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Clinical Trial Results:
A Phase 2b, Multicentre, Multinational, Double-blind, Dose-finding Study, incorporating an open label substudy, in Adult Patients with Type I, III or IV Osteogenesis Imperfecta Treated with setrusumab (BPS804)

Summary
EudraCT number	2016-005096-27
Trial protocol	DK GB FR
Global end of trial date	12 Nov 2020

Results information
Results version number	v1(current)
This version publication date	01 Mar 2022
First version publication date	01 Mar 2022
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

MBPS205

ISRCTN number

US NCT number

NCT03118570

WHO universal trial number (UTN)

Other trial identifiers

IND Number: 113385

Sponsor organisation name

Ultragenyx Pharmaceutical Inc.

Sponsor organisation address

60 Leveroni Court, Novato, United States, California 94949

Public contact

Medical Information, Ultragenyx Pharmaceutical Inc., 001 888- 756-8567, medinfo@ultragenyx.com

Scientific contact

Medical Information, Ultragenyx Pharmaceutical Inc., 001 888- 756-8567, medinfo@ultragenyx.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

12 Nov 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Nov 2020

Was the trial ended prematurely?

Main objective of the trial

To demonstrate that setrusumab increases radial trabecular volumetric bone mineral density (Tr. vBMD) on high resolution peripheral quantitative computed tomography (HRpQCT) and bone strength on finite element analysis (FEA) in patients with OI Type I, III or IV

Protection of trial subjects

The investigator or his/her representative explained the nature of the study to the participant or his/her legally authorised representative and answered all questions regarding the study. Participants was informed that their participation was voluntary. Participants or their legally authorised representative were required to sign a statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study centre.

Background therapy

For the duration of the study participants receive a daily dose of 500 mg calcium and/or 800 I.U. vitamin D as background treatment. Following the end of setrusumab therapy all participants had the option to receive a dose of zoledronic acid at 12 and 18 months, prescribed at the discretion of the treating physician and in line with local guidelines.

Evidence for comparator

Actual start date of recruitment

11 Sep 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 17

Country: Number of subjects enrolled

Denmark: 9

Country: Number of subjects enrolled

France: 17

Country: Number of subjects enrolled

United States: 61

Country: Number of subjects enrolled

Canada: 8

Worldwide total number of subjects

112

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)

105

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were randomized 1:1:1:1 to 3 doses of setrusumab (20 mg/kg, 8 mg/kg and 2 mg/kg) and placebo for a 12-month Treatment Period.

Screening details

Per Protocol Amendment 4, participants originally randomized to the placebo group were reassigned to receive 20 mg/kg open-label setrusumab (1 discontinued study prior to the transition). Two participants in the setrusumab 20 mg/kg open-label group were randomized into this group after Amendment 4 and did not receive placebo.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

With the exception of the open-label treatment arm, investigators and participants remained blinded to each participant’s assigned study treatment throughout the course of the study.

Are arms mutually exclusive

Setrusumab 20 mg/kg (Blinded)

Arm description

Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Arm type

Experimental

Investigational medicinal product name

setrusumab

Investigational medicinal product code

BPS804

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

60-minute infusion

Investigational medicinal product name

zoledronic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

15-minute infusion (Following the end of setrusumab therapy all participants had the option to receive a dose of zoledronic acid at 12 and 18 months, prescribed at the discretion of the treating physician and in line with local guidelines.)

Setrusumab 8 mg/kg (Blinded)

Arm description

Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Arm type

Experimental

Investigational medicinal product name

setrusumab

Investigational medicinal product code

BPS804

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

60-minute infusion

Investigational medicinal product name

zoledronic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Setrusumab 2 mg/kg (Blinded)

Arm description

Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Arm type

Experimental

Investigational medicinal product name

setrusumab

Investigational medicinal product code

BPS804

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

60-minute infusion

Investigational medicinal product name

zoledronic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Setrusumab 20 mg/kg (Open-Label)

Arm description

Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Participants were randomized to this group after amendment 4.

Arm type

Experimental

Investigational medicinal product name

setrusumab

Investigational medicinal product code

BPS804

Other name

Pharmaceutical forms

Powder for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

60-minute infusion

Investigational medicinal product name

zoledronic acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Placebo

Arm description

Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Due to a protocol amendment, placebo was actually received for an average of 5 months. Participants originally randomized to the placebo group were reassigned to receive 20 mg/kg open-label setrusumab after amendment 4.

Arm type

Experimental

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

60-minute infusion

Number of subjects in period 1	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)	Setrusumab 20 mg/kg (Open-Label)	Placebo
Started	31	29	30	2	20
Completed	26	22	25	17	0
Not completed	5	7	5	4	20
Consent withdrawn by subject	-	1	4	1	-
Other, not specified	1	3	-	-	-
Transferred to other arm/group	-	-	-	-	19
Adverse event	2	-	-	2	1
Lost to follow-up	2	3	1	1	-
Joined	0	0	0	19	0
Transferred in from other group/arm	-	-	-	19	-

Baseline characteristics

Top of page

Reporting group title

Setrusumab 20 mg/kg (Blinded)

Reporting group description

Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 8 mg/kg (Blinded)

Reporting group description

Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 2 mg/kg (Blinded)

Reporting group description

Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 20 mg/kg (Open-Label)

Reporting group description

Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Participants were randomized to this group after amendment 4.

Reporting group title

Placebo

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are "double-counted" for this analysis. (The total column represents the baseline values only for the n=112 enrolled participants.)

Reporting group values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)	Setrusumab 20 mg/kg (Open-Label)	Placebo	Total
Number of subjects	31	29	30	21	20
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	40.6 ± 13.73	40.4 ± 14.34	47.2 ± 12.42	41.6 ± 14.82	40.9 ± 14.68	-
Gender categorical
Units: Subjects
Female	17	20	21	15	14	73
Male	14	9	9	6	6	39
Ethnicity
Units: Subjects
Hispanic or Latino	3	1	2	1	1	4
Not Hispanic or Latino	27	27	28	20	19	107
Unknown or Not Reported	1	1	0	0	0	1
Race
Units: Subjects
Black or African American	2	1	1	0	0	4
White	29	27	29	21	20	107
Not Collected or Not Reported	0	1	0	0	0	1

End points

Top of page

Reporting group title

Setrusumab 20 mg/kg (Blinded)

Reporting group description

Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 8 mg/kg (Blinded)

Reporting group description

Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 2 mg/kg (Blinded)

Reporting group description

Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 20 mg/kg (Open-Label)

Reporting group description

Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Participants were randomized to this group after amendment 4.

