Nasal Poly-ICLC (Hiltonol®) in Healthy COVID-19 Vaccinated Adults

Study Overview
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Brief Summary
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This is a randomized (4:1) Phase 1 b safety trial in adults who have completed their full COVID-19 vaccination schedule at least 30 days prior to study entry.

Detailed Description
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An initial cohort of 13 participants will receive 2 cycles of drug or placebo per the schedule below under carefully monitored conditions, including examinations to observe and document administration site reaction following consecutive administration cycles of the drug. 10 participants will receive drug and 3 will receive placebo. The safety stopping rule is to implement an enrollment pause if 2 dose limiting toxicity (DLT, see section 5.1) out of the first six or 3 DLTs out of the first 10 participants receiving drug are observed in either cycle 1 or cycle 2. The independent DSMB will conduct a review of the safety data to determine the relatedness of the DLTs to the drug exposure and provide a recommendation to continue. Thus, if safety events are determined to be not (or unlikely) related to drug exposure the trial may resume. The independent DSMB will review safety and tolerance data before the study can continue. If at most 2 DLTs out of the 10 participants receiving drug are observed, then a Phase Ib expansion cohort will open. The expansion cohort will receive 3 cycles of therapy. A total of 30 participants will be accrued and randomized 4:1 to receive drug (N=24) or placebo (N=6). There will be extensive assessment of toxicity and an early stopping rule to implement an enrollment pause and independent DSMB review of safety data to determine relatedness to drug exposure for recommendation of trial continuation, will be employed as above. Safety and tolerability will be the primary endpoint but secondary endpoints include changes in immunological parameters.

Official Title
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A Phase I-Ib, Double-blinded, Randomized Repeated Dose Single Center, Safety and Immunogenicity Study of Nasal Poly-ICLC (Hiltonol®) in Healthy COVID-19 Vaccinated Adults

Conditions
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COVID - 19

Intervention / Treatment
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* Drug: Poly-ICLC (Hiltonol®) or Placebo
* Drug: Poly-ICLC (Hiltonol®) or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Enrollment Phase I Cohort A: Subjects must be between 18 and 69 years of age. Phase 1b Cohort B: Subjects must be 18 years of age or older. In order to mitigate risk, no participants over age 70 will be recruited in Cohort A. Asymptomatic; defined by experiencing none of the symptoms identified in the Symptom Questionnaire fever cough dyspnea fatigue muscle or joint pain sore throat stuffy or runny nose nausea/vomiting headache confusion diarrhea loss of smell or taste Nasopharyngeal swab for COVID-19 at screening with negative diagnosis of SARS-CoV-2 Willing and able to provide blood, nasopharyngeal swab, and nasal mononuclear samples Healthy individuals fully vaccinated with a COVID-19 vaccine and who have had their last dose of COVID-19 vaccination at least 30 days prior to study entry. Healthy individuals vaccinated with a COVID-19 booster shot are eligible for enrollment. The vaccination dates of the doses, and specific vaccine received will be recorded. Able to provide informed consent Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use adequate methods of contraception (described below) during the study treatment and through 90 days after the last dose of study medication. Female participants of childbearing potential are all those except participants who are surgically sterile, who have medically documented ovarian failure, or who are at least 1 year postmenopausal Acceptable Hematologic, renal and liver functions as follows: 1. Absolute neutrophil count > 1000/mcL 2. Platelets > 50,000/mcL 3. Hemoglobin >9 g/dL 4. Serum Creatinine ≤ 2.5 mg/dl 5. Liver Function: Total bilirubin ≤1.5 mg/dl AST ≤ 2.0 mg/dl (≤120 IU or 3x ULN) Exclusion Criteria Individuals not yet fully vaccinated with a COVID-19 vaccine. Receipt of any blood product in past 120 days Allergic rhinitis, chronic sinusitis, or other nasal inflammatory disease that requires daily intranasal or oral medication Chronic medical problems that require daily nasal administration of medication Prior nasal or sinus surgery including trans nasal approaches to brain Chronic pulmonary conditions including severe asthma, COPD, or chronic bronchitis Autoimmune hepatitis, decompensated liver disease, cardiac ischemia, congestive heart failure, cardiac arrhythmia, neutropenia, thrombocytopenia, severe renal insufficiency Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the principal investigator, would affect participant safety and/or compliance Symptoms consistent with COVID-19 infection (fevers, acute onset cough, shortness of breath) at time of screening Nucleic acid testing evidence of COVID-19 infection at time of screening Participants must not be pregnant or nursing due to the unknown potential for congenital abnormalities and the potential of this regimen to harm nursing infants. Has a diagnosis of primary immunodeficiency Has uncontrolled hypertension that in the opinion of the principal investigator poses unacceptable risk. Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is acceptable Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator Principle investigator believes that for one or multiple reasons the participant will be unable to comply with all study visits, or if they believe the trial is not clinically in the best interest of the participant Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, intravenous immune globulins, monoclonal antibodies, receptor traps) Active, untreated tuberculosis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Intranasal Poly-ICLC (Hiltonol®) or Placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Cohort<br>A randomized (4:1) initial safety cohort of 13 patients will receive 2 cycles of drug (N=10) or placebo (N=3) | Drug: Poly-ICLC (Hiltonol®) or Placebo<br>* The safety cohort (Cohort A) consists of 13 patients who will be randomized to receive 2 cycles of the study drug (N10) or 2 placebo cycles (N3).<br>* Other names: Safety;|
| Experimental: Expansion Cohort<br>A randomized (4:1) expansion cohort will receive 3 cycles of drug (N=24) or placebo (N=6). A total of 30 patients will be accrued. | Drug: Poly-ICLC (Hiltonol®) or Placebo<br>* The expansion cohort will receive 3 cycles of therapy. A total of 30 patients will be accrued and randomized 4:1 to receive drug (N=24) or placebo (N=6).<br>* Other names: Expansion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of nasally administered Poly-ICLC (Hiltonol®) in healthy adults. | Safety will be measured and tabulated by the number (percent) of participants who experience DLTs (grade 3/4 adverse events) from the start of therapy through the end of the follow up period (day 91), according to DAIDS. | 91 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the response of the body to the study drug (pharmacodynamics) | Characterize the pharmacodynamics of the local and systemic innate immune response to repeated doses of intranasal Poly-ICLC (Hiltonol®) by investigating the effects on nasal mononuclear cells and systemic inflammatory markers | 91 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS CoV-2, COVID, Prevention, Poly-ICLC, Viral Infection