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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Sars-CoV2, Covid-19

Intervention / Treatment
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* Drug: Peginterferon Lambda-1A
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Cohort A - Ambulatory Inclusion Criteria Adult patients between the ages of 18 and 75 years. Confirmed COVID-19 infection by PCR within 7 days of symptom onset (fever, respiratory symptoms, sore throat). Discharged to home isolation. Willing and able to sign informed consent. Willing and able to follow-up by daily phone or videoconference. 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 Requirement for hospital admission 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. Pregnancy (or positive urine pregnancy test) or lactating The following pre-existing medical conditions: Known seizure disorder Known retinal disease requiring therapy Known autoimmune condition requiring therapy more intensive than intermittent non-steroidal anti-inflammatories in the prior 6 months (rheumatoid arthritis, lupus, inflammatory bowel disease) Known history of chronic obstructive pulmonary disease (COPD) or asthma associated with functional impairment Known cirrhosis with any history of decompensation (ascites, variceal bleeding or hepatic encephalopathy) Known chronic kidney disease with estimated creatinine clearance < 50 mL/minute or need for dialysis Severe psychiatric disorder - schizophrenia, bipolar disorder, depression with prior suicidality 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 Advanced cancer or other illness with life expectancy of < 1 year Known alcohol or drug dependence that in the opinion of the investigator would impair study participation Known prior intolerance to interferon treatment Enrolment in another clinical trial with use of any investigational agent in the prior 30 days Use of off-label therapy for COVID-19 Cohort B - Hospitalized Inclusion Criteria Adult patients over age 18 SARS-CoV-2 RNA-positive on nasopharyngeal swab/respiratory specimen within 10 days of symptom onset Admitted to hospital for management of COVID-19 Willing and able to provide informed consent 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 Severity of illness Respiratory failure (requiring>6L O2 or intubation in the ER) Shock - systolic BP<90 mmHg or mean arterial BP<60 mmHg after fluid resuscitation Pregnancy (or positive urine pregnancy test) or lactating The following pre-existing medical conditions: Known seizure disorder Known retinal disease requiring therapy Known autoimmune condition requiring therapy more intensive than intermittent non-steroidal anti-inflammatories in the prior 6 months (rheumatoid arthritis, lupus, inflammatory bowel disease) Known cirrhosis with any history of decompensation (ascites, variceal bleeding or hepatic encephalopathy) Known chronic kidney disease with estimated creatinine clearance < 30 mL/minute or need for dialysis Severe psychiatric disorder - uncontrolled schizophrenia, bipolar disorder, depression with prior suicidality 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 Known prior intolerance to interferon treatment Enrolment in another clinical trial with use of an antiviral agent in the prior 30 days (co-enrollment with immunomodulatory agents permitted) Use of off-label therapy for COVID-19 Any of the following abnormal laboratory indices Hemoglobin < 100 mg/dL Platelet count < 75,000 cells/mm3 Absolute neutrophil count < 1,000 cells/mm3 Estimated creatinine clearance < 30 cc/mL Total bilirubin > 2x upper limit of normal (ULN) Alanine aminotransferase (ALT) > 5x ULN Aspartate aminotransferase (AST) > 5x ULN Lipase or amylase > 2x ULN Random blood glucose > 20 mmol/L

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ambulatory Cohort - Treatment<br>to receive a single dose of peginterferon lambda 180µg SC at baseline (day 0). | Drug: Peginterferon Lambda-1A<br>* Peginterferon lambda is a covalent conjugate of human recombinant non-pegylated IFN lambda (IFN L) and a 20-kDa linear PEG chain. Peginterferon lambda Injection is a sterile, nonpyrogenic, ready-to-use solution (0.4 mg/mL) that is clear to opalescent, colorless to pale yellow, and essentially free of particles. Lambda Injection is provided in a 1-mL long Type I glass syringe (0.18 mg/syringe) with a staked 29-gauge, 1/2- inch, thin-walled needle. The syringe has a rigid needle shield and is stoppered with a plunger stopper. Syringes are prefilled with a solution of Peginterferon lambda Injection, mannitol, L-histidine, polysorbate 80, hydrochloric acid, and water for injection; they are intended for a single use at adjustable doses. The syringe is marked with dose indicator lines, which are used as a reference point for administering the correct dose.<br>|
| Placebo Comparator: Ambulatory Cohort - placebo<br>Patients in the arm will be given a single injection of 0.9% sodium chloride (normal saline) solution at baseline (day 0). A plastic 1 mL syringe will be prefilled by the study pharmacy. Each syringe will contain 0.5 mL (0.45 mL to match the volume of the Interferon plus 0.05 mL overfill) to allow for needle priming by the unblinded study nurse. | Other: placebo<br>* injection of 0.9% sodium chloride (normal saline) solution. A plastic 1 mL syringe will be prefilled by the study pharmacy. Each syringe will contain 0.5 mL (0.45 mL to match the volume of the Interferon plus 0.05 mL overfill) to allow for needle priming by the unblinded study nurse.<br>|
| Experimental: Hospitalized Cohort - Treatment<br>To receive a dose of peginterferon lambda 180µg SC at baseline and a second dose on day 5. | Drug: Peginterferon Lambda-1A<br>* Peginterferon lambda is a covalent conjugate of human recombinant non-pegylated IFN lambda (IFN L) and a 20-kDa linear PEG chain. Peginterferon lambda Injection is a sterile, nonpyrogenic, ready-to-use solution (0.4 mg/mL) that is clear to opalescent, colorless to pale yellow, and essentially free of particles. Lambda Injection is provided in a 1-mL long Type I glass syringe (0.18 mg/syringe) with a staked 29-gauge, 1/2- inch, thin-walled needle. The syringe has a rigid needle shield and is stoppered with a plunger stopper. Syringes are prefilled with a solution of Peginterferon lambda Injection, mannitol, L-histidine, polysorbate 80, hydrochloric acid, and water for injection; they are intended for a single use at adjustable doses. The syringe is marked with dose indicator lines, which are used as a reference point for administering the correct dose.<br>|
| Placebo Comparator: Hospitalized Cohort - placebo<br>Patients in the arm will be given an injection of 0.9% sodium chloride (normal saline) solution at baseline (day 0). A plastic 1 mL syringe will be prefilled by the study pharmacy. Each syringe will contain 0.5 mL (0.45 mL to match the volume of the Interferon plus 0.05 mL overfill) to allow for needle priming by the unblinded study nurse. Patients will be administered a second dose of placebo on day 5. | Other: placebo<br>* injection of 0.9% sodium chloride (normal saline) solution. A plastic 1 mL syringe will be prefilled by the study pharmacy. Each syringe will contain 0.5 mL (0.45 mL to match the volume of the Interferon plus 0.05 mL overfill) to allow for needle priming by the unblinded study nurse.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A (Ambulatory) - Proportion swab negative at day 7 (Primary efficacy endpoint) | The proportion of participants with negative SARS-CoV-2 RNA on nasopharyngeal swab. | At day 7 | 
| Cohort A (Ambulatory) - Treatment-emergent and treatment related serious adverse events (Primary Safety Endpoint) | The rate of treatment-emergent and treatment-related serious adverse events (SAEs) | Day 0 to Day 28 | 
| Cohort B (Hospitalized) - Ordinal Scale (Primary Efficacy Endpoint) | Clinical status on an ordinal scale at Day 14 | At Day 14 | 
| Cohort B (Hospitalized) - treatment-emergent and treatment-related serious adverse events (Primary Safety Endpoint) | The rate of treatment-emergent and treatment-related serious adverse events (SAEs) | Day 0 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A (Ambulatory) - Symptom Resolution (Clinical Outcome #1) | Time to resolution of symptoms (fever, cough, diarrhea) | Day 0 to Day 14 | 
| Cohort A (Ambulatory) - Symptom severity scores (Clinical Outcome #2) | Change in relative categorical symptom scores (respiratory, gastrointestinal, fever) - none, mild, moderate, severe and no change, worse, better | Day 0 to Day 7 | 
| Cohort A (Ambulatory) - Hospitalization (Clinical Outcome #3) | Proportion with need for hospital admission | Day 0 to Day 14 | 
| Cohort A (Ambulatory) - Adverse and serious adverse events (Clinical Outcome #4) | Adverse events and serious adverse events | Day 0 to Day 14 | 
| Cohort A (Ambulatory) - Swab negative at day 3 (Virologic/Immunological Outcome #1) | Proportion negative for SARS-CoV-2 RNA by nasopharyngeal swab | At Day 3 | 
| Cohort A (Ambulatory) - Time RNA negativity (Virologic/Immunological Outcome #2) | Time to SARS-CoV-2 RNA negativity on mid-turbinate nasal swab or saliva | Day 0 to Day 14 | 
| Cohort A (Ambulatory) - Proportion viremic (Virologic/Immunological Outcome #3) | Proportion with SARS-CoV-2 RNA in blood. | Day 0 and Day 7 | 
| Cohort A (Ambulatory) - Proportion with antibodies (Virologic/Immunological Outcome #4) | Proportion with SARS-CoV-2 antibodies blood | Day 0 and Day 7 | 
| Cohort A (Ambulatory) - Correlation with interferon lambda 4 genotype (Virologic/Immunological Outcome #5) | Correlation of virologic response with interferon lambda 4 (IFNL4) genotype | Through day 7 | 
| Cohort A (Ambulatory) - Symptoms in household contacts (Transmission Outcome #1) | Proportion with symptom development in household contacts (categorical symptom type yes/no) | Day 0 to Day 14 | 
| Cohort A (Ambulatory) - COVID-19 in household contacts (Transmission Outcome #2) | Proportion with confirmed diagnosis of COVID-19 in household contacts | At Day 30 | 
| Cohort B (Hospitalized) - Ordinal scale (Clinical Outcome #1) | Clinical status on the ordinal scale | At Days 7, 21 and 28 | 
| Cohort B (Hospitalized) - ICU admission (Clinical Outcome #2) | Proportion with ICU admission during hospitalization | Day 0 to day 28 | 
| Cohort B (Hospitalized) - Need for intubation (Clinical Outcome #3) | Proportion with need for intubation | Day 0 to Day 14 and to Day 28 | 
| Cohort B (Hospitalized) - Length of hospital stay (Clinical Outcome #4) | Length of hospital stay (days) | Day 0 to Day 14 | 
| Cohort B (Hospitalized) - Change in respiratory symptom score (Clinical Outcome #5) | Change in respiratory symptom score (score 0 to 7 with higher scores indicating more severe disease) | Day 0 to 7, Day 0 to 14, and Day 0 to 28 | 
| Cohort B (Hospitalized) - All-cause mortality (Clinical Outcome #6) | All-cause mortality | At day 28 and day 90 | 
| Cohort B (Hospitalized) - Readmission to hospital (Clinical Outcome #7) | Proportion with readmission to hospital | From Day 0 -28 and from Day 0 - 90 | 
| Cohort B (Hospitalized) - COVID-19-related mortality (Clinical Outcome #8) | COVID-19-related mortality | At day 28 | 
| Cohort B (Hospitalized) - Adverse (AEs) and Serious Adverse Events (SAEs) (Clinical Outcome #9) | Adverse (AEs) and Serious Adverse Events (SAEs) | Day 0 to day 28 | 
| Cohort B (Hospitalized) - Dose reduction or dose omission (Clinical Outcome #10) | Frequency of dose reduction or dose omission for the second dose of peginterferon lambda | Day 5 to day 9 | 
| Cohort B (Hospitalized) - Time to viral negativity (Virologic/Immunological Outcome #1) | Time to SARS-CoV-2 RNA negativity. | Day 0 - Day 28 | 
| Cohort B (Hospitalized) - Proportion negative swab. (Virologic/Immunological Outcome #2) | Proportion negative for SARS-CoV-2 RNA by mid-turbinate swab | Days 0-7, 10, 12, 14, 18, 21, 25 and 28 | 
| Cohort B (Hospitalized) - Quantitative viral load by nasal swab (Virologic/Immunological Outcome #3) | Change in quantitative SARS-CoV-2 RNA by mid-turbinate swab over time | Day 0 - Day 28 | 
| Cohort B (Hospitalized) - Correlation with interferon lambda 4 (IFNL4) genotype (Virologic/Immunological Outcome #4) | Correlation of virologic response with interferon lambda 4 (IFNL4) genotype | Through Day 14 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #5) | Change in hemoglobin over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #6) | Change in white blood cell count over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #7) | Change in lymphocyte count over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #8) | Change in platelet count over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #9) | Change in ALT over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #10) | Change in AST over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #11) | Change in ALP over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #12) | Change in bilirubin over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #13) | Change in albumin over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #14) | Change in ferritin over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #15) | Change in lactate dehydrogenase over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #16) | Change in c-reactive protein over time | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #17) | Change in D-dimers over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #18) | Change in creatine kinase over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #19) | Change in troponin over time. | From Day 0 - Day 7 and to Day 14, 21, and 28 | 
| Cohort B (Hospitalized) - Proportion with Antibody (Virologic/Immunological) Outcome #20) | Proportion with SARS-CoV-2 Antibody. | At Day 7, 14, 21, and 28 | 
| Cohort B (Hospitalized) - Proportion with viremia (Virologic/Immunological Outcome #21) | Proportion with SARS-CoV-2 RNA in blood | Day 0, Day 7, 14, 21, and 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peginterferon lambda