A Phase IIa, Proof-of-Concept, Placebo-Controlled, Randomised Trial to Investigate the Efficacy and Safety of Oxfendazole as a Macrofilaricidal Drug in Adults Harbouring Lymphatic Filarial Worms

Abstract

Introduction

Lymphatic filariasis (LF) remains a significant public health concern, with India contributing nearly 55% of the global disease burden and placing approximately 487 million people at risk of infection. Despite the success of mass drug administration (MDA) programs in reducing microfilaraemia, the current regimens have limited macrofilaricidal activity, which hinders the achievement of LF elimination goals. The development of safe and effective drugs targeting adult filarial worms is, therefore, a critical priority. This phase IIa, proof-of-concept study aims to evaluate the efficacy, safety, and pharmacokinetic (PK) profile of oxfendazole in adults with confirmed LF. The primary objective is to estimate the proportion of participants with no detectable adult worm motility on ultrasonography (USG) at 6 months post-treatment, serving as a marker of macrofilaricidal efficacy. Secondary objectives include assessment of safety and tolerability, while exploratory objectives involve the characterization of the PK profile of oxfendazole in the study population.

Methods

The study is designed as a phase IIa, randomised, double-blind, placebo-controlled trial with three arms. Participants will be randomised to receive either 400 mg or 800 mg of oxfendazole, or a matching placebo, administered orally once daily for five consecutive days. Oxfendazole, a benzimidazole and structural analogue of flubendazole, has shown promising macrofilaricidal activity in preclinical models, demonstrating complete clearance of adult worms in mice. Phase I clinical studies have established its safety and tolerability in humans, supporting its progression to further clinical evaluation. Ethics approval has been obtained by the independent ethics committees (IEC) of all the participating study sites. This study will be performed in accordance with the Helsinki Declaration of 1964 and its later amendments, ICH-GCP, applicable regulatory requirements and approved study protocol. The details of ethics committee approvals are available in the supplementary material.

Planned Outcomes

The findings from this trial will be pivotal in guiding the clinical development of oxfendazole, particularly in defining an optimal dosing regimen for use as a macrofilaricidal agent. If successful, this intervention could represent a significant advancement toward the elimination of LF. This study supports India’s national target to eliminate LF by 2027 and aligns with the World Health Organization’s global elimination goal by 2030.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s40121-026-01419-z.

Key Summary Points

High disease burden: LF remains a major public health challenge, with India contributing approximately 55% of the global burden and approximately 487 million people at risk.

Unmet need: Current MDA regimens reduce microfilaraemia but lack effective macrofilaricidal activity, limiting elimination efforts.

Study design: Phase IIa, randomised, double-blind, placebo-controlled trial evaluating oxfendazole (400 mg, 800 mg vs placebo) for 5 days in adults with confirmed LF.

Primary outcome: Proportion of participants with absence of adult worm motility on ultrasonography at 6 months, indicating macrofilaricidal efficacy.

Significance: Findings will inform optimal dosing and could accelerate LF elimination, aligning with India’s 2027 target and World Health Organization goal of 2030.

Introduction

Background and Rationale

Lymphatic filariasis (LF) is a neglected tropical disease that affects an estimated population of around 31 million in India [1]. Brancoftian filariasis caused by Wuchereria bancrofti, transmitted by culex species of mosquitoes, accounts for most cases in India.

The current management therapy is five pronged and includes (a) MDA of three drugs namely ivermectin, albendazole and diethylcarbamazine, given annually or biannually; (b) morbidity management and disability prevention that aims to treat acute recurrent attacks of acute dermatolymphangioadenitis (ADLA), management of lymphoedema, surgery for hydrocele and treating acute infections, and consequently progression of the disease; (c) integrated vector management (IVM) that includes larvicidal measures, personal protection against mosquitoes in the form of ointments/creams/bed nets and measures against adult mosquitos (aerosols/sprays) etc.; (d) high Level advocacy which includes intersectoral convergence with allied departments and ministries such as the Ministry of Water and Sanitation, Ministry of Panchayati Raj, Ministry of Human Resource Development (HRD), Ministry of Urban and Rural Development; and (e) innovative approaches such as leveraging existing digital platforms for LF and exploring alternative diagnostics [2].

Despite these strategies, challenges remain in reducing the prevalence to a level at which transmission is probably no longer sustainable and recrudescence is unlikely to occur, even in the absence of MDA. It may be noted that all the above strategies focus on hindering the transmission, rather than killing the adult filarial worm. Standard drugs used for MDA inhibit the embryogenesis temporarily and have contributed to the reduction in the prevalence of LF, though they do not treat the disease permanently because of a lack of pronounced macrofilaricidal effect i.e. killing the adult worm.

Oxfendazole, an analogue of flubendazole, currently available as a veterinary drug and is used extensively in multiple parasitic diseases among animals. Its primary mode of action involves interaction with the eukaryotic cytoskeletal protein tubulin [3], inhibiting microtubule polymerization. This results in the destruction of cell structure and consequent death of the parasite. Oxfendazole has been identified as a potential candidate with macrofilaricidal activity against Litomosoides sigmodontis and Brugia malayi and complete clearance of adult worms in mice models [4]. Considering the preclinical efficacy data, the key determinant of efficacy is the maintenance of plasma levels above approximately 100 ng/mL over 5 days (based on subcutaneous treatment at 1 mg/kg in mice) [5]. Population PK modelling of plasma concentrations of oxfendazole and its metabolites using nonlinear mixed effects predicted that a dose ranging from 400 mg to 800 mg for five consecutive days is expected to achieve the desired plasma levels, thus establishing efficacy in humans in 92% and 97% of treated participants respectively [6].

This proposed proof-of-concept phase II study aims to evaluate oxfendazole's efficacy, safety and PK profile in patients with LF. This data will be pivotal in guiding further clinical development and establishing a well-defined dosing strategy for oxfendazole and will facilitate its potential application as a definitive cure for debilitating filarial infection. The study is sponsored by the Indian Council of Medical Research (ICMR), New Delhi, and is being performed in collaboration with the Drugs for Neglected Disease Initiative (DNDi). DNDi has been previously involved in preparing a human formulation of oxfendazole and conducting its first in-human studies.

Objectives

The primary objective of the study is to estimate the proportion of participants with no worm motility as seen on ultrasonography (USG) at 6 months after starting the intervention, among men and women aged 18–60 years, harbouring at least one adult filarial worm, receiving placebo or 400 mg orally administered oxfendazole for 5 days or 800 mg orally administered oxfendazole for 5 days.

The secondary objectives of the study are:

1. To estimate the proportion of participants with no worm motility as seen on USG at 1 and 3 months.

2. To estimate the mean change in the microfilaria (mf) load at 1, 3 and 6 months as compared to the baseline.

3. To estimate the change in proportion of participants positive for the circulating filarial antigen at 1, 3 and 6 months as compared to the baseline.

4. To estimate the proportion of participants with adverse events (AEs) and serious adverse events (SAEs) during the 6 months follow-up period.

Exploratory objectives:

1. To capture the PK profile of oxfendazole and its metabolites following first dose (in cycle 1) after single dose oral administration of 400 and 800 mg of oxfendazole.

2. To capture the steady state PK of oxfendazole and its metabolites after multiple dose oral administration (on day 5) of 400 and 800 mg of oxfendazole.

Methods

Study Design

The study is planned as a two-stage adaptive design study (Fig. 1). Since there is no evidence for safety of oxfendazole in patients with LF, stage I of this study is designed as a sentinel stage with staggered ascending cohort to adequately monitor, control and evaluate the safety of the drug in patients with LF. Stage II is a parallel, randomised double-blind, placebo-controlled trial designed to evaluate the efficacy of two doses of oxfendazole as a dose ranging study i.e. 800 mg and 400 mg for 5 days.

Fig. 1.

Study design

Intervention Description

Stage I is an open-label safety cohort at one of the study sites. This stage will enrol six participants, i.e. two groups of three participants in each sequence, on 400 mg and 800 mg doses of the investigational product (IP). All the drugs are to be administered orally, once daily for 5 days. Each subsequent dose cohort would start on or after 7 days of the first dose of the previous cohort.

Stage II is a double-blind, randomised, parallel-group, placebo-controlled, multiple-dose study in 66 participants with LF. Three parallel groups in a 1:1:1 ratio will receive five doses of either of placebo, 400 mg oxfendazole or 800 mg oxfendazole. Stage II may be adapted as a two-arm study with 400 mg of oxfendazole and placebo, depending on whether 800 mg oxfendazole used in stage I was associated with safety signals.

The IP used in the study is manufactured at a GMP-certified manufacturing facility (Syngene International Limited, India). The IP labels are approved by the Central Licensing Authority of India. The IP is labelled by a third-party vendor (Bilcare Research, India) to maintain blinding during the labelling process.

Sample Selection

The participants will be identified through a field survey, where people in the age group of 18 to 60 years will undergo a rapid antigen blood test to detect circulating filarial antigen. If positive they will undergo a battery of biochemical investigations and USG for identification of live filarial worm at the hospital. Eligible and consenting participants will then be admitted on the night before dosing and a night blood smear taken for baseline mf status and load. The participant will then be randomised.

Eligibility Criteria

Inclusion Criteria

1. Adults aged 1–60 years (both inclusive), of all genders, with a confirmed diagnosis of LF, with or without symptoms

2. Body weight ≥ 40 kg

3. Filarial test strip (FTS) positive (confirm presence of circulating filarial antigen, CFA)

4. Harbour at least one motile worm detected by USG

5. Agree to practice at least one highly effective method of contraception up till 3 months after randomisation

Exclusion Criteria

1. Symptoms, physical signs, vital signs or biological/laboratory signs suggestive of past or present systemic disorders, including but not limited to, cardiovascular, pulmonary, cutaneous, immunodeficiency, psychiatric disorders, drug/alcohol abuse and other abnormalities likely to interfere with the interpretation results of the test) or to significantly affect the study outcomes as judged by the investigator

2. Abnormal hepatic enzymes level that are more than 1.5 times the upper limit of normal values

3. Renal impairment confirmed by serum creatinine levels exceeding the upper limit of normal values

4. Clinical condition requiring chronic medication—diabetes, hypertension, chronic kidney disease, hypothyroidism, chronic respiratory disease, malignancy, human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS); any other clinical condition requiring long-term medication (at the discretion of the physician)

5. Currently participating in any other drug trial or having participated in a trial in a period less than five half-lives of the investigational product

6. Any antifilarial drug intake in the previous month

7. Known HIV-positive status

8. Hemoglobin below 10 mg/dL at baseline

9. Epileptic seizures within the past 10 years

10. Acute and/or febrile illness requiring therapy within 14 days prior to baseline

11. Use of concomitant medications that are contraindicated with albendazole and/or known hypersensitivity to albendazole or any other ingredient in its formulation

12. Unacceptably high tobacco, alcohol or drug abuse

13. Pregnant (by urine pregnancy test) or breastfeeding women

14. Anyone who is planning to relocate to another state within the next 6 months

15. Participant with LF who needs surgical intervention

Investigational Products and Study Treatment

Oxfendazole and placebo are being provided by DNDi in blister packs of 100-mg tablets.

Each participant will be in the study for a period of 6 months. The details of the timelines of enrolment, assessments and visits are provided is Table 1 (available in the online supplementary material).

Planned Outcomes

Primary Outcome

1. Parasitological cure (no adult worm motility) at 6 months identified by USG. It will be assessed as the proportion of participants with no worm motility at 6 months as seen on USG.

Secondary Outcomes

1. Parasitological cure (no adult worm motility) at 1 and 3 months identified by USG, assessed by the proportion of participants with no worm motility at 1 and 3 months as seen on USG.

2. Absolute value and mean change in microfilaria load at 1, 3 and 6 months as compared to the baseline.

3. Change in proportion of participants positive for circulating antigen at 1, 3 and 6 months as compared to the baseline.

4. The proportion of participants with AEs and SAEs within 6 months of starting the intervention.

5. The proportion of participants with change of laboratory parameters and vital signs as compared to the baseline recorded as AE.

6. C_max, T_max, AUC_0–t, AUC_0–inf, t_1/2 of oxfendazole and its metabolites following first dose.

7. Average steady state plasma concentration, percentage fluctuation (variation between maximum and minimum concentration at steady state) (on day 5).

