Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose Escalation and Proof-of-Concept Study to Evaluate the Safety and Efficacy of Razuprotafib in Hospitalized Subjects With Coronavirus Disease 2019
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 31
- 试验地点
- 7
- 主要终点
- Number and Percent of Subjects Who Were Alive and Free of Respiratory Failure Prior to Day 7 and Day 28
研究概览
简要总结
This was a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter, dose escalation and proof-of-concept study to evaluate the safety and efficacy of razuprotafib, administered 3 times daily (TID) (every 8 hours [Q8H]), in hospitalized subjects with moderate to severe Coronavirus disease 2019 (COVID-19) receiving standard of care therapy.
The study was planned to include 2 parts with Part 1 comprising the dose escalation period of the study and Part 2 comprising the proof-of-concept safety and efficacy period of the study.
详细描述
Part 1 was to be a 2-step dose escalation that included approximately 60 subjects. Part 1, Step 1 was to include 30 subjects, and Part 1, Step 2 was to include 30 subjects. Part 1 was designed to primarily focus on safety; however, efficacy data was to be collected and analyzed as well.
Despite the Data Review Committee (DRC) recommendation to continue the study, after completion of Part 1, Step 1, the Sponsor elected to discontinue the study due to business-related reasons. Recruitment challenges and slow site startup led to delays in completing the study in a practical timeframe, and were the primary reasons to discontinue the study. No further subjects were recruited after Part 1, Step 1 completion. A full analysis of the data from Part 1, Step 1 was conducted and is presented in this report.
Part 1, Step 2 and Part 2 was not conducted.
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
- Triple (Participant, Investigator, Outcomes Assessor)
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
- •Ability to understand and provide informed consent;
- •Males and non-pregnant females 18 years of age or older at the time of Screening;
- •Laboratory-confirmed active SARS-CoV-2 infection within 72 hours prior to randomization, or (if testing results cannot be obtained) by evidence of progressive disease suggestive of ongoing SARS-CoV-2 infection;
- •Females of childbearing potential must be willing to completely abstain or agree to use a highly effective method of contraception through Day 28; and have a negative urine pregnancy test during Screening;
- •Currently hospitalized, receiving standard of care therapy for COVID-19, and meets the criteria for moderate or severe COVID-19, as follows: Moderate = symptoms of moderate illness with COVID-19, which could include any symptom of mild illness or shortness of breath with exertion and with respiratory rate at 20 or greater breaths/min, Peripheral capillary oxygen saturation (SpO2) >93% on room air at sea level, or heart rate at 90 or greater beats/min; Severe = symptoms suggestive of severe systemic illness with COVID-19, which could include any symptom of moderate illness, shortness of breath at rest, or respiratory distress, and respiratory rate at 30 or greater breaths/min, heart rate at 125 or greater beats/min, or SpO2 >93% on room air at sea level or (partial pressure of oxygen:fraction of inspired oxygen (PaO2:FiO2) <300.
排除标准
- •Inability to initiate study drug within 12 hours after randomization;
- •Female of childbearing potential who is unable or unwilling to forego breastfeeding through Day 28;
- •Systolic blood pressure <100 mmHg;
- •In shock or requiring pressor support;
- •Respiratory failure, defined as subjects who are on mechanical ventilation; are receiving oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen of 0.5 or greater), noninvasive positive pressure ventilation, or extracorporeal membrane oxygenation (ECMO); or have a clinical diagnosis of respiratory failure (ie, clinical need for 1 of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation);
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of normal (ULN);
- •Total bilirubin >2 × ULN;
- •Estimated glomerular filtration rate <30 mL/min or receiving hemodialysis or hemofiltration;
- •Moribund subject not expected to survive 24 hours in the opinion of the treating clinical team;
- •Any concurrent serious medical condition (eg, active malignancies on chemotherapy, post organ transplant, end stage congestive heart failure) or not likely to respond to treatment;
- •Decision to withhold life-sustaining treatment; Note: In the event of cardiac arrest, the decision to withhold cardiopulmonary resuscitation only does not fulfill this exclusion criterion.
- •Use of cytochrome P450 (CYP) 2 subfamily C, polypeptide 8 (2C8) substrates (eg, repaglinide, paclitaxel, or cerivastatin) or CYP3A4 substrates (eg, amlodipine, budesonide, dasabuvir, enzalutamide, imatinib, lopinavir, loperamide, saquinavir, sildenafil, midazolam, or montelukast);
- •Use of CYP2C8 inhibitors (eg, gemfibrozil, fluvoxamine, or ketoconazole);
- •Participation in another investigational study during the present study through the last visit (Day 28); or
- •Previous randomization in this study.
研究组 & 干预措施
Razuprotafib 10 mg
Active Comparator
干预措施: Razuprotafib Subcutaneous Solution (Drug)
Placebo
Placebo Comparator
干预措施: Placebo Subcutaneous Solution (Drug)
Razuprotafib 20 mg
Active Comparator
干预措施: Razuprotafib Subcutaneous Solution (Drug)
结局指标
主要结局
Number and Percent of Subjects Who Were Alive and Free of Respiratory Failure Prior to Day 7 and Day 28
时间窗: Baseline up to Day 7 and Day 28
All results were summarized descriptively by treatment arm and expressed as proportions, along with corresponding 95%CI of the difference between response rates, and p-values using Cochran-Mantel-Haenszel (CMH). The 95% CI will be constructed using the normal approximation method. Respiratory failure was defined as subjects who were on invasive mechanical ventilation; received oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20L/min with fraction of delivered oxygen ≥0.5) noninvasive positive pressure ventilation or extracorporeal membrane oxygenation; or had a clinical diagnosis of respiratory failure (ie, clinical need for 1 of the preceding therapies, but preceding therapies not able to be administered in setting of resource limitation).Subjects who died prior to the study timepoint (Day 7 or Day 28) were imputed based on the worst outcome.
次要结局
- Summary of Change From Baseline in C-Reactive Protein (CRP) at Day 7 and 28(at Day 7 and 28)
- Summary of The Mean Change From Baseline in D-Dimer at Day 7 and 28(at Day 7 and 28)
- Length of Hospitalization and Not Requiring Invasive Mechanical Ventilation From Baseline to Day 7 and Day 28 (or Death)(Baseline up to Day 7 and Day 28)
- Number of Participants Who Improve by at Least 2 Categories on the NIAID 8-point Ordinal Scale From Baseline to Day 7 and Baseline to Day 28(from baseline to Day 7 and baseline to Day 28)
- Number of Participants Who Were Discharged and Free of Respiratory Failure Prior to Day 7 and Day 28(Day 7 and Day 28)
- Number of Participants Alive and Not Requiring Invasive Mechanical Ventilation at Any Time(Baseline up to Day 28)
- Change in PaO2:FiO2 Ratio From Baseline to Day 7 and Baseline to Day 28(Baseline up to Day 7 and Day 28)
- Number of Participants in Each Category of the NIAID 8-point Ordinal Scale at Day 7 and Day 28(Baseline, Day 7, and Day 28)
- Time to Reach Grade 6, 7, or 8 on the NIAID 8-Point Ordinal Scale(From Screening through the end of the study (up to 28 days))
- Number of Participants Who Worsen by Greater Than or Equal to 2 Categories on The NIAID 8-point Ordinal Scale From Baseline to Day 7 and Day 28(From baseline to Day 7 and Day 28)
- The Number and Percent of Participants Who Experienced All-Cause Mortality at Day 7 and Day 28(Baseline up to Day 7 and Day 28)
- Length of Hospitalization From Baseline to Day 7 and Day 28 (or Death)(From Baseline to Day 7 or Day 28 (or Death))
- Number of Participants Who Improve by Greater or Equal to 2 Categories on the NIAID 8-point Ordinal Scale From Baseline to Day 7 and Day 28(Baseline to Day 7 and Day 28)
- Time to Return to Prehospitalization Oxygen Requirement(up to 28 days)