A Phase Ia Trial Comparing the Pharmacokinetics/Pharmacodynamics, Safety, and Preliminary Efficacy of HHK001 and Enantone in Patients With Endometriosis

Phase 1Not Yet RecruitingNCT07793162

The Third Xiangya Hospital of Central South University20 enrolled

Overview

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.

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

Interventions

HHK001 (Leuprorelin Acetate Microspheres for Injection)DRUG

HHK001 is an improved formulation of Enantone; both are leuprorelin acetate microspheres for injection, a gonadotropin-releasing hormone (GnRH) agonist. A single dose of 3.75 mg is administered by subcutaneous injection at the lower edge of the deltoid muscle of the upper arm.

Enantone (Leuprorelin Acetate Microspheres for Injection)DRUG

Enantone is leuprorelin acetate microspheres for injection, a gonadotropin-releasing hormone (GnRH) agonist, used as the active comparator. A single dose of 3.75 mg is administered by subcutaneous injection at the lower edge of the deltoid muscle of the upper arm.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 45 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Voluntarily sign the informed consent form; 2. Female, aged 18-45 years, body weight \>= 40 kg, body mass index 19-28 kg/m2; 3. The most recent menstrual cycle before screening is 21-35 days; 4. 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 \[except rescue medication\]); 5. Cervical cytology (TCT/LCT) result shows no intraepithelial lesion or malignancy (NILM) \[results from this study center within 1 year before screening are acceptable\]; 6. 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). Exclusion Criteria: 1. 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; 2. 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); 3. 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); 4. Receipt of GnRH agonists/antagonists (including investigational products in clinical trials) within 12 weeks before screening or during screening; 5. 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.; 6. Receipt of traditional Chinese medicine for endometriosis within 4 weeks before screening or during screening; 7. 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; 8. Previous surgery of the hypothalamus or pituitary gland; 9. Any surgery within 4 weeks before screening or during screening (except endometriosis-related surgery), or planned surgery or invasive procedures after enrollment; 10. History of miscarriage within 4 weeks before screening or during screening; 11. 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; 12. 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); 13. Acute blood loss or blood donation \>= 400 mL within 4 weeks before screening or during screening, or planned blood donation after enrollment; 14. History of blood phobia, needle phobia, or difficult venous blood collection; 15. History of alcohol dependence, drug abuse, or drug addiction; 16. Pregnancy or lactation, or positive pregnancy test; 17. Other conditions assessed as unsuitable for participation in this trial.

Outcomes

Primary Outcomes

Maximum Plasma Concentration (Cmax) of Leuprorelin

Cmax of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Time frame: 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 Last Quantifiable Concentration (AUC0-t) of Leuprorelin

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

AUC0-inf of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Secondary Outcomes

Time to Maximum Plasma Concentration (Tmax) of Leuprorelin

Tmax of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Elimination Half-Life (t1/2) of Leuprorelin

t1/2 of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Apparent Clearance (CL/F) of Leuprorelin

CL/F of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Apparent Volume of Distribution (Vd/F) of Leuprorelin

Vd/F of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Area Under the Curve From Time Zero to 7 Days (AUC0-7d) of Leuprorelin

AUC0-7d of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Area Under the Curve From Time Zero to 28 Days (AUC0-28d) of Leuprorelin

AUC0-28d of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Area Under the Curve From 28 Days to 56 Days (AUC28d-56d) of Leuprorelin

AUC28d-56d of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Area Under the Curve From Time Zero to 56 Days (AUC0-56d) of Leuprorelin

AUC0-56d of leuprorelin in plasma, determined by non-compartmental analysis of concentration-time data.

Estradiol (E2) Concentration at Each Assessment Time Point

Estradiol (E2) concentration measured by the central laboratory at each scheduled assessment time point.

Time frame: 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

Percentage of participants with estradiol (E2) \<= 50 pg/mL.

Time frame: Days 21, 29, 35, 42, 49, 57, 63, and 70 post-dose (Days 49-70: HHK001 group only)

Estradiol Moderate Suppression Rate

Percentage of participants with 30 pg/mL \< estradiol (E2) \<= 50 pg/mL.

Time frame: Days 21, 29, 35, 42, 49, 57, 63, and 70 post-dose (Days 49-70: HHK001 group only)

Adverse Events and Serious Adverse Events

Number, severity, and relationship to study drug of treatment-emergent adverse events, coded using MedDRA by System Organ Class (SOC) and Preferred Term (PT).

Time frame: 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

Change from baseline in body temperature measured according to routine practice at the study site at each scheduled assessment.

Time frame: 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

Number of participants with at least one post-baseline abnormal laboratory test result in hematology, urinalysis, coagulation, or serum chemistry that is assessed by the investigator as clinically significant. Each participant will be counted once regardless of the number of abnormalities.

Time frame: 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

Change from baseline in heart rate measured using a 12-lead electrocardiogram at each scheduled assessment.

Time frame: 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

Number of participants with at least one clinically significant abnormal finding identified by an investigator-conducted physical examination of general appearance, skin and mucosa, lymph nodes, head and neck, chest, abdomen, and spine and extremities. Each participant will be counted once regardless of the number of findings.

Time frame: 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

Change from baseline in lumbar spine bone mineral density measured by dual-energy X-ray absorptiometry.

Time frame: 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

Change from baseline in the overall pain Visual Analog Scale (VAS) score at each assessment time point.

Time frame: Screening (Day -35 to Day -1), Day 29 (both groups), and Day 57 (HHK001 group only)

Change From Baseline in Estradiol (E2) Concentration

Change from baseline in estradiol (E2) concentration measured by the central laboratory at each scheduled post-dose assessment.

Time frame: 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

Change from baseline in systolic blood pressure at each scheduled assessment.

Time frame: 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

Change from baseline in diastolic blood pressure at each scheduled assessment.

Time frame: 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

Change from baseline in pulse rate at each scheduled assessment.

Time frame: 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

Change from baseline in respiratory rate at each scheduled assessment.

Time frame: 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

Change from baseline in PR interval measured using a 12-lead electrocardiogram at each scheduled assessment.

Time frame: 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

Change from baseline in QRS interval measured using a 12-lead electrocardiogram at each scheduled assessment.

Time frame: 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

Change from baseline in QT interval measured using a 12-lead electrocardiogram at each scheduled assessment.

Time frame: 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

Change from baseline in QTcF interval calculated using the Fridericia formula from a 12-lead electrocardiogram at each scheduled assessment.

Time frame: 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

Number of participants with at least one 12-lead electrocardiogram diagnostic finding assessed by the investigator as clinically significant. Each participant will be counted once regardless of the number of findings.

Time frame: 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

Change from baseline in lumbar spine Z-score measured by dual-energy X-ray absorptiometry.

Time frame: Screening (baseline); Day 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.

Change From Baseline in Femoral Neck Bone Mineral Density

Change from baseline in femoral neck bone mineral density measured by dual-energy X-ray absorptiometry.

Time frame: Screening (baseline); Day 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.

Change From Baseline in Femoral Neck Z-Score

Change from baseline in femoral neck Z-score measured by dual-energy X-ray absorptiometry.

Time frame: Screening (baseline); Day 29 (both groups); Day 57 (HHK001 group only); and early withdrawal.

A Phase Ia Trial Comparing the Pharmacokinetics/Pharmacodynamics, Safety, and Preliminary Efficacy of HHK001 and Enantone in Patients With Endometriosis

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts