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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 33
- 试验地点
- 8
- 主要终点
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
研究概览
简要总结
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)
详细描述
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:
- Randomize to currently enrolling treatment arm.
- 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.
- 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.
- Draw blood for baseline pGSN levels, C-reactive protein (CRP), procalcitonin level, and 10 ml aliquot to be frozen for subsequent biomarker assays.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
visibly indistinguishable therapy
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed consent obtained from subject
- •Domicile: home, assisted living, rehabilitation facility, or nursing home (as long as the prospective participant is capable of providing written informed consent)
- •Duration of infection precipitating hospitalization by history <14 days
- •Planned or actual admission to hospital with a primary diagnosis of CAP within 24 hours of presentation to the hospital
- •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
排除标准
- •Pregnant or lactating women
- •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)
- •Use of any investigational drug in the past 30 days
- •Hospitalization during the last 30 days
- •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
- •Active underlying cancer treated with systemic chemotherapy or radiation therapy during the last 30 days
- •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)
- •Active congestive heart failure, myocardial infarction, or pulmonary embolism; cardiopulmonary arrest in last 30 days
- •Weight >100 kg
- •Otherwise unsuitable for study participation in the opinion of the investigator
研究组 & 干预措施
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
干预措施: Recombinant Human Plasma Gelsolin (Drug)
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
干预措施: Normal Saline Placebo (Other)
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
干预措施: Recombinant Human Plasma Gelsolin (Drug)
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
干预措施: Normal Saline Placebo (Other)
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
干预措施: Recombinant Human Plasma Gelsolin (Drug)
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
干预措施: Normal Saline Placebo (Other)
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
干预措施: Recombinant Human Plasma Gelsolin (Drug)
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
干预措施: Normal Saline Placebo (Other)
结局指标
主要结局
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: 0-28 days
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.
次要结局
- Pharmacokinetics (PK) (Area Under the Rhu-pGSN Concentration - Time Curve)(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))(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.)