Celgosivir or Modipafant as Treatment for Adult Participants With Uncomplicated Dengue Fever in Singapore

NCT02569827 | Withdrawn Phase 1 DMC

• 1 other identifier: Cel01
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Dengue Fever

Keywords

Uncomplicated Dengue Fever; Treatment; Phase Ib/IIa; single centre; double-blind; placebo-controlled; parallel-group dose ranging trial; Modipafant; Celgosivir

Outcome Measures

Primary Outcomes (2)

• Viral load AUC for viremia

  Area under the curve (AUC) for serum viral load from baseline to Study Day 5 of Celgosivir dosing

  Day 1 to Day 5

• Platelet nadir

  Lowest platelet count recorded from baseline to Study Day 5 of Modipafant dosing

  Day 1 to Day 5

Secondary Outcomes (4)

• Fever clearance time (days)

  Day 1 to 28

• Duration of illness

  Day 1 to 28

• Maximum percentage haemoconcentration

  Day 1 to 28

• Time to NS1 clearance

  Day 1 to 28

Study Arms (4)

Cohort 1

PLACEBO COMPARATOR

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.

Drug: Placebo

Cohort 2

ACTIVE COMPARATOR

Modipafant 50 mg Q12H alternating with placebo Q12H for 5 days (total of 10 modipafant doses = 500 mg)

Drug: Modipafant 50mg

Cohort 3

ACTIVE COMPARATOR

Modipafant 100 mg Q12H alternating with placebo Q12H 5 days (total of 10 modipafant doses = 1000 mg)

Drug: Modipafant 100mg

Cohort 4

ACTIVE COMPARATOR

Celgosivir 150 mg Q6H for 5 days (total of 20 doses = 3000 mg total).

Drug: Celgosivir

Interventions

Celgosivir DRUG

Celgosivir 150 mg Q6H for 5 days (total of 20 doses = 3000 mg celgosivir total).

Cohort 4

Modipafant 50mg DRUG

Modipafant 50 mg Q12H alternating with placebo Q12H for 5 days (total of 10 modipafant doses = 500 mg modipafant)

Cohort 2

Placebo DRUG

Placebo Q6H for 5 days

Cohort 1

Modipafant 100mg DRUG

Modipafant 100 mg Q12H alternating with placebo Q12H for 5 days (total of modipafant 10 doses = 1000 mg modipafant)

Cohort 3

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, aged 21-65 years;
• 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;
• Fever (\> 37.5°C) or history of fever at screening
• \< 48 hours of fever history
• Positive NS1 strip assay or reverse-transcriptase polymerase chain reaction (RT-PCR).
• Able and willing to give written informed consent; and,
• Willing to be an inpatient from Study Screening to Study Day 5 and to return to hospital on study Days 14 and 28.
• Willing to keep a study diary from Study Day 5 to Day 14.

You may not qualify if:

• 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.
• 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;

Sponsors & Collaborators

• Singapore General Hospital: lead
• Duke-NUS Graduate Medical School: collaborator
• 60 Degrees Pharmaceuticals LLC: collaborator

Study Sites (1)

Singhealth Investigational Medicine Unit

Singapore, 169608, Singapore

Location

Related Publications (5)

• Low JG, Sung C, Wijaya L, Wei Y, Rathore APS, Watanabe S, Tan BH, Toh L, Chua LT, Hou Y, Chow A, Howe S, Chan WK, Tan KH, Chung JS, Cherng BP, Lye DC, Tambayah PA, Ng LC, Connolly J, Hibberd ML, Leo YS, Cheung YB, Ooi EE, Vasudevan SG. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis. 2014 Aug;14(8):706-715. doi: 10.1016/S1473-3099(14)70730-3. Epub 2014 May 28.

  PMID: 24877997 BACKGROUND

• Rathore AP, Paradkar PN, Watanabe S, Tan KH, Sung C, Connolly JE, Low J, Ooi EE, Vasudevan SG. Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model. Antiviral Res. 2011 Dec;92(3):453-60. doi: 10.1016/j.antiviral.2011.10.002. Epub 2011 Oct 12.

  PMID: 22020302 BACKGROUND

• Watanabe S, Rathore AP, Sung C, Lu F, Khoo YM, Connolly J, Low J, Ooi EE, Lee HS, Vasudevan SG. Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial. Antiviral Res. 2012 Oct;96(1):32-5. doi: 10.1016/j.antiviral.2012.07.008. Epub 2012 Jul 31.

  PMID: 22867971 BACKGROUND

• Whitby K, Pierson TC, Geiss B, Lane K, Engle M, Zhou Y, Doms RW, Diamond MS. Castanospermine, a potent inhibitor of dengue virus infection in vitro and in vivo. J Virol. 2005 Jul;79(14):8698-706. doi: 10.1128/JVI.79.14.8698-8706.2005.

  PMID: 15994763 BACKGROUND

• Watanabe S, Chan KW, Dow G, Ooi EE, Low JG, Vasudevan SG. Optimizing celgosivir therapy in mouse models of dengue virus infection of serotypes 1 and 2: The search for a window for potential therapeutic efficacy. Antiviral Res. 2016 Mar;127:10-9. doi: 10.1016/j.antiviral.2015.12.008. Epub 2016 Jan 13.

  PMID: 26794905 DERIVED

MeSH Terms

Conditions

Dengue

Interventions

celgosivir; modipafant

Condition Hierarchy (Ancestors)

Mosquito-Borne Diseases; Vector Borne Diseases; Infections; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral

Study Officials

• Jenny Low, Dr

  Singapore General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2015
• First Posted: October 7, 2015
• Study Start: December 1, 2018
• Primary Completion: August 8, 2019
• Study Completion: August 8, 2019
• Last Updated: March 23, 2020

Record last verified: 2020-03

Locations

SG (1)