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    Clinical Trial Results:
    An Open-label Study Investigating the Safety and Efficacy of rhPTH(1-84) in Subjects with Hypoparathyroidism

    Summary
    EudraCT number
    		 2017-003067-36
    Trial protocol
    		 HU   DK  
    Global end of trial date
    14 Apr 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Apr 2021
    First version publication date
    30 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SHP634-404
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03364738
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, ClinicalTransparency@takeda.com
    Scientific contact
    Study Director, Shire, ClinicalTransparency@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the proportion of subjects who achieved total serum calcium (albumin corrected) values in the range of 7.5 mg/dL (1.875 mmol/L) – upper limit of normal (ULN) and to further characterize the safety of rhPTH(1-84) in adult subjects with hypoparathyroidism (HPT).
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and in compliance with all applicable industry regulations, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996), European Union (EU) Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    22
    EEA total number of subjects
    11
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    19
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects with HPT who completed SHP634-101 (2015-004757-40) study were eligible and enrolled in this extension study which was conducted at 10 sites in the United States, Denmark, Hungary and Canada between 26 September 2018 (first participant first visit) and 14 April 2020 (last participant last visit).

    Pre-assignment
    Screening details
    		 A total of 22 subjects were enrolled and treated in the study, of which 14 subjects completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 rhPTH(1-84)
    Arm description
    		 Subjects received recombinant human parathyroid hormone (rhPTH) (1-84) (Natpara) 50 microgram (mcg), injection, subcutaneously, once daily in the thigh (alternate thigh every day) up to 52 weeks (end of treatment [EOT])/ early termination (ET). Dose escalation was done up to 100 mcg 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) (8-9 milligrams per deciliter [mg/dL]). Administered dose was maintained once a participant achieved a stable ACSC level of 2-2.25 mmol/L (8-9 mg/dL) and had minimized supplement (active vitamin D and calcium supplement) doses. If ACSC was greater than (>) 2.25 mmol/L (>9.0 mg/dL), a starting dose of 25 mcg was administered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human recombinant parathyroid Hormone
    Investigational medicinal product code
    SHP634
    Other name
    Natpara
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received rhPTH(1-84) 50 mcg, injection, subcutaneously, once daily in the thigh (alternate thigh every day) up to Week 52 (end of treatment [EOT]).

    Number of subjects in period 1
    		rhPTH(1-84)
    Started
    22
    Completed
    14
    Not completed
    8
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
         Early termination due to FDA recall of rhPTH(1-84)
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rhPTH(1-84)
    Reporting group description
    		 Subjects received recombinant human parathyroid hormone (rhPTH) (1-84) (Natpara) 50 microgram (mcg), injection, subcutaneously, once daily in the thigh (alternate thigh every day) up to 52 weeks (end of treatment [EOT])/ early termination (ET). Dose escalation was done up to 100 mcg 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) (8-9 milligrams per deciliter [mg/dL]). Administered dose was maintained once a participant achieved a stable ACSC level of 2-2.25 mmol/L (8-9 mg/dL) and had minimized supplement (active vitamin D and calcium supplement) doses. If ACSC was greater than (>) 2.25 mmol/L (>9.0 mg/dL), a starting dose of 25 mcg was administered.

    Reporting group values
    		 rhPTH(1-84) Total
    Number of subjects
    		 22 22
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50 ( 11.39 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 18 18
        Male
    		 4 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Not Hispanic or Latino
    		 21 21
        Unknown or Not Reported
    		 1 1
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Black or African American
    		 1 1
        White
    		 20 20
        Native Hawaiian or other Pacific Islander
    		 0 0
        Native American And Caucasian
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    rhPTH(1-84)
    Reporting group description
    		 Subjects received recombinant human parathyroid hormone (rhPTH) (1-84) (Natpara) 50 microgram (mcg), injection, subcutaneously, once daily in the thigh (alternate thigh every day) up to 52 weeks (end of treatment [EOT])/ early termination (ET). Dose escalation was done up to 100 mcg 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) (8-9 milligrams per deciliter [mg/dL]). Administered dose was maintained once a participant achieved a stable ACSC level of 2-2.25 mmol/L (8-9 mg/dL) and had minimized supplement (active vitamin D and calcium supplement) doses. If ACSC was greater than (>) 2.25 mmol/L (>9.0 mg/dL), a starting dose of 25 mcg was administered.

