| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021041 |
| E.1.2 | Term | Hypoparathyroidism |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate, over a 24-week period, that once-daily dosing with NPSP 558 across a dose range of 50 µg, 75 µg or 100 µg SC, is a safe and effective hormone replacement therapy for the treatment of patients with hypoparathyroidism caused by surgery (thyroid, parathyroid or other neck surgery), autoimmune disease, idiopathic disease or abnormalities of parathyroid glands that reduce synthesis or secretion of PTH. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to demonstrate that 24 weeks of treatment with once-daily NPSP 558 across a dose range of 50 µg, 75 µg or 100 µg SC is associated with improvements from Baseline measurements in urinary calcium excretion. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult males or females 18 to 65 years of age. Those < 25 years old will be examined radiologically to ensure epiphyseal closure;
2. History of hypoparathyroidism for ≥ 18 months post-diagnosis, inclusive of historical biochemical evidence of hypocalcemia and concomitant serum intact PTH < 15 pg/mL on 2 test dates at least 21 days apart within 12 months prior to randomization;
3. Requirement for supplemental oral calcium treatment > 1000 mg per day over and above normal dietary calcium intake;
4. Serum thyroid function tests within normal laboratory limits at screening. For patients on thyroid hormone replacement therapy, the dose must have been stable for at least 3 months prior to screening;
5. Serum magnesium levels should be within normal laboratory limits;
6. Serum 25-hydroxyvitamin D [25(OH)D] level ≤ 120 ng/mL (normal range 20 80 ng/mL);
7. Creatinine clearance > 30 mL/min on two separate measurements at screening OR creatinine clearance > 60 mL/min AND serum creatinine < 1.5 mg/dL at screening;
8. With regard to female patients: women who are postmenopausal for ≥ 2 years and women who are surgically sterilized can be enrolled. Women of child-bearing potential (WOCBP) are excluded from the study.
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| E.4 | Principal exclusion criteria |
1. Hypoparathyroidism resulting from an activating mutation in the CaSR gene or impaired responsiveness to PTH (pseudohypoparathyroidism);
2. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism, such as active hyperthyroidism, Paget's disease, insulin-dependent diabetes mellitus (IDDM) or poorly controlled Type II diabetes mellitus (HbA1C > 8), severe and chronic cardiac, liver or renal disease, Cushing's syndrome, neuromuscular disease such as rheumatoid arthritis, myeloma, pancreatitis, malnutrition, rickets, recent prolonged immobility, active malignancy, primary or secondary hyperparathyroidism, a history of parathyroid carcinoma, hypopituitarism, acromegaly, or multiple endocrine neoplasia types I and II;
3. To be eligible, patients with a history of thyroid cancer must be documented to be disease-free for a period of at least 5 years.
4. Patients dependent on regular parenteral calcium infusions (eg calcium gluconate) to maintain calcium homeostasis;
5. Patients that have undergone gastric resection or have active peptic ulcer disease requiring medical therapy;
6. Use of prohibited medications such as loop diuretics, raloxifene hydrochloride, lithium, estrogens, progestins, methotrexate, or systemic corticosteroids within respective prohibited periods;
7. Previous treatment with PTH-like drugs, including PTH(1-84), PTH(1-34) or other N terminal fragments or analogs of PTH or PTH-related protein within the prohibited period;
8. Other drugs known to influence calcium and bone metabolism such as bisphosphonates, calcitonin, fluoride, or cinacalcet hydrochloride within the prohibited period;
9. Seizure disorder/epilepsy with a history of a seizure within the previous 6 months;
10. Presence of open epiphyses;
11. Irradiation to the skeleton within 5 years;
12. Serum 25-hydroxyvitamin D levels > 120 ng/mL (normal 20 – 80 ng/mL);
13. Any disease or condition in the opinion of the Investigator that has a high probability of precluding the patient from completing the study or where the patient cannot or will not appropriately comply with study requirements;
14. Participation in any other investigational trial in which receipt of investigational drug or device occurred within 30 days prior to screening for this study;
15. Women of childbearing potential unless surgically sterilized or are postmenopausal for ≥ 2 years;
16. History of diagnosed drug or alcohol dependence within the previous 3 years;
17. Clinical history of renal calculi within the past 12 months;
18. History of gout;
19. Disease processes that may adversely affect gastrointestinal absorption, including but not limited to short bowel syndrome, bowel resection, tropical sprue, celiac disease, ulcerative colitis, and Crohn’s disease;
20. Chronic/severe cardiac disease including but not limited to cardiac insufficiency, arrhythmias, bradycardia (resting heart rate < 60 beats/minute), or hypotension (systolic and diastolic blood pressures < 100 and 60 mmHg, respectively);
21. History of cerebrovascular accident (CVA).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
A responder is defined as a patient that demonstrates at least a 50% reduction from Baseline amounts of oral calcium supplementation and at least a 50% reduction from Baseline amounts of vitamin D metabolite/analog therapy by Week 24 of the study. Patients should have a clinically stable serum calcium level that is established to the satisfaction of the Investigator at Baseline and is maintained or normalized by Week 24 of the study.
At the end of the treatment phase it is aimed that patients should have a serum calcium that is clinically stable in the opinion of the Investigator and just below or within the lower half of the normal range.
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| 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 | No |
| 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) | 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 | No |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 | Information not present in EudraCT |
| 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 |
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| 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
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| Last visit of the last subject |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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