Trial Outcomes & Findings for An Efficacy and Safety Trial of Intravenous Zoledronic Acid Twice Yearly in Osteoporotic Children Treated With Glucocorticoids (NCT NCT00799266)

Last Updated: 2020-09-02

Results Overview

Lumbar Spine Bone Mineral Density (BMD) Z-score was determined by the central imaging vendor before first treatment and at Month 12. The methods to be used to measure Lumbar Spine BMD Z-score were described in the respective DXA Manuals provided by central imaging vendor. Positive changes from baseline indicated an improvement in condition.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

34 participants

Primary outcome timeframe

Month 12

Results posted on

2020-09-02

Participant Flow

This study was conducted in 12 centers in 6 countries: Australia (1), Canada (5), Hungary (1), United Kingdom (2), Russian Federation (2), and South Africa (1).

The Participant Flow and Baseline Characteristics were done on the Intention-to-treat (ITT) population. All efficacy analyses were done on the Modified Intention-to-treat (MITT) population and all safety analyses were based on Safety population.

Participant milestones

Participant milestones
Measure	Zoledronic Acid Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid	Placebo Twice yearly i.v of infusion of Placebo (similar dosing as active drug)
Overall Study STARTED	18	16
Overall Study Modified Intention-to-treat (MITT)	17	16
Overall Study Safety Set	18	16
Overall Study COMPLETED	15	15
Overall Study NOT COMPLETED	3	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid	Placebo Twice yearly i.v of infusion of Placebo (similar dosing as active drug)
Overall Study Adverse Event	0	1
Overall Study Subject withdrew consent	3	0

Baseline Characteristics

Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid n=18 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Total n=34 Participants Total of all reporting groups
Age, Continuous	13.0 Years STANDARD_DEVIATION 3.50 • n=18 Participants	12.3 Years STANDARD_DEVIATION 3.42 • n=16 Participants	12.6 Years STANDARD_DEVIATION 3.43 • n=34 Participants
Sex: Female, Male Female	6 Participants n=18 Participants	5 Participants n=16 Participants	11 Participants n=34 Participants
Sex: Female, Male Male	12 Participants n=18 Participants	11 Participants n=16 Participants	23 Participants n=34 Participants
Race/Ethnicity, Customized Caucasian	13 Participants n=18 Participants	14 Participants n=16 Participants	27 Participants n=34 Participants
Race/Ethnicity, Customized Black	2 Participants n=18 Participants	1 Participants n=16 Participants	3 Participants n=34 Participants
Race/Ethnicity, Customized Asian	2 Participants n=18 Participants	0 Participants n=16 Participants	2 Participants n=34 Participants
Race/Ethnicity, Customized Native American	1 Participants n=18 Participants	1 Participants n=16 Participants	2 Participants n=34 Participants
Race/Ethnicity, Customized Pacific Islander	0 Participants n=18 Participants	0 Participants n=16 Participants	0 Participants n=34 Participants
Race/Ethnicity, Customized Othe	0 Participants n=18 Participants	0 Participants n=16 Participants	0 Participants n=34 Participants
Lumbar Spine Bone Mineral Density (BMD) Z-score	-2.127 Z-score STANDARD_DEVIATION 0.7863 • n=17 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	-2.379 Z-score STANDARD_DEVIATION 0.8975 • n=16 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	-2.249 Z-score STANDARD_DEVIATION 0.8385 • n=33 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score
Lumbar Spine Bone Mineral Content (BMC)	31.886 gram (g) STANDARD_DEVIATION 15.1062 • n=17 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	22.605 gram (g) STANDARD_DEVIATION 6.6054 • n=16 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	27.386 gram (g) STANDARD_DEVIATION 12.5195 • n=33 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score
Total body Bone Mineral Content (BMC)	1550.556 gram (g) STANDARD_DEVIATION 592.0670 • n=16 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	1050.610 gram (g) STANDARD_DEVIATION 253.0759 • n=14 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	1317.248 gram (g) STANDARD_DEVIATION 523.8133 • n=30 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score
Serum Procollagen type 1 amino-terminal propeptide (P1NP)	313.54 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 284.541 • n=16 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	368.90 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 235.226 • n=14 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	339.37 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 259.750 • n=30 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score
Serum Bone specific alkaline phosphatase (BSAP)	31.559 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 22.6619 • n=16 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	43.414 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 32.8200 • n=14 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	37.092 nanogram per milliliter (ng/mL) STANDARD_DEVIATION 28.0122 • n=30 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score
Serum Cross linked N-telopeptide (NTX)	34.359 nmol BCE/L STANDARD_DEVIATION 22.0490 • n=16 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	39.192 nmol BCE/L STANDARD_DEVIATION 14.5823 • n=14 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	36.615 nmol BCE/L STANDARD_DEVIATION 18.7829 • n=30 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score
Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP-5b)	7.010 U/L STANDARD_DEVIATION 2.9998 • n=16 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	8.595 U/L STANDARD_DEVIATION 4.5650 • n=14 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	7.750 U/L STANDARD_DEVIATION 3.8266 • n=30 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score
Vertebral Morphometry (mid-to-posterior height ratio)	0.982 mid-to-posterior height ratio STANDARD_DEVIATION 0.0428 • n=10 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	0.976 mid-to-posterior height ratio STANDARD_DEVIATION 0.0788 • n=13 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	0.979 mid-to-posterior height ratio STANDARD_DEVIATION 0.0643 • n=23 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score
Second metacarpal cortical width	0.40 millimeter (mm) STANDARD_DEVIATION 0.194 • n=9 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	0.41 millimeter (mm) STANDARD_DEVIATION 0.144 • n=12 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score	0.40 millimeter (mm) STANDARD_DEVIATION 0.163 • n=21 Participants • Modified Intention-to-treat (MITT) population = All patients with baseline and at least one post-baseline lumbar spine BMD Z-score

PRIMARY outcome

Timeframe: Month 12

Population: The Modified Intention-to-treat (MITT) population, which consisted of all randomized patients who had both baseline and at least one post-baseline lumbar spine BMD Z-score, was considered.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 12	0.168 Z-score Standard Error 0.1449	0.582 Z-score Standard Error 0.1279

SECONDARY outcome

Timeframe: Month 6

Lumbar Spine Bone Mineral Density (BMD) Z-score was determined by the central imaging vendor before first treatment and at Month 6. The methods to be used to measure Lumbar Spine BMD Z-score were described in the respective DXA Manuals provided by central imaging vendor. Positive changes from baseline indicated an improvement in condition.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score at Month 6	0.157 Z-score Standard Error 0.14	0.447 Z-score Standard Error 0.13

SECONDARY outcome

Timeframe: Month 6, Month 12

Lumbar Spine BMC was determined by the central imaging vendor before first treatment and at Months 6 and 12. The methods to be used to measure BMC were described in the respective DXA Manuals.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in Lumbar Spine BMC at Month 6 and 12 Lumbar Spine (LS) BMC Change at Month 6	2.131 g Standard Error 0.70	4.110 g Standard Error 0.63
Mean Change From Baseline in Lumbar Spine BMC at Month 6 and 12 Lumbar Spine (LS) BMC Change at Month 12	4.295 g Standard Error 1.32	6.450 g Standard Error 1.18

SECONDARY outcome

Timeframe: Month 6, Month 12

Total body BMC was all determined by the central imaging vendor before first treatment and at Months 6 and 12. The methods to be used to measure BMC were described in the respective DXA Manuals.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in Total Body BMC at Month 6 and 12 Total BMC Change at Month 6	95.214 g Standard Error 28.74	129.272 g Standard Error 24.23
Mean Change From Baseline in Total Body BMC at Month 6 and 12 Total BMC Change at Month 12	140.064 g Standard Error 51.90	220.805 g Standard Error 42.74

SECONDARY outcome

Timeframe: Month 6, Month 12

Serum Procollagen type 1 amino-terminal propeptide (P1NP) was collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in Serum P1NP at Months 6 and 12 P1NP Change at Month 6	77.497 nanogram per milliliter (ng/mL) Standard Error 56.15	-134.285 nanogram per milliliter (ng/mL) Standard Error 48.80
Mean Change From Baseline in Serum P1NP at Months 6 and 12 P1NP Change at Month 12	150.166 nanogram per milliliter (ng/mL) Standard Error 68.0933	-230.966 nanogram per milliliter (ng/mL) Standard Error 59.1977

SECONDARY outcome

Timeframe: Month 6, Month 12

Bone specific alkaline phosphatase (BSAP) were collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in BSAP at Months 6 and 12 BSAP Change at Month 6	3.810 nanogram per milliliter (ng/mL) Standard Error 4.05	-7.413 nanogram per milliliter (ng/mL) Standard Error 3.63
Mean Change From Baseline in BSAP at Months 6 and 12 BSAP Change at Month 12	6.450 nanogram per milliliter (ng/mL) Standard Error 4.9010	-13.984 nanogram per milliliter (ng/mL) Standard Error 4.3814

SECONDARY outcome

Timeframe: Month 6, Month 12

Serum Cross linked N-telopeptide (NTX) were collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in Serum NTX at Months 6 and 12 NTX Change at Month 6	7.192 nmol BCE/L Standard Error 4.74	-13.746 nmol BCE/L Standard Error 4.23
Mean Change From Baseline in Serum NTX at Months 6 and 12 NTX Change at Month 12	7.440 nmol BCE/L Standard Error 4.23	-20.134 nmol BCE/L Standard Error 3.76

SECONDARY outcome

Timeframe: Month 6, Month 12

Serum Tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) was collected before first treatment (baseline) and at Months 6 and Month 12 according to the instructions provided in the Laboratory Manual. The samples were analyzed in batches at the laboratory.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in Serum TRAP-5b at Months 6 and 12 TRAP 5b Change at Month 6	0.313 U/L Standard Error 0.74	-1.561 U/L Standard Error 0.65
Mean Change From Baseline in Serum TRAP-5b at Months 6 and 12 TRAP 5b Change at Month 12	0.109 U/L Standard Error 0.81	-1.728 U/L Standard Error 0.73

SECONDARY outcome

Timeframe: Month 12

New vertebral fractures were defined as fractures of Genant Grade 1 or higher that occurred at lumbar or thoracic spine from first dose infusion to the end of the study.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Number of Participants With New Vertebral Fractures at Month 12	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Month 12

Vertebral morphometry (or concave index) was calculated using the average ratio between mid-height and posterior height from L1 to L4 and performed by a central reader.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in Vertebral Morphometry at Month 12	-0.0003 Ratio Standard Error 0.01	-0.018 Ratio Standard Error 0.01

SECONDARY outcome

Timeframe: Month 3, Month 6, Month 9 and Month 12

Pain was evaluated at each visit (in office and telephone visit) at randomization, Months 3, 6, 9 and 12 using the Faces Pain Scale-Revised (FPS-R). Children were selecting the face that best fits their pain. The pain score ranged from 0 (No Pain) to 10 (Very Much Pain). The reduction in pain from baseline by visit was evaluated based on whether or not patients had a decrease in their FPS-R from baseline. If pain remained the same or worsened from baseline a patient was classified as '0' and if the pain scale decreased then the patient was classified as '1'.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Percentage of Patients With Reduction in Pain at Months 3, 6, 9 and 12 Month 3	53.8 Percentage of Patients	37.5 Percentage of Patients
Percentage of Patients With Reduction in Pain at Months 3, 6, 9 and 12 Month 6	50.0 Percentage of Patients	37.5 Percentage of Patients
Percentage of Patients With Reduction in Pain at Months 3, 6, 9 and 12 Month 9	46.2 Percentage of Patients	33.3 Percentage of Patients
Percentage of Patients With Reduction in Pain at Months 3, 6, 9 and 12 Month 12	57.1 Percentage of Patients	31.3 Percentage of Patients

SECONDARY outcome

Timeframe: Month 12

Left posteroanterior (PA) hand/wrist X-ray were taken at Visit 1 and at the Month 12 visit to assess bone age and the between-treatment differences for change in 2nd metacarpal cortical width at Month 12 relative to baseline. If a fracture of the left upper extremity precluded radiographic imaging, then the right hand was evaluated for this purpose. In this case, the right hand was be imaged at both Visit 1 and at Month 12. The information was used in the assessment of bone density.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Mean Change From Baseline in 2nd Metacarpal Cortical Width at Month 12	0.03 millimeter (mm) Standard Error 0.047	-0.01 millimeter (mm) Standard Error 0.040

SECONDARY outcome

Timeframe: Month 12

Urine was collected overnight or for at least 4 waking hours from all patients able to provide specimens, to measure urinary concentration of zoledronic acid at Month 12. Only descriptive analysis done.

Outcome measures

Outcome measures
Measure	Placebo Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=17 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Urinary Concentration of Zoledronic Acid at Month 12	—	1643.3 ng/mL Standard Deviation 2846.34

SECONDARY outcome

Timeframe: Baseline through Month 12

Population: The Safety population, which consisted of all patients who had been exposed to at least one infusion of study drug, was considered.

Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that zoledronic acid is safe for the treatment of osteoporotic children treated with glucocorticoids through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis done.

Outcome measures

Outcome measures
Measure	Placebo n=16 Participants Twice yearly i.v of infusion of Placebo (similar dosing as active drug)	Zoledronic Acid n=18 Participants Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid
Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids AEs by Primary System Organ Class (SOC)	75.0 Percentage of Participants	83.3 Percentage of Participants
Safety of Zoledronic Acid for the Treatment of Osteoporotic Children Treated With Glucocorticoids SAEs by Primary System Organ Class (SOC)	6.3 Percentage of Participants	27.8 Percentage of Participants

Adverse Events

Zoledronic Acid

Serious events: 5 serious events

Other events: 14 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Zoledronic Acid n=18 participants at risk Twice yearly 0.05 mg/kg (max 5 mg) i.v infusion (at least 30 minutes) of zoledronic acid	Placebo n=16 participants at risk Twice yearly i.v of infusion of Placebo (similar dosing as active drug)
Gastrointestinal disorders Abdominal pain	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Gastrointestinal disorders Crohn's disease	11.1% 2/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Gastrointestinal disorders Diarrhoea	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Gastrointestinal disorders Nausea	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Gastrointestinal disorders Vomiting	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
General disorders Acute phase reaction	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
General disorders Pyrexia	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Infections and infestations Clostridium difficile infection	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Infections and infestations Varicella zoster virus infection	0.00% 0/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	6.2% 1/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Investigations Weight decreased	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Metabolism and nutrition disorders Hypocalcaemia	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Musculoskeletal and connective tissue disorders Bone pain	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Musculoskeletal and connective tissue disorders Myalgia	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Nervous system disorders Headache	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Nervous system disorders Seizure	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Nervous system disorders Status epilepticus	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.
Psychiatric disorders Abnormal behaviour	5.6% 1/18 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.	0.00% 0/16 • Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 9 years and 3 months.