Expansion of a Dengue-1 Live Virus Human Challenge

Study Overview
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Brief Summary
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To evaluate the effectiveness of candidate dengue vaccine formulations, it is prudent to develop an appropriate challenge model. This study supports the expansion of the data set of the current Dengue 1 Live Virus Human Challenge (DENV-1-LVHC) model to produce uncomplicated dengue-like illness.

Detailed Description
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This is an expansion of a previous study conducted under NCT02372175. In this study up to nine healthy subjects between 18 and 45 years old will be inoculated with Dengue 1 Live Virus Human Challenge (DENV-1-LVHC) at a dose used in the previous study. Subjects will be closely monitored for the first 28 days with continued follow up through 6 months. Clinical and laboratory parameters, viremia and antibody levels will be assess. The goal is to expand the data set of symptoms produced by uncomplicated dengue-like illness.

Official Title
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Phase One, Open Label Expansion of a Dengue-1-Virus-Live Virus Human Challenge - (DENV-1-LVHC) Virus Strain.

Conditions
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Dengue

Intervention / Treatment
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* Biological: Dengue-1 Virus-Live Virus Human Challenge (DENV-1-LVHC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-45 at the time of consent Ability and willingness to sign informed consent Passing score on comprehension test of at least 75%, with up to 3 attempts Available for the study period Willing to use contraception for the duration of the study Provide consent for release of medical history records from primary care physician, college or university, urgent care or emergency room visit Exclusion Criteria: Female: pregnant or lactating Heavy menstrual bleeding within the last 6 months- menstrual periods lasting longer than 6 days, or requiring 5 or more pads or tampons per day. Female subjects using an intrauterine device (IUD) or Mirena® Female subjects with fibroids or uterine polyps, endometriosis, adenomyosis, and uterine scarring (e.g., after D&C) Blood tests confirming infection with human immunodeficiency virus- 1 (HIV-1), hepatitis C, hepatitis B (assessed by HbsAg) virus, or positive antibodies to the flaviviruses (FV) dengue, West Nile, Yellow Fever, Japanese encephalitis, or Zika. Active Diabetes or active peptic ulcer disease (PUD) Chronic obstructive pulmonary disease (COPD) or coronary artery disease (CAD) Known or suspected congenital or acquired immunodeficiency; or receipt of immunomodulation therapy such as anti-cancer chemotherapy or radiation therapy; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months) Current, or a history of, auto-immune disease History of Guillain-Barré syndrome (GBS) Any history of FV infection or FV vaccination; or planned FV vaccination, outside the study protocol, during the study period Diagnosis with Bipolar Disorder or Schizophrenia, hospitalization in the past year for a mental health disorder, or any other psychiatric condition, which in the opinion of the investigator prevents the subject from participating in the study. Planned travel during the study period (180 days) which would interfere with the ability to complete all study visits Recent (in the past 4 weeks) travel to any dengue endemic area. These potential subjects may be eligible for enrollment a minimum of 4 weeks later Any grade 2 laboratory abnormalities prior to inoculation for the tests specified in Table 18 and Table 19 of the protocol, except those listed in exclusion criteria 16 Subjects with the following grade 1 or greater lab abnormalities: Creatinine; Liver Function Tests - ALT, AST; Hemoglobin (females and males); White Blood Cell (WBC) decrease; Platelets decreased; Prothrombin Time (PT); Partial Thromboplastin Time (PTT); Fibrinogen decrease Significant screening physical examination abnormalities at the discretion of the investigator Women who intend to become pregnant or men who intend to father a child during the study period (approximately 180 days) Hives, shortness of breath, swelling of the lips or throat, or hospitalization related to a previous vaccination or an allergy to specific medications/animals for which antigens may be in the virus preparations to include: shellfish allergy, fetal bovine serum, L-glutamine, neomycin and streptomycin Planning to donate blood in the 1 year following inoculation with dengue Recent blood donation within prior 56 days of inoculation Receipt of blood products or antibodies within 56 days of inoculation or during the study period Participation (active or follow-up phase) or planned participation in another vaccine, drug, medical device, or medical procedure clinical trial in the 4 weeks prior to this trial, during the trial, or 6 months following inoculation in this clinical trial Recent or scheduled receipt of any vaccine 4 weeks prior to or after virus inoculation Beliefs that bar the administration of blood products or transfusions Positive urine screen for cocaine, amphetamines, or opiates Currently taking Methadone or Suboxone Currently taking anti-coagulant medication, aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) Chronic migraine headaches, defined as more than 15 headache days per month over a 3 month period of which more than 8 are migraines, in the absence of medication over use Chronic medical condition that, in the opinion of the investigator, impacts subject safety.