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

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ClinicalTrials.gov Identifier: NCT00103740
Recruitment Status : Completed
First Posted : February 15, 2005
Results First Posted : May 2, 2012
Last Update Posted : June 4, 2012
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Paget's Disease of Bone
Interventions Drug: zoledronic acid
Drug: placebo to zoledronic acid
Drug: Risedronate
Drug: Placebo to risedronate
Drug: Calcium and vitamin D supplements
Enrollment 185
Recruitment Details  
Pre-assignment Details 371 patients were screened. 185 patients were randomized.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description 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. 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.
Period Title: Period 1 - Core
Started 92 93
Completed 85 89
Not Completed 7 4
Reason Not Completed
Adverse Event             1             0
Protocol Violation             3             2
Patient withdrew consent             3             2
Period Title: Period 2 - Extended Observation Period
Started 78 63
Completed 9 [1] 27 [1]
Not Completed 69 36
Reason Not Completed
Lost to Follow-up             7             6
Withdrew for nonclinical reason             21             13
Clinical reason other than Paget's             5             6
Death             6             2
Amendment 6 informed consent not signed             30             9
[1]
Includes patients retreated for Paget's disease and patients discontinued when sponsor ended study
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 92 93 185
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 92 participants 93 participants 185 participants
71.3  (9.42) 68.2  (11.15) 69.8  (10.41)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 92 participants 93 participants 185 participants
Female
30
  32.6%
36
  38.7%
66
  35.7%
Male
62
  67.4%
57
  61.3%
119
  64.3%
1.Primary Outcome
Title Number of Patients Who Had Therapeutic Response at 6 Months
Hide Description 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.
Time Frame Baseline, 6 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified intent to treat population: all randomized patients with both baseline and at least one post-baseline serum alkaline phosphatase measurement. Missing values at 6 months were imputed using the last post-baseline measurement prior to 6 months.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 88 89
Measure Type: Number
Unit of Measure: participants
84 67
2.Secondary Outcome
Title Relative Change in Serum Alkaline Phosphatase in U/L at Day 28
Hide Description The percent change in serum alkaline phosphatase from baseline to Day 28 was measured.
Time Frame Baseline and 28 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized patients. Participants with observations at baseline and 28 days were included in this analysis.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 79 85
Mean (Standard Deviation)
Unit of Measure: percent change
-49.1  (14.55) -24.3  (18.19)
3.Secondary Outcome
Title Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10
Hide Description The percent change in serum C-telopeptide from baseline to Day 10 was measured.
Time Frame Baseline and day 10
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 10 were included in this analysis.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 60 70
Mean (Standard Deviation)
Unit of Measure: percent change
-74.2  (123.73) -40.1  (34.70)
4.Secondary Outcome
Title Relative Change in Urine α-CTx in ug/mmol at Day 10
Hide Description The percent change in urine α-CTx from baseline to Day 10 was measured.
Time Frame Baseline and day 10
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 10 were included in this analysis.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 67 70
Mean (Standard Deviation)
Unit of Measure: percent change
-87.5  (39.33) -28.7  (68.22)
5.Secondary Outcome
Title Time to First Therapeutic Response
Hide Description 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.
Time Frame 182 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized patients.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 92 93
Median (Inter-Quartile Range)
Unit of Measure: days
64
(33 to 65)
91
(64 to 181)
6.Secondary Outcome
Title Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28
Hide Description 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).
Time Frame Day 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized patients. Participants with observations at day 28 were included in this analysis.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 88 88
Measure Type: Number
Unit of Measure: participants
8 1
7.Secondary Outcome
Title Change in Pain Severity at Day 182
Hide Description 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.
Time Frame Baseline and day 182
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 182 were included in this analysis.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 50 46
Mean (Standard Deviation)
Unit of Measure: units on a scale
-0.5  (1.74) -0.1  (2.02)
8.Secondary Outcome
Title Change in Pain Interference at Day 182
Hide Description 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.
Time Frame Baseline and day 182
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 182 were included in this analysis.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 49 45
Mean (Standard Deviation)
Unit of Measure: units on a scale
-0.5  (1.97) 0.0  (1.89)
9.Secondary Outcome
Title Number of Participants With a Loss of Therapeutic Response During the Extended Observation Period
Hide Description 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.
Time Frame 8 years was the maximum
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension period.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 78 63
Measure Type: Number
Unit of Measure: participants
10 42
10.Secondary Outcome
Title Number of Participants With a Partial Disease Relapse During the Extended Observation Period
Hide Description 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.
Time Frame 8 years was the maximum
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension period.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 78 63
Measure Type: Number
Unit of Measure: participants
9 37
11.Secondary Outcome
Title Number of Participants With a Disease Relapse During the Extended Observation Period
Hide Description 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.
Time Frame 8 years was maximum
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension period.
Arm/Group Title Zoledronic Acid and Placebo to Risedronate Risedronate and Placebo to Zoledronic Acid
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 78 63
Measure Type: Number
Unit of Measure: participants
0 15
Time Frame [Not Specified]
Adverse Event Reporting Description The safety population consisted of all randomized patients who were exposed to study drug.
 
Arm/Group Title Zoledronic Acid Risedronate
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Zoledronic Acid Risedronate
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Zoledronic Acid Risedronate
Affected / at Risk (%) Affected / at Risk (%)
Total   4/88 (4.55%)   3/90 (3.33%) 
General disorders     
Chest pain  1  0/88 (0.00%)  1/90 (1.11%) 
Infections and infestations     
Enterobacter sepsis  1  1/88 (1.14%)  0/90 (0.00%) 
Escherichia infection  1  1/88 (1.14%)  0/90 (0.00%) 
Injury, poisoning and procedural complications     
Femur fracture  1  1/88 (1.14%)  0/90 (0.00%) 
Humerus fracture  1  0/88 (0.00%)  1/90 (1.11%) 
Spinal fracture  1  1/88 (1.14%)  0/90 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  1/88 (1.14%)  0/90 (0.00%) 
Nervous system disorders     
Cerebrovascular accident  1  1/88 (1.14%)  0/90 (0.00%) 
Reproductive system and breast disorders     
Endometrial hyperplasia  1  0/88 (0.00%)  1/90 (1.11%) 
Respiratory, thoracic and mediastinal disorders     
Asthma  1  1/88 (1.14%)  0/90 (0.00%) 
Dyspnoea  1  1/88 (1.14%)  0/90 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Zoledronic Acid Risedronate
Affected / at Risk (%) Affected / at Risk (%)
Total   40/88 (45.45%)   28/90 (31.11%) 
Gastrointestinal disorders     
Constipation  1  5/88 (5.68%)  2/90 (2.22%) 
Diarrhoea  1  6/88 (6.82%)  7/90 (7.78%) 
Nausea  1  6/88 (6.82%)  3/90 (3.33%) 
General disorders     
Fatigue  1  6/88 (6.82%)  2/90 (2.22%) 
Influenza like illness  1  13/88 (14.77%)  6/90 (6.67%) 
Infections and infestations     
Influenza  1  5/88 (5.68%)  2/90 (2.22%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  5/88 (5.68%)  4/90 (4.44%) 
Bone pain  1  6/88 (6.82%)  2/90 (2.22%) 
Nervous system disorders     
Dizziness  1  5/88 (5.68%)  4/90 (4.44%) 
Headache  1  9/88 (10.23%)  6/90 (6.67%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
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 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.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00103740     History of Changes
Obsolete Identifiers: NCT00051649
Other Study ID Numbers: CZOL446H2305
ZOL446K2305 ( Other Identifier: Novartis Pharmaceuticals )
First Submitted: February 14, 2005
First Posted: February 15, 2005
Results First Submitted: April 5, 2012
Results First Posted: May 2, 2012
Last Update Posted: June 4, 2012