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 Observational Period

The core study looked at the effect of Zoledronic Acid given once as an intravenous (i.v.) infusion compared to 60 days of oral Risedronate in patients with Paget's disease of bone. The effect was demonstrated in the reduction of serum alkaline phosphatase (SAP). 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; Dietary supplement: Calcium and Vitamin D; Drug: Risedronate; Drug: Placebo to Zoledronic Acid

• Study Type: Interventional
• Enrollment (Actual): 172
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Concord, Australia
    • Novartis Investigative Site
  • Fitzroy, Australia
    • Novartis Investigative Site
  • Geelong, Australia
    • Novartis Investigative Site
  • Kogarah, Australia
    • Novartis Investigative Site
  • Maroochydore, Australia
    • Novartis Investigative Site
  • Nedlands, Australia
    • Novartis Investigative Site
• Canada
  • Calgary, Canada
    • Novartis Investigative Site
  • London, Canada
    • Novartis Investigative Site
  • Montreal, Canada
    • Novartis Investigative Site
  • Ste-Foy, Canada
    • Novartis Investigative Site
  • Toronto, Canada
    • Novartis Investigative Site
• New Zealand
  • Auckland, New Zealand
    • Novartis Investigative Site
  • Christchurch, New Zealand
    • Novartis Investigative Site
• Spain
  • Salamanca, Spain
    • Novartis Investigative Site
• United Kingdom
  • Liverpool, United Kingdom
    • Novartis Investigative Site
  • Manchester, United Kingdom
    • Novartis Investigative Site
  • Nottingham, United Kingdom
    • Novartis Investigative Site
  • Oxford, United Kingdom
    • Novartis Investigative Site
  • Penarth, United Kingdom
    • Novartis Investigative Site
  • Pernarth, United Kingdom
    • Novartis Investigative Site
  • Stanmore, United Kingdom
    • Novartis Investigative Site
  • Vale of Glamorgan, United Kingdom
    • Novartis Investigative Site
• United States
  • California
    • Santa Monica, California, United States, 90414
      • Novartis Investigative Site
  • Colorado
    • Lakewood, Colorado, United States, 80227
      • Novartis Investigative Site
  • Florida
    • Boca Raton, Florida, United States, 33433
      • Novartis Investigative Site
    • Miami, Florida, United States, 33101
      • Novartis Investigative Site
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Novartis Investigative Site
  • Massachusetts
    • Worcester, Massachusetts, United States, 01601
      • Novartis Investigative Site
  • Michigan
    • Detroit, Michigan, United States, 48021
      • Novartis Investigative Site
  • New York
    • New York, New York, United States, 10029
      • Novartis Investigative Site
    • Syracuse, New York, United States, 13210
      • Novartis Investigative Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Novartis Investigative Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Novartis Investigative Site
  • Rhode Island
    • Providence, Rhode Island, United States, 02908
      • 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
• Serum alkaline phosphatase (SAP) 2 times upper limit normal (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 gastrointestinal disorders
• History of iritis, uveitis
• Calculated creatinine clearance < 30 ml/min at baseline
• Evidence of vitamin D deficiency

Other protocol-defined inclusion/exclusion criteria applied.

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 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.	Drug: Zoledronic Acid; Zoledronic acid 5 mg in 5 mL of sterile water intravenous infusion.; Other Names: Reclast, Aclasta; Drug: Placebo to Risedronate; Oral placebo of risedronate capsules.; Dietary supplement: Calcium and Vitamin D; 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 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.	Dietary supplement: Calcium and Vitamin D; Calcium and vitamin D supplements were supplied.; Drug: Risedronate; Oral risedronate 30 mg capsules.; Other Names: Actonel; Drug: Placebo to Zoledronic Acid; 5 mL of sterile water one dose intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Achieve Therapeutic Response at 6 Months.	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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Relative Change in Serum Alkaline Phosphatase (SAP) in Units Per Liter (U/L) at Day 28	The percent change in serum alkaline phosphatase from baseline to day 28 was measured.	Baseline and day 28
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 Alpha C-telopeptide (α-CTx) in ug/mmol at Day 10	The percent change in urine alpha C-telopeptide from baseline to day 10 was measured.	Baseline and day 10
Time to First Therapeutic Response	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.	182 days
Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28 Relative to Baseline	Normalization of serum alkaline phosphatase occurred if the serum alkaline phosphatase measurement fell within the normal range.	Baseline and day 28
Change in Pain Severity Score	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 Score	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 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 the maximum

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: January 1, 2001
• Primary Completion (Actual): March 1, 2004
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: January 14, 2003
• First Submitted That Met QC Criteria: January 14, 2003
• First Posted (Estimate): January 15, 2003

Study Record Updates

• Last Update Posted (Estimate): May 15, 2012
• Last Update Submitted That Met QC Criteria: May 9, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: Bisphosphonate; non-inferiority; SAP; therapeutic response; SAP excess; extended observation period
• 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: CZOL446H2304; ZOL446K2304 (Other Identifier: Novartis Pharmaceuticals)