IC14 in Adult Patients With Dengue Fever

Study Overview
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Brief Summary
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Randomized, double-blind, placebo-controlled, safety, PK/PD and preliminary efficacy study of intravenous IC14 in adult patients in a dengue-endemic region presenting with fever > 38°C for < 48 hours with a positive NS1 strip assay or reverse-transcriptase polymerase chain reaction assay for dengue virus.

Detailed Description
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The study will be conducted in two parts and will include an open label phase of a single dose of IC14 (Part A) and a randomized phase of multiple doses of IC14 and placebo (Part B). Up to 52 patients will be enrolled in both parts of the study. Part A will consist of 12 patients given one of three doses of IC14 as a single dose open-label . Each patient must complete 14 days before the enrollment of subsequent patients. Part A subjects will be hospitalized for 4 days. During and at the end of 4-day admission to the clinical research unit, and on Study Days 5, 6, 7, 14, 21 and 32, Part A patients will have their health status assessed. The last subject in Part A must complete 32 days of participation before Part B of the trial is opened. Part B consists of 40 patients randomized equally to one of 4 dosing regimens which will include a single dose or multiple doses of IC14 or placebo given at different dosing frequencies. In Part B, Cohort 1 and 2 subjects (single dose) will be inpatient for 4 days and Cohort 3 and 4 subjects (four daily doses) will be inpatient for 5 days. During and at the end of the admission to the clinical research unit, and on Study Days 5, 6, 7, 14, 21 and 32, Part B patients will have their health status assessed.

Official Title
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A Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Safety, Pharmacokinetic, Pharmacodynamic and Preliminary Efficacy Study of IC14 in Adult Patients With Dengue Fever

Conditions
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Dengue Fever

Intervention / Treatment
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* Biological: IC14
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Fever > 38°C for < 48 hours and clinical presentation consistent with dengue fever. Positive NS1 strip assay or reverse-transcriptase polymerase chain reaction (RT-PCR) assay for dengue virus. Informed consent form signed and dated by the patient. Subject able to give informed consent and able to comply with all study visits and all study procedures. Females of childbearing potential should be using and committed to continue using acceptable birth control methods. Sexual abstinence (inactivity) for 1 month prior to screening through study completion; or Intrauterine device (IUD) in place for at least 3 months prior to study through study completion; or Stable hormonal contraception for at least 3 months prior to study through study completion; or Surgical sterilization (vasectomy) of male partner at least 6 months prior to study. To be considered of non-childbearing potential, females should be surgically sterilized (bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 2 months prior to study) or be post-menopausal and at least 3 years since last menses. Exclusion Criteria One or more of the following dengue warning signs and symptoms: Intense and continuous abdominal pain (referred pain or on palpation); Persistent vomiting; Fluid accumulation (ascites, pleural effusion, or pericardial effusion); Postural hypotension and/or collapse; Painful hepatomegaly > two centimeters below the right costal margin; Mucosal bleeding; Major bleeding (hematemesis and/or melena); Lethargy and/or irritability; Diminished urine output; Hypothermia; Progressive increase in hematocrit or 20% above baseline or normal for age; Abrupt drop in platelets; Respiratory discomfort. One or more of the following signs and symptoms of severe dengue, such as: Severe plasma extravasation, leading to shock evidenced by one or more of the following: Tachycardia; Cold distal extremities; Weak, thready pulse; Slow capillary refill (> 2 seconds); Pulse pressure < 20 mmHg; Tachypnea; or Oliguria (<1.5 mL/kg/hr). Systolic blood pressure < 90 mmHg or decrease >40 mmHg; Cyanosis; Fluid accumulation with respiratory discomfort; Severe bleeding; or Severe organ impairment, evidenced by one or more of the following: Liver impairment (AST >1000 U/L, international normalized ratio >1.5); Renal impairment (serum creatinine ≥1.5 mg/dL); or Myocarditis, pericarditis, or clinical heart failure (by chest x-ray, echocardiography, electrocardiogram, or cardiac enzymes if available). Female who is pregnant, lactating or of childbearing potential. Self-reported or suspected congenital or acquired immunodeficiency (including HIV infection); or receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the previous 3 months). Prior vaccination against dengue fever. Significant chronic illness that, in the opinion of the Investigator, would interfere with study validity, conduct or completion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A/Single Dose<br>IC14 0.5, 1.0 or 2.0 mg/kg IV as a single dose (subjects are assigned and not randomized to this arm. When Part A is complete, Enrollment to Part B will commence). | Biological: IC14<br>* recombinant chimeric anti-human CD14 monoclonal antibody<br>|
| Experimental: Part B/Cohort 1<br>IC14 4 mg/kg/day IV or placebo IV x 1 day. | Biological: IC14<br>* recombinant chimeric anti-human CD14 monoclonal antibody<br>Drug: Placebo<br>* Inactive<br>|
| Experimental: Part B/Cohort 2<br>IC14 8 mg/kg/day IV or placebo IV x 1 day. | Biological: IC14<br>* recombinant chimeric anti-human CD14 monoclonal antibody<br>Drug: Placebo<br>* Inactive<br>|
| Experimental: Part B/Cohort 3<br>IC14 2 mg/kg/day IV x 1 day followed by IC14 1 mg/kg/day IV x 3 days or placebo IV daily for 4 days. | Biological: IC14<br>* recombinant chimeric anti-human CD14 monoclonal antibody<br>Drug: Placebo<br>* Inactive<br>|
| Experimental: Part B/Cohort 4<br>IC14 4 mg/kg/day IV x 1 day followed by IC14 2 mg/kg/day IV x 3 days or placebo IV daily for 4 days. | Biological: IC14<br>* recombinant chimeric anti-human CD14 monoclonal antibody<br>Drug: Placebo<br>* Inactive<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (safety, tolerability) | Number of patients with treatment-related adverse events as classified according to MedDRA | 32 days | 
| Area under the curve of IC14 serum concentration | Area under the curve of IC14 serum concentration | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dengue viral load | Impact of treatment on dengue viral load measured by quantitative viral load and plasma NS1 viral protein | 32 days | 
| Fever | Impact of treatment on duration of fever | 32 days | 
| Dengue symptom score | Impact of treatment on dengue symptom severity (0 normal] to 24 [worst]) | 32 days | 
| Disease severity | Impact of treatment on duration of hospitalization; incidence and duration of intensive care unit admission; and incidence of progression to dengue with warning signs or severe dengue | 32 days | 
| Mortality | Impact of treatment on survival | 32 days |