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

Endocrine System Diseases Clinical Trial

— PaTHway  

Official title:

PaTHway 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04701203
• Other study ID #: TCP-304
• Secondary ID: 2020-003380-26
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: February 16, 2021
• Est. completion date: January 2025

Study information

• Verified date: January 2024
• Source: Ascendis Pharma A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

During the first 26 weeks of the trial, participants will be randomly assigned to one of two groups: one group will receive TransCon PTH and one group will receive placebo. All subjects will start with a fixed dose of study drug and will be individually and progressively titrated to an optimal dose over a 10 week period, followed by an individualized dosing period up to 16 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. This is a global trial that will be conducted in, but not limited to, the United States, Canada, Germany, and Denmark.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 82
• Est. completion date: January 2025
• Est. primary completion date: January 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Males and females, =18 years of age

2. 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 serum PTH levels

3. Requirement for doses of SoC (e.g., calcitriol, alfacalcidol, calcium supplements) at or above a minimum threshold:

• For countries other than Japan: 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, or calcium should be stable for at least 5 weeks prior to Screening

• For Japan: requirement for a dose of calcitriol =1.0 µg/day, or alfacalcidol =2.0 µg/day for at least 12 weeks prior to Screening. In addition, the dose of calcitriol or alfacalcidol should be stable for at least 5 weeks prior to Screening. In Japan only (due to local practice and dietary patterns), there is no requirement to exceed a minimum dose of calcium supplements

4. Optimization of supplements prior to randomization to achieve the target serum levels of:

• 25(OH) vitamin D levels of 20-80 ng/mL (49-200 nmol/L) and

• Magnesium level in the normal range, or just below the normal range and

• Albumin-adjusted or ionized sCa level in the normal range, or just below the normal range

5. 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)

6. BMI 17- 40 kg/m2 at Screening

7. If =25 years of age, radiological evidence of epiphyseal closure based on X-ray of nondominant wrist and hand

8. 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/mL

9. If treated with thyroid hormone replacement therapy, the dose must have been stable for at least 5 weeks prior to Screening

10. eGFR =30 mL/min/1.73 m2 during Screening

11. Able to perform daily subcutaneous self-injections of study drug (or have a designee to perform injections) via a pre-filled injection pen

12. Able and willing to provide written and signed informed consent in accordance with GCP

Exclusion Criteria:

1. Impaired responsiveness to PTH (pseudohypoparathyroidism) which is characterized as PTH-resistance, with elevated PTH levels in the setting of hypocalcemia

2. 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 basal cell skin cancer); active hyperparathyroidism; parathyroid carcinoma within 5 years prior to Screening; acromegaly; or multiple endocrine neoplasia types 1 and 2

3. High risk thyroid cancer within 2 years, requiring suppression of TSH <0.2 mIU/mL

4. 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)

5. Use of thiazide diuretic within 4 weeks prior to the 24-hour urine collection scheduled to occur within 1 week prior to Visit 1

6. 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

7. 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

8. 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

9. Non-hypocalcemic seizure disorder with a history of a seizure within 26 weeks prior to Screening

10. 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

11. Pregnant or lactating women

12. 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

13. Diagnosed drug or alcohol dependence within 3 years prior to Screening

14. 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

15. Chronic or 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 in the setting of white coat hypertension/anxiety may not be exclusionary and a measurement can be repeated prior to randomization

16. Cerebrovascular accident within 5 years prior to Screening

17. Within 26 weeks prior to Screening: acute colic due to nephrolithiasis, or acute gout. Subjects with asymptomatic renal stones are permitted

18. 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

19. 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

20. Known allergy or sensitivity to PTH or any of the excipients [metacresol, mannitol, succinic acid, NaOH/(HCl)]

21. Likely to be non-compliant with respect to trial conduct

22. Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule

Related Conditions & MeSH terms

• Endocrine System Diseases
• Hypoparathyroidism
• Parathyroid Diseases

Intervention

Combination Product:
• TransCon PTH
TransCon PTH drug product 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 subcutaneous injection.
• Placebo
Placebo is supplied as a solution containing the formulation buffer for TransCon PTH in a single-patient-use prefilled pen intended for subcutaneous injection.

Locations

Country	Name	City	State
Canada	Ascendis Pharma Investigational Site	Halifax	Nova Scotia
Canada	Ascendis Pharma Investigational Site	Oakville	Ontario
Canada	Ascendis Pharma Investigational Site	Québec	Quebec
Denmark	Ascendis Pharma Investigational Site	Aarhus	Midtjylland
Denmark	Ascendis Pharma Investigational Site	København	Hovedstaden
Germany	Ascendis Pharma Investigational Site	Dresden	Sachsen
Hungary	Ascendis Pharma Investigational Site	Budapest
Hungary	Ascendis Pharma Investigational Site	Szeged	Csongrad
Italy	Ascendis Pharma Investigational Site	Bologna	Emilia-Romagna
Italy	Ascendis Pharma Investigational Site	Pisa	Piacenza
Italy	Ascendis Pharma Investigational Site	Roma	Lazio
Norway	Ascendis Pharma Investigational Site	Oslo
United States	Ascendis Pharma Investigational Site	Austin	Texas
United States	Ascendis Pharma Investigational Site	Chicago	Illinois
United States	Ascendis Pharma Investigational Site	Fort Worth	Texas
United States	Ascendis Pharma Investigational Site	Greenville	North Carolina
United States	Ascendis Pharma Investigational Site	New York	New York
United States	Ascendis Pharma Investigational Site	Reno	Nevada
United States	Ascendis Pharma Investigational Site	Rochester	Minnesota
United States	Ascendis Pharma Investigational Site	San Francisco	California
United States	Ascendis Pharma Investigational Site	Spokane	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Ascendis Pharma Bone Diseases A/S

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  Germany,  Hungary,  Italy,  Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy - Primary endpoint	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	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
Secondary	Change from baseline in HPES Symptom - Cognitive Domain score	Change from baseline in Hypoparathyroidism Patient Experience Scale (HPES) Symptom - Cognitive Domain score, a disease-specific patient reported outcome, at 26 weeks of treatment	26 weeks
Secondary	Change from baseline in HPES Impact - Physical Functioning Domain score	Change from baseline in Hypoparathyroidism Patient Experience Scale (HPES) Impact - Physical Functioning Domain score, a disease-specific patient reported outcome, at 26 weeks of treatment	26 weeks
Secondary	Change from baseline in HPES Impact - Daily Life Domain score	Change from baseline in Hypoparathyroidism Patient Experience Scale (HPES) Impact - Daily Life Domain score, a disease-specific patient reported outcome, at 26 weeks of treatment	26 weeks
Secondary	Change from baseline in SF-36 Physical Functioning subscale score	Change from baseline in the 36-item Short Form Survey (SF-36) Physical Functioning subscale score, a generic health survey, at 26 weeks of treatment	26 weeks