Dengue Fever Clinical Trial
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
Verified date | March 2020 |
Source | Singapore General Hospital |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Withdrawn |
Enrollment | 0 |
Est. completion date | August 8, 2019 |
Est. primary completion date | August 8, 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 21 Years to 65 Years |
Eligibility |
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. |
Country | Name | City | State |
---|---|---|---|
Singapore | Singhealth Investigational Medicine Unit | Singapore |
Lead Sponsor | Collaborator |
---|---|
Singapore General Hospital | 60 Degrees Pharmaceuticals LLC, Duke-NUS Graduate Medical School |
Singapore,
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | Platelet nadir | Lowest platelet count recorded from baseline to Study Day 5 of Modipafant dosing | Day 1 to Day 5 | |
Secondary | Fever clearance time (days) | 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 | Day 1 to 28 | |
Secondary | Duration of illness | 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 | Day 1 to 28 | |
Secondary | Maximum percentage haemoconcentration | Determined by comparison of the maximum haematocrit detected in the acute phase as compared to baseline | Day 1 to 28 | |
Secondary | Time to NS1 clearance | Day 1 to 28 |
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