Paget's Disease of Bone
Conditions
Keywords
Zoledronic acid, risedronate, Paget's disease of bone
Brief summary
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.
Interventions
DRUGzoledronic acid
5 mg zoledronic acid in 5 mL of sterile water for infusion
5 mL of sterile water for infusion
DRUGRisedronate
30mg oral tablets overencapsulated to match the placebo capsules
oral capsules
DRUGCalcium and vitamin D supplements
Calcium and vitamin D supplements were supplied
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Had Therapeutic Response at 6 Months | Baseline, 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10 | Baseline and day 10 | The percent change in serum C-telopeptide from baseline to Day 10 was measured. |
| Relative Change in Urine α-CTx in ug/mmol at Day 10 | Baseline and day 10 | The percent change in urine α-CTx from baseline to Day 10 was measured. |
| Time to First Therapeutic Response | 182 days | 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. |
| Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28 | 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). |
| Relative Change in Serum Alkaline Phosphatase in U/L at Day 28 | Baseline and 28 days | The percent change in serum alkaline phosphatase from baseline to Day 28 was measured. |
| Change in Pain Interference at Day 182 | Baseline and 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. |
| Number of Participants With a Loss of Therapeutic Response During the Extended Observation Period | 8 years was the maximum | 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. |
| Number of Participants With a Partial Disease Relapse During the Extended Observation Period | 8 years was the maximum | 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. |
| Number of Participants With a Disease Relapse During the Extended Observation Period | 8 years was maximum | 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. |
| Change in Pain Severity at Day 182 | Baseline and 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. |
Countries
Australia, Belgium, Canada, France, Germany, New Zealand, South Africa, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
371 patients were screened. 185 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 92 |
| 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. | 93 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 - Core | Adverse Event | 1 | 0 |
| Period 1 - Core | Patient withdrew consent | 3 | 2 |
| Period 1 - Core | Protocol Violation | 3 | 2 |
| Period 2 - Extended Observation Period | Amendment 6 informed consent not signed | 30 | 9 |
| 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 | Lost to Follow-up | 7 | 6 |
| Period 2 - Extended Observation Period | Withdrew for nonclinical reason | 21 | 13 |
Baseline characteristics
| Characteristic | Zoledronic Acid and Placebo to Risedronate | Risedronate and Placebo to Zoledronic Acid | Total |
|---|---|---|---|
| Age Continuous | 71.3 years STANDARD_DEVIATION 9.42 | 68.2 years STANDARD_DEVIATION 11.15 | 69.8 years STANDARD_DEVIATION 10.41 |
| Sex: Female, Male Female | 30 Participants | 36 Participants | 66 Participants |
| Sex: Female, Male Male | 62 Participants | 57 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 40 / 88 | 28 / 90 |
| serious Total, serious adverse events | 4 / 88 | 3 / 90 |
Outcome results
Primary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Number of Patients Who Had Therapeutic Response at 6 Months | 84 participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Patients Who Had Therapeutic Response at 6 Months | 67 participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Change in Pain Interference at Day 182 | -0.5 units on a scale | Standard Deviation 1.97 |
| Risedronate and Placebo to Zoledronic Acid | Change in Pain Interference at Day 182 | 0.0 units on a scale | Standard Deviation 1.89 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Change in Pain Severity at Day 182 | -0.5 units on a scale | Standard Deviation 1.74 |
| Risedronate and Placebo to Zoledronic Acid | Change in Pain Severity at Day 182 | -0.1 units on a scale | Standard Deviation 2.02 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Number of Participants With a Disease Relapse During the Extended Observation Period | 0 participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Participants With a Disease Relapse During the Extended Observation Period | 15 participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Number of Participants With a Loss of Therapeutic Response During the Extended Observation Period | 10 participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Participants With a Loss of Therapeutic Response During the Extended Observation Period | 42 participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Number of Participants With a Partial Disease Relapse During the Extended Observation Period | 9 participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Participants With a Partial Disease Relapse During the Extended Observation Period | 37 participants |
Secondary
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).
Time frame: Day 28
Population: Intent-to-treat population: all randomized patients. Participants with observations at day 28 were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28 | 8 participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28 | 1 participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Relative Change in Serum Alkaline Phosphatase in U/L at Day 28 | -49.1 percent change | Standard Deviation 14.55 |
| Risedronate and Placebo to Zoledronic Acid | Relative Change in Serum Alkaline Phosphatase in U/L at Day 28 | -24.3 percent change | Standard Deviation 18.19 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10 | -74.2 percent change | Standard Deviation 123.73 |
| Risedronate and Placebo to Zoledronic Acid | Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10 | -40.1 percent change | Standard Deviation 34.7 |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Relative Change in Urine α-CTx in ug/mmol at Day 10 | -87.5 percent change | Standard Deviation 39.33 |
| Risedronate and Placebo to Zoledronic Acid | Relative Change in Urine α-CTx in ug/mmol at Day 10 | -28.7 percent change | Standard Deviation 68.22 |
Secondary
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.
Time frame: 182 days
Population: Intent-to-treat population: all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid and Placebo to Risedronate | Time to First Therapeutic Response | 64 days |
| Risedronate and Placebo to Zoledronic Acid | Time to First Therapeutic Response | 91 days |