A Study of RLS-0071 in Patients With Acute Lung Injury Due to COVID-19 Pneumonia in Early Respiratory Failure

Study Overview
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Brief Summary
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The aim of this study will test the safety, tolerability, and efficacy of RLS-0071 for approximately 28 days in comparison to a placebo control in patients with acute lung injury due to COVID-19 pneumonia in early respiratory failure. Patients will be randomized and double-blinded for two parts, a single-ascending dose (SAD) part and a multiple-ascending dose (MAD) part. The name of the study drug involved in this study is: RLS-0071.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Two-Part Study to Evaluate the Safety, Tolerability, Preliminary Efficacy, PK, & PD of RLS-0071 in Patients With Acute Lung Injury Due to COVID-19 Pneumonia in Early Respiratory Failure

Conditions
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Acute Lung Injury, ALI, COVID-19

Intervention / Treatment
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* Drug: RLS-0071 10 mg/kg
* Drug: RLS-0071 40 mg/kg
* Drug: Placebo
* Drug: RLS-0071 10 mg/kg
* Drug: RLS-0071 40 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed COVID-19 based on positive SARS-CoV-2 viral RNA PCR or antigen test. Hypoxemia. Radiographic evidence of opacification consistent with viral-related pneumonia. Weight less than 150 kg. Provide written informed consent. Exclusion Criteria: Endotracheal intubation and mechanical ventilation. Noninvasive positive pressure ventilation without endotracheal intubation. Requires chronic oxygen therapy. Treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs)/immunosuppressive agents for ≥ 4 weeks duration within 3 months prior to the Screening visit. Use of oral corticosteroids in a dose higher than prednisone 15 mg or equivalent per day for ≥ 4 weeks duration within 3 months prior to the Screening visit. Systemic autoimmune disease. Participation in any clinical research study evaluating an investigational product or therapy within 3 months prior to the Screening visit, Presence of any of the following abnormal laboratory values at Screening: absolute neutrophil count < 2,000/mm3, aspartate aminotransferase or alanine aminotransferase > 5 × upper limit of normal (ULN), platelets < 50,000/mm3. D-dimer > 2 × ULN at Screening, as evidence of potential disseminated intravascular coagulation (DIC). Has confounding medical conditions, including poorly controlled diabetes, uncontrolled New York Heart Association Class III congestive heart failure, clinically significant arrhythmias not controlled by medication, idiopathic pulmonary fibrosis, interstitial lung disease, or chronic obstructive pulmonary disease. Has bacterial sepsis currently or suspicion thereof. Has cancer currently and is receiving active treatment (including radiation therapy or chemotherapy) or malignancy within the last 5 years, with the exception of curable cancer (eg, basal or squamous cell skin cancer, cervical cancer in situ, nonmedullary thyroid carcinoma) that has been adequately treated (eg, excision). Prior history of myocardial infarction or angina, stroke or transient ischemic attack (TIA), pulmonary embolism or deep vein thrombosis. Is moribund and not expected to survive 48 hours following Screening or for whom no further aggressive treatment such as mechanical ventilation is planned.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Study intervention, RLS-0071 or placebo, will be administered as an IV infusion over 30 minutes (± 10 minutes). The following dose groups are planned: Part A (Single-Ascending Dose): Cohort 1: low dose (single infusion) vs. placebo Cohort 2: high dose (single infusion) vs. placebo Part B (Multiple-Ascending Dose): Cohort 3: low dose administered q8 hours (± 1 hour) vs. placebo for 3 days (9 doses) Cohort 4: high dose administered q8 hours (± 1 hour) vs. placebo for 3 days (9 doses)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br> | Drug: RLS-0071 10 mg/kg<br>* Single dose IV infusion of 10 mg/kg RLS-0071<br>Drug: Placebo<br>* The placebo control will be commercial sterile saline (0.9% Sodium Chloride Injection, United States Pharmacopoeia [USP]).<br>|
| Experimental: Cohort 2<br> | Drug: RLS-0071 40 mg/kg<br>* Single dose IV infusion of 40 mg/kg RLS-0071<br>Drug: Placebo<br>* The placebo control will be commercial sterile saline (0.9% Sodium Chloride Injection, United States Pharmacopoeia [USP]).<br>|
| Placebo Comparator: Placebo Cohorts 1 and 2<br>Placebo will be administered at the same volume and duration of IV infusion corresponding to the cohort dosing schedule. | Drug: Placebo<br>* The placebo control will be commercial sterile saline (0.9% Sodium Chloride Injection, United States Pharmacopoeia [USP]).<br>|
| Experimental: Cohort 3<br> | Drug: Placebo<br>* The placebo control will be commercial sterile saline (0.9% Sodium Chloride Injection, United States Pharmacopoeia [USP]).<br>Drug: RLS-0071 10 mg/kg<br>* Multiple dose IV infusion of 10 mg/kg RLS-0071 administered every 8 hours for approximately 3 days (9 consecutive doses)<br>|
| Experimental: Cohort 4<br> | Drug: Placebo<br>* The placebo control will be commercial sterile saline (0.9% Sodium Chloride Injection, United States Pharmacopoeia [USP]).<br>Drug: RLS-0071 40 mg/kg<br>* Multiple dose IV infusion of 40 mg/kg RLS-0071 administered every 8 hours for approximately 3 days (9 consecutive doses)<br>|
| Placebo Comparator: Placebo Cohorts 3 and 4<br>Placebo will be administered at the same volume and duration of IV infusion corresponding to the cohort dosing schedule. | Drug: Placebo<br>* The placebo control will be commercial sterile saline (0.9% Sodium Chloride Injection, United States Pharmacopoeia [USP]).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of Adverse Events, including Serious Adverse Events, by treatment group and dose level, including the frequency of premature discontinuation of study intervention due to Adverse Events. |  | Through study completion at Day 28 following last dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of clinically significant changes from baseline in clinical laboratory values, ADA, autoantibody panel, vital signs, physical examination, ECG, radiography, and concomitant medications. |  | Through study completion at Day 28 following last dose; (if positive ADA/antibodies, Day 90 and Day 180 following last dose). | 
| Number of patients with positive ADA titers after receiving a single dose (Part A) or multiple doses (Part B) of RLS-0071. |  | Through study completion at Day 28 following last dose; (if positive ADA/antibodies, Day 90 and Day 180 following last dose). | 
| Estimates of single-dose maximum plasma concentration (Cmax) for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose. | 
| Estimates of single-dose time to maximum plasma concentration (Tmax) for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose. | 
| Estimates of single-dose minimum plasma concentration (Cmin) for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose. | 
| Estimates of single-dose area under the plasma concentration-time curve (AUC) for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose. | 
| Estimates of single-dose apparent total volume of distribution for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose. | 
| Estimates of single-dose apparent total body clearance for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing), 5 and 30 minutes after start of dosing, and 1, 2, 3, 4, 5, 6, 7, 8,12, 18, 24, 36, and 48 hours after the start of dosing, up to 28 days following last dose. | 
| Estimates of single-dose apparent first-order terminal elimination half-life for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion | 
| Estimates of multiple-dose maximum plasma concentration (Cmax) for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion). | 
| Estimates of multiple-dose peak time to maximum plasma concentration (Tmax) for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion). | 
| Estimates of multiple-dose area under the plasma concentration-time curve (AUC) for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion). | 
| Estimates of multiple-dose average plasma drug concentration observed (Cavg) for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion). | 
| Estimates of multiple-dose trough concentration prior to dose administration (Ctrough). |  | Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion). | 
| Estimates of multiple-dose apparent total volume of distribution for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion). | 
| Estimates of multiple-dose apparent first-order terminal elimination half-life for RLS-0071. |  | Pre-Dose (within 30 minutes before start of dosing); 30 minutes after the start of dosing; and 1, 2, 4, 6, 12, 18, 24, 36, and 48 hours after the start of dosing. The last PK sample will be taken 48 hours following the last dosing (the 9th infusion). | 
| Assessment of dose response relationship of single and multiple doses of RLS-0071 on C1q levels and the complement activity assay. |  | Through study completion at Day 28 following last dose. | 
| Overall survival. |  | Through Day 15 and through study completion at Day 28 following last dose. | 
| Incidence of progression to respiratory failure requiring mechanical ventilation. |  | Days on ventilation while in the hospital through study completion at Day 28. | 
| Incidence of transfer to the ICU. |  | Through Day 15 following last dose; through study completion at Day 28 following last dose; and duration of ICU stay days in the hospital post-dose through study completion at Day 28. | 
| Duration of hospitalization after treatment (days). |  | Through study completion at Day 28 following last dose. | 
| Incidence, severity, and duration after treatment (days) of fever (≥ 39.0°C). |  | Through study completion at Day 28 following last dose. | 
| Incidence, severity, and duration after treatment (days) of cough per investigator assessment of CTCAE's latest version. |  | Through study completion at Day 28 following last dose. | 
| Duration of requirement for supplemental oxygen after treatment (days). |  | Through study completion at Day 28 following last dose. | 
| PaO2/FiO2 |  | Through study completion at Day 28 following last dose. | 
| Incidence, severity, and duration after treatment (days) of new cardiovascular events as assessed by the investigator (e.g. myocardial infarction, stroke, TIA, ischemic limb) with CTCAE's latest version. |  | Through Day 15 and through study completion at Day 28 following last dose. | 
| Incidence, severity, and duration after treatment (days) of respiratory acidosis as assessed by the investigator with CTCAE's latest version. |  | Through Day 15 and through study completion at Day 28 following last dose. | 
| Incidence and duration after treatment (days) of dialysis. | Dialysis will be assessed by the investigator with CTCAE's latest version. | Through Day 15 and through study completion at Day 28 following last dose. | 
| Levels of complement activity (eg, CH50). |  | Through study completion at Day 28 following last dose. | 
| Levels of C1q (free and bound to RLS-0071). |  | Through study completion at Day 28 following last dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lung Injury, Sars-CoV2, COVID-19, COVID-19 pneumonia, Early Respiratory Failure, ALI