Study of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients

NCT ID: NCT04590586

Last Updated: 2022-06-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 515 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-24
• Study Completion Date: 2021-08-03

Brief Summary

The primary objective of this study is to evaluate the time to confirmed clinical recovery in participants hospitalized with COVID-19. Candidate agents will be evaluated frequently for efficacy and safety, with candidate agents being added to and/or removed from the study on an ongoing basis, depending on the results of their evaluation.

Detailed Description

This adaptive, randomized, placebo-controlled platform study is designed to rapidly assess multiple candidate agents as treatments for COVID-19 in hospitalized patients. Candidate agents will be evaluated frequently (through ongoing monitoring) for futility and safety, with candidate agents being added to and/or removed from the study on an ongoing basis, depending on the results of their evaluation.

For inclusion, participants will need to be hospitalized with a clinical status of Grade 2 to Grade 5, as defined by the following Clinical Severity Status 8-Point Ordinal Scale:

1. Death

2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices

4. Hospitalized, requiring supplemental oxygen

5. Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care (COVID-19 related or otherwise)

6. Hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care

7. Not hospitalized, limitation on activities and/or requiring home oxygen

8. Not hospitalized, no limitations on activities

Participants will be randomized equally to either the candidate agent plus standard of care (SoC) or placebo plus SoC in a double-blind fashion. Participants who are randomized to placebo plus SoC will subsequently be randomized equally to a matching placebo corresponding to an available agent whose sub-protocol the patient qualified for (ie, a 2-stage randomization). Each participant in the placebo plus SoC group will only receive one type of placebo. Randomization will be stratified by baseline clinical severity of 2 on the 8-point ordinal scale (yes/no) and remdesivir use at baseline (yes/no).

The study will evaluate each candidate agent separately as an add-on to the SoC to assess safety and efficacy. The comparator group for a candidate agent will include participants randomized to the placebo arm of any sub-protocol according to the following conditions:

• Apremilast sub-protocol: participants who were enrolled concurrently to apremilast and who would have been eligible for the apremilast sub-protocol.
• Lanadelumab sub-protocol: at a site where at least one participant was randomized to either lanadelumab active or placebo arms.
• Zilucoplan sub-protocol: at a site where at least one participant was randomized to either the zilucoplan active or placebo arms.

Conditions

COVID-19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Apremilast + Standard of Care

Participants will be randomized to receive 30 mg apremilast orally twice a day (BID) in addition to standard of care treatment for 14 days or until hospital discharge, death, or discontinuation of investigational product, whichever occurred first.

Group Type: EXPERIMENTAL

Standard of care

Intervention Type: DRUG

Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

Apremilast

Intervention Type: DRUG

Apremilast administered orally as a tablet.

Apremilast Placebo + Standard of Care

Participants will be randomized to receive matching placebo to apremilast orally twice a day in addition to standard of care treatment for 14 days or until hospital discharge, death, or discontinuation of investigational product, whichever occurred first.

Group Type: PLACEBO_COMPARATOR

Standard of care

Intervention Type: DRUG

Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

Apremilast placebo

Intervention Type: DRUG

Matching apremilast placebo administered orally as a tablet.

Lanadelumab + Standard of Care

Participants will be randomized to receive lanadelumab 300 mg by intravenous infusion on Day 1, and a second dose administered on Day 4 in addition to standard of care.

Group Type: EXPERIMENTAL

Standard of care

Intervention Type: DRUG

Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

Lanadelumab

Intervention Type: DRUG

Lanadelumab administered as an intravenous (IV) infusion.

Lanadelumab Placebo + Standard of Care

Participants will be randomized to receive placebo to lanadelumab by intravenous infusion on Day 1, and a second dose administered on Day 4 in addition to standard of care.

Group Type: PLACEBO_COMPARATOR

Standard of care

Intervention Type: DRUG

Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

Lanadelumab placebo

Intervention Type: DRUG

Matching lanadelumab placebo (normal saline) administered as an intravenous (IV) infusion.

Zilucoplan + Standard of Care

Participants will be randomized to receive 32.4 mg zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment in addition to standard of care.

Group Type: EXPERIMENTAL

Standard of care

Intervention Type: DRUG

Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

Zilucoplan

Intervention Type: DRUG

Zilucoplan administered as a subcutaneous (sc) injection in the abdomen, thigh, or upper arm.

Zilucoplan Placebo + Standard of Care

Participants will be randomized to receive placebo to zilucoplan by subcutaneous injection every day for 14 days, or until discharge if discharge was before 14 days of treatment in addition to standard of care.

Group Type: PLACEBO_COMPARATOR

Standard of care

Intervention Type: DRUG

Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

Zilucoplan placebo

Intervention Type: DRUG

Matching zilucoplan placebo administered as a subcutaneous (sc) injection in the abdomen, thigh, or upper arm.

Interventions

Standard of care

Standard of care (SoC) treatment for COVID-19 infection in line with institutional practice. The SoC may change as new information becomes available about treating COVID-19.

Intervention Type: DRUG

Apremilast

Apremilast administered orally as a tablet.

Intervention Type: DRUG

Apremilast placebo

Matching apremilast placebo administered orally as a tablet.

Intervention Type: DRUG

Lanadelumab

Lanadelumab administered as an intravenous (IV) infusion.

Intervention Type: DRUG

Lanadelumab placebo

Matching lanadelumab placebo (normal saline) administered as an intravenous (IV) infusion.

Intervention Type: DRUG

Zilucoplan

Zilucoplan administered as a subcutaneous (sc) injection in the abdomen, thigh, or upper arm.

Intervention Type: DRUG

Zilucoplan placebo

Matching zilucoplan placebo administered as a subcutaneous (sc) injection in the abdomen, thigh, or upper arm.

Intervention Type: DRUG

Other Intervention Names

Otezla; TAKHZYRO™; TAK-743

Eligibility Criteria

Inclusion Criteria

• Adults (≥18 years of age) with active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by laboratory tests and/or point of care tests (eg, commercial or public health assay, which is approved for emergency use). If no diagnostic test results are available that have been obtained during the previous 72 hours, then a test should be performed as part of the screening assessment.
• A score of Grade 2 (hospitalized, on invasive mechanical ventilation or ECMO), Grade 3 (hospitalized, on noninvasive ventilation or high-flow oxygen devices), Grade 4 (hospitalized, requiring supplemental oxygen), or Grade 5 (hospitalized, not requiring supplemental oxygen, requiring ongoing medical care [COVID-19 related or otherwise]), as defined by an 8 point ordinal scale.
• Male participants:

• A male participant must agree to use contraception during the treatment period and for at least 6 weeks after the last dose of study treatment and refrain from donating sperm during this period.
• Female participants:

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
• Not a woman of childbearing potential (WOCBP). OR
• A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 6 weeks after the last dose of study treatment.
• Ability to provide informed consent signed by the study participant or legally authorized representative.
• Ability and willingness to participate in telephone/telemedicine follow-up visits if needed.
• Zilucoplan only: Antibiotic prophylaxis: all participants must be willing to take antibiotic prophylaxis concomitantly, starting with the first dose of zilucoplan or placebo.

Exclusion Criteria

• Participant has any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the participant (eg, compromise their well-being) or that could prevent, limit, or confound the protocol-specified assessments (eg, participants unable to swallow study medication tablets).
• Stage 4 severe chronic kidney disease or requiring dialysis.
• Screening 12-lead electrocardiogram (ECG) with a measurable QTc interval according to Fridericia correction (QTcF) ≥ 500 ms.
• Anticipated transfer to another hospital that is not a study center within 72 hours.
• Participants who are currently pregnant or who are not willing to discontinue breastfeeding.
• Participants participating in another clinical study of an investigational medicinal product or other unapproved (or investigational) treatment for COVID-19.
• Active tuberculosis or a history of incompletely treated tuberculosis.
• Active, uncontrolled systemic bacterial or fungal infection(s).
• Apremilast only: Current treatment with apremilast, or another agent of similar mechanism of action, for any indication within 1 week prior to first dose of investigational product.
• Apremilast only: Concurrent use at screening or randomization of cytochrome P450 (CYP)3A inducers (eg, rifampin, phenobarbital, carbamazepine) within 1 week prior to first dose of investigational product.
• Apremilast only: Known hypersensitivity to apremilast or any excipients in formulation.
• Lanadelumab only: Known or suspected hypersensitivity to lanadelumab or any of its excipients.
• Lanadelumab only: Previous (within 3 months prior to baseline) or current use of immunomodulators (eg, methotrexate, azathioprine, 6-mercaptopurine, tumor necrosis factor [TNF] α inhibitor, Janus kinase [JAK] inhibitor, alpha-integrin inhibitor).
• Lanadelumab only: Known or suspected venous thromboembolism.
• Lanadelumab only: Previous (within 3 months [or 5 half-lives, whichever is greater] of screening) or current use of plasma kallikrein (pKal) inhibitor or bradykinin receptor blocker.
• Zilucoplan only: Participants with unresolved or suspected infection with Neisseria meningitidis or a past history of N. meningitidis (eg, in a complement-deficient patient).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Pinnacle Research Group LLC

Anniston, Alabama, United States

Good Samaritan Hospital

Bakersfield, California, United States

Sharp Chula Vista Medical Center

Chula Vista, California, United States

El Centro Regional Medical Center

El Centro, California, United States

University of California Irvine Medical Center

Orange, California, United States

Riverside Community Hospital

Riverside, California, United States

University of California Davis Health System

Sacramento, California, United States

National Institute of Clinical Research

South El Monte, California, United States

UF Health Shands Hospital

Gainesville, Florida, United States

Memorial Hospital Jacksonville

Jacksonville, Florida, United States

Grady Health System

Atlanta, Georgia, United States

Great Lakes Clinical Trials

Chicago, Illinois, United States

The University of Iowa

Iowa City, Iowa, United States

Harper University Hospital

Detroit, Michigan, United States

Sinai Grace Hospital

Detroit, Michigan, United States

Detroit Receiving Hospital

Royal Oak, Michigan, United States

University of Tennessee Health Sciences Center

Memphis, Tennessee, United States

Medical City Ft. Worth

Fort Worth, Texas, United States

University of Texas Health Science Center at Houston

Houston, Texas, United States

Texoma Medical Center

Sherman, Texas, United States

MultiCare Health System Institute for Research and Innovation

Tacoma, Washington, United States

Hospital San Juan de Dios

Ramos Mejía, Buenos Aires, Argentina

Hospital General de Agudos Dr. J. M. Ramos Mejia

Ciudad Autonoma Buenos Aires, , Argentina

Hospital General de Agudos Dr. Ignacio Pirovano

Ciudad Autonoma Buenos Aires, , Argentina

Clinica Adventista Belgrano

Ciudad Autonoma Buenos Aires, , Argentina

Hospital Italiano de Rosario

Rosario, , Argentina

Chronos Pesquisa Clinica

Brasília, Federal District, Brazil

HC-UFG - Hospital das Clínicas da Universidade Federal de Goiás

Goiânia, Goiás, Brazil

Santa Casa de Misericórdia de Belo Horizonte

Belo Horizonte, Minas Gerais, Brazil

Hospital de Clínicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, Brazil

UNESP - Faculdade de Medicina da Universidade Estadual Paulista - Campus Botucatu

Botucatu, São Paulo, Brazil

Praxis Pesquisa Médica

Santo André, São Paulo, Brazil

Hospital Base Osorno

Osorno, , Chile

Hospital General de Tijuana

Tijuana, Baja California Norte, Mexico

Hospital Civil de Guadalajara Dr. Juan I. Menchaca

Guadalajara, Jalisco, Mexico

Universidad Autonoma de Nuevo Leon, Hospital Universitario Dr. Jose Eleuterio Gonzalez

Monterrey, Nuevo León, Mexico

Hospital Civil de Culiacan

Culiacán, Sinaloa, Mexico

TSBIH "Krasnoyarsk Interdistrict Clinical Hospital of Emergency Medical Care n.a. N.S. Karpovich

Krasnoyarsk, , Russia

SBIH of Moscow "Infectious Clinical Hospital # 1 of Department of Healthcare of Moscow"

Moscow, , Russia

SPb SBIH "Alexandrovskaya City Hospital"

Saint Petersburg, , Russia

St-George Hospital

Saint Petersburg, , Russia

SPb SBIH "Nikolaevskaya Hospital"

Saint Petersburg, , Russia

SPb SBIH "City Pokrovskaya Hospital"

Saint Petersburg, , Russia

SPb SBIH "City Hospital # 40 of Kurortnyi region"

Sestroretsk, , Russia

Nelson Mandela Academic Clinical Research Unit (NeMACRU)

Mthatha, Eastern Cape, South Africa

Johese Clinical Research: Unitas

Centurion, Gauteng, South Africa

MERC SiReN

Johannesburg, Gauteng, South Africa

Drs Sarvan and Moodley

Durban, KwaZulu-Natal, South Africa

Tread Research

Cape Town, Western Cape, South Africa

Tiervlei Trial Centre

Cape Town, Western Cape, South Africa

2 Military Hospital Internal Medicine

Cape Town, Western Cape, South Africa

Dr JM Engelbrecht Trial Site

Somerset West, Western Cape, South Africa

Clinical Projects Research SA (PTY) LTD

Worcester, Western Cape, South Africa

Communal Noncommercial Profit "Clinical City Hospital 16 of Dnipro Regional Council"

Dnipro, , Ukraine

CNE of Kharkov RC Reg Cl Infectious Hospital

Kharkiv, , Ukraine

Communal Non-Commercial Medical Enterprise "O.T.Bohayevskyi Kremenchuk City Hospital #1"

Kremenchuk, , Ukraine

City Clinical infectious Hospital

Odesa, , Ukraine

Municipal Non-Profit Enterprise Central City Hospital Of Rivne City Council

Rivne, , Ukraine

CCH #1 Vinnytsia M.I.Pyrogov NMU Ch of Infectious Diseases

Vinnytsia, , Ukraine

Countries

United States; Argentina; Brazil; Chile; Mexico; Russia; South Africa; Ukraine

References

Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Reference Type: DERIVED

PMID: 34473343 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

COV-01

Identifier Type: -

Identifier Source: org_study_id