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

Covid-19 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04402060
• Other study ID #: APL9-COV-201
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 28, 2020
• Est. completion date: February 13, 2021

Study information

• Verified date: March 2022
• Source: Apellis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: February 13, 2021
• Est. primary completion date: February 13, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Ards
• Coronavirus
• Coronavirus Infection
• Coronavirus Infections
• COVID
• Covid-19
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Sars-CoV2
• Severe Acute Respiratory Syndrome
• Severe Acute Respiratory Syndrome Coronavirus 2
• Syndrome

Intervention

Drug:
• APL-9
Complement (C3) Inhibitor

Other:
• Vehicle Control
Normal saline of equal volume to active arm

Locations

Country	Name	City	State
Brazil	UPECLIN - Unidade de Pesquisa Clínica da Faculdade de Medicina de Botucatu - FMB/UNESP	Botucatu	São Paulo
Brazil	Hospital Angelina Caron	Campina Grande Do Sul	Paraná
Brazil	Hospital São Lucas da PUCRS	Porto Alegre	Rio Grande Do Sul
Brazil	Irmandade da Santa Casa de Misericordia de Porto Alegre	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
United States	Cambridge Medical Trials	Alexandria	Louisiana
United States	University at Buffalo	Buffalo	New York
United States	Northwestern University, Feinberg School of Medicine	Chicago	Illinois
United States	Lutheran Health Physicians	Fort Wayne	Indiana
United States	University of California at San Francisco - Fresno	Fresno	California
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Baptist Medical Center Beaches	Jacksonville Beach	Florida
United States	Norton Audobon Hospital	Louisville	Kentucky
United States	Norton Women's and Children's Hospital	Louisville	Kentucky
United States	Loyola University Medical Center	Maywood	Illinois
United States	Westchester General Hospital	Miami	Florida
United States	Rutgers University - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Columbia University	New York	New York
United States	California Pacific Medical Center	San Francisco	California
United States	Ascension Providence Hospital	Southfield	Michigan
United States	Texas A&M College of Medicine - Scott and White	Temple	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Apellis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects Who Experienced Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	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.	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
Secondary	Hospital Length of Stay	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.	Part 2: Day 1 up to Day 58
Secondary	Overall Survival	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.	Part 2: Day 1 up to Day 58 (until the safety follow-up assessment 30 days after last study treatment [+7 days])
Secondary	Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score Over Time	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.	Part 2: Baseline (Day 1) and Days 3, 5, 7, 11, 15 and end of treatment (EOT) visit (up to Day 21)
Secondary	Total Duration of Mechanical Ventilation	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.	Part 2: Day 1 up to Day 58
Secondary	Total Duration of Oxygen Therapy	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.	Part 2: Day 1 up to Day 58
Secondary	Serum Concentration of APL-9 Over Time	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.	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)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3 and C4	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.	Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Components C3a, C4a, C5a and Terminal Complement Complex (TCC)	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.	Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Complement Bb	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.	Part 1: Baseline (Day 1) and EOT visit (up to Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Complement Activation: Alternative Complement Pathway Hemolytic Activity (AH50)	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.	Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Reticulocytes	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.	Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Schistocytes	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.	Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Lactate Dehydrogenase	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.	Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: D-Dimer and Ferritin	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.	Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Coagulopathy: Haptoglobin and Fibrinogen	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.	Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Inflammation: C-reactive Protein (CRP)	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.	Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)
Secondary	Change From Baseline at EOT Visit in Biomarkers of Inflammation: Tumor Necrosis Factor Alpha (TNFa), Interleukin-1-beta (IL-1ß) and Interleukin-6 (IL-6)	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 TNFa, IL-1ß and IL-6.	Part 1: Baseline (Day 1) and EOT visit (Day 7); Part 2: Baseline (Day 1) and EOT visit (up to Day 21)