A Single-Center, Randomized, Open-Label, Phase Ia Trial Comparing the Pharmacokinetics/Pharmacodynamics, Safety, and Preliminary Efficacy of HHK001 and Enantone (Leuprorelin Acetate Microspheres for Injection) in Patients With Endometriosis
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 20
- 主要终点
- Maximum Plasma Concentration (Cmax) of Leuprorelin
研究概览
简要总结
This study compares the pharmacokinetics/pharmacodynamics (PK/PD), safety, and preliminary efficacy of a single 3.75 mg dose of HHK001 (Leuprorelin Acetate Microspheres for Injection, an improved formulation) versus Enantone (Leuprorelin Acetate Microspheres for Injection) in patients with endometriosis. Approximately 20 patients will be enrolled and randomized in a 1:1 ratio to receive a single subcutaneous injection of HHK001 or Enantone. The post-dose blood sampling/follow-up period is 6 weeks for the Enantone group and 10 weeks for the HHK001 group.
详细描述
Study Design and Population:
This is a single-center, randomized, open-label, parallel-group, Phase Ia study in patients with endometriosis. The study compares the PK/PD, safety, and preliminary efficacy of HHK001 and Enantone at the same dose (3.75 mg, single administration) to preliminarily evaluate the formulation improvement advantages of HHK001. HHK001 is an improved new drug of Enantone; both are leuprorelin acetate microspheres for injection, belonging to the pharmacological class of gonadotropin-releasing hormone (GnRH) agonists. Through optimization of the microsphere formulation process, HHK001 is expected to provide a smoother drug release profile with a longer dosing interval (expected to be extendable to 8 weeks).
Approximately 20 patients will be randomized in a 1:1 ratio to the HHK001 group or the Enantone group (10 participants per group). Participants receive a single subcutaneous injection of 3.75 mg of the assigned study drug at the lower edge of the deltoid muscle of the upper arm (left or right side) on Day 1 to Day 5 of the menstrual period. The screening period is up to 8 weeks; the post-dose blood sampling/follow-up period is 6 weeks for the Enantone group (through Day 42) and 10 weeks for the HHK001 group (through Day 70).
Assessments include pharmacokinetic blood sampling (dense sampling on Day 1; sparse sampling on Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, 42, 49, 57, 63, and 70), pharmacodynamic evaluation (estradiol levels), safety evaluations (adverse events, vital signs, physical examination, laboratory tests, electrocardiogram, and bone mineral density), and preliminary efficacy evaluation (overall pain Visual Analog Scale score).
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
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Voluntarily sign the informed consent form;
- •Female, aged 18-45 years, body weight >= 40 kg, body mass index 19-28 kg/m2;
- •The most recent menstrual cycle before screening is 21-35 days;
- •Diagnosed with endometriosis (previously diagnosed by histopathology, or confirmed by ultrasound or magnetic resonance imaging during screening); participants with concomitant adenomyosis or uterine fibroids are eligible; and assessed by the investigator as suitable for GnRH agonist therapy (no other therapeutic interventions allowed from the start of screening [except rescue medication]);
- •Cervical cytology (TCT/LCT) result shows no intraepithelial lesion or malignancy (NILM) [results from this study center within 1 year before screening are acceptable];
- •No plans for childbearing, oocyte cryopreservation, or oocyte donation from the start of screening until 3 months after dosing, and agreement to use effective contraception (complete abstinence, barrier methods, or non-medicated intrauterine device; no contraceptive medications allowed).
排除标准
- •Allergy to GnRH agonists/antagonists (e.g., leuprorelin, triptorelin, goserelin, cetrorelix, ganirelix, degarelix), or a history of allergy to >= 3 substances, or currently in an allergic state;
- •Contraindications to the rescue medication (ibuprofen) (e.g., allergy to non-steroidal anti-inflammatory drugs, active peptic ulcer, or other conditions assessed by the investigator as contraindications);
- •Current or previous osteoporosis/osteopenia, pituitary tumor, epilepsy, depressive disorder, thromboembolic events (e.g., myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary embolism), malignant tumors, abnormal uterine bleeding of unknown nature, or other conditions assessed by the investigator as unsuitable for this trial (e.g., diseases with acute/chronic pain, coagulation disorders, mental disorders, and various severe or unstable diseases);
- •Receipt of GnRH agonists/antagonists (including investigational products in clinical trials) within 12 weeks before screening or during screening;
- •Receipt of medications that may significantly affect hypothalamic-pituitary-gonadal axis hormone levels within 4 weeks before screening or during screening, such as estrogens/progestins/androgens and their derivatives/receptor modulators, aromatase inhibitors, etc.;
- •Receipt of traditional Chinese medicine for endometriosis within 4 weeks before screening or during screening;
- •Last treatment with an investigational product (drug or device) in a previous clinical trial <= 4 weeks before screening (or <= 12 weeks or 5 half-lives for therapeutic biological products, whichever is longer), or not yet withdrawn from another interventional clinical trial before enrollment;
- •Previous surgery of the hypothalamus or pituitary gland;
- •Any surgery within 4 weeks before screening or during screening (except endometriosis-related surgery), or planned surgery or invasive procedures after enrollment;
- •History of miscarriage within 4 weeks before screening or during screening;
- •Screening examination results meeting any of the following: systolic blood pressure >= 160 mmHg, diastolic blood pressure >= 100 mmHg, platelet count <= 90 x 10^9/L, hemoglobin <= 80 g/L, alanine aminotransferase >= 2 x ULN, aspartate aminotransferase >= 2 x ULN, total bilirubin >= 1.5 x ULN, serum creatinine >= 1.5 x ULN, glycated hemoglobin (HbA1c) >= 8.0%, Z-score <= -2.0 at any site on dual-energy X-ray absorptiometry, hepatitis B surface antigen positive with HBV DNA > ULN, hepatitis C virus antibody positive, human immunodeficiency virus antibody positive, or positive syphilis serology;
- •Abnormal skin at the proposed injection sites (left and right upper arms) that affects dosing or assessment of injection site reactions (e.g., skin lesions, rashes);
- •Acute blood loss or blood donation >= 400 mL within 4 weeks before screening or during screening, or planned blood donation after enrollment;
- •History of blood phobia, needle phobia, or difficult venous blood collection;
- •History of alcohol dependence, drug abuse, or drug addiction;
- •Pregnancy or lactation, or positive pregnancy test;
- •Other conditions assessed as unsuitable for participation in this trial.
