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

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).

Inclusion criteria

• 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).

Exclusion criteria

• 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.