Clinical trial NCT04354259: Interferon Lambda for Immediate Antiviral Therapy at Diagnosis in COVID-19
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sars-CoV2
Covid-19
Keywords: peginterferon lambda
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Michael Garron Hospital
First posted: 2020-04-21
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cohort A (Ambulatory) - Proportion swab negative at day 7 (Primary efficacy endpoint)
timeFrame: At day 7
measure: Cohort A (Ambulatory) - Treatment-emergent and treatment related serious adverse events (Primary Safety Endpoint)
timeFrame: Day 0 to Day 28
measure: Cohort B (Hospitalized) - Ordinal Scale (Primary Efficacy Endpoint)
timeFrame: At Day 14
measure: Cohort B (Hospitalized) - treatment-emergent and treatment-related serious adverse events (Primary Safety Endpoint)
timeFrame: Day 0 to Day 28
Secondary outcomes:
measure: Cohort A (Ambulatory) - Symptom Resolution (Clinical Outcome #1)
timeFrame: Day 0 to Day 14
measure: Cohort A (Ambulatory) - Symptom severity scores (Clinical Outcome #2)
timeFrame: Day 0 to Day 7
measure: Cohort A (Ambulatory) - Hospitalization (Clinical Outcome #3)
timeFrame: Day 0 to Day 14
measure: Cohort A (Ambulatory) - Adverse and serious adverse events (Clinical Outcome #4)
timeFrame: Day 0 to Day 14
measure: Cohort A (Ambulatory) - Swab negative at day 3 (Virologic/Immunological Outcome #1)
timeFrame: At Day 3
measure: Cohort A (Ambulatory) - Time RNA negativity (Virologic/Immunological Outcome #2)
timeFrame: Day 0 to Day 14
measure: Cohort A (Ambulatory) - Proportion viremic (Virologic/Immunological Outcome #3)
timeFrame: Day 0 and Day 7
measure: Cohort A (Ambulatory) - Proportion with antibodies (Virologic/Immunological Outcome #4)
timeFrame: Day 0 and Day 7
measure: Cohort A (Ambulatory) - Correlation with interferon lambda 4 genotype (Virologic/Immunological Outcome #5)
timeFrame: Through day 7
measure: Cohort A (Ambulatory) - Symptoms in household contacts (Transmission Outcome #1)
timeFrame: Day 0 to Day 14
measure: Cohort A (Ambulatory) - COVID-19 in household contacts (Transmission Outcome #2)
timeFrame: At Day 30
measure: Cohort B (Hospitalized) - Ordinal scale (Clinical Outcome #1)
timeFrame: At Days 7, 21 and 28
measure: Cohort B (Hospitalized) - ICU admission (Clinical Outcome #2)
timeFrame: Day 0 to day 28
measure: Cohort B (Hospitalized) - Need for intubation (Clinical Outcome #3)
timeFrame: Day 0 to Day 14 and to Day 28
measure: Cohort B (Hospitalized) - Length of hospital stay (Clinical Outcome #4)
timeFrame: Day 0 to Day 14
measure: Cohort B (Hospitalized) - Change in respiratory symptom score (Clinical Outcome #5)
timeFrame: Day 0 to 7, Day 0 to 14, and Day 0 to 28
measure: Cohort B (Hospitalized) - All-cause mortality (Clinical Outcome #6)
timeFrame: At day 28 and day 90
measure: Cohort B (Hospitalized) - Readmission to hospital (Clinical Outcome #7)
timeFrame: From Day 0 -28 and from Day 0 - 90
measure: Cohort B (Hospitalized) - COVID-19-related mortality (Clinical Outcome #8)
timeFrame: At day 28
measure: Cohort B (Hospitalized) - Adverse (AEs) and Serious Adverse Events (SAEs) (Clinical Outcome #9)
timeFrame: Day 0 to day 28
measure: Cohort B (Hospitalized) - Dose reduction or dose omission (Clinical Outcome #10)
timeFrame: Day 5 to day 9
measure: Cohort B (Hospitalized) - Time to viral negativity (Virologic/Immunological Outcome #1)
timeFrame: Day 0 - Day 28
measure: Cohort B (Hospitalized) - Proportion negative swab. (Virologic/Immunological Outcome #2)
timeFrame: Days 0-7, 10, 12, 14, 18, 21, 25 and 28
measure: Cohort B (Hospitalized) - Quantitative viral load by nasal swab (Virologic/Immunological Outcome #3)
timeFrame: Day 0 - Day 28
measure: Cohort B (Hospitalized) - Correlation with interferon lambda 4 (IFNL4) genotype (Virologic/Immunological Outcome #4)
timeFrame: Through Day 14
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #5)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #6)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #7)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #8)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #9)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #10)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #11)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #12)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #13)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #14)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #15)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #16)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #17)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #18)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #19)
timeFrame: From Day 0 - Day 7 and to Day 14, 21, and 28
measure: Cohort B (Hospitalized) - Proportion with Antibody (Virologic/Immunological) Outcome #20)
timeFrame: At Day 7, 14, 21, and 28
measure: Cohort B (Hospitalized) - Proportion with viremia (Virologic/Immunological Outcome #21)
timeFrame: Day 0, Day 7, 14, 21, and 28
Other outcomes:
Locations:
city: Botucatu
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Botucatu
city: Sao Paulo
country: Brazil
facility: Hospital das Clínicas São Paulo
city: São Paulo
country: Brazil
facility: Hospital Alemão Oswaldo Cruz
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Toronto
country: Canada
facility: Michael Garron Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: University Health Network, Toronto
name: Jordan Feld, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Feld JJ, Kandel C, Biondi MJ, Kozak RA, Zahoor MA, Lemieux C, Borgia SM, Boggild AK, Powis J, McCready J, Tan DHS, Chan T, Coburn B, Kumar D, Humar A, Chan A, O'Neil B, Noureldin S, Booth J, Hong R, Smookler D, Aleyadeh W, Patel A, Barber B, Casey J, Hiebert R, Mistry H, Choong I, Hislop C, Santer DM, Lorne Tyrrell D, Glenn JS, Gehring AJ, Janssen HLA, Hansen BE. Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial. Lancet Respir Med. 2021 May;9(5):498-510. doi: 10.1016/S2213-2600(20)30566-X. Epub 2021 Feb 5.
citation: Lee JS, Shin EC. The type I interferon response in COVID-19: implications for treatment. Nat Rev Immunol. 2020 Oct;20(10):585-586. doi: 10.1038/s41577-020-00429-3.
citation: Moschen AR. IBD in the time of corona - vigilance for immune-mediated diseases. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):529-530. doi: 10.1038/s41575-020-0333-5.