Clinical trial NCT05947955: Rhu-pGSN for Acute Respiratory Distress Syndrome (ARDS)
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome
Infections
Keywords: moderate to severe ARDS
respiratory failure
rhu-pGSN
Lead sponsor: BioAegis Therapeutics Inc.
Sponsor class: INDUSTRY
Collaborators: name: Biomedical Advanced Research and Development Authority
First posted: 2023-07-17
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1 randomization to rhu-pGSN or saline placebo arm
Primary purpose: TREATMENT

Brief summary: 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 ≤150) 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: Potential subjects hospitalized with pneumonia or other infections are to be screened within 24 hours of diagnosis of ARDS. The Sponsor aims to identify as early as possible patients in the hospital who have developed acute hypoxemic respiratory failure within 7 days of the precipitating infection (often fever, rigors, chills, increased heart rate, increased respiratory rate, pain, cough, etc.) leading to ARDS resulting in mechanical or noninvasive ventilation or high-flow nasal oxygen (HFNO) supplementation with ≥50% O2 at a flow rate of ≥30 L/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:

1. 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 \[P/F ratio\] ≤150. The P/F ratio will be computed from the most recent arterial blood gas obtained no more than 12 hours earlier than randomization. For potential subjects on high-flow nasal oxygen with ≥50% O2 at a flow rate of ≥30 L/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.
2. 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.
3. Perform pregnancy test (urine or blood) for women of childbearing potential if not already performed during the current hospitalization.
4. Collect pretreatment blood samples for measurement of baseline pGSN and analysis of antibodies against pGSN.
5. 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.
6. Obtain blood and sputum cultures and electrocardiogram (EKG) per SOC (if not already performed). Document the site of infection by collecting specimens as indicated: 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.
7. Measure routine lab tests 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.
8. If eligibility criteria are satisfied, the subject will be randomized 1:1 (rhu-pGSN:placebo) by site to a treatment group and treated within 12 hours of randomization and no later than 48 hours after the diagnosis of moderate-to-severe ARDS.

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, rhu-pGSN is not to be kept at room temperature for \>2 hours prior to beginning study drug administration.

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 through a 0.2 μm filter. The syringe, filter, and extension tubing for administration 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 28. All-cause mortality will also be assessed on Days 7 and 14. Discharged subjects will undergo follow-up evaluation on Days 14 and 28, preferably but not necessarily in person. Survival at Day 60 will be confirmed by telephonic contact or after 3 failed attempts, review of hospital and public records that document survival or death.

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) and 28, 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 5 periodic reviews of safety data emphasizing deaths and SAEs and will monitor stopping rules to pause enrollment. There will be no pause on enrollment during the planned unblinded periodic reviews. These reviews will be performed after the first 50, 100, 200, 300, and 400 subjects in the Safety Analysis Set have either 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 unblinded data. Based on the results of each of the planned periodic reviews, the study will be paused only if there is a relative increase of 25 percentage points in the incidence of death or SAEs in the rhu-pGSN treatment group compared to the placebo group. A futility analysis will be performed at the 300-subject review. 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. Enrollment will continue during all safety analyses unless otherwise recommended by the DSMB chair.

Eligibility criteria: Inclusion Criteria:

1. Infection followed within a week of documented bilateral infiltrates/opacities consistent with ARDS, as assessed by the admitting emergency department, clinic, intensivist, or ward physician or equivalent caregiver or a radiologist

   * Investigator or designee to note radiologic findings in the electronic case report form (eCRF)
   * Radiology report and conclusion should be summarized in the eCRF
   * A digital copy of the radiograph uploaded and saved for review
2. 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 ≤150). 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 50% 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 (ARDS Definition Task Force 2012), these measures will not be mandated as entry criteria.
3. Age ≥18 years
4. Informed consent obtained from subject/next of kin/legal proxy
5. 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
6. During the course of the study starting at screening and for at least 3 months after their final study treatment:

   1. Female subjects of childbearing potential must agree to use 2 medically accepted and approved birth control methods
   2. 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
   3. All subjects must agree not to donate sperm or eggs

Exclusion Criteria:

1. 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.
2. Presence of systemic fungal, yeast, parasitic, or mycobacterial infection
3. Current or planned receipt of extracorporeal membrane oxygenation (ECMO)
4. Pregnant or lactating women
5. Previous splenectomy
6. Any vaccination in the previous 30 days
7. Participation in an investigational clinical trial (e.g., device, drug, or biologic) in the previous 30 days
8. Known allergy to study drug or excipients
9. Weight \>125 kg
10. 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
11. Transplantation of hematopoietic or solid organs, graft versus host disease, or post-transplant lymphoproliferative disease
12. Chronic mechanical ventilation or dialysis
13. 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.