    Primary: Percentage of Subjects 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

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    End point title
    		 Percentage of Subjects 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 [1]
    End point description
    Percentage of subjects who achieved ACSC values >= to range of 1.875 mmol/L and <= ULN at Week 24 was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here, “number of subjects analysed” were subjects who were evaluable for this end point.
    End point type
    Primary
    End point timeframe
    At Week 24
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    21
    Units: percentage of subjects
    100
    No statistical analyses for this end point

    Primary: Percentage of Subjects 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])

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    End point title
    		 Percentage of Subjects 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]) [2]
    End point description
    Percentage of subjects who achieved ACSC values >= to range of 1.875 mmol/L and <= ULN at Week 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84).
    End point type
    Primary
    End point timeframe
    At Week 52 (EOT)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: percentage of subjects
        number (not applicable)
    95.5
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [3]
    End point description
    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. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84).
    End point type
    Primary
    End point timeframe
    From start of study drug administration to end of study (Week 56)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: Subjects
        Subjects with TEAEs
    17
        Subjects with serious TEAEs
    4
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change in Clinical Laboratory Values

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    End point title
    		 Number of Subjects With Clinically Significant Change in Clinical Laboratory Values [4]
    End point description
    Clinical laboratory assessment included hematology, serum chemistry, urine chemistry and urinalysis. The investigator will assess out-of-range clinical laboratory values for clinical significance, to indicate whether or not the values are clinically significant. Any changes in clinical laboratory results which were deemed clinically significant by the investigator was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84).
    End point type
    Primary
    End point timeframe
    From start of study drug administration to end of study (Week 56)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change in Vital Sign

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    End point title
    		 Number of Subjects With Clinically Significant Change in Vital Sign [5]
    End point description
    Vital sign parameters included: temperature, pulse rate, respiration rate, systolic and diastolic blood pressure. Any changes in vital signs which were deemed clinically significant by the investigator was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84).
    End point type
    Primary
    End point timeframe
    From start of study drug administration to end of study (Week 56)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change in Electrocardiogram (ECG) Parameters

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    End point title
    		 Number of Subjects With Clinically Significant Change in Electrocardiogram (ECG) Parameters [6]
    End point description
    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. Any change in ECG assessments which were deemed clinically significant by the investigator was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84).
    End point type
    Primary
    End point timeframe
    From start of study drug administration to end of study (Week 56)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change in Estimated Glomerular Filtration Rate (eGFR) Values

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    End point title
    		 Number of Subjects With Clinically Significant Change in Estimated Glomerular Filtration Rate (eGFR) Values [7]
    End point description
    Estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology (CDK-epi) formula. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84).
    End point type
    Primary
    End point timeframe
    From start of study drug administration to end of study (Week 56)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change in Serum Creatinine Value

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    End point title
    		 Number of Subjects With Clinically Significant Change in Serum Creatinine Value [8]
    End point description
    eGFR was assessed by measuring serum creatinine. Serum creatinine level was obtained directly from laboratory results. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84).
    End point type
    Primary
    End point timeframe
    From start of study drug administration to end of study (Week 56)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Positive Anti-Parathyroid Hormone Antibodies at Week 24

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    End point title
    		 Number of Subjects With Positive Anti-Parathyroid Hormone Antibodies at Week 24 [9]
    End point description
    Number of participants with positive anti-parathyroid hormone antibodies at Week 24 was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “number of subjects analysed” were subjects who were evaluable for this end point.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    21
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Positive Anti-Parathyroid Hormone Antibodies at Week 52 (EOT)

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    End point title
    		 Number of Subjects With Positive Anti-Parathyroid Hormone Antibodies at Week 52 (EOT) [10]
    End point description
    Number of subjects with positive anti-parathyroid hormone antibodies at Week 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “number of subjects analysed” were subjects who were evaluable for this end point.
    End point type
    Primary
    End point timeframe
    Week 52 (EOT)
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    21
    Units: Subjects
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Albumin Corrected Serum Calcium (ACSC) Concentration at Weeks 24 and 52 (EOT)

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    End point title
    		 Change From Baseline in Albumin Corrected Serum Calcium (ACSC) Concentration at Weeks 24 and 52 (EOT)
    End point description
    Change from baseline in ACSC concentration at Weeks 24 and 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change at Week 24 (n =21)
    -0.024 ( 0.2065 )
        Change at Week 52 (EOT) (n =22)
    -0.076 ( 0.1497 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Phosphate Concentration at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT)

