC0-inf of bezlotoxumab after treatment of adults with bezlotoxumab.

Study Overview

• Status: Completed
• Conditions: Clostridium Difficile Infection
• Intervention / Treatment: Biological: Bezlotoxumab; Drug: Placebo; Drug: Antibacterial drug treatment (ABD)

Detailed Description

Historical adult pharmacokinetic data is from NCT01241552 and NCT01513239.

• Study Type: Interventional
• Enrollment (Actual): 148
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5016KEH
    • Hospital Privado de Cordoba ( Site 2102)
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1199ABB
      • Hospital Italiano de Buenos Aires. ( Site 2103)
• Brazil
  • Sao Paulo, Brazil, 04039-001
    • Instituto de Oncologia Pediatrica - GRAACC - Unifesp ( Site 0205)
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-321
      • Santa Casa de Misericordia de Belo Horizonte ( Site 0208)
  • Parana
    • Curitiba, Parana, Brazil, 80060-900
      • Hospital de Clinicas da Universidade Federal do Parana ( Site 0203)
    • Curitiba, Parana, Brazil, 80250-060
      • Hospital Pequeno Principe ( Site 0200)
  • Rio Grande Do Sul
    • Santa Maria, Rio Grande Do Sul, Brazil, 97105-900
      • Hospital Universitario da Universidade Federal de Santa Maria ( Site 0209)
• Colombia
  • Antioquia
    • Medellin, Antioquia, Colombia, 05034
      • Hospital Pablo Tobon Uribe-Infectology pediatric ( Site 2166)
  • Distrito Capital De Bogota
    • Bogota, Distrito Capital De Bogota, Colombia, 110131
      • Fundacion Cardioinfantil Instituto de Cardiologia ( Site 2163)
    • Bogotá, Distrito Capital De Bogota, Colombia, 110111
      • Fundacion Santa Fe de Bogota ( Site 2167)
  • Valle Del Cauca
    • Cali, Valle Del Cauca, Colombia, 760032
      • Fundacion Valle del Lili ( Site 2161)
    • Cali, Valle Del Cauca, Colombia, 760042
      • Centro Medico Imbanaco ( Site 2160)
• Czechia
  • Praha 5, Czechia, 150 06
    • 2. LF UK a FN Motol ( Site 2003)
  • Brno-mesto
    • Brno, Brno-mesto, Czechia, 61300
      • Fakultni Nemocnice Brno Bohunice ( Site 2000)
  • Plzensky Kraj
    • Plzen Lochotin, Plzensky Kraj, Czechia, 304 60
      • Fakultni nemocnice Plzen ( Site 2001)
• Germany
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg Eppendorf ( Site 1402)
  • Nordrhein-Westfalen
    • Muenster, Nordrhein-Westfalen, Germany, 48149
      • Universitaetsklinikum Muenster ( Site 1400)
• Hungary
  • Budapest, Hungary, 1094
    • Semmelweis University-II.sz. Gyermekgyógyászati Klinika ( Site 2201)
  • Budapest, Hungary, 1097
    • Del-pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet ( Site 2202)
  • Csongrad
    • Szeged, Csongrad, Hungary, 6720
      • SZTE Szent-Gyorgyi Albert Klinikai Kozpont ( Site 2200)
• Malaysia
  • Kuala Lumpur, Malaysia, 50300
    • Hospital Kuala Lumpur ( Site 3100)
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88996
      • Sabah Womens & Childrens Hospital ( Site 3101)
• Mexico
  • Mexico City, Mexico, 04530
    • Instituto Nacional de Pediatria ( Site 0503)
  • Mexico City, Mexico, 06720
    • Hospital Infantil de Mexico Federico Gomez ( Site 0501)
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64400
      • Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 0508)
    • Monterrey, Nuevo Leon, Mexico, 64710
      • Instituto Tecnologico y de Estudios Superiores de Monterrey ( Site 0502)
• Norway
  • Oslo, Norway, 0372
    • Oslo universitetssykehus ( Site 1500)
  • Vestfold
    • Bergen, Vestfold, Norway, 5053
      • Haukeland universitetssykehus ( Site 1501)
• Poland
  • Kujawsko-pomorskie
    • Bydgoszcz, Kujawsko-pomorskie, Poland, 85-030
      • Wojewodzki Szpital Obserwacyjno Zakazny ( Site 2404)
  • Lodzkie
    • Lodz, Lodzkie, Poland, 91-347
      • Wojewodzki Specjalistyczny Szpital im. dr W. Bieganskiego w Lodzi ( Site 2400)
  • Mazowieckie
    • Lomianki, Mazowieckie, Poland, 05-092
      • SPZOZ im. Dzieci Warszawy w Dziekanowie Lesnym ( Site 2405)
    • Warszawa, Mazowieckie, Poland, 04-730
      • Instytut Pomnik Centrum Zdrowia Dziecka ( Site 2406)
  • Warminsko-mazurskie
    • Olsztyn, Warminsko-mazurskie, Poland, 10-561
      • Wojewodzki Specjalistyczny Szpital Dzieciecy ( Site 2410)
• Portugal
  • Braga, Portugal, 4710-243
    • Hospital de Braga ( Site 1600)
  • Lisboa, Portugal, 1099-023
    • Inst. Portugues de Oncologia de Lisboa Francisco Gentil EPE ( Site 1605)
  • Lisboa, Portugal, 1169-045
    • Centro Hospitalar de Lisboa Central EPE. Hospital D. Estefania ( Site 1601)
  • Porto, Portugal, 4200-072
    • Instituto Portugues de Oncologia Do Porto Francisco Gentil E.P.E. ( Site 1603)
• Romania
  • Bucuresti, Romania, 021105
    • Institutul National de Boli Infectioase Prof. Dr. Matei Bals ( Site 2501)
  • Bucuresti, Romania, 030303
    • Spitalul Clinic de Boli Infectioase si Tropicale Dr. Victor Babes ( Site 2500)
  • Constanta, Romania, 900708
    • Spitalul Clinic de Boli Infectioase Constanta ( Site 2504)
  • Cluj
    • Cluj-Napoca, Cluj, Romania, 400348
      • Spitalul Clinic de Boli Infectioase Cluj-Napoca ( Site 2502)
• South Africa
  • Eastern Cape
    • Port Elizabeth, Eastern Cape, South Africa, 6001
      • Phoenix Pharma Pty Ltd ( Site 2607)
  • Gauteng
    • Centurion, Gauteng, South Africa, 1692
      • Johese Clinical Research ( Site 2605)
    • Johannesburg, Gauteng, South Africa, 1860
      • Chris Hani Baragwanath Academic Hospital ( Site 2602)
    • Pretoria, Gauteng, South Africa, 0208
      • Molotlegi Street ( Site 2603)
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7700
      • Red Cross War Memorial Children's Hospital ( Site 2601)
• Spain
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Nino Jesus ( Site 1701)
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz ( Site 1703)
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio ( Site 1705)
  • Barcelona
    • Esplugues de Llobregat, Barcelona, Spain, 08950
      • Hospital Universitario Sant Joan de Deu ( Site 1704)
• Sweden
  • Stockholms Lan
    • Stockholm, Stockholms Lan, Sweden, 17176
      • ITCC Barnokologen Astrid Lindgrens Barnsjukhus NKS ( Site 1800)
  • Vastra Gotalands Lan
    • Goteborg, Vastra Gotalands Lan, Sweden, 416 85
      • Barncancercentrum ( Site 1801)
• United Kingdom
  • Leeds, United Kingdom, LS1 3EX
    • Leeds Teaching Hospitals NHS Trust ( Site 1901)
  • Worcestershire
    • Southampton, Worcestershire, United Kingdom, SO16 6YD
      • Southampton General Hospital ( Site 1900)
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital - Los Angeles ( Site 0021)
    • San Francisco, California, United States, 94158
      • UCSF Medical Center ( Site 0049)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital - Colorado ( Site 0013)
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Children's Center for Digestive Healthcare ( Site 0052)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago ( Site 0019)
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Our Lady of the Lake Hospital ( Site 0007)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Rubenstein Child Health Building ( Site 0034)
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center-Floating Hospital for Children ( Site 0046)
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester ( Site 0004)
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University ( Site 0037)
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Einstein Center ( Site 0041)
    • New York, New York, United States, 10032
      • Columbia University Medical Center/ MSCHONY ( Site 0042)
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical Center, University Hospital ( Site 0027)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System ( Site 0025)
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center ( Site 0024)
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center ( Site 0029)
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital ( Site 0050)
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center ( Site 0022)
  • Texas
    • San Antonio, Texas, United States, 78207
      • The Children's Hospital of San Antonio ( Site 0009)
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital ( Site 0001)
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Childrens Hospital ( Site 0028)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At screening has suspected or confirmed Clostridium difficile infection (CDI), and is receiving or is planning to receive a 10- to 21-day course of antibacterial drug treatment for CDI
• At study infusion has a diagnosis of CDI confirmed by a diagnostic assay which detects the presence of C. difficile toxin in stool, and is still receiving antibacterial drug treatment for CDI
• Female is not pregnant, and not breastfeeding; but if of childbearing potential agrees to follow contraceptive guidance during the treatment period and for at least 12 weeks after the last dose of study treatment
• Participant and/or parent or caregiver must be able to read, understand, and complete the daily diary

