A Phase 1 Double-Blind, Placebo-Controlled, Randomized Multiple Dose Escalation Study to Evaluate the Safety, Tolerance, and Pharmacokinetics/Pharmacodynamics of a New GMP Formulation of Intravenous Artesunate if Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Number of Participants With AEs Occurring in Greater Frequency in the 2.0 mg/kg IV AS Group Then in the Placebo Group to Access Safety and Tolerability of AS
研究概览
简要总结
The purpose of this study is to establish the safety, tolerability, and pharmacokinetics of a multiple dose of the antimalarial drug artesunate.
详细描述
This study was a Phase 1b, randomized, double-blind, placebo-controlled trial using multiple ascending doses of intravenous artensunate (AS) to determine it's safety, tolerability, and PK in healthy subjects. Subjects were screened within 21 days of dosing. At the screening visit, subject underwent baseline assessments: vital signs were recorded; a physical examination, urinalysis, urine drug screen, and urine pregnancy test were performed; a complete blood cell count (CBC) with differential and indices, reticulocyte count, coagulation markers, and blood chemistry assessments were performed and medical and medication history was collected. Eligible subjects were scheduled for a 6-hour pre-dose electrocardiogram (ECG) and vital sign assessment with measurements taken at approx. the same times as Day 1 (dosing day). On Day 0, subjects were admitted to the clinical pharmacology unit to begin the inpatient phase of the study. Subjects had a brief physical examination and all procedures for the inpatient stay were reviewed. On Day 1, pre-dose vital signs and ECG were performed. Subjects then received study drug or placebo by IV bolus infusion. Subjects were closely monitored by evaluating hemodynamic measurements, periodic ECGs, and assessment of spontaneously reported AEs. Blood was drawn for blood count and chemistry analysis 6h and 24h after each dose. PK blood samples were drawn pre-dose and approx. 5min, 20min, 40min, 1h, 2h, 4h, 6h, and 24h after each dose. On Days 2 and 3 subjects received their second and third doses, respectively, of study drug or placebo with the same monitoring and laboratory measurements as for the first dose. Subjects were discharged 24 hours after the 3rd dose of drug or placebo and were followed as outpatients on Days 7, 10, and 15.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adult males and non-pregnant, non-lactating females
- •Have a normal ECG that may include benign PAC's and PVC's, 1st degree AV block, 2nd degree AV block, Wenckebach
- •Have a normal blood pressure (BP) and heart rate (HR). These will be measured after resting supine for about 3 minutes. Normal BP is defined as less than 140 mm Hg systolic and less than 90 mm Hg diastolic. Normal baseline HR is 50 to 90 bpm without symptoms.
- •Body mass index between 18 and 29 kg/m**2 or, if out of range, not clinically significant (within 15% of their ideal body weight).
- •Be able to verbalize understanding of the consent form, provide written informed consent and verbalize willingness to complete study procedures
- •Have a physical examination that demonstrates no clinically significant contraindication for participating in the study. This would include documentation of any abnormal movements suggesting neurological pathology and ECG tracings to document an abnormalities in cardiac conduction
- •If female, have a negative serum pregnancy test at screening and urine pregnancy test on pre-admission and admission, or be postmenopausal, or have had a hysterectomy, or have been sterilized, AND, if still able to bear children, agree to practice effective contraception for the duration of the study and for a period of 12 weeks after stopping study drug.
- •Active duty participants must be on leave during the inpatient phase of the study.
排除标准
- •Have received any investigational drug or vaccine in the period 0 to 16 weeks before entry to the study.
- •Have been on a liquid protein diet in the last year
- •Have any clinically important physical findings, laboratory abnormalities, or histories of Rx or OTC drug use that may, in the judgement of a study investigator, impact study interpretation or affect subject safety
- •Have used any prescription drugs within 14 days prior to admission or most non-prescription drugs including herbals or dietary supplements within 7 days prior to admission (at the investigator's discretion).
- •Existence of any surgical or medical condition that, in the judgement of the clinical investigator, might interfere with the distribution, metabolism or excretion of the drug
- •Presence of history of drug allergy requiring treatment. Hay fever is allowed unless it is active or has required treatment within the previous 2 months
- •Donation or loss of greater than 400 ml of blood in the period 0 to 12 weeks before entry to the study.
- •Serious adverse reaction or hypersensitivity to any drug, particularly artemisinin derivatives
- •CAGE (screening test for alcoholism) postitive (2 out of 4 criteria) or has a history of recent alcohol abuse
- •Use of illicit drugs
- •Family history (in 1st degree relatives) of sudden cardiac death or prolonged QT/QTc syndrome
- •History of seizure (excluding febrile seizures in childhood), episodes of unexplained syncope, or trouble with balance, undiagnosed hearing deficits, and other neurological disorder
- •History of severe psychiatric disorder or hospitalization for severe psychiatric disorder
- •Current job or personal habit of reversed sleep-wake cycle
- •History of cardiac disease to include cardiomyopathy, valvular disease, arrhythmia, ischemia, or enlarged heart
- •Presence of hepatitis B surface antigen (Hbs-Ag), hepatitis C antibody (antiHCV) or HIV type 1 at screening
- •A finding or history of hematuria (excluding menses-related hematuria) during subject screening
研究组 & 干预措施
2 mg/kg Intravenous Artesunate
2 mg/kg of Intravenous artesunate
干预措施: Intravenous Artesunate (Drug)
4 mg/kg Intravenous Artesunate
4 mg/kg of Intravenous artesunate
干预措施: Intravenous Artesunate (Drug)
8 mg/kg Intravenous Artesunate
8 mg/kg of Intravenous artesunate
干预措施: Intravenous Artesunate (Drug)
Placebo
Mannitol (200 mg/vial) diluted in phosphate buffer and delivered in an equivalent volume by subject's weight as artesunate.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants With AEs Occurring in Greater Frequency in the 2.0 mg/kg IV AS Group Then in the Placebo Group to Access Safety and Tolerability of AS
时间窗: up to 21 days
Comparison of number of participants with AEs reported for the placebo control and those treated with the 2.0 mg/kg of IV AS to access safety and tolerability
Number of Participants With AEs
时间窗: up to 21 days
The general strategy of the safety analysis was to examine the clinical tolerability and laboratory safety parameter data and determine if there were any trends amongst the dose levels concerning all AEs and drug related AEs.
次要结局
- Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL)(Pre-dose, 5, 20, 40 minutes after infusion and 1, 2, 4, 8, 24 and 72 hours after infusion)
- Tmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (hr)(Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion)
- Cardiovascular Responses: Number of Participants With Changes in Blood Pressure and Heart Rate After Infusion(screening, on Day -1, on Days 1, 2, and 3, and at each follow-up visit)
- Range of Pharmacokinetic Parameters for Artesunic Acid After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL)(Pre-dose, 5, 20, 40 minutes after infusion and 1, 2, 4, 8, 24 and 72 hours after infusion)
- Range of Pharmacokinetic Parameters for Dihydroartemisinin (DHA) After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng*hr/mL)(Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion)
- Cmax Assessment After Single 2.0, 4.0 and 8.0 mg/kg Dose of Artesunate Daily for 3 Days (ng/mL)(Pre-dose, 5, 20, 40 minutes after infution and 1, 2, 4, 8, 24 and 72 hours after infusion)