Adaptive Dengue Antiviral Platform Trial

Official title

Adaptive Dengue Antiviral Platform Trial (ADAPT): a Phase 2 Randomized, Adaptive, Open Label Trial for Antiviral Screening in Patients With Early Symptomatic Dengue

Overview

This is a randomized, open-label adaptive platform trial aiming to screen the antiviral effectiveness of the experimental drug(s) in early dengue infection * Primary objectives: * To determine the antiviral effectiveness of the experimental drug(s) in early dengue infection * To assess the safety and tolerability of the experimental drug(s) in dengue patients * Secondary objective: * To assess the effect of the experimental drug(s) in dengue patients on physiological, clinical and virological parameters

Detailed description

This is a randomized, open-label adaptive platform trial investigating the antiviral effectiveness of various intervention arms in patients with lab-confirmed dengue and less than 48 hours of fever. The antiviral candidates in this trial will include the repurposed antiviral drugs, novel small molecule drugs and dengue monoclonal antibody. Patients will be randomly allocated between available treatment arms and compared to standard of care ("no study drug": no placebos will be made for this trial).

The current sites include Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam and Universiti Malaya Medical Centre, Kuala Lumpur, Malaysia. Local ethical approvals have been released. Other sites and countries may be added in due course.

This is a continually running adaptive platform trial, which begins with initial candidate drugs (a total of 4 arms): molnupiravir, remdesivir and VIS513 (a dengue monoclonal antibody). New therapies may be added and poorly performing arms or interventions meeting pre-specific thresholds for in vivo antiviral efficacy will be removed.

The sample size is adaptive with multiple planned interim analyses. The number of patients recruited depends on the results. For each intervention studied the sample size will be adaptive and determined by pre-specified stopping rules for futility and efficacy. Patients are invited to participate in the trial if they present at the healthcare settings with early symptomatic dengue virus infection (less than 48 hours since the onset of fever and positive NS1 antigen test) and can be able to return for follow up visits at 30 and 60 days after randomization.

The randomization ratios will be uniform for all available and eligible arms (1:1:1...).

Interventions

• Drug Molnupiravir 400 mg
  This is an antiviral drug (an RNA dependent RNA polymerase inhibitor, with broad spectrum antiviral activity) currently approved for use in treatment for COVID-19 patients. In this trial, its antiviral effectiveness on the early phase of dengue virus infection will be assessed.
• Drug VIS513 (a monoclonal antibody)
  VIS513 is an engineered humanised monoclonal antibody produced by recombinant DNA technology in a mammalian cell (i.e. Chinese hamster ovary) line. It was discovered in the USA by Visterra Inc and subsequently technology for manufacturing and further development was transferred to Serum Institute of India Pvt. Ltd., Pune, India. It has shown potent, specific neutralization of all four serotypes of DENV.
• Drug Remdesivir 100mg
  Remdesivir (GS-443902) is a nucleoside analogue - RNA dependent RNA polymerase inhibitor. In a meta-analysis of 10 RCTs and 32 observational studies reporting on the use of Remdesivir in COVID-19, remdesivir reduced mortality from severe disease and shortened time to clinical improvement. In this trial, its antiviral effectiveness on the early phase of dengue virus infection will be assessed

Primary outcome measures

• Viral clearance rate [Time frame: From randomization until day 5 of study]
• Number of AEs (grade 3, 4 and 5) [Time frame: Until day 30 post-enrolment]

Secondary outcome measures (9)

• Area under the viremia curve [Time frame: From randomisation until day 5 of study]
• Viral log reduction [Time frame: up to 48 hours of study]
• NS1 clearance time [Time frame: up to day 5]
• Number of patients progress to severe dengue (WHO 2009 criteria) [Time frame: From enrolment until discharge, assessed up to 30 days]
• Number of patients requiring for ICU admission [Time frame: From enrolment until discharge, assessed up to 30 days]
• Fever clearance time [Time frame: From enrolment until discharge, assessed up to 30 days]
• Platelet nadir [Time frame: Until day 30 post-enrolment]
• Maximum AST/ALT [Time frame: Until day 30 post-enrolment]
• Change in haematocrit [Time frame: Until day 30 post-enrolment]

Eligibility criteria

Inclusion criteria

• Female or male patients with a clinical diagnosis of dengue virus infection and less than 48 hours of fever
• Positive NS1 rapid diagnostic test
• >= 10 years or ≥ 18 years of age (depending on license of therapeutic being evaluated)
• Patient is able to give written informed consent or assent for full participation in the study.
• Agreement to stay in hospital for duration of the intervention (most will be 5 days) and follow-up visits at day 30 and 60 post enrolment.

Exclusion criteria

• Meets criteria for severe dengue at baseline (severe plasma leakage leading to dengue shock syndrome, fluid accumulation with respiratory distress, severe bleeding, severe organ involvement - AST/ALT>1000 U/L, impaired consciousness, multiple organ dysfunction)
• Pregnancy (either clinically confirmed or by urine dipstick for human chorionic gonadotrophin hormone)
• Breastfeeding women
• Localising features suggesting an alternative/additional diagnosis, e.g. pneumonia, sepsis
• Renal failure (baseline eGFR < 30ml/min)
• History or presence of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, neuropsychiatric, autoimmune, dermatologic or immunosuppressive disorders
• History of allergic disease, allergic reactions or known hypersensitivity to any component of the study product (Mild non-medication allergies allowed)
• Any condition that, in the opinion of the investigator, would complicate or compromise the study or well-being of the participant
• Participation or planned participation in a study involving the administration of an investigational compound within the past one month.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Malaysia · 1 center

• Universiti Malaya Medical Centre — Kuala Lumpur

Vietnam · 1 center

• Hospital for Tropical Diseases, Ho Chi Minh city — Ho Chi Minh City

Identifiers

NCT: NCT06551844 · 71DX

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