| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypoparathyroidism (HP) in Adults |
|
| E.1.1.1 | Medical condition in easily understood language |
| Reduction of secretion or activity of parathyroid hormone (PTH) in adults. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021041 |
| E.1.2 | Term | Hypoparathyroidism |
| E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of daily TransCon PTH
- 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
- To assess the treatment effect of daily TransCon PTH on daily pill burden (vitamin D and calcium)
- To assess the treatment effect of daily TransCon PTH on serum phosphate, serum magnesium, and calcium x phosphate product (sCa x sP product)
- To assess the treatment effect of daily TransCon PTH on hypocalcemia and hypercalcemia symptoms, emergency room (ER) visits, and hospitalizations
- To assess anti-PTH and anti-PEG antibody responses |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. 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 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 |
|
| E.4 | Principal 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 12 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 (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 [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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints:
At 4 weeks of treatment, the proportion of subjects with:
-Albumin-adjusted or ionized sCa within the normal range, and
-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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoint:
At 4 weeks of treatment, the proportion of subjects with:
-Albumin-adjusted or ionized 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
Other Secondary Efficacy Endpoints:
-Primary and key secondary efficacy endpoints measured at predefined timepoints over the Extension Period
At 4 weeks of treatment and at predefined timepoints over the Extension Period:
-Calcium and vitamin D doses
-Number of SOC supplements (pill burden)
-Spot AM FECa
-Serum phosphate
-Serum magnesium
-sCa x sP product, including proportion of subjects with sCa x sP product ≤55 mg2/dL2, ≤52 mg2/dL2, and ≤44 mg2/dL2
-Albumin-adjusted or ionized sCa
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At 4 weeks of treatment and at predefined timepoints over the Extension Period. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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