研究组 & 干预措施
HHK001
Participants receive a single subcutaneous injection of HHK001 (Leuprorelin Acetate Microspheres for Injection) 3.75 mg at the lower edge of the deltoid muscle of the upper arm on Day 1 to Day 5 of the menstrual period. Post-dose blood sampling and follow-up last 10 weeks (through Day 70). Approximately 10 participants.
干预措施: HHK001 (Leuprorelin Acetate Microspheres for Injection) (Drug)
Enantone
Participants receive a single subcutaneous injection of Enantone (Leuprorelin Acetate Microspheres for Injection) 3.75 mg at the lower edge of the deltoid muscle of the upper arm on Day 1 to Day 5 of the menstrual period. Post-dose blood sampling and follow-up last 6 weeks (through Day 42). Approximately 10 participants.
干预措施: Enantone (Leuprorelin Acetate Microspheres for Injection) (Drug)
结局指标
主要结局
Maximum Plasma Concentration (Cmax) of Leuprorelin
时间窗: Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only)
Cmax of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of Leuprorelin
时间窗: Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only)
AUC0-t of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.
Area Under the Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Leuprorelin
时间窗: Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only)
AUC0-inf of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.
次要结局
- Time to Maximum Plasma Concentration (Tmax) of Leuprorelin(Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only))
- Elimination Half-Life (t1/2) of Leuprorelin(Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only))
- Apparent Clearance (CL/F) of Leuprorelin(Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only))
- Apparent Volume of Distribution (Vd/F) of Leuprorelin(Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only))
- Area Under the Curve From Time Zero to 7 Days (AUC0-7d) of Leuprorelin(Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only))
- Area Under the Curve From Time Zero to 28 Days (AUC0-28d) of Leuprorelin(Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only))
- Area Under the Curve From 28 Days to 56 Days (AUC28d-56d) of Leuprorelin(Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only))
- Area Under the Curve From Time Zero to 56 Days (AUC0-56d) of Leuprorelin(Pre-dose on Day 1 and post-dose sampling: Day 1 (dense sampling), Days 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); additional sampling on Days 49, 57, 63, and 70 (HHK001 group only))
- Estradiol (E2) Concentration at Each Assessment Time Point(Baseline (pre-dose) and post-dose assessment visits on Days 1, 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); Days 49, 57, 63, and 70 (HHK001 group only))
- Estradiol Castration Rate(Days 21, 29, 35, 42, 49, 57, 63, and 70 post-dose (Days 49-70: HHK001 group only))
- Estradiol Moderate Suppression Rate(Days 21, 29, 35, 42, 49, 57, 63, and 70 post-dose (Days 49-70: HHK001 group only))
- Adverse Events and Serious Adverse Events(From signing of informed consent through study completion (up to Day 70 in the HHK001 group / Day 42 in the Enantone group))
- Change From Baseline in Body Temperature(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Number of Participants With Clinically Significant Abnormal Laboratory Test Results(Screening (baseline); Days 14 and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Heart Rate Measured by 12-Lead Electrocardiogram(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Number of Participants With Clinically Significant Abnormal Findings Identified by Investigator-Conducted Physical Examination(Screening (baseline); Days 14 and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Lumbar Spine Bone Mineral Density(Screening (baseline); Day 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Overall Pain Visual Analog Scale (VAS) Score(Screening (Day -35 to Day -1), Day 29 (both groups), and Day 57 (HHK001 group only))
- Change From Baseline in Estradiol (E2) Concentration(Baseline (pre-dose) and post-dose assessment visits on Days 1, 2, 3, 5, 8, 11, 14, 21, 25, 29, 35, and 42 (both groups); Days 49, 57, 63, and 70 (HHK001 group only))
- Change From Baseline in Systolic Blood Pressure(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Diastolic Blood Pressure(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Pulse Rate(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Respiratory Rate(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in PR Interval Measured by 12-Lead Electrocardiogram(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in QRS Interval Measured by 12-Lead Electrocardiogram(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in QT Interval Measured by 12-Lead Electrocardiogram(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in QTcF Interval Measured by 12-Lead Electrocardiogram(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Number of Participants With Clinically Significant Abnormal 12-Lead Electrocardiogram Findings(Screening; Day 1 (within 3 hours pre-dose and 2 hours ±30 minutes post-dose); Days 2, 8, 14, and 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Lumbar Spine Z-Score(Screening (baseline); Day 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Femoral Neck Bone Mineral Density(Screening (baseline); Day 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
- Change From Baseline in Femoral Neck Z-Score(Screening (baseline); Day 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.)
研究者
Guoping Yang
Professor of Clinical Pharmacology
The Third Xiangya Hospital of Central South University