Celgosivir or Modipafant as Treatment for Adult Participants With Uncomplicated Dengue Fever in Singapore
|Dengue Fever||Drug: Celgosivir Drug: Modipafant 50mg Drug: Placebo Drug: Modipafant 100mg||Phase 1 Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Treatment
|Official Title:||A Phase Ib/IIa Single Centre, Double-blind, Double-dummy, Placebo-controlled, Parallel-group Dose Ranging Trial in Adult Participants With Uncomplicated Dengue Fever in Singapore|
- Viral load AUC for viremia [ Time Frame: Day 1 to Day 5 ]Area under the curve (AUC) for serum viral load from baseline to Study Day 5 of Celgosivir dosing
- Platelet nadir [ Time Frame: Day 1 to Day 5 ]Lowest platelet count recorded from baseline to Study Day 5 of Modipafant dosing
- Fever clearance time (days) [ Time Frame: Day 1 to 28 ]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
- Duration of illness [ Time Frame: Day 1 to 28 ]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
- Maximum percentage haemoconcentration [ Time Frame: Day 1 to 28 ]Determined by comparison of the maximum haematocrit detected in the acute phase as compared to baseline
- Time to NS1 clearance [ Time Frame: Day 1 to 28 ]
|Anticipated Study Start Date:||July 2017|
|Estimated Study Completion Date:||August 2018|
|Estimated Primary Completion Date:||August 2018 (Final data collection date for primary outcome measure)|
Placebo Comparator: Cohort 1
Placebo Q6H for 5 days
A total of 72 participants (18 participants per group assuming up to two drop-outs per group) will be assigned in a randomised double-blind fashion.
Placebo Q6H for 5 days
Active Comparator: Cohort 2
Modipafant 50 mg Q12H alternating with placebo Q12H for 5 days (total of 10 modipafant doses = 500 mg)
Drug: Modipafant 50mg
Modipafant 50 mg Q12H alternating with placebo Q12H for 5 days (total of 10 modipafant doses = 500 mg modipafant)
Active Comparator: Cohort 3
Modipafant 100 mg Q12H alternating with placebo Q12H 5 days (total of 10 modipafant doses = 1000 mg)
Drug: Modipafant 100mg
Modipafant 100 mg Q12H alternating with placebo Q12H for 5 days (total of modipafant 10 doses = 1000 mg modipafant)
Active Comparator: Cohort 4
Celgosivir 150 mg Q6H for 5 days (total of 20 doses = 3000 mg total).
Celgosivir 150 mg Q6H for 5 days (total of 20 doses = 3000 mg celgosivir total).
This trial is a single centre, double-blind, double-dummy, placebo-controlled parallel-group, dose ranging study in adult participants with uncomplicated dengue fever. The study will be conducted in two parts:
In Part 1, 72 otherwise healthy participants (18 participants per group, assuming up to 2 dropouts per group) with uncomplicated dengue fever meeting the inclusion/exclusion criteria will be randomised to receive treatment with placebo, celgosivir or modipafant. Participants will be randomised in parallel to one of Cohorts 1 to 4:
- Cohort 1: Placebo Q6Hours for 5 days
- Cohort 2: Modipafant 50 mg Q12Hours alternating with placebo Q12Hours for 5 days (total of 10 modipafant doses = 500 mg);
- Cohort 3: Modipafant 100 mg Q12Hours alternating with placebo Q12Hours 5 days (total of 10 modipafant doses = 1000 mg);
- Cohort 4: Celgosivir 150 mg Q6H for 5 days (total of 20 doses = 3000 mg total).
As modipafant is untested in uncomplicated dengue fever patients, a double-blinded sentinel group consisting of 4 participants randomised in a 1:1:1:1 ratio of Cohort 1: Cohort 2: Cohort 3: Cohort 4 will complete treatment to Study Day 5 prior to continuing enrolment of the remaining participants. Remaining 68 participants will be enrolled in parallel in a double-blinded fashion.
Participants will be evaluated during screening (< 24 hours before Study Day 1) and on Study Days 1-5, 14 and 28. Participants will be confined in the SingHealth Investigational Medicine Unit (IMU) from screening until end of study assessments on Study Day 5 and return to the clinic at Day 14 and 28 as outpatients. All patients will receive capsules Q6H for 5 days prepared by an open-label pharmacist according to the randomisation plan.
Interim Analysis: The treatment regimen chosen for Part 2 will be based on the analysis of Part 1 data. A detailed Statistical Analysis Plan (SAP) will be prepared for approval by the Sponsor prior to performing any unblinded analysis for presentation to personnel designated as being blinded to the randomization. A data safety monitoring board (DSMB) will conduct a blinded review of source verified safety data. If there are no safety concerns, an independent statistician will perform an unblinded futility analysis of preliminary efficacy data from the four cohorts; blinding to treatment group (celgosivir or modipafant) will be maintained, however placebo will be unblinded. If futility is concluded, the Sponsor may elect to discontinue the study. 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02569827
|Contact: Abigail Wongfirstname.lastname@example.org|
|Singhealth Investigational Medicine Unit|
|Singapore, Singapore, 169608|
|Principal Investigator:||Jenny Low, Dr||Singapore General Hospital|