Trial Outcomes & Findings for Safety and Efficacy Trial With Zoledronic Acid for the Treatment of Paget's Disease of Bone, Including an Extended Observation Period (NCT NCT00051636)

Last Updated: 2012-05-15

Results Overview

Therapeutic response is defined as a reduction of at least 75% from baseline (Visit 1) in total serum alkaline phosphatase excess (difference between measured level and midpoint to the normal range) or normalization of serum alkaline phosphatase at the end of six months.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

172 participants

Primary outcome timeframe

6 months

Results posted on

2012-05-15

Participant Flow

172 participants entered period 1; of these, 127 were identified as treatment responders and entered the extended observation period 2. Responders defined as patient who had ≥75% decrease from baseline in serum alkaline phosphatase (SAP) excess (difference between measured level and midpoint of normal range) or SAP within normal range at 6 months.

Participant milestones

Participant milestones
Measure	Zoledronic Acid and Placebo to Risedronate Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Period 1 - Core STARTED	90	82
Period 1 - Core COMPLETED	86	76
Period 1 - Core NOT COMPLETED	4	6
Period 2- Extended Observation Period STARTED	75	52
Period 2- Extended Observation Period COMPLETED	5	22
Period 2- Extended Observation Period NOT COMPLETED	70	30

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid and Placebo to Risedronate Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Period 1 - Core Adverse Event	2	2
Period 1 - Core Protocol Violation	1	0
Period 1 - Core Withdrawal by Subject	1	2
Period 1 - Core Lost to Follow-up	0	2
Period 2- Extended Observation Period Lost to Follow-up	5	4
Period 2- Extended Observation Period withdrew for nonclinical reason	12	7
Period 2- Extended Observation Period Clinical reasons other than Paget's	9	2
Period 2- Extended Observation Period Death	4	5
Period 2- Extended Observation Period Amendment 6 Informed Consent Not Signed	40	12

Baseline Characteristics

Safety and Efficacy Trial With Zoledronic Acid for the Treatment of Paget's Disease of Bone, Including an Extended Observation Period

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid and Placebo to Risedronate n=90 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=82 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Total n=172 Participants Total of all reporting groups
Age Continuous	70.4 years STANDARD_DEVIATION 10.25 • n=39 Participants	72.1 years STANDARD_DEVIATION 9.91 • n=41 Participants	71.2 years STANDARD_DEVIATION 10.10 • n=35 Participants
Sex: Female, Male Female	28 Participants n=39 Participants	21 Participants n=41 Participants	49 Participants n=35 Participants
Sex: Female, Male Male	62 Participants n=39 Participants	61 Participants n=41 Participants	123 Participants n=35 Participants

PRIMARY outcome

Timeframe: 6 months

Population: Modified intent to treat population: all randomized patients with both baseline and at least one post-baseline serum alkaline phosphatase measurement. Missing values at 6 months were imputed using the last post-baseline measurement prior to 6 months.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=88 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=82 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Number of Patients Who Achieve Therapeutic Response at 6 Months.	85 participants	60 participants

SECONDARY outcome

Timeframe: Baseline and day 28

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and 28 days were included in this analysis.

The percent change in serum alkaline phosphatase from baseline to day 28 was measured.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=79 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=79 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Relative Change in Serum Alkaline Phosphatase (SAP) in Units Per Liter (U/L) at Day 28	-48.8 percent change Standard Deviation 11.51	-28.4 percent change Standard Deviation 17.72

SECONDARY outcome

Timeframe: Baseline and day 10

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 10 were included in this analysis.

The percent change in serum C-telopeptide from baseline to day 10 was measured.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=75 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=72 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10	-85.4 percent change Standard Deviation 18.00	-36.7 percent change Standard Deviation 69.58

SECONDARY outcome

Timeframe: Baseline and day 10

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 10 were included in this analysis.

The percent change in urine alpha C-telopeptide from baseline to day 10 was measured.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=77 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=73 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Relative Change in Urine Alpha C-telopeptide (α-CTx) in ug/mmol at Day 10	-90.3 Percent change Standard Deviation 13.19	-29.9 Percent change Standard Deviation 37.52

SECONDARY outcome

Timeframe: 182 days

Population: Intent-to-treat population: all randomized patients.

A therapeutic response was defined as a reduction of at least 75% from baseline (Visit 1) in serum alkaline phosphatase excess (difference between measured level and midpoint to the normal range) or normalization of serum alkaline phosphatase.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=90 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=82 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Time to First Therapeutic Response	64 Days Interval 61.0 to 65.0	78 Days Interval 64.0 to 178.0

SECONDARY outcome

Timeframe: Baseline and day 28

Population: Intent-to-treat population: all randomized patients. Participants with observations at day 28 were included in this analysis.

Normalization of serum alkaline phosphatase occurred if the serum alkaline phosphatase measurement fell within the normal range.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=88 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=82 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28 Relative to Baseline	5 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline and day 182

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 182 were included in this analysis.

Change in pain severity score from Brief Pain Inventory-Short Form (BPI-SF). This scale values are 0 to 10, a lower score means little to no pain while a higher score means greater pain.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=51 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=46 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Change in Pain Severity Score	-0.5 Units on a scale Standard Deviation 1.77	-0.7 Units on a scale Standard Deviation 2.22

SECONDARY outcome

Timeframe: Baseline and day 182

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 182 were included in this analysis.

Change in pain interference score from Brief Pain Inventory-Short Form (BPI-SF). This scale values are 0 to 10, a lower score means little to no pain while a higher score means greater pain.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=51 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=45 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Change in Pain Interference Score	-0.2 Units on a scale Standard Deviation 1.97	0.1 Units on a scale Standard Deviation 1.72

SECONDARY outcome

Timeframe: 8 years was the maximum

Population: Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension period.

Extended observation period. A therapeutic response is defined as a reduction of at least 75% from baseline in serum alkaline phosphatase excess or normalization of serum alkaline phosphatase.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=75 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=52 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Number of Participants With a Loss of Therapeutic Response During the Extended Observation Period	8 Participants	29 Participants Interval 368.0 to

SECONDARY outcome

Timeframe: 8 years was the maximum

Population: Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension period.

Extended observation period. A partial disease relapse was defined as an increase in serum alkaline phosphatase \>= 50% from the serum alkaline phosphatase measurement at month 6 and at least 1.25 times the upper normal limit.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=75 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=52 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Number of Participants With a Partial Disease Relapse During the Extended Observation Period	6 Participants	26 Participants Interval 547.0 to

SECONDARY outcome

Timeframe: 8 years was the maximum

Population: Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension period.

Extended observation period. A disease relapse was defined as the occurrence of a serum alkaline phosphatase level that was \>= 80% of baseline serum alkaline phosphatase value.

Outcome measures

Outcome measures
Measure	Zoledronic Acid and Placebo to Risedronate n=75 Participants Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=52 Participants Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Number of Participants With a Disease Relapse During the Extended Observation Period	0 Participants	7 Participants Interval 1739.0 to

Adverse Events

Zoledronic Acid and Placebo to Risedronate

Serious events: 5 serious events

Other events: 71 other events

Deaths: 0 deaths

Risedronate and Placebo to Zoledronic Acid

Serious events: 8 serious events

Other events: 58 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis

Phone: 862-778-8300

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 (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Zoledronic Acid and Placebo to Risedronate n=89 participants at risk Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=82 participants at risk Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Cardiac disorders Acute coronary syndrome	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Abdominal pain	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Constipation	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Dysphagia	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Asthenia	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Difficulty in walking	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Pyrexia	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Rigors	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Hepatobiliary disorders Hepatic cyst	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Cellulitis orbital	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Lower respiratory tract infection	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Staphylococcal infection	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Urinary tract infection	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Metabolism and nutrition disorders Hypocalcaemia	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Arthritis	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Spinal column stenosis	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
Nervous system disorders Embolic stroke	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
Psychiatric disorders Confusional state	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Renal and urinary disorders Renal impairment	0.00% 0/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
Surgical and medical procedures Leg amputation	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
Surgical and medical procedures Sympathectomy	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
Vascular disorders Peripheral ischaemia	1.1% 1/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.

Measure	Zoledronic Acid and Placebo to Risedronate n=89 participants at risk Participants received zoledronic acid 5 mg intravenous infusion one dose, 60 days of oral placebo to risedronate, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Risedronate and Placebo to Zoledronic Acid n=82 participants at risk Participants received 60 days of oral risedronate 30 mg, one intravenous infusion of placebo to zoledronic acid, calcium 500 mg twice a day and vitamin D 400 to 1000 international units daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.
Gastrointestinal disorders Constipation	5.6% 5/89 The safety population consisted of all randomized patients who were exposed to study drug.	7.3% 6/82 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Diarrhoea	5.6% 5/89 The safety population consisted of all randomized patients who were exposed to study drug.	3.7% 3/82 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Dyspepsia	7.9% 7/89 The safety population consisted of all randomized patients who were exposed to study drug.	3.7% 3/82 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Nausea	11.2% 10/89 The safety population consisted of all randomized patients who were exposed to study drug.	9.8% 8/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Fatigue	9.0% 8/89 The safety population consisted of all randomized patients who were exposed to study drug.	6.1% 5/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Influenza like illness	6.7% 6/89 The safety population consisted of all randomized patients who were exposed to study drug.	4.9% 4/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Oedema peripheral	5.6% 5/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Pain	7.9% 7/89 The safety population consisted of all randomized patients who were exposed to study drug.	6.1% 5/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Pyrexia	12.4% 11/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Rigors	14.6% 13/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Influenza	9.0% 8/89 The safety population consisted of all randomized patients who were exposed to study drug.	7.3% 6/82 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Nasopharyngitis	9.0% 8/89 The safety population consisted of all randomized patients who were exposed to study drug.	12.2% 10/82 The safety population consisted of all randomized patients who were exposed to study drug.
Injury, poisoning and procedural complications Fall	9.0% 8/89 The safety population consisted of all randomized patients who were exposed to study drug.	4.9% 4/82 The safety population consisted of all randomized patients who were exposed to study drug.
Metabolism and nutrition disorders Hypocalcaemia	5.6% 5/89 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/82 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Arthralgia	12.4% 11/89 The safety population consisted of all randomized patients who were exposed to study drug.	18.3% 15/82 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Back pain	5.6% 5/89 The safety population consisted of all randomized patients who were exposed to study drug.	9.8% 8/82 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Bone pain	10.1% 9/89 The safety population consisted of all randomized patients who were exposed to study drug.	7.3% 6/82 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Myalgia	11.2% 10/89 The safety population consisted of all randomized patients who were exposed to study drug.	4.9% 4/82 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	10.1% 9/89 The safety population consisted of all randomized patients who were exposed to study drug.	11.0% 9/82 The safety population consisted of all randomized patients who were exposed to study drug.
Nervous system disorders Dizziness	11.2% 10/89 The safety population consisted of all randomized patients who were exposed to study drug.	3.7% 3/82 The safety population consisted of all randomized patients who were exposed to study drug.
Nervous system disorders Headache	11.2% 10/89 The safety population consisted of all randomized patients who were exposed to study drug.	13.4% 11/82 The safety population consisted of all randomized patients who were exposed to study drug.
Nervous system disorders Lethargy	10.1% 9/89 The safety population consisted of all randomized patients who were exposed to study drug.	1.2% 1/82 The safety population consisted of all randomized patients who were exposed to study drug.