MK-7625A Plus Metronidazole Versus Meropenem in Pediatric... | NCT03217136

NCT03217136

ID	Type	Description	Link
MK-7625A-035	Other Identifier	Merck
2016-004820-41	EudraCT Number

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Ceftolozane/Tazobactam + Metronidazole	Experimental	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.	Drug: Ceftolozane/Tazobactam Drug: Metronidazole
Meropenem + Placebo for Metronidazole	Active Comparator	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for Metronidazole administered IV every 8 hours for 5 to 14 days.	Drug: Meropenem Drug: Placebo for Metronidazole

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Ceftolozane/Tazobactam	Drug	Ceftolozane 20 mg/kg (maximum 1 g) and tazobactam 10 mg/kg (maximum 0.5 g/dose) administered IV every 8 hours for between 5 to 14 days.	Ceftolozane/Tazobactam + Metronidazole

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants Experiencing ≥1 Adverse Events (AEs)	An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented.	Up to approximately 75 days
Number of Participants Who Discontinued Study Therapy Due to AE(s)	An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE is presented.	Up to approximately 18 days

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Participants With a Clinical Response of "Cure" at the End of Treatment (EOT) Visit	The percentage of participants who had a clinical outcome of "cure" at the time of the EOT visit is presented. The "cure" clinical outcome was defined as complete resolution or marked improvement in signs and symptoms of the complicated intra-abdominal infection (cIAI) or return to pre-infection signs and symptoms such that no further antibiotic therapy (intravenous or oral) or surgical or drainage procedure is required for treatment of the cIAI. Participants who were missing clinical response data were considered treatment failures.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Has a legally acceptable representative who provides documented informed consent/assent for the trial.
Aged from birth (defined as >32 weeks gestational age and ≥7 days postnatal) to <18 years of age.
Require IV antibacterial therapy for the treatment of presumed or documented cIAI.
Has an operative procedure for the current diagnosis and management of cIAI planned or completed within 24 hours of the first dose of an antibacterial drug. Note: Participants with a diagnosis of necrotizing enterocolitis are exempt and not required to have surgery planned or completed in order to be eligible.
Has in compliance baseline intra-abdominal specimen collection.
Is not of reproductive potential; but if of reproductive potential agrees to avoid becoming pregnant or impregnating a partner during screening, while receiving study treatment and for at least 30 days after the last dose of study treatment.
Female of reproductive potential is not pregnant, and not planning to become pregnant within 30 days of the last day of treatment administration; and is nonlactating.

Exclusion Criteria:

Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days prior to the first dose of study treatment in this current trial.
Has previously participated in any trial of ceftolozane or ceftolozane/tazobactam or has enrolled previously in the current trial and been discontinued.
Has a history of any moderate or severe hypersensitivity (e.g, anaphylaxis), allergic reaction, or other contraindication to any of the following: β-lactam antibiotics (e.g, penicillins, cephalosporins, and carbapenems), β-lactamase inhibitors (e.g, tazobactam, sulbactam, clavulanic acid, avibactam), or metronidazole.
Has an IAI within the past 1 year prior to randomization known to be caused by a pathogen resistant to either IV study treatment.
Has a concomitant infection at the time of randomization that requires non-study systemic antibacterial therapy in addition to IV study treatment or oral step-down therapy.
Has received potentially therapeutic antibacterial therapy for a duration more than 24 hours during the 48 hours preceding the first dose of study treatment, unless is considered to be failing antibiotic therapy for cIAI.
Has any of the following: a) intractable cIAI that the investigator anticipates would require more than 14 days of study treatment; b) abdominal wall abscess; c) small bowel obstruction; d) ischemic bowel disease without perforation; e) traumatic bowel perforation with surgery within 12 hours of perforation; f) perforation of gastroduodenal ulcers requiring surgery within 24 hours of perforation; g) suspected uncomplicated intra-abdominal infection (e.g, cholecystitis without rupture or extension beyond the gallbladder wall); h) acute suppurative cholangitis; i) infected necrotizing pancreatitis; j) pancreatic abscess.
Has moderate or severe impairment of renal function.
Has a seizure disorder or is anticipated to be treated with divalproex sodium or valproic acid during the course of study treatment.
Is receiving, or is expected to receive, any prohibited medications.
Has any rapidly progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure, or septic shock.
Has an immunocompromising condition.
Has a history of malignancy ≤5 years prior to signing informed consent.
Is planning to receive suppressive/prophylactic antibiotics with gram-negative activity after completion of study treatment.

