Trial Outcomes & Findings for Safety and Efficacy Trial With Zoledronic Acid for the Treatment of Paget's Disease of Bone, Including an Extended Observation Period (NCT NCT00103740)

NCT ID: NCT00103740

Last Updated: 2012-06-04

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 185 participants
• Primary outcome timeframe: Baseline, 6 months
• Results posted on: 2012-06-04

Participant Flow

371 patients were screened. 185 patients were randomized.

Participant milestones

Measure	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.	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.
Period 1 - Core STARTED	92	93
Period 1 - Core COMPLETED	85	89
Period 1 - Core NOT COMPLETED	7	4
Period 2 - Extended Observation Period STARTED	78	63
Period 2 - Extended Observation Period COMPLETED	9	27
Period 2 - Extended Observation Period NOT COMPLETED	69	36

Reasons for withdrawal

Measure	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.	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.
Period 1 - Core Adverse Event	1	0
Period 1 - Core Protocol Violation	3	2
Period 1 - Core Patient withdrew consent	3	2
Period 2 - Extended Observation Period Lost to Follow-up	7	6
Period 2 - Extended Observation Period Withdrew for nonclinical reason	21	13
Period 2 - Extended Observation Period Clinical reason other than Paget's	5	6
Period 2 - Extended Observation Period Death	6	2
Period 2 - Extended Observation Period Amendment 6 informed consent not signed	30	9

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Zoledronic Acid and Placebo to Risedronate n=92 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=93 Participants 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 n=185 Participants Total of all reporting groups
Age Continuous	71.3 years STANDARD_DEVIATION 9.42 • n=5 Participants	68.2 years STANDARD_DEVIATION 11.15 • n=7 Participants	69.8 years STANDARD_DEVIATION 10.41 • n=5 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	36 Participants n=7 Participants	66 Participants n=5 Participants
Sex: Female, Male Male	62 Participants n=5 Participants	57 Participants n=7 Participants	119 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 6 months

Population: 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.

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.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=88 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=89 Participants 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.
Number of Patients Who Had Therapeutic Response at 6 Months	84 participants	67 participants

SECONDARY outcome

Timeframe: Baseline and 28 days

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and 28 days were included in this analysis.

The percent change in serum alkaline phosphatase from baseline to Day 28 was measured.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=79 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=85 Participants 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.
Relative Change in Serum Alkaline Phosphatase in U/L at Day 28	-49.1 percent change Standard Deviation 14.55	-24.3 percent change Standard Deviation 18.19

SECONDARY outcome

Timeframe: Baseline and day 10

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 10 were included in this analysis.

The percent change in serum C-telopeptide from baseline to Day 10 was measured.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=60 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=70 Participants 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.
Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10	-74.2 percent change Standard Deviation 123.73	-40.1 percent change Standard Deviation 34.70

SECONDARY outcome

Timeframe: Baseline and day 10

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 10 were included in this analysis.

The percent change in urine α-CTx from baseline to Day 10 was measured.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=67 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=70 Participants 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.
Relative Change in Urine α-CTx in ug/mmol at Day 10	-87.5 percent change Standard Deviation 39.33	-28.7 percent change Standard Deviation 68.22

SECONDARY outcome

Timeframe: 182 days

Population: Intent-to-treat population: all randomized patients.

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.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=92 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=93 Participants 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.
Time to First Therapeutic Response	64 days Interval 33.0 to 65.0	91 days Interval 64.0 to 181.0

SECONDARY outcome

Timeframe: Day 28

Population: Intent-to-treat population: all randomized patients. Participants with observations at day 28 were included in this analysis.

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).

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=88 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=88 Participants 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.
Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28	8 participants	1 participants

SECONDARY outcome

Timeframe: Baseline and day 182

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 182 were included in this analysis.

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.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=50 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=46 Participants 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.
Change in Pain Severity at Day 182	-0.5 units on a scale Standard Deviation 1.74	-0.1 units on a scale Standard Deviation 2.02

SECONDARY outcome

Timeframe: Baseline and day 182

Population: Intent-to-treat population: all randomized patients. Participants with observations at baseline and day 182 were included in this analysis.

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.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=49 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=45 Participants 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.
Change in Pain Interference at Day 182	-0.5 units on a scale Standard Deviation 1.97	0.0 units on a scale Standard Deviation 1.89

SECONDARY outcome

Timeframe: 8 years was the maximum

Population: Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension 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.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=78 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=63 Participants 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.
Number of Participants With a Loss of Therapeutic Response During the Extended Observation Period	10 participants Interval 2218.0 to	42 participants Interval 344.0 to 1605.0

SECONDARY outcome

Timeframe: 8 years was the maximum

Population: Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension 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.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=78 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=63 Participants 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.
Number of Participants With a Partial Disease Relapse During the Extended Observation Period	9 participants Interval 2218.0 to	37 participants Interval 373.0 to 1652.0

SECONDARY outcome

Timeframe: 8 years was maximum

Population: Extended modified Intent-to-treat population: patients who had at least one serum alkaline phosphatase measurement during the extension 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.

Outcome measures

Measure	Zoledronic Acid and Placebo to Risedronate n=78 Participants 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.	Risedronate and Placebo to Zoledronic Acid n=63 Participants 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.
Number of Participants With a Disease Relapse During the Extended Observation Period	0 participants	15 participants Interval 1084.0 to

Adverse Events

Zoledronic Acid

Serious events: 4 serious events

Other events: 40 other events

Deaths: 0 deaths

Risedronate

Serious events: 3 serious events

Other events: 28 other events

Deaths: 0 deaths

Serious adverse events

Measure	Zoledronic Acid n=88 participants at risk 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.	Risedronate n=90 participants at risk 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.
General disorders Chest pain	0.00% 0/88 The safety population consisted of all randomized patients who were exposed to study drug.	1.1% 1/90 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Enterobacter sepsis	1.1% 1/88 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/90 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Escherichia infection	1.1% 1/88 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/90 The safety population consisted of all randomized patients who were exposed to study drug.
Injury, poisoning and procedural complications Femur fracture	1.1% 1/88 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/90 The safety population consisted of all randomized patients who were exposed to study drug.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/88 The safety population consisted of all randomized patients who were exposed to study drug.	1.1% 1/90 The safety population consisted of all randomized patients who were exposed to study drug.
Injury, poisoning and procedural complications Spinal fracture	1.1% 1/88 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/90 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Back pain	1.1% 1/88 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/90 The safety population consisted of all randomized patients who were exposed to study drug.
Nervous system disorders Cerebrovascular accident	1.1% 1/88 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/90 The safety population consisted of all randomized patients who were exposed to study drug.
Reproductive system and breast disorders Endometrial hyperplasia	0.00% 0/88 The safety population consisted of all randomized patients who were exposed to study drug.	1.1% 1/90 The safety population consisted of all randomized patients who were exposed to study drug.
Respiratory, thoracic and mediastinal disorders Asthma	1.1% 1/88 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/90 The safety population consisted of all randomized patients who were exposed to study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.1% 1/88 The safety population consisted of all randomized patients who were exposed to study drug.	0.00% 0/90 The safety population consisted of all randomized patients who were exposed to study drug.

Other adverse events

Measure	Zoledronic Acid n=88 participants at risk 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.	Risedronate n=90 participants at risk 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.
Gastrointestinal disorders Constipation	5.7% 5/88 The safety population consisted of all randomized patients who were exposed to study drug.	2.2% 2/90 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Diarrhoea	6.8% 6/88 The safety population consisted of all randomized patients who were exposed to study drug.	7.8% 7/90 The safety population consisted of all randomized patients who were exposed to study drug.
Gastrointestinal disorders Nausea	6.8% 6/88 The safety population consisted of all randomized patients who were exposed to study drug.	3.3% 3/90 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Fatigue	6.8% 6/88 The safety population consisted of all randomized patients who were exposed to study drug.	2.2% 2/90 The safety population consisted of all randomized patients who were exposed to study drug.
General disorders Influenza like illness	14.8% 13/88 The safety population consisted of all randomized patients who were exposed to study drug.	6.7% 6/90 The safety population consisted of all randomized patients who were exposed to study drug.
Infections and infestations Influenza	5.7% 5/88 The safety population consisted of all randomized patients who were exposed to study drug.	2.2% 2/90 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Arthralgia	5.7% 5/88 The safety population consisted of all randomized patients who were exposed to study drug.	4.4% 4/90 The safety population consisted of all randomized patients who were exposed to study drug.
Musculoskeletal and connective tissue disorders Bone pain	6.8% 6/88 The safety population consisted of all randomized patients who were exposed to study drug.	2.2% 2/90 The safety population consisted of all randomized patients who were exposed to study drug.
Nervous system disorders Dizziness	5.7% 5/88 The safety population consisted of all randomized patients who were exposed to study drug.	4.4% 4/90 The safety population consisted of all randomized patients who were exposed to study drug.
Nervous system disorders Headache	10.2% 9/88 The safety population consisted of all randomized patients who were exposed to study drug.	6.7% 6/90 The safety population consisted of all randomized patients who were exposed to study drug.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER