| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypoparathyroidism in Adults |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hypoparathyroidism is a disease where the pharathyroid horomone production or activity is reduced. |
|
| 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 treatment effect of daily TransCon PTH on serum calcium levels, and therapeutic doses of active vitamin D (i.e., calcitriol or alfacalcidol) and calcium at 26 weeks of treatment. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of daily TransCon PTH
• To assess the treatment effect of daily TransCon PTH on hypoparathyroidism patient
experience scale (HPES) domain scores
• To assess the treatment effect of daily TransCon PTH on PD markers (including sCa) and active vitamin D and calcium doses
• To assess the treatment effect of daily TransCon PTH on sP, CxP (albumin-adjusted sCa x sP product) and sMg.
• To assess anti-PTH, anti-TransCon PTH and anti-polyethylene glycol (PEG) antibody responses
• To assess the treatment effect during Extension Period
• To assess the treatment effect of daily TransCon PTH on
− BMD and trabecular bone score (TBS) by DXA
− Bone turnover markers (serum P1NP and CTx)
• To assess the impact of treatment on patient-reported health-related QOL and a clinician reported outcome (ClinRO) assessment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 history of hypocalcemia in the setting of inappropriately low serum PTH levels (Hypocalcemia is defined as a value below the reference range for normal at the performing laboratory. Inappropriately low serum PTH levels are defined as at or below the median value of the reference range for normal at the performing laboratory while the concomitant serum calcium is low. If specific lab results at the time of original diagnosis are not available, as historical diagnosis affirming these two components is adequate for inclusion).
3. Requirement for doses of SOC eg, 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 (eg, 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.
* Excluding individuals receiving PTH-like drugs within 12 weeks of the screening visit, who need only demonstrate a stable requirement for elemental calcium and active vitamin D above minimum thresholds for 5 weeks prior to the screening visit.
** Does not preclude occasional (≤2/week) PRN doses of calcium and/or active vitamin D for symptomatic hypocalcemia
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 i.e.: ≥1.3 mg/dL (0.53 mmol/L) and
• Albumin-adjusted or ionized sCa level in the normal range, or *just below the normal range, i.e.:
− Albumin-adjusted sCa 7.8-10.6 mg/dL (or 1.95-2.64 mmol/L)
− Ionized sCa 4.40-5.29 mg/dL (or 1.10-1.32 mmol/L)
*Just below the normal range implies the numerical range of 7.8-8.2 mg/dL (or 1.95-2.06 mmol/L) for albumin-adjusted sCa and the numerical range of 4.40-4.636 mg/dL (or 1.10-1.159 mmol/L) for ionized sCa.
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)
Note: Although 24-hour urine samples prior to Screening may be done on or off thiazide therapy, thiazide therapy is prohibited during the trial; and the 24-hour urine collection scheduled prior to Visit 1 must be done while off thiazides for at least 4 weeks prior to collection
6. BMI 17- 40 kg/m2 at Screening
7. If ≤25 years of age, radiological evidence of epiphyseal closure based on X-ray of non-dominant 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/L
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 SC 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 ICF in accordance with GCP.
13. For France only: The subject is obligated to be affiliated with, or beneficiary of a social security system or assimilated. |
|
| E.4 | Principal 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; bone Paget disease; 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 non-melanoma 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/L
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; Note: Male subjects must use a condom, or his female partner of childbearing potential must use an effective form of contraception (as per CTFG definition), from the beginning of screening to the last trial visit
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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
At 26 weeks of treatment, the proportion of subjects with:
• Albumin-adjusted sCa measured within 4 weeks prior to and on the Week 26 visit are within the normal range (8.3-10.6mg/dL) *; and
• Independence from active vitamin D** and
• Independence from therapeutic doses of calcium (i.e., taking calcium supplements ≤600 mg/day). This dose of calcium ≤600 mg/day in the form of tablets, powder, liquid suspension, or transdermal patch is considered as "supplemental" to meeting recommended daily intake for general health,
as opposed to a "therapeutic" dose to treat hypoparathyroidism*** and
• No increase in prescribed study drug within 4 weeks prior to Week 26
visit****
* Except for at the Week 26 visit, confirmation that an albumin-adjusted sCa is "abnormal" requires 2 consecutive results outside the normal range within 4 weeks prior to the Week 26 visit.
**Independence from active vitamin D will be defined as a daily standing dose equal to zero on all days AND use of any PRN vitamin D ≤7 days within 4 weeks prior to the Week 26 visit.
***Independence from therapeutic calcium will be defined as average daily standing dose ≤600 mg AND use of PRN doses on ≤7 days within 4 weeks prior to the Week 26 visit.
****Dose decrease permitted for safety reasons. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| evaluated at 26 weeks of treatment |
|
| E.5.2 | Secondary end point(s) |
Change from baseline at 26 weeks of treatment:
• HPES Symptom - Physical domain score
• HPES Symptom - Cognitive domain score
• HPES Impact - Physical functioning domain score
• HPES Impact - Daily life domain score
• 36-Item Short Form Survey (SF-36) Physical functioning subscale score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| evaluated at 26 weeks of treatment |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| After 26 weeks, all patients will be included in an open-label extension up to 3 years |
|
| 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 | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 | Yes |
| 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 |
| Canada |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Norway |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of trial is defined as the last subject last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 13 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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