Safety and Efficacy Study of rhPTH(1-84) in Subjects With Hypoparathyroidism

Study Overview
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Brief Summary
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This study is open to adults with hypoparathyroidism who complete the SHP634-101 study (PARALLAX Study). The purpose of this study is to see if rhPTH(1-84) is safe and effective in adults with hypoparathyroidism who previously participated in the SHP634-101 study. All participants enrolled in this study will receive rhPTH(1-84) once-daily for 52 weeks via an injection. Patients who complete the SHP634-101 study will have the option to screen for this extension study.

Official Title
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An Open-label Study Investigating the Safety and Efficacy of rhPTH(1-84) in Subjects With Hypoparathyroidism

Conditions
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Hypoparathyroidism

Intervention / Treatment
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* Biological: rhPTH(1-84)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An understanding, ability, and willingness to fully comply with study procedures and restrictions Ability to voluntarily provide written, signed, and dated informed consent to participate in the study. Previously completed the SHP634-101 (NCT02781844) study, including the 30-day follow-up. Male or non-pregnant, non-lactating female subjects who agree to comply with applicable contraceptive requirements of the protocol or females of non-childbearing potential. Exclusion Criteria: Received investigational study drug, aside from that received in study SHP634-101 (NCT02781844), within 3 months prior to the screening visit. 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, that in the opinion of the investigator, would make the subject unsuitable for this study. Received parathyroid hormone (PTH), PTH analog, or parathyroid hormone fragment 1-34 [PTH(1-34)] treatment within the last 30 days from the screening visit. Subjects with a history of parathyroid hormone intolerance, based on investigator determination. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis as determined by the investigator 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 . Subjects who are at increased baseline risk for osteosarcoma such as subjects with Paget's disease of bone or unexplained elevations of alkaline phosphatase, young adult subjects with open epiphyses, subjects with hereditary disorders predisposing to osteosarcoma or subjects with a prior history of external beam or implant radiation therapy involving the skeleton. Use of the following medications prior to administration of investigational product within: 30 days-loop diuretics, lithium, systemic corticosteroids (medical judgment is required by the investigator. Primarily high doses of systemic corticosteroids [example (eg), prednisone] should be excluded. Stable doses of hydrocortisone [eg, as treatment for Addison's disease] may be acceptable). 3 months-cinacalcet hydrochloride 6 months-fluoride tablets, oral bisphosphonates, methotrexate, growth hormone, digoxin 12 months-intravenous bisphosphonates, drug or alcohol abuse, as determined by the investigator Presence of any clinically significant results from laboratory tests, vital signs assessments, or electrocardiograms (ECG), that in the opinion of the investigator, would make the subject unsuitable for this study. Any medical condition or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for this study. History of a clinically significant illness during the 4 weeks prior to dosing, that in the opinion of the investigator, would make the subject unsuitable for this study. History of any clinically significant surgery or procedure within 8 weeks of first dose, as determined by the investigator or expected to undergo a major surgical procedure during the trial. History of an allergic response(s) to PTH, PTH analogs, or PTH(1-34), or other clinically significant allergies, that in the opinion of the investigator, would make the subject unsuitable for this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhPTH(1-84)<br>Participants will receive rhPTH(1-84) subcutaneous (SC) injection in the thigh (alternate thigh every day) once daily (QD) of an escalating dose from 50 microgram (mcg) to a maximum of 100 mcg increased in increments of 25 mcg no more frequently than every 2 to 4 weeks, with the goal of achieving or maintaining albumin-corrected serum calcium (ACSC) levels in the range of 2-2.25 millimoles per liter (mmol/L) (8.0-9.0 milligrams per deciliter [mg/dL]). Once a participant achieves a stable ACSC (2-2.25 mmol/L [8.0-9.0mg/dL]) and has minimized supplement doses, they will be maintained at that dose of rhPTH(1-84). If ACSC is greater than (>) 2.25 mmol/L (>9.0 mg/dL), a starting dose of 25 mcg will be administered. | Biological: rhPTH(1-84)<br>* Participants will receive rhPTH(1-84) SC injection in the thigh (alternate thigh every day) QD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Total Albumin-corrected Serum Calcium (ACSC) Values Greater Than or Equal to (>=) to the Range of 7.5 mg/dL (1.875 mmol/L) and Less Than or Equal to (<=) Upper Limit of Normal (ULN) at Week 24 | Percentage of participants who achieved ACSC values >= to range of 1.875 mmol/L and <= ULN at Week 24 was reported. | At Week 24 | 
| Percentage of Participants With Total ACSC Values >= to the Range of 7.5 mg/dL (1.875 mmol/L) and <=ULN at Week 52 (End-of-treatment [EOT]) | Percentage of participants who achieved ACSC values >= to range of 1.875 mmol/L and <= ULN at Week 52 (EOT) was reported. | At Week 52 (EOT) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A Serious Adverse Event (SAE) was any untoward medical occurrence (whether considered to be related to investigational product or not) that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality/birth defect, and is an important medical event. TEAEs were defined as AEs with a start date on or after the first dose of investigational product or a start date before the date of the first dose of investigational product that increased in severity or after the date of the first dose. | From start of study drug administration to end of study (Week 56) | 
| Number of Participants With Clinically Significant Change in Clinical Laboratory Values | Clinical laboratory assessment included hematology, serum chemistry, urine chemistry and urinalysis. Clinical significance was judged by the investigator based upon the out of range values of standard range set for each parameter. Any changes in clinical laboratory results which were deemed clinically significant by the investigator was reported. | From start of study drug administration to end of study (Week 56) | 
| Number of Participants With Clinically Significant Change in Vital Sign | Vital sign parameters included: temperature, pulse rate, respiration rate, systolic and diastolic blood pressure. Clinical significance was judged by the investigator based upon the out of range values of standard range set for each parameter. Any changes in vital signs which were deemed clinically significant by the investigator was reported. | From start of study drug administration to end of study (Week 56) | 
| Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Parameters | Twelve-lead ECGs was performed in triplicate with a minimum 2-minute gap between traces. The participant rested in the supine position for at least 5 minutes before collecting the ECG. Assessment of ECG parameters included: heart rate, RR interval, PR interval, QRS interval, QT interval, and QTc interval. Clinical significance was judged by the investigator based upon the out of range values of standard range set for each parameter. Any change in ECG assessments which were deemed clinically significant by the investigator was reported. | From start of study drug administration to end of study (Week 56) | 
| Number of Participants With Clinically Significant Change in Estimated Glomerular Filtration Rate (eGFR) Values | eGFR was calculated using the chronic kidney disease epidemiology (CDK-epi) formula. Clinical significance was judged by the investigator based upon the out of range values of standard range set for parameter. Any change in eGFR assessments which were deemed clinically significant by the investigator was reported. | From start of study drug administration to end of study (Week 56) | 
| Number of Participants With Clinically Significant Change in Serum Creatinine Value | eGFR was assessed by measuring serum creatinine. Serum creatinine level was obtained directly from laboratory results. Clinical significance was judged by the investigator based upon the out of range values of standard range set for parameter. Any change in serum creatinine assessments which were deemed clinically significant by the investigator was reported. | From start of study drug administration to end of study (Week 56) | 
| Number of Participants With Positive Anti-Parathyroid Hormone Antibodies at Week 24 | Number of participants with positive anti-parathyroid hormone antibodies at Week 24 was reported. | Week 24 | 
| Number of Participants With Positive Anti-Parathyroid Hormone Antibodies at Week 52 (EOT) | Number of participants with positive anti-parathyroid hormone antibodies at Week 52 (EOT) was reported. | Week 52 (EOT) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Albumin Corrected Serum Calcium (ACSC) Concentration at Weeks 24 and 52 (EOT) | Change from baseline in ACSC concentration at Weeks 24 and 52 (EOT) was reported. | Baseline, Weeks 24 and 52 (EOT) | 
| Change From Baseline in Serum Phosphate Concentration at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT) | Change from baseline in serum phosphate concentration at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT) was reported. | Baseline, Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT) | 
| Change From Baseline in ACSC-phosphate Product at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT) | Change from baseline in ACSC-phosphate product at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT) was reported. Here mmol^2/L^2 is abbreviated as millimoles square per liter square. | Baseline, Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT) | 
| Change From Baseline in 24-hour Urine Calcium Excretion at Weeks 16, 32 and 52 (EOT) | Change from baseline in 24-hour urine calcium excretion at Weeks 16, 32 and 52 (EOT) was reported. | Baseline, Weeks 16, 32 and 52 (EOT) | 
| Percentage Change From Baseline in Prescribed Supplemental Oral Calcium Dose at Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (End of Study [EOS]) | Percentage change from baseline in prescribed supplemental oral calcium dose at Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS) were reported. | Baseline and at Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS) | 
| Percentage Change From Baseline in Prescribed Supplemental Active Vitamin D Dose at Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS) | Percentage change from baseline in prescribed supplemental oral calcium dose at Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS) were reported. | Baseline, Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS) | 
| Percentage Change From Baseline in Serum Bone-specific Alkaline Phosphatase at Weeks 8, 24 and 52 (EOT) | Percentage change from baseline in serum bone-specific alkaline phosphatase at Weeks 8, 24 and 52 (EOT) was reported. | Baseline, Weeks 8, 24 and 52 (EOT) | 
| Percentage Change From Baseline in Serum Osteocalcin at Weeks 8, 24 and 52 (EOT) | Percentage change from baseline in serum osteocalcin at Weeks 8, 24 and 52 (EOT) was reported. | Baseline, Weeks 8, 24 and 52 (EOT) | 
| Percentage Change From Baseline in Procollagen 1 N-Terminal Propeptide at Weeks 8, 24 and 52 (EOT) | Percentage change from baseline in procollagen 1 N-terminal propeptide at Weeks 8, 24 and 52 (EOT) was reported. | Baseline, Weeks 8, 24 and 52 (EOT) | 
| Percentage Change From Baseline in Type I Collagen C-Telopeptides at Weeks 8, 24 and 52 (EOT) | Percentage change from baseline in type I collagen C-telopeptides at Week 8, 24 and 52 (EOT) was reported. | Baseline, Weeks 8, 24 and 52 (EOT) | 
| Percentage Change From Baseline in Type I Collagen N-Telopeptides at Weeks 8, 24 and 52 (EOT) | Percentage change from baseline in type I collagen N-telopeptides at Week 8, 24 and 52 (EOT) was reported. | Baseline, Weeks 8, 24 and 52 (EOT) |