Paget's Disease of Bone
Conditions
Keywords
Bisphosphonate, SAP, SAP excess, non-inferiority, therapeutic response, extended observation period
Brief summary
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.
Interventions
DRUGZoledronic Acid
Zoledronic acid 5 mg in 5 mL of sterile water intravenous infusion.
DRUGRisedronate
Oral risedronate 30 mg capsules.
Oral placebo of risedronate capsules.
5 mL of sterile water one dose intravenous infusion.
DIETARY_SUPPLEMENTCalcium and Vitamin D
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 * 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Achieve Therapeutic Response at 6 Months. | 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. |
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 Alpha C-telopeptide (α-CTx) in ug/mmol at Day 10 | Baseline and day 10 | The percent change in urine alpha C-telopeptide from baseline to day 10 was measured. |
| Time to First Therapeutic Response | 182 days | 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. |
| Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28 Relative to Baseline | Baseline and day 28 | Normalization of serum alkaline phosphatase occurred if the serum alkaline phosphatase measurement fell within the normal range. |
| Relative Change in Serum Alkaline Phosphatase (SAP) in Units Per Liter (U/L) at Day 28 | Baseline and day 28 | The percent change in serum alkaline phosphatase from baseline to day 28 was measured. |
| Change in Pain Interference Score | 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 the 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 Score | 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, Canada, New Zealand, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
172 participants entered period 1; of these, 127 were identified as treatment responders and entered the extended observation period 2. Responders defined as patient who had ≥75% decrease from baseline in serum alkaline phosphatase (SAP) excess (difference between measured level and midpoint of normal range) or SAP within normal range at 6 months.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 90 |
| 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. | 82 |
| Total | 172 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 - Core | Adverse Event | 2 | 2 |
| Period 1 - Core | Lost to Follow-up | 0 | 2 |
| Period 1 - Core | Protocol Violation | 1 | 0 |
| Period 1 - Core | Withdrawal by Subject | 1 | 2 |
| Period 2- Extended Observation Period | Amendment 6 Informed Consent Not Signed | 40 | 12 |
| Period 2- Extended Observation Period | Clinical reasons other than Paget's | 9 | 2 |
| Period 2- Extended Observation Period | Death | 4 | 5 |
| Period 2- Extended Observation Period | Lost to Follow-up | 5 | 4 |
| Period 2- Extended Observation Period | withdrew for nonclinical reason | 12 | 7 |
Baseline characteristics
| Characteristic | Zoledronic Acid and Placebo to Risedronate | Risedronate and Placebo to Zoledronic Acid | Total |
|---|---|---|---|
| Age Continuous | 70.4 years STANDARD_DEVIATION 10.25 | 72.1 years STANDARD_DEVIATION 9.91 | 71.2 years STANDARD_DEVIATION 10.1 |
| Sex: Female, Male Female | 28 Participants | 21 Participants | 49 Participants |
| Sex: Female, Male Male | 62 Participants | 61 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 71 / 89 | 58 / 82 |
| serious Total, serious adverse events | 5 / 89 | 8 / 82 |
Outcome results
Primary
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.
Time frame: 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 Achieve Therapeutic Response at 6 Months. | 85 participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Patients Who Achieve Therapeutic Response at 6 Months. | 60 participants |
Secondary
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.
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 Score | -0.2 Units on a scale | Standard Deviation 1.97 |
| Risedronate and Placebo to Zoledronic Acid | Change in Pain Interference Score | 0.1 Units on a scale | Standard Deviation 1.72 |
Secondary
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.
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 Score | -0.5 Units on a scale | Standard Deviation 1.77 |
| Risedronate and Placebo to Zoledronic Acid | Change in Pain Severity Score | -0.7 Units on a scale | Standard Deviation 2.22 |
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 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 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 | 7 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 | 8 Participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Participants With a Loss of Therapeutic Response During the Extended Observation Period | 29 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 | 6 Participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Participants With a Partial Disease Relapse During the Extended Observation Period | 26 Participants |
Secondary
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.
Time frame: Baseline and 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 Relative to Baseline | 5 Participants |
| Risedronate and Placebo to Zoledronic Acid | Number of Patients Who Achieved Serum Alkaline Phosphatase Normalization at Day 28 Relative to Baseline | 0 Participants |
Secondary
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.
Time frame: Baseline and day 28
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 (SAP) in Units Per Liter (U/L) at Day 28 | -48.8 percent change | Standard Deviation 11.51 |
| Risedronate and Placebo to Zoledronic Acid | Relative Change in Serum Alkaline Phosphatase (SAP) in Units Per Liter (U/L) at Day 28 | -28.4 percent change | Standard Deviation 17.72 |
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 | -85.4 percent change | Standard Deviation 18 |
| Risedronate and Placebo to Zoledronic Acid | Relative Change in Serum C-telopeptide (CTx) in ng/mL at Day 10 | -36.7 percent change | Standard Deviation 69.58 |
Secondary
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.
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 Alpha C-telopeptide (α-CTx) in ug/mmol at Day 10 | -90.3 Percent change | Standard Deviation 13.19 |
| Risedronate and Placebo to Zoledronic Acid | Relative Change in Urine Alpha C-telopeptide (α-CTx) in ug/mmol at Day 10 | -29.9 Percent change | Standard Deviation 37.52 |
Secondary
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.
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 | 78 Days |