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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Paget's Disease of Bone

Intervention / Treatment
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* Drug: Zoledronic Acid
* Drug: Risedronate
* Drug: Placebo to Risedronate
* Drug: Placebo to Zoledronic Acid
* Dietary Supplement: Calcium and Vitamin D


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zoledronic Acid and Placebo to Risedronate<br>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<br>* Zoledronic acid 5 mg in 5 mL of sterile water intravenous infusion.<br>* Other names: Reclast, Aclasta;Drug: Placebo to Risedronate<br>* Oral placebo of risedronate capsules.<br>Dietary Supplement: Calcium and Vitamin D<br>* Calcium and vitamin D supplements were supplied.<br>|
| Active Comparator: Risedronate and Placebo to Zoledronic Acid<br>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. | Drug: Risedronate<br>* Oral risedronate 30 mg capsules.<br>* Other names: Actonel;Drug: Placebo to Zoledronic Acid<br>* 5 mL of sterile water one dose intravenous infusion.<br>Dietary Supplement: Calcium and Vitamin D<br>* Calcium and vitamin D supplements were supplied.<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bisphosphonate, SAP, SAP excess, non-inferiority, therapeutic response, extended observation period