| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10021041 |
| E.1.2 | Term | <Manually entered code. Term in E.1.1> |
|
| 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 demonstrate 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.
|
|
| E.2.2 | Secondary objectives of the trial |
| To demonstrate that once-daily dosing with NPSP 558 across a dose range of 50 µg, 75 µg or 100 µg SC is able to normalize calcium homeostasis while improving tolerability compared to standard of care. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated informed consent form (ICF) before any study-related procedures are performed prior to screening.
2. Adult males or females 18 to 85 years of age (prior to screening). Those < 25 years old will be examined radiologically to ensure epiphyseal closure prior to randomization.
3. History of hypoparathyroidism for ≥ 18 months post-diagnosis, inclusive of historical biochemical evidence of hypocalcemia and concomitant serum intact PTH concentrations below the lower limit of the laboratory normal range on 2 test dates at least 21 days apart within 12 months prior to randomization.
4. Requirement for active vitamin D metabolite/analog therapy with calcitriol ≥0.25 ug per day or alphacalcidol ≥0.50 ug per day prior to randomization. Requirement for supplemental oral calcium treatment ≥ 1000 mg per day over and above normal dietary calcium intake (see Appendix 2 for normal Dietary Reference Intake table by age and sex) prior to randomization.
5. Serum thyroid function tests within normal laboratory limits at screening for all subjects not receiving thyroid hormone replacement therapy. For patients on thyroid hormone replacement therapy, the dose must have been stable for at least 3 months prior to screening and the thyroxine (T4) value may be outside the laboratory limits of normal.
6. Serum magnesium levels should be within laboratory normal limits at the end of the Optimization period. Subjects with low serum magnesium should undergo supplementation at a clinically appropriate level until the serum magnesium is within the normal range by the end of the Optimization period and normal serum magnesium should be maintained throughout the study.
7. Serum 25-hydroxyvitamin D [25(OH)D] level ≤ 1.5-fold the laboratory upper limit of normal at the end of the Optimization period. Patients with low serum 25(OH)D levels at screening will undergo supplementation with active vitamin D during the Optimization period. Patients with serum 25(OH)D levels above the laboratory upper limit of normal will have active vitamin D supplements withdrawn during the Optimization period. Serum 25(OH)D levels that are within the normal range must be confirmed by the end of the Optimization period. See Section 5.4.2 (prior to randomization).
8. Creatinine clearance > 30 mL/min on two separate measurements OR creatinine clearance > 60 mL/min and serum creatinine < 1.5 mg/dL by the end of the Optimization period (prior to randomization).
9. Capable of providing written informed consent.
10. Prior to screening, able to perform daily SC self-injections of study medication (or have designee perform injection) via a multi-dose injection pen into the thigh.
11. Willingness and ability to comply with the protocol (prior to screening).
12. With regard to female patients: women who are postmenopausal [absence of menses for ≥ 2 years with confirmed follicle stimulating hormone (FSH) test] and women who are surgically sterilized can be enrolled. Women of childbearing potential must have a negative pregnancy test at Randomization and be willing to use two medically acceptable methods of contraception for the duration of the study (see Appendix 5) with pregnancy testing at every scheduled visit.
|
|
| E.4 | Principal exclusion criteria |
Patients who have any of the following during the screening visit are not eligible for enrollment in this study:
1. Known history of 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 and thiazide diuretics, raloxifene hydrochloride, lithium, estrogens and progestins for hormone replacement therapy, methotrexate, or systemic corticosteroids within respective prohibited periods. (Refer to section 5.4.1)
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 6 months prior to screening.
8. Other drugs known to influence calcium and bone metabolism, such as calcitonin, fluoride tablets, or cinacalcet hydrochloride within the prohibited period.
9. Use of oral bisphosphonates within the previous 6 months or IV bisphosphonate preparations within the previous 12 months prior to screening.
10. Seizure disorder/epilepsy with a history of a seizure within the previous 6 months prior to screening.
11. Presence of open epiphyses.
12. Irradiation (radiotherapy) to the skeleton within 5 years.
13. Serum 25-hydroxyvitamin D levels greater than 1.5-fold the laboratory upper limit of normal prior to randomization.
14. 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.
15. Participation in any other investigational trial in which receipt of investigational drug or device occurred within 6 months prior to screening for this study.
16. Pregnant or lactating women.
17. History of diagnosed drug or alcohol dependence within the previous 3 years.
18. Clinical history of renal calculi within the past 12 months.
19. History of gout.
20. 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.
21. 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).
22. History of cerebrovascular accident (CVA).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The proportion of patients that demonstrate by Visit 16 (Week 24) of the study:
• At least a 50% reduction from Baseline amounts of oral calcium supplementation AND
• At least a 50% reduction from Baseline amounts of active vitamin D metabolite/analog therapy AND
• An albumin-corrected total serum calcium concentration that is normalized or maintained compared to the Baseline value (≥7.5 mg/dL) and does not exceed the upper limit of the laboratory normal range.
|
|
| 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 | 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
| 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 | 5 |
| 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 | 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 |
|
| 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
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
Print