Exclusion Criteria:

• Has an uncontrolled chronic diarrheal illness
• Has a known hypersensitivity to bezlotoxumab, its active substance and/or any of its excipients
• At randomization, their planned course of antibacterial drug treatment for CDI is longer than 21 days
• At screening has received any listed prohibited prior and concomitant treatments and procedures
• Has previously participated in this study, has previously received bezlotoxumab, has received an experimental monoclonal antibody against C. difficile toxin B, or has received a vaccine directed against C. difficile or its toxins.
• Has received an investigational study agent within the previous 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 period

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bezlotoxumab; Participants receive 10 mg of bezlotoxumab per kg body weight via a single 60-minute (±10 minutes) intravenous (IV) infusion on Day 1. Additionally, participants receive background antibacterial drug treatment (ABD) for 10-21 days per institutional guidelines, at the investigator's discretion. Dose may then be changed based on results from initial 12 participants.	Biological: Bezlotoxumab; A single intravenous (IV) infusion of 10 mg of bezlotoxumab per kg body weight. Dose may then be changed based on results from initial 12 participants.; Other Names: MK-6072; Drug: Antibacterial drug treatment (ABD); ABD will be administered for 10-21 days including the duration of ABD prior to the screening visit, during the screening period, and after the infusion of study treatment, per institutional guidelines, at the investigator's discretion. ABD is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.
Placebo Comparator: Placebo; Participants receive placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose via a single 60-minute (±10 minutes) IV infusion on Day 1. Additionally, participants receive background ABD for 10-21 days per institutional guidelines, at the investigator's discretion.	Drug: Placebo; A single IV infusion of placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose.; Drug: Antibacterial drug treatment (ABD); ABD will be administered for 10-21 days including the duration of ABD prior to the screening visit, during the screening period, and after the infusion of study treatment, per institutional guidelines, at the investigator's discretion. ABD is defined as the receipt of oral metronidazole, oral vancomycin, intravenous (IV) metronidazole concurrent with oral vancomycin, oral fidaxomicin, or oral fidaxomicin concurrent with IV metronidazole.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-Time Curve of Bezlotoxumab From Time 0 to Infinity (AUC0-inf)	Blood samples were collected at specified intervals for the determination of AUC0-inf. AUC0-inf was defined as the area under the concentration-time curve of bezlotoxumab from time zero to infinity. Per protocol, AUC0-inf of bezlotoxumab was determined for each age cohort.	Day 1 (2 hours postdose), Days 10, 29, 57, and 85
Percentage of Participants Who Experienced an Adverse Event (AE)	An AE was defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product and does not imply any judgment about causality. Per protocol, percentage of participants with AEs in the bezlotoxumab and placebo groups were presented.	Up to approximately 12 weeks
Percentage of Participants Who Discontinued Study Due to an AE	An AE was defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product and does not imply any judgment about causality. Per protocol, percentage of participants who discontinued study due to AEs in the bezlotoxumab and placebo groups were presented.	Up to approximately 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Had a Clostridium Difficile Infection (CDI) Recurrence	CDI recurrence was defined as diarrhea recurrence (new episode of diarrhea after initial clinical response [ICR] as defined by a change in normal bowel habits for ≥2 days with either watery diarrhea or at least 6 unformed bowel movements [UBMs] within 48-hours) associated with a positive stool test for C. difficile toxin, and for which the participant, in the investigator's opinion, requires and receives ABD treatment for CDI. Per protocol, percentage of participants who had a CDI recurrence in the bezlotoxumab and placebo groups were reported.	Up to approximately 12 Weeks
