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

Clostridium Difficile Infection Clinical Trial

— MODIFY III  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03182907
• Other study ID #: 6072-001
• Secondary ID: MK-6072-0012017-
• Status: Completed
• Phase: Phase 3
• Start date: March 27, 2018
• Est. completion date: May 12, 2022

Study information

• Verified date: July 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

Historical adult pharmacokinetic data is from NCT01241552 and NCT01513239.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 148
• Est. completion date: May 12, 2022
• Est. primary completion date: May 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Clostridium Difficile Infection
• Clostridium Infections
• Communicable Diseases
• Infections

Intervention

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.

Drug:
• Placebo
A single IV infusion of placebo for bezlotoxumab consisting of either 0.9% sodium chloride or 5% dextrose.
• 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.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Colombia,  Czechia,  Germany,  Hungary,  Malaysia,  Mexico,  Norway,  Poland,  Portugal,  Romania,  South Africa,  Spain,  Sweden,  United Kingdom, 

References & Publications (1)

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 fo — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Merck Clinical Trial Information