Evaluation of the Safety and Efficacy of Eneboparatide (AZP-3601) in Patients With Chronic Hypoparathyroidism

Study Overview
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Brief Summary
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This study is investigating the safety and efficacy of eneboparatide (AZP-3601) in patients with chronic hypoparathyroidism (cHP). During the first 24 weeks of the trial, participants will be randomized to receive eneboparatide or placebo. Study treatment is blinded: patients and doctors will not know which group each patient has been randomized to. All patients will start with a fixed dose of study treatment (eneboparatide or placebo), administered subcutaneously with a pre-filled pen. Study treatment will be individually titrated. After completion of the first 24 weeks, patients will be treated in the open label extension part of the study for 28 weeks. During this phase, all patients (including patients that were in the placebo group) will receive eneboparatide.

Official Title
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A Phase 3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Efficacy and Safety of Eneboparatide (AZP-3601), a Parathyroid Hormone Receptor Agonist, in Patients With Chronic Hypoparathyroidism (CALYPSO)

Conditions
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Chronic Hypoparathyroidism, Endocrine System Diseases, Parathyroid Diseases

Intervention / Treatment
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* Combination Product: eneboparatide
* Combination Product: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and Females, 18-80 years of age Patients with cHP for ≥12 months at the time of screening Two paired measurements of showing low parathyroid hormone (PTH) and serum calcium either below normal or within normal under standard of care Requirement for therapy with calcitriol ≥0.5 mcg per day or alphacalcidol ≥1 mcg per day, and requirement for supplemental oral calcium treatment ≥1000 mg per day over and above patient's dietary calcium intake at Day 1 visit Successful completion of the Optimization period based on two consecutive measurements of albumin-adjusted serum calcium at least 1 week apart within the range of 7.8 to 9.0 mg/dL and with no more than 25% of change in the daily dose of any of active vitamin D and oral calcium supplements between the two measurements Thyroid-stimulating hormone (TSH) within the lower limit of normal and 1.5-fold of the upper limit of normal at screening; if on suppressive therapy for a history of thyroid cancer, TSH level must be ≥0.2 mIU/mL and thyroid medication should be stable for at least 6 weeks prior to treatment Prior to start of treatment: Magnesium level within laboratory normal limits 25(OH) vitamin D levels of 30-70 ng/mL (75-175 nmol/L) eGFR ≥30 mL/min/1.73m² during screening Able to perform daily subcutaneous self-injections of study drug (or have a designee to perform injections) via a pre-filled injection pen Female patients of non-childbearing potential or using an effective method of contraception throughout the study. Women of childbearing potential should have a negative pregnancy test. Able and willing to provide written and signed informed consent in accordance with GCP Exclusion Criteria: Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation Clinically significant abnormal values at screening for hematology, clinical chemistry, coagulation or urinalysis Abnormal arterial pressure at screening, defined as (1) systolic blood pressure <100 mmHg, or (2) systolic blood pressure >150 mmHg, and/or diastolic blood pressure >100 mmHg. Heart rate at rest outside the range of 50-100 beats/minute at screening Clinically significant abnormal standard 12-lead electrocardiogram indicative of severe cardiac disease Known history of autosomal-dominant hypocalcemia or known pseudohypoparathyroidism (impaired responsiveness to PTH) Any current disease (other than hypoparathyroidism) that might affect calcium metabolism, calcium-phosphate homeostasis or PTH levels Patients with increased risk for osteosarcoma Current uncontrolled active disease processes that may adversely affect gastrointestinal absorption History of cerebrovascular accident within 6 months prior to screening History of active uncontrolled malignancy over the past 2 years at time of screening History of any other cancer other than thyroid cancer (except basal cell skin cancer or squamous cell skin cancer) who have not been disease-free for a period of at least 2 years at the time of screening Acute gout <2 months prior to screening Dependent on parenteral calcium infusions to maintain calcium homeostasis Use of medications such as loop and thiazide diuretics, raloxifene hydrochloride, lithium, methotrexate, cardiac glycosides or systemic corticosteroids within 4 weeks prior to start of treatment Previous treatment with PTH/parathyroid hormone-related protein-like drugs, including PTH(1-84) and PTH(1-34) within 3 months of screening Use of other drugs known to influence calcium and bone metabolism within 4 weeks of screening Use of oral bisphosphonates within 6 months of screening or intravenous bisphosphonate within 12 months of screening Use of denosumab within 18 months of screening Seizure disorder/epilepsy with history of a seizure within 6 months of screening History of symptomatic urinary tract calculi within 3 months of screening Irradiation to the skeleton within 2 years of screening Pregnant or breastfeeding female patients Participation in any other interventional study in which the patient received an investigational drug or device within 2 months or within 5 times the half-life of the investigational drug (whichever comes first) prior to screening Any disease or condition that, in the opinion of the investigator, may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the study treatment or procedures, including treated malignancies that are likely to recur within the approximate duration of the trial Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule Known allergy or sensitivity to PTH or any of the excipients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo-controlled, double-blind study, with patients randomized in a 2:1 ratio to receive eneboparatide or placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: eneboparatide<br>Starting dose of 20 mcg; Administered once daily by subcutaneous injection | Combination Product: eneboparatide<br>* Supplied as a solution (concentration of 250 mcg/mL or 500 mcg/mL) in single-patient-use prefilled pens<br>* Other names: AZP-3601;|
| Placebo Comparator: Placebo<br>Administered once daily by subcutaneous injection | Combination Product: Placebo<br>* Placebo is supplied as a solution (containing the excipient solution for eneboparatide) in single-patient-use prefilled pens<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Primary Endpoint | After 24 weeks of treatment, the proportion of patients in the eneboparatide treatment group vs. placebo: Achieving complete independence from active vitamin D; Achieving independence from therapeutic doses of oral calcium (i.e. taking oral elemental calcium supplements ≤600 mg/day); and With albumin-adjusted serum calcium within the normal range (8.3 to 10.6 mg/dL). | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypercalciuria | Proportion of patients who had hypercalciuria at baseline and normalize 24-hour urinary calcium excretion level (i.e., achieve <250 mg/24 hours for females or <300 mg/24 hours for males) | 24 weeks | 
| Change from baseline in the HPT-DD-SE - Physical Domain score | Change from baseline in patient's symptoms, as assessed by the average weekly HPT-DD-SE physical domain score in the eneboparatide treatment group vs. placebo | 24 weeks | 
| Change from baseline in the HPT-DD-SE - Cognitive Domain score | Change from baseline in patient's symptoms, as assessed by the average weekly HPT-DD-SE cognitive domain score in the eneboparatide treatment group vs. placebo | 24 weeks | 
| Change from baseline in the HPT-LIQ - Physical Functioning Domain score | Change from baseline in the HPT-LIQ Physical Functioning domain score, in the eneboparatide treatment group vs. placebo | 24 weeks | 
| Change from baseline in the SF-36 Physical Functioning subscore | Change from baseline in the SF-36 Physical Functioning subscore in the eneboparatide treatment group vs. placebo | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoparathyroidism