A Study of APL-9 in Adults With Mild to Moderate ARDS Due to COVID-19
- Conditions
- Covid-19ArdsCoronavirusCoronavirus InfectionSevere Acute Respiratory SyndromeSevere Acute Respiratory Syndrome Coronavirus 2Sars-CoV2COVIDAcute Respiratory Distress Syndrome
- Interventions
- Other: Vehicle ControlDrug: APL-9
- Registration Number
- NCT04402060
- Lead Sponsor
- Apellis Pharmaceuticals, Inc.
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 72
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Isotonic saline plus SOC Vehicle Control - 180 mg APL-9 IV plus SOC APL-9 -
- Primary Outcome Measures
Name Time Method Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs 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
Name Time Method Hospital Length of Stay 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.
Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Alternative Complement Pathway Hemolytic Activity (AH50) 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.
Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time 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.
Total Duration of Mechanical Ventilation 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.
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen 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.
Overall Survival 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.
Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4 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.
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) 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.
Total Duration of Oxygen Therapy 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.
Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC) 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.
Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Complement Bb 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.
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Schistocytes 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.
Change From Baseline at EOT Visit in Biomarkers of Inflammation: C-reactive Protein (CRP) 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.
Serum Concentration of APL-9 Over Time 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.
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Reticulocytes 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.
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Lactate Dehydrogenase 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.
Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin 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.
Trial Locations
- Locations (24)
Rutgers University - Robert Wood Johnson Medical School
🇺🇸New Brunswick, New Jersey, United States
California Pacific Medical Center
🇺🇸San Francisco, California, United States
Westchester General Hospital
🇺🇸Miami, Florida, United States
University of California at San Francisco - Fresno
🇺🇸Fresno, California, United States
Baptist Medical Center Beaches
🇺🇸Jacksonville Beach, Florida, United States
Northwestern University, Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Lutheran Health Physicians
🇺🇸Fort Wayne, Indiana, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Norton Women's and Children's Hospital
🇺🇸Louisville, Kentucky, United States
Norton Audobon Hospital
🇺🇸Louisville, Kentucky, United States
Cambridge Medical Trials
🇺🇸Alexandria, Louisiana, United States
Ascension Providence Hospital
🇺🇸Southfield, Michigan, United States
University at Buffalo
🇺🇸Buffalo, New York, United States
Columbia University
🇺🇸New York, New York, United States
Texas A&M College of Medicine - Scott and White
🇺🇸Temple, Texas, United States
Hospital Angelina Caron
🇧🇷Campina Grande Do Sul, Paraná, Brazil
Irmandade da Santa Casa de Misericordia de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital São Lucas da PUCRS
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital Estadual Mario Covas
🇧🇷Santo André, Sao Paulo, Brazil
CEMEC - Centro Multidisciplinar de Estudos Clinicos LTDA EPP
🇧🇷São Bernardo Do Campo, Sao Paulo, Brazil
Hospital Alemao Oswaldo Cruz
🇧🇷São Paulo, Sao Paulo, Brazil
Hospital Santa Marcelina
🇧🇷São Paulo, Sao Paulo, Brazil
UPECLIN - Unidade de Pesquisa Clínica da Faculdade de Medicina de Botucatu - FMB/UNESP
🇧🇷Botucatu, São Paulo, Brazil