A Study to Learn if Recombinant Human Parathyroid Hormone [rhPTH(1-84)] Can Improve Symptoms and Metabolic Control in Adults With Hypoparathyroidism (BALANCE)
Condition: Hypoparathyroidism
MeSH terms: Hypoparathyroidism
Intervention: rhPTH (1-84); Placebo
Intervention description: rhPTH (1-84) SC injection.; Placebo QD SC injection.
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 93.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: rhPTH[1-84); Parathyroid hormone; Hypocalcemia; Hypoparathyroidism

Summary:

      Recombinant human parathyroid hormone, also known as if rhPTH(1-84), is a medicine to treat
      people with Hypothyroidism. The main aim of this study is to learn if rhPTH(1-84) can improve
      symptoms in adults with hypoparathyroidism.

      In this study, participants will receive 1 of 2 treatments: rhPTH(1-84) or a placebo. A
      placebo looks like the medicine being studied but does not have medicine in it. In this
      study, the placebo will be a standard treatment which is either active Vitamin D, or active
      Vitamin D with calcium. Active Vitamin D is a form of vitamin D that has a faster effect on
      the body. These treatments will be given as a daily injection just under the skin.
      Participants will not know which treatment they received, nor will their study doctors. This
      is to help make sure the results are more reliable. All participants will also take active
      vitamin D and calcium supplements during treatment.

      Participants will record their symptoms in a tool called the hypoparathyroidism symptom
      diary. This tool is used to assess symptoms and their impact and will give an overall score
      for each participant.

      The study doctors will also check for side effects from the study treatments.

      After treatment, researchers will check if there is any difference in the diary scores
      between the 2 treatment groups. A difference in score means there is a difference in symptoms
      and their impact. From this, researchers will learn if symptoms have improved for
      participants treated with rhPTH(1-84) compared with those treated with placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has an understanding, ability, and willingness to fully comply with study procedures
             and restrictions.

          -  Is able to voluntarily provide a signed and dated informed consent form before any
             study-related procedures are performed.

          -  Is an adult male or female 18 to 85 years of age, inclusive.

          -  In participants 18-25 years of age, has radiological evidence of epiphyseal closure
             based on bone age X-ray (single posteroanterior X-ray of left wrist and hand) before
             randomization.

          -  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.

          -  During the Week -3 screening visit, the participant 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).

          -  The participant must have a Hypoparathyroidism Symptom Diary (HPT-SD) symptom subscale
             Sum Score of greater than or equal to (>=) 10 during the 14-day period immediately
             prior to the baseline (Week 0) visit (Day -14 to Day -1). In addition, the participant
             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.

          -  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.

               1. The participant must be taking >= 0.5 microgram (mcg)/day of calcitriol or >=1.0
                  mcg/day of alfacalcidol.

               2. If the participant is treated with a lower dose of active vitamin D the
                  participant must also be taking calcium supplements of at least 800 milligrams
                  per day (mg/day) of elemental calcium.

          -  Has serum thyroid-stimulating hormone (TSH) results within normal laboratory limits at
             screening for all participants not receiving thyroid hormone replacement therapy. For
             participants 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 participant treated with thyroid hormone may
             be allowed if there is no anticipated need for a change in thyroid hormone dose during
             the trial.

          -  Has serum 25-hydroxyvitamin D levels >=50 nmol/L (nanomoles per liter) (20 nanograms
             per milliliter [ng/mL]) and less than (<) 1.5 times the upper limit of normal (ULN)
             for the central laboratory normal range.

          -  Has estimated glomerular filtration rate (eGFR) greater than (>) 30 milliliter per
             minute per 1.73 square meters (ml/min/1.73m^2).

          -  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.

          -  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.

          -  With regard to female participants: women who are postmenopausal (12 consecutive
             months of spontaneous amenorrhea and age >= 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.

        Exclusion Criteria:

          -  History of hypoparathyroidism resulting from a known activating mutation in the CaSR
             gene or impaired responsiveness to PTH (pseudohypoparathyroidism).

          -  Any disease that might affect calcium metabolism or calcium-phosphate 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.

          -  Very low or very high blood calcium level (eg, ACSC <1.87 mmol/L [<7.5 mg/dL] or
             >=2.97 mmol/L [>=11.9 mg/dL]) at the Week -3 screening visit. Results from the central
             laboratory must be used for this assessment.

          -  Blood calcium level above the ULN at the baseline (Week 0) visit. Results from a local
             laboratory may be used for this assessment.

          -  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.

          -  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.

          -  Use of other drugs known to influence calcium and bone metabolism, such as calcitonin,
             fluoride tablets, or cinacalcet hydrochloride, within the prohibited period.

          -  Use of oral bisphosphonates within the previous 6 months or intravenous bisphosphonate
             preparations within the previous 24 months before screening.

          -  Nonhypocalcemic seizure disorder with a history of a seizure within the previous 6
             months before screening. Participants with a history of seizures that occur in the
             setting of hypocalcemia are allowed.

          -  The participant 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.

          -  Any disease or condition that, in the opinion of the investigator, may require
             treatment or make the participant 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.

          -  Pregnant or lactating women.

          -  Known or suspected intolerance or hypersensitivity to the investigational product,
             closely-related compounds, or any of the stated ingredients.

          -  History of diagnosed drug or alcohol dependence within the previous 3 years.

          -  Poorly controlled short bowel syndrome, bowel resection, tropical sprue, celiac
             disease, ulcerative colitis, and Crohn disease.

          -  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).

          -  History of cerebrovascular accident.