8. Accumulation following multiple (five) doses.

As the primary endpoint is the identification of filarial dance sign (FDS) on USG, which requires specialized expertise, all participating sonographers will complete a centralized, standardized training module led by a single expert radiologist prior to trial initiation. Study procedures, machine calibration, and scoring will be strictly governed by a study-specific standard operating procedure (SOP) dedicated to the uniform identification and grading of the FDS. Recognizing that individual worm counts are structurally impractical, the primary visual metric will be the tracking of distinct lymphatic nest counts. Furthermore, to verify true macrofilaricidal activity and eliminate false-positive endpoints, any initial observation of absent motility will mandate a confirmatory repeat USG within 24–72 h. Persistent lack of motility across both scans is strictly required to classify a nest as non-viable; otherwise, it will be classified as viable. Additionally, the statistical analysis plan includes a planned sensitivity analysis using this robust binary motility outcome to cross-verify primary efficacy endpoints.

To ensure participant safety following exposure to the IP, safety laboratory assessments, including liver function tests, renal function tests, hematology parameters and urinalysis, will be performed at day 3, day 6, and the 1-month follow-up visit from day 1 (the day of first dosing). These assessments will be conducted to monitor any potential treatment-related changes in organ function and to support the safety evaluation of oxfendazole.

Exploratory Outcomes: PK Analysis

Blood samples will be collected for measurement of plasma concentrations of oxfendazole, its primary metabolite as specified in Supplementary Table 1 (Schedule of Activities).

A total of 20 samples of approximately 3-mL volume each will be collected for PK assessments during stage I (n = 6) and II (n = 66) of the study. Samples will be shipped with data logger, and stored in a freezer at − 80 °C ± 10 °C, until completion of analysis. The Advanced Centre for Treatment, Research and Education in Cancer (ACTREC) clinical pharmacology lab will develop and validate a bioanalytical liquid chromatography–mass spectrometry (LCMS)/MS method to quantify oxfendazole and its metabolite. Genetic analyses will not be performed on these plasma samples.

Data Management and Statistical Methods

Data Management

All trial-related data are being recorded in source documents by the site research team and subsequently entered in an electronic case report form (eCRF). Each participant is assigned a unique participant identifier (UPI) to ensure confidentiality and prevent identification of individuals from the study data. Similarly, all biological samples collected during the study will be labelled with the corresponding UPI.

Participant-related data is being stored in a secure, password-protected electronic database accessible only to authorized study personnel at the respective clinical sites. Access to the database is role-based and restricted to authorized users only.

The eCRF system is maintaining an audit trail documenting all data entries, modifications and corrections, including the date, time and identity of the user making the changes. Sponsor-designated monitors will perform source data verification (SDV) to ensure the accuracy, completeness and consistency of the data recorded in the eCRF, as per the predefined monitoring plan. Any discrepancies identified during monitoring will be addressed through queries raised to the site investigators and resolved in a timely manner.

A medical monitor periodically reviews the clinical data to ensure medical accuracy and completeness. Data cleaning will be performed continuously throughout the conduct of the study and will be finalized after the last participant’s last visit. Once the clinical data management team confirms data completeness and quality, the database will be formally locked, after which the final dataset will be provided to the biostatistician for statistical analysis according to the pre-specified statistical analysis plan.

All data management procedures are being conducted in compliance with applicable regulatory requirements and Good Clinical Practice (GCP) guidelines to ensure the integrity, confidentiality and reliability of the trial data.

Sample Size Estimation

As this is a phase IIa study, there is no previous data available for use of oxfendazole among patients with LF.

All patients in endemic areas are being provided mass drug administration (MDA). There is evidence that diethylcarbamazine (DEC) may have some activity against adult filarial worms [7–9]. For the study, it has been assumed that there will be clearance of worms in 30% of patients (due to natural death as well as effect of DEC or DEC + albendazole that is being given annually/biannually) at 6 months.

On the basis of the preclinical efficacy outcomes, it has been assumed that there will be worm clearance in 90% of the patients in the two intervention arms. Considering the above assumptions, power of 90% and alpha of 0.025, the sample size in each of the three groups is 18 for stage II. Assuming 20% dropout/ loss to follow-up, the sample size is kept as 22 in each group. Sixty-six participants would be required in stage II of the current proof-of-concept trial. Additionally, six participants will be required in the sentinel cohort, which will be included only in the safety analysis and not in the primary efficacy analysis. Thus the total sample size of study will be 72 participants.

Given the absence of prior clinical efficacy data of oxfendazole in patients with LF, the expected worm clearance rate in the intervention groups was estimated on the basis of available preclinical efficacy findings and the objectives of this phase IIa proof-of-concept study. In validated animal models of filariasis, oxfendazole demonstrated substantial activity against adult filarial worms, with near-complete or complete clearance observed in experimental settings [4]. Although efficacy observed in preclinical models may not directly translate to humans, the assumed 90% worm clearance rate was selected as a study planning parameter to evaluate whether oxfendazole could achieve a clinically meaningful macrofilaricidal effect. Existing public health interventions, including MDA regimens involving diethylcarbamazine, albendazole and/or ivermectin, are assumed to result in approximately 30% adult worm clearance over 6 months through a combination of residual macrofilaricidal activity and natural worm attrition. Therefore, a higher clearance threshold was considered appropriate to demonstrate a clear proof-of-concept signal for a novel macrofilaria-targeted therapy. The assumed treatment effect was not intended to represent an established clinical efficacy estimate but rather a predefined target to assess whether oxfendazole could provide a substantial therapeutic advantage over the expected background clearance rate and support further clinical development.

Primary and Secondary Endpoint Analysis

All statistical analyses will be conducted in accordance with International Council for Harmonisation (ICH) E9 guidelines and the statistical analysis plan (SAP). The data will be analysed using STATA version 17, licensed to ICMR.

Primary Endpoint Analysis

The primary endpoint is the proportion of participants with adult filarial worms at 6 months post-treatment. The null hypothesis assumes no difference among the three groups (oxfendazole 400 mg for 5 days, oxfendazole 800 mg for 5 days, and placebo). The primary efficacy analysis will compare the treatment arms using a two-sided chi-square test or its appropriate variant. To control the overall type I error rate (α = 0.05) across the two dose levels, hierarchical testing using the Hochberg method will be applied. Statistical significance for each dose level will be claimed if the p value meets the pre-specified threshold as per hierarchical testing.

Secondary Endpoint Analysis

Secondary endpoints, including mf load response and CFA positivity, will be analysed using logistic regression, adjusting for baseline mf score and time. Other secondary outcomes such as worm motility at 1 and 3 months, change in mf load, and CFA positivity will be summarized descriptively and analysed per pre-specified methods. Safety endpoints, including AEs, vital signs, ECG, physical examinations and laboratory parameters, will be summarized descriptively by treatment group and visit.

No formal interim efficacy analysis is planned. However, the data safety monitoring board (DSMB) will review safety data after each stage, typically 7 days post-first dose in stage I. The DSMB will provide recommendations for progression to the next stage based solely on safety considerations and will not assess efficacy data. Decisions to halt or modify the trial will be made according to DSMB recommendations in consultation with the sponsor.

Methods for Additional Analyses (e.g. Subgroup Analyses)

Exploratory analyses will include PK evaluations. Non-compartmental PK analyses (C_max, T_max, C_min, AUC_0–t, t_1/2, degree of fluctuation) will be performed using Pumas software.

Methods in Analysis to Handle Protocol Non-adherence and Any Statistical Methods to Handle Missing Data

Protocol non-adherence is addressed through the definition of analysis populations. The primary analysis will use the modified intent-to-treat (mITT) population, which excludes participants with major protocol violations. A supporting per protocol set (PPS) analysis will also be conducted to evaluate the robustness of the results. If the size of the full analysis set (FAS) and PPS differs by more than 15%, both analyses will be presented.

For handling missing data in the primary analysis, the mITT population will use all available cases without imputation. A secondary sensitivity analysis on the ITT population will use the last observation carried forward (LOCF) method, carrying forward the last available efficacy assessment (e.g. from 1 or 3 months) to the 6-month time point. An additional analysis will replace missing values with the baseline value.

Strengths

This phase IIa, proof-of-concept clinical trial evaluating oxfendazole for LF possesses several methodological and contextual strengths. The two-stage design—comprising an initial open-label sentinel safety cohort followed by a double-blind, randomised, placebo-controlled phase—ensures stepwise dose escalation, rigorous safety monitoring, and overall scientific robustness. The randomised, double-blind design minimizes bias and enhances the internal validity of the findings, while the placebo-controlled approach is ethically and scientifically appropriate, given the absence of a definitive standard-of-care macrofilaricidal therapy. Inclusion of both male and female participants will address safety and efficacy in the target adult population.

Conducting the study in India adds to its public health relevance, as the country accounts for nearly 55% of the global LF burden, with an estimated 487 million people at risk of infection. The inpatient management of participants for 7 days during treatment and immediate post-dosing observation provides a controlled environment that enhances safety oversight, compliance and consistency in data collection. Furthermore, the inclusion of PK assessments represents a significant strength, enabling evaluation of drug exposure and potential correlations with efficacy and safety outcomes. These data will be instrumental in optimizing dosing strategies and informing subsequent phase studies aimed at developing oxfendazole as a macrofilaricidal agent.

Limitations

Certain limitations should be acknowledged. The exclusion of participants with chronic comorbidities such as diabetes, hypertension, and hepatic or renal disorders may restrict the generalizability of the findings to broader patient populations. However, this restriction is justified for a phase IIa study primarily designed to establish safety and preliminary efficacy, where minimizing confounding factors and ensuring participant safety remain paramount. The requirement for 7 days of hospitalization, while essential for close monitoring and accurate PK sampling, may impose a practical burden on participants and potentially influence recruitment. Nevertheless, participants will receive compensation for wage loss and travel expenses as approved by the respective institutional ethics committees, mitigating potential inconvenience.

As an early-phase proof-of-concept study, the sample size was primarily driven by efficacy considerations and was not powered to detect rare or uncommon AEs. Therefore, while the study provides important preliminary safety data, larger studies will be required to further characterize the safety profile of oxfendazole and identify less frequent AEs.

Ethics

Ethics approval has been obtained by the independent ethics committees (IECs) of all the participating study sites. This study will be performed in accordance with the Helsinki Declaration of 1964 and its later amendments, ICH-GCP, applicable regulatory requirements and approved study protocol. The details of ethics committee approvals are available in the supplementary material.

The inclusion of a control arm in this protocol aligns with international ethical standards. The trial will exclusively enrol participants harbouring live adult worms who do not exhibit immediate clinical indications for acute therapeutic or surgical intervention. To ensure no participant is deprived of standard public health preventive measures, the standard government-mandated MDA triple therapy (albendazole + diethylcarbamazine + ivermectin) will be systematically administered to every participant across all study arms immediately upon the completion of their individual scheduled trial follow-up period. Any participant developing acute manifestations (e.g. lymphangitis or acute lymphedema) prior to the trial will be excluded to receive immediate standard medical care.

Given that oxfendazole is being evaluated in patients with LF for the first time, a mandatory 7-day inpatient hospitalization protocol will be enforced immediately following drug administration. This requirement serves as a primary safety safeguard to monitor for direct drug toxicities and to immediately manage potential systemic or localized host inflammatory reactions triggered by the rapid death and lysis of adult filarial worms. To ensure this safety stay does not impose a socioeconomic burden, all participants will receive pre-determined reimbursement for verified loss of wages, alongside the provision of all transport, meals and inpatient accommodation as approved by reviewing ethics committee.

Furthermore, in the event of any SAE, compensation will be provided in accordance with the recommendations of the IEC and/or the Indian regulatory authority, in line with applicable national regulatory requirements.

Collection and Recording of AEs

All untoward medical events occurring in participants from the time of informed consent will be recorded. Events occurring after consent but prior to study drug administration will be documented in the participant’s medical history or current medical condition section of the eCRF. These pre-treatment events are not considered AEs unless they worsen during the study, in which case the onset date will be recorded as the date of worsening. Any event meeting criteria for a SAE must be reported using the SAE report form and submitted to the sponsor with the investigator’s signature.

AEs occurring after initiation of study treatment, whether related to the study drug or a study-required procedure, will be recorded in the eCRF with appropriate causality assessment. Events unrelated to the study drug but related to study procedures will be documented as “not related to study drug”. All SAEs, irrespective of causality, will be reported to the sponsor and regulatory authorities.

Follow-up of AEs

All AEs and SAEs will be followed until resolution, stabilization or until explained by another cause, with the final outcome documented in the participant’s medical record and eCRF. Participants lost to follow-up will be noted accordingly. Follow-up information includes changes in severity, outcomes, treatment provided, and continuation or withdrawal from the study.

Regulatory Reporting of SAEs

Investigators will promptly notify the sponsor of any SAE to meet ethical and legal responsibilities and ensure participant safety. The sponsor is responsible for reporting SAEs to regulatory authorities, including the Central Drugs Standard Control Organization (CDSCO), IECs, and investigators in accordance with New Drugs and Clinical Trial Rules (NDCT) 2019 rules. Investigators will also report SAEs through the SUGAM online portal, with all personnel trained in its use prior to site initiation.

