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

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ClinicalTrials.gov Identifier: NCT03324880
Recruitment Status : Recruiting
First Posted : October 30, 2017
Last Update Posted : October 16, 2018
Sponsor:
Information provided by (Responsible Party):
Shire

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 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)]
Actual Study Start Date : February 15, 2018
Estimated Primary Completion Date : December 26, 2020
Estimated Study Completion Date : December 26, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones

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




Primary Outcome Measures :
  1. Change From Baseline in Hypoparathyroidism Symptom Diary (HPT-SD) Symptom Subscale Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness and depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4 and for items 10-13, it ranges from Not at all=0 to Very much=2. For symptom subscale score, the average score of the symptom items 1-7 will be calculated.


Secondary Outcome Measures :
  1. Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire contains 13 fatigue-related questions. The responses to the 13 items on the FACIT-Fatigue questionnaire are each measured on a 4-point Likert scale. Thus, the total score ranges from 0 to 52. High scores represent less fatigue.

  2. Change From Baseline 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 ]
    The SF-36 is a validated instruments that question participants about perceived physical and mental health and function. The SF-36 consists of 8 scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health), which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight; the lower the score the more disability. Change in PCS derived from SF-36v2 at Week 26 will be reported.

  3. Change From Baseline in Hypoparathyroidism Symptom Diary (HPT-SD) Impact Subscale Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness and depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4 and for items 10-13, it ranges from Not at all=0 to Very much=2. For Impact subscale, the average score of the impact items 10-13 will be calculated.

  4. Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HPT-SD) Impact Items Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness and depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4 and for items 10-13, it ranges from Not at all=0 to Very much=2.

  5. Change From Baseline in Hypoparathyroidism Symptom Diary (HPT-SD) Symptom Item Anxiety (item 8) Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness and depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4 and for items 10-13, it ranges from Not at all=0 to Very much=2.

  6. Change From Baseline in Hypoparathyroidism Symptom Diary (HPT-SD) Symptom Item Sadness or Depression (Item 9) Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness and depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4 and for items 10-13, it ranges from Not at all=0 to Very much=2.

  7. Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HPT-SD) Symptom Items Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness and depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4 and for items 10-13, it ranges from Not at all=0 to Very much=2. The change in individual symptom item scores will be reported.

  8. Number of Participants With Response at Week 26 [ Time Frame: Baseline to Week 26 ]
    Response is defined as a 30% reduction in HPT-SD symptom subscale score from baseline. The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness and depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4 and for items 10-13, it ranges from Not at all=0 to Very much=2. For symptom subscale score, the average score of the symptom items 1-7 will be calculated.

  9. Change From Baseline in the Most Bothersome Symptom Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The HPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness and depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4 and for items 10-13, it ranges from Not at all=0 to Very much=2. The Most Bothersome Symptom Score will be analyzed.

  10. Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) assessment is a 37-item instrument. Each item will be scored from 0=Not at all to 4=Very much.

  11. Change From Baseline in Individual Domains of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26 [ Time Frame: Baseline, Week 26 ]
    The SF-36 is a validated instruments that question participants about perceived physical and mental health and function. The SF-36 consists of 8 scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health), which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight; the lower the score the more disability. Change in the score of individual domains of SF-36v2 at Week 26 will be reported.

  12. Change From Baseline in Mental Component Summary (MCS) Score of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26 [ Time Frame: Baseline, Week 26 ]
    The SF-36 is a validated instruments that question participants about perceived physical and mental health and function. The SF-36 consists of 8 scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, and mental health), which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight; the lower the score the more disability. Change in the MCS of SF-36v2 at Week 26 will be reported.

  13. Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Hypoparathyroidism (WPAI:Hypoparathyroidism) Score at Week 26 [ Time Frame: Baseline, Week 26 ]
    The WPAI:Hypoparathyroidism will be used to assess how hypoparathyroidism affects partcipants' ability to work and perform regular activities. Concepts that the WPAI:Hypoparathyroidism measures include time missed from work and impairment of work and other regular activities due to specific health problems. The change from baseline in the questionnaire response will be reported.

  14. Change From Baseline 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 ]
    The PGI-S is a verbal rating scale asks the respondent to best describe how their symptoms severity. Response options are no symptoms, mild, moderate, severe and very severe. Mean change in scores of PGI-S at Week 26 will be reported.

