Study of BBIL's ROTAVAC® and ROTAVAC 5CM Vaccines in Zambia

Study Overview
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Brief Summary
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The study is being conducted to evaluate and compare the immunogenicity of ROTAVAC® and ROTAVAC 5D 28 days after the last dose of the vaccine, when administered to infants in a three-dose schedule at 6, 10 and 14 weeks 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 with ROTAVAC® and ROTAVAC 5D, and of Rotarix® when administered to infants in a two-dose schedule at 6 and 10 weeks of age.

Detailed Description
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This study is designed as a Phase IIb, single center, randomized, controlled, open label study with 3 groups of infants (n=150 per group) receiving either three doses of ROTAVAC® three doses of ROTAVAC 5D or two doses of Rotarix®. 450 participants will be randomized (1:1:1) to receive ROTAVAC®, ROTAVAC 5D or Rotarix®. The three doses of ROTAVAC® and ROTAVAC 5D will be administered at 6, 10 and 14 weeks of age whereas two doses of Rotarix® will be administered at 6 and 10 weeks of age. All vaccines will be administered concomitantly with EPI vaccines including Diphtheria, Tetanus, Pertussis, Haemophilus influenzae type b and Hepatitis B vaccine (DTwP-Hib-HepB), Pneumococcal conjugate vaccine and OPV at 6, 10 and 14 weeks and IPV at week 14 (when switched to in Zambia). The participants will be monitored for 30 minutes following vaccine administration for immediate adverse events. A blood sample will be obtained from all the participating infants before first vaccination and four weeks after the last vaccine dose. This would mean that the blood sample will be collected at approximately 14 weeks of age for infants in the Rotarix® arm and 18 weeks for infants in the ROTAVAC® groups. Enhanced passive/Active surveillance for vaccine reactogenicity (solicited reactions) over the 7-day period after each vaccination will be conducted on all infants. In addition, surveillance for unsolicited AEs, SAEs including intussusception will be carried out over the period between first vaccination and four weeks after the last vaccination on all infants. The study will compare the immunogenicity of the two formulations of ROTAVAC® i.e. ROTAVAC® vs. ROTAVAC 5D and will descriptively analyze the immune response to Rotarix®. Primary immunogenicity analysis of all samples will be based on a validated ELISA which uses strain WC3 as a substrate. A subset of the samples (50 pairs/arms) collected will also be tested by a validated ELISA which uses strain 89-12 (G1P8 virus) as a substrate. This trial will generate immunogenicity and safety data on ROTAVAC® and ROTAVAC 5D outside of India. Presentation of data to Zambian Ministry of Health, WHO and in peer reviewed open access publications will be key audiences targeted for communication of results.

Official Title
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An Open-label, Randomized, Controlled, Single Centre, Phase IIb Study to Assess the Immunogenicity, Reactogenicity and Safety of Three Live Oral Rotavirus Vaccines, ROTAVAC® , ROTAVAC 5CM and Rotarix® in Healthy Zambian Infants

Conditions
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Diarrhea, Diarrhea Rotavirus

Intervention / Treatment
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* Biological: ROTAVAC®
* Biological: ROTAVAC 5D
* Biological: Rotarix®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy infant as established by medical history and clinical examination before entering the study. Age: 6-8 weeks (42-56 days, both days inclusive) confirmed by Immunization Record. Infants received age-appropriate EPI vaccines till enrolment. Ability and willingness to provide informed consent as per local consenting procedures. Parent can be contacted on phone and confirms intention to remain in the study area with the participant during the study period. Exclusion Criteria: Presence of diarrhea or vomiting in the previous 72 hours or on the day of enrolment (temporary exclusion). Presence of fever on the day of enrolment (temporary exclusion). Acute disease at the time of enrolment (temporary exclusion). Concurrent participation in another clinical trial throughout the entire timeframe of this study. Presence of severe malnutrition (weight-for-height z-score < -3SD median). 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 child's health or is likely to result in non-conformance to the protocol. History of congenital abdominal disorders, intussusception, abdominal surgery Known or suspected impairment of immunological function based on medical history and physical examination. Prior receipt or intent to receive rotavirus and other age specified EPI vaccines outside of the study center and during study participation. A known sensitivity or allergy to any component of the study vaccine. Clinically detectable significant congenital or genetic defect. History of persistent diarrhea (defined as diarrhea more than 14 days). Participant's parents not able, available or willing to accept active follow-up by the study staff. Has received any 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. History of any neurologic disorders or seizures. Any medical condition in the parents/infants that, in the judgment of the investigator, would interfere with or serves as a contraindication to protocol adherence or a participant's parent's/legally acceptable representative's ability to give informed consent. Participant is a direct descendant (child or grandchild) of any person employed by the Sponsor, the CRO, the PI or study site personnel.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 8 Weeks

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: Phase IIb, single center, randomized, controlled, open label study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ROTAVAC 5D<br>Bharat Biotech International Ltd's new Rotavirus vaccine, ROTAVAC 5D is a live, attenuated G9P[11] monovalent vaccine at a dose of 0.5mL containing NLT log 10^5.0 focus forming units (FFU) per dose. 5D is in liquid form. | Biological: ROTAVAC 5D<br>* 0.5 ml of the vaccine will be administered orally thrice at 6, 10 and 14 weeks of age.<br>|
| Experimental: ROTAVAC®<br>Bharat Biotech International Ltd's licensed rotavirus vaccine, ROTAVAC® is a live, attenuated G9P[11] monovalent vaccine at a dose of 0.5mL containing NLT log 10^5.0 focus forming units (FFU) per dose. ROTAVAC® is in frozen form and is thawed till fully liquid prior to administration. | Biological: ROTAVAC®<br>* 0.5 ml of the vaccine will be administered orally thrice at 6, 10 and 14 weeks of age.<br>|
| Active Comparator: Rotarix®<br>GSK Biologicals' licensed rotavirus vaccine, Rotarix® is a live attenuated RIX4414 strain of human rotavirus of the G1P[8] type containing not less than 106.0 CCID50 (cell culture infectious dose 50%) of the RIX 4414 strain of human rotavirus. | Biological: Rotarix®<br>* 1.5 ml of the liquid vaccine will be administered orally twice at 6 and 10 weeks of age.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentration Using WC3 as the Viral Lysate | GMC of serum anti-rotavirus IgA antibodies as measured by enzyme linked immunosorbent assay (ELISA) using WC3 (heterologous to vaccine strain) as the viral lysate. WC3 strain of rotavirus used in the ELISA assay was heterologous to the 116E strain contained in the vaccines ROTAVAC 5D® and ROTAVAC®. | 28 day after last dose of the study vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immediate Adverse Events | Percentage of participants reporting immediate adverse events after each vaccination | within 30 minutes' post-vaccination. | 
| Solicited Adverse Events | Percentage of participants reporting solicited post-vaccination reactogenicity (fever, diarrhea, vomiting, decreased appetite, irritability, decreased activity level) | 7 day period after each vaccination. | 
| Unsolicited Adverse Events | Percentage of participants reporting unsolicited AEs at a rate >5%. | From first vaccination through 4 weeks after the last vaccination. | 
| Serious Adverse Events | Percentage of participants reporting SAEs | From first vaccination through 4 weeks after the last vaccination of each study participant. Immunogenicity | 
| Seroconversion Rate in Each of the Three Arms as Measured by ELISA Using WC3 as the Viral Lysate | Seroconversion is defined as a post-vaccination serum anti-rotavirus IgA antibody concentration of at least 20 U/mL if a baseline concentration is < 20 U/mL or a post-vaccination serum anti-rotavirus IgA antibody concentration of ≥ 2-fold baseline level if a baseline concentration is ≥ 20 U/mL. WC3 strain of rotavirus used in the ELISA assay was heterologous to the 116E strain contained in the vaccines ROTAVAC® and ROTAVAC 5D®. | 28 days after last dose of study vaccine. | 
| Seropositivity Rate in Each of the Three Vaccine Arms as Measured by ELISA Using WC3 as the Viral Lysate | Seropositivity is defined as serum anti-rotavirus IgA antibody concentration ≥ 20 U/mL. WC3 strain of rotavirus used in the ELISA assay was heterologous to the 116E strain contained in the vaccines ROTAVAC® and ROTAVAC 5D®. | 28 days after last dose of study vaccine | 
| Seroresponse Rate in Each of the Three Vaccine Arms as Measured by ELISA Using WC3 as the Viral Lysate | Seroresponse will be assessed as a four-fold, three-fold and two- fold rise in antibody concentration from baseline. Seroresponse will be assessed as a four-fold, three-fold and two-fold rise in antibody concentration from baseline. WC3 strain of rotavirus used in the ELISA assay was heterologous to the 116E strain contained in the vaccines ROTAVAC® and ROTAVAC 5D®. | 28 days after last dose of study vaccine | 
| Geometric Mean Fold Rise (GMFR) in Each of the Three Vaccine Arms as Measured by ELISA Using WC3 as the Viral Lysate | GMFR in each of the ROTAVAC 5D®, ROTAVAC® and Rotarix® vaccine arms. WC3 strain of rotavirus used in the ELISA assay was heterologous to the 116E strain contained in the vaccines ROTAVAC® and ROTAVAC 5D®. | At 28 days after last dose of study vaccine in reference to baseline. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diarrhea, Rotavirus, ROTAVAC, Rotavirus vaccine