Percentage of Participants Who Had a Sustained Clinical Response (SCR)	SCR was defined as the ICR of baseline CDI episode (improvement in number and character of bowel movements and doesn't require further CDI therapy within 2 days after completion of up to 21 days of ABD treatment for CDI) and no CDI recurrence (diarrhea recurrence associated with a positive stool test for C. difficile toxin, and for which the participant, in investigator's opinion, requires and receives ABD for CDI). Per protocol, percentage of participants who had a SCR in bezlotoxumab and placebo groups were presented.	Up to approximately 12 Weeks
Percentage of High-Risk Participants Who Experienced a CDI Recurrence	CDI recurrence was defined as diarrhea recurrence (new diarrhea episode after ICR defined by change in normal bowel habits for ≥2 days with watery diarrhea or at least 6 UBMs within 48-hours) with positive stool test for C. difficile toxin for which participant, in investigator's opinion, requires and receives ABD for CDI. High-risk was meeting ≥1 criteria at/before randomization: a) was immunocompromised b) had ≥1 CDI episode prior to baseline episode c) had severe CDI baseline episode d) had C. difficile ribotype027 in stool at baseline CDI episode e) received ≥1 systemic ABD known to increase CDI risk. Per protocol, percentage of high-risk participants who experienced a CDI recurrence in the bezlotoxumab and placebo groups were presented.	Up to approximately 12 Weeks
Percentage of High-Risk Participants Who Experienced a SCR	SCR was ICR of baseline CDI episode (improvement in number and character of bowel movements and doesn't require further CDI therapy within 2 days after completion of up to 21 days of ABD for CDI) and no CDI recurrence (diarrhea recurrence with positive stool test for C. difficile toxin, for which participant, in investigator's opinion, requires and receives ABD for CDI). High-risk was meeting ≥1 criteria: a) was immunocompromised b) had ≥1 episodes of CDI prior to baseline episode c) had severe CDI baseline episode d) had C. difficile ribotype027 in stool at baseline CDI episode e) received ≥1 systemic ABD known to increase CDI risk. Per protocol, percentage of high-risk participants who had SCR in bezlotoxumab and placebo groups were presented.	Up to approximately 12 Weeks
Percentage of Participants Who Experienced One or More Infusion Related Reaction	Infusion related reaction included events meeting any of the 3 criteria: 1) acute onset of an illness involving skin, mucosal tissue, or both and at least 1 of the following: respiratory compromise, reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 2) two or more of the following after onset of study infusion: involving skin-mucosal tissue, respiratory compromise, reduced BP or associated symptoms, or persistent gastrointestinal symptoms 3) reduced BP after onset of infusion or >30% decrease in systolic BP from baseline. Per protocol, percentage of participants experiencing 1 or more infusion-related reactions within 24 hours following the start of study medication infusion were reported.	Up to approximately 24 hours after infusion on Day 1
Percentage of Participants Who Had Positive Antibodies to Bezlotoxumab	Blood samples were collected to determine antibodies to bezlotoxumab. Per protocol, percentage of participants with treatment-emergent positive antibodies to bezlotoxumab following single infusion of bezlotoxumab were reported for each age cohort.	Up to approximately 12 Weeks

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Sferra TJ, Merta T, Neely M, Murta de Oliveira C, Lassaletta A, Fortuny Guasch C, Dorr MB, Winchell G, Su FH, Perko S, Fernsler D, Waskin H, Holden SR. Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III). J Pediatric Infect Dis Soc. 2023 Jun 30;12(6):334-341. doi: 10.1093/jpids/piad031.

Helpful Links

• Merck Clinical Trial Information

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2018
• Primary Completion (Actual): May 12, 2022
• Study Completion (Actual): May 12, 2022

Study Registration Dates

• First Submitted: June 8, 2017
• First Submitted That Met QC Criteria: June 8, 2017
• First Posted (Actual): June 9, 2017

Study Record Updates

• Last Update Posted (Actual): July 27, 2023
• Last Update Submitted That Met QC Criteria: July 25, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Infections; Communicable Diseases; Clostridium Infections; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: 6072-001; 2017-000070-11 (EudraCT Number); MK-6072-001 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No