A Phase III Clinical Trial to Evaluate the Protective Efficacy of Three Doses of Oral Rotavirus Vaccine (ORV) 116E

Study Overview
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Brief Summary
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The trial is a phase III randomized, double-blind, placebo-controlled trial with the primary objective of evaluating the efficacy of three doses of ORV 116E, 10^5.0 FFU, against severe rotavirus gastroenteritis, in comparison with a placebo in India.

Detailed Description
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The trial is a phase III randomized, double-blind, placebo-controlled trial with the primary objective of evaluating the efficacy of three doses of ORV 116E, 10^5.0 FFU, against severe rotavirus gastroenteritis, in comparison with a placebo in India. The clinical trial is not a global trial. Three administrations of ORV 116E will be co-administered with childhood vaccines (which will include vaccines against diphtheria, pertussis, tetanus, Haemophilus influenzae B and Hepatitis B and OPV) at 6 to 7 weeks, greater than or equal to 10 weeks and greater than or equal to 14 weeks of age. 6800 subjects will be enrolled in three sites - Delhi, Pune (Maharashtra) and Vellore (Tamil Nadu) and followed up till the age of 2 years (24 months + up to 14 days). Multiple trial sites are included to ensure greater demographic distribution to obtain evidence of cross immunity and quicker recruitment of the necessary number of subjects. The subjects to be included from these sites would be representative of the population of India. The protocol has been reviewed by the institutional review boards of the Society for Applied Studies (New Delhi), KEM Hospital Research Centre (Pune), Christian Medical College (Vellore). Ethics clearance has also been obtained from the Department of Biotechnology, Government of India and Western Institutional Review Board.

Official Title
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A Phase III, Randomized, Double Blind, Placebo Controlled Trial to Evaluate the Protective Efficacy of Three Doses of Oral Rotavirus Vaccine (ORV) 116E, Against Severe Rotavirus Gastroenteritis in Infants

Conditions
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Viral Gastroenteritis Due to Rotavirus

Intervention / Treatment
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* Biological: ORV 116E
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least one parent(s) or legally acceptable representative's consent for participation and are able to understand study procedures Subjects aged 6 to 7 weeks at recruitment No plans to move in the next 24 months Exclusion Criteria: Administration of rotavirus vaccine in the past Presence of any illness requiring hospital referral (temporary exclusion) Known case of immunodeficiency disease, known HIV positive Known case of chronic gastroenteritis disease Any other conditions which in the judgment of the investigator warrant exclusion (e.g. no exclusion criteria but seems ill, investigators suspects neglect) Diarrhea on the day of enrollment (temporary exclusion)

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 7 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Rotavirus Vaccine 116E (ORV 116E)<br>Oral Rotavirus Vaccine 116E (ORV 116E), 10^5.0 FFU of Bharat Biotech International Limited, 3 doses of 0.5 mL at 4 week intervals | Biological: ORV 116E<br>* Oral Rotavirus Vaccine 116E (ORV 116E), 10^5.0 FFU of Bharat Biotech International Limited, 3 doses of 0.5mL at 4 week intervals<br>* Other names: ROTAVAC;|
| Placebo Comparator: Placebo<br>3 doses of 0.5 mL at 4 week intervals | Biological: Placebo<br>* 3 doses of 0.5 mL at 4 week intervals<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy against severe rotavirus gastroenteritis (>=11 on the 20 point Vesikari scoring scale) caused by non vaccine rotavirus | Efficacy of ORV 116E will be assessed in comparison to a placebo against severe rotavirus gastroenteritis (>=11 on the 20 point Vesikari scoring scale) caused by non vaccine rotavirus in all subjects from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days. | Up to 2 years of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy against severe rotavirus gastroenteritis (>=11 on the 20 point Vesikari scoring scale) caused by non vaccine rotavirus | Efficacy of ORV 116E will be assessed in comparison to a placebo against severe rotavirus gastroenteritis (>=11 on the 20 point Vesikari scoring scale) caused by non vaccine rotavirus occurring at least 14 days following the third dose till the age of 12 months + up to 14 days | Up to 1 year of age | 
| Efficacy against severe rotavirus gastroenteritis (>=11 on the 20 point Vesikari scoring scale) caused by non vaccine rotavirus | Efficacy of ORV 116E will be assessed in comparison to a placebo for severe rotavirus gastroenteritis (>=11 on the 20 point Vesikari scoring scale) caused by non vaccine rotavirus occurring from the age of 12 months till the age of 2 years (24 months) + up to 14 days | From the age of 12 months till the age of 2 years of age | 
| Efficacy against severe rotavirus gastroenteritis (>=11 on the 20 point Vesikari scoring scale) caused by non vaccine rotavirus in intent-to-treat population | Efficacy of ORV 116E will be assessed in comparison to a placebo against severe rotavirus gastroenteritis (>=11 on the 20 point Vesikari scoring scale) caused by non vaccine rotavirus in the intent-to-treat population till the age of 2 years (24 months) + up to 14 days. | Up to 2 years of age | 
| Efficacy against any severity of gastroenteritis caused by a non vaccine rotavirus | Efficacy of ORV 116E will be assessed in comparison to a placebo for any severity of gastroenteritis caused by non vaccine rotavirus from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of age | 
| Efficacy against any severity of gastroenteritis irrespective of etiology | Efficacy of ORV 116E will be assessed in comparison to a placebo for any severity of gastroenteritis irrespective of etiology from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of Age | 
| Efficacy against severe (>=11 on the 20 point Vesikari scoring scale) gastroenteritis irrespective of etiology | Efficacy of ORV 116E will be assessed in comparison to a placebo for severe (≥11 on the 20 point Vesikari scoring scale) gastroenteritis irrespective of etiology from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of age | 
| Efficacy to prevent hospitalization and/or supervised rehydration therapy (equivalent to WHO plan B or C) in a treatment facility/hospital for gastroenteritis caused by non vaccine rotavirus | Efficacy of ORV 116E will be assessed in comparison to a placebo to prevent hospitalization and/or supervised re-hydration therapy (equivalent to WHO plan B or C) in a treatment facility/hospital for gastroenteritis caused by non vaccine rotavirus from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of age | 
| Efficacy to prevent hospitalization and/or supervised rehydration therapy (equivalent to WHO plan B or C) in a treatment facility/hospital for gastroenteritis of any etiology | Efficacy of ORV 116E will be assessed in comparison to a placebo to prevent hospitalization and/or supervised re-hydration therapy (equivalent to WHO plan B or C) in a treatment facility/hospital for gastroenteritis of any etiology from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of age | 
| Efficacy to prevent hospitalization and/or supervised re-hydration therapy (equivalent to WHO plan B or C) in a treatment facility/hospital for severe gastroenteritis caused by non vaccine rotavirus | Efficacy of ORV 116E will be assessed in comparison to a placebo to prevent hospitalization and/or supervised re-hydration therapy (equivalent to WHO plan B or C) in a treatment facility/hospital for severe gastroenteritis caused by non vaccine rotavirus from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of age | 
| Efficacy to prevent hospitalization and/or supervised re-hydration therapy (equivalent to WHO plan B or C) in a treatment facility/hospital for severe gastroenteritis of any etiology | Efficacy of ORV 116E will be assessed in comparison to a placebo to prevent hospitalization and/or supervised re-hydration therapy (equivalent to WHO plan B or C) in a treatment facility/hospital for severe gastroenteritis of any etiology from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of age | 
| Efficacy against very severe rotavirus gastroenteritis (≥16 on the 20-point Vesikari scoring system) caused by non vaccine rotavirus | Efficacy of ORV 116E will be assessed in comparison to placebo against very severe rotavirus gastroenteritis (≥16 on the 20-point Vesikari scoring system) caused by non vaccine rotavirus from 14 days following the 3rd dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of age | 
| Safety of ORV 116E for immediate adverse events and serious adverse events in comparison to a placebo | Safety of ORV 116E for immediate adverse events and serious adverse events in comparison to a placebo will be assessed in all the subjects, from day of 1st dose till the age of 2 years (24 months) + up to 14 days. | Up to 2 years of age | 
| Safety of ORV 116E for adverse events in a subset | Safety of ORV 116E for adverse events assessed daily in the 2 week period following each dose in comparison to a placebo in first one third of the enrolled subjects in all the three sites | 2 weeks period following each administration | 
| Safety of ORV 116E for intussusception events | Safety of ORV 116E for intussusception events in comparison to a placebo will be assessed in all subjects, from day of 1st dose till the age of 2 years (24 months) + up to 14 days | Up to 2 years of age | 
| Immunogenicity rates to three doses of the ORV 116E and vaccine virus shedding rates after each of the three doses of the ORV 116E in a subset | Immunogenicity rates to three doses of the ORV 116E and vaccine virus shedding rates after each of the three doses of the ORV 116E in comparison to a placebo will be ascertained in approximately 150 subjects at each site. | 28 days after administration of third dose |