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    End point title
    		 Change From Baseline in Serum Phosphate Concentration at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT)
    End point description
    Change from baseline in serum phosphate concentration at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change at Week 4 (n =21)
    -0.167 ( 0.1816 )
        Change at Week 8 (n =21)
    -0.124 ( 0.2252 )
        Change at Week 16 (n =21)
    -0.107 ( 0.2583 )
        Change at Week 24 (n =21)
    -0.160 ( 0.2303 )
        Change at Week 32 (n =20)
    -0.089 ( 0.1809 )
        Change at Week 40 (n =17)
    -0.121 ( 0.2542 )
        Change at Week 52 (EOT) (n =22)
    -0.114 ( 0.2590 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in ACSC-phosphate Product at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT)

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    End point title
    		 Change From Baseline in ACSC-phosphate Product at Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT)
    End point description
    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. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 16, 24, 32, 40 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: mmol^2/L^2
    arithmetic mean (standard deviation)
        Change at Week 4 (n =21)
    -0.31 ( 0.462 )
        Change at Week 8 (n =21)
    -0.19 ( 0.537 )
        Change at Week 16 (n =21)
    -0.16 ( 0.609 )
        Change at Week 24 (n =21)
    -0.38 ( 0.556 )
        Change at Week 32 (n =20)
    -0.29 ( 0.456 )
        Change at Week 40 (n =17)
    -0.29 ( 0.572 )
        Change at Week 52 (EOT) (n =22)
    -0.34 ( 0.539 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in 24-hour Urine Calcium Excretion at Weeks 16, 32 and 52 (EOT)

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    End point title
    		 Change From Baseline in 24-hour Urine Calcium Excretion at Weeks 16, 32 and 52 (EOT)
    End point description
    Change from baseline in 24-hour urine calcium excretion at Weeks 16, 32 and 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “number of subjects analysed” were subjects who were evaluable for this end point and “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 16, 32 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    21
    Units: millimoles per day (mmol/day)
    arithmetic mean (standard deviation)
        Change at Week 16 (n =21)
    -0.22 ( 4.741 )
        Change at Week 32 (n =20)
    -3.13 ( 4.103 )
        Change at Week 52 (EOT) (n =20)
    -2.53 ( 4.421 )
    No statistical analyses for this end point

    Secondary: 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])

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    End point title
    		 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])
    End point description
    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. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points. Data for Week 56 was not collected as study was early terminated due to FDA recall of rhPTH(1-84) (Natpara). Here "99999" refers to data not available and we have added it as space-fillers.
    End point type
    Secondary
    End point timeframe
    Baseline and at Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: percentage change
    arithmetic mean (standard deviation)
        Percentage change at Week 4 (n =21)
    -14.30 ( 34.269 )
        Percentage change at Week 8 (n =21)
    -29.08 ( 38.019 )
        Percentage change at Week 16 (n =21)
    -36.94 ( 45.665 )
        Percentage change at Week 24 (n =21)
    -49.05 ( 49.049 )
        Percentage change at Week 32 (n =20)
    -55.58 ( 44.268 )
        Percentage change at Week 40 (n =17)
    -56.36 ( 45.168 )
        Percentage change at Week 52 (EOT) (n =22)
    -48.55 ( 45.237 )
        Percentage change at Week 56 (EOS) (n =0)
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Prescribed Supplemental Active Vitamin D Dose at Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS)

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    End point title
    		 Percentage Change From Baseline in Prescribed Supplemental Active Vitamin D Dose at Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS)
    End point description
    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. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “number of subjects analysed” were subjects who were evaluable for this end point and “n” were subjects who were evaluable for the end point at given time points. Data for Week 56 was not collected as study was early terminated due to FDA recall of rhPTH(1-84) (Natpara). Here "99999" refers to data not available and we have added it as space-fillers.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 16, 24, 32, 40, 52 (EOT) and 56 (EOS)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    21
    Units: percentage change
    arithmetic mean (standard deviation)
        Percentage change at Week 4 (n =20)
    -57.50 ( 40.995 )
        Percentage change at Week 8 (n =20)
    -70.00 ( 39.217 )
        Percentage change at Week 16 (n =20)
    -80.83 ( 27.185 )
        Percentage change at Week 24 (n =20)
    -85.42 ( 25.055 )
        Percentage change at Week 32 (n =19)
    -90.79 ( 17.324 )
        Percentage change at Week 40 (n =16)
    -90.10 ( 18.564 )
        Percentage change at Week 52 (EOT) (n =21)
    -77.38 ( 43.870 )
        Percentage change at Week 56 (EOS) (n =0)
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Serum Bone-specific Alkaline Phosphatase at Weeks 8, 24 and 52 (EOT)