Primary outcomes:
measure: All-cause mortality at day 28
timeFrame: 28 days
Secondary outcomes:
measure: Ventilator-free days
timeFrame: 28 days
measure: All-cause mortality at day 60
timeFrame: 60 days
measure: Proportion of surviving subjects without respiratory support
timeFrame: 28 days
measure: Time to death and proportions of subjects dying over time
timeFrame: 28 days
measure: Time to discontinuation of respiratory support and proportions without respiratory support
timeFrame: 28 days
measure: Frequency of intubation
timeFrame: 28 days
measure: Days in the ICU and in the hospital
timeFrame: 28 days
measure: Frequency of RRT
timeFrame: 28 days
measure: SAEs and AEs
timeFrame: 28 days
Other outcomes:
Locations:
city: Irvine
country: United States
facility: University of California Irvine Medical Center
state: California
city: Augusta
country: United States
facility: Wellstar MCG Augusta University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University - Pulmonary and Critical Care Medicine
state: Illinois
city: Louisville
country: United States
facility: University of Louisville Hospital - Jewish Hospital
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville-Jewish Hospital
state: Kentucky
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Hannibal
country: United States
facility: Hannibal Regional Hospital
state: Missouri
city: Englewood
country: United States
facility: Englewood Hospital Medical Center
state: New Jersey
city: Houston
country: United States
facility: McGovern Medical School - UT Physicians Pulmonary Medicine - Texas Medical Center
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Health
state: Texas
city: Charleroi
country: Belgium
facility: CHU Charleroi Marie Curie Hospital
city: Liege
country: Belgium
facility: Centre Hospitalier Regional de la Citadelle
city: Ottignies
country: Belgium
facility: Clinique Saint-Pierre Ottignies
city: Sofia
country: Bulgaria
facility: Acibadem City Clinic UMHAT Tokuda - Sofia
city: Sofia
country: Bulgaria
facility: Military Medical Academy
city: Sofia
country: Bulgaria
facility: UMHAT "Alexandrovska" EAD
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: North Vancouver
country: Canada
facility: Lions Gate Hospital
state: British Columbia
city: Toronto
country: Canada
facility: University Health Network (UHN)-Toronto General Hospital (TGH)
state: Ontario
city: Calgary
country: Canada
facility: Peter Lougheed Centre
city: Calgary
country: Canada
facility: Rocky View General Hospital
city: Calgary
country: Canada
facility: South Health Campus
city: Brno
country: Czechia
facility: St. Anne's University Hospital
city: Prague
country: Czechia
facility: University Hospital Královské Vinohrady
city: Prague
country: Czechia
facility: General University Hospital
city: Kremlin Bicêtre
country: France
facility: Hôpital du Kremlin Bicêtre, APHP
city: Melun
country: France
facility: Centre Hospitalier de Melun-Senart
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Tenon Hospital
city: Strasbourg
country: France
facility: Nouvel Hopital Civil
city: Homburg
country: Germany
facility: Saarland University Hospital
city: Jena
country: Germany
facility: Jena University Hospital
city: Munich
country: Germany
facility: University Hospital LMU Munich
city: Budapest
country: Hungary
facility: National Institute of Pulmonology
city: Gyor
country: Hungary
facility: Petz Aladár University Teaching Hospital
city: Kisvarda
country: Hungary
facility: Szent Damján Greek Catholic Hospital
city: Nyiregyhaza
country: Hungary
facility: Szabolcs-Szatmar-Bereg County Teaching Hospital, Andras Josa Hospital
city: Siófok, Semmelweis
country: Hungary
facility: Hospital of Siofok
city: Szombathely
country: Hungary
facility: Teaching Hospital of Vas County
city: Veszprém
country: Hungary
facility: Ferenc Csolnoky Hospital of Veszprem County
city: Brescia
country: Italy
facility: Asst-Spedali Civili di Brescia
city: Rome
country: Italy
facility: Fondazione Policlinico A. Gemelli IRCCS
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Apeldoorn
country: Netherlands
facility: Gelre Hospitals, Department of ICU
city: Ede
country: Netherlands
facility: Gelderse Vallei Hospital
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
city: Bucharest
country: Romania
facility: Spital Universitar de Urgenta ELIAS (University Emergency Hospital Elias)
city: Timisoara
country: Romania
facility: Clinical County Hospital Timisoara
city: Tirgu Mures
country: Romania
facility: County Clinical Hospital Tirgu Mures
city: Barcelona
country: Spain
facility: Hospital Clínic Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario de Getafe
city: Madrid
country: Spain
facility: Clínico San Carlos
city: Tarragona
country: Spain
facility: Hospital Universitari de Tarragona Joan XXIII
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Plymouth
country: United Kingdom
facility: Derriford Hospital (University Hospitals Plymouth Hospital Trust)
city: Wakefield
country: United Kingdom
facility: Pinderfields Hospital (Mid Yorkshire Teaching NHS Trust)
Study officials:
References: