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

Primary Purpose

Hypoparathyroidism, Endocrine System Diseases, Parathyroid Diseases

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
TransCon PTH
Placebo for TransCon PTH
Sponsored by
Ascendis Pharma A/S
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypoparathyroidism focused on measuring Hypoparathyroidism, Parathyroid Hormone, PTH(1-34), Prodrug, Sustained Release, TransCon PTH, Parathyroid Hormone Replacement Therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  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.
  3. 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.
  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.
  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:

  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 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.
  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 (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.
  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.
  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.

Sites / Locations

  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Experimental

Arm Label

TransCon PTH 15 mcg

TransCon PTH 18 mcg

TransCon PTH 21 mcg

Placebo

Open-Label Extension Period

Arm Description

TransCon PTH 15 mcg delivered once daily by subcutaneous injection

TransCon PTH 18 mcg delivered once daily by subcutaneous injection

TransCon PTH 21 mcg delivered once daily by subcutaneous injection

Placebo mimicking 15, 18, or 21 mcg of TransCon PTH delivered once daily by subcutaneous injection

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
June 20, 2019
Last Updated
August 10, 2023
Sponsor
Ascendis Pharma A/S
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1. Study Identification

Unique Protocol Identification Number
NCT04009291
Brief Title
A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH in Adults With Hypoparathyroidism
Acronym
PaTH Forward
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 27, 2019 (Actual)
Primary Completion Date
March 6, 2020 (Actual)
Study Completion Date
March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ascendis Pharma A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoparathyroidism, Endocrine System Diseases, Parathyroid Diseases
Keywords
Hypoparathyroidism, Parathyroid Hormone, PTH(1-34), Prodrug, Sustained Release, TransCon PTH, Parathyroid Hormone Replacement Therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
59 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TransCon PTH 15 mcg
Arm Type
Experimental
Arm Description
TransCon PTH 15 mcg delivered once daily by subcutaneous injection
Arm Title
TransCon PTH 18 mcg
Arm Type
Experimental
Arm Description
TransCon PTH 18 mcg delivered once daily by subcutaneous injection
Arm Title
TransCon PTH 21 mcg
Arm Type
Experimental
Arm Description
TransCon PTH 21 mcg delivered once daily by subcutaneous injection
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo mimicking 15, 18, or 21 mcg of TransCon PTH delivered once daily by subcutaneous injection
Arm Title
Open-Label Extension Period
Arm Type
Experimental
Arm Description
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.
Intervention Type
Combination Product
Intervention Name(s)
TransCon PTH
Intervention Description
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.
Intervention Type
Combination Product
Intervention Name(s)
Placebo for TransCon PTH
Intervention Description
Placebo is supplied as a clear solution containing the formulation buffer for TransCon PTH in a pre-filled pen intended for subcutaneous injection.
Primary Outcome Measure Information:
Title
Efficacy - Primary Endpoint During the Blinded Period
Description
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
Time Frame
Week 4
Secondary Outcome Measure Information:
Title
Efficacy - Key Secondary Endpoint During the Blinded Period
Description
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
Time Frame
Week 4

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aimee Shu, MD
Organizational Affiliation
Ascendis Pharma A/S Medical Monitor/Medical Expert
Official's Role
Study Director
Facility Information:
Facility Name
Ascendis Pharma Investigational Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Ascendis Pharma Investigational Site
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55901
Country
United States
Facility Name
Ascendis Pharma Investigational Site
City
Great Neck
State/Province
New York
ZIP/Postal Code
11021
Country
United States
Facility Name
Ascendis Pharma Investigational Site
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Ascendis Pharma Investigational Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Ascendis Pharma Investigational Site
City
Oakville
State/Province
Ontario
ZIP/Postal Code
L6M 1M1
Country
Canada
Facility Name
Ascendis Pharma Investigational Site
City
Aalborg
ZIP/Postal Code
9000
Country
Denmark
Facility Name
Ascendis Pharma Investigational Site
City
Aarhus
ZIP/Postal Code
8200
Country
Denmark
Facility Name
Ascendis Pharma Investigational Site
City
Kobenhavn
ZIP/Postal Code
2200
Country
Denmark
Facility Name
Ascendis Pharma Investigational Site
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Ascendis Pharma Investigational Site
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
Ascendis Pharma Investigational Site
City
Milan
ZIP/Postal Code
20132
Country
Italy
Facility Name
Ascendis Pharma Investigational Site
City
Pisa
ZIP/Postal Code
56124
Country
Italy
Facility Name
Ascendis Pharma Investigational Site
City
Rome
ZIP/Postal Code
00128
Country
Italy
Facility Name
Ascendis Pharma Investigational Site
City
Oslo
ZIP/Postal Code
0176
Country
Norway

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34347093
Citation
Khan AA, Rejnmark L, Rubin M, Schwarz P, Vokes T, Clarke B, Ahmed I, Hofbauer L, Marcocci C, Pagotto U, Palermo A, Eriksen E, Brod M, Markova D, Smith A, Pihl S, Mourya S, Karpf DB, Shu AD. PaTH Forward: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of TransCon PTH in Adult Hypoparathyroidism. J Clin Endocrinol Metab. 2022 Jan 1;107(1):e372-e385. doi: 10.1210/clinem/dgab577.
Results Reference
result

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

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