PaTHway CHINA TRIAL: A Trial to Investigating the Safety, Tolerability and Efficacy of TransCon PTH in Adults With Hypoparathyroidism

Study Overview
=================
Brief Summary
-----------------
This study is limited to conduct in China only. The primary objective is to assess the treatment effect of daily TransCon PTH on serum calcium (sCa) levels within the normal range and stopping from therapeutic doses of active vitamin D (calcitriol) or active vitamin D analogue (alfacalcidol) and calcium at 26 weeks of treatment. All subjects will start with 18 mcg of study drug and will be individually and progressively titrated to an optimal dose over a 26-week double blind period, followed by an open label extension period up to 156 weeks. 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 26 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.

Detailed Description
-----------------
Not Provided

Official Title
-----------------
PaTHway CHINA TRIAL: A Phase 3, 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
-----------------
Hypoparathyroidism, Parathyroid Hormone Deficiency, Endocrine System Diseases, Parathyroid Diseases

Intervention / Treatment
-----------------
* Drug: TransCon PTH
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females, ≥18 years of age Subjects with postsurgical chronic HP, or auto-immune, genetic, or idiopathic HP for at least 26 weeks. Diagnosis of HP is established based on historic hypocalcemia in the setting of inappropriately low (below the ULN of local laboratory) serum PTH levels. Requirement for doses of SoC (e.g., calcitriol, alfacalcidol, calcium supplements) at or above a minimum threshold: • requirement for a dose of calcitriol ≥0.5 μg/day, or alfacalcidol ≥1.0 μg/day and (elemental) calcium ≥800 mg/day (e.g., calcium citrate, calcium carbonate etc.) for at least 12 weeks prior to Screening. In addition, the dose of calcitriol, or alfacalcidol, and calcium should be stable for at least 5 weeks prior to Screening Optimization of supplements prior to randomization to achieve the target serum levels of: 25(OH) vitamin D levels of 10-100 ng/mL (25-250 nmol/L) and Magnesium level in the normal range, or just below the normal range i.e.: ≥1.3 mg/dL (0.53 mmol/L) and Albumin-adjusted sCa level in the normal range, or just below the normal range, i.e.: 7.8-10.6 mg/dL (or 1.95-2.64 mmol/L) The subject demonstrates a 24-hour uCa excretion of ≥125 mg/24h (on a sample collected within 52 weeks prior to Screening or during the Screening Period) BMI 17- 40 kg/m2 at Screening If ≤25 years of age, radiological evidence of epiphyseal closure based on X-ray of non-dominant wrist and hand Thyroid-stimulating hormone (TSH) within normal laboratory limits within the 6 weeks prior to Visit 1; if on suppressive therapy for a history of thyroid cancer, TSH level must be ≥0.2 mIU/L If treated with thyroid hormone replacement therapy, the dose must have been stable for at least 5 weeks prior to Screening eGFR ≥30 mL/min/1.73 m2 during Screening Able to perform daily SC self-injections of study drug (or have a designee to perform injections) via a pre-filled injection pen Able and willing to provide written and signed ICF in accordance with GCP Exclusion Criteria: 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 disease of bone; severe hypomagnesemia; type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus (HbA1C >9%, documented HbA1C result drawn within 12 weeks prior to Screening is acceptable); severe and chronic liver, or renal disease; Cushing syndrome; multiple myeloma; active pancreatitis; malnutrition; rickets; recent prolonged immobility; active malignancy (other than low-risk well differentiated thyroid cancer or non-melanoma skin cancer); active hyperparathyroidism; parathyroid carcinoma within 5 years prior to Screening; acromegaly;or multiple endocrine neoplasia High risk thyroid cancer within 2 years, requiring suppression of TSH <0.2 mIU/L Long term use of loop diuretics, phosphate binders (other than calcium supplements), digoxin, lithium, methotrexate, biotin >30 µg/day, or systemic corticosteroids (other than as replacement therapy) Use of thiazide diuretic within 4 weeks prior to the 24-hour urine collection scheduled to occur within 1 week prior to Visit 1 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 4 weeks prior to Screening 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 Screening Use of osteoporosis therapies known to influence calcium and bone metabolism, i.e., bisphosphonate (oral or intravenous [IV]), denosumab, raloxifene, or romosozumab therapies within 2 years prior to Screening Non-hypocalcemic seizure disorder with a history of a seizure within 26 weeks prior to Screening Increased risk for osteosarcoma, such as those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, 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 Male who has a female partner who intends to become pregnant or is of childbearing potential and is unwilling to use adequate contraceptive methods during the trial Diagnosed drug or alcohol dependence within 3 years prior to Screening Disease processes that adversely affect gastrointestinal absorption, including but not limited to short bowel syndrome, significant small bowel resection, gastric bypass, tropical sprue, active celiac disease, active ulcerative colitis, active Crohn's disease, gastroparesis and AIRE gene mutations with malabsorption Severe cardiac disease within 26 weeks prior to Screening including but not limited to congestive heart failure, myocardial infarction, severe or uncontrolled arrhythmias, bradycardia (resting heart rate <48 beats/minute, unless chronic and asymptomatic), symptomatic hypotension or systolic BP <80 mm Hg or diastolic <40 mm Hg or poorly controlled hypertension (systolic BP >165 mm Hg or diastolic >95 mm Hg). In the absence of a prior history of hypertension, an isolated BP >165/95 mm Hg in the setting of white coat hypertension/anxiety may not be exclusionary and a measurement can be repeated prior to randomization Cerebrovascular accident within 5 years prior to Screening Within 26 weeks prior to Screening: acute colic due to nephrolithiasis, or acute gout. Subjects with asymptomatic renal stones are permitted Participation in any other interventional trial in which receipt of investigational drug or device occurred within 8 weeks (or within 5.5 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 investigational product or procedures, including treated malignancies that are likely to recur within the approximate 3.5-year duration of the trial Known allergy or sensitivity to PTH or any of the excipients [metacresol, mannitol, succinic acid, NaOH/(HCl)] 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized 3:1 to receive either TransCon PTH or placebo: TransCon PTH 18 μg/day* , co-administered with SoC Placebo for TransCon PTH (excipient solution) 18 μg/day, co-administered with SoC
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TransCon PTH<br>TransCon PTH at a starting dose of 18 mcg delivered once daily by subcutaneous injection | Drug: TransCon PTH<br>* TransCon PTH is supplied as a solution with a concentration of 0.3 mg PTH(1-34)/mL in a single-patient-use prefilled pen intended for SC injection.<br>|
| Placebo Comparator: placebo<br>Placebo for TransCon PTH at a starting dose of 18 mcg delivered once daily by subcutaneous injection | Drug: placebo<br>* Placebo is supplied as a solution containing the formulation buffer for TransCon PTH in a single-patient-use prefilled pen intended for subcutaneous injection.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of subjects who meet primary efficacy endpoint at 26 weeks of treatment | The proportion of subjects with albumin-adjusted sCa within the normal range, and independence from active vitamin D, and independence from therapeutic doses of calcium (i.e., taking calcium supplements ≤600 mg/day), and no increase in prescribed study drug within 4 weeks prior to Week 26 visit | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in HPES Symptom - Physical Domain score | Change from baseline in Hypoparathyroidism Patient Experience Scale (HPES) Symptom - Physical Domain score, a disease-specific patient reported outcome, at 26 weeks of treatment | 26 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hypoparathyroidism, TransCon PTH, Parathyroid Hormone deficiency, PTH1-34