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

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

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.

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.

Inclusion Criteria for Enrollment

1. 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.

2. Asymptomatic; defined by experiencing none of the symptoms identified in the Symptom Questionnaire

   1. fever
   2. cough
   3. dyspnea
   4. fatigue
   5. muscle or joint pain
   6. sore throat
   7. stuffy or runny nose
   8. nausea/vomiting
   9. headache
   10. confusion
   11. diarrhea
   12. loss of smell or taste

3. Nasopharyngeal swab for COVID-19 at screening with negative diagnosis of SARS-CoV-2

4. Willing and able to provide blood, nasopharyngeal swab, and nasal mononuclear samples

5. 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.

6. Able to provide informed consent

7. 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

8. 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

1. Individuals not yet fully vaccinated with a COVID-19 vaccine.

2. Receipt of any blood product in past 120 days

3. Allergic rhinitis, chronic sinusitis, or other nasal inflammatory disease that requires daily intranasal or oral medication

4. Chronic medical problems that require daily nasal administration of medication

5. Prior nasal or sinus surgery including trans nasal approaches to brain

6. Chronic pulmonary conditions including severe asthma, COPD, or chronic bronchitis

7. Autoimmune hepatitis, decompensated liver disease, cardiac ischemia, congestive heart failure, cardiac arrhythmia, neutropenia, thrombocytopenia, severe renal insufficiency

8. Psychiatric or cognitive illness or recreational drug/alcohol use that in the opinion of the principal investigator, would affect participant safety and/or compliance

9. Symptoms consistent with COVID-19 infection (fevers, acute onset cough, shortness of breath) at time of screening

10. Nucleic acid testing evidence of COVID-19 infection at time of screening

11. 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.

12. Has a diagnosis of primary immunodeficiency

13. Has uncontrolled hypertension that in the opinion of the principal investigator poses unacceptable risk.

14. Has active autoimmune disease that has required systemic treatment in the past 1 year

    1. (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
    2. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is acceptable

15. 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

16. 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

17. Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, intravenous immune globulins, monoclonal antibodies, receptor traps)

18. Active, untreated tuberculosis