A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Two-Part (SAD and MAD) Study to Assess the Safety, Tolerability, and Pharmacokinetics of ARN-75039 When Administered by the Oral Route in Healthy Adult Subjects.
概览
- 阶段
- 1 期
- 干预措施
- ARN-75039 oral capsules
- 疾病 / 适应症
- Lassa Virus Infection
- 发起方
- Arisan Therapeutics, Inc.
- 入组人数
- 94
- 试验地点
- 2
- 主要终点
- The type and frequency of treatment-emergent adverse events (TEAEs)
- 状态
- 已完成
- 最后更新
- 昨天
概览
简要总结
ARN-75039 is proposed for the treatment of subjects with LASV infection, Lassa hemorrhagic fever, a potentially fatal human disease associated with Lassa viruses, with the most significant unmet medical need. ARN-75039-101 study was a randomized, double-blind, placebo-controlled study that assessed the safety, tolerability, and PK of escalating single and multiple doses of ARN 75039 when administered by the oral route in healthy adult subjects in six single ascending dose (SAD - Part 1) cohorts and five multiple ascending dose (MAD - Part 2) cohorts.
详细描述
In Part 1 (SAD), eight subjects per cohort (except for 10 subjects in cohort 3, evaluating the effects of food) were enrolled to receive the study drug orally in the fed state. Within each cohort of eight subjects, the first two subjects (Sentinel) were randomly assigned in a 1:1 ratio to receive a single dose of ARN-75039 capsules or placebo (microcrystalline cellulose). After the medical monitor reviewed the first 3 days of blinded safety for these subjects, an additional 6 subjects (the remaining cohort) were randomly assigned in a 5:1 (active: placebo) ratio. Within the food-effect cohort of 10 subjects, the first two subjects (Sentinel) were randomly assigned in a 1:1 ratio to receive ARN-75039 capsules or a placebo in the fasted state. After the medical monitor reviewed the first three days of blinded safety for these subjects, an additional 8 subjects (the rest of the cohort) were randomly assigned in a 7:1 (active: placebo) ratio. The Part 2 (MAD) dosing plan consisted of two days of lead-in doses followed by eight days of maintenance dosing. All doses were administered twice daily (BID), approximately 10 hours apart: * Day 1: a single dose of ARN-75039 3 times (3×) the maintenance dose, followed by a single dose of 2× the maintenance dose * Day 2: Two doses of 2× the maintenance dose * Day 3 through Day 10: BID dosing of the maintenance dose Dose escalation within the SAD and MAD portions was performed after review by the Safety Monitoring Committee (SMC) of blinded safety and available PK data from all subjects in all available cohorts through study Day 8. The MAD part of the study was initiated after the safety and PK data from the SAD part were reviewed by the Food and Drug Administration (FDA), and the Sponsor and FDA determined that it was safe to proceed. The SMC also evaluated the PK profile of ARN-75039, when available, to determine if a threshold exposure associated with potential anti-viral activity was achieved, which corresponded to the recommended Phase 2 dose (RP2D). The study was conducted in three study periods (Screening Period, Treatment Period, and Follow-up Period). During the Treatment Period, safety was assessed at each study visit, and PK assessments were conducted at specific time points per the assessment schedule. Subjects who received at least one dose of the study drug were instructed and encouraged to complete all study visits. Subjects in the Treatment period had spans of residency at the study site as well as ambulatory periods in each part of the study. Subjects returned to the study site for follow-up evaluations according to the Schedule of Assessments (SOA) during the Treatment Period. After completing the Treatment Period, subjects entered the Safety Follow-up Period, consisting of 14 days for the SAD part of the study and 28 days for the MAD part, culminating in an End-of-study (EOS) visit. For subjects who withdrew from the study prematurely, the EOS visit was conducted within seven days after the last study drug dose.
研究者
入排标准
入选标准
- •Is male or female, age 18 to 55 years, inclusive, at Screening.
- •Body mass index (BMI) between 18.5 and 35 kg/m2, inclusive, at Screening.
- •In good general health, determined by no clinically significant findings in the opinion of the Investigator from medical history, physical examination, 12-lead electrocardiogram (ECG), clinical laboratory findings, and vital signs at Screening and Day -1 or
- •Hemoglobin, hematocrit, white blood cell count, absolute neutrophil count, and platelet count results within the laboratory reference range at Screening; subjects with Gilbert's disease with associated abnormalities of liver function tests are eligible for enrollment. Tests may be repeated at the discretion of the Investigator to confirm abnormalities.
- •Estimated glomerular filtration rate (eGFR) based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation of ≥ 80 mL/min/1.73m2 at Screening
- •Females of childbearing potential must practice effective contraception per national regulatory guidelines for clinical trials from Screening, throughout the study and for 28 days after the EOS visit.
- •Females of childbearing potential must have a negative pregnancy test at Screening and within 24 hours prior to dosing of study drug; for post-menopausal subjects, a blood sample will also be tested for follicle stimulating hormone (FSH) to confirm post-menopausal status (as verified by an FSH of ≥40). Surgically sterile females are eligible; however, proof via medical records will be required.
- •Males must agree to not donate sperm and/or to use condoms during sexual intercourse from the time of the first study drug administration and for 90 days following the last dose of study drug, and females must agree not to donate eggs from the time of the first study drug administration and for 60 days following the last dose of study drug.
- •Must be Willing and able to comply with measures to avoid photosensitivity reactions (i.e., avoidance of outdoor sun exposure and tanning; consistent use of long sleeve shirts, long pants, hats, and sunglasses; consistent use of SPF 75 or greater sunscreen when outdoors) from Day 1 through Day 8 in Part 1 and through Day 25 in Part
- •Able to provide informed consent.
排除标准
- •Any clinically significant underlying illness in the opinion of the Investigator.
- •Poor venous access.
- •Inability to ingest all capsules of a multi-capsule dose within 5 minutes of ingestion of the first capsule.
- •Prior exposure to ARN-
- •Positive serology for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) at Screening; subjects with adequately treated HCV are eligible for enrollment.
- •Positive test for SARS-CoV-2 infection on Day -
- •Consumption of Seville oranges, grapefruit or grapefruit juice within 72 hours prior to Day 1 or during the study.
- •History of drug or alcohol abuse within 1 year of Screening in the opinion of the investigator, or a positive test for drugs of abuse or alcohol at Screening or Day -
- •Use of any prescription or over-the-counter (OTC) medications, including food supplements, vitamins, herbal medications (e.g., St. John's wort), and cannabis, with the exception of contraceptive medications and as needed (prn) acetaminophen or paracetamol (not exceeding 2 grams/day) within 7 days prior to study drug administration and through the EOS visit.
- •History of malignancy, except adequately treated basal cell carcinoma or in situ carcinoma of the uterine cervix.
研究组 & 干预措施
ARN-75039 oral capsules
Escalating single or multiple doses of ARN-75039 oral capsules
干预措施: ARN-75039 oral capsules
Placebo (microcrystalline cellulose)
Specified weight of placebo (microcrystalline cellulose) corresponding to the dose of ARN-75039 within the same cohort and encapsulating it in a HPMC capsule prior to dosing.
干预措施: Placebo
结局指标
主要结局
The type and frequency of treatment-emergent adverse events (TEAEs)
时间窗: Day 1 through 14 days post dose for SAD cohorts, and 28 days post last study dose for MAD cohorts.
Incidence of AEs and SAEs
Incidence of Treatment-Emergent Adverse Events (TEAEs)
时间窗: From first dose through the End-of-Study (EOS) visit: Part 1 (SAD), through Day 15/EOS; Food-effect cohort, through the second treatment period and Day 29/EOS; Part 2 (MAD), from Day 1 through Day 39/EOS.
A treatment-emergent adverse event (TEAE) was defined as any adverse event that began or worsened after administration of the study drug (ARN-75039 or placebo) through the End-of-Study visit.
Incidence of Treatment-Emergent Serious Adverse Events (TESAEs)
时间窗: From first dose through the End-of-Study (EOS) visit: Part 1 (SAD), through Day 15/EOS; Food-effect cohort, through the second treatment period and Day 29/EOS; Part 2 (MAD), from Day 1 through Day 39/EOS.
Number of participants with at least one treatment-emergent Serious adverse event (TESAE). A TESAE is any adverse event that starts or worsens after administration of study drug (ARN-75039 or placebo).
次要结局
- Determination of the recommended phase 2 dose (RP2D)(Day 1 through 14 days post dose for SAD cohorts and 28 days post last study dose for MAD cohorts.)
- Determine Maximum Plasma concentrations of ARN-75039(Day 1 through Day 8 post dose for SAD and FE cohorts, and 28 days post last study dose for MAD cohorts.)
- Determination of time to maximum concentration (Tmax)(Day 1 through Day 8 post dose for SAD and FE cohorts, and 28 days post last study dose for MAD cohorts.)
- Determination of terminal half life(Day 1 through Day 8 post dose for SAD and FE cohorts, and 28 days post last study dose for MAD cohorts.)
- Determination of plasma exposure (AUC0-t, AUC0-inf)(Day 1 through Day 8 post dose for SAD and FE cohorts, and 28 days post last study dose for MAD cohorts.)
- Part 1-SAD: Cmax(Day 1 predose and at 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 168 (Day 8), and 336 (Day 15/EOS) hours postdose.)
- Part 1-SAD: Tmax(Day 1 predose and at 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 168 (Day 8), and 336 (Day 15/EOS) hours postdose.)
- Part 1-SAD: Terminal Half-life(Derived from plasma samples collected from Day 1 predose through 336 hours (Day 15/EOS) postdose.)
- Part 1-SAD: AUC(Day 1 predose and at 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 12, 24 (Day 2), 48 (Day 3), 72 (Day 4), 168 (Day 8), and 336 (Day 15/EOS) hours postdose.)
- Part 2-MAD: Cmax0-10h(Day 1 and Day 10: predose and at 0.5, 1, 2, 4, 6, 8, and 10 hours after the morning dose.)
- Part 2-MAD: Tmax0-10h.(Day 1 and Day 10: predose and at 0.5, 1, 2, 4, 6, 8, and 10 hours after the morning dose.)
- Part 2-MAD: AUC0-10h(Day 1 and Day 10: predose and at 0.5, 1, 2, 4, 6, 8, and 10 hours after the morning dose.)