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

Randomized, Double-Blind, Safety and Efficacy Trial With Intravenous Zoledronic Acid for the Treatment of Paget's Disease of Bone Using Risedronate as a Comparator, Including an Extended Observation Period

The primary objective of this core study was to show non-inferiority of zoledronic acid to risedronate, with respect to the proportion of patients who achieved therapeutic response. The extended observation period included participants of the core study who responded to treatment.

Study Overview

• Status: Completed
• Conditions: Paget's Disease of Bone
• Intervention / Treatment: Drug: zoledronic acid; Drug: Placebo to risedronate; Drug: Calcium and vitamin D supplements; Drug: placebo to zoledronic acid; Drug: Risedronate

• Study Type: Interventional
• Enrollment (Actual): 185
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Fitzroy, Australia
    • Novartis Investigative Site
  • Kogarah, Australia
    • Novartis Investigative Site
  • Newcastle, Australia
    • Novartis Investigative Site
  • Parkville, Australia
    • Novartis Investigative Site
  • St. Leonards, Australia
    • Novartis Investigative Site
• Belgium
  • Brussels, Belgium
    • Novartis Investigative Site
  • Gent, Belgium
    • Novartis Investigative Site
• Canada
  • Montreal, Canada
    • Novartis Investigative Site
• France
  • Angers, France
    • Novartis Investigative Site
  • Dreux Cedex, France
    • Novartis Investigative Site
  • Marseille, France
    • Novartis Investigative Site
  • Nice Cedex, France
    • Novartis Investigative Site
  • Paris Cedex, France
    • Novartis Investigative Site
  • Rouen Cedex, France
    • Novartis Investigative Site
  • Toulouse, France
    • Novartis Investigative Site
• Germany
  • Berlin, Germany
    • Novartis Investigative Site
  • Frankfurt, Germany
    • Novartis Investigative Site
  • Leipzig, Germany
    • Novartis Investigative Site
  • Leverkusen, Germany
    • Novartis Investigative Site
  • Wirzburg, Germany
    • Novartis Investigative Site
• New Zealand
  • Christchurch, New Zealand
    • Novartis Investigative Site
• South Africa
  • Cape Town, South Africa
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain
    • Novartis Investigative Site
  • Madrid, Spain
    • Novartis Investigative Site
  • Malaga, Spain
    • Novartis Investigative Site
  • Salamanca, Spain
    • Novartis Investigative Site
  • Santiago de Compostela, Spain
    • Novartis Investigative Site
  • Valencia, Spain
    • Novartis Investigative Site
• United Kingdom
  • Liverpool, United Kingdom
    • Novartis Investigative Site
  • London, United Kingdom
    • Novartis Investigative Site
  • Oxford, United Kingdom
    • Novartis Investigative Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85732
      • Novartis Investigative Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80901
      • Novartis Investigative Site
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Novartis Investigative Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Novartis Investigative Site
  • New York
    • Syracuse, New York, United States, 13210
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Novartis Investigative Site
  • South Carolina
    • Columbia, South Carolina, United States, 29209
      • Novartis Investigative Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53592
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 30 years or older
• SAP 2 times ULN
• Confirmed diagnosis of Paget's disease of the bone (by x-ray, magnetic resonance imaging, computerized tomography, radioisotope imaging, etc.).
• 90 days washout calcitonin
• 180 day washout bisphosphonate

Exclusion Criteria:

• Allergic reaction to bisphosphonates
• History of upper GI disorders
• History of iritis, uveitis
• Calculated creatinine clearance < 30 ml/min at baseline
• Evidence of vitamin D deficiency

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zoledronic acid and placebo to risedronate; Participants received zoledronic acid 5.0 mg i.v. infusion one dose, 60 days of oral placebo to risedronate, calcium 500mg bid and vitamin D 400 to 1000 IU daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Drug: zoledronic acid; 5 mg zoledronic acid in 5 mL of sterile water for infusion; Drug: Placebo to risedronate; oral capsules; Drug: Calcium and vitamin D supplements; Calcium and vitamin D supplements were supplied
Active Comparator: Risedronate and placebo to zoledronic acid; Participants received 60 days of oral risedronate 30 mg, one i.v. infusion of placebo to zoledronic acid infusion, calcium 500mg bid and vitamin d 400 to 1000 IU daily during the core period, and received only calcium and vitamin D supplements during the extended observation period.	Drug: Calcium and vitamin D supplements; Calcium and vitamin D supplements were supplied; Drug: placebo to zoledronic acid; 5 mL of sterile water for infusion; Drug: Risedronate; 30mg oral tablets overencapsulated to match the placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Had Therapeutic Response at 6 Months	A therapeutic response was defined as a reduction of at least 75% from baseline (Visit 1) in serum alkaline phosphatase (SAP) excess (difference between measured level and midpoint to the normal range) or normalization of SAP at the end of six months.	Baseline, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change in Serum Alkaline Phosphatase in U/L at Day 28	The percent change in serum alkaline phosphatase from baseline to Day 28 was measured.	Baseline and 28 days
Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10	The percent change in serum C-telopeptide from baseline to Day 10 was measured.	Baseline and day 10
Relative Change in Urine α-CTx in ug/mmol at Day 10	The percent change in urine α-CTx from baseline to Day 10 was measured.	Baseline and day 10
Time to First Therapeutic Response	Therapeutic response was defined as a reduction of at least 75% from baseline in serum alkaline phosphatase excess (difference between measured level and midpoint to the normal range) or normalization of serum alkaline phosphatase.	182 days
Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28	Normalization of serum alkaline phosphatase occurred if the serum alkaline phosphatase measurement fell within the normal range. Central laboratory reference ranges for serum alkaline phosphatase: 31-110 U/L (female & male 20-58 years) and 35-115 U/L (female & male >58 years).	Day 28
Change in Pain Severity at Day 182	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.	Baseline and day 182
Change in Pain Interference at Day 182	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.	Baseline and day 182
Number of Participants With a Loss of Therapeutic Response During the Extended Observation 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.	8 years was the maximum
Number of Participants With a Partial Disease Relapse During the Extended Observation 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.	8 years was the maximum
Number of Participants With a Disease Relapse During the Extended Observation 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.	8 years was maximum

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: April 1, 2002
• Primary Completion (Actual): December 1, 2003
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: February 14, 2005
• First Submitted That Met QC Criteria: February 14, 2005
• First Posted (Estimate): February 15, 2005

Study Record Updates

• Last Update Posted (Estimate): June 4, 2012
• Last Update Submitted That Met QC Criteria: May 29, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: Zoledronic acid, risedronate, Paget's disease of bone
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Bone Diseases; Osteitis Deformans; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Micronutrients; Membrane Transport Modulators; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Vitamin D; Calcium; Zoledronic Acid; Risedronic Acid; Etidronic Acid
• Other Study ID Numbers: CZOL446H2305; ZOL446K2305 (Other Identifier: Novartis Pharmaceuticals)