Reporting group title

Placebo

Reporting group description

Primary: Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12

Top of page

End point title

Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12 ^[1] ^[2]

End point description

Assessed by high resolution peripheral quantitative computed tomography (HRpQCT). HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presents the ratio of the means between the visit and Baseline from analysis of covariance (ANCOVA). Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment (per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms). Participants with an assessment at given time point.

End point type

Primary

End point timeframe

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.

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: Statistical analyses are attached in a word document due to system limitations.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: ratio
number (confidence interval 95%)	1.004 (0.987 to 1.021)	0.993 (0.975 to 1.012)	0.992 (0.974 to 1.011)

Attachments

Untitled (Filename: Endpoint 1 Stat Analyses.docx)

No statistical analyses for this end point

Primary: Change From Baseline in Radial Bone Strength (Failure Load) at Month 12

Top of page

End point title

Change From Baseline in Radial Bone Strength (Failure Load) at Month 12 ^[3] ^[4]

End point description

Assessed by finite element analysis (FEA) of models generated from HRpQCT images of the distal radius. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.

End point type

Primary

End point timeframe

Baseline, Month 12 (EOT)

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: Statistical analyses are attached in a word document due to system limitations.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	28	22	25
Units: newton (N)
least squares mean (standard error)	61.25 ± 21.669	32.25 ± 24.342	8.86 ± 23.200

Attachments

Untitled (Filename: Endpoint 2 Stat Analyses.docx)

No statistical analyses for this end point

Primary: Change From Baseline in Radial Bone Strength (Stiffness) at Month 12

Top of page

End point title

Change From Baseline in Radial Bone Strength (Stiffness) at Month 12 ^[5] ^[6]

End point description

Assessed by FEA of models generated from HRpQCT images of the distal radius. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.

End point type

Primary

End point timeframe

Baseline, Month 12 (EOT)

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: Statistical analyses are attached in a word document due to system limitations.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	28	22	25
Units: N/mm
least squares mean (standard error)	1638.70 ± 625.808	1422.00 ± 703.275	209.89 ± 671.777

Attachments

Untitled (Filename: Endpoint 3 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set

Top of page

End point title

Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set ^[7]

End point description

Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT), 18, 24

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms. Open-Label arm data for this endpoint are presented as a separate endpoint.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: ratio
number (confidence interval 95%)
Radial: Month 6; n=26, 25, 25	1.007 (0.993 to 1.021)	1.000 (0.986 to 1.015)	0.998 (0.984 to 1.013)
Radial: Month 12; n=28, 22, 24	1.004 (0.987 to 1.021)	0.993 (0.975 to 1.012)	0.992 (0.974 to 1.011)
Radial: Month 18; n=23, 17, 23	1.002 (0.984 to 1.020)	0.992 (0.973 to 1.013)	0.979 (0.962 to 0.997)
Radial: Month 24; n=21, 16, 16	0.997 (0.972 to 1.023)	0.998 (0.970 to 1.027)	0.979 (0.951 to 1.008)
Tibial: Month 6; n=23, 20, 17	1.004 (0.986 to 1.022)	1.016 (0.996 to 1.036)	0.990 (0.969 to 1.012)
Tibial: Month 12; n=24, 17, 15	0.991 (0.940 to 1.046)	1.018 (0.955 to 1.086)	0.973 (0.909 to 1.042)
Tibial: Month 18; n=20, 13, 16	0.989 (0.945 to 1.035)	1.042 (0.985 to 1.102)	0.983 (0.933 to 1.036)
Tibial: Month 24; n=19, 12, 11	1.000 (0.949 to 1.054)	1.062 (0.995 to 1.133)	1.017 (0.949 to 1.090)

Attachments

Untitled (Filename: Endpoint 4 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm

Top of page

End point title

Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm ^[8]

End point description

Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. Analysis Population: All participants in the open-label arm who took at least 1 dose of study treatment. n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms. Full Analysis Set data for this endpoint are presented as a separate endpoint.

End point values	Setrusumab 20 mg/kg (Open-Label)
Number of subjects analysed	21
Units: ratio
number (confidence interval 95%)
Radial: Month 6; n=17	0.994 (0.972 to 1.017)
Radial: Month 12; n=16	1.011 (0.986 to 1.036)
Tibial: Month 6; n=15	1.013 (0.991 to 1.035)
Tibial: Month 12; n=15	1.035 (0.975 to 1.099)

Attachments

Untitled (Filename: Endpoint 5 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set

Top of page

End point title

Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set ^[9]

End point description

Assessed by FEA of models generated from HRpQCT images of the distal radius. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT), 18, 24

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: newton
least squares mean (confidence interval 95%)
Radial: Month 6; n=26, 25, 26	31.22 (-1.80 to 64.23)	39.95 (6.63 to 73.27)	-3.28 (-36.57 to 30.00)
Radial: Month 12; n=28, 22, 25	61.25 (18.03 to 104.46)	32.25 (-16.30 to 80.80)	8.86 (-37.41 to 55.13)
Radial: Month 18; n=23, 17, 24	50.39 (19.11 to 81.68)	43.11 (6.79 to 79.42)	-10.53 (-41.86 to 20.80)
Radial: Month 24; n=21, 16, 17	-19.59 (-72.66 to 33.47)	45.03 (-14.40 to 104.47)	-50.65 (-108.69 to 7.39)
Tibial: Month 6; n=23, 20, 17	46.00 (-24.91 to 116.92)	45.91 (-28.16 to 119.98)	-65.33 (-146.39 to 15.72)
Tibial: Month 12; n=24, 17, 15	76.15 (-11.23 to 163.54)	60.20 (-42.63 to 163.04)	-65.96 (-175.43 to 43.51)
Tibial: Month 18; n=20, 13, 16	50.69 (-34.55 to 135.93)	88.33 (-13.67 to 190.32)	-49.50 (-144.93 to 45.94)
Tibial: Month 24; n=19, 12, 11	-24.75 (-126.76 to 77.27)	41.37 (-86.68 to 169.43)	-74.94 (-208.22 to 58.34)

Attachments

Untitled (Filename: Endpoint 6 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm

Top of page

End point title

Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm ^[10]

End point description

Assessed by FEA of models generated from HRpQCT images of the distal radius. All participants in the open-label arm who took at least 1 dose of study treatment. n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Open-Label)
Number of subjects analysed	21
Units: newton
least squares mean (confidence interval 95%)
Radial: Month 6; n=16	110.16 (61.30 to 159.01)
Radial: Month 12; n=15	88.32 (28.55 to 148.09)
Tibial: Month 6; n=15	69.78 (-8.61 to 148.18)
Tibial: Month 12; n=15	112.92 (10.76 to 215.07)

Attachments

Untitled (Filename: Endpoint 7 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set

Top of page

End point title

Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set ^[11]

End point description

Assessed by FEA of models generated from HRpQCT images of the distal radius. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT), 18, 24

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: N/mm
least squares mean (confidence interval 95%)
Radial: Month 6; n=26, 25, 26	795.67 (-34.71 to 1626.04)	1048.61 (209.47 to 1887.75)	109.65 (-728.52 to 947.82)
Radial: Month 12; n=28, 22, 25	1638.70 (390.57 to 2886.83)	1422.00 (19.37 to 2824.64)	209.89 (-1129.93 to 1549.71)
Radial: Month 18; n=23, 17, 24	1295.98 (390.54 to 2201.42)	803.50 (-263.21 to 1870.21)	-215.92 (-1132.78 to 700.94)
Radial: Month 24; n=21, 16, 17	-625.46 (-1888.53 to 637.60)	1172.45 (-265.87 to 2610.76)	-1258.55 (-2663.69 to 146.60)
Tibial: Month 6; n=23, 20, 17	1344.84 (-296.83 to 2986.52)	1051.40 (-708.46 to 2811.25)	-1356.71 (-3284.14 to 570.73)
Tibial: Month 12; n=24, 17, 15	2326.63 (221.71 to 4431.55)	1543.85 (-973.70 to 4061.40)	-1428.87 (-4118.78 to 1261.03)
Tibial: Month 18; n=20, 13, 16	1047.16 (-1070.79 to 3165.11)	1697.21 (-861.80 to 4256.23)	-815.38 (-3247.85 to 1617.09)
Tibial: Month 24; n=19, 12, 11	-1250.69 (-4131.64 to 1630.26)	622.77 (-2966.46 to 4212.01)	-1844.84 (-5695.04 to 2005.37)

Attachments

Untitled (Filename: Endpoint 8 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm

Top of page

End point title

Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm ^[12]

End point description

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Open-Label)
Number of subjects analysed	21
Units: N/mm
least squares mean (confidence interval 95%)
Radial: Month 6; n=16	5056.51 (3404.58 to 6708.45)
Radial: Month 12; n=15	4992.82 (3056.80 to 6928.84)
Tibial: Month 6; n=15	4225.92 (1840.16 to 6611.68)
Tibial: Month 12; n=15	5827.81 (2601.54 to 9054.08)

Attachments

Untitled (Filename: Endpoint 9 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12

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End point title

Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12 ^[13]

End point description

Fracture assessment, confirmed by central radiographic reading, was carried out for peripheral including all major long bones, minor bone (digits, ribs) and vertebral fractures. Fractures without clinical symptoms, detected only by means of radiographic investigations, were not included in the analysis. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Month 12 (EOT)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: percentage of participants
number (not applicable)
Peripheral	6.5	17.2	13.3
Vertebral	0	0	0
Long-Bone	3.2	13.8	3.3
Any	16.1	34.5	23.3

No statistical analyses for this end point

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6

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End point title

Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6 ^[14]

End point description

BMD was evaluated by dual-energy x-ray absorptiometry (DXA). T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Month 6

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: T-score
least squares mean (confidence interval 95%)
Lumbar; n=24, 25, 26	0.273 (0.142 to 0.405)	0.338 (0.213 to 0.464)	0.110 (-0.014 to 0.233)
Total Body; n=23, 24, 27	0.072 (-0.049 to 0.194)	0.071 (-0.048 to 0.189)	0.122 (0.009 to 0.235)
Femoral Neck; n=21, 19, 24	-0.024 (-0.143 to 0.095)	0.102 (-0.023 to 0.226)	0.087 (-0.026 to 0.199)

Attachments

Untitled (Filename: Endpoint 11 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6

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End point title

Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6 ^[15]

End point description

BMD was evaluated by DXA. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Month 6

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: g/cm^2
least squares mean (confidence interval 95%)
Lumbar; n=24, 25, 26	4.06 (2.12 to 6.00)	4.70 (2.86 to 6.55)	1.58 (-0.24 to 3.40)
Total Body; n=23, 24, 27	0.77 (-0.38 to 1.92)	0.83 (-0.29 to 1.94)	1.21 (0.14 to 2.28)
Femoral Neck; n=21, 19, 24	-0.42 (-2.51 to 1.68)	1.64 (-0.57 to 3.84)	1.61 (-0.38 to 3.59)

Attachments

Untitled (Filename: Endpoint 12 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12

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End point title

Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12 ^[16]

End point description

BMD was evaluated by DXA. T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Month 12 (EOT)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: T-score
least squares mean (confidence interval 95%)
Lumbar; n=24, 22, 25	0.587 (0.427 to 0.746)	0.486 (0.324 to 0.648)	0.174 (0.022 to 0.327)
Total Body; n=23, 22, 26	0.181 (0.051 to 0.310)	0.199 (0.068 to 0.330)	0.108 (-0.015 to 0.231)
Femoral Neck; n=21, 18, 22	0.163 (0.008 to 0.319)	0.159 (-0.007 to 0.326)	0.104 (-0.053 to 0.260)

Attachments

Untitled (Filename: Endpoint 13 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12

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End point title

Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12 ^[17]