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    End point title
    		 Percentage Change From Baseline in Serum Bone-specific Alkaline Phosphatase at Weeks 8, 24 and 52 (EOT)
    End point description
    Percentage change from baseline in serum bone-specific alkaline phosphatase at Weeks 8, 24 and 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 24 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: percentage change
    arithmetic mean (standard deviation)
        Percentage change at Week 8 (n =20)
    29.90 ( 31.575 )
        Percentage change at Week 24 (n =21)
    89.14 ( 54.452 )
        Percentage change at Week 52 (EOT) (n =22)
    94.08 ( 75.066 )
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Serum Osteocalcin at Weeks 8, 24 and 52 (EOT)

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    End point title
    		 Percentage Change From Baseline in Serum Osteocalcin at Weeks 8, 24 and 52 (EOT)
    End point description
    Percentage change from baseline in serum osteocalcin at Weeks 8, 24 and 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 24 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: percentage change
    arithmetic mean (standard deviation)
        Percentage change at Week 8 (n =21)
    61.74 ( 68.363 )
        Percentage change at Week 24 (n =21)
    225.91 ( 130.798 )
        Percentage change at Week 52 (EOT) (n =22)
    294.93 ( 215.100 )
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Procollagen 1 N-Terminal Propeptide at Weeks 8, 24 and 52 (EOT)

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    End point title
    		 Percentage Change From Baseline in Procollagen 1 N-Terminal Propeptide at Weeks 8, 24 and 52 (EOT)
    End point description
    Percentage change from baseline in procollagen 1 N-terminal propeptide at Weeks 8, 24 and 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 24 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: percentage change
    median (standard deviation)
        Percentage change at Week 8 (n =21)
    119.98 ( 161.156 )
        Percentage change at Week 24 (n =21)
    412.46 ( 248.423 )
        Percentage change at Week 52 (EOT) (n =22)
    476.07 ( 377.383 )
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Type I Collagen C-Telopeptides at Weeks 8, 24 and 52 (EOT)

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    End point title
    		 Percentage Change From Baseline in Type I Collagen C-Telopeptides at Weeks 8, 24 and 52 (EOT)
    End point description
    Percentage change from baseline in type I collagen C-telopeptides at Week 8, 24 and 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 24 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: percentage change
    arithmetic mean (standard deviation)
        Percentage change at Week 8 (n =21)
    124.62 ( 160.564 )
        Percentage change at Week 24 (n =21)
    254.26 ( 198.947 )
        Percentage change at Week 52 (EOT) (n =22)
    227.13 ( 182.262 )
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Type I Collagen N-Telopeptides at Weeks 8, 24 and 52 (EOT)

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    End point title
    		 Percentage Change From Baseline in Type I Collagen N-Telopeptides at Weeks 8, 24 and 52 (EOT)
    End point description
    Percentage change from baseline in type I collagen N-telopeptides at Week 8, 24 and 52 (EOT) was reported. Safety analysis population consisted of all subjects who had received at least 1 dose of rhPTH(1-84). Here “n” were subjects who were evaluable for the end point at given time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 8, 24 and 52 (EOT)
    End point values
    		 rhPTH(1-84)
    Number of subjects analysed
    22
    Units: percentage change
    arithmetic mean (standard deviation)
        Percentage change at Week 8 (n =21)
    71.33 ( 99.933 )
        Percentage change at Week 24 (n =21)
    183.23 ( 160.350 )
        Percentage change at Week 52 (EOT) (n =22)
    231.80 ( 270.229 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of screening up to end of study (Week 56)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    rhPTH(1-84)
    Reporting group description
    		 Subjects received rhPTH(1-84) (Natpara) 50 mcg, injection, subcutaneously, once daily in the thigh (alternate thigh every day) up to 52 weeks (EOT/ET). Dose escalation was done up to 100 mcg in increments of 25 mcg no more frequently than every 2 to 4 weeks, with the goal of achieving or maintaining ACSC levels in the range of 2-2.25 mmol/L (8-9 mg/dL). Administered dose was maintained once a participant achieved a stable ACSC level of 2-2.25 mmol/L (8-9 mg/dL) and had minimized supplement (active vitamin D and calcium supplement) doses. If ACSC was >2.25 mmol/L (>9.0 mg/dL), a starting dose of 25 mcg was administered.

    Serious adverse events
    		 rhPTH(1-84)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 22 (18.18%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 rhPTH(1-84)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 22 (45.45%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    7
    Migraine
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    3
    Paraesthesia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    7
    Vomiting
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    6
    Myalgia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Osteoarthritis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Tendonitis
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    5
    Hypocalcaemia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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