A Phase 3, Randomised, Open-Label, Non-Inferiority Trial Evaluating Anti-Rabies Monoclonal Antibody Cocktail (Twinrab <sup>TM</sup>) Against Human Rabies Immunoglobulin (HRIG)

Abstract

Background: Rabies is a zoonotic disease caused by RNA (ribonucleic acid) viruses of the genus, Lyssavirus of the family, Rhabdoviridae. Limited supply, cost and potential for severe adverse effects observed with the blood derived rabies immunoglobulin products has led to the search for alternative therapies. To address this issue, Cadila Healthcare Ltd. in collaboration with the World Health Organization (WHO) has developed an anti-rabies monoclonal antibody cocktail based product. Methods: This was a phase 3, randomized, multi-centric, open-label, comparator-controlled, non-inferiority trial conducted in 308 patients with WHO category III suspected rabies exposures. Patients meeting the eligibility criteria were assigned to one of the two treatment arms, TwinrabTM or Human rabies immunoglobulin (HRIG; Imogam® Rabies-HT), in a ratio of 1:1. The study drug was administered to patients on Day 0. Five doses of rabies vaccine were also administered (Day 0, 3, 7, 14 and 28) to all the patients following the WHO Essen Schedule. The primary endpoint was the difference in responders [assessed as Rapid Fluorescent Focus Inhibition Test (RFFIT) titre ≥0·5 IU/mL on Day 14] in the TwinrabTM arm as compared to the HRIG arm. Findings: Three hundred and eight patients were randomized; 130 (90·28%) patients in the TwinrabTM arm and 134 (94·37%) patients in the HRIG arm had an RFFIT titre ≥0·5 IU/ml in the per-protocol (PP) population. The Geometric Mean of RFFIT titre in the same population on Day 14 was 4·38 and 4·85 IU/mL respectively, in the TwinrabTM and the HRIG arms. In the modified intent to treat (mITT) population on Day 14, there were 133 (89·86%) responders in the TwinrabTM arm and 137 (90·73%) responders in the HRIG arm. There were no deaths or any other serious adverse events reported during the study period in any of the treatment arms. Interpretation: This study confirmed that TwinrabTM is non-inferior to HRIG in terms of providing an unbroken window of protection as assessed by RFFIT titers up to Day 84. This trial also establishes the safety of TwinrabTM in patients with WHO category III suspected rabies exposures. Trial Registration: CTRI/2017/07/009038. Funding Statement: This trial was sponsored and funded by CHL., Ahmedabad, India. Declaration of Interests: All authors declared no competing interests. Ethics Approval Statement: Written informed consent was given by all study subjects and by parents/legal guardians in cases of children. The consent process was audio-visually recorded at the time of screening for all subjects, as per the local regulations. This trial was initiated after obtaining the approvals of Ethics Committees (ECs), Drugs Controller General of India (DCGI) (dated 17 March 2017) and registering the trial with the Clinical Trial Registry of India (CTRI). This trial was conducted in accordance with the applicable local regulations.