Comparison of Ibandronate - Zoledronate Regarding Nephrotoxicity in Multiple Myeloma

Study Overview
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Brief Summary
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This multicenter, open-label trial will randomize participants with multiple myeloma to a regimen of ibandronate or zoledronate in order to compare the incidence of nephrotoxicity, measured as creatinine clearance (CrCl) reduction greater than (>) 30 percent (%) or an absolute value of 30 milliliters per minute (mL/min) or lower.

Official Title
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COMPARE: Comparison of Ibandronate - Zoledronate Regarding Nephrotoxicity in Patients With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Ibandronate
* Drug: Zoledronate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed multiple myeloma, Stage II-III as per Salmon and Durie (1975) Indication for biphosphonate therapy Exclusion Criteria: Previous therapy with ibandronate or zoledronate within the past 12 months Renal insufficiency with serum creatinine >3.0 mg/dL or >265 micromoles per liter (µmol/L) or CrCl <30 mL/min Hypersensitivity to ibandronate, zoledronate, or other biphosphonates Presence of secondary malignomas, apart from basaliomas and cervical carcinoma in situ Severe accompanying illness with organ impairment Osteonecrosis of the jaw at the start of the study Life expectancy ≤12 months

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibandronate<br>Participants with multiple myeloma will be randomized to receive ibandronate every 4 weeks for a planned duration of 92 weeks. | Drug: Ibandronate<br>* Ibandronate will be administered via 15-minute intravenous (IV) infusion as 6 milligrams (mg) every 4 weeks for 92 weeks.<br>* Other names: Bondronat;|
| Active Comparator: Zoledronate<br>Participants with multiple myeloma will be randomized to receive zoledronate every 4 weeks for a planned duration of 92 weeks. | Drug: Zoledronate<br>* Zoledronate will be administered via 15-minute IV infusion as 4 mg every 4 weeks for 92 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Deterioration in Renal Function According to Reduction in Creatinine Clearance (CrCl) From Baseline to Week 44 | CrCl was calculated from blood samples using the Cockcroft-Gault formula. Relevant deterioration in renal function was defined as CrCl reduction of 30 percent (%) from Baseline or an absolute value less than or equal to (≤) 30 milliliters per minute (mL/min) at Week 44. The last available value on/before Week 44 was used in the calculation. The percentage of participants with deterioration in renal function at Week 44 was reported. | Baseline, Week 44 | 
| Percentage of Participants With Deterioration in Renal Function According to Reduction in CrCl From Baseline to Week 92 | CrCl was calculated from blood samples using the Cockcroft-Gault formula. Relevant deterioration in renal function was defined as CrCl reduction of 30% from Baseline or an absolute value ≤30 mL/min at Week 92. The last available value on/before Week 92 was used in the calculation. The percentage of participants with deterioration in renal function at Week 92 was reported. | Baseline, Week 92 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Skeletal-Related Events (SREs) | SREs were defined according to the Bondronat Summary of Product Characteristics (SmPC) to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. The percentage of participants with at least 1 SRE during the study was reported. | From Baseline to end of study (up to Week 96) | 
| Time to First SRE | SREs were defined according to the Bondronat SmPC to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. Time to first SRE was defined as the time from first dose of study drug to the time of SRE during the study. The median time to first SRE was estimated by Kaplan-Meier analysis and expressed in days. | From Baseline to end of study (up to Week 96) | 
| Number of SREs for Each Participant | SREs were defined according to the Bondronat SmPC to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. The number of SREs was averaged across all participants, including those participants who did not experience SREs during the study. | From Baseline to end of study (up to Week 96) | 
| Percentage of Participants With Osteonecrosis of Jaw | The percentage of participants with at least 1 event of osteonecrosis of jaw during the study was reported. | From Baseline to end of study (up to Week 96) | 
| Number of Events of Osteonecrosis of Jaw for Each Participant | The number of events of osteonecrosis of jaw was averaged across all participants, including those participants who did not experience the event during the study. | From Baseline to end of study (up to Week 96) | 
| Percentage of Participants With Zoledronate Dose Reduction | The percentage of participants with at least 1 zoledronate dose reduction during the study was reported. | From Baseline to end of study (up to Week 96) | 
| Number of Zoledronate Dose Reductions for Each Participant | The number of zoledronate dose reductions was averaged across all participants, including those participants who did not have any dose reductions during the study. | From Baseline to end of study (up to Week 96) | 
| Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG) | The percent change in B-NAG was calculated as [Week 44 or 92 B-NAG minus Baseline B-NAG] divided by Baseline B-NAG, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation. | Baseline and Weeks 44, 92 | 
| Percent Change From Baseline in Alpha (A) 1-Microglobulin | The percent change in A1-microglobulin was calculated as [Week 44 or 92 A1-microglobulin minus Baseline A1-microglobulin] divided by Baseline A1-microglobulin, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation. | Baseline and Weeks 44, 92 | 
| Percent Change From Baseline in Gamma-Glutamyltransferase (GGT) | The percent change in GGT was calculated as [Week 44 or 92 GGT minus Baseline GGT] divided by Baseline GGT, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation. | Baseline and Weeks 44, 92 | 
| Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline | Elevation in SCr was defined as an increase greater than (>) 0.5 milligrams per deciliter (mg/dL) for participants with Baseline SCr less than (<) 1.4 mg/dL, or an increase >1.0 mg/dL for participants with Baseline SCr greater than or equal to (≥) 1.4 mg/dL. For the Week 44 analysis, the last available value on/before Week 44 was used. For the Week 92 analysis, the last available value on/before Week 92 was used. The percentage of participants with elevation of SCr at Weeks 44 and 92 was reported. | Baseline and Weeks 44, 92 | 
| Percent Change From Baseline in CrCl | CrCl was calculated from blood samples using the Cockcroft-Gault formula, and was also measured by urinalysis. The percent change in CrCl was calculated as [Week 44 or 92 CrCl minus Baseline CrCl] divided by Baseline CrCl, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation. | Baseline and Weeks 44, 92 |