Dengue fever is an acute febrile illness transmitted by mosquitoes, which affects half the world's population. There are 96 million symptomatic infections, 500,0000 hospitalisations and 25,000 deaths per year attributed to the disease. The economic burden is $12 billion. In Singapore, as elsewhere, the incidence of the disease continues to increase despite aggressive control measures. At present there are no approved medicines for treating dengue fever. Only supportive fluid replacement therapy is used to treat vascular leakage in patients with severe illness. Therefore there is an urgent need to find alternative treatments. Experiments in the laboratory have shown that Celgosivir and modipafant inhibit dengue virus and improve mouse survival. Both drugs have previously been used in humans with good safety records, so investigators are taking this one step further to find out how well it works in dengue patients. Investigators plan to enroll dengue patients within 48 hours of fever onset and assign them to one of four treatment groups over five days. Together with the support from the industry partner, 60°Pharmaceuticals PLC, the investigators will determine the safety and effectiveness of these drugs on acute dengue patients and pave the way forward for dengue antiviral medicines to reach patients.
Name: Celgosivir
Description: Celgosivir 150 mg Q6H for 5 days (total of 20 doses = 3000 mg celgosivir total).Type: DrugCohort 4
Name: Modipafant 50mg
Description: Modipafant 50 mg Q12H alternating with placebo Q12H for 5 days (total of 10 modipafant doses = 500 mg modipafant)Type: DrugCohort 2
Name: Placebo
Description: Placebo Q6H for 5 daysType: DrugCohort 1
Name: Modipafant 100mg
Description: Modipafant 100 mg Q12H alternating with placebo Q12H for 5 days (total of modipafant 10 doses = 1000 mg modipafant)Type: DrugCohort 3
Description: Area under the curve (AUC) for serum viral load from baseline to Study Day 5 of Celgosivir dosing
Measure: Viral load AUC for viremia Time: Day 1 to Day 5Description: Lowest platelet count recorded from baseline to Study Day 5 of Modipafant dosing
Measure: Platelet nadir Time: Day 1 to Day 5Description: The time from the start of treatment to the start of the first 24-hour period during which the tympanic or oral temperature remains below 37.5°C
Measure: Fever clearance time (days) Time: Day 1 to 28Description: A 24-hour reduction in duration of illness that is treatment related is deemed clinically relevant. Draft criteria to support this include: Absence of fever (< 37.4˚C) for at least 24 hours
Measure: Duration of illness Time: Day 1 to 28Description: Determined by comparison of the maximum haematocrit detected in the acute phase as compared to baseline
Measure: Maximum percentage haemoconcentration Time: Day 1 to 28Allocation: Randomized
Parallel Assignment
There is one SNP
If a signal is detected, a sample size calculation will be undertaken for Part 2. The Sponsor will convene a Scientific Advisory Board (SAB) who will then review unblinded log10 serum viral load AUC for viraemia and platelet count data to recommend which dosing monotherapy dosing regimen to advance to Part 2. If the recommended sample size for Part 2 exceeds the maximum specified for Part 1 and 2 (a total combined sample size of N = 132 participants) for a monotherapy, the Sponsor will submit a major amendment for Institutional Review Board/ Health Science Authority (IRB/HSA) consideration prior to initiating Part 2. For Part 2, up to 60 otherwise healthy participants with uncomplicated dengue fever meeting the inclusion/exclusion criteria will be assigned in a randomised double-blind fashion to: - Cohort 5: (i) celgosivir monotherapy 150 mg Q6H, OR (ii) modipafant monotherapy (either 50 mg Q12H or 100 mg Q12H) - Cohort 6: Placebo extension for 5 days of treatment. --- Q12H ---
If a signal is detected, a sample size calculation will be undertaken for Part 2. The Sponsor will convene a Scientific Advisory Board (SAB) who will then review unblinded log10 serum viral load AUC for viraemia and platelet count data to recommend which dosing monotherapy dosing regimen to advance to Part 2. If the recommended sample size for Part 2 exceeds the maximum specified for Part 1 and 2 (a total combined sample size of N = 132 participants) for a monotherapy, the Sponsor will submit a major amendment for Institutional Review Board/ Health Science Authority (IRB/HSA) consideration prior to initiating Part 2. For Part 2, up to 60 otherwise healthy participants with uncomplicated dengue fever meeting the inclusion/exclusion criteria will be assigned in a randomised double-blind fashion to: - Cohort 5: (i) celgosivir monotherapy 150 mg Q6H, OR (ii) modipafant monotherapy (either 50 mg Q12H or 100 mg Q12H) - Cohort 6: Placebo extension for 5 days of treatment. --- Q12H --- --- Q12H ---