A Multiple Myeloma Trial in Patients With Bone Metastases - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Multiple Myeloma
Intervention:	Drug: zoledronic acid

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
15 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.
30 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.

Participant Flow: Overall Study

	15 - Minute Infusion	30 - Minute Infusion
STARTED	90 ^[1]	89 ^[2]
Safety Population (Including Site 74)	88	88
Safety Population (Excluding Site 74)	85 ^[3]	84 ^[4]
COMPLETED	15	17
NOT COMPLETED	75	72
Adverse Event	8	8
Abnormal laboratory value(s)	20	14
Lack of Efficacy	0	3
Condition no longer requires study drug	7	4
Protocol Violation	5	2
Withdrawal by Subject	11	15
Lost to Follow-up	3	7
Administrative problems	12	13
Death	9	6

[1]	2 Participants in the 15-minute infusion group did not receive study drug.
[2]	1 Participants in the 30-minute infusion group did not receive study drug.
[3]	Because of GCP violations at Site 74, post-baseline data for 3 patients in this arm were excluded.
[4]	Because of GCP violations at Site 74, post-baseline data for 4 patients in this arm were excluded.

Baseline Characteristics

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Reporting Groups

	Description
15 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.
30 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.
Total	Total of all reporting groups

Baseline Measures

	15 - Minute Infusion	30 - Minute Infusion	Total
Number of Participants [units: participants]	88	88	176
Age ^[1] [units: participants]
<=18 years	0	0	0
Between 18 and 65 years	39	47	86
>=65 years	49	41	90
Age [units: years] Mean ± Standard Deviation	64.3 ± 11.95	64.0 ± 11.54	64.1 ± 11.7
Gender [units: participants]
Female	32	39	71
Male	56	49	105
Race/Ethnicity, Customized [units: participants]
Caucasian	70	69	139
Black	9	13	22
Asian	1	1	2
Other	8	5	13
Region of Enrollment [units: participants]
United States	88	88	176
Time since diagnosis ^[2] [units: months] Mean ± Standard Deviation	12.5 ± 24.3	9.7 ± 14.1	11.1 ± 19.8
Calculated creatinine clearance [units: mL/min] Mean ± Standard Deviation	87.3 ± 32.6	89.3 ± 39.5	88.3 ± 36.1

[1]	Demographic data is provided for the entire Safety Population.
[2]	This baseline measurement was based on n=86, 87.

Outcome Measures

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1. Primary:

The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months [ Time Frame: Baseline and 12 Months ]

Measure Type	Primary
Measure Title	The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months
Measure Description	The primary renal safety endpoint was the number of participants with a clinically relevant increase in serum creatinine at 12 months. Serum creatinine was determined prior to each zoledronic acid infusion for all Participants and was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value.
Time Frame	Baseline and 12 Months
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population: enrolled patients who received at least one dose of study medication, exluding site 74.

Reporting Groups

	Description
15 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.
30 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.

Measured Values

	15 - Minute Infusion	30 - Minute Infusion
Number of Participants Analyzed [units: participants]	85	84
The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months [units: Participants]	17	13

No statistical analysis provided for The Number of Participants With a Significant Increase in Serum Creatinine at 12 Months

2. Primary:

The Number of Participants With Disease Progression [ Time Frame: 24 Months ]

Measure Type	Primary
Measure Title	The Number of Participants With Disease Progression
Measure Description	No text entered.
Time Frame	24 Months
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population; enrolled patients who received at least one dose of study medication.

Reporting Groups

	Description
15 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.
30 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.

Measured Values

	15 - Minute Infusion	30 - Minute Infusion
Number of Participants Analyzed [units: participants]	85	84
The Number of Participants With Disease Progression [units: Participants]	28	20

No statistical analysis provided for The Number of Participants With Disease Progression

3. Secondary:

The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months [ Time Frame: Baseline and 24 Months ]

Measure Type	Secondary
Measure Title	The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months
Measure Description	Serum Creatinine was considered to be significantly increased if there was an increase of 0.5 mg/dL or more or a doubling of the baseline serum creatinine value.
Time Frame	Baseline and 24 Months
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population; enrolled patients who received at least one dose of study medication.

Reporting Groups

	Description
15 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.
30 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.

Measured Values

	15 - Minute Infusion	30 - Minute Infusion
Number of Participants Analyzed [units: participants]	85	84
The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months [units: Participants]	24	23

No statistical analysis provided for The Number of Participants With a Significant Increase in Serum Creatinine at 24 Months

4. Secondary:

Time to First Significant Increase in Serum Creatinine [ Time Frame: Up to 24 months ]

Measure Type	Secondary
Measure Title	Time to First Significant Increase in Serum Creatinine
Measure Description	Median time to event in participants who had a clinically relevant increase in serum creatinine.
Time Frame	Up to 24 months
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population; enrolled patients who received at least one dose of study medication. The medians shown are only for patients who had a significant increase by 24 months.

Reporting Groups

	Description
15 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.
30 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.

Measured Values

	15 - Minute Infusion	30 - Minute Infusion
Number of Participants Analyzed [units: participants]	24	23
Time to First Significant Increase in Serum Creatinine [units: weeks] Median ( Full Range )	21.6 ( 4.1 to 65.0 )	24.4 ( 2.6 to 93.9 )

No statistical analysis provided for Time to First Significant Increase in Serum Creatinine

5. Secondary:

Zoledronic Acid Concentrations [ Time Frame: 24 months ]

Measure Type	Secondary
Measure Title	Zoledronic Acid Concentrations
Measure Description	Samples for drug concentration analysis were drawn at 10 and 15 minutes into the infusion for participants in the 15-minute infusion group and at 25 and 30 minutes into the infusion for patients in the 30-minute infusion group. The mean and median zoledronic acid concentrations were greater in the 15-minute group than in the 30-minute group at both sampling timepoints.
Time Frame	24 months
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacokinetic (PK) population was analyzed for zoledronic acid concentration. Participants were considered to be in the PK population if they had evaluable PK data.

Reporting Groups

	Description
15 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 15-minute infusion time, but increasing to a 30-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12 weeks.
30 - Minute Infusion	Participants received 4 mg zoledronic acid intravenously, in 250 mL of fluid, every 3–4 weeks for up to 24 months, over a 30-minute infusion time, but increasing to a 45-minute infusion time if they experienced a clinically relevant rise in serum creatinine that resolved in less than 12-weeks.

Measured Values

	15 - Minute Infusion	30 - Minute Infusion
Number of Participants Analyzed [units: participants]	70	63
Zoledronic Acid Concentrations [units: ng/mL] Mean ± Standard Deviation
First Collection (10 minutes, 25 minutes)	231.1 ± 185.4	186.3 ± 54.4
Second Collection (15 minutes, 30 minutes)	248.8 ± 92.0	172.0 ± 48.3

No statistical analysis provided for Zoledronic Acid Concentrations

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial; or disclosure of the trial results in their entirety.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Study Director
Organization: Novatis Pharmaceuticals
phone: 862-778-8300

No publications provided

Responsible Party:	External Affairs, Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT00104104 History of Changes
Other Study ID Numbers:	CZOL446EUS97, US97
Study First Received:	February 22, 2005
Results First Received:	January 6, 2011
Last Updated:	June 27, 2011
Health Authority:	United States: Institutional Review Board