Covid-19, Sars-CoV2
Conditions
Keywords
peginterferon lambda
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.
Interventions
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.
OTHERplacebo
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.
Sponsors
Michael Garron Hospital
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A (Ambulatory) - Proportion swab negative at day 7 (Primary efficacy endpoint) | At day 7 | The proportion of participants with negative SARS-CoV-2 RNA on nasopharyngeal swab. |
| Cohort A (Ambulatory) - Treatment-emergent and treatment related serious adverse events (Primary Safety Endpoint) | Day 0 to Day 28 | The rate of treatment-emergent and treatment-related serious adverse events (SAEs) |
| Cohort B (Hospitalized) - Ordinal Scale (Primary Efficacy Endpoint) | At Day 14 | Clinical status on an ordinal scale at Day 14 |
| Cohort B (Hospitalized) - treatment-emergent and treatment-related serious adverse events (Primary Safety Endpoint) | Day 0 to Day 28 | The rate of treatment-emergent and treatment-related serious adverse events (SAEs) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort B (Hospitalized) - Length of hospital stay (Clinical Outcome #4) | Day 0 to Day 14 | Length of hospital stay (days) |
| Cohort A (Ambulatory) - Symptom Resolution (Clinical Outcome #1) | Day 0 to Day 14 | Time to resolution of symptoms (fever, cough, diarrhea) |
| Cohort A (Ambulatory) - Symptoms in household contacts (Transmission Outcome #1) | Day 0 to Day 14 | Proportion with symptom development in household contacts (categorical symptom type yes/no) |
| Cohort A (Ambulatory) - Symptom severity scores (Clinical Outcome #2) | Day 0 to Day 7 | Change in relative categorical symptom scores (respiratory, gastrointestinal, fever) - none, mild, moderate, severe and no change, worse, better |
| Cohort A (Ambulatory) - Hospitalization (Clinical Outcome #3) | Day 0 to Day 14 | Proportion with need for hospital admission |
| Cohort A (Ambulatory) - Adverse and serious adverse events (Clinical Outcome #4) | Day 0 to Day 14 | Adverse events and serious adverse events |
| Cohort A (Ambulatory) - Swab negative at day 3 (Virologic/Immunological Outcome #1) | At Day 3 | Proportion negative for SARS-CoV-2 RNA by nasopharyngeal swab |
| Cohort A (Ambulatory) - Time RNA negativity (Virologic/Immunological Outcome #2) | Day 0 to Day 14 | Time to SARS-CoV-2 RNA negativity on mid-turbinate nasal swab or saliva |
| Cohort A (Ambulatory) - Proportion viremic (Virologic/Immunological Outcome #3) | Day 0 and Day 7 | Proportion with SARS-CoV-2 RNA in blood. |
| Cohort A (Ambulatory) - Proportion with antibodies (Virologic/Immunological Outcome #4) | Day 0 and Day 7 | Proportion with SARS-CoV-2 antibodies blood |
| Cohort A (Ambulatory) - Correlation with interferon lambda 4 genotype (Virologic/Immunological Outcome #5) | Through day 7 | Correlation of virologic response with interferon lambda 4 (IFNL4) genotype |
| Cohort B (Hospitalized) - Change in respiratory symptom score (Clinical Outcome #5) | Day 0 to 7, Day 0 to 14, and Day 0 to 28 | Change in respiratory symptom score (score 0 to 7 with higher scores indicating more severe disease) |
| Cohort B (Hospitalized) - All-cause mortality (Clinical Outcome #6) | At day 28 and day 90 | All-cause mortality |
| Cohort B (Hospitalized) - Readmission to hospital (Clinical Outcome #7) | From Day 0 -28 and from Day 0 - 90 | Proportion with readmission to hospital |
| Cohort B (Hospitalized) - COVID-19-related mortality (Clinical Outcome #8) | At day 28 | COVID-19-related mortality |
| Cohort B (Hospitalized) - Adverse (AEs) and Serious Adverse Events (SAEs) (Clinical Outcome #9) | Day 0 to day 28 | Adverse (AEs) and Serious Adverse Events (SAEs) |
| Cohort B (Hospitalized) - Dose reduction or dose omission (Clinical Outcome #10) | Day 5 to day 9 | Frequency of dose reduction or dose omission for the second dose of peginterferon lambda |
| Cohort B (Hospitalized) - Time to viral negativity (Virologic/Immunological Outcome #1) | Day 0 - Day 28 | Time to SARS-CoV-2 RNA negativity. |
| Cohort B (Hospitalized) - Proportion negative swab. (Virologic/Immunological Outcome #2) | Days 0-7, 10, 12, 14, 18, 21, 25 and 28 | Proportion negative for SARS-CoV-2 RNA by mid-turbinate swab |
| Cohort B (Hospitalized) - Quantitative viral load by nasal swab (Virologic/Immunological Outcome #3) | Day 0 - Day 28 | Change in quantitative SARS-CoV-2 RNA by mid-turbinate swab over time |
| Cohort B (Hospitalized) - Correlation with interferon lambda 4 (IFNL4) genotype (Virologic/Immunological Outcome #4) | Through Day 14 | Correlation of virologic response with interferon lambda 4 (IFNL4) genotype |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #5) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in hemoglobin over time. |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #6) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in white blood cell count over time. |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #7) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in lymphocyte count over time. |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #8) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in platelet count over time. |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #9) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in ALT over time. |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #10) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in AST over time. |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #11) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in ALP over time. |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #12) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in bilirubin over time. |
| Cohort B (Hospitalized) - Safety Markers (Virologic/Immunological Outcome #13) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in albumin over time. |
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #14) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in ferritin over time. |
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #15) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in lactate dehydrogenase over time. |
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #16) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in c-reactive protein over time |
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #17) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in D-dimers over time. |
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #18) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in creatine kinase over time. |
| Cohort B (Hospitalized) - Inflammatory Markers (Virologic/Immunological Outcome #19) | From Day 0 - Day 7 and to Day 14, 21, and 28 | Change in troponin over time. |
| Cohort A (Ambulatory) - COVID-19 in household contacts (Transmission Outcome #2) | At Day 30 | Proportion with confirmed diagnosis of COVID-19 in household contacts |
| Cohort B (Hospitalized) - Proportion with viremia (Virologic/Immunological Outcome #21) | Day 0, Day 7, 14, 21, and 28 | Proportion with SARS-CoV-2 RNA in blood |
| Cohort B (Hospitalized) - Proportion with Antibody (Virologic/Immunological) Outcome #20) | At Day 7, 14, 21, and 28 | Proportion with SARS-CoV-2 Antibody. |
| Cohort B (Hospitalized) - Ordinal scale (Clinical Outcome #1) | At Days 7, 21 and 28 | Clinical status on the ordinal scale |
| Cohort B (Hospitalized) - ICU admission (Clinical Outcome #2) | Day 0 to day 28 | Proportion with ICU admission during hospitalization |
| Cohort B (Hospitalized) - Need for intubation (Clinical Outcome #3) | Day 0 to Day 14 and to Day 28 | Proportion with need for intubation |
Countries
Brazil, Canada
Outcome results
None listed