Double-blind Extension of HORIZON Pivotal Fracture Trial (Zoledronic Acid in the Treatment of Postmenopausal Osteoporosis)

This study has been completed.

Sponsor:

Information provided by:

Novartis

ClinicalTrials.gov Identifier:

NCT00145327

First received: September 1, 2005

Last updated: June 24, 2011

Last verified: June 2011

History of Changes

Results First Received: January 21, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Osteoporosis
Interventions:	Drug: Zoledronic Acid Drug: Placebo

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This was an international, multicenter, randomized, double-blind 3-year extension study in postmenopausal women with osteoporosis who had completed participation in the CZOL446H2301 (NCT00049829) core study. The extension study started 17 May 2005 (First patient enrolled) and ended 24 Nov 2009 (Last patient completed).

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Patients who were receiving zoledronic acid in the core study were randomized in a 1:1 fashion to receive either zoledronic acid or placebo in the extension study. Patients who were receiving placebo in the core study were assigned to zoledronic acid in the extension study in order to retain the core study blind.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

Patients who were receiving zoledronic acid in the core study were randomized in a 1:1 fashion to receive either zoledronic acid or placebo in the extension study.

Patients who were receiving placebo in the core study were assigned to zoledronic acid in the extension study in order to retain the core study blind.

Reporting Groups

	Description
Zoledronic Acid 6	Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.
Zoledronic Acid 3 Placebo 3	Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.
Placebo 3 Zoledronic Acid 3	Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.

Participant Flow: Overall Study

	Zoledronic Acid 6	Zoledronic Acid 3 Placebo 3	Placebo 3 Zoledronic Acid 3
STARTED	616 ^[1]	617	1223 ^[2]
COMPLETED	474	493	975
NOT COMPLETED	142	124	248
Withdrawal by Subject	77	72	164
Death	26	18	30
Adverse Event	14	11	22
Lost to Follow-up	9	14	14
Administrative problems	12	9	13
Protocol Violation	2	0	2
Abnormal laboratory value(s)	1	0	2
Missing – not stated	1	0	1

[1]	Group Z6 and Group Z3P3 have randomized participants.
[2]	Group P3Z3 have non-randomized participants

Baseline Characteristics

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Reporting Groups

	Description
Zoledronic Acid 6	Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.
Zoledronic Acid 3 Placebo 3	Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.
Placebo 3 Zoledronic Acid 3	Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.
Total	Total of all reporting groups

Baseline Measures

	Zoledronic Acid 6	Zoledronic Acid 3 Placebo 3	Placebo 3 Zoledronic Acid 3	Total
Number of Participants [units: participants]	616	617	1223	2456
Age [units: Years] Mean ± Standard Deviation	75.5 ± 4.88	75.5 ± 4.89	75.6 ± 4.95	75.5 ± 4.92
Gender [units: Participants]
Female	616	617	1223	2456
Male	0	0	0	0

Outcome Measures

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1. Primary:

Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3 [ Time Frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72; end of extension study) ]

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2. Secondary:

Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP [ Time Frame: Year 4.5 ]

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3. Secondary:

Bone Resorption and Formation Biochemical Markers at Year 6: P1NP [ Time Frame: Year 6 ]

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4. Secondary:

Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3 [ Time Frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54) ]

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5. Secondary:

Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3 [ Time Frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 ]

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Measure Type	Secondary
Measure Title	Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3
Measure Description	The percentage change in BMD as measured by DXA at Year 6 relative to Year 3. It was derived as 100 * (BMD at Year 6 - BMD at Year 3)/(BMD at Year 3).
Time Frame	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intention to treat (ITT) population included all patients who were randomized or enrolled in the extension study at Visit 8. The number of patients analyzed = the number of patients with measurements at Year 6 and Year 3 as determined by the analysis window.

Reporting Groups

	Description
Zoledronic Acid 6	Patients who received Zoledronic acid for 3 years in the core study (CZOL446H2301; NCT00049829) received a single intravenous infusion of 5 mg Zoledronic acid once a year for 3 years (at Months 36, 48 and 60) in this extension study for a total of 6 years of treatment.
Zoledronic Acid 3 Placebo 3	Patients who were treated with Zoledronic acid for 3 years in the core study received a single intravenous matching Placebo infusion once a year for 3 years in this extension study.
Placebo 3 Zoledronic Acid 3	Patients who were treated with placebo for 3 years in the core study received 5 mg Zoledronic acid in a single intravenous infusion once a year for 3 years (at Months 36, 48 and 60) in this extension study.

Measured Values

	Zoledronic Acid 6	Zoledronic Acid 3 Placebo 3	Placebo 3 Zoledronic Acid 3
Number of Participants Analyzed [units: participants]	100	84	128
Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3 [units: Percentage change in BMD] Mean ± Standard Error	3.473 ± 0.4653	1.606 ± 0.4550	8.875 ± 0.5398

No statistical analysis provided for Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3

6. Secondary:

Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3 [ Time Frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54) ]

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7. Secondary:

Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3 [ Time Frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72) ]

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8. Secondary:

Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3 [ Time Frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54) ]

Show Outcome Measure 8

9. Secondary:

Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3 [ Time Frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72) ]

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10. Secondary:

Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures [ Time Frame: Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 ]

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11. Secondary:

Number of Participants With Incidence of Clinical Fracture [ Time Frame: Extension Baseline (Year 3; Month 36) to Year 6 ]

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12. Secondary:

Qualitative Bone Biopsy Parameters [ Time Frame: End of Study Visit at Year 6 ]

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13. Secondary:

Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion [ Time Frame: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 3 infusion ]

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14. Secondary:

Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion [ Time Frame: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 4 infusion ]

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15. Secondary:

Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion [ Time Frame: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 5 infusion ]

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16. Secondary:

The Number of Participants With Clinically Significant Laboratory Parameters [ Time Frame: Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to Year 6 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Study Director
Organization: Novartis Pharmaceuticals
phone: 862-778-8300

No publications provided by Novartis

Publications automatically indexed to this study:

Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, Cummings SR, Hue TF, Lippuner K, Lakatos P, Leung PC, Man Z, Martinez RL, Tan M, Ruzycky ME, Su G, Eastell R. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012 Feb;27(2):243-54.

Responsible Party:	External Affairs, Novartis
ClinicalTrials.gov Identifier:	NCT00145327 History of Changes
Other Study ID Numbers:	CZOL446H2301E1
Study First Received:	September 1, 2005
Results First Received:	January 21, 2011
Last Updated:	June 24, 2011
Health Authority:	United States: Food and Drug Administration

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