  15. Change From Baseline 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 ]
    The PGI-C is verbal rating scale asks the respondent to best describe change in symptoms compared to the beginning of study. Response options are very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse. Mean change in scores of PGI-C at Week 26 will be reported.

  16. Change From Baseline in In-Clinic Neurocognitive Assessment Scores at Week 24 [ Time Frame: Baseline, Week 24 ]
    The neurocognitive test battery will include tests evaluating the frontal-executive domain, which encompasses functions attributable to the prefrontal cortex and its connections to the basal ganglia (mostly striatum). The tests will include the CogState (CS) Brief Battery (including the Detection: speed [range from 2.001 to 6; lower scores (LS) indicate improvement (IMP)], Identification: speed [range from 2.001 to 6; LS indicate IMP], One Card Learning: accuracy [range from 0 to 1.5708; higher scores (HS) indicate IMP], One Back: speed [range from 2.001 to 6; LS indicate IMP]), CS Groton Maze Learning Test: total errors (range from 0 to infinity; LS indicate IMP), CS International Shopping List Task (ISLT): number of correct responses (range from 0 to infinity; HS indicate IMP), and CS ISLT -Delayed Recall:number of correct responses (range from 0 to infinity; HS indicate IMP). Change in in-clinic neurocognitive assessment scores at Week 24 will be reported.

  17. Change From Baseline in At-Home Neurocognitive Assessment Scores at Week 24 [ Time Frame: Baseline, Week 24 ]
    The neurocognitive test battery will include tests evaluating the frontal-executive domain, which encompasses functions attributable to the prefrontal cortex and its connections to the basal ganglia (mostly striatum). The tests will include the CogState (CS) Brief Battery (including the Detection: speed [range from 2.001 to 6; lower scores (LS) indicate improvement (IMP)], Identification: speed [range from 2.001 to 6; LS indicate IMP], One Card Learning: accuracy [range from 0 to 1.5708; higher scores (HS) indicate IMP], One Back: speed [range from 2.001 to 6; LS indicate IMP]), CS Groton Maze Learning Test: total errors (range from 0 to infinity; LS indicate IMP), CS International Shopping List Task (ISLT): number of correct responses (range from 0 to infinity; HS indicate IMP), and CS ISLT -Delayed Recall:number of correct responses (range from 0 to infinity; HS indicate IMP). Changes in at-home neurocognitive assessment scores (CS Brief Battery) at Week 24 will be reported.

  18. Change From Baseline in 24-hour Urine Calcium Excretion at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in 24-hour urine calcium excretion at Week 26 will be reported.

  19. Change From Baseline in Serum Phosphate Level at Week 26 [ Time Frame: Baseline, Week 26 ]
    Change in serum phosphate level at Week 26 will be reported.

  20. Change From Baseline 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 at Week 26 will be reported.

  21. Number of Participants With Albumin-corrected Serum Calcium Control at Week 26 [ Time Frame: Week 26 ]
    Number of participants with albumin-corrected serum calcium between 1.875 millimoles 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.

  22. Number of Participants who Achieve Composite Criteria for Albumin-corrected Serum Calcium Concentration, Vitamin D Dose and Oral Calcium Supplement Dose at Week 26 [ Time Frame: Baseline to Week 26 ]
    Number of participants achieving composite criteria of the following: albumin-corrected serum calcium between 1.875 mmol/L (7.5 mg/dL) and the ULN for the central laboratory normal range, dose of active vitamin D decreased by 50% and at least a 50% reduction from the baseline oral calcium supplement dose at Week 26 will be reported.

  23. Change From Baseline in Bone Turnover Markers at Week 26 [ Time Frame: Baseline, Week 26 ]
    Bone turnover markers includes serum bone-specific alkaline phosphatase, procollagen amino-terminal peptide, C-terminal telopeptide of type 1 collagen, and osteocalcin.

  24. 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.



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
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 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 (μg)/day of calcitriol or >=1.0 μg/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 mmol/L (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.

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 +1 866 842 5335 ClinicalTransparency@shire.com

  Show 35 Study Locations
Sponsors and Collaborators
Shire
Investigators
Study Director: Shire Director Shire

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: October 16, 2018
Last Verified: October 2018
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