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

Covid-19 Clinical Trial

— ILIAD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04354259
• Other study ID #: 20-5334
• Status: Completed
• Phase: Phase 2
• Start date: May 13, 2020
• Est. completion date: December 8, 2022

Study information

• Verified date: December 2023
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 157
• Est. completion date: December 8, 2022
• Est. primary completion date: August 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Covid-19
• Sars-CoV2

Intervention

Drug:
• Peginterferon Lambda-1A
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.

Other:
• placebo
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.

Locations

Country	Name	City	State
Brazil	Hospital das Clínicas da Faculdade de Medicina de Botucatu	Botucatu
Brazil	Hospital das Clínicas São Paulo	Sao Paulo
Brazil	Hospital Alemão Oswaldo Cruz	São Paulo
Canada	University of Calgary	Calgary	Alberta
Canada	Michael Garron Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University Health Network	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
University Health Network, Toronto	Michael Garron Hospital

Countries where clinical trial is conducted

Brazil,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Cohort B (Hospitalized) - Ordinal Scale (Primary Efficacy Endpoint)	Clinical status on an ordinal scale at Day 14	At Day 14
Primary	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	Cohort A (Ambulatory) - Symptom Resolution (Clinical Outcome #1)	Time to resolution of symptoms (fever, cough, diarrhea)	Day 0 to Day 14
Secondary	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
Secondary	Cohort A (Ambulatory) - Hospitalization (Clinical Outcome #3)	Proportion with need for hospital admission	Day 0 to Day 14
Secondary	Cohort A (Ambulatory) - Adverse and serious adverse events (Clinical Outcome #4)	Adverse events and serious adverse events	Day 0 to Day 14
Secondary	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
Secondary	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
Secondary	Cohort A (Ambulatory) - Proportion viremic (Virologic/Immunological Outcome #3)	Proportion with SARS-CoV-2 RNA in blood.	Day 0 and Day 7
Secondary	Cohort A (Ambulatory) - Proportion with antibodies (Virologic/Immunological Outcome #4)	Proportion with SARS-CoV-2 antibodies blood	Day 0 and Day 7
Secondary	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
Secondary	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
Secondary	Cohort A (Ambulatory) - COVID-19 in household contacts (Transmission Outcome #2)	Proportion with confirmed diagnosis of COVID-19 in household contacts	At Day 30
Secondary	Cohort B (Hospitalized) - Ordinal scale (Clinical Outcome #1)	Clinical status on the ordinal scale	At Days 7, 21 and 28
Secondary	Cohort B (Hospitalized) - ICU admission (Clinical Outcome #2)	Proportion with ICU admission during hospitalization	Day 0 to day 28
Secondary	Cohort B (Hospitalized) - Need for intubation (Clinical Outcome #3)	Proportion with need for intubation	Day 0 to Day 14 and to Day 28
Secondary	Cohort B (Hospitalized) - Length of hospital stay (Clinical Outcome #4)	Length of hospital stay (days)	Day 0 to Day 14
Secondary	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
Secondary	Cohort B (Hospitalized) - All-cause mortality (Clinical Outcome #6)	All-cause mortality	At day 28 and day 90
Secondary	Cohort B (Hospitalized) - Readmission to hospital (Clinical Outcome #7)	Proportion with readmission to hospital	From Day 0 -28 and from Day 0 - 90
Secondary	Cohort B (Hospitalized) - COVID-19-related mortality (Clinical Outcome #8)	COVID-19-related mortality	At day 28
Secondary	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
Secondary	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
Secondary	Cohort B (Hospitalized) - Time to viral negativity (Virologic/Immunological Outcome #1)	Time to SARS-CoV-2 RNA negativity.	Day 0 - Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Cohort B (Hospitalized) - Proportion with Antibody (Virologic/Immunological) Outcome #20)	Proportion with SARS-CoV-2 Antibody.	At Day 7, 14, 21, and 28
Secondary	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