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

A 3-year, Double-blind Extension to CZOL446H2301 to Evaluate the Long-term Safety and Efficacy of Zoledronic Acid in the Treatment of Osteoporosis in Postmenopausal Women Taking Calcium and Vitamin D

This extension study is designed to assess the long term safety and efficacy of zoledronic acid in postmenopausal women with osteoporosis who have participated in the CZOL446H2301 (NCT00049829): HORIZON Pivotal Fracture Trial. This extension study began after the 3-year core study ended. Baseline is the same as Year 3.

Study Overview

• Status: Completed
• Conditions: Osteoporosis
• Intervention / Treatment: Drug: Zoledronic Acid; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 2456
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Nuernberg, Germany
    • Novartis
• United States
  • Arizona
    • Tucson, Arizona, United States, 85723
      • Southern Arizona VA
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Science
  • California
    • Beverly Hills, California, United States, 90211
      • Osteoporosis Medical Center
    • San Diego, California, United States, 92103
      • Osteoporosis Prevention Center
    • Walnut Creek, California, United States, 94598
      • Diablo Clinical Research, Inc
  • Colorado
    • Lakewood, Colorado, United States, 80227
      • Colorado Center for Bone Research
  • Florida
    • Ft. Lauderdale, Florida, United States, 33334
      • CRIA Research
    • Stuart, Florida, United States, 34996
      • Radiant Research
    • West Palm Beach, Florida, United States, 33409
      • Comprehensive Clinical Trials, LLC
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • United Osteoporosis Centers (UOC)
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Center for Clinical Research
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • School Of Medicine
    • Munster, Indiana, United States, 46321
      • Medical Specialist Clinical Research Center
  • Kansas
    • Wichita, Kansas, United States, 67207
      • Heartland Research Associates, LLC
  • Maine
    • Bangor, Maine, United States, 04401
      • Maine Center for Osteoporosis Research and Education
  • Maryland
    • Hagerstown, Maryland, United States, 21740
      • Osteoporosis Clinical Trial Center
  • Massachusetts
    • Worcester, Massachusetts, United States, 01610
      • Clinical Pharmacology Study Groups
  • Missouri
    • St. Louis, Missouri, United States, 62110
      • Washington University Center for Clinical Studies
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • New Mexico Clinical Research and Osteoporosis Center Inc
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop U Hospital
  • North Dakota
    • Fargo, North Dakota, United States, 58104
      • Odyssey Research Services/CCRC Internal Medical
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Bone Health and Osteoporosis Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19131
      • Thomas Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh
    • Wyomissing, Pennsylvania, United States, 19610
      • Radiant Research
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital, Endocrinology Clinical Research Unit
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • University of Tennessee Health Science
  • Virginia
    • Richmond, Virginia, United States, 23249
      • McGuire Veterans Affairs Medical Center
    • Richmond, Virginia, United States, 23298
      • VA Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98144
      • Puget Sound Osteoporosis Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 68 years to 90 years (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients who have received 3 infusions in the HORIZON-Pivotal Fracture (PFT) Study.

Exclusion Criteria:

• Poor kidney, eye, or liver health
• Use of certain therapies for osteoporosis in the HORIZON-PFT study (other than the study medication)
• Abnormal calcium levels in the blood

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Zoledronic Acid; Zoledronic Acid 5 mg in 100 mL physiologic 0.9% normal saline for intravenous infusion.; Other Names: Reclast, Aclasta
Placebo Comparator: 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.	Drug: Placebo; 100 mL physiologic 0.9% normal saline for intravenous infusion.; Other Names: Reclast, Aclasta
Experimental: 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.	Drug: Zoledronic Acid; Zoledronic Acid 5 mg in 100 mL physiologic 0.9% normal saline for intravenous infusion.; Other Names: Reclast, Aclasta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change in Bone Mineral Density (BMD) of Femoral Neck at Year 6 Relative to Year 3	The primary efficacy variable was the percentage change in BMD of the femoral neck as measured by dual x-ray absorptiometry (DXA) at Year 6 relative to Year 3. It was derived as 100 *(femoral neck BMD at Year 6 - femoral neck BMD at Year 3) / (femoral neck BMD at Year 3).	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72; end of extension study)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone Resorption and Formation Biochemical Markers at Year 4.5: P1NP	The amount of serum n-terminal propeptide of type I collagen (P1NP) as determined by the central laboratory.	Year 4.5
Bone Resorption and Formation Biochemical Markers at Year 6: P1NP	The amount of serum P1NP as determined by the central laboratory	Year 6
Percentage Change in BMD of Lumbar Spine at Year 4.5 Relative to Year 3	The percentage change in BMD as measured by DXA at Year 4.5 relative to Year 3. It was derived as 100 * (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)
Percentage Change in BMD of Lumbar Spine at Year 6 Relative to Year 3	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).	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6
Percentage Change in BMD of Distal Radius at Year 4.5 Relative to Year 3	The percentage change in BMD as measured by DXA at Year 4.5 relative to Year 3. It was derived as 100 * (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)
Percentage Change in BMD of Distal Radius at Year 6 Relative to Year 3	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).	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72)
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 4.5 Relative to Year 3	The percentage change in BMD as measured by DXA at 4.5 relative to Year 3. It was derived as 100 * (BMD at Year 4.5 - BMD at Year 3)/(BMD at Year 3).	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 4.5 (Month 54)
Percentage Change in BMD of Femoral Neck, Total Hip and Trochanter at Year 6 Relative to Year 3	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).	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6 (Month 72)
Percentage of Patients With New and New/Worsening Morphometric Vertebral Fractures	Lateral vertebral x-rays were performed at the final core study visit and at Year 6 and read by a central expert reader at a central imaging laboratory to assess for new or new/worsening morphometric vertebral fracture. The percentage of patients with new morphometric vertebral fractures (observed for the first time) and patients with either new or worsening morphometric vertebral fractures was calculated.	Year 3 (Extension Baseline; Month 36 prior to the first treatment of the extension study) and Year 6
Number of Participants With Incidence of Clinical Fracture	Clinical fracture excludes finger, toe, and facial bone fractures. Clinical vertebral fracture includes thoracic spine fracture and lumbar spine fracture. Non-vertebral fracture excludes clinical vertebral, finger, toe, and facial bone fractures.	Extension Baseline (Year 3; Month 36) to Year 6
Qualitative Bone Biopsy Parameters	Unpaired transiliac crest bone biopsy was performed for histomorphometry, which was obtained after double tetracycline labeling. No data were collected for Patients who received Placebo for the first 3 years of the study (Placebo 3 Zoledronic Acid 3).	End of Study Visit at Year 6
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 3 Infusion	Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after study drug infusion in Z6 patients compared to Z3P3 patients and in P3Z3 patients.	Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 3 infusion
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 4 Infusion	Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after Year 4 study drug infusion.	Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 4 infusion
Change in Serum Creatinine From Baseline to 9-11 Days Post Year 5 Infusion	Serum creatinine measurements performed by a central laboratory was used to evaluate acute changes in renal function 9-11 days after Year 5 study drug infusion.	Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to 9-11 days after the Year 5 infusion
The Number of Participants With Clinically Significant Laboratory Parameters	Evaluate the laboratory key profile such as Calcium, Creatinine and Urea. The number of patients with clinically significant calcium, creatinine and urea were reported.	Extension Baseline (Year 3; Month 36 prior to the first treatment of the extension study) to Year 6

Collaborators and Investigators

• Sponsor: Novartis

Publications and helpful links

General Publications

• Eastell R, Boonen S, Cosman F, Reid IR, Palermo L, Cummings SR, Black DM. Relationship between pretreatment rate of bone loss and bone density response to once-yearly ZOL: HORIZON-PFT extension study. J Bone Miner Res. 2015 Mar;30(3):570-4. doi: 10.1002/jbmr.2361.
• 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. doi: 10.1002/jbmr.1494. Erratum In: J Bone Miner Res. 2012 Dec;27(12):2612.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Actual): November 1, 2009
• Study Completion (Actual): November 1, 2009

Study Registration Dates

• First Submitted: September 1, 2005
• First Submitted That Met QC Criteria: September 1, 2005
• First Posted (Estimate): September 5, 2005

Study Record Updates

• Last Update Posted (Estimate): June 28, 2011
• Last Update Submitted That Met QC Criteria: June 24, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: Osteoporosis, Zoledronic Acid
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: CZOL446H2301E1