Study to Assess the Blood Concentrations and Actions of Recombinant Human Parathyroid Hormone (rhPTH [1-84]) When Given Once and Twice Daily to Participants With Hypoparathyroidism
Condition: Hypoparathyroidism
MeSH terms: Hypoparathyroidism
Intervention: 25mcg rhPTH(1-84); 50mcg rhPTH(1-84); 100mcg rhPTH(1-84)
Intervention description: Participants will receive rhPTH(1-84) as twice-daily regimen (12 hours apart) of two 25mcg doses without calcium in cohort 1 and with calcium in cohort 3.; Participants will receive rhPTH(1-84) as twice daily regimen (12 hours apart) of two 50mcg doses without calcium in cohort 2 and with calcium in cohort 4; Participants will receive rhPTH(1-84) as once-daily regimen of one 100 mcg dose without calcium in cohort 1 and 2 and with calcium in cohort 3 and 4 in the morning.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study is being conducted to characterize the effects of twice daily administration of
      rhPTH(1-84) on the way the body handles rhPTH(1-84) as well as its actions and safety and
      tolerability over the course of 24 hours as compared with the current once daily dosing
      regimen of marketed rhPTH(1-84) (marketed in the United States as Natpara® and in the EU as
      Natpar).
    

Eligibility criteria:

        Inclusion Criteria:

          1. An understanding, ability, and willingness to fully comply with study procedures and
             restrictions.

          2. Ability to voluntarily provide written, signed, and dated informed consent as
             applicable to participate in the study.

          3. Adult men or women aged greater than or equal (>=) 18 years at the time of consent.
             The date of participant signature of the informed consent is defined as the beginning
             of the Screening Period. The Screening Period for this study may encompass both the
             Administrative Screening Period (if needed) and the Clinical Screening Period. For
             purposes of this inclusion criterion, age will only be assessed at the time the
             informed consent is first signed by the study participant.

          4. History of hypoparathyroidism for >=12 months, post-diagnosis, inclusive of historical
             biochemical evidence of hypocalcemia with concomitant serum intact parathyroid hormone
             (PTH) concentrations below the lower limit of the laboratory normal range.

          5. Requirement for supplemental oral calcium treatment >=1000 milligrams (mg) elemental
             calcium per day.

          6. Requirement for therapy with active forms of vitamin D at a minimum dose of >=0.25
             microgram (mcg) per day (that is, >=0.25 mcg calcitriol or equivalent per day).

          7. Serum calcium level within the laboratory normal reference range based on clinical
             chemistry lab results at the Clinical Screening Visit (based on central and/or local
             lab results) and Treatment Period 1, Day -2 (based on central and/or local lab
             results), or if outside of normal range, considered not clinically significant by the
             investigator.

          8. Urinary calcium excretion >=200mg (5 millimolar [mmol])/24 hour (h), based on a
             24-hour collection, collected anytime during the Clinical Screening Period, but prior
             to check-in to the Clinical Research Center (CRC) at Treatment Period 1, Day -2 (based
             on central and/or local lab results).

          9. Serum magnesium level within the laboratory normal range at the Clinical Screening
             Visit or, if outside of normal range, considered not clinically significant by the
             investigator.

         10. Serum thyroid function tests within normal laboratory limits at the Clinical Screening
             Visit, or, if outside of normal range, considered as not clinically significant by the
             investigator.

         11. Serum 25-hydroxyvitamin D (25(OH)D) level between the lower limit of normal and
             1.5-fold the laboratory upper limit of normal, or, if outside of this range,
             considered not clinically significant by the investigator, at the Clinical Screening
             Visit.

         12. Serum creatinine less than (<) 1.5 mg/ decilitre (dL) (<133 micromole [mmol]/ litre
             [L]) AND estimated creatinine clearance greater than (>) 60 millilitre (mL)/minute
             (>1.002mL/ Second [s]) at the Clinical Screening Visit, and serum creatinine <1.5
             mg/dL (<133mmol/L) at Treatment Period 1, Day -2.

         13. Male or non-pregnant, non-lactating female who agrees to comply with any applicable
             contraceptive requirements of the protocol or females of non-childbearing potential.

        Exclusion Criteria:

          1. Participation in any other investigational drug study in which the last dose of
             investigational drug occurred within 3 months prior to Day 1 of Treatment Period 1 (or
             within 5 half-lives, if elimination half-life is greater than 18 days).

          2. Presence or history of a clinically significant disorder involving the cardiovascular,
             respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine (with
             exception of the condition under study), or neurologic system(s) or psychiatric
             disease as determined by the investigator.

          3. Known history of hypoparathyroidism resulting from an activation mutation in the
             calcium sensing receptor (CaSR) gene or impaired responsiveness to PTH
             (pseudohypoparathyroidism).

          4. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis
             other than hypoparathyroidism, including but not limited to, active hyperthyroidism;
             poorly controlled insulin-dependent diabetes mellitus or type 2 diabetes mellitus;
             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, bone metastases or a history of
             skeletal malignancies; primary or secondary hyperparathyroidism; a history of
             parathyroid carcinoma; hypopituitarism, acromegaly; or multiple endocrine neoplasia
             types 1 and 2, as determined by the investigator.

        5 . In male and female rats, parathyroid hormone caused an increase in the incidence of
        osteosarcoma (a malignant bone tumor). The occurrence of osteosarcoma was dependent on
        parathyroid hormone dose and treatment duration. This effect was observed at parathyroid
        hormone exposure levels ranging from 3 to 71 times the exposure levels in humans receiving
        a 100 mcg dose of rhPTH(1-84). Therefore, participant who are at increased baseline risk
        for osteosarcoma such as participant with Paget's disease of bone or unexplained elevations
        of alkaline phosphatase, pediatric and young adult participants with open epiphyses,
        participants with hereditary disorders predisposing to osteosarcoma or participant with a
        prior history of external beam or implant radiation therapy involving the skeleton are
        excluded.

        6. Participants who have a known history of hypercalcemia during initiation of treatment
        with PTH, PTH analogues or fragments of PTH.

        7. Participants who have a known history of hypocalcemia following abrupt withdrawal of
        treatment with PTH, PTH analogues or fragments of PTH.

        8. Participant dependent on regular parenteral calcium infusions (example, calcium
        gluconate) to maintain calcium homeostasis within 3 months prior to enrollment, as
        determined by the investigator.

        9. Use of the following medications prior to administration of investigational product
        within: 14 days- thiazide diuretics; 30 days - loop diuretics, lithium, systemic
        corticosteroids (medical judgment is required by the investigator. Primarily high doses of
        systemic corticosteroids [example, prednisone] should be excluded. Stable doses of
        hydrocortisone [example, as treatment for Addison's disease] may be acceptable); 3 months -
        calcitonin, cinacalcet hydrochloride, treatment with rhPTH(1-84) or N-terminal PTH or
        PTH-related peptide fragments or analogs; For females: changes in hormone replacement
        therapy within 3 months are excluded. Stable (>=3 months) hormone replacement therapy is
        acceptable; 6 months - fluoride tablets, oral bisphosphonates, methotrexate, growth
        hormone, digoxin, raloxifene or similar selective estrogen receptor modulators (SERMs); 12
        months - intravenous bisphosphonates, drug or alcohol abuse, as determined by the
        investigator.

        10. Presence of any clinically significant results from laboratory tests, vital signs
        assessments, or electrocardiograms (ECGs), as judged by the investigator.

        11. Twelve-lead ECG values (average of triplicate readings) demonstrating QTc>450
        millisecond (msec) (males) or >470 msec (females) at the Clinical Screening Visit and/or
        any time points up to and including predose of Day 1 (Period 1).

        12. Any medical condition or prior therapy that, in the opinion of the investigator, would
        make the participant unsuitable for this study.

        13. Positive test result for any of the following viral infections at the Clinical
        Screening Visit: Hepatitis B surface antigen; hepatitis C; human immunodeficiency virus
        (HIV) 14. Known significant bleeding diathesis that could preclude multiple venipunctures
        as determined by the investigator.

        15. Participants who have donated a total of 100 mL to 499 mL of whole blood within 30 days
        prior to dosing, or participants who have donated a total of more than 499 mL of whole
        blood within 56 days prior to dosing.

        16. A positive screen for drugs of abuse at the Clinical Screening Visit, and/or a positive
        screen for drugs of abuse and alcohol at check-in to the CRC at Treatment Period 1.
        Participants taking prescription medications that might be detected during the urine screen
        for drugs of abuse may be enrolled per the investigator's medical judgment.

        17. History of a clinically significant illness during the 4 weeks prior to dosing (as
        determined by the investigator).

        18. History of any clinically significant surgery or procedure within the past 8 weeks, as
        determined by the investigator.

        19. History of an allergic response(s) to PTH or PTH analogs, or other clinically
        significant allergies, as determined by the investigator.