A Phase II, Randomized, Assessor-blind, Multicenter, Multi-dose, Placebo-controlled Study Assessing the Safety and Anti-coronavirus Response of Brequinar Combined With Dipyridamole in Patients With Mild to Moderate SARS-CoV-2 Infection.
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 26
- 试验地点
- 7
- 主要终点
- Safety and Tolerability of the Brequinar-dipyridamole Combination in COVID-19 Subjects
研究概览
简要总结
A Phase 2 multi-center, assessor-blind, randomized study to assess the safety, tolerability, and antiviral activity of brequinar in combination with dipyridamole.
详细描述
This is a Phase 2 clinical trial in two parts. The first part of the trial will study up to 64 subjects using a dose escalation approach, with 16 subjects per cohort for up to 4 cohorts. The brequinar dose will start at 50 mg per day in Cohort 1, escalating in the next cohort of 16 to 100 mg, then to 150 mg, and finally to 200 mg if safety parameters are met. The dipyridamole dose will be 75 mg three times a day (TID) for subjects assigned to the combination arm for all cohorts. All subjects will also receive standard of care (SOC) for treatment of patients with COVID-19 infection. After identifying the highest brequinar dose that is safe and well tolerated, 48 subjects will be treated in an expansion part comparing the chosen brequinar dose in combination with 75 mg dipyridamole TID to the chosen dose of brequinar alone. The combination of brequinar and dipyridamole shows potent in vitro antiviral activity by blocking DHODH and the pyrimidine salvage pathway, respectively, and the purpose of this study is to establish the safety and antiviral effect of the combination.
During the dose escalation part of the study, subjects with confirmed mild to moderate COVID-19 will receive 5 days of one of the following oral doses: brequinar alone, brequinar in combination with dipyridamole, or placebo. Subjects will have a Screening Visit followed as soon as possible with Study Day 1. Study visits (virtual or in person) will take place at Screening and on specified days. The visits that include bloodwork must be conducted at the study site or arrangements made for sample collection at the subject's home or other appropriate location. Other visits/visit activities for that visit may be conducted remotely using telemedicine or other remote technique. A viral load sample, vital signs (respiratory rate, heart rate, body temperature and SpO2), and a symptom assessment will be completed on specified days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
All staff will be blinded to treatment with the exception of the pharmacist and any staff recording study drug administration.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to provide informed consent for the trial, written, electronic, verbal, or other method deemed acceptable by the institution and IRB.
- •Subjects between ≥18 and ≤65 years of age.
- •Subjects found positive for SARS-CoV-2 either by rapid antigen test or by reverse transcription polymerase chain reaction (RT-PCR) using ICMR-validated kit.
- •Note: Test need not be repeated in those with possession of confirmed positive report, but positive result test date must be ≤5 days of first dose of study drug.
- •Mild or Moderate COVID-19 as per latest updated version of CLINICAL MANAGEMENT PROTOCOL for COVID-19 (in adults) released by Government of India Ministry of Health and Family Welfare Directorate General of Health Services (EMR Division).
- •The effects of brequinar on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation, and for 90 days after completion of brequinar administration.
- •Male subjects must agree to refrain from sperm donation and female subjects must agree to refrain from ovum donation from initial study drug administration until 90 days after the last dose of brequinar.
- •At least one non-respiratory COVID-19 symptom characterized as mild to moderate by the Investigator including but not limited to fatigue, chills, fever, body aches, nasal congestion, nausea, vomiting, or other sign or symptom commonly associated with COVID-19 in the opinion of the investigator. Symptom onset must be ≤5 days prior to first dose. Subject must have one or more signs/symptoms present at first dose.
- •Willing to participate in the PK subset if at one of the identified sites.
- •Able to swallow capsules.
排除标准
- •Have an oxygen saturation of <90% while breathing ambient air.
- •Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the subject.
- •Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test.
- •Treatment with another DHODH inhibitor (e.g., leflunomide, teriflunomide) or other agents known to cause bone marrow suppression leading to thrombocytopenia.
- •Ongoing treatment with aspirin and or dipyridamole, famotidine or cimetidine. Remdesivir and ivermectin are prohibited through Study Day
- •Steroids are permitted per the guidelines.
- •Platelets ≤125,000 cell/mm
- •Hemoglobin <10 gm/dL.
- •Absolute neutrophil count <1000 cells/mm
- •Renal dysfunction, i.e., creatinine clearance <30 mL/min.
- •AST or ALT >3 x ULN, or total bilirubin >ULN. Gilbert's Syndrome is allowed.
- •Bleeding disorders or blood loss requiring transfusion in the six weeks preceding enrollment.
- •Ongoing gastrointestinal ulcer, or gastrointestinal bleeding within 6 weeks of first dose.
- •Chronic hepatitis B infection, active hepatitis C infection, active liver disease and/or cirrhosis per subject report.
- •Heart failure, current uncontrolled cardiovascular disease, including unstable angina, uncontrolled arrhythmias, major adverse cardiac event within 6 months (e.g., stroke, myocardial infarction, hospitalization due to heart failure, or revascularization procedure).
研究组 & 干预措施
Brequinar monotherapy
Brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met.
干预措施: Brequinar Sodium (Drug)
Placebo
Placebo matching brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met.
干预措施: Placebo (Drug)
Brequinar-Dipyridamole Combination
Brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met. All subjects assigned to this arm will also receive dipyridamole 75 mg tablets TID.
干预措施: Brequinar Sodium (Drug)
Brequinar-Dipyridamole Combination
Brequinar oral capsules will be administered once daily for 5 days using a dose-escalation approach. Planned doses include 50 mg, 100 mg, 150 mg, and 200 mg. Dosing will start at 50 mg and be escalated to the next higher dose if cohort stopping rules are not met. All subjects assigned to this arm will also receive dipyridamole 75 mg tablets TID.
干预措施: Dipyridamole 75 MG (Drug)
结局指标
主要结局
Safety and Tolerability of the Brequinar-dipyridamole Combination in COVID-19 Subjects
时间窗: Day 29
There were no subjects who experienced grade 3 and 4 toxicities and serious adverse events (SAEs) considered by the investigator to be related to the combination, brequinar alone or placebo alone. therefore frequencies of these events could not be compared.
次要结局
- Reduction in Percentage of Subjects Requiring Hospital Admission/Re-admission as an In-patient for >24 Hours(Day 29)
- Reduction of SARS-CoV-2 Levels Using qPCR Through Day 29 and at Days 4, 8, 12, 15, 22, and 29(Day 29)
- Reduction in Time to Symptom Improvement(Day 29)
- Reduction in Percentage of Subjects Requiring Medical Attended Visits, e.g., Hospitalization, Emergency Room Visits, Urgent Care/Family Doctor Visits(Day 29)
- Reduction in Percentage of Subjects Requiring Supplemental Support Such as Oxygen(Day 29)