Evaluation of Subcutaneous Palopegteriparatide in Adults with Hypoparathyroidism: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2024-512967-29-00
Protocol: TransCon PTH TCP-201
Sponsor: Ascendis Pharma Bone Diseases A/S

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Diseases & Conditions

Hypoparathyroidism

Objectives

The primary objective of this study is to evaluate the **effectiveness** of daily TransCon PTH on serum and urine calcium levels (FECa) and active vitamin D and calcium doses after 4 weeks of treatment in adults with **hypoparathyroidism**. This is clinically relevant as it aims to address the management of calcium and vitamin D homeostasis, which is crucial for patients with this condition.

Secondary objectives include:

Assessing the **safety** and tolerability of daily TransCon PTH.
Evaluating the effectiveness of TransCon PTH on serum and urine calcium levels (FECa) and active vitamin D and calcium doses during the extension period.
Assessing the treatment effect on daily pill burden of vitamin D and calcium.
Evaluating the treatment effect on serum phosphate, serum magnesium, and calcium x phosphate product (sCa x sP product).
Assessing the treatment effect on symptoms of hypocalcemia and hypercalcemia, emergency room visits, and hospitalizations.
Evaluating anti-PTH and anti-PEG antibody responses.

Participants

The clinical trial involves a total of **38 participants** diagnosed with **hypoparathyroidism (HP) in adults**. The study population includes both **males and females aged 18 years and older**. Participants are required to have a stable health status, specifically those with postsurgical chronic HP or auto-immune, genetic, or idiopathic HP for at least 26 weeks. The selection criteria ensure that participants are capable of performing daily subcutaneous self-injections of the study drug or have a designee to perform the injection. The trial does not include a vulnerable population. Participants are expected to maintain a stable dose of active vitamin D and calcium supplements prior to the study, with specific target levels for vitamin D, magnesium, and serum calcium. The body mass index (BMI) of participants ranges from 17 to 40 kg/m², and they must have an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73m². Additionally, thyroid-stimulating hormone (TSH) levels must be within normal laboratory limits, and if on thyroid hormone replacement therapy, the dose must be stable for at least 12 weeks prior to the study. The trial population was selected based on these criteria to ensure the safety and reliability of the study outcomes.

Plans and Procedures

The clinical trial is a **Phase 2**, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with an open-label extension. It aims to investigate the safety, tolerability, and efficacy of **TransCon PTH** administered subcutaneously daily in adults with **hypoparathyroidism**. The trial is designed to assess the effectiveness of daily TransCon PTH on serum and urine calcium levels, as well as active vitamin D and calcium doses, over a treatment period of 4 weeks. The study is expected to conclude by March 2025, with recruitment having commenced in October 2019.

Participants will be involved in the study for a maximum treatment period of 266 days. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be adults aged 18 years or older, capable of performing daily subcutaneous self-injections, and having a confirmed diagnosis of chronic hypoparathyroidism for at least 26 weeks. Participants must also be on a stable dose of active vitamin D and calcium supplements prior to screening.

Study visits are structured to ensure comprehensive monitoring and data collection. The screening visit will involve a thorough assessment of eligibility criteria, including laboratory tests and medical history review. Follow-up visits will occur at regular intervals to evaluate the primary and secondary endpoints, such as serum calcium levels and the need for vitamin D and calcium supplementation. The end-of-study visit will finalize data collection and assess the overall impact of the treatment.

Participants may be withdrawn from the study if they experience adverse events that compromise their safety, fail to comply with study procedures, or if the investigator deems it necessary for any other reason. The trial's primary endpoint is the proportion of subjects achieving normal albumin-adjusted serum calcium levels and reduced calcium excretion without the need for active vitamin D supplements at 4 weeks. Secondary endpoints include similar measures with adjusted criteria for calcium supplementation.

