A Study of APL-9 in Adults With Mild to Moderate ARDS Due to COVID-19

• ClinicalTrials.gov Identifier: NCT04402060
• Recruitment Status: Completed
• First Posted: May 26, 2020
• Results First Posted: March 23, 2022
• Last Update Posted: March 23, 2022
• Sponsor: Apellis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Apellis Pharmaceuticals, Inc.

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety and effectiveness of APL-9 in adults with mild to moderate ARDS (acute respiratory distress syndrome) caused by COVID-19 who are hospitalized and require supplemental oxygen therapy with or without mechanical ventilation.

It is thought that COVID-19 activates the complement system, part of the immune system that responds to infection or tissue damage, and increases inflammation in the lungs. APL-9 has been designed to inhibit or block activation of part of the complement pathway, and potentially reduce inflammation in the lungs.

Part 1 of the study is open-label to evaluate safety; all participants will receive APL-9 plus standard of care. Part 2 of the study is double-blind, randomized; participants will receive either APL-9 or the vehicle-control plus standard of care.

Condition or disease	Intervention/treatment	Phase
COVID; Covid-19; Coronavirus; Coronavirus Infection; Severe Acute Respiratory Syndrome; Severe Acute Respiratory Syndrome Coronavirus 2; Sars-CoV2; Ards; Acute Respiratory Distress Syndrome	Drug: APL-9; Other: Vehicle Control	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blinded, Vehicle-Controlled, Multicenter, Parallel-Group Study of APL-9 in Mild to Moderate Acute Respiratory Distress Syndrome Due to COVID-19
• Actual Study Start Date: May 28, 2020
• Actual Primary Completion Date: February 13, 2021
• Actual Study Completion Date: February 13, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 180 mg APL-9 IV plus SOC	Drug: APL-9; Complement (C3) Inhibitor
Placebo Comparator: Isotonic saline plus SOC	Other: Vehicle Control; Normal saline of equal volume to active arm

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: From the first dose of study drug and up to 30 (+7) days after the last dose of study drug. Part 1: Day 1 up to Day 44; Part 2: Day 1 up to Day 58 ]
   TEAEs were defined as those adverse events that developed or worsened in severity after initiation of the first dose of study drug and up to 30 (+7) days beyond the last dose of study drug. A serious TEAE was any TEAE or suspected adverse reaction that, in the view of either the Investigator or Sponsor, resulted in any of the following outcomes: death; is life threatening; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; or a congenital anomaly/birth defect.

Secondary Outcome Measures :

1. Hospital Length of Stay [ Time Frame: Part 2: Day 1 up to Day 58 ]
   Hospital length of stay was defined as randomization date to hospital discharge. For subjects with death of any cause or withdrawal of study participation, hospital length of stay was imputed with the longest hospital length of stay observed in the study. Median hospital length of stay was estimated using the Kaplan-Meier method.
2. Overall Survival [ Time Frame: Part 2: Day 1 up to Day 58 (until the safety follow-up assessment 30 days after last study treatment [+7 days]) ]
   Overall survival was defined as randomization date to death of any cause, censored at the last day known to be alive. Median overall survival was estimated using the Kaplan-Meier method.
3. Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time [ Time Frame: Part 2: Baseline (Day 1) and Days 3, 5, 7, 11, 15 and end of treatment (EOT) visit (up to Day 21) ]
   The SOFA score is an aggregate score based on objective measures of 6 organ systems: respiratory, coagulation, hepatic, cardiovascular, neurologic, and renal. The minimum value is 0 and maximum value is 24. Higher scores indicate worse outcomes. A subject with a SOFA score of zero was defined as being free of organ failure.
4. Total Duration of Mechanical Ventilation [ Time Frame: Part 2: Day 1 up to Day 58 ]
   Total duration of mechanical ventilation was calculated from the randomization date and was defined as days on mechanical ventilation during the study participation. For subjects with death of any cause (or withdrawal of study participation), total duration of mechanical ventilation was imputed with the longest duration observed in the study. Any subject who was not on mechanical ventilation at the randomization date was excluded. Median total duration of mechanical ventilation was estimated using the Kaplan-Meier method.
5. Total Duration of Oxygen Therapy [ Time Frame: Part 2: Day 1 up to Day 58 ]
   Total duration of oxygen therapy was calculated from randomization date and was defined as days on mechanical ventilation or supplemental oxygen during the study participation. For subjects with death of any cause (or withdrawal of study participation), total duration of oxygen therapy was imputed with the longest duration observed in the study. Any subject who was not on mechanical ventilation or supplemental oxygen at the randomization date was excluded. Median total duration of oxygen therapy was estimated using the Kaplan-Meier method.
6. Serum Concentration of APL-9 Over Time [ Time Frame: Part 1: Day 1 (pre- and post-dose) and Days 3, 5 and 7 (including EOT visit); Part 2: Day 1 (pre- and post-dose) and Days 3, 5, 7, 11, 15 and EOT visit (up to Day 21) ]
   To evaluate pharmacokinetics (PK), blood samples were collected at pre-specified timepoints and serum concentrations of APL-9 were determined. Blood was collected 3 times on Day 1: prior to the initial infusion, as soon as possible following the initial infusion (within 5-10 minutes) prior to the continuous infusion, and at 2 hours after the beginning of the continuous infusion. Blood was then collected once daily between 1-2 hours after the first dose on Days 3, 5, 7, 11 (if treatment was ongoing), Day 15 (if treatment was ongoing) and at the EOT visit.
7. Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
   To evaluate pharmacodynamic (PD) parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarkers C3 and C4.
8. Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
   To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarkers C3a, C4a, C5a and TCC.
9. Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Complement Bb [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
   To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarker Bb, a marker of alternative pathway activation.
10. Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Alternative Complement Pathway Hemolytic Activity (AH50) [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
    To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for complement biomarker AH50.
11. Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Reticulocytes [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
    To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker reticulocytes. Percentage (%) of reticulocytes was calculated as (Number of Reticulocytes / Number of Red Blood Cells) X 100.
12. Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Schistocytes [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
    To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker schistocytes.
13. Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Lactate Dehydrogenase [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
    To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarker lactate dehydrogenase.
14. Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
    To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarkers D-dimer and ferritin.
15. Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
    To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the coagulation biomarkers haptoglobin and fibrinogen.
16. Change From Baseline at EOT Visit in Biomarkers of Inflammation: C-reactive Protein (CRP) [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
    To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the inflammatory cytokine CRP.
17. Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFα), Interleukin-1-beta (IL-1β) and Interleukin-6 (IL-6) [ Time Frame: Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21) ]
    To evaluate PD parameters, blood samples were collected at pre-specified timepoints. Results are presented for change from baseline to EOT visit for the inflammatory cytokines TNFα, IL-1β and IL-6.

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:

• Be at least 18 years of age at time of informed consent
• Diagnosis of active SARS CoV 2 infection using viral RNA or viral antigen within 7 days of screening
• Respiratory failure requiring oxygen supplementation or either invasive or noninvasive mechanical ventilation with PaO2/FiO2 ratio >100 mm Hg. Respiratory failure cannot be fully explained by cardiac failure or fluid overload.

Exclusion Criteria:

• Treatment with immune checkpoint inhibitors, or other immunomodulators within 3 months prior to study enrollment (however, treatment with convalescent plasma, steroids, IL-6 inhibitors, and antiviral agents is NOT excluded)
• Active bacterial, fungal, or parasitic infection
• History of neuromuscular degenerative disease (eg, amyotrophic lateral sclerosis, Duchenne muscular dystrophy, or multiple sclerosis)
• Current participation in an interventional clincial trial
• Subjects who have, at screening, been on mechanical ventilation for >7 days Have evidence of kidney and liver failure at screening
• Have a hereditary complement deficiency
• Pregnancy or breastfeeding

Contacts and Locations

Locations

United States, California

University of California at San Francisco - Fresno

Fresno, California, United States, 93701

California Pacific Medical Center

San Francisco, California, United States, 94115

United States, Florida

Baptist Medical Center Beaches

Jacksonville Beach, Florida, United States, 32250

Westchester General Hospital

Miami, Florida, United States, 40241

United States, Illinois

Northwestern University, Feinberg School of Medicine

Chicago, Illinois, United States, 60611

Loyola University Medical Center

Maywood, Illinois, United States, 60153

United States, Indiana

Lutheran Health Physicians

Fort Wayne, Indiana, United States, 46804

United States, Iowa

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States, 52242

United States, Kentucky

Norton Women's and Children's Hospital

Louisville, Kentucky, United States, 40207

Norton Audobon Hospital

Louisville, Kentucky, United States, 40217

United States, Louisiana

Cambridge Medical Trials

Alexandria, Louisiana, United States, 71301

United States, Michigan

Ascension Providence Hospital

Southfield, Michigan, United States, 48075

United States, New Jersey

Rutgers University - Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States, 08903

United States, New York

University at Buffalo

Buffalo, New York, United States, 14203

Columbia University

New York, New York, United States, 10032

United States, Texas

Texas A&M College of Medicine - Scott and White

Temple, Texas, United States, 76508

Brazil

Hospital Angelina Caron

Campina Grande Do Sul, Paraná, Brazil, 83430-000

Irmandade da Santa Casa de Misericordia de Porto Alegre

Porto Alegre, Rio Grande Do Sul, Brazil, 90020-090

Hospital São Lucas da PUCRS

Porto Alegre, Rio Grande Do Sul, Brazil, 91530-001

Hospital Estadual Mario Covas

Santo André, Sao Paulo, Brazil, 09190-615

CEMEC - Centro Multidisciplinar de Estudos Clinicos LTDA EPP

São Bernardo Do Campo, Sao Paulo, Brazil, 0917-090

Hospital Alemao Oswaldo Cruz

São Paulo, Sao Paulo, Brazil, 01323-020

Hospital Santa Marcelina

São Paulo, Sao Paulo, Brazil, 08270-120

UPECLIN - Unidade de Pesquisa Clínica da Faculdade de Medicina de Botucatu - FMB/UNESP

Botucatu, São Paulo, Brazil, 18618-686

Sponsors and Collaborators

Apellis Pharmaceuticals, Inc.

  Study Documents (Full-Text)

Documents provided by Apellis Pharmaceuticals, Inc.:

Study Protocol  [PDF] November 9, 2020

Statistical Analysis Plan  [PDF] May 11, 2021

More Information

• Responsible Party: Apellis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04402060
• Other Study ID Numbers: APL9-COV-201
• First Posted: May 26, 2020
• Results First Posted: March 23, 2022
• Last Update Posted: March 23, 2022
• Last Verified: March 2022

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

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Severe Acute Respiratory Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Syndrome; Disease; Pathologic Processes; Respiratory Tract Infections; Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury