Safety, Tolerability, and Pharmacokinetics of Clesrovimab (MK-1654) in Infants (MK-1654-002)

Phase 1

Completed

Conditions: Respiratory Tract Infection
Respiratory Syncytial Virus

Interventions: Drug: Clesrovimab
Drug: Placebo

Registration Number: NCT03524118

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and incidence of anti-drug antibodies (ADAs) of single ascending doses of clesrovimab in healthy pre-term (born at 29 to 35 weeks gestational age) and full-term (born at \>35 weeks gestational age) infants. Participants will be randomized into 1 of 4 dose escalation panels (Panels A to D); an additional panel (Panel E) of full-term infants will receive the same dose as Panel D. Key safety and tolerability variables will be reviewed after each dose panel prior to administering the next-highest dose.

Detailed Description: Participants in Dose Panels A, B, C, D1, and E1 will be followed for up to 365 days. After protocol Amendment 4 (AM4), participants in Dose Panels D2 and E2 will be followed for up to 545 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 183

Inclusion Criteria

is healthy, based on screening safety laboratory, medical history, and physical examination results
is a pre-term infant (born at 29 weeks to 35 weeks gestational age [inclusive]) or a full-term infant (born at over 35 weeks gestational age), as confirmed in medical records
weighs ≥2 kg at screening

Exclusion Criteria

has been recommended to receive palivizumab per local standard of care
has ≥1 documented out-of-range safety laboratory results (adjusted for age) at the time of screening
has a known hypersensitivity to any component of the respiratory syncytial virus (RSV) monoclonal antibody
has a history of congenital or acquired immunodeficiency (e.g., splenomegaly)
has documented human immunodeficiency virus (HIV) infection, hepatitis B (HBsAg positive), or hepatitis C (HCV ribonucleic acid [RNA] positive)
has known history of functional or anatomic asplenia
has a diagnosis of failure to thrive within 14 days of screening
has known or history of a coagulation disorder contraindicating intramuscular injection
has received or is expected to receive blood products (except irradiated platelets) within 3 months prior to enrollment
has prior known documented RSV infection
has hemodynamically significant congenital heart disease
has chronic lung disease of prematurity requiring ongoing medical therapy
has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that, in the opinion of the investigator, might expose the participant to undue risk by participating in the study, confound the results of the study, or interfere with the participant's participation for the full duration of the study
has any history of malignancy prior to randomization
if any of the following apply, the Day 1 visit may be rescheduled for a time when these criteria are not met:
has had a recent febrile illness (rectal temperature 38.1°C [100.5°F] or higher or axillary temperature 37.8°C [100.0°F] or higher) within 72 hours pre-dose
is not up-to-date on required vaccinations per local pediatric vaccine schedule at time of screening
has received inactivated or component vaccines (eg, influenza, hepatitis B) less than 14 days pre-dose
has received live, attenuated, non-study licensed pediatric vaccines (e.g., Bacillus Calmette-Guerin vaccine) less than 30 days pre-dose
has received any prior vaccine or monoclonal antibody (mAb) for the prevention of RSV
is currently participating in or has participated in an interventional clinical study with an investigational compound or device at any time prior to first dose administration or while participating in this current study (participants enrolled in observational studies may be included and will be reviewed on a case-by-case basis for approval by the Sponsor)
has enrolled previously in this study and been discontinued
participant's mother participated in a RSV vaccine clinical study while pregnant and participant is ≤3 months of chronological age
is unable to provide blood sample at screening
cannot be adequately followed for safety according to the protocol plan
has a parent/legally acceptable representative who is unlikely to adhere to study procedures, keep appointments, or is planning to relocate during the study
is, or has, an immediate family member (eg, spouse, parent/guardian, sibling, or child) who is directly involved with the study at the site or with the Sponsor