Name	Affiliation	Role
Medical Director	Merck Sharp & Dohme LLC	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Children's Hospital - Los Angeles ( Site 2508)		Los Angeles	California	90027	United States
Children's Hospital of Orange County ( Site 2502)

PubMed Identifier	Type	Citation	Retractions
37000942	Result	Jackson CA, Newland J, Dementieva N, Lonchar J, Su FH, Huntington JA, Bensaci M, Popejoy MW, Johnson MG, De Anda C, Rhee EG, Bruno CJ. Safety and Efficacy of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem From a Phase 2, Randomized Clinical Trial in Pediatric Participants With Complicated Intra-abdominal Infection. Pediatr Infect Dis J. 2023 Jul 1;42(7):557-563. doi: 10.1097/INF.0000000000003911. Epub 2023 Mar 29.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
FG001	Meropenem

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Sep 14, 2020

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants Experiencing ≥1 Adverse Events (AEs)

An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented.

All randomized participants who received any amount of study treatment.

Posted

Count of Participants

Participants

Up to approximately 75 days

ID	Title	Description
OG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
OG001	Meropenem	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

Units	Counts
Participants	OG00070 OG00121

Title

Denominators

Categories

Title	Measurements
	OG00056 OG00113

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Difference in Percentage (C/T+MTZ minus MERO)					Difference in Percentage	18.1			2-Sided	95	-2.6	41.1					Other	The Miettinen & Nurminen method was used.

Primary

Number of Participants Who Discontinued Study Therapy Due to AE(s)

All randomized participants who received any amount of study treatment.

Posted

Count of Participants

Participants

Up to approximately 18 days

ID	Title	Description
OG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
OG001	Meropenem	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

Units	Counts
Participants	OG000

Secondary

Percentage of Participants With a Clinical Response of "Cure" at the End of Treatment (EOT) Visit

The percentage of participants who had a clinical outcome of "cure" at the time of the EOT visit is presented. The "cure" clinical outcome was defined as complete resolution or marked improvement in signs and symptoms of the complicated intra-abdominal infection (cIAI) or return to pre-infection signs and symptoms such that no further antibiotic therapy (intravenous or oral) or surgical or drainage procedure is required for treatment of the cIAI. Participants who were missing clinical response data were considered treatment failures.

All randomized participants who received any amount of study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.

Posted

Number

95% Confidence Interval

Percentage of participants

Up to approximately 27 days

ID	Title	Description
OG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
OG001	Meropenem	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

Secondary

Percentage of Participants With a Clinical Response of "Cure" at the Test of Cure (TOC) Visit

The percentage of participants who had a clinical outcome of "cure" at the time of the TOC visit is presented. The "cure" clinical outcome was defined as complete resolution or marked improvement in signs and symptoms of the complicated intra-abdominal infection (cIAI) or return to pre-infection signs and symptoms such that no further antibiotic therapy (intravenous or oral) or surgical or drainage procedure is required for treatment of the cIAI. Participants who were missing clinical response data were considered treatment failures.

Posted

Number

95% Confidence Interval

Percentage of participants

Up to approximately 39 days

ID	Title	Description
OG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
OG001	Meropenem	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

Secondary

Percentage of Participants With Microbiological Eradication at the EOT Visit

The percentage of participants who achieved either eradication or presumed eradication of each baseline infecting pathogen by the time of the EOT visit is presented. Eradication was defined as absence of the baseline pathogen(s) in a postbaseline specimen appropriately obtained from the original site of infection. Presumed eradication was defined as absence of material to culture in a participant who is assessed as having partial improvement, or clinical cure. In the event of multiple baseline pathogens, the least favorable microbiological response from all possible baseline pathogens was used.

