Trial Outcomes & Findings for Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP) (NCT NCT01163149)

Last Updated: 2019-03-13

Results Overview

Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP)

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

19 participants

Primary outcome timeframe

Baseline, Week 24

Results posted on

2019-03-13

Participant Flow

Participant milestones

Participant milestones
Measure	0.3 mg/kg Asfotase Alfa Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total). Following completion of the Week 24 visit, all subjects were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug.	0.5 mg/kg Asfotase Alfa Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total). Following completion of the Week 24 visit, all subjects were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug.	Concurrent Control No asfotase alfa during first 24 weeks (primary treatment period). Following completion of the Week 24 visit, all subjects were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug.
Primary Treatment Period STARTED	7	6	6
Primary Treatment Period COMPLETED	7	6	6
Primary Treatment Period NOT COMPLETED	0	0	0
Extension Treatment Period STARTED	7	6	6
Extension Treatment Period COMPLETED	5	5	4
Extension Treatment Period NOT COMPLETED	2	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	0.3 mg/kg Asfotase Alfa Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total). Following completion of the Week 24 visit, all subjects were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug.	0.5 mg/kg Asfotase Alfa Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total). Following completion of the Week 24 visit, all subjects were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug.	Concurrent Control No asfotase alfa during first 24 weeks (primary treatment period). Following completion of the Week 24 visit, all subjects were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug.
Extension Treatment Period Withdrawal by Subject	2	0	1
Extension Treatment Period Adverse Event	0	1	0
Extension Treatment Period Noncompliance	0	0	1

Baseline Characteristics

Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Concurrent Control n=6 Participants No asfotase alfa during first 24 weeks (primary treatment period). Following completion of the Week 24 visit, all subjects randomized to the concurrent control cohort were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug	Total n=19 Participants Total of all reporting groups	0.3 mg/kg Asfotase Alfa n=7 Participants Asfotase alfa: Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (total of 2.1 mg/kg/week) during Primary Treatment Period through Week 24. Following completion of the Week 24 visit, all subjects were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug.	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa: Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total) during Primary Treatment Period through Week 24. Following completion of the Week 24 visit, all subjects were eligible to participate in an open-label extension treatment period. In this extension period, all subjects were treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects received 1 mg/kg/day 6 days/week until regulatory approval of the drug.
Age, Continuous	21.0 years n=5 Participants	53.0 years n=4 Participants	45.0 years n=5 Participants	55.0 years n=7 Participants
Age, Customized Age at Onset of Symptoms	0.88 years n=5 Participants	2.0 years n=4 Participants	2.0 years n=5 Participants	2.0 years n=7 Participants
Age, Customized Age Group · Adolescent (12-17 years)	3 Participants n=5 Participants	6 Participants n=4 Participants	2 Participants n=5 Participants	1 Participants n=7 Participants
Age, Customized Age Group · Adult (≥ 18 years)	3 Participants n=5 Participants	13 Participants n=4 Participants	5 Participants n=5 Participants	5 Participants n=7 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	12 Participants n=4 Participants	6 Participants n=5 Participants	4 Participants n=7 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	7 Participants n=4 Participants	1 Participants n=5 Participants	2 Participants n=7 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=5 Participants	0 Participants n=7 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	19 Participants n=4 Participants	7 Participants n=5 Participants	6 Participants n=7 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=5 Participants	0 Participants n=7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=5 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=5 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=5 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=5 Participants	0 Participants n=7 Participants
Race (NIH/OMB) White	5 Participants n=5 Participants	18 Participants n=4 Participants	7 Participants n=5 Participants	6 Participants n=7 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=5 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=5 Participants	0 Participants n=7 Participants
Hypophosphatasia (HPP) Phenotype Infantile (<6 months)	1 Participants n=5 Participants	4 Participants n=4 Participants	1 Participants n=5 Participants	2 Participants n=7 Participants
Hypophosphatasia (HPP) Phenotype Juvenile (≥ 6 months to < 18 years)	5 Participants n=5 Participants	14 Participants n=4 Participants	5 Participants n=5 Participants	4 Participants n=7 Participants
Hypophosphatasia (HPP) Phenotype Adult (≥ 18 years)	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=5 Participants	0 Participants n=7 Participants

PRIMARY outcome

Timeframe: Baseline, Week 24

Population: Full analysis set (intent-to-treat, all randomized patients)

Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP)

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=7 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=6 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=13 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP)	-254.96 ng/mL Standard Deviation 196.206	-564.27 ng/mL Standard Deviation 624.009	3.13 ng/mL Standard Deviation 242.721	-397.72 ng/mL Standard Deviation 455.249

PRIMARY outcome

Timeframe: Baseline, Week 24

Population: Full analysis set (intent-to-treat, all randomized patients)

Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma inorganic pyrophosphate (PPi)

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=7 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=6 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=13 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi)	-2.027 uM Standard Deviation 1.4381	-2.185 uM Standard Deviation 1.3304	-1.052 uM Standard Deviation 2.9248	-2.100 uM Standard Deviation 1.3335

PRIMARY outcome

Timeframe: Up to 288 weeks exposure to asfotase alfa

Population: Safety Set. Control group and asfotase alfa Cohorts during the primary treatment period (first 24 weeks of study); all patients with asfotase alfa exposure during open-label extension treatment period.

The safety and tolerability of daily subcutaneous (SC) injections of asfotase alfa was assessed by routine monitoring of patients for treatment-emergent adverse events (TEAEs) and injection-associated reactions (IARs).

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=7 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=6 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=19 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Safety and Tolerability of Asfotase Alfa Any TEAE	243 Number of Treatment-Emergent Events	81 Number of Treatment-Emergent Events	45 Number of Treatment-Emergent Events	1145 Number of Treatment-Emergent Events
Safety and Tolerability of Asfotase Alfa Not related TEAEs	110 Number of Treatment-Emergent Events	69 Number of Treatment-Emergent Events	45 Number of Treatment-Emergent Events	731 Number of Treatment-Emergent Events
Safety and Tolerability of Asfotase Alfa Related TEAEs	133 Number of Treatment-Emergent Events	12 Number of Treatment-Emergent Events	0 Number of Treatment-Emergent Events	414 Number of Treatment-Emergent Events
Safety and Tolerability of Asfotase Alfa Injection site reactions	133 Number of Treatment-Emergent Events	12 Number of Treatment-Emergent Events	0 Number of Treatment-Emergent Events	385 Number of Treatment-Emergent Events
Safety and Tolerability of Asfotase Alfa Serious TEAEs	1 Number of Treatment-Emergent Events	1 Number of Treatment-Emergent Events	4 Number of Treatment-Emergent Events	29 Number of Treatment-Emergent Events
Safety and Tolerability of Asfotase Alfa TEAEs leading to withdrawal	0 Number of Treatment-Emergent Events	0 Number of Treatment-Emergent Events	0 Number of Treatment-Emergent Events	2 Number of Treatment-Emergent Events
Safety and Tolerability of Asfotase Alfa Deaths	0 Number of Treatment-Emergent Events	0 Number of Treatment-Emergent Events	0 Number of Treatment-Emergent Events	0 Number of Treatment-Emergent Events

SECONDARY outcome

Timeframe: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.

Population: Full analysis set (intent-to-treat, all randomized patients)

A DXA scan was performed to evaluate bone mineral content (BMC) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks).

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=7 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=6 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=19 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMC Week 24	-3.288 g Standard Deviation 7.7669	1.214 g Standard Deviation 2.2154	1.288 g Standard Deviation 0.9161	-0.787 g Standard Deviation 5.5411
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMC Week 48	1.160 g Standard Deviation NA Data available for only 1 subject	4.530 g Standard Deviation NA Data available for only 1 subject	2.320 g Standard Deviation 1.3990	2.495 g Standard Deviation 1.5438
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMC Week 96	0.082 g Standard Deviation 1.4046	4.345 g Standard Deviation 4.0466	2.907 g Standard Deviation 2.0087	2.403 g Standard Deviation 3.1702
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMC Week 144	1.630 g Standard Deviation 1.8719	5.043 g Standard Deviation 5.5955	4.533 g Standard Deviation 1.4621	3.866 g Standard Deviation 3.7577
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMC Week 192	1.080 g Standard Deviation 2.0082	4.725 g Standard Deviation 6.4843	2.910 g Standard Deviation 0.2910	3.310 g Standard Deviation 4.3124
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMC Week 240	0.550 g Standard Deviation 2.4042	6.807 g Standard Deviation 5.7557	-0.673 g Standard Deviation 0.1644	2.438 g Standard Deviation 4.8626
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip Total BMC Week 288	—	-2.780 g Standard Deviation NA Data available for only 1 subject	—	-2.780 g Standard Deviation NA Data available for only 1 subject
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip Total BMC Last Overall Exposure	0.080 g Standard Deviation 1.8713	3.604 g Standard Deviation 5.8284	0.328 g Standard Deviation 2.0062	1.512 g Standard Deviation 4.0224
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMC Week 24	2.477 g Standard Deviation 2.5616	2.768 g Standard Deviation 2.0007	1.432 g Standard Deviation 1.7824	2.598 g Standard Deviation 2.2488
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMC Week 48	2.420 g Standard Deviation NA Data available for only 1 subject	5.550 g Standard Deviation NA Data available for only 1 subject	4.842 g Standard Deviation 5.7882	4.597 g Standard Deviation 4.8298
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMC Week 96	3.356 g Standard Deviation 4.4566	4.174 g Standard Deviation 3.7068	7.330 g Standard Deviation 5.6953	4.605 g Standard Deviation 4.5680
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMC Week 144	2.086 g Standard Deviation 5.2198	5.828 g Standard Deviation 3.9791	6.710 g Standard Deviation 4.0174	4.744 g Standard Deviation 4.6193
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMC Week 192	2.094 g Standard Deviation 16.4419	6.162 g Standard Deviation 4.1628	5.197 g Standard Deviation 5.7568	4.434 g Standard Deviation 9.9797
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMC Week 240	3.536 g Standard Deviation 17.0957	3.298 g Standard Deviation 2.4931	5.037 g Standard Deviation 4.7161	3.925 g Standard Deviation 10.2539
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMC Week 288	20.190 g Standard Deviation NA Data available for only 1 subject	6.500 g Standard Deviation NA Data available for only 1 subject	—	13.705 g Standard Deviation 10.1894
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMC Last Overall Exposure	4.306 g Standard Deviation 14.5714	5.130 g Standard Deviation 3.5930	6.714 g Standard Deviation 5.1113	5.256 g Standard Deviation 9.5103
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMC Week 24	-21.871 g Standard Deviation 35.4370	41.454 g Standard Deviation 20.0358	237.248 g Standard Deviation 414.0877	4.514 g Standard Deviation 43.5228
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMC Week 48	49.820 g Standard Deviation NA Data available for only 1 subject	72.530 g Standard Deviation NA Data available for only 1 subject	30.228 g Standard Deviation 82.4369	39.070 g Standard Deviation 69.2934
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMC Week 96	7.537 g Standard Deviation 74.2838	59.604 g Standard Deviation 97.9214	98.018 g Standard Deviation 111.9259	46.428 g Standard Deviation 93.5046
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMC Week 144	-48.236 g Standard Deviation 111.6604	17.446 g Standard Deviation 173.3574	92.063 g Standard Deviation 107.9837	15.307 g Standard Deviation 138.3534
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMC Week 192	-121.916 g Standard Deviation 92.0001	23.938 g Standard Deviation 195.8402	50.375 g Standard Deviation 99.6281	-20.599 g Standard Deviation 151.5153
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMC Week 240	-97.706 g Standard Deviation 106.6581	82.310 g Standard Deviation 223.0794	40.572 g Standard Deviation 162.1575	0.231 g Standard Deviation 172.0218
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMC Week 288	-243.080 g Standard Deviation NA Data available for only 1 subject	-144.660 g Standard Deviation NA Data available for only 1 subject	—	-193.870 g Standard Deviation 69.5934
Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMC Last Overall Exposure	-113.296 g Standard Deviation 178.8050	11.252 g Standard Deviation 217.5674	82.548 g Standard Deviation 128.7017	-19.063 g Standard Deviation 188.0498

SECONDARY outcome

Timeframe: Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288.

Population: Full analysis set (intent-to-treat, all randomized patients)

A DXA scan was performed to evaluate bone bone mineral density (BMD) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks).

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=7 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=6 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=19 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMD Last Overall Exposure	-0.0115 g/cm2 Standard Deviation 0.03899	0.0658 g/cm2 Standard Deviation 0.07776	0.0207 g/cm2 Standard Deviation 0.07549	0.0282 g/cm2 Standard Deviation 0.07038
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMD Last Overall Exposure	-0.0501 g/cm2 Standard Deviation 0.07360	-0.0298 g/cm2 Standard Deviation 0.08785	-0.0224 g/cm2 Standard Deviation 0.05773	-0.0360 g/cm2 Standard Deviation 0.07036
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMD Week 24	0.0477 g/cm2 Standard Deviation 0.07710	0.0094 g/cm2 Standard Deviation 0.02441	0.0195 g/cm2 Standard Deviation 0.01642	0.0251 g/cm2 Standard Deviation 0.05361
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMD Week 48	0.0190 g/cm2 Standard Deviation NA Data available for only 1 subject	0.0240 g/cm2 Standard Deviation NA Data available for only 1 subject	0.0590 g/cm2 Standard Deviation 0.04109	0.0465 g/cm2 Standard Deviation 0.03729
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMD Week 96	0.0003 g/cm2 Standard Deviation 0.00532	0.0780 g/cm2 Standard Deviation 0.06703	0.0480 g/cm2 Standard Deviation 0.04943	0.0415 g/cm2 Standard Deviation 0.05542
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMD Week 144	0.0340 g/cm2 Standard Deviation 0.02524	0.0923 g/cm2 Standard Deviation 0.07682	0.0933 g/cm2 Standard Deviation 0.04150	0.0751 g/cm2 Standard Deviation 0.05741
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMD Week 192	0.0135 g/cm2 Standard Deviation 0.00919	0.0983 g/cm2 Standard Deviation 0.10856	0.0563 g/cm2 Standard Deviation 0.07100	0.0654 g/cm2 Standard Deviation 0.08327
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMD Week 240	0.0115 g/cm2 Standard Deviation 0.02192	0.1137 g/cm2 Standard Deviation 0.05701	-0.0073 g/cm2 Standard Deviation 0.06178	0.0428 g/cm2 Standard Deviation 0.07481
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Hip total BMD Week 288	—	-0.0200 g/cm2 Standard Deviation NA Data available for only 1 subject	—	-0.0200 g/cm2 Standard Deviation NA Data available for only 1 subject
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMD Week 24	0.0269 g/cm2 Standard Deviation 0.02113	0.0272 g/cm2 Standard Deviation 0.01492	0.0098 g/cm2 Standard Deviation 0.02475	0.0270 g/cm2 Standard Deviation 0.01802
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMD Week 48	0.0480 g/cm2 Standard Deviation NA Data available for only 1 subject	0.0590 g/cm2 Standard Deviation NA Data available for only 1 subject	0.0914 g/cm2 Standard Deviation 0.05647	0.0806 g/cm2 Standard Deviation 0.04978
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMD Week 96	0.0414 g/cm2 Standard Deviation 0.05230	0.0554 g/cm2 Standard Deviation 0.04271	0.1158 g/cm2 Standard Deviation 0.08060	0.0644 g/cm2 Standard Deviation 0.06210
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMD Week 144	0.0200 g/cm2 Standard Deviation 0.06257	0.0850 g/cm2 Standard Deviation 0.05323	0.1138 g/cm2 Standard Deviation 0.05734	0.0700 g/cm2 Standard Deviation 0.06688
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMD Week 192	0.0554 g/cm2 Standard Deviation 0.13220	0.0766 g/cm2 Standard Deviation 0.04180	0.1123 g/cm2 Standard Deviation 0.05197	0.0792 g/cm2 Standard Deviation 0.08423
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMD Week 240	0.0750 g/cm2 Standard Deviation 0.14168	0.0455 g/cm2 Standard Deviation 0.04107	0.1027 g/cm2 Standard Deviation 0.04786	0.0745 g/cm2 Standard Deviation 0.09073
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMD Week 288	0.1860 g/cm2 Standard Deviation NA Data available for only 1 subject	0.0700 g/cm2 Standard Deviation NA Data available for only 1 subject	—	0.1280 g/cm2 Standard Deviation 0.08202
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Lumbar Spine BMD Last Overall Exposure	0.0737 g/cm2 Standard Deviation 0.11346	0.0492 g/cm2 Standard Deviation 0.04649	0.1194 g/cm2 Standard Deviation 0.04999	0.0799 g/cm2 Standard Deviation 0.08241
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMD Week 24	-0.0003 g/cm2 Standard Deviation 0.01788	-0.0122 g/cm2 Standard Deviation 0.01055	0.0206 g/cm2 Standard Deviation 0.03173	-0.0052 g/cm2 Standard Deviation 0.01589
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMD Week 48	0.0050 g/cm2 Standard Deviation NA Data available for only 1 subject	0.0090 g/cm2 Standard Deviation NA Data available for only 1 subject	0.0178 g/cm2 Standard Deviation 0.05277	0.0147 g/cm2 Standard Deviation 0.04342
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMD Week 96	-0.0103 g/cm2 Standard Deviation 0.03523	-0.0100 g/cm2 Standard Deviation 0.04136	0.0230 g/cm2 Standard Deviation 0.04872	-0.0019 g/cm2 Standard Deviation 0.04059
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMD Week 144	-0.0250 g/cm2 Standard Deviation 0.03662	-0.0278 g/cm2 Standard Deviation 0.05823	-0.0060 g/cm2 Standard Deviation 0.04721	-0.0206 g/cm2 Standard Deviation 0.04542
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMD Week 192	-0.0532 g/cm2 Standard Deviation 0.02477	-0.0220 g/cm2 Standard Deviation 0.07088	-0.0212 g/cm2 Standard Deviation 0.06209	-0.0329 g/cm2 Standard Deviation 0.05358
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMD Week 240	-0.0426 g/cm2 Standard Deviation 0.05601	-0.0122 g/cm2 Standard Deviation 0.08610	-0.0493 g/cm2 Standard Deviation 0.06965	-0.0353 g/cm2 Standard Deviation 0.06615
Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) Whole Body BMD Week 288	-0.1140 g/cm2 Standard Deviation NA Data available for only 1 subject	-0.0710 g/cm2 Standard Deviation NA Data available for only 1 subject	—	-0.0925 g/cm2 Standard Deviation 0.03041

SECONDARY outcome

Timeframe: Baseline, Week 24 (primary treatment period) and up to 288 weeks of asfotase alfa exposure

Population: Full analysis set (intent-to-treat, all randomized patients). Among the 6 control subjects, only 4 had both a Baseline and Week 24 value.

The patient was instructed to walk the length of a pre-measured hallway for 6 minutes. The primary measurement was distance walked (in meters).

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=7 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=6 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=19 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT) Change from Baseline to Week 24	64.7 meters Standard Deviation 73.04	43.5 meters Standard Deviation 43.18	13.5 meters Standard Deviation 69.77	54.9 meters Standard Deviation 59.71
Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT) Change from Baseline Last Overall Exposure	89.4 meters Standard Deviation 81.32	2.2 meters Standard Deviation 121.79	74.4 meters Standard Deviation 107.40	56.2 meters Standard Deviation 104.85

SECONDARY outcome

Timeframe: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).

Population: Full analysis set (intent-to-treat, all randomized patients)

A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Volume/Bone Volume (%). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=6 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=12 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume	1.213 percentage of volume Standard Deviation 3.2488	-2.845 percentage of volume Standard Deviation 2.3769	0.200 percentage of volume Standard Deviation 4.7679	-0.816 percentage of volume Standard Deviation 3.4434

SECONDARY outcome

Timeframe: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).

Population: Full analysis set (intent-to-treat, all randomized patients)

A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Thickness (um). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=6 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=6 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=12 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Thickness	-0.013 um Standard Deviation 3.6333	-1.516 um Standard Deviation 2.3556	-1.132 um Standard Deviation 6.0884	-0.764 um Standard Deviation 3.0229

SECONDARY outcome

Timeframe: Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups).

Population: Full analysis set (intent-to-treat, all randomized patients)

A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Mineralization Lag Time (days). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit.

Outcome measures

Outcome measures
Measure	0.3 mg/kg Asfotase Alfa n=4 Participants Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa n=5 Participants Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control n=5 Participants Control (no asfotase alfa) during primary treatment period (first 24 weeks)	Combined Asfotase Alfa Group n=9 Participants Subjects from Cohort 1 and Cohort 2 treated with asfotase alfa during primary treatment period (first 24 weeks)
Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Mineralization Lag Time	-908.255 days Standard Deviation 1313.6158	-126.946 days Standard Deviation 142.2929	78.296 days Standard Deviation 167.0895	-474.195 days Standard Deviation 909.2779

Adverse Events

0.3 mg/kg Asfotase Alfa (First 24 Weeks)

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

0.5 mg/kg Asfotase Alfa (First 24 Weeks)

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Concurrent Control (First 24 Weeks)

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Cumulative Exposure to Asfotase Alfa

Serious events: 9 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Director of Clinical Trials

Alexion Pharmaceuticals, Inc.

Phone: 475-230-2596

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	0.3 mg/kg Asfotase Alfa (First 24 Weeks) n=7 participants at risk Asfotase alfa Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total)	0.5 mg/kg Asfotase Alfa (First 24 Weeks) n=6 participants at risk Asfotase alfa Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total)	Concurrent Control (First 24 Weeks) n=6 participants at risk No asfotase alfa treatment during primary treatment period: first 24 weeks. After 24 weeks, Control Group subjects were eligible to begin asfotase alfa treatment in the open-label extension treatment period.	Cumulative Exposure to Asfotase Alfa n=19 participants at risk Adverse events occurring in subjects from Cohort 1, Cohort 2 and original Control group during exposure to asfotase alfa.
Musculoskeletal and connective tissue disorders Pain in Extremity	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	10.5% 2/19 • Number of events 2 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Nervous system disorders Convulsion	14.3% 1/7 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	10.5% 2/19 • Number of events 3 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Musculoskeletal and connective tissue disorders Muscular Weakness	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Nervous system disorders Headache	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Nervous system disorders Intracranial Pressure Increased	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
General disorders Chills	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 3 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
General disorders Device Dislocation	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
General disorders Injection Site Hypersensitivity	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Gastrointestinal disorders Colitis	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Gastrointestinal disorders Hypoaesthesia Oral	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Infections and infestations Abscess	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Infections and infestations Cellulitis	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 2 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Infections and infestations Endocarditis	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Infections and infestations Enterovirus Infection	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Infections and infestations Staphylococcal Abscess	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 2 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Infections and infestations Staphylococcal Infection	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	16.7% 1/6 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Congenital, familial and genetic disorders Arnold-Chiari Malformation	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Ear and labyrinth disorders Tympanic Membrane Perforation	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Immune system disorders Anaphylactoid Reaction	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adrenal Adenoma	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	16.7% 1/6 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	5.3% 1/19 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Infections and infestations Gastroenteritis	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	16.7% 1/6 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/19 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Injury, poisoning and procedural complications Femur Fracture	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	16.7% 1/6 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/19 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.
Injury, poisoning and procedural complications Humerus Fracture	0.00% 0/7 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/6 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	16.7% 1/6 • Number of events 1 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.	0.00% 0/19 • up to 288 weeks Only adverse events with an onset date are included in the cumulative exposure category.