Phase III Study of Liquid Formulation of ROTAVIN

Study Overview
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Brief Summary
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This study is conducted to demonstrate non-inferiority in the immunogenicity of the liquid formulation of ROTAVIN in comparison to currently licensed frozen formulation of the vaccine (ROTAVIN-M1), 28 days after the second vaccination when administered as two dose series starting at 2-3 months of age. The study will also assess the reactogenicity of the vaccine 7 days after each vaccination and safety from first vaccination up to 4 weeks after the last vaccination.

Detailed Description
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The study is designed as a phase III, randomized, partially double-blinded, active controlled study with two groups of infants receiving vaccines at the ratio of 2:1 (liquid formulation of ROTAVIN to frozen formulation ROTAVIN-M1), to compare their immunogenicity and safety. Two doses of vaccine will be administered 8 weeks apart with the first vaccine administration between 60-91 days of age. All childhood vaccines as per the Expanded Program for Immunization of the Government of Vietnam (including Diphtheria, Tetanus, Pertussis, Haemophilus influenzae type b and Hepatitis B vaccine (DTwPHib-HepB), and Oral Polio Vaccine at at 2, 3 and 4 months of age) will be allowed as per the immunization schedule. Active surveillance for vaccine reactogenicity (solicited reactions) over the 7-day period after each vaccination, unsolicited adverse events (AEs) for 4 weeks after each vaccination and serious adverse events (SAEs) including intussusception over the period between first vaccination and four weeks after the last vaccination will be conducted for all infants. This trial will generate immunogenicity and safety data which would be submitted to Ministry of Health in Vietnam for license of new formulation of ROTAVIN vaccine.

Official Title
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A Phase III, Randomized, Partially Double- Blind, Active Control Study to Compare the Immunogenicity and Safety of a Liquid Formulation of ROTAVIN With the Currently Licensed Frozen Formulation of the Vaccine (ROTAVIN-M1), in Healthy Vietnamese Infants

Conditions
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Diarrhea, Diarrhea Rotavirus

Intervention / Treatment
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* Biological: ROTAVIN (liquid formulation)
* Biological: ROTAVIN-M1 (frozen formulation)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy infants as established by medical history and clinical examination before entering the study. Age: 60-91 days (both days inclusive) at the time of enrollment. Parental/legally acceptable representative ability and willingness to provide written informed consent. Parent/legally acceptable representative who intends to remain in the area with the child during the study period. Exclusion Criteria: Presence of diarrhea or vomiting in the previous 72 hours or on the day of enrollment (temporary exclusion). Presence of fever on the day of enrollment (temporary exclusion). Acute disease at the time of enrollment (temporary exclusion). Concurrent participation in another clinical trial at any point throughout the entire time frame for this study. Presence of significant malnutrition (weight-for-height z-score < -3 SD median) Presence of any systemic disorder (cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrine, immunological, dermatological, neurological, cancer, or autoimmune disease) as determined by medical history and / or physical examination which would compromise the participant's health or is likely to result in nonconformance to the protocol. History of congenital abdominal disorders, intussusception, or abdominal surgery. Known or suspected impairment of immunological function based on medical history and physical examination. Household contact with an immunosuppressed individual or pregnant woman. Prior receipt of rotavirus or an intent to receive this vaccine from outside of the study center during study participation. Prior receipt of Expanded Program on Immunization (EPI) vaccination during past 7 days or plan to receive them within next 7 days. A known sensitivity or allergy to any components of the study vaccine. History of allergy to antibiotic kanamycin. Clinically detectable significant congenital or genetic defect. History of persistent diarrhea (defined as diarrhea that lasts 14 days or longer). Receipt of immunoglobulin therapy and / or blood products since birth or planned administration during the study period. History of chronic administration (defined as more than 14 days) of immunosuppressants including corticosteroids. Infants on inhaled or topical steroids may be permitted to participate in the study. Any medical condition in the parent/legally acceptable representative or infant which, in the judgment of the Investigator, would interfere with or serves as a contraindication to protocol adherence.