All randomized participants who received any amount of study treatment and had at least 1 pathogen identified from the baseline intra-abdominal culture, regardless of susceptibility to study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.

Posted

Number

95% Confidence Interval

Percentage of participants

Up to approximately 27 days

ID	Title	Description
OG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
OG001	Meropenem	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

Secondary

Percentage of Participants With Microbiological Eradication at the TOC Visit

The percentage of participants who achieved either eradication or presumed eradication of each baseline infecting pathogen by the time of the TOC visit is presented. Eradication was defined as absence of the baseline pathogen(s) in a postbaseline specimen appropriately obtained from the original site of infection. Presumed eradication was defined as absence of material to culture in a participant who is assessed as having partial improvement, or clinical cure. In the event of multiple baseline pathogens, the least favorable microbiological response from all possible baseline pathogens was used.

Posted

Number

95% Confidence Interval

Percentage of participants

Up to approximately 39 days

ID	Title	Description
OG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
OG001	Meropenem	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Constipation	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected70 at risk EG0010 events0 affected21 at risk
Faecaloma	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected70 at risk EG0010 events0 affected21 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected70 at risk EG0010 events0 affected21 at risk
Intra-abdominal fluid collection	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected70 at risk EG0010 events0 affected21 at risk
Abdominal sepsis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected70 at risk EG0010 events0 affected21 at risk
Arthritis bacterial	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected70 at risk EG0010 events0 affected21 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected70 at risk EG0010 events0 affected21 at risk
Pneumonia	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0002 events2 affected70 at risk EG0010 events0 affected21 at risk
White blood cell count increased	Investigations	MedDRA 23.0	Systematic Assessment	EG0001 events1 affected70 at risk EG0010 events0 affected21 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0004 events4 affected70 at risk EG0010 events0 affected21 at risk
Thrombocytosis	Blood and lymphatic system disorders	MedDRA 23.0	Systematic Assessment	EG0006 events6 affected70 at risk EG0011 events1 affected21 at risk
Tachycardia	Cardiac disorders	MedDRA 23.0	Systematic Assessment	EG0005 events5 affected70 at risk EG0011 events1 affected21 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0008 events7 affected70 at risk EG0010 events0 affected21 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG00014 events13 affected70 at risk EG0015 events5 affected21 at risk
Vomiting	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment	EG0008 events7 affected70 at risk EG0011 events1 affected21 at risk
Pyrexia	General disorders	MedDRA 23.0	Systematic Assessment	EG00010 events9 affected70 at risk EG0017 events3 affected21 at risk
Nasopharyngitis	Infections and infestations	MedDRA 23.0	Systematic Assessment	EG0003 events3 affected70 at risk EG0014 events3 affected21 at risk
Incision site pain	Injury, poisoning and procedural complications	MedDRA 23.0	Systematic Assessment	EG0007 events7 affected70 at risk EG0011 events1 affected21 at risk
Alanine aminotransferase increased	Investigations	MedDRA 23.0	Systematic Assessment	EG0004 events4 affected70 at risk EG0011 events1 affected21 at risk
Aspartate aminotransferase increased	Investigations	MedDRA 23.0	Systematic Assessment	EG0005 events5 affected70 at risk EG0011 events1 affected21 at risk
Platelet count increased	Investigations	MedDRA 23.0	Systematic Assessment	EG0005 events5 affected70 at risk EG0012 events2 affected21 at risk
Hypertension	Vascular disorders	MedDRA 23.0	Systematic Assessment	EG0004 events4 affected70 at risk EG0010 events0 affected21 at risk

ID	Term
D009593	Nitroimidazoles
D009574	Nitro Compounds
D009930	Organic Chemicals
D007093	Imidazoles
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D013845	Thienamycins
D015780	Carbapenems
D047090	beta-Lactams
D007769	Lactams
D000577	Amides
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring

ID	Title	Description
BG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.
BG001	Meropenem	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Ceftolozane/Tazobactam + Metronidazole	Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days.	0	71	8	70	46	70
EG001	Meropenem	Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days.	0	23	0	21	10	21

ID	Term
C000594038	ceftolozane, tazobactam drug combination
D008795	Metronidazole
D000077731	Meropenem