End point description

End point type

Secondary

End point timeframe

Baseline, Month 12 (EOT)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: g/cm^2
least squares mean (confidence interval 95%)
Lumbar; n=24, 22, 25	8.55 (6.13 to 10.97)	6.79 (4.34 to 9.25)	2.50 (0.19 to 4.81)
Total Body; n=23, 22, 26	1.98 (0.70 to 3.25)	2.03 (0.73 to 3.33)	1.06 (-0.16 to 2.27)
Femoral Neck; n= 21, 18, 22	3.30 (0.64 to 5.96)	2.65 (-0.20 to 5.51)	1.90 (-0.77 to 4.56)

Attachments

Untitled (Filename: Endpoint 14 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Total vBMD (Radial and Tibial) Over Time

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End point title

Change From Baseline in Total vBMD (Radial and Tibial) Over Time ^[18]

End point description

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT), 18, and 24

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: ratio
number (confidence interval 95%)
Radial, Month 6; n=26, 25, 26	1.011 (0.999 to 1.022)	0.995 (0.984 to 1.007)	1.000 (0.989 to 1.012)
Radial, Month 12; n=28, 22, 25	1.017 (1.006 to 1.029)	1.008 (0.995 to 1.021)	0.999 (0.986 to 1.011)
Radial, Month 18; n=23, 17, 24	1.013 (1.000 to 1.026)	0.992 (0.978 to 1.007)	0.996 (0.983 to 1.009)
Radial, Month 24; n=21, 16, 17	0.998 (0.984 to 1.012)	1.009 (0.994 to 1.025)	0.985 (0.969 to 1.000)
Tibial, Month 6; n=23, 20, 17	1.017 (1.001 to 1.033)	1.011 (0.995 to 1.028)	0.995 (0.977 to 1.031)
Tibial, Month 12; n=24, 17, 15	1.024 (1.004 to 1.045)	1.011 (0.988 to 1.035)	0.989 (0.965 to 1.014)
Tibial, Month 18; n=20, 13, 16	1.020 (0.997 to 1.045)	1.021 (0.992 to 1.050)	0.987 (0.961 to 1.014)
Tibial, Month 24; n=19, 12, 11	1.001 (0.982 to 1.021)	1.025 (1.001 to 1.050)	0.994 (0.970 to 1.019)

Attachments

Untitled (Filename: Endpoint 15 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time

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End point title

Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time ^[19]

End point description

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT), 18, and 24

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: ratio
number (confidence interval 95%)
Radial, Month 6; n=26, 25, 26	1.004 (0.997 to 1.010)	1.002 (0.996 to 1.009)	0.998 (0.992 to 1.005)
Radial, Month 12; n=28, 22, 25	1.005 (0.998 to 1.012)	1.003 (0.995 to 1.010)	1.001 (0.993 to 1.008)
Radial, Month 18; n=23, 17, 24	1.011 (1.001 to 1.021)	1.001 (0.989 to 1.012)	1.007 (0.997 to 1.017)
Radial, Month 24; n=21, 16, 17	1.011 (0.999 to 1.022)	1.018 (1.005 to 1.031)	1.002 (0.989 to 1.015)
Tibial, Month 6; n=23, 20, 17	1.012 (1.003 to 1.022)	0.997 (0.987 to 1.007)	0.998 (0.987 to 1.008)
Tibial, Month 12; n=24, 17, 15	1.017 (1.008 to 1.026)	1.004 (0.993 to 1.014)	0.998 (0.987 to 1.009)
Tibial, Month 18; n=20, 13, 16	1.024 (1.009 to 1.039)	1.004 (0.986 to 1.022)	0.993 (0.976 to 1.009)
Tibial, Month 24; n=19, 12, 11	1.020 (1.004 to 1.035)	1.017 (0.998 to 1.036)	0.996 (0.976 to 1.017)

Attachments

Untitled (Filename: Endpoint 16 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set

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End point title

Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set ^[20]

End point description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment.

End point type

Secondary

End point timeframe

Baseline, Month 6, Month 12 (EOT)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: participants
Month 6: Body Height	0	0	0
Month 6: Weight	0	0	0
Month 6: BMI	0	0	0
Month 12: Body Height	0	0	0
Month 12: Weight	0	0	0
Month 12: BMI	0	0	0

No statistical analyses for this end point

Secondary: Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12

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End point title

Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12 ^[21]

End point description

Lean and fat body mass was evaluated using whole body DXA (including the head). Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: grams
least squares mean (confidence interval 95%)
Month 6: Lean; n=23, 24, 27	519.152 (13.020 to 1025.284)	-410.664 (-903.724 to 82.395)	168.206 (-306.981 to 643.393)
Month 12: Lean; n=23, 22, 26	867.668 (204.535 to 1530.801)	-225.474 (-901.083 to 450.136)	184.164 (-448.625 to 816.953)
Month 6: Fat; n=23, 24, 27	42.567 (-771.815 to 856.949)	105.420 (-676.720 to 887.561)	426.388 (-326.298 to 1179.074)
Month 12: Fat; n=23, 22, 26	421.266 (-629.870 to 1472.401)	-85.495 (-1136.234 to 965.245)	792.485 (-191.238 to 1776.208)

Attachments

Untitled (Filename: Endpoint 18 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12

Top of page

End point title

Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12 ^[22]

End point description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 1, 3, 6, 9, 12 (EOT)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: μg/L
least squares mean (confidence interval 95%)
Month 1; n=30, 27, 29	24.349 (18.604 to 30.095)	14.288 (8.221 to 20.354)	0.060 (-5.827 to 5.948)
Month 3; n=29, 27, 25	17.903 (11.412 to 24.395)	6.735 (0.015 to 13.455)	0.640 (-6.389 to 7.670)
Month 6; n=27, 28, 27	13.096 (5.468 to 20.725)	6.665 (-0.788 to 14.118)	-0.429 (-8.116 to 7.258)
Month 9; n=27, 25, 26	7.265 (-0.115 to 14.644)	0.238 (-7.353 to 7.830)	-2.254 (-9.820 to 5.312)
Month 12; n=25, 20, 20	5.452 (-3.362 to 14.267)	4.172 (-5.529 to 13.874)	4.428 (-5.689 to 14.545)

Attachments

Untitled (Filename: Endpoint 19 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12

Top of page

End point title

Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12 ^[23]

End point description

Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 1, 3, 6, 9, 12 (EOT)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: μg/L
least squares mean (confidence interval 95%)
Month 1; n=30, 27, 29	-0.077 (-0.100 to -0.054)	-0.047 (-0.071 to -0.022)	-0.041 (-0.064 to -0.017)
Month 3; n=29, 27, 25	-0.044 (-0.071 to -0.016)	-0.029 (-0.058 to 0.000)	-0.043 (-0.073 to -0.013)
Month 6; n=27, 28, 27	-0.013 (-0.055 to 0.028)	-0.025 (-0.065 to 0.016)	-0.028 (-0.069 to 0.014)
Month 9; n=27, 25, 26	-0.020 (-0.067 to 0.026)	-0.039 (-0.087 to 0.009)	-0.031 (-0.079 to 0.017)
Month 12; n=25, 20, 20	-0.037 (-0.083 to 0.010)	-0.002 (-0.053 to 0.049)	-0.034 (-0.087 to 0.019)

Attachments

Untitled (Filename: Endpoint 20 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 12 Health Survey (SF-12) Physical Component Summary Score at Months 6 and 12

Top of page

End point title

Change From Baseline in Short Form 12 Health Survey (SF-12) Physical Component Summary Score at Months 6 and 12 ^[24]

End point description

The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these 8 domains and 2 summary measures of physical and mental health: The Physical Component Summary and the Mental Component Summary. The total score for the Physical Component Summary ranges from 0 to 100, where higher scores reflect better physical functioning. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: score on a scale
least squares mean (confidence interval 95%)
Month 6; n=27, 29, 27	0.672 (-1.788 to 3.132)	-0.463 (-2.821 to 1.895)	1.342 (-1.129 to 3.814)
Month 12; n=26, 26, 26	-1.178 (-3.698 to 1.341)	-0.994 (-3.488 to 1.501)	2.171 (-0.352 to 4.695)

Attachments

Untitled (Filename: Endpoint 21 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in SF-12 Mental Component Summary Score at Months 6 and 12

Top of page

End point title

Change From Baseline in SF-12 Mental Component Summary Score at Months 6 and 12 ^[25]

End point description

The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these 8 domains and 2 summary measures of physical and mental health: The Physical Component Summary and the Mental Component Summary. The total score for the Mental Component Summary ranges from 0 to 100, where higher scores reflect better mental health functioning. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: score on a scale
least squares mean (confidence interval 95%)
Month 6; n=27, 29, 27	0.966 (-2.064 to 3.996)	-0.492 (-3.411 to 2.427)	-1.133 (-4.202 to 1.936)
Month 12; n=26, 26, 26	2.807 (-0.216 to 5.831)	-1.473 (-4.457 to 1.511)	-1.664 (-4.694 to 1.366)

Attachments

Untitled (Filename: Endpoint 22 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Index (Utility) Score on EuroQol 5-Dimension 5-Level Descriptive System (EQ-5D-5L) Score at Months 6 and 12

Top of page

End point title

Change From Baseline in Index (Utility) Score on EuroQol 5-Dimension 5-Level Descriptive System (EQ-5D-5L) Score at Months 6 and 12 ^[26]

End point description

The EQ-5D-5L is a standardised measure of health status comprised of a descriptive system of 5 health-related quality of life states (i.e., mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS) of overall health. Each dimension is rated on a 5-point response scale indicating severity of problems, where 1 is “no problems” and 5 is “extreme problems”. The 5 questions are scored and together contribute to the EQ-5D index (utility) score between 0 and 1 (1 being perfect health). Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 6 and 12 (EOT)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: score on a scale
least squares mean (confidence interval 95%)
Month 6; n=27, 28, 26	0.0627 (-0.0105 to 0.1359)	0.0362 (-0.0343 to 0.1067)	-0.0383 (-0.1121 to 0.0354)
Month 12; n=26, 25, 26	0.0424 (-0.0163 to 0.1012)	0.0252 (-0.0332 to 0.0837)	0.0214 (-0.0365 to 0.0793)

Attachments

Untitled (Filename: Endpoint 23 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in Osteogenesis Imperfecta Specific Quality of Life Questionnaire for Adults (OIQoL-A) Total Score at Months 6 and 12

Top of page

End point title

Change From Baseline in Osteogenesis Imperfecta Specific Quality of Life Questionnaire for Adults (OIQoL-A) Total Score at Months 6 and 12 ^[27]

End point description

The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The total score is calculated on a 0-100 scale, where higher scores indicate a greater (negative) impact on quality of life. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: score on a scale
least squares mean (confidence interval 95%)
Month 6; n=27, 25, 26	-3.584 (-8.491 to 1.324)	-1.848 (-6.899 to 3.203)	-0.649 (-5.751 to 4.452)
Month 12; n=25, 24, 25	-1.668 (-7.395 to 4.059)	-0.587 (-6.310 to 5.137)	-3.846 (-9.592 to 1.901)

Attachments

Untitled (Filename: Endpoint 24 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in OIQoL-A Pain Subscale Score at Months 6 and 12

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End point title

Change From Baseline in OIQoL-A Pain Subscale Score at Months 6 and 12 ^[28]

End point description

The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The Pain subscale ranges from 0 to 10, with higher value representing worse pain. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: score on a scale
least squares mean (confidence interval 95%)
Month 6; n=27, 26, 26	-3.990 (-11.267 to 3.287)	-3.906 (-11.239 to 3.426)	-6.003 (-13.495 to 1.489)
Month 12; n=26, 26, 25	-3.655 (-11.505 to 4.195)	-4.968 (-12.709 to 2.772)	-7.178 (-15.183 to 0.827)

Attachments

Untitled (Filename: Endpoint 25 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Change From Baseline in OIQoL-A Activity Subscale Score at Months 6 and 12

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End point title

Change From Baseline in OIQoL-A Activity Subscale Score at Months 6 and 12 ^[29]

End point description

The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The Activities subscale ranges from 0 to 100, with higher value representing increased difficulty. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 6, 12 (EOT)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)
Number of subjects analysed	31	29	30
Units: score on a scale
least squares mean (confidence interval 95%)
Month 6; n=27, 26, 26	-5.980 (-11.597 to -0.363)	-2.722 (-8.397 to 2.953)	1.907 (-3.906 to 7.719)
Month 12; n=26, 25, 25	-0.964 (-8.006 to 6.079)	4.489 (-2.620 to 11.598)	-1.630 (-8.869 to 5.609)

Attachments

Untitled (Filename: Endpoint 26 Stat Analyses.docx)

No statistical analyses for this end point

Secondary: Percentage of Participants Who Were Positive for Anti-Setrusumab Antibodies at Any Time During the Study up to Month 14

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End point title

Percentage of Participants Who Were Positive for Anti-Setrusumab Antibodies at Any Time During the Study up to Month 14

End point description

Serum samples were screened for antibodies binding to setrusumab using a validated assay method by or under the supervision of the sponsor. Safety Population: all participants who received at least 1 dose of study drug. The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are reflected in both arms for this analysis.

End point type

Secondary

End point timeframe

up to Month 14

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)	Setrusumab 20 mg/kg (Open-Label)	Placebo
Number of subjects analysed	31	29	30	21	20
Units: percentage of participants
number (not applicable)
Binding Antibodies	16.1	17.2	16.7	9.5	15.0
Neutralizing Antibodies	16.1	17.2	16.7	0	0
Both Binding and Neutralizing Antibodies	16.1	17.2	16.7	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Adverse Events (AEs), Treatment-Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation or Death

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End point title

Percentage of Participants With Adverse Events (AEs), Treatment-Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation or Death

End point description

An AE is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; is another important medical event. The intensity for each AE was graded as mild, moderate or severe, according to the investigator's judgement. An event was considered related to study drug if there were a "reasonable possibility" of a relationship, according to the investigator's clinical judgment. A TEAE was defined as an event occurring or worsening on or after the first dose of study medication. Safety Population: all participants who received at least 1 dose of study drug. The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are reflected in both arms

End point type

Secondary

End point timeframe

Non-serious AEs: up to Month 14; Serious AEs: up to Month 24. (Average duration of exposure to placebo was 5 months and for setrusumab was 11 month plus follow-up to 24 months.)

End point values	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)	Setrusumab 20 mg/kg (Open-Label)	Placebo
Number of subjects analysed	31	29	30	21	20
Units: percentage of participants
number (not applicable)
All AEs	100.0	96.6	90.0	100.0	90.0
TEAEs	100.0	96.6	90.0	95.2	80.0
Treatment-Related TEAEs	71.0	41.4	36.7	42.9	25.0
Serious TEAEs	12.9	24.1	23.3	23.8	10.0
Treatment-Related Serious TEAEs	6.5	0	0	9.5	0
TEAEs Leading to Death	0	0	0	0	0
TEAEs Leading to Permanent Study Treatment Discon.	6.5	0	0	9.5	5.0

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Non-serious AEs: up to Month 14; Serious AEs: up to Month 24. (Average duration of exposure to placebo was 5 months and for setrusumab was 11 month plus follow-up to 24 months.)

Adverse event reporting additional description

Safety Population: all participants who received at least 1 dose of study drug. The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are reflected in both arms for this analysis.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Setrusumab 20 mg/kg (Blinded)

Reporting group description

Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 8 mg/kg (Blinded)

Reporting group description

Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 2 mg/kg (Blinded)

Reporting group description

Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Setrusumab 20 mg/kg (Open-Label)

Reporting group description

Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

Reporting group title

Placebo

Reporting group description

Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Due to a protocol amendment, placebo was actually received for an average of 5 months.

Serious adverse events	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)	Setrusumab 20 mg/kg (Open-Label)	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 31 (12.90%)	7 / 29 (24.14%)	7 / 30 (23.33%)	5 / 21 (23.81%)	2 / 20 (10.00%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fracture of penis
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ilium fracture
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous haematoma
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Scapula fracture
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Platybasia
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuritis
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Blindness unilateral
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Visual impairment
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Noninfective sialoadenitis
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fracture nonunion
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Anal abscess
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint abscess
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Setrusumab 20 mg/kg (Blinded)	Setrusumab 8 mg/kg (Blinded)	Setrusumab 2 mg/kg (Blinded)	Setrusumab 20 mg/kg (Open-Label)	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	29 / 31 (93.55%)	28 / 29 (96.55%)	27 / 30 (90.00%)	19 / 21 (90.48%)	16 / 20 (80.00%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	2 / 30 (6.67%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	1	0	2	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Chest pain
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	2 / 21 (9.52%)	0 / 20 (0.00%)
occurrences all number	0	1	0	2	0
Fatigue
subjects affected / exposed	3 / 31 (9.68%)	2 / 29 (6.90%)	7 / 30 (23.33%)	3 / 21 (14.29%)	0 / 20 (0.00%)
occurrences all number	4	2	7	4	0
Influenza like illness
subjects affected / exposed	1 / 31 (3.23%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	2	0	0	0
Injection site extravasation
subjects affected / exposed	1 / 31 (3.23%)	1 / 29 (3.45%)	0 / 30 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	1	1	0	1	1
Malaise
subjects affected / exposed	0 / 31 (0.00%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	16	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 31 (0.00%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	2	0	0	0
Pain
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	2 / 30 (6.67%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	2	0	2	1	0
Peripheral swelling
subjects affected / exposed	0 / 31 (0.00%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	2	0	0	1
Pyrexia
subjects affected / exposed	1 / 31 (3.23%)	2 / 29 (6.90%)	2 / 30 (6.67%)	2 / 21 (9.52%)	2 / 20 (10.00%)
occurrences all number	5	3	2	3	2
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	2 / 30 (6.67%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	0	0	2	1	0
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	0	0	0	3	1
Menorrhagia
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 31 (6.45%)	2 / 29 (6.90%)	2 / 30 (6.67%)	3 / 21 (14.29%)	0 / 20 (0.00%)
occurrences all number	2	2	2	4	0
Dyspnoea
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	2 / 30 (6.67%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	2	0	0
Investigations
Alanine aminotransferase abnormal
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Alanine aminotransferase increased
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	1	0	0
Aspartate aminotransferase abnormal
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Aspartate aminotransferase increased
subjects affected / exposed	2 / 31 (6.45%)	1 / 29 (3.45%)	1 / 30 (3.33%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	2	1	1	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	3 / 30 (10.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	0	1	3	1	1
Lipase increased
subjects affected / exposed	1 / 31 (3.23%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	2	0	0	1
Prothrombin time prolonged
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	3 / 30 (10.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	0	1	3	2	1
Vitamin D decreased
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	2 / 30 (6.67%)	2 / 21 (9.52%)	0 / 20 (0.00%)
occurrences all number	0	1	3	2	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 31 (3.23%)	2 / 29 (6.90%)	1 / 30 (3.33%)	3 / 21 (14.29%)	0 / 20 (0.00%)
occurrences all number	1	3	1	5	0
Fall
subjects affected / exposed	6 / 31 (19.35%)	4 / 29 (13.79%)	3 / 30 (10.00%)	2 / 21 (9.52%)	2 / 20 (10.00%)
occurrences all number	8	4	5	3	3
Foot fracture
subjects affected / exposed	3 / 31 (9.68%)	4 / 29 (13.79%)	3 / 30 (10.00%)	6 / 21 (28.57%)	1 / 20 (5.00%)
occurrences all number	3	5	3	8	2
Hand fracture
subjects affected / exposed	1 / 31 (3.23%)	3 / 29 (10.34%)	2 / 30 (6.67%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	3	2	0	0
Infusion related reaction
subjects affected / exposed	4 / 31 (12.90%)	3 / 29 (10.34%)	1 / 30 (3.33%)	2 / 21 (9.52%)	0 / 20 (0.00%)
occurrences all number	12	9	1	2	0
Joint dislocation
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	3 / 21 (14.29%)	0 / 20 (0.00%)
occurrences all number	0	0	2	9	0
Joint injury
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	0	0	0	3	1
Ligament sprain
subjects affected / exposed	3 / 31 (9.68%)	1 / 29 (3.45%)	2 / 30 (6.67%)	1 / 21 (4.76%)	2 / 20 (10.00%)
occurrences all number	3	1	2	1	2
Limb injury
subjects affected / exposed	0 / 31 (0.00%)	3 / 29 (10.34%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	4	1	0	0
Muscle strain
subjects affected / exposed	1 / 31 (3.23%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	3	0	0	0
Procedural pain
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	1	0	0
Rib fracture
subjects affected / exposed	2 / 31 (6.45%)	3 / 29 (10.34%)	3 / 30 (10.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	4	5	0	0
Tooth fracture
subjects affected / exposed	3 / 31 (9.68%)	2 / 29 (6.90%)	6 / 30 (20.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	4	3	12	0	0
Wound
subjects affected / exposed	0 / 31 (0.00%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	2	0	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	3 / 30 (10.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	3	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	3 / 30 (10.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	3	0	1
Headache
subjects affected / exposed	4 / 31 (12.90%)	5 / 29 (17.24%)	6 / 30 (20.00%)	7 / 21 (33.33%)	2 / 20 (10.00%)
occurrences all number	4	13	8	11	4
Hypoaesthesia
subjects affected / exposed	3 / 31 (9.68%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	3	0	1	0	0
Migraine
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	3 / 30 (10.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	3	0	0
Paraesthesia
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Trigeminal neuralgia
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	2 / 30 (6.67%)	2 / 21 (9.52%)	0 / 20 (0.00%)
occurrences all number	1	0	3	2	0
Increased tendency to bruise
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 31 (0.00%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	2	0	0	0
Middle ear effusion
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Eye disorders
Blepharospasm
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0
Gastrointestinal disorders
Dental caries
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	0	1	0	1	1
Diarrhoea
subjects affected / exposed	4 / 31 (12.90%)	3 / 29 (10.34%)	2 / 30 (6.67%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	4	4	2	1	1
Dyspepsia
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 31 (3.23%)	2 / 29 (6.90%)	1 / 30 (3.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	2	1	0	0
Nausea
subjects affected / exposed	2 / 31 (6.45%)	3 / 29 (10.34%)	5 / 30 (16.67%)	2 / 21 (9.52%)	2 / 20 (10.00%)
occurrences all number	2	4	10	2	2
Toothache
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	1 / 30 (3.33%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	2	0	1	1	0
Vomiting
subjects affected / exposed	3 / 31 (9.68%)	1 / 29 (3.45%)	1 / 30 (3.33%)	3 / 21 (14.29%)	1 / 20 (5.00%)
occurrences all number	3	1	1	3	1
Skin and subcutaneous tissue disorders
Ecchymosis
subjects affected / exposed	1 / 31 (3.23%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	1	0	0	1
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	2 / 30 (6.67%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	0	0	2	1	0
Renal colic
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	15 / 31 (48.39%)	8 / 29 (27.59%)	9 / 30 (30.00%)	8 / 21 (38.10%)	5 / 20 (25.00%)
occurrences all number	29	17	24	12	5
Back pain
subjects affected / exposed	6 / 31 (19.35%)	4 / 29 (13.79%)	8 / 30 (26.67%)	4 / 21 (19.05%)	1 / 20 (5.00%)
occurrences all number	7	4	13	5	1
Bone pain
subjects affected / exposed	4 / 31 (12.90%)	3 / 29 (10.34%)	4 / 30 (13.33%)	2 / 21 (9.52%)	0 / 20 (0.00%)
occurrences all number	4	3	6	3	0
Muscle spasms
subjects affected / exposed	2 / 31 (6.45%)	1 / 29 (3.45%)	2 / 30 (6.67%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	2	2	2	1	0
Musculoskeletal chest pain
subjects affected / exposed	2 / 31 (6.45%)	1 / 29 (3.45%)	3 / 30 (10.00%)	2 / 21 (9.52%)	0 / 20 (0.00%)
occurrences all number	2	1	4	4	0
Musculoskeletal discomfort
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	1
Myalgia
subjects affected / exposed	2 / 31 (6.45%)	1 / 29 (3.45%)	0 / 30 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	3	2	0	1	1
Neck pain
subjects affected / exposed	1 / 31 (3.23%)	1 / 29 (3.45%)	4 / 30 (13.33%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	1	1	10	1	0
Pain in extremity
subjects affected / exposed	5 / 31 (16.13%)	5 / 29 (17.24%)	3 / 30 (10.00%)	4 / 21 (19.05%)	1 / 20 (5.00%)
occurrences all number	5	8	3	8	1
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 31 (3.23%)	1 / 29 (3.45%)	0 / 30 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	1	1	0	1	1
Cystitis
subjects affected / exposed	0 / 31 (0.00%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	1	0	0	1
Ear infection
subjects affected / exposed	3 / 31 (9.68%)	1 / 29 (3.45%)	0 / 30 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	3	1	0	1	0
Gastroenteritis
subjects affected / exposed	3 / 31 (9.68%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	3	3	0	0	1
Herpes zoster
subjects affected / exposed	2 / 31 (6.45%)	1 / 29 (3.45%)	0 / 30 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	1	0	0	0
Influenza
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	0 / 30 (0.00%)	4 / 21 (19.05%)	1 / 20 (5.00%)
occurrences all number	2	0	0	4	3
Lower respiratory tract infection
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	1 / 30 (3.33%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	1
Nasopharyngitis
subjects affected / exposed	5 / 31 (16.13%)	3 / 29 (10.34%)	4 / 30 (13.33%)	5 / 21 (23.81%)	3 / 20 (15.00%)
occurrences all number	5	4	4	9	5
Sinusitis
subjects affected / exposed	2 / 31 (6.45%)	3 / 29 (10.34%)	4 / 30 (13.33%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	3	6	0	0
Tooth abscess
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	2 / 30 (6.67%)	0 / 21 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	4	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 31 (3.23%)	0 / 29 (0.00%)	1 / 30 (3.33%)	1 / 21 (4.76%)	1 / 20 (5.00%)
occurrences all number	1	0	1	1	1
Urinary tract infection
subjects affected / exposed	3 / 31 (9.68%)	3 / 29 (10.34%)	2 / 30 (6.67%)	3 / 21 (14.29%)	1 / 20 (5.00%)
occurrences all number	4	4	3	4	1
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 31 (0.00%)	0 / 29 (0.00%)	0 / 30 (0.00%)	2 / 21 (9.52%)	1 / 20 (5.00%)
occurrences all number	0	0	0	2	1
Type 2 diabetes mellitus
subjects affected / exposed	0 / 31 (0.00%)	2 / 29 (6.90%)	0 / 30 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	2	0	0	1
Vitamin D deficiency
subjects affected / exposed	2 / 31 (6.45%)	0 / 29 (0.00%)	1 / 30 (3.33%)	1 / 21 (4.76%)	0 / 20 (0.00%)
occurrences all number	2	0	1	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

27 Jan 2017

• Change to OI-QoL-A endpoints

02 May 2017

• Added 60-day Follow-up Period per UK regulatory agency • Clarified the schedule of activities

18 Jan 2018

• Adjusted the primary analysis to 12 months • Removed DXA vertebral fracture assessment as study endpoint

18 May 2018

• Placebo arm was replaced by 20 mg/kg of setrusumab open-label treatment arm • Addition of 12-month Follow-up Period following the double-blind Treatment Period

12 Dec 2018

• Addition of optional zoledronic acid therapy during Follow-up Period

19 Jul 2019

• Clarified open-label data on Tr. vBMD (tibia & radius) on HRpQCT and bone strength on FEA would be assessed up to Month 12

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 Phase 2b, Multicentre, Multinational, Double-blind, Dose-finding Study, incorporating an open label substudy, in Adult Patients with Type I, III or IV Osteogenesis Imperfecta Treated with setrusumab (BPS804)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12

Primary: Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12

Primary: Change From Baseline in Radial Bone Strength (Failure Load) at Month 12

Primary: Change From Baseline in Radial Bone Strength (Failure Load) at Month 12

Primary: Change From Baseline in Radial Bone Strength (Stiffness) at Month 12

Primary: Change From Baseline in Radial Bone Strength (Stiffness) at Month 12

Secondary: Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set

Secondary: Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set

Secondary: Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm

Secondary: Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm

Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm

Secondary: Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12

Secondary: Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12

Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12

Secondary: Change From Baseline in Total vBMD (Radial and Tibial) Over Time

Secondary: Change From Baseline in Total vBMD (Radial and Tibial) Over Time

Secondary: Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time

Secondary: Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time

Secondary: Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set

Secondary: Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set

Secondary: Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12

Secondary: Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12

Secondary: Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12

Secondary: Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12

Secondary: Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12

Secondary: Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12

Secondary: Change From Baseline in Short Form 12 Health Survey (SF-12) Physical Component Summary Score at Months 6 and 12

Secondary: Change From Baseline in Short Form 12 Health Survey (SF-12) Physical Component Summary Score at Months 6 and 12

Secondary: Change From Baseline in SF-12 Mental Component Summary Score at Months 6 and 12

Secondary: Change From Baseline in SF-12 Mental Component Summary Score at Months 6 and 12

Secondary: Change From Baseline in Index (Utility) Score on EuroQol 5-Dimension 5-Level Descriptive System (EQ-5D-5L) Score at Months 6 and 12

Secondary: Change From Baseline in Index (Utility) Score on EuroQol 5-Dimension 5-Level Descriptive System (EQ-5D-5L) Score at Months 6 and 12

Secondary: Change From Baseline in Osteogenesis Imperfecta Specific Quality of Life Questionnaire for Adults (OIQoL-A) Total Score at Months 6 and 12

Secondary: Change From Baseline in Osteogenesis Imperfecta Specific Quality of Life Questionnaire for Adults (OIQoL-A) Total Score at Months 6 and 12

Secondary: Change From Baseline in OIQoL-A Pain Subscale Score at Months 6 and 12

Secondary: Change From Baseline in OIQoL-A Pain Subscale Score at Months 6 and 12

Secondary: Change From Baseline in OIQoL-A Activity Subscale Score at Months 6 and 12

Secondary: Change From Baseline in OIQoL-A Activity Subscale Score at Months 6 and 12

Secondary: Percentage of Participants Who Were Positive for Anti-Setrusumab Antibodies at Any Time During the Study up to Month 14

Secondary: Percentage of Participants Who Were Positive for Anti-Setrusumab Antibodies at Any Time During the Study up to Month 14

Secondary: Percentage of Participants With Adverse Events (AEs), Treatment-Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation or Death

Secondary: Percentage of Participants With Adverse Events (AEs), Treatment-Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation or Death

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2b, Multicentre, Multinational, Double-blind, Dose-finding Study, incorporating an open label substudy, in Adult Patients with Type I, III or IV Osteogenesis Imperfecta Treated with setrusumab (BPS804)