A Phase 1b/2a Study of the Safety and Pharmacokinetics of Rhu-plasma Gelsolin in Hospitalized Subjects With CAP

A Double-blind, Placebo-controlled, Dose-escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Plasma Gelsolin Added to Standard of Care in Subjects Hospitalized for Acute Community-acquired Pneumonia

A Phase 1b/2a, Double-blind, Placebo-controlled, Dose-escalation Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Plasma gelsolin (rhu-pGSN) Added to Standard of Care in Subjects Hospitalized for Acute Community-acquired Pneumonia (CAP)

Study Overview

• Status: Completed
• Conditions: Community-acquired Pneumonia
• Intervention / Treatment: Drug: Recombinant Human Plasma Gelsolin; Other: Normal Saline Placebo

Detailed Description

A total of 32 patients hospitalized with CAP will be randomized sequentially into 4 ascending dosing levels. Each dosing cohort will include 8 subjects randomized 3:1 rhu-pGSN:placebo (6 rhu-pGSN subjects:2 placebo subjects). Patient, caregiver, and sponsor will be blinded to treatment. An unblinded pharmacist will prepare the infusion, but otherwise have no contact with subject.

Dose will be based on actual body weight. Dose escalation will involve 3 dose levels of rhu-pGSN (6, 12, and 24 mg/kg) in patients admitted for CAP. Dose escalation will only occur after post-therapy safety information on all subjects in the prior cohort has been reviewed at Day 7 for the single-dose [SD] and multiple-ascending dose [MAD] arms. The MAD portion of the study will commence once single doses of 6 mg/kg of rhu-pGSN are shown to be acceptably safe. The first 2 doses must be administered in the hospital, but the third dose can be given in a monitored outpatient setting where appropriate. Discharged subjects will return for follow-up 7 days after the initiation of therapy (Day 7) and on Day 28 for the End-of-Study Visit.

To assess safety and tolerability starting at the initiation of study therapy, subjects will undergo physical examinations (PE; including vital sign measurements), adverse event (AE) assessments, concomitant medication assessments, safety laboratory testing, and electrocardiograms (EKG) completed locally, and other testing as per local custom.

Once informed consent is obtained, the following procedures will be performed:

1. Randomize to currently enrolling treatment arm.
2. Perform PE and document radiographic evidence of pneumonia if not previously completed in preceding 36 hours; calculate Confusion, Urea >7 mmol/L, Respiratory rate ≥30/min, Blood pressure systolic <90 or diastolic ≤60, and age ≥65 years (CURB-65), Sequential Organ Failure Assessment (SOFA), and Pneumonia Severity Index (PSI) scores.
3. Obtain blood and sputum cultures, routine/standard labs, and EKG per standard of care (SOC) (if not already performed). The microbiology lab is encouraged to also perform sputum Gram-stains, antigen detection, immunoassay, and genomic diagnostic tests when available.
4. Draw blood for baseline pGSN levels, C-reactive protein (CRP), procalcitonin level, and 10 ml aliquot to be frozen for subsequent biomarker assays.

Screening laboratory and other tests can serve as baseline values for participants (no need to repeat lab tests at entry if done within the prior 36 hours unless dictated by SOC).

Obtain repeat chest x-rays (CXRs), computed tomography (CT) scans, and labs/cultures, etc. during the hospitalization if/when indicated by SOC.

Recalculate CURB-65 and ΔSOFA scores and redraw procalcitonin, pGSN, and biomarker samples on Day 3 or 4 and Day 7.

For the one dose in the SD arm and the first 2 doses in the multiple-dose arms, blood will be drawn within 30 minutes predose, immediately postdose, and 2, 8, 12 and/or 16, and 24 hours (± 30 minutes) after the end of infusion for analysis of plasma for maximum concentration (Cmax), time to maximum concentration (Tmax), terminal half-life (T1/2), area under the curve from time zero to 8 hours (AUC0-8), and area under the curve from time zero to infinity (AUCinf). Sampling at both the 12- and 16-hour time points is encouraged where feasible, but only one of these two times is required. Identical PK sampling is encouraged where feasible, but not required for the third (last) dose.

On Day 28, collect samples for analysis of pGSN levels and antibodies against pGSN.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Cairns, Queensland, Australia, 4870
      • Cairns Hospital
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Footscray, Victoria, Australia, 3011
      • Footscray Hospital
• Georgia
  • Mtskheta, Georgia, 3300
    • LTD Geo Hospitals, Mtskheta Multiprofile Medical Center
  • Rustavi, Georgia, 3700
    • JSC Rustavi Central Hospital
  • Tbilisi, Georgia, 0160
    • LTD Central University Clinic After Academic N. Kipshidze
  • Tbilisi, Georgia, 0179
    • LTD S. Khechinashvili University Hospital
  • Tbilisi, Georgia, 0191
    • LTD 5th Clinical Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Informed consent obtained from subject
2. Domicile: home, assisted living, rehabilitation facility, or nursing home (as long as the prospective participant is capable of providing written informed consent)
3. Duration of infection precipitating hospitalization by history <14 days
4. Planned or actual admission to hospital with a primary diagnosis of CAP within 24 hours of presentation to the hospital

5. Primary admitting diagnosis of pneumonia supported by a compatible clinical presentation with a documented infiltrate consistent with pneumonia on chest radiograph or CT, as assessed by the admitting emergency-department (ED), clinic, or ward physician or equivalent caregiver

   • Recommended (not mandatory) guidance/discretionary criteria defining patients with CAP:

     • At least 2 symptoms: difficulty breathing, cough, production of purulent sputum, chest pain
     • At least 2 vital sign abnormalities: fever, tachycardia, tachypnea
     • At least one finding of other clinical signs and laboratory abnormalities: hypoxemia, clinical evidence of pulmonary consolidation, an elevated total white blood cell (WBC) count or leukopenia
     • Chest imaging showing new (or presumed new or worsening) infiltrates
   • Receipt of antibiotic treatment prior to presentation does not exclude the patient

Exclusion Criteria:

1. Pregnant or lactating women
2. Intubation, vasopressor support, or admission to the intensive care unit (ICU) directly from the ED/office (fluids for responsive hypotension is not a reason for exclusion)
3. Use of any investigational drug in the past 30 days
4. Hospitalization during the last 30 days
5. Residence within the last 30 days in long-term care facility where the patient remains persistently unable to participate in the routine activities of daily living
6. Active underlying cancer treated with systemic chemotherapy or radiation therapy during the last 30 days
7. Known or suspected immunosuppressive disease or therapy (including steroid use equivalent to prednisone ≥20 mg/day for >7 days or known advanced human immunodeficiency virus (HIV) infection with CD4 count ≤200/mm3; specific testing for HIV status or CD4 count is not required but can be done at the discretion of the caregivers)
8. Active congestive heart failure, myocardial infarction, or pulmonary embolism; cardiopulmonary arrest in last 30 days
9. Weight >100 kg
10. Otherwise unsuitable for study participation in the opinion of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Single Dose 6 mg/kg; Intravenous administration of recombinant human plasma gelsolin at 6 mg/kg v. placebo (NSS) in addition to standard of care	Drug: Recombinant Human Plasma Gelsolin; Recombinant human plasma gelsolin lyophilized for reconstitution, reconstituted in sterile water; Other Names: rhu-pGSN; Other: Normal Saline Placebo; Normal saline in volume equivalent to drug; Other Names: NSS (0.9% normal saline)
EXPERIMENTAL: Multiple Dose 6 mg/kg; Intravenous administration of recombinant human plasma gelsolin at 6 mg/kg once per day for 3 days v. placebo (NSS) in addition to standard of care	Drug: Recombinant Human Plasma Gelsolin; Recombinant human plasma gelsolin lyophilized for reconstitution, reconstituted in sterile water; Other Names: rhu-pGSN; Other: Normal Saline Placebo; Normal saline in volume equivalent to drug; Other Names: NSS (0.9% normal saline)
EXPERIMENTAL: Multiple Dose 12 mg/kg; Intravenous administration of recombinant human plasma gelsolin at 12 mg/kg once per day for 3 days v. placebo (NSS) in addition to standard of care	Drug: Recombinant Human Plasma Gelsolin; Recombinant human plasma gelsolin lyophilized for reconstitution, reconstituted in sterile water; Other Names: rhu-pGSN; Other: Normal Saline Placebo; Normal saline in volume equivalent to drug; Other Names: NSS (0.9% normal saline)
EXPERIMENTAL: Multiple Dose 24 mg/kg; Intravenous administration of recombinant human plasma gelsolin at 24 mg/kg once per day for 3 days v. placebo (NSS) in addition to standard of care	Drug: Recombinant Human Plasma Gelsolin; Recombinant human plasma gelsolin lyophilized for reconstitution, reconstituted in sterile water; Other Names: rhu-pGSN; Other: Normal Saline Placebo; Normal saline in volume equivalent to drug; Other Names: NSS (0.9% normal saline)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Treatment emergent adverse events were all adverse events (AEs) that occurred subsequent to enrollment. The seriousness of adverse events was judged by the site investigator.	0-28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) (Area Under the Rhu-pGSN Concentration - Time Curve)	Determine AUC 0-t area under the plasma concentration-time curve of rhu-pGSN from 0-24 hours on dosing days (estimated by subtracting pre-injection concentrations from the measured concentrations at each time point). In the single-dose arm, the subject was given only 1 dose so that data from later days were not obtained. In the multiple-dose arms, samples were obtained for each of the 3 doses.	On Days 0-3, specimens were obtained just prior and immediately post dose and 2, 8,12 and/or 16 , and 24 hours post completion of IV administration. In the single-dose arm, only 1 dose was given and thus no data from later days were obtained.
Pharmacokinetics (PK) (Maximum Observed Rhu-pGSN Plasma Concentration (Cmax))	Maximum observed plasma concentration (Cmax) of rhu-pGSN in a 24 hours period after intravenous administration (estimated by subtracting pre-injection concentrations from the measured concentrations at each time point). For the 6 mg/kg dose, there were 4 evaluable subjects in the single-dose arm and 6 subjects in the multiple-dose arm at this dose, for a total of 10 evaluable subjects for Dose 1.	On Days 0-3, specimens were obtained just prior and immediately post dose and 2, 8, 12 and/or 16, and 24 hours post completion of IV administration. In the single-dose arm, only 1 dose was given and thus no data from later days were obtained.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Anti-pGSN Antibodies (Immunogenicity) at the End of Study (Day 28)	Number of participants who developed antibodies against pGSN at study day 28. Patients were first tested against less stringent screening criteria: if screen-positive, a stricter confirmatory test was performed; if screen-negative, no further immunogenicity testing was done.	Day 28
Baseline and Sequential Severity Scores	CURB-65 (a 5 point score in which 1 point is allocated to the presence of each of the following: Confusion, Urea >7 mmol/L, Respiratory rate ≥30 breaths min, Blood pressure systolic <90 mmHg or diastolic ≤60 mmHg, and age ≥65 years); PSI (Pneumonia Severity Index, used to predict risk of morbidity and mortality and is classified in risk classes ranging from I to V from the lowest to highest risk as follows: Class I: PSI 0, class II: PSI 1-70, class III: PSI 71-90, class IV: PSI 91-130, class V: PSI >130); SOFA (Sequential Organ Failure Assessment, measured based on 6 variables each representing an organ system scored from 0 to 4 each (normal to severe organ dysfunction/failure), and reported as the sum (range 0-24))	Days 0-28

Collaborators and Investigators

• Sponsor: BioAegis Therapeutics Inc.
• Investigators: Study Chair: Mark J DiNubile, MD, BioAegis Therapeutics Inc.

Publications and helpful links

General Publications

• Tannous A, Levinson SL, Bolognese J, Opal SM, DiNubile MJ. Safety and Pharmacokinetics of Recombinant Human Plasma Gelsolin in Patients Hospitalized for Nonsevere Community-Acquired Pneumonia. Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00579-20. doi: 10.1128/AAC.00579-20. Print 2020 Sep 21.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 28, 2018
• Primary Completion (ACTUAL): April 2, 2019
• Study Completion (ACTUAL): April 2, 2019

Study Registration Dates

• First Submitted: March 2, 2018
• First Submitted That Met QC Criteria: March 8, 2018
• First Posted (ACTUAL): March 15, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 14, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Adjunctive therapy; Recombinant human plasma gelsolin (rhu-pGSN); Severe community-acquired pneumonia (sCAP)
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia
• Other Study ID Numbers: BTI-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No