Celgosivir or Modipafant as Treatment for Adult Participants With Uncomplicated Dengue Fever in Singapore
Celgosivir or Modipafant as Treatment for Adult Participants With Uncomplicated Dengue Fever in Singapore
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.
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.
Inclusion Criteria:

 1. Male or female, aged 21-65 years;

 2. Acute febrile illness with two or more manifestations (headache, retro-orbital pain,
 myalgia, arthralgia, rash, haemorrhagic manifestations, or leucopoenia) and occurrence
 at the same location and time as other confirmed cases of dengue fever;

 3. Fever (> 37.5°C) or history of fever at screening

 4. < 48 hours of fever history

 5. Positive NS1 strip assay or reverse-transcriptase polymerase chain reaction (RT-PCR).

 6. Able and willing to give written informed consent; and,

 7. Willing to be an inpatient from Study Screening to Study Day 5 and to return to
 hospital on study Days 14 and 28.

 8. Willing to keep a study diary from Study Day 5 to Day 14.

 Exclusion Criteria:

 1. Clinical signs and symptoms for severe dengue, such as:

 -  Severe abdominal pain;

 -  Persistent vomiting;

 -  CS fluid accumulation;

 -  Mucosal bleeding;

 -  Altered mental state;

 -  Liver enlargement > 2 cm;

 -  Systolic blood pressure < 90 mmHg; and

 -  Pulse pressure < 20 mmHg.

 2. A person with any of the following laboratory values:

 -  Haematocrit >52% males; >46% females;

 -  Aspartate or alanine aminotransferase (AST or ALT) > 1000 U/L;

 -  Room air oxygen saturation < 95%;

 -  Absolute neutrophil count < 1500/µL;

 -  Platelet count < 80,000/mm3;

 -  Creatinine > 165 µmol/L males; > 130 µmol/L females;

 -  Haemoglobin < 13.0 g/dL males; < 11.0 g/dL females;

 -  Total bilirubin > 24 µmol/L; and

 -  Serum CPK > 600 U/L.

 3. History of or presently active intestinal disorders such as peptic ulcers, intestinal
 ulcers, intestinal obstructions, intestinal hernias, ulcerative colitis, malabsorption
 syndrome, celiac disease, Roemheld's syndrome (gastroesophageal regurgitation disease)
 or Crohn's disease;

 4. Severe diarrhoea (grade 2 or higher according to NIH clinical trial guidelines);

 5. Current usage of any anticoagulant drugs including, but not limited to, aspirin,
 warfarin or clopidogrel;

 6. Any other CS acute illness within seven days prior to first study drug administration;

 7. History of adverse reactions to celgosivir, castanospermine, modipafant or formulation
 excipients or history of severe drug or food allergies;

 8. Exposure to any new investigational drug within 30 days prior to the study drug
 administration;

 9. CS abnormal physical examination unrelated to dengue infection, chest X-ray or 12-lead
 ECG at screening such as QTc prolongation (> 450 msec);

 10. Women of child bearing potential (WOCBP) who are pregnant, breast feeding or unwilling
 to avoid pregnancy by the use of highly effective contraception (<1% failure rate per
 year) including oral and subcutaneous implantable hormonal contraceptives, condoms,
 diaphragm, or intra-uterine system (IUS), during the period that the experimental drug
 is administered. Prospective WOCBP must have a negative pregnancy test (point of
 care).

 11. Male participants unwilling to comply with the contraceptive requirements of the study
 as detailed in Section 4.7 (i.e. abstinence, effective barrier contraception during
 the study and for 65 days after the last dose of study drug).

 12. Current significant medical condition or illness including cardiac arrhythmias,
 cardiomyopathy or other cardiac disease, asthma or other respiratory disease, diabetes
 mellitus, renal or hepatic impairment, thyroid disease, Parkinson's disease, epilepsy
 or history of unexplained blackouts, immunocompromised state including known HIV
 infection, or any other illness that the Investigator considers should exclude the
 patient, especially those that require continuation of other medications likely to
 have an interaction with the study drug.

 13. Any condition that would render the informed consent invalid, or limit the ability of
 the participant to comply with the study requirements.

 14. Any condition that, in the opinion of the Investigator, would complicate or compromise
 the study or well-being of the participant.