Comparative Study of Immunogenicity and Safety of a 2-dose Regimen of ProQuad® Manufactured With rHA (V221-038)

Study Overview
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Brief Summary
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The primary study objectives are: To demonstrate that a 2-dose regimen of ProQuad® manufactured with recombinant Human Albumin (rHA) administered at a 3-month interval to healthy children of 11 months of age at the time of Dose 1 is as immunogenic as in healthy children of 12 months of age at the time of Dose 1. To demonstrate that a 2-dose regimen of ProQuad® rHA administered at a 3-month interval to healthy children of 9 months of age at the time of Dose 1 is as immunogenic as in healthy children of 12 months of age at the time of Dose 1. To demonstrate that a 2-dose regimen of ProQuad® rHA administered at a 3-month interval to healthy children of 11 months of age and 9 months of age at the time of Dose 1 is well-tolerated compared to children of 12 months of age at the time of Dose 1. The first primary hypothesis was that a 2-dose regimen of ProQuad® rHA, administered at a 3-month interval to children of 11 months of age, would be non-inferior in terms of antibody response rates to measles, mumps, rubella, and varicella at Day 42 following Dose 2, to the same regimen in children of 12 months of age at the time of Dose 1. If the first primary hypothesis was demonstrated, the second primary hypothesis was that a 2-dose regimen of ProQuad® rHA, administered at a 3-month interval to children of 9 months of age, would be non-inferior in terms of antibody response rates to measles, mumps, rubella, and varicella at Day 42 following Dose 2, to the same regimen in children of 12 months of age at the time of Dose 1. The secondary study objectives are: To describe the antibody titres to measles, mumps, rubella and varicella at Day 42 following Dose 1 and Dose 2 of ProQuad® rHA administered to healthy children from 9 months of age. To evaluate the safety profile of Dose 1 and Dose 2 of ProQuad® rHA administered to healthy children from 9 months of age.

Official Title
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An Open-label, Randomised, Comparative, Multi-centre Study of the Immunogenicity and Safety of a 2-dose Regimen of ProQuad® Manufactured With rHA Administered to Healthy Children From 9 Months of Age

Conditions
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Measles, Mumps, Rubella, Varicella

Intervention / Treatment
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* Biological: ProQuad® manufactured with recombinant Human Albumin (rHA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subject of either gender of 9 months of age Negative clinical history of measles, mumps, rubella, varicella or zoster Informed consent form signed by both parents or legal representative Parent(s) or legal representative able to attend all the scheduled visits with the subject and to understand and comply with the study procedures Both parent or legal representative are over 18 years of age Subject is affiliated to a health social security system Exclusion Criteria: Febrile illness in the previous 3 days Prior vaccination with a measles, mumps, rubella and/or varicella vaccine either alone or in any combination Exposure to measles, mumps, rubella, varicella and/or zoster in the previous 30 days Tuberculin test done in the previous 2 days Severe chronic disease Known active tuberculosis Known personal history of encephalopathy, seizure disorder or progressive, evolving or unstable neurological condition Hereditary problems of fructose intolerance Prior known sensitivity or allergy to any component of the vaccine Known blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems Humoral or cellular immunodeficiency, Immunosuppressive therapy [including systemic corticosteroids (a), given daily or on alternate days at high doses (>=2 mg/kg/day prednisone equivalent or >=20 mg/day if the subject's weight was >10 kg) during at least 14 days in the previous 30 days] Family history of congenital or hereditary immunodeficiency Receipt of immunoglobulins or blood-derived products in the previous 150 days or scheduled to be administered through Visit 5 Receipt of an inactivated vaccine in the previous 14 days Receipt of a live non-study vaccine in the previous 28 days Any medical condition which, in the opinion of the investigator, might have interfered with the evaluation of the study objectives Current participation or scheduled participation in any other clinical study through Visit 5

Ages Eligible for Study
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Minimum Age: 9 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: ProQuad® at 9 and 12 months<br>Pediatric participants received ProQuad® Dose 1 at 9 months of age and ProQuad® Dose 2 at 12 months of age. | Biological: ProQuad® manufactured with recombinant Human Albumin (rHA)<br>* A 2-dose regimen of ProQuad® (0.5 mL per dose) given via subcutaneous injection into the deltoid muscle at a 3-month interval. Each dose contains measles virus Enders' Edmonston strain (live attenuated), mumps virus Jeryl Lynn™ (Level B) strain (live attenuated), rubella virus Wistar RA 27 or 3 strain (live attenuated), and varicella virus Oka or Merck strain (live attenuated).<br>|
| Experimental: Arm 2: ProQuad® at 11 and 14 months<br>Pediatric participants received ProQuad® Dose 1 at 11 months of age and ProQuad® Dose 2 at 14 months of age. | Biological: ProQuad® manufactured with recombinant Human Albumin (rHA)<br>* A 2-dose regimen of ProQuad® (0.5 mL per dose) given via subcutaneous injection into the deltoid muscle at a 3-month interval. Each dose contains measles virus Enders' Edmonston strain (live attenuated), mumps virus Jeryl Lynn™ (Level B) strain (live attenuated), rubella virus Wistar RA 27 or 3 strain (live attenuated), and varicella virus Oka or Merck strain (live attenuated).<br>|
| Active Comparator: Arm 3: ProQuad at 12 and 15 months<br>Pediatric participants received ProQuad® Dose 1 at 12 months of age and ProQuad® Dose 2 at 15 months of age. | Biological: ProQuad® manufactured with recombinant Human Albumin (rHA)<br>* A 2-dose regimen of ProQuad® (0.5 mL per dose) given via subcutaneous injection into the deltoid muscle at a 3-month interval. Each dose contains measles virus Enders' Edmonston strain (live attenuated), mumps virus Jeryl Lynn™ (Level B) strain (live attenuated), rubella virus Wistar RA 27 or 3 strain (live attenuated), and varicella virus Oka or Merck strain (live attenuated).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Arm 2 and Arm 3 Meeting Antibody Immunogenicity Response Criteria Following ProQuad® Dose 2 | Immunogenicity response rates were compared in participants with baseline seronegativity from Arm 2 (received ProQuad® Dose 1 at 11 months) and Arm 3 (received ProQuad® Dose 1 at 12 months). Measles, mumps and rubella antibody levels were determined using enzyme-linked immunosorbent assay (ELISA) and varicella antibody levels were determined with glycoprotein-based ELISA (gpELISA). Response and baseline seronegativity criteria were as follows: measles antibody titre ≥255 mIU/mL in participants with baseline titre <255 mIU/mL; mumps antibody titre ≥10 ELISA Ab units/mL in participants with baseline titre <10 ELISA Ab units mL; rubella antibody titre ≥10 IU/mL in participants with baseline titre <10 IU/mL; varicella antibody titre ≥5 gpELISA units/mL in participants with baseline titre <1.25 gpELISA units/mL. | Day 132 (6 weeks after ProQuad® Dose 2) | 
| Percentage of Participants in Arm 1 and Arm 3 Meeting Antibody Immunogenicity Response Criteria Following ProQuad® Dose 2 | Immunogenicity response rates were compared in participants with baseline seronegativity from Arm 1 (received ProQuad® Dose 1 at 9 months) and Arm 3 (received ProQuad® Dose 1 at 12 months). Measles, mumps and rubella antibody levels were determined using ELISA and varicella antibody levels were determined with gpELISA. Response and baseline seronegativity criteria were as follows: measles antibody titre ≥255 mIU/mL in participants with baseline titre <255 mIU/mL; mumps antibody titre ≥10 ELISA Ab units/mL in participants with baseline titre <10 ELISA Ab units mL; rubella antibody titre ≥10 IU/mL in participants with baseline titre <10 IU/mL; varicella antibody titre ≥5 gpELISA units/mL in participants with baseline titre <1.25 gpELISA units/mL. | Day 132 (6 weeks after ProQuad® Dose 2) | 
| Percentage of Participants With Solicited Injection-site Adverse Reactions | The solicited injection-site AEs erythema, swelling, and pain were monitored for 4 days after administration of ProQuad® Dose 1. | Day 1 to Day 4 (up to 4 days after ProQuad® Dose 1) | 
| Percentage of Participants Experiencing Unsolicited Injection-site Adverse Reactions | The percentage of participants with unsolicited injection-site reactions after ProQuad® Dose 1 was determined. | Up to Day 28 (up to 28 days after ProQuad® Dose 1) | 
| Percentage of Participants Experiencing a Systemic Adverse Event After ProQuad® Dose 1 | The percentage of participants with systemic adverse events after ProQuad® Dose 1 was determined. | Up to Day 28 (up to 28 days after ProQuad® Dose 1) | 
| Percentage of Participants With Rectal (or Rectal Equivalent) Temperature ≥ 39.4°C | The percentage of participants with a rectal (or rectal equivalent) temperature ≥ 39.4°C after ProQuad® Dose 1 was determined. | Up to Day 28 (up to 28 days after ProQuad® Dose 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titres (GMT) to Measles, Mumps, Rubella, and Varicella After ProQuad® Dose 1 | Antibody titres (GMT) to measles, mumps, rubella, and varicella were determined after the first ProQuad® dose in participants with seronegative baseline values. Baseline seronegativity criteria were as follows: measles antibody titre <255 mIU/mL; mumps antibody titre <10 ELISA Ab units mL; rubella antibody titre <10 IU/mL; and varicella antibody titre <1.25 gpELISA units/mL. | Day 42 (6 weeks after ProQuad® Dose 1) | 
| GMT to Measles, Mumps, Rubella, and Varicella After ProQuad® Dose 2 | Antibody titres (GMT) to measles, mumps, rubella, and varicella were determined after the second ProQuad® dose in participants with seronegative baseline values. Baseline seronegativity criteria were as follows: measles antibody titre <255 mIU/mL; mumps antibody titre <10 ELISA Ab units mL; rubella antibody titre <10 IU/mL; and varicella antibody titre <1.25 gpELISA units/mL. | Day 132 (6 weeks after ProQuad® Dose 2) | 
| Percentage of Participants With Varicella Antibody Titre ≥ 1.25 gpELISA Units/mL | The percentage of participants with varicella antibody titre ≥ 1.25 gpELISA units/mL 6 weeks after each ProQuad® dose was determined. | Day 132 (6 weeks after ProQuad® Dose 2) | 
| Percentage of Baseline Seronegative Participants Meeting Antibody Immunogenicity Response Criteria After ProQuad® Dose 1 | The percentage of baseline seronegative participants meeting measles, mumps, rubella, and varicella antibody response criteria after the first ProQuad® dose was determined. Measles, mumps and rubella antibody levels were determined using ELISA and varicella antibody levels were determined with gpELISA. Response and baseline seronegativity criteria were as follows: measles antibody titre ≥255 mIU/mL in participants with baseline titre <255 mIU/mL; mumps antibody titre ≥10 ELISA Ab units/mL in participants with baseline titre <10 ELISA Ab units mL; rubella antibody titre ≥10 IU/mL in participants with baseline titre <10 IU/mL; varicella antibody titre ≥5 gpELISA units/mL in participants with baseline titre <1.25 gpELISA units/mL. | Day 42 (6 weeks after ProQuad® Dose 1) | 
| Percentage of Participants With Non-injection Site Rashes of Interest Following ProQuad® Dose 1 | The percentage of participants with rashes of interest after ProQuad® Dose 1 was determined. Rashes of interest consisted of measles-like rash, rubella-like rash, varicella-like rash, zoster-like rash, and mumps-like rash. | Up to Day 28 (up to 4 weeks after ProQuad® Dose 1) | 
| Percentage of Participants With Non-injection Site Rashes of Interest Following ProQuad® Dose 2 | The percentage of participants with rashes of interest after receiving ProQuad® Dose 2 was determined. Rashes of interest consisted of measles-like rash, rubella-like rash, varicella-like rash, zoster-like rash, and mumps-like rash. | Day 132 (6 weeks after ProQuad® Dose 2) |