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Clinical Trial Results:
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)]

Summary
EudraCT number	2017-000284-32
Trial protocol	GB NL SE DK ES NO PT BE IT
Global end of trial date	19 May 2022

Results information
Results version number	v1(current)
This version publication date	28 May 2023
First version publication date	28 May 2023
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SHP634-401

ISRCTN number

US NCT number

NCT03324880

WHO universal trial number (UTN)

Sponsor organisation name

Takeda

Sponsor organisation address

95 Hayden Avenue, Lexington, United States, MA 02421

Public contact

Study Director, Takeda, +1 877-825-3327, TrialDisclosures@takeda.com

Scientific contact

Study Director, Takeda, +1 877-825-3327, TrialDisclosures@takeda.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

19 May 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 May 2022

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to test the hypothesis that rhPTH(1-84) treatment resulted in superior improvements in the symptoms of hypoparathyroidism (HypoPT) as assessed by the HypoPT symptom diary (HypoPT-SD) symptom subscale compared with standard therapy.

Protection of trial subjects

Study participants were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Jan 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

United States: 4

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Denmark: 7

Country: Number of subjects enrolled

France: 6

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

Netherlands: 18

Country: Number of subjects enrolled

Norway: 6

Country: Number of subjects enrolled

Portugal: 7

Country: Number of subjects enrolled

Spain: 17

Country: Number of subjects enrolled

United Kingdom: 14

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at 35 investigative sites in Belgium, Canada, Denmark, Spain, France, United Kingdom, Italy, Netherlands, Norway, Portugal, Sweden and the United States (US) from 24 January 2018 to 19 May 2022.

Screening details

Participants with a diagnosis of symptomatic hypoparathyroidism were enrolled in 1:1 ratio to receive placebo matching rhPTH (1-84) with active vitamin D and/or calcium supplements or rhPTH (1-84) with active vitamin D and/or calcium supplements.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Assessor, Carer, Data analyst, Investigator, Subject

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants received placebo matched to rhPTH (1-84) as subcutaneous (SC) injection once daily (QD) with active vitamin D and calcium supplements up to 31.3 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo QD SC injection.

rhPTH (1-84)

Arm description

Participants received rhPTH (1-84) 50 microgram (mcg) SC injection 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 up to 32 weeks.

Arm type

Experimental

Investigational medicinal product name

rhPTH (1-84)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

rhPTH (1-84) SC injection.

Number of subjects in period 1	Placebo	rhPTH (1-84)
Started	48	45
Completed	46	39
Not completed	2	6
Consent withdrawn by subject	2	2
Product Recall	-	1
Adverse event, non-fatal	-	2
Lost to follow-up	-	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants received placebo matched to rhPTH (1-84) as subcutaneous (SC) injection once daily (QD) with active vitamin D and calcium supplements up to 31.3 weeks.

Reporting group title

rhPTH (1-84)

Reporting group description

Reporting group values	Placebo	rhPTH (1-84)	Total
Number of subjects	48	45
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	49.2 ( 12.16 )	47.8 ( 10.41 )	-
Gender categorical
Units: Subjects
Female	40	42	82
Male	8	3	11
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	4	3	7
Not Hispanic or Latino	39	31	70
Unknown or Not Reported	5	11	16
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	1	2	3
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	47	43	90
More than one race	0	0	0
Unknown or Not Reported	0	0	0
Hypoparathyroidism Symptom Diary (HPT-SD/HypoPT-SD) Symptom Subscale Score at Baseline
HypoPT-SD: 13-item patient-reported outcomes instrument incl. symptom subscale(items 1-7), anxiety(item 8), sadness/depression(item 9), impact subscale(items 10-13).Items 1-9 score: None=0 to Very severe=4; Items 10-13: Not at all=0 to Very much=2. Item score=average of daily item response over 14-day period before visit. If data were unavailable for at least 4 out of 7 days during both 7-day periods within the 14-days, score set to missing.Symptom subscale score=average of symptom items 1-7 scores.Symptom subscale score:0 to 4 points with higher scores=more severe symptoms. Placebo group n=47
Units: score on a scale
arithmetic mean (standard deviation)	2.23 ( 0.541 )	2.56 ( 0.728 )	-

End points

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Reporting group title

Placebo

Reporting group description

Participants received placebo matched to rhPTH (1-84) as subcutaneous (SC) injection once daily (QD) with active vitamin D and calcium supplements up to 31.3 weeks.

Reporting group title

rhPTH (1-84)

Reporting group description

Primary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Subscale Score at Week 26

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End point title

Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Subscale Score at Week 26

End point description

The HypoPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness or depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4; for items 10-13, it ranges from Not at all=0 to Very much=2. An item score was computed by taking the average of the daily item response over the 14-day period immediately before the visit. If data were not available for at least 4 out of 7 days during both 7-day periods within the 14-day period, the individual item score was set to missing. The symptom subscale score was computed as the average of symptom items 1-7 scores with more than 3 of the 7 symptom item scores were non-missing. Negative change in scores indicates improvement. A mixed model for repeated measures (MMRM) was used for analysis.

End point type

Primary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	38	30
Units: score on a scale
least squares mean (standard error)	-0.93 ( 0.130 )	-1.46 ( 0.137 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[1]

Method

MMRM

Parameter type

Difference in Least Squares (LS) Mean

Point estimate

-0.53

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.15

Variability estimate

Standard error of the mean

Dispersion value

0.189

Notes
[1] - 1-sided p-value was reported.

Secondary: Change From Baseline in Physical Component Summary (PCS) Derived From 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores at Week 26

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End point title

Change From Baseline in Physical Component Summary (PCS) Derived From 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores at Week 26

End point description

The SF-36 is a validated instrument that questions 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 was reported. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	29	29
Units: score on a scale
least squares mean (standard error)	4.404 ( 1.3514 )	8.646 ( 1.3406 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.015 ^[2]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

4.242

Confidence interval

level

95%

sides

2-sided

lower limit

0.413

upper limit

8.072

Variability estimate

Standard error of the mean

Dispersion value

1.9219

Notes
[2] - 1-sided p-value was reported.

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 26

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End point title

Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 26

End point description

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 5-point Likert scale, where 0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit and 4=Very much. Thus, the total score ranges from 0 to 52. High scores represent less fatigue. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	29	28
Units: score on a scale
least squares mean (standard error)	4.4 ( 1.87 )	15.0 ( 1.93 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[3]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

10.5

Confidence interval

level

95%

sides

2-sided

lower limit

5.1

upper limit

15.9

Variability estimate

Standard error of the mean

Dispersion value

2.7

Notes
[3] - 1-sided p-value was reported.

Secondary: Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Items Score at Week 26

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End point title

Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Items Score at Week 26

End point description

The HypoPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness or depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4; for items 10-13, it ranges from Not at all=0 to Very much=2. An item score was computed by taking the average of the daily item response over the 14-day period immediately before the visit. If data were not available for at least 4 out of 7 days during both 7-day periods within the 14-day period, the individual item score was set to missing. The change in individual symptom item scores was reported. Negative change in scores indicates improvement. MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	38	30
Units: score on a scale
least squares mean (standard error)
Impact on Sleep	-0.39 ( 0.086 )	-0.68 ( 0.090 )
Ability to Exercise	-0.35 ( 0.088 )	-0.71 ( 0.093 )
Ability to Complete Work	-0.39 ( 0.084 )	-0.76 ( 0.089 )
Impact Family Relationships	-0.29 ( 0.083 )	-0.66 ( 0.088 )

Statistical Analysis 1

Statistical analysis description

Impact on Sleep

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.013 ^[4]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.125

Notes
[4] - 1-sided p-value was reported.

Statistical Analysis 4

Statistical analysis description

Impact Family Relationships

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[5]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

-0.13

Variability estimate

Standard error of the mean

Dispersion value

0.121

Notes
[5] - 1-sided p-value was reported.

Statistical Analysis 3

Statistical analysis description

Ability to Complete Work

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[6]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

-0.12

Variability estimate

Standard error of the mean

Dispersion value

0.123

Notes
[6] - 1-sided p-value was reported.

Statistical Analysis 2

Statistical analysis description

Ability to Exercise

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[7]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

-0.11

Variability estimate

Standard error of the mean

Dispersion value

0.128

Notes
[7] - 1-sided p-value was reported.

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Subscale Score at Week 26

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End point title

Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Subscale Score at Week 26

End point description

The HypoPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness or depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4; for items 10-13, it ranges from Not at all=0 to Very much=2. An item score was computed by taking the average of the daily item response over the 14-day period immediately before the visit. If data were not available for at least 4 out of 7 days during both 7-day periods within the 14-day period, the individual item score was set to missing. The impact subscale score was computed as the average of impact items 10-13 scores with no impact item score was non-missing. Negative change in scores indicates improvement. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	38	30
Units: score on a scale
least squares mean (standard error)	-0.36 ( 0.076 )	-0.69 ( 0.081 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[8]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.55

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

0.112

Notes
[8] - 1-sided p-value was reported.

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Sadness or Depression (Item 9) Score at Week 26

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End point title

Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Sadness or Depression (Item 9) Score at Week 26

End point description

The HypoPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness or depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4; for items 10-13, it ranges from Not at all=0 to Very much=2. The sadness or depression item score was computed by taking the average of the daily item response over the 14-day period immediately before the visit. If data were not available for at least 4 out of 7 days during both 7-day periods within the 14-day period, the item score was set to missing. Negative change in scores indicates improvement. MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	38	30
Units: score on a scale
least squares mean (standard error)	-0.76 ( 0.137 )	-1.30 ( 0.145 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[9]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.54

Confidence interval

level

95%

sides

2-sided

lower limit

-0.93

upper limit

-0.14

Variability estimate

Standard error of the mean

Dispersion value

0.2

Notes
[9] - 1-sided p-value was reported.

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Anxiety (item 8) Score at Week 26

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End point title

Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Anxiety (item 8) Score at Week 26

End point description

The HypoPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness or depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4; for items 10-13, it ranges from Not at all=0 to Very much=2. The anxiety item score was computed by taking the average of the daily item response over the 14-day period immediately before the visit. If data were not available for at least 4 out of 7 days during both 7-day periods within the 14-day period, the anxiety item score was set to missing. Negative change in scores indicates improvement. MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	38	30
Units: score on a scale
least squares mean (standard error)	-0.79 ( 0.139 )	-1.35 ( 0.147 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[10]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-0.96

upper limit

-0.15

Variability estimate

Standard error of the mean

Dispersion value

0.203

Notes
[10] - 1-sided p-value was reported.

Secondary: Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Scores at Week 26

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End point title

Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Scores at Week 26

End point description

The HypoPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness or depression (item 9) and impact subscale (items 10-13). For items 1-9, the individual score ranges from None=0 to Very severe=4; for items 10-13, it ranges from Not at all=0 to Very much=2. An item score was computed by taking the average of the daily item response over the 14-day period immediately before the visit. If data were not available for at least 4 out of 7 days during both 7-day periods within the 14-day period, the individual item score was set to missing. Negative change in scores indicates improvement. MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	38	30
Units: score on a scale
least squares mean (standard error)
Muscle Cramps	-0.91 ( 0.150 )	-1.47 ( 0.158 )
Tingling	-1.04 ( 0.146 )	-1.58 ( 0.154 )
Numbness	-0.89 ( 0.158 )	-1.37 ( 0.167 )
Muscle Spasms	-0.87 ( 0.149 )	-1.49 ( 0.159 )
Feelings of Heaviness	-0.96 ( 0.157 )	-1.34 ( 0.166 )
Physical Fatigue	-0.89 ( 0.155 )	-1.45 ( 0.165 )
Brain Fog	-0.90 ( 0.127 )	-1.40 ( 0.134 )

Statistical Analysis 2

Statistical analysis description

Tingling

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007 ^[11]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.54

Confidence interval

level

95%

sides

2-sided

lower limit

-0.96

upper limit

-0.12

Variability estimate

Standard error of the mean

Dispersion value

0.213

Notes
[11] - 1-sided p-value was reported.

Statistical Analysis 1

Statistical analysis description

Muscle Cramps

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006 ^[12]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.56

Confidence interval

level

95%

sides

2-sided

lower limit

-0.99

upper limit

-0.12

Variability estimate

Standard error of the mean

Dispersion value

0.218

Notes
[12] - 1-sided p-value was reported.

Statistical Analysis 5

Statistical analysis description

Feelings of Heaviness

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05 ^[13]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-0.83

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.229

Notes
[13] - 1-sided p-value was reported.

Statistical Analysis 6

Statistical analysis description

Physical Fatigue

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008 ^[14]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

0.227

Notes
[14] - 1-sided p-value was reported.

Statistical Analysis 7

Statistical analysis description

Brain Fog

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[15]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.51

Confidence interval

level

95%

sides

2-sided

lower limit

-0.87

upper limit

-0.14

Variability estimate

Standard error of the mean

Dispersion value

0.186

Notes
[15] - 1-sided p-value was reported.

Statistical Analysis 3

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02 ^[16]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-0.94

upper limit

-0.02

Variability estimate

Standard error of the mean

Dispersion value

0.231

Notes
[16] - 1-sided p-value was reported.

Statistical Analysis 4

Statistical analysis description

Muscle Spasms

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[17]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-1.05

upper limit

-0.18

Variability estimate

Standard error of the mean

Dispersion value

0.219

Notes
[17] - 1-sided p-value was reported.

Secondary: Number of Participants With Response at Week 26 [Early Termination (ET)]

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End point title

Number of Participants With Response at Week 26 [Early Termination (ET)]

End point description

Response was defined as a 30% reduction in HypoPT-SD symptom subscale score from baseline. The HypoPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness or 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. An item score was computed by taking the average of the daily item response over the 14-day period immediately before the visit. If data were not available for at least 4 out of 7 days during both 7-day periods within the 14-day period, the individual item score was set to missing. The symptom subscale score was computed as the average of symptom items 1-7 scores with more than 3 of the 7 symptom item scores were non-missing. Data reported also includes results for early terminated participants.

End point type

Secondary

End point timeframe

Baseline up to Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	38	32
Units: participants	24	25

No statistical analyses for this end point

Secondary: Change From Baseline in the Most Bothersome Symptom Score at Week 26

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End point title

Change From Baseline in the Most Bothersome Symptom Score at Week 26

End point description

The HypoPT-SD is a 13-item patient-reported outcomes instrument that consists of the following items: symptom subscale (items 1-7), anxiety (item 8), sadness or 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. An item score was computed by taking the average of the daily item response over the 14-day period immediately before the visit. If data were not available for at least 4 out of 7 days during both 7-day periods within the 14-day period, the individual item score was set to missing. The Most Bothersome Symptom Score was analyzed. Negative change in scores indicates improvement. MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	38	26
Units: score on a scale
least squares mean (standard error)	-0.87 ( 0.156 )	-1.77 ( 0.174 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[18]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.37

upper limit

-0.43

Variability estimate

Standard error of the mean

Dispersion value

0.235

Notes
[18] - 1-sided p-value was reported.

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Perceived Cognitive Impairments (PCI) Score at Week 26

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End point title

Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Perceived Cognitive Impairments (PCI) Score at Week 26

End point description

The Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) assessment is a 37-item instrument. The perceived cognitive impairment and the impact on quality of life domains were assessed in this study. These 2 domains include 22 items rated on a 5-point scale. The perceived cognitive impairments subscale contains 18 items and each item has a 5-point ordinal response scale (0=Never, 1= About once a week, 2 = Two to three times a week, 3= Nearly every day, 4 = Several times a day). Each item score is calculated as (4 minus item response), and the subscale score is [sum of (4 minus item response)]*18/(number of items answered)]. The perceived cognitive impairment subscale score ranges from 0 to 72, with higher scores indicate better cognitive function. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	29	28
Units: score on a scale
least squares mean (standard error)	2.7 ( 0.74 )	4.8 ( 0.76 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.024 ^[19]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

4.3

Variability estimate

Standard error of the mean

Dispersion value

1.07

Notes
[19] - 1-sided p-value was reported.

Secondary: Change From Baseline in Individual Domains of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26

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End point title

Change From Baseline in Individual Domains of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26

End point description

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 was reported. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	29	29
Units: score on a scale
least squares mean (standard error)
Standard-Bodily Pain	4.194 ( 1.4987 )	11.404 ( 1.4919 )
Standard-General Health	3.515 ( 1.4509 )	9.061 ( 1.4463 )
Standard-Mental Health	3.719 ( 1.6098 )	11.576 ( 1.6043 )
Standard-Physical Functioning	4.833 ( 1.4850 )	9.387 ( 1.4669 )
Standard-Role-Emotional	5.228 ( 1.6322 )	13.648 ( 1.6254 )
Standard-Role-Physical	5.964 ( 1.5799 )	10.194 ( 1.5670 )
Standard-Social Functioning	6.005 ( 1.8636 )	9.814 ( 1.8661 )
Standard-Vitality	4.205 ( 1.6539 )	12.147 ( 1.6547 )

Statistical Analysis 1

Statistical analysis description

Standard-Bodily Pain

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[20]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

7.21

Confidence interval

level

95%

sides

2-sided

lower limit

2.951

upper limit

11.469

Variability estimate

Standard error of the mean

Dispersion value

2.1376

Notes
[20] - 1-sided p-value was reported.

Statistical Analysis 2

Statistical analysis description

Standard-General Health

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004 ^[21]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

5.545

Confidence interval

level

95%

sides

2-sided

lower limit

1.452

upper limit

9.638

Variability estimate

Standard error of the mean

Dispersion value

2.0542

Notes
[21] - 1-sided p-value was reported.

Statistical Analysis 3

Statistical analysis description

Standard-Mental Health

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[22]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

7.857

Confidence interval

level

95%

sides

2-sided

lower limit

3.292

upper limit

12.423

Variability estimate

Standard error of the mean

Dispersion value

2.2913

Notes
[22] - 1-sided p-value was reported.

Statistical Analysis 8

Statistical analysis description

Standard-Vitality

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[23]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

7.942

Confidence interval

level

95%

sides

2-sided

lower limit

3.253

upper limit

12.63

Variability estimate

Standard error of the mean

Dispersion value

2.353

Notes
[23] - 1-sided p-value was reported.

Statistical Analysis 5

Statistical analysis description

Standard-Role-Emotional

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[24]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

8.42

Confidence interval

level

95%

sides

2-sided

lower limit

3.8

upper limit

13.04

Variability estimate

Standard error of the mean

Dispersion value

2.3186

Notes
[24] - 1-sided p-value was reported.

Statistical Analysis 6

Statistical analysis description

Standard-Role-Physical

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.032 ^[25]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

4.23

Confidence interval

level

95%

sides

2-sided

lower limit

-0.251

upper limit

8.711

Variability estimate

Standard error of the mean

Dispersion value

2.2489

Notes
[25] - 1-sided p-value was reported.

Statistical Analysis 7

Statistical analysis description

Standard-Social Functioning

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.079 ^[26]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

3.809

Confidence interval

level

95%

sides

2-sided

lower limit

-1.502

upper limit

9.121

Variability estimate

Standard error of the mean

Dispersion value

2.6658

Notes
[26] - 1-sided p-value was reported.

Statistical Analysis 4

Statistical analysis description

Standard-Physical Functioning

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.017 ^[27]

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

4.554

Confidence interval

level

95%

sides

2-sided

lower limit

0.345

upper limit

8.763

Variability estimate

Standard error of the mean

Dispersion value

2.1123

Notes
[27] - 1-sided p-value was reported.

Secondary: Change From Baseline in Mental Component Summary (MCS) Score of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26

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End point title

Change From Baseline in Mental Component Summary (MCS) Score of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26

End point description

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 was reported. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	29	29
Units: score on a scale
least squares mean (standard error)	4.297 ( 1.5898 )	12.597 ( 1.5904 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[28]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

8.3

Confidence interval

level

95%

sides

2-sided

lower limit

3.788

upper limit

12.811

Variability estimate

Standard error of the mean

Dispersion value

2.2642

Notes
[28] - 1-sided p-value

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Impact on Quality of Life (QoL) Score at Week 26

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End point title

Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Impact on Quality of Life (QoL) Score at Week 26

End point description

The Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) assessment is a 37-item instrument. The perceived cognitive impairment and the impact on quality of life domains were assessed in this study. These 2 domains include 22 items rated on a 5-point scale. The impact on quality of life domain contains 4 items and each item has a 5-point ordinal response scale (0=Never, 1= About once a week, 2 = Two to three times a week, 3= Nearly every day, 4 = Several times a day). Each item score is calculated as (4 minus item response), and the subscale score is [sum of (4 minus item response)]*4/(number of items answered)]. The impact on quality of life subscale score ranges from 0 to 16 with higher score indicates better cognitive function. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	29	28
Units: score on a scale
least squares mean (standard error)	2.7 ( 0.74 )	4.8 ( 0.76 )

Statistical Analysis

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.024 ^[29]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

4.3

Variability estimate

Standard error of the mean

Dispersion value

1.07

Notes
[29] - 1-sided p-value was reported.

Secondary: Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Hypoparathyroidism (WPAI: Hypoparathyroidism) Score at Week 26

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End point title

Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Hypoparathyroidism (WPAI: Hypoparathyroidism) Score at Week 26

End point description

WPAI assessed impact of HypoPT on work productivity and daily activities. Concepts that WPAI: Hypoparathyroidism measures include time missed from work and impairment of work and other regular activities due to specific health problem (HypoPT). WPI was calculated based on 4 items including Q2: hours of work missed due to HPT; Q4: actual hours worked; Q5: HPT effect on productivity at work; Q6: HPT effect on daily activities. Scores for 4 subscales were calculated as Percent work time missed due to problem: Q2/(Q2+Q4)*100; Percent impairment while working due to problem: Q5/10*100; Percent overall work impairment due to problem: Q2/(Q2+Q4)+[(1(Q2/(Q2+Q4)))x(Q5/10)]*100; Percent activity impairment due to problem: Q6/10*100. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity, i.e., worse outcomes. Change from baseline in questionnaire response was reported. A MMRM was used for analysis. Percent Impairment=PI.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	29	27
Units: score on a scale
least squares mean (standard error)
Percent Work Time Missed Due to Problem(n=15,11)	2.30 ( 6.279 )	5.43 ( 7.155 )
PI While Working Due to Problem(n=14,9)	-11.7 ( 4.79 )	-26.3 ( 5.76 )
PI Overall Work, Due to Problem(n=14,9)	-11.17 ( 3.854 )	-26.08 ( 4.774 )
PI, Activity Due to Problem(n=29,27)	-10.2 ( 3.97 )	-23.3 ( 4.17 )

Statistical Analysis 1

Statistical analysis description

Percent Work Time Missed Due to Problem

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.627 ^[30]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

3.13

Confidence interval

level

95%

sides

2-sided

lower limit

-16.33

upper limit

22.6

Variability estimate

Standard error of the mean

Dispersion value

9.578

Notes
[30] - 1-sided p-value was reported.

Statistical Analysis 4

Statistical analysis description

Percent Activity Impairment Due to Problem

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014 ^[31]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-13

Confidence interval

level

95%

sides

2-sided

lower limit

-24.5

upper limit

-1.5

Variability estimate

Standard error of the mean

Dispersion value

5.78

Notes
[31] - 1-sided p-value was reported.

Statistical Analysis 3

Statistical analysis description

Percent Overall Work Impairment Due to Problem

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011 ^[32]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-14.9

Confidence interval

level

95%

sides

2-sided

lower limit

-27.42

upper limit

-2.39

Variability estimate

Standard error of the mean

Dispersion value

6.146

Notes
[32] - 1-sided p-value was reported.

Statistical Analysis 2

Statistical analysis description

Percent Impairment While Working Due to Problem

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.031 ^[33]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-14.6

Confidence interval

level

95%

sides

2-sided

lower limit

-29.9

upper limit

0.7

Variability estimate

Standard error of the mean

Dispersion value

7.52

Notes
[33] - 1-sided p-value was reported.

Secondary: Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Change (PGI-C) at Week 26

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End point title

Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Change (PGI-C) at Week 26

End point description

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 assessed using a 7-point scale: very much improved (0), much improved (1), minimally improved (2), no change (3), minimally worse (4), much worse (5), and very much worse (6). Negative change indicates improvement. Mean change in scores of PGI-C at Week 26 was be reported.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	30	28
Units: score on a scale
arithmetic mean (standard deviation)	-0.6 ( 1.04 )	-1.7 ( 1.63 )

No statistical analyses for this end point

Secondary: Change From Baseline in In-Clinic Neurocognitive Assessment Scores at Week 24

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End point title

Change From Baseline in In-Clinic Neurocognitive Assessment Scores at Week 24

End point description

Neurocognitive test battery included tests evaluating frontal-executive domain, which encompasses functions attributable to prefrontal cortex and its connections to basal ganglia (mostly striatum). Tests included 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 was reported. Analysis of Covariance (ANCOVA) was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	34	30
Units: score on a scale
least squares mean (confidence interval 95%)
Detection(n=34,30)	0.03 (0.01 to 0.06)	0.05 (0.02 to 0.08)
Identification(n=33,30)	0.02 (-0.01 to 0.05)	0.04 (0.01 to 0.07)
One Card Learning(n=33,30)	0.12 (0.07 to 0.16)	0.13 (0.08 to 0.17)
One Back (ONB)(n=33,30)	-2.43 (-9.89 to 5.02)	7.49 (-0.46 to 15.45)
Groton Maze Learning(n=33,30)	1.98 (0.73 to 3.24)	1.42 (0.08 to 2.76)
International Shopping List(n=34,30)	1.31 (0.62 to 1.99)	1.86 (1.13 to 2.59)

Statistical Analysis 1

Statistical analysis description

Detection

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.516

Method

ANCOVA

Parameter type

Difference in LS Mean

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.05

Statistical Analysis 2

Statistical analysis description

Identification

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.275

Method

ANCOVA

Parameter type

Difference in LS Mean

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.06

Statistical Analysis 3

Statistical analysis description

One Card Learning

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.777

Method

ANCOVA

Parameter type

Difference in LS Mean

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.07

Statistical Analysis 4

Statistical analysis description

One Back (ONB)

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.831

Method

ANCOVA

Parameter type

Difference in LS Mean

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.05

Statistical Analysis 5

Statistical analysis description

Groton Maze Learning (GML)

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.075

Method

ANCOVA

Parameter type

Difference in LS Mean

Point estimate

9.93

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

20.85

Statistical Analysis 6

Statistical analysis description

International Shopping List (ISL)

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.545

Method

ANCOVA

Parameter type

Difference in LS Mean

Point estimate

-0.57

Confidence interval

level

95%

sides

2-sided

lower limit

-2.41

upper limit

1.27

Statistical Analysis 7

Statistical analysis description

International Shopping List Test Delayed Recall (ISRL)

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.283

Method

ANCOVA

Parameter type

Difference in LS Mean

Point estimate

0.55

Confidence interval

level

95%

sides

2-sided

lower limit

-0.45

upper limit

1.56

Secondary: Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Severity (PGI-S) at Week 26

Top of page

End point title

Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Severity (PGI-S) at Week 26

End point description

The PGI-S is a global index that can be used to rate the severity of a specific condition. The PGI-S is a rating scale that asks the respondent to best describe how their symptoms severity. Response options are assessed as per 5-point scale: no symptoms (0), mild (1), moderate (2), severe (3), and very severe (4). Mean change in scores of PGI-S at Week 26 was reported. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	34	29
Units: score on a scale
least squares mean (standard error)	-0.8 ( 0.15 )	-1.4 ( 0.16 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.01 ^[34]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

0.22

Notes
[34] - 1-sided p-value

Secondary: Change From Baseline in 24-hour Urine Calcium Excretion at Week 26

Top of page

End point title

Change From Baseline in 24-hour Urine Calcium Excretion at Week 26

End point description

Change in 24-hour urine calcium excretion at Week 26 was reported. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	43	33
Units: millimoles per day (mmol/day)
least squares mean (standard error)	-1.99 ( 0.574 )	0.11 ( 0.651 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.991 ^[35]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

2.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

3.83

Variability estimate

Standard error of the mean

Dispersion value

0.871

Notes
[35] - 1-sided p-value was reported.

Secondary: Change From Baseline in At-Home Neurocognitive Assessment Scores at Week 26

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End point title

Change From Baseline in At-Home Neurocognitive Assessment Scores at Week 26

End point description

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	45	38
Units: score on a scale
least squares mean (confidence interval 95%)
Detection (DET)(n=45,37)	-0.01 (-0.03 to 0.00)	-0.01 (-0.03 to 0.01)
Identification (IDN)(n=45,38)	-0.01 (-0.03 to 0.01)	0.00 (-0.02 to 0.02)
One Card Learning (OCL)(n=45,37)	0.08 (0.05 to 0.11)	0.09 (0.06 to 0.12)
One Back (ONB)(n=45,38)	0.02 (0.00 to 0.04)	0.03 (0.01 to 0.05)

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.582 ^[36]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.04

Notes
[36] - 1-sided p-value was reported.

Statistical Analysis 4

Statistical analysis description

One Back Test

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.438 ^[37]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.04

Notes
[37] - 1-sided p-value was reported.

Statistical Analysis 3

Statistical analysis description

One Card Learning (OCL)

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.506 ^[38]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.06

Notes
[38] - 1-sided p-value was reported.

Statistical Analysis 2

Statistical analysis description

Identification (IDN)

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.492 ^[39]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.04

Notes
[39] - 1-sided p-value was reported.

Secondary: Change From Baseline in Serum Phosphate Level at Week 26

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End point title

Change From Baseline in Serum Phosphate Level at Week 26

End point description

Change in serum phosphate level at Week 26 was reported. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	47	40
Units: millimoles per liter (mmol/L)
least squares mean (standard error)	0.030 ( 0.0270 )	-0.145 ( 0.0289 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[40]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-0.175

Confidence interval

level

95%

sides

2-sided

lower limit

-0.254

upper limit

-0.097

Variability estimate

Standard error of the mean

Dispersion value

0.0395

Notes
[40] - 1-sided p-value was reported.

Secondary: Change From Baseline in Doses of Active Vitamin D at Week 26

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End point title

Change From Baseline in Doses of Active Vitamin D at Week 26

End point description

Changes in doses of active vitamin D at Week 26 was reported. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	47	38
Units: micrograms per day (μg/day)
least squares mean (standard error)	-5.65 ( 3.155 )	-1.57 ( 3.418 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.81 ^[41]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

4.08

Confidence interval

level

95%

sides

2-sided

lower limit

-5.06

upper limit

13.22

Variability estimate

Standard error of the mean

Dispersion value

4.654

Notes
[41] - 1-sided p-value was reported.

Secondary: Change From Baseline in Doses of Calcium Supplements at Week 26

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End point title

Change From Baseline in Doses of Calcium Supplements at Week 26

End point description

Changes in doses of calcium supplements at Week 26 was reported. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	47	40
Units: milligrams per day (mg/day)
least squares mean (standard error)	-44.3 ( 91.13 )	-375.6 ( 96.20 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007 ^[42]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-331.3

Confidence interval

level

95%

sides

2-sided

lower limit

-594.6

upper limit

-67.9

Variability estimate

Standard error of the mean

Dispersion value

132.56

Notes
[42] - 1-sided p-value was reported.

Secondary: Change From Baseline in Bone Turnover Marker Bone Specific Alkaline Phosphatase at Week 26

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End point title

Change From Baseline in Bone Turnover Marker Bone Specific Alkaline Phosphatase at Week 26

End point description

Bone turnover markers included serum bone-specific alkaline phosphatase, procollagen amino-terminal peptide, C-terminal telopeptide of type 1 collagen, and osteocalcin. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	44	37
Units: units per liter (U/L)
least squares mean (standard error)	0.69 ( 2.256 )	23.03 ( 2.365 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[43]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

22.33

Confidence interval

level

95%

sides

2-sided

lower limit

15.83

upper limit

28.84

Variability estimate

Standard error of the mean

Dispersion value

3.271

Notes
[43] - 1-sided p-value was reported.

Secondary: Change From Baseline in Albumin-corrected Serum Calcium Control at Week 26

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End point title

Change From Baseline in Albumin-corrected Serum Calcium Control at Week 26

End point description

Change From Baseline in albumin-corrected serum calcium between 1.875 millimoles per liter (mmol/L) (7.5 milligram per deciliter [mg/dL]) and upper limit of normal (ULN) for the central laboratory normal range at Week 26 was reported.

End point type

Secondary

End point timeframe

Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	47	40
Units: mmol/L
arithmetic mean (standard deviation)	-0.033 ( 0.2072 )	0.090 ( 0.2254 )

No statistical analyses for this end point

Secondary: Number of Participants who Achieve Composite Criteria for Albumin-corrected Serum Calcium Concentration, Active Vitamin D Dose and Oral Elemental Calcium Supplement Dose at Week 26

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End point title

Number of Participants who Achieve Composite Criteria for Albumin-corrected Serum Calcium Concentration, Active Vitamin D Dose and Oral Elemental Calcium Supplement Dose at Week 26

End point description

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 elemental calcium supplement dose at Week 26 was reported.

End point type

Secondary

End point timeframe

Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	47	40
Units: participants	6	21

No statistical analyses for this end point

Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

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End point title

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

End point description

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.

End point type

Secondary

End point timeframe

From start of study drug administration to 4 weeks post follow-up (up to Week 36)

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	48	45
Units: participants	46	41

No statistical analyses for this end point

Secondary: Change From Baseline in Bone Turnover Marker Type I Collagen C-Telopeptides at Week 26

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End point title

Change From Baseline in Bone Turnover Marker Type I Collagen C-Telopeptides at Week 26

End point description

Bone turnover markers included serum bone-specific alkaline phosphatase, procollagen amino-terminal peptide, C-terminal telopeptide of type 1 collagen, and osteocalcin. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	45	36
Units: nanograms per liter (ng/L)
least squares mean (standard error)	-5.0 ( 76.52 )	780.5 ( 84.00 )

Statistical Analysis 1

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[44]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

785.5

Confidence interval

level

95%

sides

2-sided

lower limit

559.6

upper limit

1011.3

Variability estimate

Standard error of the mean

Dispersion value

113.65

Notes
[44] - 1-sided p-value was reported.

Secondary: Change From Baseline in Bone Turnover Marker Osteocalcin and Procollagen 1 N-Terminal Propeptide at Week 26

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End point title

Change From Baseline in Bone Turnover Marker Osteocalcin and Procollagen 1 N-Terminal Propeptide at Week 26

End point description

Bone turnover markers included serum bone-specific alkaline phosphatase, procollagen amino-terminal peptide, C-terminal telopeptide of type 1 collagen, and osteocalcin. A MMRM was used for analysis.

End point type

Secondary

End point timeframe

Baseline, Week 26

End point values	Placebo	rhPTH (1-84)
Number of subjects analysed	45	36
Units: micrograms per liter (µg/L)
least squares mean (standard error)
Osteocalcin(n=45,36)	-0.88 ( 4.109 )	55.55 ( 4.476 )
Procollagen 1 N-Terminal Propeptide(n=45,34)	1.95 ( 22.744 )	228.52 ( 24.475 )

Statistical Analysis 2

Statistical analysis description

Procollagen 1 N-Terminal Propeptide

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[45]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

226.57

Confidence interval

level

95%

sides

2-sided

lower limit

160.17

upper limit

292.98

Variability estimate

Standard error of the mean

Dispersion value

33.425

Notes
[45] - 1-sided p-value was reported.

Statistical Analysis 1

Statistical analysis description

Osteocalcin

Comparison groups

Placebo v rhPTH (1-84)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[46]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

56.43

Confidence interval

level

95%

sides

2-sided

lower limit

44.33

upper limit

68.53

Variability estimate

Standard error of the mean

Dispersion value

6.091

Notes
[46] - 1-sided p-value was reported.

Adverse events

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Timeframe for reporting adverse events

From start of study drug administration to 4 weeks post follow-up (up to Week 36)

Adverse event reporting additional description

Safety Analysis Set included all participants in the ITT Set who took at least 1 dose of investigational product (study drug or placebo).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

rhPTH (1-84)

Reporting group description

Participants received rhPTH (1-84) 50 mcg SC injection 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 up to 32 weeks.

Reporting group title

Placebo

Reporting group description

Participants received placebo matched to rhPTH (1-84) as SC injection QD with active vitamin D and calcium supplements up to 31.3 weeks.

Serious adverse events	rhPTH (1-84)	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 45 (13.33%)	6 / 48 (12.50%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ganglioneuroma
subjects affected / exposed	1 / 45 (2.22%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 45 (2.22%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Bradyphrenia
subjects affected / exposed	1 / 45 (2.22%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 45 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	1 / 45 (2.22%)	0 / 48 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 45 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	0 / 45 (0.00%)	2 / 48 (4.17%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	3 / 45 (6.67%)	2 / 48 (4.17%)
occurrences causally related to treatment / all	1 / 3	1 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Tetany
subjects affected / exposed	0 / 45 (0.00%)	1 / 48 (2.08%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	rhPTH (1-84)	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	38 / 45 (84.44%)	41 / 48 (85.42%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 45 (2.22%)	3 / 48 (6.25%)
occurrences all number	1	3
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 45 (2.22%)	5 / 48 (10.42%)
occurrences all number	1	7
Nervous system disorders
Dizziness
subjects affected / exposed	5 / 45 (11.11%)	6 / 48 (12.50%)
occurrences all number	5	10
Headache
subjects affected / exposed	14 / 45 (31.11%)	11 / 48 (22.92%)
occurrences all number	26	12
Paraesthesia
subjects affected / exposed	6 / 45 (13.33%)	5 / 48 (10.42%)
occurrences all number	8	7
Hypoaesthesia
subjects affected / exposed	4 / 45 (8.89%)	1 / 48 (2.08%)
occurrences all number	5	1
General disorders and administration site conditions
Feeling abnormal
subjects affected / exposed	5 / 45 (11.11%)	1 / 48 (2.08%)
occurrences all number	5	1
Fatigue
subjects affected / exposed	5 / 45 (11.11%)	4 / 48 (8.33%)
occurrences all number	8	4
Gastrointestinal disorders
Nausea
subjects affected / exposed	11 / 45 (24.44%)	9 / 48 (18.75%)
occurrences all number	15	9
Diarrhoea
subjects affected / exposed	5 / 45 (11.11%)	8 / 48 (16.67%)
occurrences all number	13	8
Abdominal pain
subjects affected / exposed	1 / 45 (2.22%)	3 / 48 (6.25%)
occurrences all number	2	3
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	2 / 45 (4.44%)	3 / 48 (6.25%)
occurrences all number	2	3
Cough
subjects affected / exposed	4 / 45 (8.89%)	3 / 48 (6.25%)
occurrences all number	4	3
Psychiatric disorders
Anxiety
subjects affected / exposed	4 / 45 (8.89%)	3 / 48 (6.25%)
occurrences all number	5	3
Depression
subjects affected / exposed	4 / 45 (8.89%)	1 / 48 (2.08%)
occurrences all number	5	1
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	5 / 45 (11.11%)	2 / 48 (4.17%)
occurrences all number	5	2
Myalgia
subjects affected / exposed	3 / 45 (6.67%)	4 / 48 (8.33%)
occurrences all number	3	4
Muscular weakness
subjects affected / exposed	1 / 45 (2.22%)	3 / 48 (6.25%)
occurrences all number	1	3
Muscle spasms
subjects affected / exposed	5 / 45 (11.11%)	4 / 48 (8.33%)
occurrences all number	7	4
Bone pain
subjects affected / exposed	3 / 45 (6.67%)	3 / 48 (6.25%)
occurrences all number	4	3
Back pain
subjects affected / exposed	4 / 45 (8.89%)	2 / 48 (4.17%)
occurrences all number	5	2
Arthralgia
subjects affected / exposed	8 / 45 (17.78%)	6 / 48 (12.50%)
occurrences all number	12	10
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 45 (8.89%)	7 / 48 (14.58%)
occurrences all number	5	9
Influenza
subjects affected / exposed	4 / 45 (8.89%)	3 / 48 (6.25%)
occurrences all number	4	3
Gastroenteritis
subjects affected / exposed	3 / 45 (6.67%)	2 / 48 (4.17%)
occurrences all number	3	2
Urinary tract infection
subjects affected / exposed	3 / 45 (6.67%)	3 / 48 (6.25%)
occurrences all number	3	3
Metabolism and nutrition disorders
Hypocalcaemia
subjects affected / exposed	5 / 45 (11.11%)	9 / 48 (18.75%)
occurrences all number	5	11
Hypercalcaemia
subjects affected / exposed	4 / 45 (8.89%)	0 / 48 (0.00%)
occurrences all number	5	0
Hypokalaemia
subjects affected / exposed	0 / 45 (0.00%)	3 / 48 (6.25%)
occurrences all number	0	3

More information

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Were there any global substantial amendments to the protocol? Yes

15 Jun 2017

Following changes were implemented with Protocol Amendment 1: -Reviewed the study title to reflect the double-blind, adaptive, study design, and new primary objective evaluating symptom improvement. -Deleted references to Phase 4 in the title. -Updated to the emergency contact information. -Extended the planned study period. -Updated the number of participants to be enrolled. -Modified primary objective of the study. -Added key secondary objectives. -Reviewed all endpoints. -Modified the statistical analyses, sample size calculation and study visit schedule. -Clarified that administration of the investigational product was to take place in the morning. -Removed renal ultrasounds and bone mineral density assessments. -Reviewed eligibility criteria. -Added the EQ-5D-5L as a second HRQoL assessment and as exploratory endpoint. -Deleted the Hospital Anxiety and Depression Scale from PROs assessments to be performed in the study. -Clarified the definition of severe hypocalcemia. -Allowed participants who failed to meet all inclusion/exclusion criteria to be rescreened. -Added dose of native vitamin D supplements and effect of rhPTH(1-84) on change in the item score of the most burdensome symptom from baseline as exploratory endpoints. -Revised dosing guidelines for active vitamin D supplements, calcium supplements, and investigational product.