Timelines for SAE Reporting: The SAEs will be reported as per the timelines given in the NDCT, Government of India.

Reporting of SUSARs

All suspected unexpected serious adverse reactions (SUSARs) will be reported to relevant regulatory authorities as required. “Dear Investigator Letters” will be issued by the sponsor according to local regulations and communicated to investigators when necessary.

Dissemination

All possible efforts will be made to publish the results in a peer-reviewed, high-impact journal. The results of this study may be presented at scientific meetings. Authorship will be determined by mutual agreement and in line with International Committee of Medical Journal Editors authorship requirements.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Study Conception and Design: Gunjan Kumar, Ravi Kant, Deepa Joshi, Kavita Singh, Jerin Jose Cherian, Kattula Rao Vinay Rajan, Shikha Malik, Saibal Das, Sudipto Pallab Roy, Vijay Satam, Rishi Tuhin Guria, Dewesh Kumar, Lakhan Majhee, Anjani Kumar, Manjunath Nookala Krishnamurthy, Lokesh Kumar Sharma, Akshata Chaudhary, Ivan Scandale, Sabine Specht, Samir Sahu, Meghanad Meher, Satyasundar Gajendra Mohapatra, Aparna Mukherjee, Taruna Madan Gupta; Funding Acquisition: Gunjan Kumar, Jerin Jose Cherian, Aparna Mukherjee, Taruna Madan Gupta; Preparation of first draft: Gunjan Kumar, Ravi Kant, Deepa Joshi; Revision to manuscript based on authors comments: Gunjan Kumar, Ravi Kant, Deepa Joshi, Aparna Mukherjee; Revision to manuscript: Gunjan Kumar, Ravi Kant, Deepa Joshi, Kavita Singh, Jerin Jose Cherian, Kattula Rao Vinay Rajan, Shikha Malik, Saibal Das, Sudipto Pallab Roy, Vijay Satam, Rishi Tuhin Guria, Dewesh Kumar, Lakhan Majhee, Anjani Kumar, Manjunath Nookala Krishnamurthy, Lokesh Kumar Sharma, Akshata Chaudhary, Ivan Scandale, Sabine Specht, Samir Sahu, Meghanad Meher, Satyasundar Gajendra Mohapatra, Aparna Mukherjee, Taruna Madan Gupta; Approval of Manuscript: Gunjan Kumar, Ravi Kant, Deepa Joshi, Kavita Singh, Jerin Jose Cherian, Kattula Rao Vinay Rajan, Shikha Malik, Saibal Das, Sudipto Pallab Roy, Vijay Satam, Rishi Tuhin Guria, Dewesh Kumar, Lakhan Majhee, Anjani Kumar, Manjunath Nookala Krishnamurthy, Lokesh Kumar Sharma, Akshata Chaudhary, Ivan Scandale, Sabine Specht, Samir Sahu, Meghanad Meher, Satyasundar Gajendra Mohapatra, Aparna Mukherjee, Taruna Madan Gupta.

Funding

The study is sponsored and funded by the Indian Council of Medical Research, New Delhi. No funding or sponsorship was received for the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Conflict of Interest

Gunjan Kumar, Ravi Kant, Jerin Jose Cherian, Sudipto Pallab Roy, Aparna Mukherjee and Taruna Madan Gupta are employed by the Indian Council of Medical Research, New Delhi the sponsor and the funder of the study. The other authors, Deepa Joshi, Kavita Singh, Kattula Rao Vinay Rajan, Shikha Malik, Saibal Das, Vijay Satam, Rishi Tuhin Guria, Dewesh Kumar, Lakhan Majhee, Anjani Kumar, Manjunath Nookala Krishnamurthy, Lokesh Kumar Sharma, Akshata Chaudhary, Ivan Scandale, Sabine Specht, Samir Sahu, Meghanad Meher, and Satyasundar Gajendrea Mohapatra, declare no conflict of interest.

Ethical Approval

Ethics approval has been obtained by the IEC of all the participating study sites. This study will be performed in accordance with the Helsinki Declaration of 1964 and its later amendments, ICH-GCP, applicable regulatory requirements and approved study protocol. The details of ethics committee approvals are available in the supplementary material.