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inoculated Group<br>Dengue-1 Virus-Live Virus Human Challenge (DENV-1-LVHC) given as a single dose [0.5 mL of 6.5 x 10^3 plaque forming units/milliliter (PFU/mL)] inoculated subcutaneously. | Biological: Dengue-1 Virus-Live Virus Human Challenge (DENV-1-LVHC)<br>* Dengue subtype 1 Challenge Virus (DENV-1) strain 45AZ5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Abnormal Laboratory Parameters | Total number of all abnormal labs | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Intensity of Abnormal Laboratory Parameters | Graded according clinical laboratory normals and FDA toxicity scale | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Duration of Abnormal Laboratory Parameters | Number of days of abnormal lab | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Occurrence of Solicited Injection site symptoms | Number of solicited symptoms | 7 days post virus inoculation | 
| Intensity of Solicited Injection site symptoms | Symptoms graded according to FDA toxicity scale | 7 days post virus inoculation | 
| Duration of Solicited Injection site symptoms | Number of days per symptom | 7 days post virus inoculation | 
| Occurrence of Unsolicited Injection site symptoms | Number of unsolicited site symptoms | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Intensity of Unsolicited Injection site symptoms | Symptoms graded according to FDA toxicity scale | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Duration of Unsolicited Injection site symptoms | Number of days per symptom | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Occurrence of Solicited systemic symptoms | Number of systemic symptoms | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Intensity of Solicited systemic symptoms | Symptoms graded according to FDA toxicity scale | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Duration of Solicited systemic symptoms | Number of days per symptom | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Occurrence of Unsolicited systemic symptoms | Number of symptoms | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Intensity of Unsolicited systemic symptoms | Symptoms graded according to FDA toxicity scale | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Duration of Unsolicited systemic symptoms | Number of days per symptom | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Number of Serious Adverse Events | Total number | 28 days post virus inoculation or 7 days post hospitalization, whichever is later | 
| Number of Serious Adverse Events | Total number | 6 months post virus inoculation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incubation period before onset of fever | Number of days prior to fever | Up to 28 days post virus inoculation | 
| Viremia by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) | Levels of viremia | Up to 28 days post virus inoculation | 
| Viremia by plaque assay | Quantitation of infectious virus | Up to 28 days post virus inoculation | 
| Occurrence of fever without other identifiable cause, such as strep infection or influenza | The occurrence of fever defined as greater than or equal to 38°C (100.4°F) measured at least 2 times in 24 hours but not lasting more than 72 hours | Up to 28 days post virus inoculation | 
| Occurrence of Headache | Number of headaches | Up to 28 days post virus inoculation | 
| Grade of Headache | Graded according to FDA toxicity scale | Up to 28 days post virus inoculation | 
| Occurrence of Myalgia | Number of reported myalgias | Up to 28 days post virus inoculation | 
| Grade of Myalgia | Graded according to FDA toxicity scale | Up to 28 days post virus inoculation | 
| Occurrence of Rash | Number of rashes | Up to 28 days post virus inoculation | 
| Grade of Rash | Graded according to FDA toxicity scale | Up to 28 days post virus inoculation | 
| Occurrence of Abnormal Liver Function Test [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] | Number of abnormal liver function tests | Up to 28 days post virus inoculation | 
| Grade of Abnormal Liver Function Test [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] | Graded according clinical laboratory normals and FDA toxicity scale | Up to 28 days post virus inoculation | 
| Occurrence of Leukopenia | Number of occurrences | Up to 28 days post virus inoculation | 
| Grade of Leukopenia | Graded according clinical laboratory normals and FDA toxicity scale | Up to 28 days post virus inoculation | 
| Occurrence of Thrombocytopenia | Number of occurrences | Up to 28 days post virus inoculation | 
| Grade of Thrombocytopenia | Graded according clinical laboratory normals and FDA toxicity scale | Up to 28 days post virus inoculation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue, Flavivirus Infections, Virus Diseases