A Two-part, Double-blind, Placebo-controlled, Phase I Study of the Safety, Tolerability and Pharmacokinetics of SPR994 Following Single and Multiple Ascending Doses of SPR994 Administered Orally in Healthy Volunteers

Spero Therapeutics1 个研究点分布在 1 个国家目标入组 124 人开始时间: 2017年10月20日最近更新: 2018年8月28日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方: Spero Therapeutics
入组人数: 124
试验地点: 1
主要终点: Safety measures: adverse events

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is a double-blind, placebo-controlled, ascending dose, multi-cohort trial. The study will be conducted in 2 parts: a single ascending dose (SAD) part, followed by a multiple ascending dose (MAD) part. In SAD, all subjects will receive 1 dose of SPR994 (100, 300, 600 or 900 mg) or placebo, except for subjects enrolled in food effect cohorts in which subjects will receive one dose following a 10 hour fast and a second dose in the fed state following a minimum 5 days washout period. There is a single, optional, open-label control cohort that may enroll, in which all 8 subjects will receive Orapenem® (tebipenem pivoxil fine granules). In MAD, subjects will receive multiple doses of SPR994 (300 or 600 mg) or placebo for 14 consecutive days at either BID or TID dosing. In both parts, cohorts will be exposed to increasing doses of SPR994 with various extended release formulations.

详细描述

This study is a randomized, double-blind, placebo-controlled, combined single and multiple ascending dose (SAD and MAD) trial. Up to one hundred fifty two (152) subjects aged 18-55, who fulfill the inclusion/exclusion criteria, may be enrolled in this study. Up to a total of 17 SAD and 2 MAD cohorts of eight subjects each will be examined. Subjects in each cohort will be randomized 3:1 to receive SPR994 at doses ranging from 100 mg to 900 mg or placebo in various immediate and timed release formulations. One SAD control cohort, Cohort 12, may be enrolled in which eight subjects will receive a single dose of Orapenem® at 300 mg in a fed and fasted state. Dosing is complete in SAD Cohorts 1-3, 6 and 7. Subjects in Cohorts 1-3 received a single dose of SPR994 and subjects in food effect Cohorts 6 and 7 each received 2 doses. Subjects enrolled in SAD Cohorts 8 and beyond will receive a single dose of SPR994 or placebo in a fasted state and a second dose following a standardized meal to investigate food effect on the pharmacokinetics of SPR994 and TBPM. SAD Cohorts 8 through 10 may run in a staggered or concurrent manner before enrollment of further cohorts. Blinded pharmacokinetic data will be reviewed at the conclusion of Cohort 10 (300 mg fasted & fed). Should the PK be optimized in one of the various time released formulations, the Sponsor may decide to proceed to enrollment of the 600 mg Cohorts using the optimal formulation; other timed release formulations may also be explored at 300 mg dose in a staggered or concurrent manner until an optimal formulation(s) is identified. When an optimal formulation(s) is identified, the 600 mg Cohorts may run in a staggered or concurrent manner. SAD Cohorts 16 (100 mg fasted) and 17 (900 mg fasted) may run prior to or in a staggered or concurrent manner with MAD Cohorts 4 (300 mg) and 5 (600 mg). During the MAD part of the study, subjects will receive 27 doses of SPR994 or placebo over a period of 14 days. Based on the observed PK of SPR994 in prior cohorts, the total number of doses may be increased to 40 doses of SPR994 or placebo administered TID over 14 days; only one dose will be administered on Day 14 to allow for PK sample collection In both SAD and MAD parts of the study, the Cohorts will be exposed to increasing doses of SPR994. Each part (SAD and MAD) of the study will consist of 3 periods: a screening period, a treatment period, and a follow-up period. The safety and tolerability of SPR994 will be assessed based on the types and frequency of adverse events (AEs) reported; concomitant medication usage; and changes from baseline in physical examination, weight, vital signs, ECG, and standard clinical laboratory tests. A Safety Management Group (SMG) will review the data of cohorts prior to escalating to the next dose level.

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)

盲法说明

Subjects will be randomized in a 3:1 ratio of SPR994 to placebo. Study drug tablets, both active and placebo, are the same shape, weight and size. Those blinded to study drug assignment include the sponsor, the PI, clinical study personnel participating in subjects' care or clinical evaluations, and the subjects. Those unblinded to study drug assignment include the statisticians preparing the randomisation, pharmacy personnel, the unblinded study monitor, the bioanalytical laboratory, and the pharmacokineticist performing interim PK analysis.

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/or females (of non-childbearing potential), 18 to 55 years of age (inclusive) at the time of screening;
•Body mass index ≥ 18.5 and ≤ 29.9 (kg/m2) and 55.0 and 100.0 kg (inclusive) for all cohorts;
•Medically healthy without clinically significant (CS) abnormalities at the screening visit or Day -1, including:
•Physical examination, vital signs including temperature, heart rate, respiratory rate, and blood pressure;
•Triplicate electrocardiograms (ECGs) taken at least 1 minute apart with QT wave corrected for heart rate (HR) using Fridericia's method (QTcF) interval duration less than 450 msec obtained as an average from the triplicate screening and pre-dose Day 1 ECGs after at least 5 min in a semi-supine quiet rest;
•Haemoglobin > 12.5, haematocrit 37%, white blood cell (WBC) count > 3.5, or platelet count equal to or greater than the lower limit of normal range of the reference laboratory (may be confirmed upon repeat analysis);
•Creatinine, blood urea nitrogen (BUN), equal to or less than the upper limit of normal; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal to or < 1.5 times the upper limit of normal for the reference laboratory and confirmed on repeat analysis; results of all other clinical chemistry and urine analytes without any CS abnormality.
•Discussion between the PI and the Sponsor Medical Monitor is encouraged regarding any abnormal laboratory value that is outside of the normal range during the pre-dose period.
•Be non-smokers (including tobacco, e-cigarettes or marijuana) for at least 1 month prior to participation in the study;
•Willing and able to provide written informed consent;
•Be willing and able to comply with all study assessments and adhere to the protocol schedule;
•Have suitable venous access for blood sampling;
•If female, be of non-childbearing potential (e.g. post-menopausal as demonstrated by follicle stimulating hormone or surgical sterilization i.e., tubal ligation or hysterectomy). Provision of documentation is not required for female sterilization, verbal confirmation is adequate;
•If male, a willingness not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, a willingness to use a condom in addition to having the female partner use a highly effective method of birth control (such as an intrauterine device, diaphragm, oral contraceptives, injectable progesterone, subdermal implants, or a tubal ligation). This criterion applies to males (and/or female partners) who are surgically sterile and must be followed from the time of first study drug administration until 30 days after the final administration of study drug.

排除标准

•History or presence of significant cardiovascular, pulmonary, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or surgery within the past 3 months determined by the PI to be clinically relevant;
•History of known or suspected Clostridium difficile infection;
•History of seizure disorders, except for a single febrile seizure in childhood;
•Positive urine drug/alcohol testing at screening or Day -1;
•Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV);
•History of substance abuse or alcohol abuse (defined as greater than 2 standard drinks on average each and every day, where 1 standard drink is defined as containing 10 g of alcohol and is equivalent to 1 can or stubby of mid-strength beer, 30 ml nip spirits, or 100 ml wine) within the previous 5 years;
•Use of any prescription medication or any over-the-counter medication, including herbal products and vitamins within 7 days prior to randomization;
•Documented hypersensitivity reaction or anaphylaxis to any medication;
•Donation of blood or plasma within 30 days prior to randomization, or loss of whole blood of more than 500 mL within 30 days prior to randomization, or receipt of a blood transfusion within 1 year of study enrollment;
•Participation in another investigational clinical trial within 30 days prior to Day 1;
•Any other condition or prior therapy, which, in the opinion of the PI, would make the volunteer unsuitable for this study, including unable to cooperate fully with the requirements of the study protocol or likely to be non-compliant with any study requirements.

研究组 & 干预措施

SPR994, FI, F2, F3, F4 Oral Tablets

Experimental

SPR994 is active against multidrug-resistant Gram-negative and Gram-positive pathogens that cause serious and life-threatening infections, including extended spectrum beta-lactamase (ESBL) producers as well as strains resistant to levofloxacin and trimethoprim/sulfamethoxazole. SPR994 is administered in tablet form orally. Up to five different time released formulations of SPR994 will be studied in this protocol at 100 mg, 300 mg, 600 mg and 900 mg dosages.

SAD Cohorts: One dose (two for food effect cohort) MAD Cohorts: Twenty-seven (27) doses administered twice daily (BID) over a period of 14 days or forty doses administered three times daily (TID) over period of 14 days

干预措施: SPR994 (Drug)

Placebo Oral Tablet

Placebo Comparator

Placebo tablets (100, 300, and 600 mg) are pressed from a single placebo blend consisting of the same inactive ingredients; the active pharmaceutical ingredient (API) is replaced by Mannitol 200SD.

SAD Cohorts: One dose (two for food effect cohort) MAD Cohorts: Twenty-seven (27) doses administered BID over a period of 14 days or forty doses administered TID over a period of 14 days

干预措施: Placebo Oral Tablet (Drug)

Optional Orapenem Open-Label Control

Other

A single, optional, open-label, control cohort that may enroll, in which all 8 subjects receive Orapenem.

SAD Cohort: One dose under fasted conditions and one dose under fed conditions.

干预措施: Orapenem® (Drug)

结局指标

主要结局

Safety measures: adverse events

时间窗: SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD 1 to 20 days

The incidence and severity of AEs

Safety measures: concomitant medications

时间窗: SAD: 1 to 7 days or 1 to 13 (food effect cohort); MAD: 1 to 20 days

The type and frequency of medications used

Safety measures: physical examination

时间窗: SAD: -1 to 7 days or -1 to 13 (food effect cohort); MAD: -1 to 20 days