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Study of the Effect of Recombinant Human Parathyroid Hormone [rhPTH(1-84)] on Metabolic Control and Symptoms Among Adults With Hypoparathyroidism

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ClinicalTrials.gov Identifier: NCT03324880
Recruitment Status : Not yet recruiting
First Posted : October 30, 2017
Last Update Posted : November 6, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:
The purpose of this study is to evaluate whether adding an investigational medication called recombinant human parathyroid hormone (rhPTH[1-84]) to standard hypoparathyroidism therapy (oral calcium and active vitamin D tablets) may result in superior improvements in symptoms of hypoparathyroidism assessed by hypoparathyroidism symptom diary (HPT-SD) symptom scale compared with standard therapy.

Condition or disease Intervention/treatment Phase
Hypoparathyroidism Biological: rhPTH(1-84) Biological: Placebo Phase 4

Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled, Adaptive Study to Evaluate Symptom Improvement and Metabolic Control Among Adult Subjects With Symptomatic Hypoparathyroidism Treated With Recombinant Human Parathyroid Hormone [rhPTH(1-84)]
Anticipated Study Start Date : November 27, 2017
Estimated Primary Completion Date : March 2, 2021
Estimated Study Completion Date : June 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: rhPTH(1-84)
Participants will receive rhPTH(1-84) 50 microgram (mcg) subcutaneous (SC) injection once daily (QD), titrated within the dose range of 25-100 mcg QD as an adjunctive treatment with active vitamin D and calcium supplements based on metabolic response.
Biological: rhPTH(1-84)
rhPTH(1-84) 25, 50, 75, and 100 mcg QD SC injection will be administered
Placebo Comparator: Placebo
Participants will receive placebo matched to rhPTH(1-84) as SC injection QD with active vitamin D and calcium supplements.
Biological: Placebo
Placebo QD SC injection will be administered


Outcome Measures

Primary Outcome Measures :
  1. Change in Hypoparathyroidism Symptom Diary (HPT-SD) Symptom Subscale Score From Baseline to Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in HPT-SD symptom subscale score from baseline to Week 26 will be reported.


Secondary Outcome Measures :
  1. Change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in FACIT-fatigue score at Week 26 will be reported.

  2. Change in Physical Component Summary (PCS) Derived From 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in PCS derived from SF-36v2 at Week 26 will be reported.

  3. Percentage of Participants Achieving Minimal Clinical Important Difference (MCID) in Hypoparathyroidism Symptom Diary (HPT-SD) Symptom Subscale Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    Percentage of participants achieving MCID in HPT-SD symptom subscale score at Week 26 will be reported.

  4. Change in Hypoparathyroidism Symptom Diary (HPT-SD) Impact Subscale Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in the impact subscale score at Week 26 will be reported.

  5. Change in Hypoparathyroidism Symptom Diary (HPT-SD) Symptom Item Anxiety (item 8) and Symptom Item Sadness or Depression (Item 9) Individual Item Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in the HPT-SD symptom item anxiety (item 8) and symptom item sadness or depression at Week 26 will be reported.

  6. Change in Individual Hypoparathyroidism Symptom Diary (HPT-SD) Symptom Items Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in score of individual HPT-SD symptom items at Week 26 will be reported.

  7. Change in Individual Hypoparathyroidism Symptom Diary (HPT-SD) Impact Items Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in score of individual HPT-SD impact items at Week 26 will be reported.

  8. Change in Individual Domains and Mental Component Summary (MCS) Score of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in the score of individual domains and MCS of SF-36v2 at Week 26 will be reported.

  9. Change in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in FACT-Cog score at Week 26 will be reported.

  10. Change in Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP) Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in WPAI-SHP score at Week 26 will be reported.

  11. Change in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Severity (PGI-S) at Week 26 [ Time Frame: Baseline, Week 26 ]
    Mean change in scores of PGI-S at Week 26 will be reported.

  12. Change in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Change (PGI-C) at Week 26 [ Time Frame: Baseline, Week 26 ]
    Mean change in scores of PGI-C at Week 26 will be reported.

  13. Change in In-Clinic Neurocognitive Assessment Scores at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in in-clinic neurocognitive assessment scores at Week 24 will be reported.

  14. Change in At-Home Neurocognitive Assessment Scores at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in at-home neurocognitive assessment scores (cogstate brief battery) at Week 26 will be reported.

  15. Change in 24-hour Urine Calcium Excretion at Week 26 [ Time Frame: Baseline, Week 26 ]
    Effect of rhPTH(1-84) on change in 24-hour urine calcium excretion at Week 26 will be reported.

  16. Number of Participants With Albumin-corrected Serum Calcium Concentration at Week 26 [ Time Frame: Baseline, Week 26 ]
    Number of participants with albumin-corrected serum calcium between 1.875 millimolar per liter (mmol/L) (7.5 milligram per decilitre [mg/dL]) and upper limit of normal (ULN) for the central laboratory normal range at Week 26 will be reported.

  17. Number of Participants With Change in Serum Phosphate Level at Week 26 [ Time Frame: Baseline, Week 26 ]
    Number of participants with change in serum phosphate level at Week 26 will be reported.

  18. Change in Doses of Active Vitamin D and Calcium Supplements at Week 26 [ Time Frame: Baseline, Week 26 ]
    Changes in doses of active vitamin D and calcium supplements will be reported at Week 26.

  19. Number of Participants Achieving Albumin-corrected Serum at Week 26 [ Time Frame: Week 26 ]
    Number of participants achieving albumin-corrected serum calcium between 1.875 mmol/L (7.5 mg/dL) and the ULN for the central laboratory normal range at Week 26 will be reported.

  20. Number of Participants Achieving 50 Percent (%) Decrease in Dose of Active Vitamin D at Week 26 [ Time Frame: Week 26 ]
    Number of participants achieving 50 percent (%) decrease in dose of active vitamin D at Week 26 will be reported.

  21. Number of Participants Achieving 50 percent (%) or More Decrease in Dose of Oral Calcium Supplement at Week 26 [ Time Frame: Week 26 ]
    Number of participants achieving 50 % or more decrease in dose of oral calcium supplement at Week 26 will be reported.

  22. Markers of Bone Turnover at Week 26 [ Time Frame: Week 26 ]
    Bone turnover markers includes serum bone-specific alkaline phosphatase, procollagen amino-terminal peptide, C-terminal telopeptide of type 1 collagen, and osteocalcin. Markers of bone turnover at Week 26 will be reported.

  23. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From start of study drug administration up to Week 30 ]
    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as AEs that started or worsened on or after the date and time of the first dose of investigational product.

  24. Number of Participants With Hypocalcemic Adverse Events (AEs) [ Time Frame: From start of study drug administration up to Week 30 ]
    Hypocalcemia AEs reported in the study are categorized into severe hypocalcemia, self-treated hypocalcemia, and mild to moderate hypocalcemia that are not self-treated.

  25. Number of Participants With Clinically Significant Change in Vital Signs Reported as an Adverse Event [ Time Frame: From start of study drug administration up to Week 30 ]
    Vital sign assessments include blood pressure, pulse, body temperature, and respiratory rate.

  26. Number of Participants With Clinically Significant Change in Clinical Laboratory Results Reported as an Adverse Event [ Time Frame: From start of study drug administration up to Week 30 ]
    Clinical laboratory evaluations include serum chemistry, hematology, and urinalysis.

  27. Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Reported as an Adverse Event [ Time Frame: From start of study drug administration up to Week 30 ]
    12-lead ECG will be recorded and measured with the participant in rested supine position for at least 5 minutes.

  28. Number of Participants With Antiparathyroid Hormone (PTH) Antibodies [ Time Frame: Baseline, Week 12, Week 30 ]
    Number of participants with positive Anti-PTH antibodies will be reported.


Eligibility Criteria

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 25 years of age or younger, has radiological evidence of epiphyseal closure based on X-ray of left wrist and left hand before randomization.
  • Has a history of 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 parathyroid hormone (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).
  • Based on the results of the Hypoparathyroidism Symptom Diary (HPT-SD) administered during the first week of the screening period (from Week -3 to Week -2 visits), the participant reports at least 2 of the following symptoms that average at least moderate in intensity: muscle cramps, muscle spasms or twitching, tingling, numbness, heaviness in arms or legs, physical fatigue, or slowed or confused thinking (brain fog). Additionally, the sum score of the HPT-SD symptom subscale (items 1-7) measured during the first week of the screening period must be greater than or equal to (>=) 6. At least 4 responses must be entered for each symptom.
  • Must be treated with active vitamin D (calcitriol or alfacalcidol) alone or in conjunction with calcium supplements.

    1. If treated with active vitamin D alone, the participant must be taking >=0.5 microgram per day (mcg/day) of calcitriol or >=1.0 mcg/day of alfacalcidol. If treated with less than (<) 0.5 mcg/day of calcitriol or <1.0 mcg/day of alfacalcidol, the participant must have a history of inability to be successfully managed with a higher active vitamin D dose.
    2. If the participant is treated with active vitamin D in conjunction with calcium supplements, the participant must be taking >=0.25 mcg/day of calcitriol or >=0.5 mcg of alfacalcidol with >=1000 milligram ([mg]/day) of calcium supplement. If the participant is treated with <0.25 mcg/day of calcitriol or <0.5 mcg of alfacalcidol or <1000 mg/day of calcium supplement, the participant must have a history of inability to be successfully managed on higher doses of at least one of these supplements.
  • Has 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 reference range. A serum TSH level below the lower limit of the normal range but not undetectable in participants 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 millimolar per liter (mmol/L) (20 [nanogram per milliliter] ng/mL) and <1.5 times the upper limit of normal (ULN) for the central laboratory normal range.
  • Has estimated glomerular filtration rate (eGFR) >30 milliliter per minute per 1.73 meter square (ml/min/1.73 m^2).
  • Prior to randomization, is able to perform daily subcutaneous (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.
  • 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 calcium-sensing receptor (CaSR) gene or impaired responsiveness to PTH (pseudohypoparathyroidism).
  • Any disease that might affect calcium metabolism or calcium-phosphate homeostasis other than hypoparathyroidism, such as active hyperthyroidism; Paget disease; type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus; severe and chronic cardiac, liver, 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.
  • Albumin-corrected serum calcium level <1.875 mmol/L (7.5 [milligram per decilitre] mg/dL) or >=2.56 mmol/L (10.3 mg/dL) at the Week -3 screening visit. Results from a local laboratory may be used for this assessment.
  • Albumin-corrected serum calcium level >=2.56 mmol/L (10.3 mg/dL) 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.
  • Pregnant or lactating women.
  • History of diagnosed drug or alcohol dependence within the previous 3 years.
  • 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 disease.
  • Chronic or severe cardiac disease including but not limited to heart failure, arrhythmias, bradycardia (resting heart rate <50 beats/minute).
  • History of cerebrovascular accident.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03324880


Contacts
Contact: Shire Contact 866-842-5335 ClinicalTransparency@shire.com

Sponsors and Collaborators
Shire
Investigators
Study Director: Shire Physician Shire
More Information

Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT03324880     History of Changes
Other Study ID Numbers: SHP634-401
2017-000284-32 ( EudraCT Number )
First Posted: October 30, 2017    Key Record Dates
Last Update Posted: November 6, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shire:
rhPTH[1-84)
Parathyroid hormone
Hypocalcemia
Hypoparathyroidism

Additional relevant MeSH terms:
Hypoparathyroidism
Parathyroid Diseases
Endocrine System Diseases
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs