Trial Outcomes & Findings for 3 yr Efficacy & Safety Study of Zoledronic Acid in Post-menopausal Women With Osteoporosis Treated With Zol Acid for 6 Yrs (NCT NCT00718861)

Last Updated: 2014-10-09

Results Overview

Bone Mineral Density (BMD) measured by dual energy x-ray absorptiometry (DXA). DXA consists of two X-ray beams with different energy levels that are aimed at the patient's bones. When soft tissue absorption is subtracted out, the BMD can be determined from the absorption of each beam by bone. Percentage change from Year 6 = 100\*(Year 9 - Year 6)/Year 6.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

190 participants

Primary outcome timeframe

Year 6 (baseline) and Year 9

Results posted on

2014-10-09

Participant Flow

Participant milestones

Participant milestones
Measure	Z9 (Zoledronic Acid 9) Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Overall Study STARTED	95	95
Overall Study Safety Set	92	95
Overall Study Modified Intent to Treat	67	69
Overall Study COMPLETED	74	77
Overall Study NOT COMPLETED	21	18

Reasons for withdrawal

Reasons for withdrawal
Measure	Z9 (Zoledronic Acid 9) Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Overall Study Withdrawal by Subject	15	10
Overall Study Adverse Event	2	1
Overall Study Lost to Follow-up	2	1
Overall Study Administrative Problems	1	1
Overall Study Death	1	5

Baseline Characteristics

3 yr Efficacy & Safety Study of Zoledronic Acid in Post-menopausal Women With Osteoporosis Treated With Zol Acid for 6 Yrs

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).	Total n=190 Participants Total of all reporting groups
Age, Continuous	78 Years STANDARD_DEVIATION 4.71 • n=85 Participants	78.1 Years STANDARD_DEVIATION 4.85 • n=18 Participants	78.1 Years STANDARD_DEVIATION 4.77 • n=39 Participants
Sex: Female, Male Female	95 Participants n=85 Participants	95 Participants n=18 Participants	190 Participants n=39 Participants
Sex: Female, Male Male	0 Participants n=85 Participants	0 Participants n=18 Participants	0 Participants n=39 Participants

PRIMARY outcome

Timeframe: Year 6 (baseline) and Year 9

Population: The modified intent-to-treat (MITT) population included all patients in the ITT population who had DXA measurements of the total hip at Visit 11 (Year 6) and Visit 15 (Year 9). This was the primary population for the primary efficacy parameter.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=67 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=69 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Percentage Change in Total Hip Bone Mineral Density BMD at Year 6 (Baseline) and Year 9	-0.54 Percentage Change of BMD Standard Error 0.433	-1.31 Percentage Change of BMD Standard Error 0.427

SECONDARY outcome

Timeframe: Year 6 (extension 2 baseline), Year 7, Year 8

Population: The intent-to-treat (ITT) population included all patients who were enrolled in the extension study at Visit 12. This included patients who were randomized to Z9 and Z6P3 groups. n = the number of patients with measurements at Year 6 and follow-up visits as determined by the analysis window.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Percentage Change of Total Hip Bone Mineral Density (BMD) at Year 7 and 8 Compared to Year 6 Year 7 (n=83,76)	-0.28 percentage change of BMD Standard Error 0.336	-0.83 percentage change of BMD Standard Error 0.347
Percentage Change of Total Hip Bone Mineral Density (BMD) at Year 7 and 8 Compared to Year 6 Year 8 (n=73,72)	-0.14 percentage change of BMD Standard Error 0.311	-1.06 percentage change of BMD Standard Error 0.315

SECONDARY outcome

Timeframe: Year 6 (extension 2 baseline), Year 7, Year 8, Year 9

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Percentage Change of Femoral Neck Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 6 Year 7 (n=83,76)	-0.78 percentage change of BMD Standard Error 0.433	-1.24 percentage change of BMD Standard Error 0.447
Percentage Change of Femoral Neck Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 6 Year 8 (n=73,72)	0.00 percentage change of BMD Standard Error 0.521	-0.88 percentage change of BMD Standard Error 0.528
Percentage Change of Femoral Neck Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 6 Year 9 (n=67,69)	-1.11 percentage change of BMD Standard Error 0.554	-1.17 percentage change of BMD Standard Error 0.547

SECONDARY outcome

Timeframe: Year 0 (core baseline), Year 7, Year 8, Year 9

Population: The intent-to-treat (ITT) population included all patients who were enrolled in the extension study at Visit 12. This included patients who were randomized to Z9 and Z6P3 groups. n = the number of patients with measurements at Year 0 and follow-up visits as determined by the analysis window.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Percentage Change of Total Hip Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 0 Year 8 (n=72,71)	5.35 percentage change of BMD Standard Error 0.677	3.65 percentage change of BMD Standard Error 0.684
Percentage Change of Total Hip Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 0 Year 9 (n=67,68)	4.64 percentage change of BMD Standard Error 0.760	3.68 percentage change of BMD Standard Error 0.752
Percentage Change of Total Hip Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 0 Year 7 (n=83,75)	4.81 percentage change of BMD Standard Error 0.619	3.73 percentage change of BMD Standard Error 0.640

SECONDARY outcome

Timeframe: Year 0 (core baseline), Year 7, Year 8, Year 9

Population: The intent-to-treat (ITT) population included all patients who were enrolled in the extension study at Visit 12. This included patients who were randomized to Z9 and Z6P3 groups. n = the number of patients with measurements at Year 0 and follow-up visits as determined by the analysis window.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Percentage Change of Femoral Neck Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 0 Year 7 (n=83,75)	5.11 percentage change of BMD Standard Error 0.921	3.86 percentage change of BMD Standard Error 0.952
Percentage Change of Femoral Neck Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 0 Year 8 (n=72,71)	6.12 percentage change of BMD Standard Error 1.041	4.43 percentage change of BMD Standard Error 1.052
Percentage Change of Femoral Neck Bone Mineral Density (BMD) at Year 7, 8 and 9 Compared to Year 0 Year 9 (n=67,68)	4.16 percentage change of BMD Standard Error 0.963	3.88 percentage change of BMD Standard Error 0.954

SECONDARY outcome

Timeframe: Year 6 (extension 2 baseline), Year 7, Year 8, Year 9

Bone marker analysis: All patients had blood samples collected for analysis of serum c-terminal telopeptide of type I collagen (CTx). Serum CTX assays measure a fragment of the C-terminal telopeptide of type 1 collagen released during resorption of mature bone

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Biomarkers (Bone Markers) Serum C-terminal Telopeptide of Type I Collagen (CTx) at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 6 (n=59, 58)	0.19 ng/ml Interval 0.1 to 0.6	0.18 ng/ml Interval 0.1 to 0.5
Biomarkers (Bone Markers) Serum C-terminal Telopeptide of Type I Collagen (CTx) at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 7 (n=56, 51)	0.2 ng/ml Interval 0.1 to 0.4	0.22 ng/ml Interval 0.1 to 0.5
Biomarkers (Bone Markers) Serum C-terminal Telopeptide of Type I Collagen (CTx) at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 8 (n=51, 52)	0.22 ng/ml Interval 0.1 to 0.4	0.2 ng/ml Interval 0.1 to 0.4
Biomarkers (Bone Markers) Serum C-terminal Telopeptide of Type I Collagen (CTx) at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 9 (n=51,54)	0.22 ng/ml Interval 0.1 to 0.6	0.22 ng/ml Interval 0.1 to 0.7

SECONDARY outcome

Timeframe: Year 6 (extension 2 baseline), Year 7, Year 8, Year 9

Bone marker analysis: All patients had blood samples collected for analysis of serum n-terminal propeptide of type I collagen (P1NP) The P1NP concentration is directly proportional to the amount of new collagen laid down during bone formation.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Biomarkers (Bone Markers)Serum N-terminal Propeptide of Type I Collagen (P1NP) at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 8 (n=54, 57)	26.07 ng/ml Interval 10.9 to 59.9	25.19 ng/ml Interval 13.1 to 68.1
Biomarkers (Bone Markers)Serum N-terminal Propeptide of Type I Collagen (P1NP) at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 6 (n=88, 86)	25.89 ng/ml Interval 10.8 to 69.1	24.98 ng/ml Interval 9.9 to 65.6
Biomarkers (Bone Markers)Serum N-terminal Propeptide of Type I Collagen (P1NP) at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 7 (n=58, 65)	25.69 ng/ml Interval 12.3 to 52.9	27.79 ng/ml Interval 11.7 to 140.2
Biomarkers (Bone Markers)Serum N-terminal Propeptide of Type I Collagen (P1NP) at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 9 (n=52,56)	26.74 ng/ml Interval 12.4 to 133.4	27.41 ng/ml Interval 11.3 to 119.4

SECONDARY outcome

Timeframe: Year 6 (extension 2 baseline), Year 7, Year 8, Year 9

Bone marker analysis: All patients had blood samples collected for analysis of serum bone-specific alkaline phosphatase (BSAP).Bone-specific alkaline phosphatase (BSAP) is a useful marker of active bone formation.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Biomarkers (Bone Markers) Serum Bone-specific Alkaline Phosphatase (BSAP). at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 6 (n=59, 62)	8.16 ng/ml Interval 4.9 to 15.9	8.95 ng/ml Interval 3.9 to 16.2
Biomarkers (Bone Markers) Serum Bone-specific Alkaline Phosphatase (BSAP). at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 7 (n=58, 65)	8.4 ng/ml Interval 4.7 to 15.7	10.00 ng/ml Interval 5.1 to 19.6
Biomarkers (Bone Markers) Serum Bone-specific Alkaline Phosphatase (BSAP). at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 8 (n=54, 57)	7.84 ng/ml Interval 5.4 to 16.4	9.57 ng/ml Interval 5.6 to 15.8
Biomarkers (Bone Markers) Serum Bone-specific Alkaline Phosphatase (BSAP). at Year 6 (Extension 2 Baseline), Year 7, Year 8, Year 9 Year 9 (n=52, 56)	8.46 ng/ml Interval 5.1 to 18.3	9.94 ng/ml Interval 6.2 to 20.7

SECONDARY outcome

Timeframe: Year 6 (extension 2 baseline), Year 9 (3 years of study duration)

Morphometric vertebral fracture (VF) was assessed based on morphometry. QM (quantitative morphometry) incident VF(QM positive) was defined by at least a 20% decrease in any vertebral height (at least 4 mm). If a participant had a QM positive at any vertebrae at any visit, x-rays from all visits for participants were evaluated using Genant semi-quantitative (SQ) method for VF assessment. A fracture was defined as an SQ reading that was greater than the baseline SQ reading.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Number of Participants With New/Worsening Morphometric Vertebral Fractures at Year 9 Compared to Year 6 New/worsening Morphometric vertebra	3 participants	5 participants
Number of Participants With New/Worsening Morphometric Vertebral Fractures at Year 9 Compared to Year 6 New Morphometric vertebral fracture	3 participants	5 participants

SECONDARY outcome

Timeframe: over 3 years of study duration

Population: The intent-to-treat (ITT) population included all patients who were enrolled in the extension study at Visit 12. This included patients who were randomized to Z9 and Z6P3 groups.

The mean of time to the first clinical fracture is estimated from the area under the Kaplan-Meier curve.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Mean of Time to First Clinical Fracture	1212.05 Days Standard Error 22.96	1204.65 Days Standard Error 26.35

SECONDARY outcome

Timeframe: Year 6 (extension 2 baseline), Year 7, Year 8, Year 9

Population: The intent-to-treat (ITT) population included all patients who were enrolled in the extension study at Visit 12. This included patients who were randomized to Z9 and Z6P3 groups. n = the number of patients with evaluable measurements at both Year 6 and the post-Year 6 visit, as determined by the analysis window.

Height was measured using a stadiometer in millimeters (mm). A stadiometer is a piece of medical equipment used for measuring height. It is usually constructed out of a ruler and a sliding horizontal headpiece which is adjusted to rest on the top of the head.

Outcome measures

Outcome measures
Measure	Z9 (Zoledronic Acid 9) n=95 Participants Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 Participants Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Change in Height at Years 7, 8 and 9 Relative to Year 6 Year 9 (n=52, 48)	-13.31 millimeters (mm) Standard Error 1.975	-11.65 millimeters (mm) Standard Error 2.085
Change in Height at Years 7, 8 and 9 Relative to Year 6 Year 7 (n=58, 51)	-5.29 millimeters (mm) Standard Error 1.171	-4.84 millimeters (mm) Standard Error 1.199
Change in Height at Years 7, 8 and 9 Relative to Year 6 Year 8 (n=55, 49)	-10.16 millimeters (mm) Standard Error 1.875	-9.90 millimeters (mm) Standard Error 2.006

Adverse Events

Z9 (Zoledronic Acid 9)

Serious events: 24 serious events

Other events: 62 other events

Deaths: 0 deaths

Z6P3 (Zoledronic Acid 6 Placebo 3)

Serious events: 28 serious events

Other events: 58 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 8627788300

Results disclosure agreements

Principal investigator is a sponsor employee Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. 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 pooled data (i.e.,data from all sites) in clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Z9 (Zoledronic Acid 9) n=92 participants at risk Group Z9 patients were those who had been treated with zoledronic acid for up to 9 years in the core (CZOL446H2301) and extension studies (CZOL446H2301E1 and CZOL446H2301E2).	Z6P3 (Zoledronic Acid 6 Placebo 3) n=95 participants at risk Group Z6P3 patients were those who had been treated with zoledronic acid for 6 years in the core (CZOL446H2301) and the first extension study (CZOL446H2301E1) followed by up to 3 years of placebo in the second extension study (CZOL446H2301E2).
Cardiac disorders Atrial fibrillation	5.4% 5/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	1.1% 1/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Eye disorders Cataract	8.7% 8/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	5.3% 5/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Gastrointestinal disorders Diarrhoea	1.1% 1/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	6.3% 6/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
General disorders Fatigue	5.4% 5/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	2.1% 2/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Infections and infestations Bronchitis	5.4% 5/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	9.5% 9/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Infections and infestations Cystitis	5.4% 5/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	5.3% 5/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Infections and infestations Nasopharyngitis	9.8% 9/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	5.3% 5/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Infections and infestations Upper respiratory tract infection	3.3% 3/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	5.3% 5/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Infections and infestations Urinary tract infection	10.9% 10/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	8.4% 8/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Injury, poisoning and procedural complications Contusion	2.2% 2/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	7.4% 7/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Injury, poisoning and procedural complications Fall	8.7% 8/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	11.6% 11/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Investigations Creatinine renal clearance decreased	6.5% 6/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	0.00% 0/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Musculoskeletal and connective tissue disorders Arthralgia	18.5% 17/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	12.6% 12/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Musculoskeletal and connective tissue disorders Back pain	3.3% 3/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	13.7% 13/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.4% 5/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	8.4% 8/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Musculoskeletal and connective tissue disorders Osteoarthritis	6.5% 6/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	13.7% 13/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Musculoskeletal and connective tissue disorders Pain in extremity	9.8% 9/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	1.1% 1/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Nervous system disorders Sciatica	1.1% 1/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	5.3% 5/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Psychiatric disorders Insomnia	5.4% 5/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	1.1% 1/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.
Vascular disorders Hypertension	10.9% 10/92 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.	8.4% 8/95 The safety population included all patients in the Intent to Treat (ITT) population who received at least 1 dose of study drug during this second extension study. Adverse Events data used the safety population.