COMPARE: Comparison of Ibandronate - Zoledronate Regarding Nephrotoxicity in Multiple Myeloma

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02739594
• Collaborator: Roche Pharma AG (Industry)
• Enrollment: 89
• Locations: 56
• Arms: 2
• Duration (Months): 37.9
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Ibandronate; Drug: Zoledronate	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: COMPARE: Comparison of Ibandronate - Zoledronate Regarding Nephrotoxicity in Patients With Multiple Myeloma
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Deterioration in Renal Function According to Reduction in Creatinine Clearance (CrCl) From Baseline to Week 44 [Baseline, 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.

2. Percentage of Participants With Deterioration in Renal Function According to Reduction in CrCl From Baseline to Week 92 [Baseline, 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.

Secondary Outcome Measures

1. Percentage of Participants With Skeletal-Related Events (SREs) [From Baseline to end of study (up to Week 96)]

   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.

2. Time to First SRE [From Baseline to end of study (up to Week 96)]

   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.

3. Number of SREs for Each Participant [From Baseline to end of study (up to Week 96)]

   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.

4. Percentage of Participants With Osteonecrosis of Jaw [From Baseline to end of study (up to Week 96)]

   The percentage of participants with at least 1 event of osteonecrosis of jaw during the study was reported.

5. Number of Events of Osteonecrosis of Jaw for Each Participant [From Baseline to end of study (up to Week 96)]

   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.

6. Percentage of Participants With Zoledronate Dose Reduction [From Baseline to end of study (up to Week 96)]

   The percentage of participants with at least 1 zoledronate dose reduction during the study was reported.

7. Number of Zoledronate Dose Reductions for Each Participant [From Baseline to end of study (up to Week 96)]

   The number of zoledronate dose reductions was averaged across all participants, including those participants who did not have any dose reductions during the study.

8. Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG) [Baseline and Weeks 44, 92]

   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.

9. Percent Change From Baseline in Alpha (A) 1-Microglobulin [Baseline and Weeks 44, 92]

   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.

10. Percent Change From Baseline in Gamma-Glutamyltransferase (GGT) [Baseline and Weeks 44, 92]

    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.

11. Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline [Baseline and Weeks 44, 92]

    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.

12. Percent Change From Baseline in CrCl [Baseline and Weeks 44, 92]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Ansbach		Germany	91522
2		Aschaffenburg		Germany	63739
3		Augsburg		Germany	86150
4		Berlin		Germany	10437
5		Berlin		Germany	10707
6		Berlin		Germany	12627
7		Bremen		Germany	28239
8		Duisburg		Germany	47051
9		Duisburg		Germany	47166
10		Erlangen		Germany	91054
11		Essen		Germany	45136
12		Esslingen		Germany	73730
13		Frankfurt Am Main		Germany	60389
14		Frankfurt Am Main		Germany	65929
15		Greifswald		Germany	17475
16		Göttingen		Germany	37075
17		Güstrow		Germany	18273
18		Gütersloh		Germany	33332
19		Halle		Germany	06110
20		Hamburg		Germany	22081
21		Hamburg		Germany	22457
22		Hamm		Germany	59063
23		Hannover		Germany	30171
24		Hannover		Germany	30625
25		Herne		Germany	44625
26		Hof		Germany	95028
27		Jena		Germany	07743
28		Karlsruhe		Germany	76137
29		Kassel		Germany	34117
30		Kassel		Germany	34125
31		Koblenz		Germany	56068
32		Krefeld		Germany	47798
33		Köln		Germany	50677
34		Köln		Germany	50924
35		Leer		Germany	26789
36		Leipzig		Germany	04289
37		Ludwigshafen		Germany	67063
38		Lübeck		Germany	23562
39		Magedburg		Germany	39104
40		Minden		Germany	32427
41		Moers		Germany	47441
42		Muenster		Germany	48149
43		Mülheim		Germany	45468
44		München		Germany	80336
45		Neumünster		Germany	24534
46		Offenbach		Germany	63069
47		Offenburg		Germany	77652
48		Oldenburg		Germany	26121
49		Oldenburg		Germany	26133
50		Stuttgart		Germany	70174
51		Stuttgart		Germany	70199
52		Tübingen		Germany	72076
53		Weiden		Germany	92637
54		Wiesbaden		Germany	65191
55		Würzburg		Germany	97080
56		Zwickau		Germany	08058

