Interferon Lambda for Immediate Antiviral Therapy at Diagnosis in COVID-19

Interferon Lambda for Immediate Antiviral Therapy at Diagnosis (ILIAD): A Phase II Randomized, Double-blind, Placebo-controlled, Multicenter Trial to Evaluate the Effect of Peginterferon Lambda for the Treatment of COVID-19

Interferon lambda is one of the main arms of the innate antiviral immune response and is critical for controlling respiratory viral infections in mice. Interferon lambda has a better side effect profile than other interferons because of the limited tissue distribution of its receptor. Peginterferon lambda is a long-acting form that has been studied extensively in human trials in viral hepatitis, confirming its safety. We propose to evaluate peginterferon-lambda in ambulatory and hospitalized patients with mild to moderate COVID-19.

The study uses an adaptive design with initial enrolment in the Ambulatory cohort (Cohort A) followed by a safety assessment before initiation of enrolment in the Hospitalized cohort (Cohort B).

Ambulatory patients (Cohort A) with confirmed COVID-19 deemed well enough for home isolation will be randomized to receive a single subcutaneous injection of Peginterferon lambda 180µg or saline placebo prior to discharge. Patients will be followed remotely with visits for a repeat swab at Day 3 and 7 with the primary endpoint being the proportion positive for SARS-CoV-2 on Day 7.

Safety data will be reviewed by the Data Safety and Monitoring Committee after 50% of the Ambulatory cohort (n=60) has been enrolled. If the committee approves study continuation, enrolment will continue in the Ambulatory cohort (Cohort A) and will begin in the Hospitalized cohort (Cohort B).

Hospitalized patients (Cohort B) with moderate but not severe COVID-19 will be enrolled and randomized to Peginterferon lambda 180µg or saline placebo on Day 0 and 5. The primary endpoint will be clinical outcomes on the WHO ordinal scale. In addition to the primary endpoint on which the study is powered, numerous secondary endpoints will be evaluated. Samples will also be collected for ancillary studies to better understand predictors of disease severity and response to treatment.

Cohort A - Ambulatory

Inclusion Criteria

1. Adult patients between the ages of 18 and 75 years.

2. Confirmed COVID-19 infection by PCR within 7 days of symptom onset (fever, respiratory symptoms, sore throat).

3. Discharged to home isolation.

4. Willing and able to sign informed consent.

5. Willing and able to follow-up by daily phone or videoconference.

6. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to use adequate methods of contraception during the study and through 90 days after the last dose of study medication. Female patients of childbearing potential are all those except patients who are surgically sterile, who have medically documented ovarian failure, or who are at least 1 year postmenopausal. Adequate methods of contraception are:

   a. For female patients i. Hormonal contraceptives including progestogen injection (eg, Depo-Provera®), combined oral contraceptive pill or vaginal ring for ≥ 3 months before screening AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or ii. Intrauterine device (IUD) or intrauterine system (IUS) in place ≥ 3 months before screening AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or iii. Surgical sterilization of the partner (vasectomy ≥ 1 month before screening) AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or iv. Double-barrier methods (use of condom [male partner] with either diaphragm with spermicide or cervical cap with spermicide) from screening.

   b. For male patients i. Surgical sterilization (vasectomy ≥ 1 month before screening) AND a barrier method (use of condom or diaphragm with spermicide or cervical cap with spermicide) from screening, or ii. Consistently and correctly use a condom from screening AND female partner must agree to use a hormonal contraceptive, a nonhormonal nonbarrier method (eg, copper IUD), or a nonhormonal barrier method (eg, diaphragm with spermicide or cervical cap with spermicide).

Exclusion Criteria

1. Requirement for hospital admission

2. Current immunosuppression due to medication (steroids, biologics, chemotherapy) or underlying condition such as organ/bone marrow transplant or untreated HIV or HIV infection with detectable HIV RNA and/or CD4 count of <500.

