| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
Inappropriately low or undetectable levels of parathyroid hormone (PTH)
circulated through the body |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Biological Phenomena [G16] |
| 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 | 10051315 |
| E.1.2 | Term | Congenital hypoparathyroidism |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 | 10075900 |
| E.1.2 | Term | Primary hypoparathyroidism |
| E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
|
| 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 test the hypothesis that rhPTH(1-84) treatment can result in superior improvements in the symptoms of hypoparathyroidism assessed by the hypoparathyroidism Symptom Diary (HPT-SD) symptom subscale compared with standard therapy. |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives are to test the hypotheses that rhPTH(1-84) treatment can result in
superior improvements in:
Fatigue assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) compared with standard therapy.
The physical component summary (PCS) derived from the 36-Item Short Form Health Survey version 2
(SF-36v2) acute version compared with standard therapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has an understanding, ability, and willingness to fully comply with study procedures and
restrictions.
2. Is able to voluntarily provide a signed and dated informed consent form before any study-related procedures are performed.
3. Is an adult male or female 18 to 85 years of age, inclusive.
4. In subjects 18-25 years of age or younger, has radiological evidence of epiphyseal closure based on X-ray of left wrist and left hand before randomization.
5. Has chronic hypoparathyroidism with onset 12 months or more before screening. The diagnosis of hypoparathyroidism is established based on hypocalcemia in the setting of inappropriately low serum PTH levels.
6. During the Week -3 screening visit, the subject reports by history at least 2 of the following symptoms related to hypoparathyroidism occurring within the 2 weeks before Week -3 visit: muscle cramps, muscle spasms or twitching, tingling, numbness, heaviness in arms or legs, physical fatigue, or slowed or confused thinking (brain fog).
7. The subject must have a Hypoparathyroidism Symptom Diary (HPTSD) symptom subscale Sum Score of ≥10 during the 14-day period immediately prior to the baseline (Week 0) visit (Day -14 to Day -1). In addition, the subject must have at least 4 HPT-SD diaries completed in
the first 7 day period and at least 4 HPT-SD diaries completed in second 7 day period. See Appendix 3 for the calculation of the sum score
8. Must be treated with active vitamin D (calcitriol or alfacalcidol) alone or in conjunction with calcium supplements for at least 4 months prior to the screening visit.
- The subject must be taking ≥0.5 µg/day of calcitriol or ≥1.0 µg/day of alfacalcidol.
- If the subject is treated with a lower dose of active vitamin D the subject must also be taking calcium supplements of at least 800 mg/day of elemental calcium
9. Has thyroid-stimulating hormone (TSH) results within normal laboratory limits at screening for all subjects not receiving thyroid hormone replacement therapy. For subjects on thyroid hormone replacement therapy, the thyroid hormone dose must have been stable for at least 4 weeks before screening, and serum TSH level must be within the
central laboratory normal range. A serum TSH level below the lower limit of the normal range but not undetectable in subjects treated with thyroid hormone may be allowed if there is no anticipated need for a change in thyroid hormone dose during the trial.
10. Has serum 25-hydroxyvitamin D levels ≥50 nmol/L (20 ng/mL) and <1.5 times the upper limit of normal (ULN) for the central laboratory normal range.
11. Has estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m2.
12. Prior to randomization, is able to perform daily SC self-injections of study medication (or have a designee perform injection) via a multidose injection pen into the thigh.
13. Willing to use oral active vitamin D and calcium supplements provided for the study unless directed to remain on the supplements used prior to enrollment in the current study by the investigator after consultation with the medical monitor
14. With regard to female subjects: women who are postmenopausal (12 consecutive months
of spontaneous amenorrhea and age more than or equal to 51 years) 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 comply with any applicable contraceptive requirements of the protocol and pregnancy testing for the duration of the study. |
|
| E.4 | Principal exclusion criteria |
1. History of hypoparathyroidism resulting from a known activating mutation in the CaSR gene or impaired responsiveness to PTH (pseudohypoparathyroidism).
2. Any disease that might affect calcium metabolism or calciumphosphate homeostasis other than hypoparathyroidism, such as poorly controlled hyperthyroidism; Paget disease; type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus; severe and chronic cardiac,
liver (Child-Pugh score >9) (US FDA, 2003), or renal disease; Cushing syndrome; rheumatoid arthritis; myeloma; active pancreatitis; malnutrition; rickets; recent prolonged immobility; active malignancy (other than low-risk well differentiated thyroid cancer); primary
or secondary hyperparathyroidism; or documented parathyroid carcinoma within the previous 5 years, acromegaly, or multiple endocrine neoplasia types 1 and 2.
3. Very low or very high blood calcium level (eg, ACSC <1.87 mmol/L [<7.5mg/dL] or ≥2.97mmol/L [≥11.9 mg/dL]) at the Week -3 screening visit. Results from the central laboratory must be used for this assessment
4. If the Blood calcium level is above the ULN at the baseline (Week 0) visit, the analysis can be repeated another day as long as the next date is within the visit window for the baseline visit. If the subject does not met exclusion #4 on the repeat measure the subject may be randomized.
5. Use of prohibited medications, such as loop and thiazide diuretics, phosphate binders (other than calcium carbonate), digoxin, lithium, methotrexate, or systemic corticosteroids, within respective prohibited periods. See Section 5 (Prior and Concomitant Treatment) for a list of prohibited and restricted medications
6. Participation in any other investigational study in which receipt of investigational drug or device occurred within 6 months before screening for this study. Prior treatment with PTH-like drugs (whether commercially available or through participation in an
investigational study), including PTH(1-84), PTH(1-34), or other N-terminal fragments or analogs of PTH or PTH-related protein, within 3 months before screening.
7. Use of other drugs known to influence calcium and bone metabolism, such as calcitonin, fluoride tablets, or cinacalcet hydrochloride, within the prohibited period.
8. Use of oral bisphosphonates within the previous 6 months or intravenous bisphosphonate
preparations within the previous 24 months before screening.
9. Nonhypocalcemic seizure disorder with a history of a seizure within the previous 6 months before screening. Subjects with a history of seizures that occur in the setting of hypocalcemia are allowed.
10. The subject is at increased baseline 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 external beam or implant radiation therapy involving the skeleton.
11. Any disease or condition that, in the opinion of the investigator, may require treatment or make the subject unlikely to fully complete the study, or any condition that presents undue risk from the investigational product or procedures. For example, illness that is anticipated to be
chronic and not transient.
12. Pregnant or lactating women.
13. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related compounds, or any of the stated ingredients. Refer to the investigator's brochure for the list of excipients
14. History of diagnosed drug or alcohol dependence within the previous 3 years.
15. Poorly controlled short bowel syndrome, bowel resection, tropical sprue, celiac disease, ulcerative colitis, and Crohn disease.
16. )Chronic or severe cardiac disease including but not limited to heart failure (according to the New York Heart Association classification Class II to Class IV) (Dolgin and NYHA, 1994), arrhythmias, bradycardia (resting heart rate <50 beats/minute).
17. History of cerebrovascular accident. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in the HPT-SD symptom subscale score from baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Change in FACIT-Fatigue score at Week 26
Change in the PCS derived from SF-36v2 scores at Week 26 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| 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 |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
The date the final subject, across all sites, completes their final protocol-defined assessment. Please note that this includes the follow-up visit or
contact, whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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