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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascendis Pharma Bone Diseases A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

Trial duration

3 Sep 2019 → 17 Apr 2025

Decision date (initial)

2024-07-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-512967-29-00

EudraCT number

2018-004815-33

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess the effectiveness of daily TransCon PTH on serum and urine calcium levels (FECa) and active vitamin D and calcium doses at 4 weeks of treatment

Secondary objectives 6

1. To assess the safety and tolerability of daily TransCon PTH
2. To assess the effectiveness of daily TransCon PTH on serum and urine calcium levels (FECa) and active vitamin D and calcium doses during the Extension Period
3. To assess the treatment effect of daily TransCon PTH on daily pill burden (vitamin D and calcium)
4. To assess the treatment effect of daily TransCon PTH on serum phosphate, serum magnesium, and calcium x phosphate product (sCa x sP product)
5. To assess the treatment effect of daily TransCon PTH on hypocalcemia and hypercalcemia symptoms, emergency room (ER) visits, and hospitalizations
6. To assess anti-PTH and anti-PEG antibody responses

Conditions and MedDRA coding

Hypoparathyroidism (HP) in Adults

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Males and females aged ≥18 years
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 hypocalcemia in the setting of inappropriately low serum parathyroid hormone (PTH) levels.
3. 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
4. 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
5. BMI 17-40 kg/m2 at Visit 1
6. If ≤25 years of age, radiological evidence of epiphyseal closure based on x-ray of non-dominant wrist and hand
7. eGFR >30 mL/min/1.73m2 during Screening
8. 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
9. If treated with thyroid hormone replacement therapy, the dose must be stable for at least 12 weeks prior to Visit 1
10. Able to perform daily subcutaneous self-injections of study drug (or have a designee perform injection) via a pre-filled injection pen
11. Written, signed, informed consent of the subject

Exclusion criteria 21

1. Known activating mutation in the calcium-sensing receptor (CaSR) gene
2. Impaired responsiveness to PTH (pseudohypoparathyroidism) which is characterized as PTH-resistance, with elevated PTH levels in the setting of hypocalcemia
3. 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
4. Use of loop diuretics, phosphate binders (other than calcium carbonate/calcium citrate), digoxin, lithium, methotrexate, or systemic corticosteroids (other than replacement therapy)
5. Use of thiazide diuretic within 4 weeks prior to the Screening 24-hour urine collection or the first dose adjustment of SOC during Screening
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 12 weeks (US only: 5 weeks) prior to Visit 1
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 Visit 1
8. Use of bisphosphonates (oral or IV) or denosumab within 2 years prior to Visit 1
9. 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
10. 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
11. 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.
12. Diagnosis of drug or alcohol dependence within 3 years prior to Visit 1
13. 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
14. 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)
15. Cerebrovascular accident within 5 years prior to Visit 1
16. History of renal colic or acute gout within 52 weeks prior to Visit 1
17. 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
18. Known allergy or sensitivity to PTH or any of the excipients [metacresol, mannitol, succinic acid, NaOH/(HCl)]
19. 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
20. Likely to be non-compliant with respect to trial conduct
21. Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. At 4 weeks of treatment, the proportion of subjects with: • Albumin-adjusted sCa 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

Secondary endpoints 1

1. Key Secondary Efficacy Endpoint: At 4 weeks of treatment, the proportion of subjects with: • Albumin-adjusted sCa within the normal range and • FECa within the normal range or a reduction by at least 50% from baseline and • Not taking active vitamin D supplements and • Taking ≤500 mg/day of calcium supplements

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascendis Pharma Bone Diseases A/S

Sponsor organisation

Ascendis Pharma Bone Diseases A/S

Address

Tuborg Boulevard 12

City

Hellerup

Postcode

2900

Country

Denmark

Scientific contact point

Organisation

Ascendis Pharma Bone Diseases A/S

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Ascendis Pharma Bone Diseases A/S

Contact name

Clinical Trial Information Desk

Third parties 10

Locations

4 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 31 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications