Clinical trial NCT04590586: Study of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients
Official title: Industry Alliance Platform Trial to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalized Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2020-10-19
Enrollment: 515
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: 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.

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).

Primary outcomes:
measure: Lanadelumab Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29
timeFrame: Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29
measure: Apremilast Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29
timeFrame: Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29
measure: Zilucoplan Sub-protocol: Time to Confirmed Clinical Recovery Without Rehospitalization Through Day 29
timeFrame: Day 1 (the day of the first dose of study drug for randomized participants who received at least one dose of study drug or the day of randomization for randomized participants who did not receive any study drug) to Day 29
Secondary outcomes:
measure: Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29
timeFrame: Day 29
measure: Lanadelumab Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29
timeFrame: Baseline (Day 1) and Day 29
measure: Lanadelumab Sub-protocol: Percentage of Participants Who Died Before or on Day 29
timeFrame: Day 1 to Day 29
measure: Lanadelumab Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29
timeFrame: Day 8, Day 15, and Day 29
measure: Lanadelumab Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-point Ordinal Scale From Baseline to Day 29
timeFrame: Day 2 to Day 29
measure: Lanadelumab Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29
timeFrame: Day 1 to Day 29
measure: Lanadelumab Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29
timeFrame: Day 1 to Day 29
measure: Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery by Days 8, 15, and 29
timeFrame: Day 8, Day 15, and Day 29
measure: Lanadelumab Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery
timeFrame: Day 60
measure: Lanadelumab Sub-protocol: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From first dose of study drug to end of study (Day 60)
measure: Apremilast Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29
timeFrame: Day 29
measure: Apremilast Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29
timeFrame: Baseline (Day 1) and Day 29
measure: Apremilast Sub-protocol: Percentage of Participants Who Died Before or on Day 29
timeFrame: Day 1 to Day 29
measure: Apremilast Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29
timeFrame: Day 8, Day 15, and Day 29
measure: Apremilast Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-Point Ordinal Scale From Baseline to Day 29
timeFrame: Day 2 to Day 29
measure: Apremilast Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29
timeFrame: Day 1 to Day 29
measure: Apremilast Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29
timeFrame: Day 1 to Day 29
measure: Apremilast Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery at Days 8, 15, and 29
timeFrame: Day 8, Day 15, and Day 29
measure: Apremilast Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery
timeFrame: Day 60
measure: Apremilast Sub-protocol: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From first dose of study drug to end of study (Day 60)
measure: Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Oxygen-Free Recovery at Day 29
timeFrame: Day 29
measure: Zilucoplan Sub-protocol: Percentage of Participants With a ≥ 2-point Improvement From Baseline or Fit for Discharge on the Clinical Severity Status 8-Point Ordinal Scale at Day 29
timeFrame: Baseline (Day 1) and Day 29
measure: Zilucoplan Sub-protocol: Percentage of Participants Who Died Before or on Day 29
timeFrame: Day 1 to Day 29
measure: Zilucoplan Sub-protocol: Clinical Severity Status 8-Point Ordinal Scale Score at Days 8, 15, and 29
timeFrame: Day 8, Day 15, and Day 29
measure: Zilucoplan Sub-protocol: Worst Post-Baseline Score on Clinical Severity Status 8-Point Ordinal Scale From Baseline to Day 29
timeFrame: Day 2 to Day 29
measure: Zilucoplan Sub-protocol: Number of Intensive Care Unit (ICU) Days From Day 1 Through Day 29
timeFrame: Day 1 to Day 29
measure: Zilucoplan Sub-protocol: Number of Invasive Mechanical Ventilator Days From Day 1 Through Day 29
timeFrame: Day 1 to Day 29
measure: Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Clinical Recovery by Days 8, 15, and 29
timeFrame: Day 8, Day 15, and Day 29
measure: Zilucoplan Sub-protocol: Percentage of Participants Who Achieved Sustained Clinical Recovery
timeFrame: Day 60
measure: Zilucoplan Sub-protocol: Number of Participants With Treatment-emergent Adverse Events
timeFrame: From first dose of study drug to end of study (Day 60)
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group LLC
state: Alabama
city: Bakersfield
country: United States
facility: Good Samaritan Hospital
state: California
city: Chula Vista
country: United States
facility: Sharp Chula Vista Medical Center
state: California
city: El Centro
country: United States
facility: El Centro Regional Medical Center
state: California
city: Orange
country: United States
facility: University of California Irvine Medical Center
state: California
city: Riverside
country: United States
facility: Riverside Community Hospital
state: California
city: S. El Monte
country: United States
facility: National Institute of Clinical Research
state: California
city: Sacramento
country: United States
facility: University of California Davis Health System
state: California
city: Gainesville
country: United States
facility: UF Health Shands Hospital
state: Florida
city: Jacksonville
country: United States
facility: Memorial Hospital Jacksonville
state: Florida
city: Atlanta
country: United States
facility: Grady Health System
state: Georgia
city: Chicago
country: United States
facility: Great Lakes Clinical Trials
state: Illinois
city: Iowa City
country: United States
facility: The University of Iowa
state: Iowa
city: Detroit
country: United States
facility: Harper University Hospital
state: Michigan
city: Detroit
country: United States
facility: Sinai Grace Hospital
state: Michigan
city: Royal Oak
country: United States
facility: Detroit Receiving Hospital
state: Michigan
city: Memphis
country: United States
facility: University of Tennessee Health Sciences Center
state: Tennessee
city: Fort Worth
country: United States
facility: Medical City Ft. Worth
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Sherman
country: United States
facility: Texoma Medical Center
state: Texas
city: Tacoma
country: United States
facility: MultiCare Health System Institute for Research and Innovation
state: Washington
city: Ramos Mejia
country: Argentina
facility: Hospital San Juan de Dios
state: Buenos Aires
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Hospital General de Agudos Dr. J. M. Ramos Mejia
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Hospital General de Agudos Dr. Ignacio Pirovano
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Clinica Adventista Belgrano
city: Rosario
country: Argentina
facility: Hospital Italiano de Rosario
city: Brasília
country: Brazil
facility: Chronos Pesquisa Clinica
state: Distrito Federal
city: Goiânia
country: Brazil
facility: HC-UFG - Hospital das Clínicas da Universidade Federal de Goiás
state: Goiás
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericórdia de Belo Horizonte
state: Minas Gerais
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: Botucatu
country: Brazil
facility: UNESP - Faculdade de Medicina da Universidade Estadual Paulista - Campus Botucatu
state: Sao Paulo
city: Santo André
country: Brazil
facility: Praxis Pesquisa Médica
state: Sao Paulo
city: Osorno
country: Chile
facility: Hospital Base Osorno
city: Tijuana
country: Mexico
facility: Hospital General de Tijuana
state: Baja California Norte
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara Dr. Juan I. Menchaca
state: Jalisco
city: Monterrey
country: Mexico
facility: Universidad Autonoma de Nuevo Leon, Hospital Universitario Dr. Jose Eleuterio Gonzalez
state: Nuevo León
city: Culiacán
country: Mexico
facility: Hospital Civil de Culiacan
state: Sinaloa
city: Krasnoyarsk
country: Russian Federation
facility: TSBIH "Krasnoyarsk Interdistrict Clinical Hospital of Emergency Medical Care n.a. N.S. Karpovich
city: Moscow
country: Russian Federation
facility: SBIH of Moscow "Infectious Clinical Hospital # 1 of Department of Healthcare of Moscow"
city: Saint Petersburg
country: Russian Federation
facility: SPb SBIH "Alexandrovskaya City Hospital"
city: Saint Petersburg
country: Russian Federation
facility: St-George Hospital
city: Saint Petersburg
country: Russian Federation
facility: SPb SBIH "Nikolaevskaya Hospital"
city: Saint Petersburg
country: Russian Federation
facility: SPb SBIH "City Pokrovskaya Hospital"
city: Sestroretsk
country: Russian Federation
facility: SPb SBIH "City Hospital # 40 of Kurortnyi region"
city: Mthatha
country: South Africa
facility: Nelson Mandela Academic Clinical Research Unit (NeMACRU)
state: Eastern Cape
city: Centurion
country: South Africa
facility: Johese Clinical Research: Unitas
state: Gauteng
city: Johannesburg
country: South Africa
facility: MERC SiReN
state: Gauteng
city: Durban
country: South Africa
facility: Drs Sarvan and Moodley
state: KwaZulu-Natal
city: Cape Town
country: South Africa
facility: Tread Research
state: Western Cape
city: Cape Town
country: South Africa
facility: Tiervlei Trial Centre
state: Western Cape
city: Cape Town
country: South Africa
facility: 2 Military Hospital Internal Medicine
state: Western Cape
city: Somerset West
country: South Africa
facility: Dr JM Engelbrecht Trial Site
state: Western Cape
city: Worcester
country: South Africa
facility: Clinical Projects Research SA (PTY) LTD
state: Western Cape
city: Dnipro
country: Ukraine
facility: Communal Noncommercial Profit "Clinical City Hospital 16 of Dnipro Regional Council"
city: Kharkiv
country: Ukraine
facility: CNE of Kharkov RC Reg Cl Infectious Hospital
city: Kremenchuk
country: Ukraine
facility: Communal Non-Commercial Medical Enterprise "O.T.Bohayevskyi Kremenchuk City Hospital #1"
city: Odesa
country: Ukraine
facility: City Clinical infectious Hospital
city: Rivne
country: Ukraine
facility: Municipal Non-Profit Enterprise Central City Hospital Of Rivne City Council
city: Vinnytsia
country: Ukraine
facility: CCH #1 Vinnytsia M.I.Pyrogov NMU Ch of Infectious Diseases
Study officials:
References:
citation: 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.