Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Eneboparatide (AZP-3601) Efficacy and Safety in Chronic Hypoparathyroidism Patients
- Trial ID
- 2022-503126-12-01
- Protocol
- AZP-3601-CLI-002
- Sponsor
- Alexion Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 3 multicenter, randomized, placebo-controlled, double-blind study is to evaluate the **efficacy** of a daily treatment with eneboparatide for 24 weeks compared to placebo in patients with chronic **hypoparathyroidism**. The primary focus is on assessing the impact on therapeutic doses of active vitamin D and oral calcium, as well as on serum calcium levels. This is clinically relevant as it addresses the management of calcium homeostasis, a critical concern in hypoparathyroidism, potentially improving patient outcomes and quality of life.
Secondary objectives include: - Demonstrating the efficacy of eneboparatide on 24-hour urinary calcium excretion in patients with hypercalciuria at baseline. - Evaluating the impact on patients' physical symptoms using the HPT DD-SE questionnaire, a disease-specific patient-reported outcome (PRO). - Assessing health-related physical functioning through the HPT LIQ, another disease-specific PRO. - Comparing health-related physical functioning using the SF-36 survey. These secondary objectives aim to provide a comprehensive understanding of the treatment's impact on various aspects of patient health and quality of life, further supporting its potential therapeutic benefits.
Participants
The clinical trial involves a total of **93 participants** diagnosed with **hypoparathyroidism**. The study population includes both male and female subjects, aged between 18 and 80 years. Participants were selected based on specific inclusion criteria, ensuring they have chronic hypoparathyroidism for at least 12 months, documented low parathyroid hormone levels, and a requirement for specific therapeutic doses of active vitamin D and oral calcium. The trial population is characterized by their ability to perform daily subcutaneous self-injections or have a designee perform the injection. Lifestyle considerations include adherence to a stable dose of thyroid medication if applicable, and maintaining serum magnesium and vitamin D levels within specified limits. The study also includes vulnerable populations, with participants required to comply with effective contraceptive measures if of childbearing potential. The selection process ensures that participants meet the necessary health criteria to evaluate the efficacy of eneboparatide treatment over a 24-week period.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of eneboparatide (AZP-3601), a parathyroid hormone receptor agonist, in patients with chronic **hypoparathyroidism**. The trial is structured to include a main treatment period of 24 weeks, during which the primary efficacy objective is to demonstrate the effectiveness of daily eneboparatide treatment compared to placebo on therapeutic doses of active vitamin D, oral calcium, and serum calcium levels. The trial is expected to conclude by March 2027, with recruitment starting in December 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, medical history, and current health status. Following successful screening, participants will enter the optimization period, where their serum calcium levels will be stabilized. The main treatment period will involve regular follow-up visits to monitor efficacy and safety endpoints, including independence from active vitamin D and oral calcium, and normalization of serum calcium levels. The end-of-study visit will occur after 24 weeks of treatment, where final assessments will be conducted.
The expected length of participant involvement is approximately 6 months, including the screening, optimization, and treatment periods. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of several treatments, including **AZP-3601**, a solution for injection in a pre-filled pen. This experimental medication contains the active substance **[ALA1,3,12,GLN10,ARG11,TRP14]PTH(1-14)/[ALA18,22, LYS26]PTHRP(15-36)COOH**, also known as Eneboparatide. It is administered via **subcutaneous use**. The treatment period for AZP-3601 is up to 156 days, with a dosing schedule that is determined by the study protocol. The medication is provided by AMOLYT PHARMA and is classified as an orphan drug, with the designation number EU/3/22/2577. Participant compliance is monitored through the use of pre-filled pens, ensuring accurate dosing and administration.
Another treatment used in the study is **UN-ALFA 0,50 microgramme**, a soft capsule containing the active substance **alfacalcidol**. This medication is administered orally, with a maximum daily dose of 1 microgram and a total dose amount of 434 micrograms over a treatment period of 62 days. The capsules are manufactured by CHEPLAPHARM ARZNEIMITTEL GMBH and are used as an auxiliary treatment in the trial.
**CALCIUM ARROW 500 mg** is also included in the study as an auxiliary treatment. This medication is a tablet containing **calcium carbonate** and is administered orally. The maximum daily dose is 7800 milligrams, with a total dose amount of 3385 grams over the same 62-day treatment period. The tablets are produced by ARROW GENERIQUES.
Additionally, the study includes the use of **ROCALTROL 0,25 microgramme**, a soft capsule containing the active substance **calcitriol**. This medication is administered orally, with a maximum daily dose of 1 microgram and a total dose amount of 434 micrograms over 62 days. ROCALTROL is provided by ATNAHS PHARMA NETHERLANDS B.V. and serves as an auxiliary treatment in the trial.
A **placebo** is also utilized in the study, specifically for the AZP-3601 Pen A and Pen B. The placebo is designed to mimic the appearance and administration route of the experimental medication but contains no active substance. It is used to maintain the double-blind nature of the trial, ensuring unbiased results when comparing the efficacy and safety of AZP-3601 against the placebo.
Efficacy
The efficacy of eneboparatide (AZP-3601) in patients with chronic **hypoparathyroidism** will be assessed through a series of primary and secondary endpoints over a 24-week treatment period. The primary efficacy endpoint will evaluate the proportion of patients achieving complete independence from active vitamin D, independence from therapeutic doses of oral calcium (≤600 mg/day), and maintaining albumin-adjusted serum calcium within the normal range (8.3 to 10.6 mg/dL) in the eneboparatide treatment group compared to placebo.
Secondary efficacy endpoints will include several key measures at week 24. These will assess the normalization of 24-hour urinary calcium excretion levels in patients with baseline hypercalciuria, changes from baseline in patient symptoms using the HPT DD-SE core physical symptoms scale, and changes in the HPT-LIQ Physical Functioning domain score. Additionally, changes in the SF-36 Physical Functioning subscore will be evaluated. Further secondary endpoints will examine the proportion of patients achieving independence from active vitamin D and oral calcium, as well as maintaining normal serum calcium levels during the fixed dose period. Changes from baseline in 24-hour urinary calcium collection will also be assessed, particularly for patients with baseline hypercalciuria.
Inclusion and Exclusion Criteria
Inclusion Criteria
- (MT) Male or female patients, aged 18 to 80 years, inclusive at screening;
- (MT) Patients with cHP for at least 12 months at screening, documented on medical records
- (MT) Prior to start of study treatment, two paired serum calcium/serum parathyroid hormone (PTH) values, showing low PTH levels (<20 pg/mL), and albumin adjusted serum calcium or ionized serum calcium either: a) Below the lower limit of normal (LLN) value of the laboratory; or b) Within the normal range of the laboratory under standard of care. Note: At least one of the two paired serum calcium/serum PTH values should have been measured within the last 12 months preceding start of treatment;
- (MT) Requirement for therapy with calcitriol ≥0.5 μg per day or alphacalcidol ≥1 μg per day, and requirement for supplemental oral (elemental) calcium treatment ≥1000 mg per day over and above patient’s dietary calcium intake at Day 1 visit;
- (MT) 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;
- (MT) Either of the following: a) If on suppressive therapy for thyroid cancer, serum thyroid stimulating hormone (TSH) level should be >0.2 µIU/mL at screening and the dose of thyroid medication should be stable for at least 6 weeks prior to start of treatment; b) In other cases, serum TSH should be within the LLN and 1.5 fold upper limit of normal (ULN) at screening;
- (MT) Serum magnesium levels within laboratory normal limits prior to start of treatment;
- (MT) Serum 25hydroxy vitamin D level >30ng/mL and <70ng/mL (75 to 175nmol/L) prior to start of treatment;
- (MT) Estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration formula) ≥30 mL/minute/1.73 m² on two separate measurements with at least one recent value (i.e. at Screening visit or during the Optimization period);
- (MT) Patient able to perform daily SC self-injections of study treatment in the abdomen (or have a designee perform the injection) using a pre filled injection pen;
- (MT) a) Female patients may be of non-childbearing potential (i.e. post menopausal [absence of menstrual bleeding for 1 year prior to screening, without any other medical reason], hysterectomy or bilateral oophorectomy), or of childbearing potential. Women of childbearing potential (WOCBP) must agree to a true abstinence (when in line with the preferred and usual lifestyle of the patient) or to use an highly effective method of contraception throughout the study and for 30 days after the end of the treatment; b) For male patients: their WOCBP partner must use a highly effective method of contraception throughout the study and for 30 days after the end of the treatment;
- (MT) Negative pregnancy test at screening and at Day 1 visit for WOCBP;
- (MT) Willing and able to sign the Informed Consent Form and to comply with the requirements of the study protocol.
Exclusion Criteria
- (MT) Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation;
- (MT) Clinically significant abnormal values at screening for hematology, clinical chemistry, coagulation or urinalysis, as judged by the Investigator;
- (MT) Abnormal arterial pressure at the time of screening, defined here as either: a) Symptomatic hypotension or systolic blood pressure (SBP) <100 mmHg; or b) SBP >150 mmHg and/or diastolic blood pressure (DBP) >100 mmHg;
- (MT) Heart rate at rest outside the range of 50 to 100 beats/minute at screening;
- (MT) Clinically significant abnormal standard 12-lead electrocardiogram (ECG, after resting for at least 5 minutes in supine position) indicative of severe cardiac disease, at screening, as judged by the Investigator;
- (MT) Known history of autosomal-dominant hypocalcemia (resulting from gainoffunction calcium-sensing receptor or guanine nucleotide binding protein, alpha-11 mutations) or known pseudohypoparathyroidism (impaired responsiveness to PTH);
- (MT) Any current disease that might affect calcium metabolism, calcium phosphate homeostasis or PTH levels, other than hypoparathyroidism;
- (MT) Patients with increased risk for osteosarcoma;
- (MT) Current uncontrolled active disease processes that may adversely affect gastrointestinal absorption;
- (MT) History of cerebrovascular accident within 6 months prior to screening;
- (MT) Patients with active uncontrolled malignancy over the past 2 years at the time of screening;
- (MT) Patients with a history of any other cancer 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;
- (MT) Acute gout <2 months prior to screening;
- (MT) Patients dependent on parenteral calcium infusions (e.g. calcium gluconate) to maintain calcium homeostasis;
- (MT) Use of medications such as loop and thiazide diuretics, raloxifene hydrochloride, lithium, methotrexate, cardiac glycosides (e.g. digoxin or digitoxin) or systemic corticosteroids within 4 weeks prior to start of treatment;
- (MT) Previous treatment with PTH/parathyroid hormone-related protein-like drugs, including PTH(1-84) and PTH(1-34) within 3 months prior to screening;
- (MT) Use of Other drugs known to influence calcium and bone metabolism within 4 weeks prior to screening;
- (MT) Use of oral bisphosphonates within 6 months prior to screening or intravenous bisphosphonate preparations within 12 months prior to screening;
- (MT) Use of denosumab within 18 months prior to screening;
- (MT) Seizure disorder/epilepsy with a history of a seizure within 6 months prior to screening;
- (MT) History of symptomatic urinary tract calculi within 3 months prior to screening;
- (MT) Irradiation to the skeleton within 2 years prior to screening;
- (MT) Pregnant or breastfeeding female patients;
- (MT) Participation in any other interventional study in which the patient received an investigational drug or device study within 2 months (or within 5 times the half-life of the investigational drug [whichever comes first]) prior to screening;
- (MT) Any disease or condition that, in the opinion of the Investigator, may require treatment or make the patient unlikely to fully complete the study, 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 study;
- (MT) Any other reason that in the opinion of the Investigator would prevent the patient from completing participation or following the study schedule;
- (MT) Known allergy or sensitivity to PTH, ingredients in the study treatment (eneboparatide or placebo), oral calcium supplements, or vitamin D supplements.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Dec 2023 | 3 |
 Denmark | Not Recruiting | 01 Dec 2023 | 13 |
 France | Not Recruiting | 01 Dec 2023 | 12 |
 Germany | Not Recruiting | 01 Dec 2023 | 3 |
 Hungary | Not Recruiting | 01 Dec 2023 | 15 |
 Italy | Not Recruiting | 01 Dec 2023 | 21 |
 The Netherlands | Not Recruiting | 01 Dec 2023 | — |
 Poland | Not Recruiting | 01 Dec 2023 | 20 |
 Portugal | Not Recruiting | 01 Dec 2023 | 9 |
 Spain | Not Recruiting | 01 Dec 2023 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CALCIUM ARROW 500 mg, comprimé à sucer | Other | COMPRIMÉ À SUCER | ORAL USE | 7800 | 62 | PRD5037951 |
Placebo for AZP-3601 Pen A and Pen B | Placebo | N/A | — | — | — | N/A |
ROCALTROL 0,25 microgramme, capsule molle | Other | CAPSULE MOLLE | ORAL USE | 1 | 62 | PRD8935524 |
UN-ALFA 0,50 microgramme, capsule molle | Other | CAPSULE MOLLE | ORAL USE | 1 | 62 | PRD8824401 |
Eneboparatide | Test | SOLUTION FOR INJECTION IN PRE-FILLED PEN | SUBCUTANEOUS USE | 0 | 156 | PRD13957585 |
Eneboparatide | Test | SOLUTION FOR INJECTION IN PRE-FILLED PEN | SUBCUTANEOUS USE | 0 | 156 | PRD13957588 |