Rhu-pGSN for Acute Respiratory Distress Syndrome (ARDS)

Study Overview
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Brief Summary
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BTI-203 is a randomized, double-blind, placebo-controlled, multicenter, Phase 2 proof-of-concept (POC) study to evaluate the efficacy and safety of rhu-pGSN plus standard of care (SOC) in subjects with moderate-to-severe ARDS (P/F ratio ≤200) due to pneumonia or other infections. Potential subjects hospitalized with pneumonia or other infections are to be screened within 24 hours of diagnosis of ARDS.

Detailed Description
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Potential subjects hospitalized with pneumonia or other infections are to be screened within 24 hours of diagnosis of ARDS. We aim to identify as early as possible patients in the hospital who have developed acute hypoxemic respiratory failure within 7 days of the precipitating infection leading to ARDS resulting in mechanical or non-invasive ventilation or high-flow nasal oxygen supplementation with ≥70% O2 at a flow rate of ≥30 mL/min. Patients who do not qualify for the study at the initial screening visit because of mild ARDS may subsequently progress to moderate-to-severe ARDS and should be reassessed at least daily for the 7 days following the precipitating infection. Once informed consent is obtained, the following assessments/procedures will be performed: Confirm the potential participant has acute hypoxemic respiratory failure qualifying as moderate-to-severe ARDS for ≤48 hours following a suspected or confirmed infection within the preceding week. Moderate-to-severe ARDS is defined by the calculated or estimated ratio of arterial pressure of O2 to the fraction of inspired O2 [P/F ratio] ≤200. The P/F ratio will be computed from the most recent arterial blood gas obtained no more than 48 hours earlier than screening. For potential subjects on high-flow nasal oxygen with ≥70% O2 at a flow rate of ≥30 mL/min, the P/F ratio will be estimated assuming 50% delivered O2. If eligible and entered in the trial, the following steps should be taken. Record medical history, including concomitant medications and current clinical status. Specify the site and etiology (if known) of infection, indicating if the lung (direct ARDS) or another organ (indirect ARDS) is the primary site of infection. Perform pregnancy test (urine or blood) for women of childbearing potential if not already performed during the current hospitalization. Collect pretreatment blood samples for measurement of baseline pGSN and analysis of antibodies against pGSN. Perform physical examination and document results of the chest x-ray (CXR) and/or computed tomography (CT) scan, if CXR is inadequate if not already available as per SOC. Obtain blood and sputum cultures and electrocardiogram (EKG) per SOC (if not already performed). The clinical team will be encouraged to order sputum (bacterial, viral, and mycobacterial, as indicated) and blood cultures, sputum Gram-stains, antigen detection on respiratory and urine specimens, and syndromic nucleic acid amplification tests (NAATs) on respiratory specimens (including a viral and other respiratory pathogen polymerase chain reaction [PCR] panel), where possible. Other specimens from possible sites of infection (e.g., urine, intra-abdominal drainage, skin or soft-tissue abscesses) should be cultured when available. Measure routine lab tests and biomarkers at local (hospital) laboratory per local custom/SOC collect aliquots f- blood for subsequent biomarker assays (including, but not limited to C-reactive protein [CRP], procalcitonin, interleukin [IL]1β, IL6, IL10, and tumor necrosis factor [TNF]) for analysis at the central laboratory. If eligibility criteria are satisfied, the subject will be randomized 1:1 (rhu-pGSN:placebo) to a treatment group and treated within 12 hours of enrollment and no later than 48 hours after the diagnosis of moderate-to-severe ARDS. Subjects will be stratified by site, the type of respiratory support (mechanical ventilation vs. noninvasive ventilation/high-flow nasal oxygen [HFNO]), and the primary site of infection (lung vs. other/unknown). Randomized subjects will receive the assigned dose of rhu-pGSN or an equal volume of visibly indistinguishable sterile saline placebo as soon as possible but beginning no later than 48 hours after the diagnosis of moderate-to-severe ARDS. After reconstitution to 200 mg in a final volume of 5 mL in a 10-mL vial, rhu pGSN is not to be kept at room temperature for >2 hours prior to beginning the infusion. A single loading dose of rhu-pGSN at 24 mg/kg followed by 5 daily doses of rhu-pGSN at 12 mg/kg of measured or estimated actual body weight starting 24 hours after the loading dose or an equal volume of indistinguishable saline placebo will be administered. A window of ±2 hours will be allowed around dosing times. Study drug is administered by an IV push or pump at a rate of 5 20 mL/min through a 0.2 μm filter. The syringe, filter, and extension tubing for infusion of study drug are to be connected as close to the subjects as possible. The primary efficacy endpoint of all-cause mortality will be assessed at Day 60, with secondary endpoints assessed on Days 7, 14, 28, and 60. Discharged subjects will undergo follow-up evaluation on Days 14, 28, and 60, preferably but not necessarily in person. Screening laboratory and other tests may be used as baseline values and do not need to be repeated if performed within 24 hours prior to randomization unless otherwise dictated by SOC. However, the blood sample for analysis of pGSN levels is to be repeated if not collected within 15 minutes before initiating the first dose of study drug. Repeat CXRs and/or CT scans and labs/cultures are to be obtained during the hospitalization if/when indicated by SOC. On Days 1 (predose), 28, and 60 blood samples for analysis of antibodies against pGSN are to be collected, if possible. Repeat blood and other cultures should be obtained per SOC. An independent Data and Safety Monitoring Board (DSMB) consisting of at least 2 physicians and 1 statistician with appropriate scientific and medical expertise will be formed, and its roles and responsibilities will be described in the DSMB charter. The DSMB will perform 3 interim reviews of safety data emphasizing deaths and SAEs and will monitor stopping rules to pause enrollment. These interim reviews will occur after the first 50, 100, and 200 subjects in the Safety Analysis Set have completed 28 days of follow-up, have died, or have discontinued from the study prior to completing 28 days of follow-up. DSMB members will be provided with partially unblinded results separated into 2 groups by treatment without identifying the actual treatment. Data will be further unblinded at the discretion of the DSMB chair. Based on each of the planned interim reviews, the study will be paused pending DSMB review of fully unblinded data if there is a relative increase of 25 percentage points in the incidence of death or SAEs in either treatment group compared to the other. The Sponsor will take appropriate action based on the recommendation of the DSMB. The DSMB will also review expedited reports of any SAEs throughout the study and may request additional looks at safety data at their discretion. For non-interim safety data reviews, enrollment will continue during the safety analyses unless otherwise recommended by the DSMB chair.

Official Title
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A Phase 2 Randomized Double-blind Placebo-controlled Study To Evaluate The Efficacy And Safety Of Adjunctive Recombinant Human Plasma Gelsolin With Standard Care For Moderate-to-Severe ARDS Due To Pneumonia Or Other Infections

Conditions
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Acute Respiratory Distress Syndrome, Infections

Intervention / Treatment
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* Drug: Rhu-pGSN
* Drug: normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infection followed within a week of documented bilateral infiltrates/opacities consistent with ARDS on CXR or CT, as assessed by the admitting emergency department, clinic, intensivist, or ward physician or equivalent caregiver or a radiologist Acute hypoxemic respiratory failure (moderate-to-severe ARDS) for ≤48 hours associated with suspected or confirmed infection (moderate-to-severe ARDS defined by the ratio of arterial pressure of O2 to the fraction of inspired O2 ≤200). Eligible subjects will be intubated for mechanical ventilation, receiving noninvasive ventilation by continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP), or on HFNO at least 30 L/min of 70% or greater inspired O2. Although it is expected that most eligible subjects will be receiving positive end-expiratory pressure (PEEP) or CPAP ≥5 cm H2O consistent with the original Berlin definition (The ARDS Definition Task Force, 2012), these measures will not be mandated as entry criteria. Age ≥18 years Informed consent obtained from subject/next of kin/legal proxy During the course of the study starting at screening and for at least 6 months after their final study treatment: Female subjects of childbearing potential must agree to use 2 medically accepted/FDA-approved birth control methods Male subjects with a partner who might become pregnant must agree to use reliable forms of contraception (i.e., vasectomy, abstinence), or an acceptable method of birth control must be used by the partner All subjects must agree not to donate sperm or eggs Exclusion Criteria: Ongoing evidence or suspicion that heart failure, volume overload, pulmonary emboli, atelectasis, chronic lung disease, pleural effusion, cardiac tamponade, or constrictive pericarditis are materially contributing to the clinical or radiological findings bas assessed by the care team or Investigator; an echocardiogram is strongly recommended as part of standard care to exclude a significant contribution of systolic or diastolic heart failure and volume overload. No clear or convincing evidence of a precipitating infection during the 7 days preceding the diagnosis of ARDS in the judgement of the screening or primary care team Current or planned receipt of extracorporeal membrane oxygenation (ECMO) Pregnant or lactating women Active underlying cancer or treatment with systemic chemotherapy or radiation therapy during the last 60 days or likely to require similar treatments during the ensuing 6 months Transplantation of hematopoietic or solid organs, graft versus host disease, or post-transplant lymphoproliferative disease Chronic mechanical ventilation or dialysis Unsuitable for study participation, in the opinion of the Investigator, because of chronic, severe, end-stage, or life-limiting underlying disease unrelated to current infection likely to interfere with management and assessment of ARDS, only comfort or limited (non-aggressive) care is to be given, or life expectancy <6 months unrelated to acute infection in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Interventional Model Description: 1:1 randomization to rhu-pGSN or saline placebo arm
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rhu-pGSN Treatment<br>Subjects will receive rhu-pGSN 24 mg/kg once, followed by 5 daily doses of 12 mg/kg based on actual body weight in addition to standard care . | Drug: Rhu-pGSN<br>* Intravenous administration based on actual body weight<br>* Other names: recombinant human gelsolin;|
| Placebo Comparator: Normal Saline Placebo<br>Subjects will receive 6 doses of normal-saline placebo in volumes equivalent to subjects given rhu-pGSN in addition to standard care. | Drug: normal saline<br>* intravenous administration in the same volume as the active therapy<br>* Other names: 0.9% sterile saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| all-cause mortality rate at Study Day 60 | death for any reason through the 60-day study period | 60 days | 
| incidence of SAEs | Incidence, causality, and severity of SAEs | any time during the 60 days of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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moderate to severe ARDS, respiratory failure, rhu-pGSN