| 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 | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021041 |
| E.1.2 | Term | Hypoparathyroidism |
|
| 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 |
| Demonstrate, in a period of 24 weeks, that a sole daily dose of NPSP 558 of 50 µg, 75 µg or 100 µg SC is a safe and effective replacement hormone treatment for patients with hypoparathyroidism caused by: surgical operations (on the thyroid, parathyroid or other surgical operations on the neck), autoimmune illness, idiopathic illness or problems with the parathyroid glands which reduce the synthesis or the secretion of PTH. The efficacy will be demonstrated by the reaching or maintenance of a normal level, or with clinically acceptable stability, of total calcium in the serum corrected for albumin, at the same time as less needed for oral calcium integration and treatments with active metabolites of Vitamin D or similar. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study consist of demonstrating that 24 weeks of treatment with a single daily dose of NPSP 558 at doses of 50 µg, 75 µg or 100 µg SC are associated with an improvement in the reference measurements in the urinary excretion of calcium. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Adult male/female 18-65 years of age. Those < 25 years old will be examined radiologically to ensure epiphyseal closure. 2. Hypoparathyroidism history for &#8805; 18 months post-diagnosis, inclusive of historical biochemical evidence of hypocalcemia and concomitant PTH unchanged in the serum < 15 pg/mL in the analysis carried out on 2 different dates at a distance of at least 21 days in the 12 months prior to the randomization. 3. Requirement for supplemental oral calcium treatment > 1000 mg per day over and above normal dietary calcium intake (see Appendix 2 for the table of the normal reference intake taken with the diet on the basis of age and gender). 4. Serum thyroid function tests within normal laboratory limits during screening. For patients undergoing replacement thyroid hormone treatment, the dose must have remained stable for at least 3 months before screening. 5. The stable serum magnesium levels must be within normal laboratory limits. The subjects with low levels of serum magnesium must be subject to integration to clinically appropriate levels until the serum magnesium returns to the normal range by the end of the optimization period; in addition, normal serum magnesium must be maintained for the entire study. 6. Serum 25-hydroxyvitamin D [25(OH)D] level &#8804; 120 ng/mL (normal range 20-80 ng/mL). The patients with low levels of 25(OH)D in the serum at screening will be subject to integration of Vitamin D during the optimization period. For the patients with levels of 25(OH)D in the serum > 80 ng/mL, the integration of Vitamin D during the optimization period will be stopped. The levels of 25(OH)D in the serum within the normal levels must be confirmed at the end of the optimization period. See Section 5.4.2. 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. Capable of providing written informed consent. 9. Able to perform daily SC self-injections of the experimental drug (or have a designee perform injection) via multi-dose injection pen into the thigh. 10. Willingness and ability to understand and comply with the protocol. 11. With regard to the women patients: women who are postmenopausal for &#8805; 2 years and women who are surgically sterilized can be enrolled. Women of child-bearing potential (WOCBP) are excluded from the study. |
|
| 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. 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, insulindependent
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.
NPSP 558 CLINICAL PROTOCOL CL1-11-040 V5.0
AMENDMENT 4.0
CONFIDENTIAL 30
8. Other drugs known to influence calcium and bone metabolism, calcitonin, fluoride, or
cinacalcet hydrochloride within the prohibited period.
9. Use of oral bisphosphonates within the previous 6 months or IV bisphosphonate
preparations during the previous 12 months.
10. Seizure disorder/epilepsy with a history of a seizure within the previous 6 months.
11. Presence of open epiphyses.
12. Irradiation to the skeleton within 5 years.
13. Serum 25-hydroxyvitamin D levels > 120 ng/mL (normal 20 – 80 ng/mL).
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 30 days prior to screening for this study.
16. Women of child-bearing potential unless surgically sterilized or are postmenopausal for
_ 2 years.
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 status of patient who responds is defined as a patient who demonstrates at least 50% reduction in the oral integration of calcium, with respect to the reference values, and at least 50% reduction in metabolite of vitamin D or similar treatment with respect to the reference values at the 24th week of the study. The patients must have a level of calcium in the serum which is clinically stable, considered to be satisfactory by the experimenter as reference and maintained or normalized at the 24th week of the study. At the end of the treatment phase, the patients must have a level of calcium in the serum which is clinically stable according to the experimenter and immediately less than or within the lower half of the 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 | 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
| 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 | 1 |
| 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 |
|
| 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
| |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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