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Panel A: Pre-term clesrovimab Dose 1	Clesrovimab	Pre-term infants will receive clesrovimab Dose 1 via intramuscular (IM) injection and will be followed for up to 365 days.
Panel E2: Full-term clesrovimab Dose 4	Clesrovimab	Full-term infants enrolled after AM4 will receive clesrovimab Dose 4 via IM injection and will be followed for up to 545 days.
Panel E1: Full-term clesrovimab Dose 4	Clesrovimab	Full-term infants enrolled prior to AM4 will receive clesrovimab Dose 4 via IM injection and will be followed for up to 365 days.
Placebo	Placebo	Pre-term infants will receive placebo via IM injection.
Panel C: Pre-term clesrovimab Dose 3	Clesrovimab	Pre-term infants will receive clesrovimab Dose 3 via IM injection and will be followed for up to 365 days.
Panel D1: Pre-term clesrovimab Dose 4	Clesrovimab	Pre-term infants enrolled prior to AM4 will receive clesrovimab Dose 4 via IM injection and will be followed for up to 365 days.
Panel B: Pre-term clesrovimab Dose 2	Clesrovimab	Pre-term infants will receive clesrovimab Dose 2 via IM injection and will be followed for up to 365 days.
Panel D2: Pre-term clesrovimab Dose 4	Clesrovimab	Pre-term infants enrolled after AM4 will receive clesrovimab Dose 4 via IM injection and will be followed for up to 545 days.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced At Least One Solicited Systemic Adverse Event (AE)	Up to Day 5	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Solicited systemic AEs were monitored from Day 1 to Day 5.
Percentage of Participants Who Experienced At Least One Solicited Injection Site Adverse Event (AE)	Up to Day 5	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Solicited injection site AEs were monitored from Day 1 to Day 5.
Percentage of Participants Who Experienced At Least One Serious Adverse Event (SAE)	Up to Day 545	An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event.

Secondary Outcome Measures

Name	Time	Method
Serum Concentration of Clesrovimab on Day 365 (C365days)	Day 365	Serum concentration of clesrovimab was measured on Day 365.
Area Under the Serum-Concentration Time Curve From Zero to Infinity (AUC0-∞)	At designated time points (up to 1 year post-dose)	AUC0-∞ is a measure of the extrapolated mean concentration in serum from dosing to infinity.
Maximum Serum Concentration (Cmax) of Clesrovimab	At designated time points (up to 1 year post-dose)	Cmax is the highest observed serum drug concentration.
Time to Maximum Serum Concentration (Tmax) of Clesrovimab	At designated time points (up to 1 year post-dose)	Tmax is the time taken to reach the maximum observed plasma (Cmax) concentration of Clesrovimab.
Serum Concentration of Clesrovimab on Day 7 (C7days)	Day 7	Serum concentration of clesrovimab was measured on Day 7.
Apparent Terminal Half-life (t1/2) of Clesrovimab	At designated time points (up to 1 year post-dose)	t1/2 is the time required for 50% of drug to be cleared from serum.
Serum Concentration of Clesrovimab on Day 90 (C90days)	Day 90	Serum concentration of clesrovimab was measured on Day 90.
Serum Concentration of Clesrovimab on Day 14 (C14days)	Day 14	Serum concentration of clesrovimab was measured on Day 14.
Number of Participants With Positive Titer of Anti-Drug Antibodies (ADAs) for Clesrovimab: Panels A, B, C, D1, D2, E1, and E2	Days 14, 90, 150, 365 and 545	ADA was assessed at 2 or 3 of the following timepoints for each participant: Days 14, 90, 150, 365 and 545. ADA status for each participant was determined across the timepoints assessed. The definitions of the categories are as follows: (1) ADA Negative: participants whose ADA results were negative at all timepoints measured; (2) Non-treatment emergent positive: participants whose ADA result was positive only at baseline or if postdose titer increased by less than 2-fold relative to the baseline titer; (3) Positive response to MK-1654: participants whose ADA result was negative at baseline and positive at one or more postdose timepoints or participants whose ADA result was positive at baseline and postdose titer increased by greater than or equal to 2-fold relative to the baseline titer.
Serum Concentration of Clesrovimab on Day 150 (C150days)	Day 150	Serum concentration of clesrovimab was measured on Day 150.

Trial Locations

Locations (34): Chris Hani Baragwanath Academic Hospital ( Site 0262)
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Johannesburg, Gauteng, South Africa
Next Phase Research Alliance, LLC ( Site 0075)
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Homestead, Florida, United States
Cotton-O'Neil Clinical Research Center PediatricCare ( Site 0081)
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Topeka, Kansas, United States
Hospital Universitario La Paz ( Site 0242)
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Madrid, Spain
University of Wisconsin American Family Children's Hospital ( Site 0068)
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Madison, Wisconsin, United States
University of Texas Medical Branch at Galveston ( Site 0039)
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Galveston, Texas, United States
Centro de Investigacion Clinica Bradford Hill ( Site 0103)
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Santiago, Region M. De Santiago, Chile
Multicare Institute For Research And Innovation ( Site 0035)
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Tacoma, Washington, United States
Fundacion Universitaria de Ciencias de la Salud - Sociedad de Cirugia ( Site 0099)
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Bogota, Distrito Capital De Bogota, Colombia
Fundacion Valle del Lili ( Site 0090)
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Cali, Valle Del Cauca, Colombia
Seoul National University Hospital ( Site 0071)
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Seoul, Korea, Republic of
Severance Hospital Yonsei University Health System ( Site 0073)
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Seoul, Korea, Republic of
Samsung Medical Center ( Site 0072)
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Seoul, Korea, Republic of
Tygerberg Hospital ( Site 0261)
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Cape Town, Western Cape, South Africa
Hospital Clinico Universitario de Santiago ( Site 0241)
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Santiago de Compostela, La Coruna, Spain
Kapiolani Medical Center for Women and Children ( Site 0027)
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Honolulu, Hawaii, United States
Children's Mercy Hospital ( Site 0037)
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Kansas City, Missouri, United States
Dartmouth-Hitchcock Medical Center ( Site 0032)
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Lebanon, New Hampshire, United States
SUNY Upstate Medical University Hospital ( Site 0029)
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Syracuse, New York, United States
WakeMed Health and Hospitals ( Site 0033)
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Raleigh, North Carolina, United States
Ohio Pediatric Research Association ( Site 0066)
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Dayton, Ohio, United States
Coastal Pediatric Research ( Site 0028)
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Charleston, South Carolina, United States
Tribe Clinical Research, LLC ( Site 0082)
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Greenville, South Carolina, United States
Hospital La Florida ( Site 0050)
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Santiago, Region M. De Santiago, Chile
Centro de Atención e Investigación Médica SAS - CAIMED CHIA ( Site 0100)
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Chia, Cundinamarca, Colombia
Children's Hospital - Colorado ( Site 0067)
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Aurora, Colorado, United States
Acevedo Clinical Research Associates ( Site 0025)
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Miami, Florida, United States
Tekton Research, Inc. ( Site 0026)
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San Antonio, Texas, United States
Cincinnati Children's Hospital Medical Center ( Site 0031)
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Cincinnati, Ohio, United States
Fundacion Hospital San Vicente de Paul ( Site 0097)
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Medellin, Antioquia, Colombia
Facultad Medicina Universidad de Chile ( Site 0104)
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Santiago, Region M. De Santiago, Chile
Hospital Padre Hurtado ( Site 0102)
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Santiago, Region M. De Santiago, Chile
Universidad Pontificia Bolivariana - Clinica Universitaria Bolivariana ( Site 0098)
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Medellin, Antioquia, Colombia
MedPlus Medicina Prepagada S.A. ( Site 0095)
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Bogota, Distrito Capital De Bogota, Colombia