A Study of Extended Use of Recombinant Human Parathyroid Hormone (rhPTH(1-84)) in Hypoparathyroidism

Study Overview
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Brief Summary
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Chronic hypoparathyroidism is a life-long and irreversible disease for which the chronic administration of rhPTH(1-84) is a potential treatment option. The group of participants in the AAAE0544 core study has been taking rhPTH(1-84) for the treatment of hypoparathyroidism for up to 11 years. This study is designed to extend this experience and gain knowledge about how safe and effective rhPTH(1-84) is in participants with hypoparathyroidism over a long-term duration.

Official Title
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A Phase 4, Open-Label, Single-Center Clinical Study of Extended Use of rhPTH(1-84) in Hypoparathyroidism

Conditions
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Chronic Hypoparathyroidism, Hypoparathyroidism

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participants that are currently or previously enrolled in the core study (AAAE0544 [NCT01199614]) and have maintained uninterrupted therapy with recombinant human parathyroid hormone (rhPTH(1-84)) (transient interruptions of up to 1 month continuously off treatment may be allowed). Signed and dated informed consent form (ICF). Adult men and women 18 to 85 years of age. History of hypoparathyroidism for at least 12 months prior to rhPTH(1-84) treatment, defined by the requirement for supplemental calcium and/or active vitamin D to maintain serum calcium along with an undetectable or insufficient Parathyroid hormone (PTH) concentration. Able to perform daily subcutaneous (SC) self-injections of study medication (or have designee perform injection). Willingness and ability to understand and comply with the protocol. Women must agree to pregnancy testing and acceptable methods of contraception, as detailed in the protocol. Exclusion Criteria The participant is treated or has been treated with any investigational drug, aside from rhPTH(1-84), within 30 days of consent. As assessed by the investigator, the participant has any safety or medical issues that contraindicate participation in the study. The participant and/or the participant's parent(s) or legally-authorized representative(s) are unable to understand the nature, scope, and possible consequences of the study. The participant is unable to comply with the protocol, example, uncooperative with protocol schedule, refusal to agree to all of the study procedures, inability to return for evaluations, or is otherwise unlikely to complete the study, as determined by the investigator or the medical monitor. The participant is pregnant or lactating. Participants who are at increased baseline risk for osteosarcoma such as participant with Paget's disease of bone or unexplained new elevations of alkaline phosphatase, participants with hereditary disorders predisposing to osteosarcoma or participants with a prior history of external beam or implant radiation therapy involving the skeleton.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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 25, 50, 75, and 100 microgram (mcg) of rhPTH(1-84) subcutaneous injection to the thigh via a multidose pen injector device once daily for 36 months. The dose will be individualized based on albumin-corrected serum calcium (ACSC) and 24-hour calcium urinary excretion to achieve a serum calcium level in the lower half of the normal range. | Drug: rhPTH(1-84)<br>* Participants will receive 25, 50, 75, and 100 microgram (mcg) of rhPTH(1-84) subcutaneous injection to the thigh via a multidose pen injector device once daily for 36 months. The dose will be individualized based on Albumin-corrected Serum Calcium (ACSC) and 24-hour calcium urinary excretion to achieve a serum calcium level in the lower half of the normal range.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (402) in Concentration of Albumin-corrected Serum Calcium (ACSC) at Month 6 | Baseline (402) was defined as the last available pre-dose value in SHP634-402. | Baseline (402), Month 6 | 
| Change From Baseline (402) in Concentration of Albumin-corrected Serum Calcium (ACSC) at Month 12 | Baseline (402) was defined as the last available pre-dose value in SHP634-402. | Baseline (402), Month 12 | 
| Change From Baseline (402) in Concentration of Albumin-corrected Serum Calcium (ACSC) at Month 18 | Baseline (402) was defined as the last available pre-dose value in SHP634-402. | Baseline (402), Month 18 | 
| Change From Baseline (402) in Concentration of Albumin-corrected Serum Calcium (ACSC) at Month 24 | Baseline (402) was defined as the last available pre-dose value in SHP634-402. | Baseline (402), Month 24 | 
| Change From Baseline (402) in Concentration of Albumin-corrected Serum Calcium (ACSC) at Month 30 | Baseline (402) was defined as the last available pre-dose value in SHP634-402. | Baseline (402), Month 30 | 
| Change From Baseline (402) in Concentration of Albumin-corrected Serum Calcium (ACSC) at Month 36 | Baseline (402) was defined as the last available pre-dose value in SHP634-402. | Baseline (402), Month 36 | 
| Change From Baseline (402) in Concentration of Albumin-corrected Serum Calcium (ACSC) at End of Treatment (EOT) (up to Month 36) | Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | Baseline (402), EOT (up to Month 36) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved ACSC Concentrations Above, Below, or in the Range of 1.875 mmol/L (7.5 Milligram Per Deciliter [mg/dL]) to Upper Limit of Normal (ULN) at Month 6, 12, 18, 24, 30, 36 and EOT (up to Month 36) | EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. Albumin-corrected Serum Calcium (mmol/L) = Total Calcium (mmol/L) + 0.02 * (40 gram per liter [g/L] - Albumin [g/L]). | At Month 6, 12, 18, 24, 30, 36 and EOT (up to Month 36) | 
| Change From Baseline (402) in Urinary Calcium Excretion at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. Here, '0' in the number analyzed field signifies that no participants were evaluable at specified time point. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Concentration of Serum Phosphate Levels at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Calcium Supplement Doses and Elemental Calcium Based on Investigator-prescribed Data and Diary Data at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | Baseline, At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Active Vitamin D Supplement Dose Based on Investigator-prescribed Data and Diary Data at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Hypoparathyroidism Symptoms Diary (HPT-SD) at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | The HPT-SD was 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), Mild (1), Moderate (2), Severe (3), Very severe (4) and for items 10-13, it ranges from Not at all (0), somewhat (1), Very much (2). For symptom subscale score was calculated as average score of the items 1-7 and the impact subscale scores was calculated as average score of the items 10-13. The HPT-SD was only collected within the SHP634-402 study, as planned. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog) Assessment at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | FACT-Cog assessment was a 37-item tool with each item rated on a 5-point scale ranging from 0 to 4. It included 4 subscales: perceived cognitive impairments (CogPCI) (20 items, Item 1 - 20, score range 0-80), impact of perceived cognitive impairments on quality of life (CogQOL ) (4 items, Item 34 - 37, score range 0-16), comments from others (CogOth) (4 items, Item 21 - 24, score range 0-16) and perceived cognitive ability (CogPCA) (9 items, Item 25 - 33 score range 0-36). CogPCI subscale and comments from others subscale and two others subscale ranged as following: 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit) and 4 (very much). For all four subscales of the FACT-cog: higher scores reflect worse cognitive function. Baseline (402): the last available pre-dose value in SHP634-402. EOT: the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale Total Score at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | FACIT fatigue questionnaire contains 13 fatigue-related questions. The responses to the 13 items on the FACIT fatigue questionnaire was measured on a 4-point Likert scale (0-4). Thus, the total score ranges from 0 to 52. High scores represent less fatigue and better quality of life. For 2 questions, item 7 'I have energy' and item 8 'I am able to do my usual activities', the item response from questionnaire will be used as item score and no conversion is needed. For the rest of 11 questions, item score was calculated as 4- item response. Fatigue total score was calculated as: Fatigue Total Score = [sum of (item scores)]*13/ (number of items answered). Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Hospital Anxiety and Depression Scale (HADS) at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | The HADS was a 14-item scale that generates ordinal data. Seven of the items related to anxiety (Item 1, 3, 5, 7, 9, 11 and 13) and seven related to depression (Item 2, 4, 6, 8, 10, 12 and 14). The scale was designed to avoid reliance on aspects of conditions that are also common somatic symptoms of illness. Each item on the questionnaire was scored from 0-3, therefore, a person can score between 0 and 21 for either anxiety or depression. For each of the two sub-scores, if a participant obtain a score ranged from: 0 to 7, he is considered as normal; 8-10 = Borderline abnormal (borderline case) and 11-21 = Abnormal (case). Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Health-related Quality-of-life Measured With 36-item Short Form Health (SF-36) Survey at Month 12, 24, 36, and EOT (up to Month 36) | SF-36 was a validated questionnaire that questions participants about perceived physical and mental health and function. SF-36 consisted of 8 scaled scores, which were weighted sums of the questions in their section. Each scale was directly transformed into 0-100 scale on the assumption that each question carries equal weight; A score of zero was equivalent to maximum disability and a score of 100 was equivalent to no disability. Eight sections included in SF-36 assessment: vitality (1=none of the time to 5=all of the time), physical functioning (1=yes, limited a lot to 3=no, not limited at all), bodily pain (1=very severe to 6=none), general health (1=poor to 5=excellent), physical role (1=all of the time to 5=none of the time), emotional role (1=all of the time to 5=none of the time), social role (1=all of the time: to 5=none of the time) and mental health (1=all of the time to 5=none of the time). Baseline (402) was defined as the last available pre-dose value in SHP634-402. | Baseline (402), At Month 12, 24, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Concentration of Bone Turnover Markers at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Change from baseline in concentration of bone turnover markers included; Serum carboxy-terminal 4 telopeptide of type I collagen [s-CTX], procollagen type I amino-terminal propeptide [P1NP], osteocalcin, and sclerostin. Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. Here, '0' in the number analyzed field signifies that no participants were evaluable at specified time point. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Concentration of Bone Turnover Marker for Bone Specific Alkaline Phosphatase and Tartrate-resistant Acid Phosphatase-5b at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Change from baseline in concentration of bone turnover markers included, bone specific alkaline phosphatase [BSAP] and tartrate-resistant acid phosphatase-5b (TRAP-5b). Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. Here, '0' in the number analyzed field signifies that no participants were evaluable at specified time point. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Bone Architecture Evaluated Using Dual-energy X-ray Absorptiometry (DXA) for Bone Mineral Density (BMD) at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Change from baseline in bone architecture was assessed by using DXA. The DXA scans was evaluated for BMD of the lumbar spine (vertebra L1, L2, L3, L4), total hip and femoral neck, and distal radius. Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. Here, '0' in the number analyzed field signifies that no participants were evaluable at specified time point. | Baseline, At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Bone Architecture Evaluated Using Dual-energy X-ray Absorptiometry (DXA) for Total T-scores at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Change from baseline in bone architecture was assessed by using DXA. The DXA scans was evaluated for Total T-score of the lumbar spine (vertebra L1-L4), hip (total and femoral neck), and ⅓ distal radius. Baseline (402) was defined as the last available pre-dose value in SHP634-402. The T-score was a comparison of a person's bone density with that of a healthy 30-year-old adult of the same sex and ethnicity. T-score included: Normal: >= -1; Osteopenia: < -1 and > -2.5; Osteoporosis: <= -2.5. A lower T-score implies a lower bone mineral density. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. Here, '0' in the number analyzed field signifies that no participants were evaluable at specified time point. | Baseline, At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Change From Baseline (402) in Bone Architecture Evaluated Using High-resolution Peripheral Quantitative Computerized Tomography (HRpQCT) for Total Area of Radius and Tibia at Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | Change from baseline in bone architecture was assessed by using HRpQCT. The HRpQCT analyses included both radius and tibia of total area position. Baseline (402) was defined as the last available pre-dose value in SHP634-402. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. Here, '0' in the number analyzed field signifies that no participants were evaluable at specified time point. | Baseline (402), At Month 6, 12, 18, 24, 30, 36, and EOT (up to Month 36) | 
| Mean Bone Histology (Biopsy) of Adjusted Apposition Rate and Cancellous Minimum Apposition Rate at Month 12, and EOT (up to Month 36) | Bone histology parameters consisted of adjusted apposition rate and cancellous minimum apposition rate. An optional transiliac bone biopsy was performed for willing participants, at the discretion of the investigator a maximum of three time. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | At Month 12, and EOT (up to Month 36) | 
| Mean Bone Histology (Biopsy) of Bone Formation Rate at Month 12, and EOT (up to Month 36) | Bone histology parameters consisted of bone formation rate. An optional transiliac bone biopsy was performed for willing participants, at the discretion of the investigator a maximum of three time. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. Here, mcm^3/mcm^2/d is abbreviated as micro cubic meter per micro square meter per day. | At Month 12, and EOT (up to Month 36) | 
| Mean Bone Histology (Biopsy) of Cancellous Bone Volume, Cancellous Eroded Surface, Cancellous Mineral Surface, And Cancellous Osteoid Surface at Month 12, and EOT (up to Month 36) | Bone histology parameters consisted of cancellous bone volume, cancellous eroded surface, cancellous mineral surface, and cancellous osteoid surface. An optional transiliac bone biopsy was performed for willing participants, at the discretion of the investigator a maximum of three time. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | At Month 12, and EOT (up to Month 36) | 
| Mean Bone Histology (Biopsy) of Cancellous Osteoid Thickness and Cortical Width at Month 12, and EOT (up to Month 36) | Bone histology parameters consisted of cancellous osteoid thickness and cortical width. An optional transiliac bone biopsy was performed for willing participants, at the discretion of the investigator a maximum of three time. EOT was defined as the last determination of response during the treatment period (from the date of first dose to the date of last dose + 1 day), was analyzed in addition to the scheduled visits. | At Month 12, and EOT (up to Month 36) |