Ages Eligible for Study
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Minimum Age: 60 Days
Maximum Age: 91 Days

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
Interventional Model Description: Eligible infants will be randomized to receive either ROTAVIN or ROTAVIN-M1 vaccines in the ratio of 2:1.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ROTAVIN Liquid Formulation<br>Participants received two doses of ROTAVIN liquid formulation vaccine orally 8 weeks apart with the first dose administered at 60-91 days of age. | Biological: ROTAVIN (liquid formulation)<br>* Live attenuated human rotavirus vaccine containing ≥ 2x10^6 plaque forming units (PFU) of strain G1P[8] per dose of 2 mL.<br>|
| Active Comparator: ROTAVIN-M1 Frozen Formulation<br>Participants received two doses of ROTAVIN-M1 frozen formulation vaccine orally 8 weeks apart with the first dose administered at 60-91 days of age. | Biological: ROTAVIN-M1 (frozen formulation)<br>* Live attenuated human rotavirus vaccine containing ≥ 2x10^6 PFU of strain G1P[8] per dose of 2 mL.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentration (GMC) of Serum Anti-rotavirus Immunoglobulin A (IgA) Antibodies 28 Days After Second Vaccination | Serum anti-rotavirus IgA antibodies were measured using a validated enzyme linked immunosorbent assay (ELISA) at the Cincinnati Children's Hospital Medical Center (CCHMC), Division of Infectious Diseases in Cincinnati, Ohio USA. | Day 85 (28 days after the second vaccination) | 
| Number of Participants With Solicited Reactions Within 7 Days of Vaccination | Solicited post-vaccination reactogenicity included fever, diarrhea, vomiting, decreased appetite, irritability, and decreased activity level during the seven-day period after each vaccination. Parents were asked to record reactions on a post-immunization diary card. Solicited reactions were graded for severity on a scale from mild to severe based on the level of symptoms. | 7 days after each vaccination (Days 1 to 8 and 57 to 64) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Seroconversion 28 Days After the Second Vaccination | Seroconversion is defined as a post-vaccination serum anti-rotavirus IgA antibody concentration of at least 20 U/mL if the baseline concentration was < 20 U/mL or a post- vaccination serum anti-rotavirus IgA antibody concentration of ≥ 4-fold baseline level if the baseline concentration was ≥ 20 U/mL. | 28 days after the second vaccination (Day 85) | 
| Percentage of Participants With Seropositivity at Baseline and 28 Days After the Second Vaccination | Seropositivity is defined as serum IgA antibody concentration ≥ 20 U/mL | Baseline (Day 1) and at 28 days after the second vaccination (Day 85) | 
| Number of Participants With Immediate Adverse Events (AEs) | After each vaccination participants were observed at the clinic site for at least 30 minutes to check for any immediate AEs including episodes of vomiting and allergic reaction to vaccine. Immediate AEs include all reactions that occurred within 30 minutes of each vaccination. Reactions were graded for severity per the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1, of the US National Institute of Health: Grade 1: Mild symptoms causing no or minimal interference with usual social & functional activities; intervention not indicated. Grade 2: Moderate symptoms causing greater than minimal interference with usual activities; intervention indicated. Grade 3: Severe symptoms causing inability to perform usual activities; intervention or hospitalization indicated. Grade 4: Potentially life-threatening symptoms; intervention indicated to prevent permanent impairment, persistent disability, or death Grade 5: Death | Within 30 minutes after each vaccination on Day 1 and Day 57 | 
| Number of Participants With Unsolicited Adverse Events | An unsolicited AE was any AE that occurred after vaccination, whether or not deemed related to the product, that was not solicited, or, any solicited reaction that started after 7 days post-vaccination. Severity of unsolicited AEs was graded per the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Grade 1: Mild symptoms causing no or minimal interference with usual social & functional activities; intervention not indicated Grade 2: Moderate symptoms causing greater than minimal interference with usual activities; intervention indicated Grade 3: Severe symptoms causing inability to perform usual activities; intervention or hospitalization indicated Grade 4: Potentially life-threatening symptoms; intervention indicated to prevent permanent impairment, persistent disability, or death Grade 5: Death The clinician classified the causality of each AE as related if there was reasonable possibility that the product caused the event. | From vaccination through 28 days after each dose (Days 1 to 28 and 57 to 85) | 
| Number of Participants With Serious Adverse Events Including Intussusception | All Serious adverse events (SAEs), including cases of intussusception, were recorded at all time points between first vaccination and last visit. An SAE was defined as any untoward medical occurrence that: Resulted in death, Was life threatening, Required inpatient hospitalization or prolongation of existing hospitalization, Resulted in persistent or significant disability / incapacity, Was a congenital anomaly or a birth defect, Medically important event Investigator-confirmed cases of intussusception also qualified as an SAE in this study. Intussusception is the infolding (telescoping) of one segment of the intestine within another, usually resulting in a blockage of the intestine. | From first vaccination through 28 days after the last vaccination; 85 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ROTAVIN, Rotavirus vaccine, Rotavirus, Diarrhea