Sponsors and Collaborators

• Hoffmann-La Roche
• Roche Pharma AG

Investigators

• Study Chair: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02739594
• Other Study ID Numbers: ML18508; 2005-003264-38
• First Posted: Apr 15, 2016
• Last Update Posted: Jul 22, 2016
• Last Verified: Jun 1, 2016

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Ibandronic Acid; Zoledronic Acid

Study Results

Participant Flow

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute intravenous (IV) infusion as 6 milligrams (mg) every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Period Title: Overall Study
STARTED	46	43
Completed at Week 44	11	5
Completed at Week 96	10	10
COMPLETED	21	15
NOT COMPLETED	25	28

Baseline Characteristics

Arm/Group Title	Ibandronate	Zoledronate	Total
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Total of all reporting groups
Overall Participants	41	40	81
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (9.4)	69.1 (9.1)	67.2 (9.4)
Sex: Female, Male (Count of Participants)
Female	15 36.6%	14 35%	29 35.8%
Male	26 63.4%	26 65%	52 64.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Deterioration in Renal Function According to Reduction in Creatinine Clearance (CrCl) From Baseline to Week 44
Description	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.
Time Frame	Baseline, Week 44

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Number (95% Confidence Interval) [percentage of participants]	9.8 23.9%	12.5 31.3%

2. Primary Outcome

Title	Percentage of Participants With Deterioration in Renal Function According to Reduction in CrCl From Baseline to Week 92
Description	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.
Time Frame	Baseline, Week 92

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Number (95% Confidence Interval) [percentage of participants]	14.6 35.6%	12.5 31.3%

3. Secondary Outcome

Title	Percentage of Participants With Skeletal-Related Events (SREs)
Description	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.
Time Frame	From Baseline to end of study (up to Week 96)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Number (95% Confidence Interval) [percentage of participants]	22.0 53.7%	30.0 75%

4. Secondary Outcome

Title	Time to First SRE
Description	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.
Time Frame	From Baseline to end of study (up to Week 96)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Median (Full Range) [days]	393.0	244.5

5. Secondary Outcome

Title	Number of SREs for Each Participant
Description	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.
Time Frame	From Baseline to end of study (up to Week 96)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Mean (Standard Deviation) [SREs]	0.3 (0.6)	0.5 (1.1)

6. Secondary Outcome

Title	Percentage of Participants With Osteonecrosis of Jaw
Description	The percentage of participants with at least 1 event of osteonecrosis of jaw during the study was reported.
Time Frame	From Baseline to end of study (up to Week 96)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Number (95% Confidence Interval) [percentage of participants]	0.0 0%	0.0 0%

7. Secondary Outcome

Title	Number of Events of Osteonecrosis of Jaw for Each Participant
Description	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.
Time Frame	From Baseline to end of study (up to Week 96)

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Mean (Standard Deviation) [events of osteonecrosis of jaw]	0.0 (0.0)	0.0 (0.0)

8. Secondary Outcome

Title	Percentage of Participants With Zoledronate Dose Reduction
Description	The percentage of participants with at least 1 zoledronate dose reduction during the study was reported.
Time Frame	From Baseline to end of study (up to Week 96)

Outcome Measure Data

Analysis Population Description

ITT Population; only the Zoledronate arm was included.

Arm/Group Title	Zoledronate
Arm/Group Description	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	30.0 73.2%

9. Secondary Outcome

Title	Number of Zoledronate Dose Reductions for Each Participant
Description	The number of zoledronate dose reductions was averaged across all participants, including those participants who did not have any dose reductions during the study.
Time Frame	From Baseline to end of study (up to Week 96)

Outcome Measure Data

Analysis Population Description

ITT Population; only the Zoledronate arm was included.

Arm/Group Title	Zoledronate
Arm/Group Description	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	40
Mean (Standard Deviation) [dose reductions]	0.8 (1.4)

10. Secondary Outcome

Title	Percent Change From Baseline in N-Acetyl-Beta-D-Glucosaminidase (B-NAG)
Description	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.
Time Frame	Baseline and Weeks 44, 92

Outcome Measure Data

Analysis Population Description

ITT Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for the endpoint.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	38	37
Week 44	-15.7	10.6
Week 92	-17.2	9.3

11. Secondary Outcome

Title	Percent Change From Baseline in Alpha (A) 1-Microglobulin
Description	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.
Time Frame	Baseline and Weeks 44, 92

Outcome Measure Data

Analysis Population Description

ITT Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for the endpoint.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	38	37
Week 44	0.0	0.0
Week 92	0.0	0.0

12. Secondary Outcome

Title	Percent Change From Baseline in Gamma-Glutamyltransferase (GGT)
Description	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.
Time Frame	Baseline and Weeks 44, 92

Outcome Measure Data

Analysis Population Description

ITT Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for the endpoint.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	38	37
Week 44	-6.0	3.8
Week 92	-2.5	3.8

13. Secondary Outcome

Title	Percentage of Participants With Elevation of Serum Creatinine (SCr) From Baseline
Description	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.
Time Frame	Baseline and Weeks 44, 92

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Week 44	2.4 5.9%	2.5 6.3%
Week 92	7.3 17.8%	2.5 6.3%

14. Secondary Outcome

Title	Percent Change From Baseline in CrCl
Description	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.
Time Frame	Baseline and Weeks 44, 92

Outcome Measure Data

Analysis Population Description

ITT Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for the endpoint. The number of participants who provided data within the specified timeframe for each analysis (n) is shown in the table.

Arm/Group Title	Ibandronate	Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.	Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
Measure Participants	41	40
Week 44, Calculated/Blood (n=41,40)	-0.5 (28.5)	-0.4 (21.7)
Week 44, Measured/Urinalysis (n=37,37)	6.9 (53.0)	3.9 (37.3)
Week 92, Calculated/Blood (n=41,40)	-0.7 (31.9)	-4.3 (20.3)
Week 92, Measured/Urinalysis (n=37,37)	3.1 (45.6)	2.0 (39.1)

Adverse Events

Time Frame	From Baseline to end of study (up to Week 96)
Adverse Event Reporting Description	Safety Population: All participants who received at least one dose of study medication and completed at least one follow-up assessment visit.
Arm/Group Title	Ibandronate		Zoledronate
Arm/Group Description	Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.		Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.
All Cause Mortality
	Ibandronate		Zoledronate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ibandronate		Zoledronate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/46 (58.7%)		18/43 (41.9%)
Blood and lymphatic system disorders
Anaemia	0/46 (0%)		1/43 (2.3%)
Febrile neutropenia	1/46 (2.2%)		0/43 (0%)
Normochromic normocytic anaemia	0/46 (0%)		1/43 (2.3%)
Pancytopenia	1/46 (2.2%)		0/43 (0%)
Thrombocytopenia	1/46 (2.2%)		0/43 (0%)
Cardiac disorders
Arrhythmia	1/46 (2.2%)		0/43 (0%)
Atrial fibrillation	1/46 (2.2%)		0/43 (0%)
Cardiac failure	1/46 (2.2%)		1/43 (2.3%)
Myocardial infarction	0/46 (0%)		1/43 (2.3%)
Gastrointestinal disorders
Diarrhoea	2/46 (4.3%)		0/43 (0%)
Diverticulum	1/46 (2.2%)		0/43 (0%)
Enteritis	0/46 (0%)		1/43 (2.3%)
Gastrointestinal haemorrhage	1/46 (2.2%)		0/43 (0%)
Vomiting	1/46 (2.2%)		0/43 (0%)
General disorders
Asthenia	1/46 (2.2%)		0/43 (0%)
General physical health deterioration	2/46 (4.3%)		0/43 (0%)
Pyrexia	2/46 (4.3%)		0/43 (0%)
Infections and infestations
Abscess oral	0/46 (0%)		1/43 (2.3%)
Bronchitis	1/46 (2.2%)		0/43 (0%)
Bronchopneumonia	1/46 (2.2%)		0/43 (0%)
Gastroenteritis	1/46 (2.2%)		0/43 (0%)
Herpes zoster	1/46 (2.2%)		0/43 (0%)
Implant site infection	1/46 (2.2%)		1/43 (2.3%)
Infection	3/46 (6.5%)		0/43 (0%)
Pneumocystis jiroveci pneumonia	0/46 (0%)		1/43 (2.3%)
Pneumonia	4/46 (8.7%)		1/43 (2.3%)
Septic shock	2/46 (4.3%)		1/43 (2.3%)
Urosepsis	1/46 (2.2%)		0/43 (0%)
Injury, poisoning and procedural complications
Fracture	0/46 (0%)		1/43 (2.3%)
Humerus fracture	0/46 (0%)		1/43 (2.3%)
Lumbar vertebral fracture	1/46 (2.2%)		0/43 (0%)
Post procedural swelling	1/46 (2.2%)		0/43 (0%)
Investigations
Blood creatinine increased	3/46 (6.5%)		1/43 (2.3%)
Creatinine renal clearance decreased	2/46 (4.3%)		4/43 (9.3%)
Metabolism and nutrition disorders
Decreased appetite	1/46 (2.2%)		0/43 (0%)
Diabetes mellitus	1/46 (2.2%)		0/43 (0%)
Hyperglycaemia	1/46 (2.2%)		1/43 (2.3%)
Hypokalaemia	1/46 (2.2%)		0/43 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/46 (2.2%)		0/43 (0%)
Bone pain	2/46 (4.3%)		0/43 (0%)
Intervertebral disc compression	0/46 (0%)		1/43 (2.3%)
Musculoskeletal chest pain	1/46 (2.2%)		0/43 (0%)
Pathological fracture	1/46 (2.2%)		0/43 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Multiple myeloma	4/46 (8.7%)		0/43 (0%)
Neoplasm progression	1/46 (2.2%)		0/43 (0%)
Plasmacytoma	1/46 (2.2%)		0/43 (0%)
Nervous system disorders
Dizziness	1/46 (2.2%)		0/43 (0%)
Paraplegia	0/46 (0%)		1/43 (2.3%)
Syncope	1/46 (2.2%)		1/43 (2.3%)
Renal and urinary disorders
Nephropathy toxic	0/46 (0%)		1/43 (2.3%)
Renal failure	1/46 (2.2%)		0/43 (0%)
Renal failure acute	1/46 (2.2%)		0/43 (0%)
Renal failure chronic	1/46 (2.2%)		0/43 (0%)
Renal impairment	0/46 (0%)		1/43 (2.3%)
Urinary retention	0/46 (0%)		1/43 (2.3%)
Respiratory, thoracic and mediastinal disorders
Bronchial haemorrhage	1/46 (2.2%)		0/43 (0%)
Dyspnoea	0/46 (0%)		1/43 (2.3%)
Pleural effusion	1/46 (2.2%)		0/43 (0%)
Pulmonary embolism	1/46 (2.2%)		0/43 (0%)
Skin and subcutaneous tissue disorders
Skin haemorrhage	0/46 (0%)		1/43 (2.3%)
Vascular disorders
Circulatory collapse	1/46 (2.2%)		0/43 (0%)
Other (Not Including Serious) Adverse Events
	Ibandronate		Zoledronate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/46 (93.5%)		34/43 (79.1%)
Blood and lymphatic system disorders
Anaemia	11/46 (23.9%)		11/43 (25.6%)
Leukopenia	10/46 (21.7%)		7/43 (16.3%)
Thrombocytopenia	6/46 (13%)		3/43 (7%)
Ear and labyrinth disorders
Vertigo	3/46 (6.5%)		2/43 (4.7%)
Gastrointestinal disorders
Diarrhoea	10/46 (21.7%)		8/43 (18.6%)
Nausea	6/46 (13%)		9/43 (20.9%)
Constipation	4/46 (8.7%)		4/43 (9.3%)
Vomiting	4/46 (8.7%)		1/43 (2.3%)
Dry mouth	1/46 (2.2%)		3/43 (7%)
General disorders
Oedema peripheral	7/46 (15.2%)		10/43 (23.3%)
Fatigue	7/46 (15.2%)		7/43 (16.3%)
Pyrexia	6/46 (13%)		7/43 (16.3%)
Pain	4/46 (8.7%)		4/43 (9.3%)
Chills	1/46 (2.2%)		3/43 (7%)
Chest pain	0/46 (0%)		3/43 (7%)
General physical health deterioration	3/46 (6.5%)		0/43 (0%)
Infections and infestations
Nasopharyngitis	19/46 (41.3%)		10/43 (23.3%)
Bronchitis	8/46 (17.4%)		3/43 (7%)
Candidiasis	4/46 (8.7%)		5/43 (11.6%)
Herpes zoster	2/46 (4.3%)		7/43 (16.3%)
Influenza	4/46 (8.7%)		2/43 (4.7%)
Pneumonia	3/46 (6.5%)		0/43 (0%)
Urinary tract infection	3/46 (6.5%)		0/43 (0%)
Metabolism and nutrition disorders
Decreased appetite	3/46 (6.5%)		3/43 (7%)
Hypocalcaemia	3/46 (6.5%)		0/43 (0%)
Hypokalaemia	3/46 (6.5%)		0/43 (0%)
Musculoskeletal and connective tissue disorders
Back pain	13/46 (28.3%)		9/43 (20.9%)
Pain in extremity	11/46 (23.9%)		5/43 (11.6%)
Bone pain	7/46 (15.2%)		5/43 (11.6%)
Arthralgia	2/46 (4.3%)		4/43 (9.3%)
Muscle spasms	3/46 (6.5%)		2/43 (4.7%)
Musculoskeletal chest pain	2/46 (4.3%)		3/43 (7%)
Musculoskeletal pain	1/46 (2.2%)		3/43 (7%)
Osteoarthritis	1/46 (2.2%)		3/43 (7%)
Pathological fracture	3/46 (6.5%)		1/43 (2.3%)
Pain in jaw	3/46 (6.5%)		0/43 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasmacytoma	3/46 (6.5%)		2/43 (4.7%)
Nervous system disorders
Polyneuropathy	3/46 (6.5%)		6/43 (14%)
Paraesthesia	5/46 (10.9%)		3/43 (7%)
Headache	5/46 (10.9%)		2/43 (4.7%)
Dizziness	3/46 (6.5%)		3/43 (7%)
Dysgeusia	3/46 (6.5%)		0/43 (0%)
Psychiatric disorders
Sleep disorder	2/46 (4.3%)		3/43 (7%)
Insomnia	3/46 (6.5%)		0/43 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	5/46 (10.9%)		4/43 (9.3%)
Cough	3/46 (6.5%)		3/43 (7%)
Dyspnoea exertional	4/46 (8.7%)		0/43 (0%)
Epistaxis	3/46 (6.5%)		0/43 (0%)
Skin and subcutaneous tissue disorders
Rash	4/46 (8.7%)		5/43 (11.6%)
Erythema	0/46 (0%)		4/43 (9.3%)

Limitations/Caveats

The Study was terminated as a result of slow recruitment. At the time of the decision to halt recruitment, the treatment duration was shortened to 40 weeks (instead of 92 weeks) for those participants who had not yet reached Week 48.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.