A Phase Ib/IIa, Randomized, Double Blinded, Perallel, Dosing Ranging, Placebo Controled and Proof of Concept Clinical Trial to Evaluate the Safety, Tolerability, PK and Antiviral Effect of ACC017 Tablet as Monotherapy/Combination With NRTI in Treatment naïve HIV-infected Adults
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Report the incidence, severity and seriousness of adverse events, and the relationship between drug and AE
研究概览
简要总结
ACC017 is an integrase inhibitor that will be evaluated for the treatment of HIV infection. This phase Ib/IIa, randomized, double-blind, parallel, dose ranging, placebo-controlled 'proof of concept' study is designed to evaluate the safety, tolerability, pharmacokinetics and antiviral effect of ACC017 monotherapy and combined with FTC/TAF by sequency versus placebo in treatment-naïve HIV-1 infected adults. This study includes two stages, stage one is a single dose escalation, and all subjects will be co-administrated with FTC/TAF at 200 mg/25 mg on stage two. The study consists of a screening visit, baseline period, monotherapy period, and combination therapy period. Total 36 subjects will be randomized in a 5:1 ratio to receive one of three doses of ACC017 or placebo lasting for 10 days for monotherapy followed by 18 days for combination therapy.
详细描述
This phase Ib/IIa study in HIV-infected antiretroviral naive adult subjects is conducted to evaluate the safety, tolerability, pharmacokinetics and antiviral effect of ACC017 tablet as monotherapy/combination with NRTIs and to explore the recommended dose for the future pivotal clinical trial of ACC017. The study will be conducted as two stages. Stage one will includes a dose-ranging evaluation of ACC017 5mg, 40mg and 80mg once daily compared to placebo on the basis of safety, tolerability, pharmacokinetics and antiviral activity. Subjects will be randomized in a 5:1 ratio to receive one of three doses of ACC017 or placebo. Each subject will receive ACC017 tablet as monotherapy for 10 days and then followed by a combination with NRTIs for 18 days. In monotherapy, the enrolment into the next higher dose group will commence only when investigator and sponsor both agree that ACC017 is safe and well tolerated at a given dose. Stage two is open and subjects will continue to take ACC017 at the dose given on stage one in combination with FTC/TAF tablet at 200 mg/25 mg once daily for 18 days. Subjects randomized to receive placebo in stage one will receive the equivalent dose of ACC017 combined with FTC/TAF.
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
- Double (Participant, Investigator)
盲法说明
double blinded in the stage one, open in the stage two
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 to sign the informed consent and agree to comply to the study procedures and requests
- •Age range between 18 and 65 years old at the time of signing informed consent, regardless of gender
- •Body weight ≥40 kg, and BMI range between 18.5~29.9 kg/m2 (including the borderline) at screening
- •Documented HIIV-1 infection before screening, and never receive any antiHIV-1 drugs or vaccines after the diagnosis of HIV-1 infection
- •Agree not to use any antiviral drugs other than those allowed by protocol during study period.
- •Plasma HIV RNA≥5000 copies/mL at screening;
- •CD4+ T-lymphocyte count of >200 cells/μL
排除标准
- •Diagnosis of acute HIV infection at screening or unstable AIDS related disease within 4 weeks prior to screening.
- •Had PrEP and/or PEP treatment within 1 month prior to screening.
- •Had uncontrolled severe disease judged by investigator, such as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, NYHA class III or IV or fasting glucose ≥7.0 mmol/L.
- •History of serious allergy to drugs (such as aspirin or cephalosporin antibiotics) or their ingredients' or food (a fast, life-threatening systemic allergic reaction), or allergic disease requiring drug control (such as asthma, urticaria, atopic dermatitis [eczema].).
- •Any major gastrointestinal surgery (except uncomplicated appendectomy or cholecystectomy) or any surgery affecting drug absorption, distribution, metabolism and excretion within 6 months before screening; or possible elective surgery during the trial as judged by the investigator.
- •History of cancer(except cervical carcinoma in situ, or cutaneous basal cell carcinoma, squamous cell carcinoma, and/or carcinoma in situ [Bowen's disease] that received radical surgery or treatment) within 5 years prior to screening.
- •Hb <90 g/L, or WBC count <1.5×109/L, or ANC count <0.6×109/L, or platelet count <50×109/L at screening.
- •ALT and/or AST > 2.5 times upper limit of normal (ULN), or TBIL > 1.5 × ULN, or DBIL > ULN, or ALB <30 g/L at screening.
- •SCr > 1.3 ×ULN, or Ccr <60 mL/min (Cockcroft-Gault formula) at screening,
- •Blood amylase or lipase >1.5 ×ULN
- •Subjects with a positive for HBsAg or anti-HCV, or those with anti-Tp positive who need to be treated required by investigator or their treatment period <7 days at screening.
- •Average smoked cigarettes more than 5 a day within 3 months prior to screening or unwilling to stop using any tobacco products during hospitalization.
- •Drinking more than 14 units per week within 3 months prior to screening ( 1 unit of alcohol is equivalent to 5% beer, 45 mL of 40% alcohol, 150mL of 12% alcohol), or a positive alcohol breath test at a screening or baseline visit, or unwilling to stop drink any alcohol-containing product during hospitalization.
- •Excessive consumption of tea, coffee or caffeine ( more than 8 cups per day on average, 1 cup of 250 mL) or unwilling to stop drinking tea, coffee, or caffeine during hospitalization.
- •Having taken pitaya, mango, grapefruit, star fruit or any preparations made from them, or food/drinking containing xanthine, caffeine or alcohol (e.g.chocolate, tea, coffee, cola and cocoa) or others that will affect the absorption, distribution, metabolism, excretion of drugs, within 48 hours prior to the first dose of experimental drugs, or unwilling to stop taking them during hospitalization.
- •Use of any potent or moderate CYP3A inhibitors (e.g. clarithromycin, thalimycin, ketocomazole, ketoconazole, itraconazole, and CYP3A4) or potent CYP3A4 inducers (e.g. rifampin, efavirenz,carbamazepine, phenobarbitone, phenytoin) within 14 days prior to the first dose of experimental drugs or within 5 half-lives(whichever is longer).
- •Use of any potent or moderate UGT1A inhibitors (e.g. silybin. Ritonavir) or potent UGT1A1 inducers (e.g. rifampin, carbamazepine) within 14 days prior to the first dose of experimental drugs or within 5 half-lives (whichever is longer).
- •Use of any prescription drug, nonprescription drug, Chinese traditional herbs within 14 days prior to the first dose of experimental drugs or within 5 half-lives (whichever is longer).
- •History of drug dependence (social, psychological and physical impairment due to excessive, impropriate or addictive use of substances for any non-medical reason) within 5 years prior to screening, or positive urine drug screen at screening or baseline.
- •Intolerance to venipuncture, or have a history of halo acupuncture or blood sickness, or have donated blood including component blood or have had substantial blood loss (more than 400 mL) or have received a blood transfusion within 3 months prior to screening, or plan to donate blood during study.
- •Have special dietary requirements at screening, or refuse to accept a standard diet.
- •Have participated in or are participating in another drug or medical device clinical study within 3 months prior to screening.
- •Women who are pregnant or breastfeeding or who have a positive blood pregnancy test at screening.
- •Have a birth plan (including conception, eggs or sperm donation) within 1 month before signing informed consent form until 3 months after last dose of experimental drugs or refuse to use effective any contraceptive methods.
- •Other conditions exist that, in the judgement of the investigator, make participation in this study unsuitable.
研究组 & 干预措施
Participant group 4
Stage one: Placebo
干预措施: Placebo (Drug)
Participant group 1
Stage one: ACC017 (Dose 1) Stage two: ACC017 (Dose 1)+FTC/TAF (200mg/25mg) QD
干预措施: ACC017+FTC/TAF (Drug)
Participant group 2
Stage one: ACC017 (Dose 2) Stage two: ACC017 (Dose 2)+FTC/TAF (200mg/25mg) QD
干预措施: ACC017+FTC/TAF (Drug)
Participant group 3
Stage one: ACC017 (Dose 3) Stage two: ACC017 (Dose 3)+FTC/TAF (200mg/25mg) QD
干预措施: ACC017+FTC/TAF (Drug)
结局指标
主要结局
Report the incidence, severity and seriousness of adverse events, and the relationship between drug and AE
时间窗: Day 1- Day 11
Report the incidence, severity and seriousness of adverse events, and the relationship between drug and AE
HIV-1 RNA viral load change from baseline
时间窗: Day 11
HIV-1 RNA viral load change from baseline
Proportion of patients with HIV-1 RNA viral load <50 copies/mL
时间窗: Day 29
Proportion of patients with HIV-1 RNA viral load \<50 copies/mL
Pharmacokinetics parameter: Cτ,ss
时间窗: Day 10, Day 29
Cτ,ss is defined as the steady-state plasma drug concentration at the end of the dosing interval after the last administration of a given dose on the monotherapy and combination therapy periods.
Pharmacokinetics parameter: Cmin,ss
时间窗: Day 10
Cmin,ss is defined as the minimum steady-state plasma drug concentration after the last dose of monotherapy.
Pharmacokinetics parameter: Cmax,ss
时间窗: Day 10
Cmax,ss is defined as the maximum steady-state plasma drug concentration after the last dose of monotherapy.
Pharmacokinetics parameter: AUC0-τ,ss
时间窗: Day 1- Day 10
AUC0-τ,ss is defined as the steady-state area under the plasma concentration-time curve from time zero to the any dosing interval of monotherapy.
Pharmacokinetics parameter: Tmax,ss
时间窗: Day 1-Day 10
Tmax,ss is defined as the time to reach steady-state maximum plasma concentration during monotherapy period.
Pharmacokinetics parameter: MRT0-τ,ss
时间窗: Day 1-Day 10
MRT0-τ,ss is defined as the steady-state mean residence time from time zero to any dosing interval of monotherapy.
次要结局
- Changes over time in temperature of vital signs(Day 1-Day 29)
- Changes over time in pulse of vital signs(Day 1-Day 29)
- Changes over time in systolic and diastolic blood pressure of vital signs(Day 1-Day 29)
- Changes over time in respiratory rate of vital signs(Day 1-Day 29)
- Changes over time in heart rate as measured by electrocardiogram(ECG)(Day 1-Day 29)
- Changes over time in PR interval as measured by ECG(Day 1-Day 29)
- Changes over time in QRS duration(Day 1-Day 29)
- Changes over time in QTc interval(Day 1-Day 29)
- Changes over time in weight(Day 1-Day 29)
- Pharmacokinetics parameters: Cmax(Day 1-Day 2)
- Pharmacokinetics parameters: Cτ(Day 2)
- Pharmacokinetics parameters: AUC0-τ(Day 2)
- Pharmacokinetics parameters: Tmax(Day 1- Day 2)
- Pharmacokinetics parameters: MRT0-τ(Day 1- Day 2)
- Report the incidence, severity and seriousness of adverse events, and the relationship between drug and AE(Day 11-Day 29)
- HIV-1 RNA viral load changes from baseline over time(Day 2-Day 4, Day 8-Day 11, Day 21, Day 29)
- Proportion of patients with HIV-1 RNA viral load <50 copies/mL(Day 11)
- Proportion of patients with HIV-1 RNA viral load <200 copies/mL(Day 11, Day 29)
- The proportion of patients with HIV-1 RNA viral load <400 copies/mL(Day 11, Day 29)
- Changes in viral load from baseline to HIV-1 RNA viral load at nadir(Day 11)
- The proportion of nadir HIV-1 RNA <50 copies/mL(Day 11)