Treatment

The clinical trial involves the administration of **TransCon PTH**, an experimental medication designed for the treatment of **hypoparathyroidism**. The active substance in TransCon PTH is **palopegteriparatide**, a synthetically manufactured peptide classified under the origin of "Protein - Other." The pharmaceutical form of TransCon PTH is a solution for injection, provided in a pre-filled pen. The medication is administered subcutaneously, with a maximum daily dose of 60 micrograms. The treatment period extends up to 266 days. The pre-filled pen is available in three different dosages: 168 µg PTH(1-34)/0.56 mL, 294 µg PTH(1-34)/0.98 mL, and 420 µg PTH(1-34)/1.4 mL. The administration of TransCon PTH is conducted daily, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.

In addition to the experimental treatment, the study includes a placebo-controlled group to evaluate the efficacy and safety of TransCon PTH. The placebo is administered in a similar manner to the experimental drug, ensuring blinding and maintaining the integrity of the trial. The trial is designed as a randomized, double-blind, parallel-group study with an open-label extension, allowing for comprehensive assessment of the treatment's impact on serum and urine calcium levels, as well as active vitamin D and calcium doses over a 4-week period. The study aims to provide valuable insights into the potential benefits of TransCon PTH for individuals with hypoparathyroidism.

Efficacy

The efficacy of TransCon PTH in the treatment of **Hypoparathyroidism** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is defined as the proportion of subjects who, at 4 weeks of treatment, achieve albumin-adjusted serum calcium (sCa) within the normal range, a spot morning fractional excretion of calcium (FECa) within the normal range (≤2%) or a reduction by at least 50% from baseline, are not taking active vitamin D supplements, and are taking ≤1000 mg/day of calcium supplements.

The key secondary efficacy endpoint will also be evaluated at 4 weeks of treatment. It includes the proportion of subjects with albumin-adjusted sCa within the normal range, FECa within the normal range or a reduction by at least 50% from baseline, not taking active vitamin D supplements, and taking ≤500 mg/day of calcium supplements. These endpoints will be measured using laboratory tests to assess serum and urine calcium levels, as well as the doses of active vitamin D and calcium supplements. The assessments are scheduled to occur at the 4-week mark of the treatment period.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Males and females aged ≥18 years
Subjects with postsurgical chronic HP or auto-immune, genetic, or idiopathic HP for at least 26 weeks. Diagnosis of HP is established based on hypocalcemia in the setting of inappropriately low serum parathyroid hormone (PTH) levels.
On a stable dose* for at least 12 weeks (US only: or 4 weeks if on Natpara as of September 2019) prior to Screening of: − ≥0.25 µg BID of calcitriol (active vitamin D) or ≥0.5 µg BID or ≥1.0 µg daily of alfacalcidol (active vitamin D) and − ≥400 mg BID calcium citrate or carbonate − If subject has a history of hypercalcemia on such doses, subject may be taking <0.25 µg BID of calcitriol, <0.5 µg BID or < 1.0 µg daily of alfacalcidol, or <400 mg BID of calcium citrate or carbonate, with approval of Medical Monitor/Medical Expert *Does not preclude occasional (<3/week) rescue doses of active vitamin D and/or calcium for symptomatic hypocalcemia
Optimization of supplements prior to randomization to achieve the target levels of: − 25(OH) vitamin D levels of 30-70 ng/mL (75-175 pmol/mL) and − Magnesium level within the normal range* and − Albumin-adjusted or ionized serum calcium (sCa) level in the lower half of the normal range *If subject has a history of inability to be successfully managed within the normal range for magnesium level, a level slightly below the normal range is acceptable with approval of the Medical Monitor/Medical Expert
BMI 17-40 kg/m2 at Visit 1
If ≤25 years of age, radiological evidence of epiphyseal closure based on x-ray of non-dominant wrist and hand
eGFR >30 mL/min/1.73m2 during Screening
Thyroid-stimulating hormone (TSH) within normal laboratory limits within the 12 weeks prior to Visit 1; if on suppressive therapy for thyroid cancer, TSH level must be ≥0.2 µIU/mL
If treated with thyroid hormone replacement therapy, the dose must be stable for at least 12 weeks prior to Visit 1
Able to perform daily subcutaneous self-injections of study drug (or have a designee perform injection) via a pre-filled injection pen
Written, signed, informed consent of the subject

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Exclusion Criteria

Known activating mutation in the calcium-sensing receptor (CaSR) gene
Impaired responsiveness to PTH (pseudohypoparathyroidism) which is characterized as PTH-resistance, with elevated PTH levels in the setting of hypocalcemia
Any disease that might affect calcium metabolism or calcium-phosphate homeostasis or PTH levels other than HP, such as active hyperthyroidism; Paget’s disease; hypomagnesemia; type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus; severe and chronic cardiac, liver, or renal disease; Cushing syndrome; rheumatoid arthritis; multiple myeloma; active pancreatitis; malnutrition; rickets; recent prolonged immobility; active malignancy (other than low-risk well differentiated thyroid cancer or basal cell skin cancer); parathyroid carcinoma within 5 years prior to Screening; acromegaly; multiple endocrine neoplasia types 1 and 2
Use of loop diuretics, phosphate binders (other than calcium carbonate/calcium citrate), digoxin, lithium, methotrexate, or systemic corticosteroids (other than replacement therapy)
Use of thiazide diuretic within 4 weeks prior to the Screening 24-hour urine collection or the first dose adjustment of SOC during Screening
Use of PTH-like drugs (whether commercially available or through participation in an investigational trial) including PTH(1-84), PTH(1-34), or other N-terminal fragments or analogs of PTH or PTH-related protein within 12 weeks (US only: 5 weeks) prior to Visit 1
Use of other drugs known to influence calcium and bone metabolism, such as calcitonin, fluoride tablets (> 0.5 mg/day), strontium, or cinacalcet hydrochloride within 12 weeks prior to Visit 1
Use of bisphosphonates (oral or IV) or denosumab within 2 years prior to Visit 1
Non-hypocalcemic seizure disorder with a history of a seizure within 26 weeks prior to Visit 1 NOTE: History of seizures that occur in the setting of hypocalcemia is not exclusionary
Increased risk for osteosarcoma, such as those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, hereditary disorders predisposing to osteosarcoma, or with a prior history of substantial external beam or implant radiation therapy involving the skeleton
Pregnant or lactating women. NOTE: Highly effective contraception is required for sexually active women of childbearing potential during the trial and for 2 weeks after the last dose of study drug, and pregnancy testing will be performed throughout the trial. Sexually active women of childbearing potential who are unwilling to use highly effective contraception are excluded from the trial.
Diagnosis of drug or alcohol dependence within 3 years prior to Visit 1
Disease processes that may adversely affect gastrointestinal absorption including but not limited to short bowel syndrome, bowel resection, gastric bypass, tropical sprue, active celiac disease, active ulcerative colitis, gastroparesis, AIRE gene mutations with malabsorption, and active Crohn’s disease
Chronic or severe cardiac disease within 26 weeks prior to Visit 1 including but not limited to congestive heart failure, myocardial infarction, QTcF >430 msec (males) or >450 msec (females), severe or uncontrolled arrhythmias, bradycardia (resting heart rate <50 beats/minute), symptomatic hypotension, systolic BP <80 mm Hg or diastolic <40 mm Hg, or poorly controlled hypertension (systolic BP >150 mm Hg or diastolic >95 mm Hg)
Cerebrovascular accident within 5 years prior to Visit 1
History of renal colic or acute gout within 52 weeks prior to Visit 1
Any disease or condition that, in the opinion of the investigator, may make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the investigational product or procedures, including treated malignancies that are likely to recur within the approximate 1-year duration of the trial
Known allergy or sensitivity to PTH or any of the excipients [metacresol, mannitol, succinic acid, NaOH/(HCl)]
Participation in another clinical trial in which receipt of investigational drug or device occurred within 8 weeks (or at least 5.5 times the half-life of the investigational drug) prior to Visit 1
Likely to be non-compliant with respect to trial conduct
Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule