A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH in Adults With Hypoparathyroidism

Study Overview
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Brief Summary
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During the first four weeks of the trial, participants will be randomly assigned to one of four groups: three groups will receive fixed doses of TransCon PTH and one group will receive placebo. TransCon PTH or placebo will be administered as a subcutaneous injection using a pre-filled injection pen. Neither trial participants nor their doctors will know who has been assigned to each group. After the four weeks, participants will continue in the trial as part of a long-term extension study. During the extension, all participants will receive TransCon PTH, with the dose adjusted to their individual needs. This is a global trial that will be conducted in, but not limited to, the United States, Canada, Germany, Denmark, and Norway.

Official Title
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PaTH Forward: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial With an Open-Label Extension, Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Subcutaneously Daily in Adults With Hypoparathyroidism

Conditions
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Hypoparathyroidism, Endocrine System Diseases, Parathyroid Diseases

Intervention / Treatment
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* Combination Product: TransCon PTH
* Combination Product: Placebo for TransCon PTH


Participation Criteria
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Eligibility 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. On a stable dose for at least 12 weeks (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. 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. 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. 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 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. 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 (see Appendix 7) 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. 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.

Ages Eligible for Study
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Minimum Age: 18 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: Double-blind, placebo controlled, parallel group with subjects randomized into 4 treatment groups (1:1:1:1): Transcon PTH 15 mcg/day, TransCon PTH 18 mcg/day, TransCon PTH 21 mcg/day, placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TransCon PTH 15 mcg<br>TransCon PTH 15 mcg delivered once daily by subcutaneous injection | Combination Product: TransCon PTH<br>* TransCon PTH drug product is supplied as a clear solution containing TransCon PTH with a nominal PTH(1-34) content of 0.3 mg/mL in a pre-filled pen intended for subcutaneous injection.<br>|
| Experimental: TransCon PTH 18 mcg<br>TransCon PTH 18 mcg delivered once daily by subcutaneous injection | Combination Product: TransCon PTH<br>* TransCon PTH drug product is supplied as a clear solution containing TransCon PTH with a nominal PTH(1-34) content of 0.3 mg/mL in a pre-filled pen intended for subcutaneous injection.<br>|
| Experimental: TransCon PTH 21 mcg<br>TransCon PTH 21 mcg delivered once daily by subcutaneous injection | Combination Product: TransCon PTH<br>* TransCon PTH drug product is supplied as a clear solution containing TransCon PTH with a nominal PTH(1-34) content of 0.3 mg/mL in a pre-filled pen intended for subcutaneous injection.<br>|
| Placebo Comparator: Placebo<br>Placebo mimicking 15, 18, or 21 mcg of TransCon PTH delivered once daily by subcutaneous injection | Combination Product: Placebo for TransCon PTH<br>* Placebo is supplied as a clear solution containing the formulation buffer for TransCon PTH in a pre-filled pen intended for subcutaneous injection.<br>|
| Experimental: Open-Label Extension Period<br>Subjects who complete the four-week blinded period are assigned to open-label treatment with TransCon PTH for up to 262 weeks, with up to an initial 14 weeks of TransCon PTH titration and standard of care optimization, followed by approximately 248 weeks of individualized dosing. | Combination Product: TransCon PTH<br>* TransCon PTH drug product is supplied as a clear solution containing TransCon PTH with a nominal PTH(1-34) content of 0.3 mg/mL in a pre-filled pen intended for subcutaneous injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Primary Endpoint During the Blinded Period | The percentage of subjects with albumin-adjusted serum calcium within the normal range, and spot morning fractional excretion of calcium (spot AM FECa) within normal range (≤2%) or a reduction by at least 50% from baseline, and not taking active vitamin D supplements, and taking ≤1000 mg/day of calcium supplements | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Key Secondary Endpoint During the Blinded Period | The percentage of subjects with albumin-adjusted serum calcium within the normal range, and spot AM FECa within the normal range (≤2%) or a reduction by at least 50% from baseline, and not taking active vitamin D supplements, and taking ≤ 500 mg/day of calcium supplements | Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoparathyroidism, Parathyroid Hormone, PTH(1-34), Prodrug, Sustained Release, TransCon PTH, Parathyroid Hormone Replacement Therapy