TOGETHER - Toronto: Trial to Evaluate the Effect of Peginterferon Lambda for the Treatment of COVID-19

• ClinicalTrials.gov Identifier: NCT04967430
• Recruitment Status: Active, not recruiting
• First Posted: July 19, 2021
• Last Update Posted: April 5, 2022
• Sponsor: University Health Network, Toronto
• Information provided by (Responsible Party): University Health Network, Toronto

Study Description

Brief Summary:

Interferon (IFN) lambda is one of the fundamental responses of the innate immune system. Peginterferon lambda is a long-acting form that has been studied extensively in human trials in viral hepatitis, confirming it safety and tolerability. It is particularly attractive for consideration in the use of acute respiratory illness due to the high expression of the lambda receptor in lung epithelia. We propose to evaluate peginterferon-lambda in ambulatory patients with mild to moderate COVID-19.

Condition or disease	Intervention/treatment	Phase
Sars-CoV2; Covid19	Drug: Peginterferon Lambda-1A; Other: Placebo	Phase 3

Detailed Description:

In this study, individuals who attend an Assessment Centre/Emergency Department to be swabbed for COVID-19 and deemed well enough for home isolation will be informed about the study. There will be two major routes of recruitment. Where feasible, a rapid point-of-care (POC) laminar flow based COVID-19 test (the Abbott PanBio) will be performed and those who do not have a POC test at the assessment centre will be tested by PCR.

Interested participants who contact study staff will be confirmed to have a positive COVID-19 test. Once confirmed will be further screened for eligibility criteria by research study staff. After review, a consent form will be emailed to the participant and informed consent will be obtained through witnessed telephone consent from the participant or a substitute decision maker (SDM). Participants who consent will be randomized to receive a single subcutaneous injection of Peginterferon lambda 180µg or saline placebo.

Patients will be followed remotely with visits. In addition, participants will also attend outpatient clinic for swabs and blood work for routine laboratory and inflammatory markers on Days 7 and 14 with the primary endpoint being the time to SARS-CoV-2 RNA negativity and the proportion with COVID-19 related emergency room assessment >6 hours, hospitalization or death by Day 28. Numerous secondary endpoints will be evaluated as well.

Safety data will be reviewed by the Data Safety and Monitoring Committee after the first 50% of randomized participants complete 14 days of follow-up after treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 763 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: TOGETHER-Toronto: A Phase III Randomized, Double-blind, Placebo-controlled, Multicenter, Trial to Evaluate the Effect of Peginterferon Lambda for the Treatment of COVID-19
• Actual Study Start Date: August 27, 2021
• Actual Primary Completion Date: March 21, 2022
• Estimated Study Completion Date: June 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment; To receive a dose of peginterferon lambda 180mcg SC at baseline (Day 0).	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.
Placebo Comparator: Placebo; Patients in this arm will receive a single SC dose 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; The placebo will be 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.

Outcome Measures

Primary Outcome Measures :

1. COVID-19 related urgent care visit, emergency room assessment, hospitalization or death by Day 28 (Primary efficacy endpoint) [ Time Frame: At day 28 ]
   Proportion with COVID-19-related emergency room assessment, hospitalization, or death by Day 28
2. SARS-CoV-2 RNA negativity (Primary virological endpoint) [ Time Frame: Day 0 to Day 28 ]
   The time to SARS-CoV-2 RNA negativity.
3. Treatment-emergent and treatment-related serious adverse events (Primary safety endpoint) [ Time Frame: Day 0 to Day 28 ]
   The rate of treatment-emergent and treatment-related serious adverse events (SAEs) by Day 28.

Secondary Outcome Measures :

1. Respiratory symptom resolution (Clinical Outcome #1) [ Time Frame: Day 0 to Day 28 ]
   Time to resolution of respiratory symptoms.
2. Hospitalization (Clinical outcome #2) [ Time Frame: Day 0 to Day 28 ]
   Hospitalization for any cause
3. Death (Clinical outcome #3) [ Time Frame: Day 0 to Day 28 ]
   Death due to respiratory or cardiovascular causes
4. All symptom resolution (Clinical outcome #4) [ Time Frame: Day 0 to Day 28 ]
   Time to resolution of all symptoms (return to usual state of heath).
5. Oxygen saturation on room air (Clinical outcome #5) [ Time Frame: Day 0 to Day 14 ]
   Proportion of days with oxygen saturation below 93% on room air by Day 14
6. Seeking care from healthcare professional for COVID-19 (Clinical outcome #6) [ Time Frame: Day 0 - Day 14 ]
   Proportion seeking care from primary care provider/walk-in clinic or study healthcare provider for COVID-19.
7. Hospital Admission (Clinical outcome #7) [ Time Frame: Day 0 to Day 28 ]
   Duration of hospital admission up to Day 28
8. Time to viral negativity (Virologic/immunological outcome #1) [ Time Frame: Day 0 to Day 14 ]
   Time to SARS-CoV-2 RNA negativity.
9. Mean log of SARS-CoV-2 RNA (Virologic/immunological outcome #2) [ Time Frame: Day 3, 5, 7, 10 and 14 ]
   Difference in mean SARS-CoV-2 RNA in log copies/mL
10. Mean log decline in SARS-CoV-2 RNA (Virologic/immunological outcome #3) [ Time Frame: Day 3, 5, 7, 10 and 14 ]
    Difference in mean log decline in SARS-CoV-2 RNA.
11. Negative for SARS-CoV-2 RNA (Virologic/immunological outcome #4) [ Time Frame: Day 3 ]
    Proportion negative for SARS-CoV-2 RNA.
12. Negative for SARS-CoV-2 RNA (Virologic/immunological outcome #5) [ Time Frame: Day 7 ]
    Proportion negative for SARS-CoV-2 RNA.
13. Negative for SARS-CoV-2 RNA (Virologic/immunological outcome #6) [ Time Frame: Day 14 ]
    Proportion negative for SARS-CoV-2 RNA.
14. Proportion with antibodies (Virologic/immunological outcome #7) [ Time Frame: Day 0, 7, 14 and 90 ]
    Proportion with SARS-CoV-2 antibodies in blood.
15. Correlation with interferon lambda 4 genotype (Virologic/immunological outcome #8) [ Time Frame: Day 0 to Day 28 ]
    Correlation of response with interferon lambda 4 (IFNL4) genotype.
16. Laboratory markers (Virologic/immunological outcome #9) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in hemoglobin over time
17. Laboratory markers (Virologic/immunological outcome #10) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in white blood cell count over time
18. Laboratory markers (Virologic/immunological outcome #11) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in lymphocyte count over time.
19. Laboratory markers (Virologic/immunological outcome #12) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in ALT over time.
20. Laboratory markers (Virologic/immunological outcome #13) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in AST over time.
21. Laboratory markers (Virologic/immunological outcome #14) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in ALP over time.
22. Laboratory markers (Virologic/immunological outcome #15) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in total bilirubin over time.
23. Inflammatory markers (Virologic/immunological outcome #16) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in lactate dehydrogenase over time.
24. Inflammatory markers (Virologic/immunological outcome #17) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in c-reactive protein over time.
25. Inflammatory markers (Virologic/immunological outcome #18) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in D-dimers over time.
26. Inflammatory markers (Virologic/immunological outcome #19) [ Time Frame: Day 0 to Day 7 and Day 7 to Day 14. ]
    Change in creatine kinase over time.
27. COVID-19 in household contacts (Transmission outcome #1) [ Time Frame: Day 0 to Day 28 ]
    Confirmed diagnosis of COVID-19 in household contacts.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult 18 years of age or older.
2. Symptomatic and within 7 days of symptom onset.

3. High risk for severe disease (as defined by one or more of the following):

   1. Age >50
   2. Diabetes mellitus requiring therapy
   3. Hypertension on medication
   4. BMI >30 kg/m2
   5. Cardiovascular disease
   6. Asthma requiring chronic controller medication
   7. Symptomatic respiratory disease
   8. Immunosuppressed patients (to maximum of 10mg prednisone daily +/- other immunosuppressive agents)
   9. Documented fever (>38C)
   10. One or more of the following symptoms: cough, shortness of breath (SOB), pleuritic chest pain and/or myalgias (to a maximum of 25% of enrollment)
4. Discharged to home isolation.
5. Willing and able to provide informed consent (including by substitute decision maker).
6. Willing and able to follow-up by phone or videoconference.
7. 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.

Exclusion Criteria:

1. Pregnancy (or positive urine pregnancy test) or lactating.
2. More than 14 days following completion of SARS-CoV-2 vaccition series

3. The following pre-existing medical conditions:

   1. Known cirrhosis with any history of decompensation (ascites, variceal bleeding or hepatic encephalopathy)
   2. Known chronic kidney disease with estimated creatinine clearance < 30 mL/minute or need for dialysis
   3. Uncontrolled severe psychiatric disorder - schizophrenia, bipolar disorder, depression with prior suicidality
   4. Uncontrolled seizures or seizure in the prior 1 month
   5. 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 alcohol or drug dependence that in the opinion of the investigator would impair study participation.
5. Known prior intolerance to interferon treatment.
6. Enrolment in another clinical trial testing an antiviral agent or receipt of an antiviral agent for COVID-19 in the past 7 days.
7. Use of investigational, off-label therapy for COVID-19, or unproven therapy for COVID-19.

Contacts and Locations

Locations

Canada, Ontario

Toronto General Hospital

Toronto, Ontario, Canada, M5G 2C4

Sponsors and Collaborators

University Health Network, Toronto

Investigators

• Principal Investigator: Jordan Feld, MD; University Health Network, Toronto

More Information

• Responsible Party: University Health Network, Toronto
• ClinicalTrials.gov Identifier: NCT04967430
• Other Study ID Numbers: JF-12-2020; 21-5018 ( Other Identifier: University Health Network )
• First Posted: July 19, 2021
• Last Update Posted: April 5, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Health Network, Toronto:

Peginterferon lambda

Additional relevant MeSH terms:

COVID-19; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases