Endocrine System Diseases, Hypoparathyroidism, Parathyroid Diseases
Conditions
Keywords
Hypoparathyroidism, Parathyroid Hormone, TransCon PTH, PTH(1-34), Prodrug, Sustained Release, Parathyroid Hormone Replacement Therapy, Palopegteriparatide
Brief summary
During the first 26 weeks of the trial, participants were randomly assigned to one of two groups: one group received TransCon PTH and one group received placebo. All participants started with study drug at a dose of 18 mcg/day and were individually and progressively titrated to an optimal dose in dose increments of 3 mcg/day. TransCon PTH or placebo were administered as a subcutaneous injection using a pre-filled injection pen. Neither trial participants nor their doctors knew who had been assigned to each group. After the 26 weeks, participants continued in the trial as part of a long-term extension study. During the extension, all participants received TransCon PTH, with the dose adjusted to their individual needs. This was a global trial that was conducted in the United States, Canada, Germany, Denmark, Norway, Italy, and Hungary.
Interventions
COMBINATION_PRODUCTTransCon 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.
COMBINATION_PRODUCTPlacebo
Placebo is supplied as a solution containing the formulation buffer for TransCon PTH in a single-patient-use prefilled pen intended for subcutaneous injection.
Sponsors
Ascendis Pharma Bone Diseases A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Double-blind, placebo controlled, parallel group with participants randomized into two treatment groups (3:1): TransCon PTH at a starting dose of 18 mcg/day and titrated to an optimal dose, and placebo for TransCon PTH
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - Primary Endpoint During the Blinded Period | 26 weeks | The primary endpoint was a multi-component endpoint that included the percentage of participants who met the following criteria at 26 weeks of blinded treatment: 1) albumin-adjusted serum calcium measured within 4 weeks prior to and on Week 26 visit within the normal range (8.3 to 10.6 mg/dL), and 2) independence from active vitamin D within 4 weeks prior to Week 26 visit (i.e., all daily standing dose of active vitamin D equal to zero AND use of PRN ≤7 days during the 4 weeks), and 3) independence from therapeutic doses of calcium within 4 weeks prior to Week 26 visit (i.e., average daily standing dose of elemental calcium ≤600 mg AND use of PRN doses on ≤7 days during the 4 weeks), and 4) no increase in prescribed study drug within 4 weeks prior to Week 26 visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 26 in HPES Symptom - Physical Domain Score | 26 weeks | Change from baseline in Hypoparathyroidism Patient Experience Scale (HPES) Symptom - Physical Domain score, a disease-specific patient reported outcome, at 26 weeks of treatment. The measure uses a scale of 0-100 and values represent the change in scores from baseline. A decrease in HPES score denotes an improvement in hypoparathyroidism disease related physical symptoms. |
| Change From Baseline to Week 26 in HPES Symptom - Cognitive Domain Score | 26 weeks | Change from baseline in Hypoparathyroidism Patient Experience Scale (HPES) Symptom - Cognitive Domain score, a disease-specific patient reported outcome, at 26 weeks of treatment. The measure uses a scale of 0-100 and values represent the change in scores from baseline. A decrease in HPES score denotes an improvement in hypoparathyroidism disease related cognitive symptoms. |
| Change From Baseline to Week 26 in HPES Impact - Physical Functioning Domain Score | 26 weeks | 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. The measure uses a scale of 0-100 and values represent the change in scores from baseline. A decrease in HPES score denotes an improvement in physical functioning health-related quality of life. |
| Change From Baseline to Week 26 in HPES Impact - Daily Life Domain Score | 26 weeks | 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. The measure uses a scale of 0-100 and values represent the change in scores from baseline. A decrease in HPES score denotes an improvement in daily health-related quality of life. |
| Change From Baseline to Week 26 in SF-36 Physical Functioning Subscale Score | 26 weeks | 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. The Physical Functioning subscale uses a range of 19-57.6 and values represent the change in scores from baseline. An increase in SF-36 score denotes an improvement in physical functioning health-related quality of life. |
Countries
Canada, Denmark, Germany, Hungary, Italy, Norway, United States
Contacts
STUDY_DIRECTORStudy Director, MD
Ascendis Pharma A/S
Participant flow
Recruitment details
Overall, 84 subjects were randomized and 82 subjects were dosed. Enrollment of subjects occurred in seven countries: Canada, Denmark, Germany, Italy, Hungary, Norway, and the United States.
Pre-assignment details
A total of 106 subjects were screened and 84 of these met eligibility criteria and were enrolled into the study. Two subjects randomized to TransCon PTH were not treated (1 subject was diagnosed with a recurrence of cancer, and 1 subject withdrew consent). A total of 82 subjects were therefore included in the Intent-to-Treat (ITT) and the Safety analysis populations.
Participants by arm
| Arm | Count |
|---|---|
| TransCon PTH TransCon PTH at a starting dose of 18 mcg delivered once daily by subcutaneous injection and titrated to an optimal dose
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. | 61 |
| Placebo Placebo for TransCon PTH delivered once daily by 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. | 21 |
| Total | 82 |
Baseline characteristics
| Characteristic | TransCon PTH | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 13.13 | 47.3 years STANDARD_DEVIATION 11.43 | 48.6 years STANDARD_DEVIATION 12.67 |
| Body Mass Index | 27.27 kg/m^2 STANDARD_DEVIATION 5.813 | 29.47 kg/m^2 STANDARD_DEVIATION 5.691 | 27.83 kg/m^2 STANDARD_DEVIATION 5.828 |
| Height | 168.22 cm STANDARD_DEVIATION 8.353 | 166.67 cm STANDARD_DEVIATION 8.831 | 167.82 cm STANDARD_DEVIATION 8.45 |
| Race/Ethnicity, Customized Asian | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 57 Participants | 18 Participants | 75 Participants |
| Race/Ethnicity, Customized Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 57 Participants | 19 Participants | 76 Participants |
| Sex: Female, Male Female | 46 Participants | 18 Participants | 64 Participants |
| Sex: Female, Male Male | 15 Participants | 3 Participants | 18 Participants |
| Weight | 77.18 kg STANDARD_DEVIATION 17.335 | 81.61 kg STANDARD_DEVIATION 15.631 | 78.31 kg STANDARD_DEVIATION 16.932 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 61 | 0 / 21 | 1 / 80 |
| other Total, other adverse events | 50 / 61 | 20 / 21 | 72 / 80 |
| serious Total, serious adverse events | 5 / 61 | 2 / 21 | 20 / 80 |
Outcome results
Primary
Efficacy - Primary Endpoint During the Blinded Period
The primary endpoint was a composite endpoint defined as the percentage of subjects who met the following criteria at 26 weeks of blinded treatment: 1) albumin-adjusted serum calcium measured within 4 weeks prior to and on Week 26 visit within the normal range (8.3 to 10.6 mg/dL), and 2) independence from active vitamin D within 4 weeks prior to Week 26 visit (i.e., all daily standing dose of active vitamin D equal to zero AND use of PRN ≤7 days during the 4 weeks), and 3) independence from therapeutic doses of calcium within 4 weeks prior to Week 26 visit (i.e., average daily standing dose of elemental calcium ≤600 mg AND use of PRN doses on ≤7 days during the 4 weeks), and 4) no increase in prescribed study drug within 4 weeks prior to Week 26 visit.
Time frame: 26 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TransCon PTH | Efficacy - Primary Endpoint During the Blinded Period | 78.7 Percentage of participants |
| Placebo | Efficacy - Primary Endpoint During the Blinded Period | 4.8 Percentage of participants |
Comparison: For the primary efficacy endpoint, the Cochran-Mantel Haenszel test stratified by etiology of hypoparathyroidism (postsurgical or other) was used to compare the proportion of participants meeting the composite primary endpoint in the TransCon PTH versus placebo groups. Participants without week 26 albumin-adjusted serum calcium or with \>25% (ie, \>7 days) missing diary data of active vitamin D or elemental calcium during the 4 weeks before week 26 were considered non-responders.p-value: <0.0001t-test, 2 sided
Secondary
Change From Baseline to Week 26 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. The measure uses a scale of 0-100 and values represent the change in scores from baseline. A decrease in HPES score denotes an improvement in daily health-related quality of life.
Time frame: 26 weeks
Population: The overall number of participants analyzed represents the number of subjects with both baseline and Week 26 visit values available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TransCon PTH | Change From Baseline to Week 26 in HPES Impact - Daily Life Domain Score | -17.65 units on a scale |
| Placebo | Change From Baseline to Week 26 in HPES Impact - Daily Life Domain Score | -0.36 units on a scale |
Comparison: ANCOVA model with unequal variance was used to analyze the key secondary Endpoints. The change from baseline is variable of interest at week 26 and was included in the model as response variables. Treatment assignment and etiology of hypoparathyroidism were entered as fixed effects and baseline value of the variable of interest was entered as a covariate.p-value: =0.0061t-test, 2 sided
Secondary
Change From Baseline to Week 26 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. The measure uses a scale of 0-100 and values represent the change in scores from baseline. A decrease in HPES score denotes an improvement in physical functioning health-related quality of life.
Time frame: 26 weeks
Population: The overall number of participants analyzed represents the number of subjects with both baseline and Week 26 visit values available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TransCon PTH | Change From Baseline to Week 26 in HPES Impact - Physical Functioning Domain Score | -18.29 units on a scale |
| Placebo | Change From Baseline to Week 26 in HPES Impact - Physical Functioning Domain Score | -1.01 units on a scale |
Comparison: ANCOVA model with unequal variance was used to analyze the key secondary Endpoints. The change from baseline is variable of interest at week 26 and was included in the model as response variables. Treatment assignment and etiology of hypoparathyroidism were entered as fixed effects and baseline value of the variable of interest was entered as a covariate.p-value: =0.0046t-test, 2 sided
Secondary
Change From Baseline to Week 26 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. The measure uses a scale of 0-100 and values represent the change in scores from baseline. A decrease in HPES score denotes an improvement in hypoparathyroidism disease related cognitive symptoms.
Time frame: 26 weeks
Population: The overall number of participants analyzed represents the number of subjects with both baseline and Week 26 visit values available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TransCon PTH | Change From Baseline to Week 26 in HPES Symptom - Cognitive Domain Score | -20.49 units on a scale |
| Placebo | Change From Baseline to Week 26 in HPES Symptom - Cognitive Domain Score | -6.16 units on a scale |
Comparison: ANCOVA model with unequal variance was used to analyze the key secondary Endpoints. The change from baseline is variable of interest at week 26 and was included in the model as response variables. Treatment assignment and etiology of hypoparathyroidism were entered as fixed effects and baseline value of the variable of interest was entered as a covariate.p-value: =0.0055t-test, 2 sided
Secondary
Change From Baseline to Week 26 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. The measure uses a scale of 0-100 and values represent the change in scores from baseline. A decrease in HPES score denotes an improvement in hypoparathyroidism disease related physical symptoms.
Time frame: 26 weeks
Population: The overall number of participants analyzed represents the number of subjects with both baseline and Week 26 visit values available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TransCon PTH | Change From Baseline to Week 26 in HPES Symptom - Physical Domain Score | -21.01 units on a scale |
| Placebo | Change From Baseline to Week 26 in HPES Symptom - Physical Domain Score | -4.81 units on a scale |
Comparison: ANCOVA model with unequal variance was used to analyze the key secondary Endpoints. The change from baseline is variable of interest at week 26 and was included in the model as response variables. Treatment assignment and etiology of hypoparathyroidism were entered as fixed effects and baseline value of the variable of interest was entered as a covariate.p-value: =0.0038t-test, 2 sided
Secondary
Change From Baseline to Week 26 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. The Physical Functioning subscale uses a range of 19-57.6 and values represent the change in scores from baseline. An increase in SF-36 score denotes an improvement in physical functioning health-related quality of life.
Time frame: 26 weeks
Population: The overall number of participants analyzed represents the number of subjects with both baseline and Week 26 visit values available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TransCon PTH | Change From Baseline to Week 26 in SF-36 Physical Functioning Subscale Score | 5.29 units on a scale |
| Placebo | Change From Baseline to Week 26 in SF-36 Physical Functioning Subscale Score | 0.12 units on a scale |
Comparison: ANCOVA model with unequal variance was used to analyze the key secondary Endpoints. The change from baseline is variable of interest at week 26 and was included in the model as response variables. Treatment assignment and etiology of hypoparathyroidism were entered as fixed effects and baseline value of the variable of interest was entered as a covariate.p-value: =0.0347t-test, 2 sided