3. Pregnancy (or positive urine pregnancy test) or lactating

4. The following pre-existing medical conditions:

   1. Known seizure disorder
   2. Known retinal disease requiring therapy
   3. Known autoimmune condition requiring therapy more intensive than intermittent non-steroidal anti-inflammatories in the prior 6 months (rheumatoid arthritis, lupus, inflammatory bowel disease)
   4. Known history of chronic obstructive pulmonary disease (COPD) or asthma associated with functional impairment
   5. Known cirrhosis with any history of decompensation (ascites, variceal bleeding or hepatic encephalopathy)
   6. Known chronic kidney disease with estimated creatinine clearance < 50 mL/minute or need for dialysis
   7. Severe psychiatric disorder - schizophrenia, bipolar disorder, depression with prior suicidality
   8. Any other underlying medical (cardiac, liver, renal, neurological, respiratory) or psychiatric condition that in the view of the investigator would preclude use of peginterferon lambda

5. Advanced cancer or other illness with life expectancy of < 1 year

6. Known alcohol or drug dependence that in the opinion of the investigator would impair study participation

7. Known prior intolerance to interferon treatment

8. Enrolment in another clinical trial with use of any investigational agent in the prior 30 days

9. Use of off-label therapy for COVID-19

Cohort B - Hospitalized

Inclusion Criteria

1. Adult patients over age 18

2. SARS-CoV-2 RNA-positive on nasopharyngeal swab/respiratory specimen within 10 days of symptom onset

3. Admitted to hospital for management of COVID-19

4. Willing and able to provide informed consent

5. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to use adequate methods of contraception during the study and through 90 days after the last dose of study medication. Female patients of childbearing potential are all those except patients who are surgically sterile, who have medically documented ovarian failure, or who are at least 1 year postmenopausal. Adequate methods of contraception are:

   a. For female patients: i. Hormonal contraceptives including progestogen injection (eg, Depo-Provera®), combined oral contraceptive pill or vaginal ring for ≥ 3 months before screening AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or ii. Intrauterine device (IUD) or intrauterine system (IUS) in place ≥ 3 months before screening AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or iii. Surgical sterilization of the partner (vasectomy ≥ 1 month before screening) AND a barrier method (use of condom [male partner] or diaphragm with spermicide or cervical cap with spermicide) from screening, or iv. Double-barrier methods (use of condom [male partner] with either diaphragm with spermicide or cervical cap with spermicide) from screening.

   b. For male patients: i. Surgical sterilization (vasectomy ≥ 1 month before screening) AND a barrier method (use of condom or diaphragm with spermicide or cervical cap with spermicide) from screening, or ii. Consistently and correctly use a condom from screening AND female partner must agree to use a hormonal contraceptive, a nonhormonal nonbarrier method (eg, copper IUD), or a nonhormonal barrier method (eg, diaphragm with spermicide or cervical cap with spermicide).

Exclusion Criteria

1. Severity of illness

   1. Respiratory failure (requiring>6L O2 or intubation in the ER)
   2. Shock - systolic BP<90 mmHg or mean arterial BP<60 mmHg after fluid resuscitation

2. Pregnancy (or positive urine pregnancy test) or lactating

3. The following pre-existing medical conditions:

   1. Known seizure disorder
   2. Known retinal disease requiring therapy
   3. Known autoimmune condition requiring therapy more intensive than intermittent non-steroidal anti-inflammatories in the prior 6 months (rheumatoid arthritis, lupus, inflammatory bowel disease)
   4. Known cirrhosis with any history of decompensation (ascites, variceal bleeding or hepatic encephalopathy)
   5. Known chronic kidney disease with estimated creatinine clearance < 30 mL/minute or need for dialysis
   6. Severe psychiatric disorder - uncontrolled schizophrenia, bipolar disorder, depression with prior suicidality
   7. Any other underlying medical (cardiac, liver, renal, neurological, respiratory) or psychiatric condition that in the view of the investigator would preclude use of peginterferon lambda

4. Known prior intolerance to interferon treatment

5. Enrolment in another clinical trial with use of an antiviral agent in the prior 30 days (co-enrollment with immunomodulatory agents permitted)

6. Use of off-label therapy for COVID-19

7. Any of the following abnormal laboratory indices

   1. Hemoglobin < 100 mg/dL
   2. Platelet count < 75,000 cells/mm3
   3. Absolute neutrophil count < 1,000 cells/mm3
   4. Estimated creatinine clearance < 30 cc/mL
   5. Total bilirubin > 2x upper limit of normal (ULN)
   6. Alanine aminotransferase (ALT) > 5x ULN
   7. Aspartate aminotransferase (AST) > 5x ULN
   8. Lipase or amylase > 2x ULN
   9. Random blood glucose > 20 mmol/L