03 May 2018

Following changes were implemented with Protocol Amendment 2: -Removed first blinded interim analysis. -Clarified that active vitamin D and/or calcium could be increased, decreased, and/or stopped during titration and that the investigational product was given with active vitamin D and/or calcium supplements. -Clarified language in the primary and key secondary objectives. -Added descriptive analyses and secondary objective based on for HypoPT-SD symptom subscale score. -Revised secondary endpoint about metabolic control (and criteria). -Added secondary objectives. -Revised number of participants anticipated to be enrolled at each site. -Clarified follow-up procedures. - Revised several inclusion criteria for clarity and accuracy with current clinical guidances. -Added serum TSH level was as an assessment to be performed at the Week 26 visit (EOT visit). -Added between visit predose nadir and postdose peak levels. -Added urine pregnancy test to assessments to be performed at Week 30 visit. -Clarified that protocol allows local laboratories to be used for evaluation. -Added phone call day before the baseline (Week 0) visit and EOT (Week 26). -Added denosumab to the list of common excluded treatments. -Clarified if active vitamin D and/or calcium supplements need to be taken. - Removed qualitative cystine from the urine chemistry parameters.

10 Nov 2020

Following changes were implemented with Protocol Amendment 3: -Revised sample size and power estimates for the interim and final analyses. -Updated time of the call to remind participants to complete PRO instruments to 2 days prior the applicable visits. -Defined type of follow-up EOS contact; on-site visit for participants who discontinue treatment with rhPTH(1-84) or phone call for participants on commercial rhPTH(1-84). -Removed restriction to maintain daily dietary intake of calcium, phosphate and sodium prior to blood draws and during the 24-hour urine collections.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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)]

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Subscale Score at Week 26

Primary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Subscale Score at Week 26

Secondary: Change From Baseline in Physical Component Summary (PCS) Derived From 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores at Week 26

Secondary: Change From Baseline in Physical Component Summary (PCS) Derived From 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores at Week 26

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 26

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score at Week 26

Secondary: Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Items Score at Week 26

Secondary: Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Items Score at Week 26

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Subscale Score at Week 26

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Impact Subscale Score at Week 26

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Sadness or Depression (Item 9) Score at Week 26

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Sadness or Depression (Item 9) Score at Week 26

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Anxiety (item 8) Score at Week 26

Secondary: Change From Baseline in Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Anxiety (item 8) Score at Week 26

Secondary: Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Scores at Week 26

Secondary: Change From Baseline in Individual Hypoparathyroidism Symptom Diary (HypoPT-SD) Symptom Item Scores at Week 26

Secondary: Number of Participants With Response at Week 26 [Early Termination (ET)]

Secondary: Number of Participants With Response at Week 26 [Early Termination (ET)]

Secondary: Change From Baseline in the Most Bothersome Symptom Score at Week 26

Secondary: Change From Baseline in the Most Bothersome Symptom Score at Week 26

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Perceived Cognitive Impairments (PCI) Score at Week 26

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Perceived Cognitive Impairments (PCI) Score at Week 26

Secondary: Change From Baseline in Individual Domains of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26

Secondary: Change From Baseline in Individual Domains of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26

Secondary: Change From Baseline in Mental Component Summary (MCS) Score of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26

Secondary: Change From Baseline in Mental Component Summary (MCS) Score of 36-Item Short Form Health Survey Version 2 (SF-36v2) at Week 26

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Impact on Quality of Life (QoL) Score at Week 26

Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) Impact on Quality of Life (QoL) Score at Week 26

Secondary: Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Hypoparathyroidism (WPAI: Hypoparathyroidism) Score at Week 26

Secondary: Change From Baseline in Work Productivity and Activity Impairment Questionnaire: Hypoparathyroidism (WPAI: Hypoparathyroidism) Score at Week 26

Secondary: Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Change (PGI-C) at Week 26

Secondary: Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Change (PGI-C) at Week 26

Secondary: Change From Baseline in In-Clinic Neurocognitive Assessment Scores at Week 24

Secondary: Change From Baseline in In-Clinic Neurocognitive Assessment Scores at Week 24

Secondary: Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Severity (PGI-S) at Week 26

Secondary: Change From Baseline in Scores of Patient's Assessment of Overall Health Status Using Patient Global Impression of Severity (PGI-S) at Week 26

Secondary: Change From Baseline in 24-hour Urine Calcium Excretion at Week 26

Secondary: Change From Baseline in 24-hour Urine Calcium Excretion at Week 26

Secondary: Change From Baseline in At-Home Neurocognitive Assessment Scores at Week 26

Secondary: Change From Baseline in At-Home Neurocognitive Assessment Scores at Week 26

Secondary: Change From Baseline in Serum Phosphate Level at Week 26

Secondary: Change From Baseline in Serum Phosphate Level at Week 26

Secondary: Change From Baseline in Doses of Active Vitamin D at Week 26

Secondary: Change From Baseline in Doses of Active Vitamin D at Week 26

Secondary: Change From Baseline in Doses of Calcium Supplements at Week 26

Secondary: Change From Baseline in Doses of Calcium Supplements at Week 26

Secondary: Change From Baseline in Bone Turnover Marker Bone Specific Alkaline Phosphatase at Week 26

Secondary: Change From Baseline in Bone Turnover Marker Bone Specific Alkaline Phosphatase at Week 26

Secondary: Change From Baseline in Albumin-corrected Serum Calcium Control at Week 26

Secondary: Change From Baseline in Albumin-corrected Serum Calcium Control at Week 26

Secondary: Number of Participants who Achieve Composite Criteria for Albumin-corrected Serum Calcium Concentration, Active Vitamin D Dose and Oral Elemental Calcium Supplement Dose at Week 26

Secondary: Number of Participants who Achieve Composite Criteria for Albumin-corrected Serum Calcium Concentration, Active Vitamin D Dose and Oral Elemental Calcium Supplement Dose at Week 26

Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

Secondary: Change From Baseline in Bone Turnover Marker Type I Collagen C-Telopeptides at Week 26

Secondary: Change From Baseline in Bone Turnover Marker Type I Collagen C-Telopeptides at Week 26

Secondary: Change From Baseline in Bone Turnover Marker Osteocalcin and Procollagen 1 N-Terminal Propeptide at Week 26

Secondary: Change From Baseline in Bone Turnover Marker Osteocalcin and Procollagen 1 N-Terminal Propeptide at Week 26

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
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)]