Trial Outcomes & Findings for Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants (NCT NCT00622505)

Last Updated: 2021-05-26

Results Overview

SRE was defined as pathological bone fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or hypercalcemia of malignancy (HCM). SRE was assessed by centrally read radiographic bone surveys.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

121 participants

Primary outcome timeframe

1 year

Results posted on

2021-05-26

Participant Flow

This study was conducted at 67 centers in the United States (US) from 07 November 2007 to 03 April 2012.

A total of 121 participants with Advanced Multiple Myeloma were enrolled in this study. By study design, any participants who had a Skeletal-related Event (SRE) in Zoledronic Acid Every 12 Weeks group was switched to Zoledronic Acid Every 4 Weeks or 12 Weeks group and reported as Zoledronic Acid Every 4 Weeks or 12 Weeks group, respectively.

Participant milestones

Participant milestones
Measure	Zoledronic Acid Every 12 Weeks Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Overall Study STARTED	79	42
Overall Study COMPLETED	50	19
Overall Study NOT COMPLETED	29	23

Reasons for withdrawal

Reasons for withdrawal
Measure	Zoledronic Acid Every 12 Weeks Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Overall Study Adverse Event	9	7
Overall Study Abnormal Laboratory Value(s)	3	5
Overall Study Abnormal Test Procedure Result(s)	1	0
Overall Study Withdrawal by Subject	12	5
Overall Study Administrative Problems	2	4
Overall Study Death	2	2

Baseline Characteristics

Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).	Total n=121 Participants Total of all reporting groups
Age, Continuous	62.8 years STANDARD_DEVIATION 9.91 • n=5 Participants	65.8 years STANDARD_DEVIATION 12.66 • n=7 Participants	63.8 years STANDARD_DEVIATION 10.99 • n=5 Participants
Sex: Female, Male Female	36 Participants n=5 Participants	21 Participants n=7 Participants	57 Participants n=5 Participants
Sex: Female, Male Male	43 Participants n=5 Participants	21 Participants n=7 Participants	64 Participants n=5 Participants

PRIMARY outcome

Timeframe: 1 year

Population: ITT analysis set included all participants who were enrolled in this study.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Percentage of Participants With ≥1 SRE at the End of 1 Year on Study	0 percentage of participants Upper and lower limits of 95% CI were not estimable due to the smaller number of participants with the event.	0.17 percentage of participants Interval 0.05 to 0.28

SECONDARY outcome

Timeframe: Up to 2 years

Population: ITT analysis set included all participants who were enrolled in this study.

The time to first SRE is defined as the date of enrollment to the date of the first occurrence of any SRE on the study. SRE includes pathological fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or HCM. Participants who drop-out was treated as censored observations. Time to first SRE on the study was assessed by the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Time to First SRE on Study	NA years The median and 95 % CI was not estimable because there were too few events (low incidence of observed SREs) to calculate the median and 95 % CI.	NA years The median and 95 % CI was not estimable because there were too few events (low incidence of observed SREs) to calculate the median and 95 % CI.

SECONDARY outcome

Timeframe: Years 1 and 2

Population: ITT analysis set included all participants who were enrolled in the study. Number analyzed signifies the number of participants with data available for analysis at given time point.

Pathologic bone fractures are defined as bone fractures that occur spontaneously or as a result of trivial trauma.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Percentage of Participants Who Experienced Pathologic Bone Fracture Year 2	0.00 percentage of participants Upper and lower limits of 95% CI were not estimable due to smaller number of participants with the event.	0.03 percentage of participants Interval 0.0 to 0.08
Percentage of Participants Who Experienced Pathologic Bone Fracture Year 1	0.00 percentage of participants Upper and lower limits of 95% CI were not estimable due to smaller number of participants with the event.	0.07 percentage of participants Interval 0.0 to 0.15

SECONDARY outcome

Timeframe: Years 1 and 2

Population: ITT analysis set included all participants who were enrolled in the study. Number analyzed signifies the number of participants with data available for analysis at given time point.

Spinal cord compression is caused by the impingement of a tumor on the spinal cord and is associated with neurologic impairment and/or back pain.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Percentage of Participants Who Experienced Spinal Cord Compression Year 1	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.	0.07 percentage of participants Interval 0.0 to 0.15
Percentage of Participants Who Experienced Spinal Cord Compression Year 2	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.

SECONDARY outcome

Timeframe: Years 1 and 2

Population: ITT analysis set included all participants who were enrolled in the study. Number analyzed signifies the number of participants with data available for analysis at given time point.

Radiation therapy to bone events includes irradiation of bone to palliate painful lesions, to treat or prevent pathologic fractures, or to treat or prevent spinal cord compression.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Percentage of Participants Who Experienced Radiation to Bone Year 1	0.00 percentage of participants Upper and lower limits of 95% CI were not estimable due to smaller number of participants with the event.	0.10 percentage of participants Interval 0.01 to 0.18
Percentage of Participants Who Experienced Radiation to Bone Year 2	0.00 percentage of participants Upper and lower limits of 95% CI were not estimable due to smaller number of participants with the event.	0.11 percentage of participants Interval 0.01 to 0.2

SECONDARY outcome

Timeframe: Years 1 and 2

Population: ITT analysis set includes all participants who were enrolled in this study. Number analyzed signifies the number of participants with data available for analysis at given time point.

Surgery to bone events includes surgical procedures that are performed to set or stabilize pathologic fractures or areas of spinal cord compression and surgical procedures that are performed to prevent an imminent pathologic fracture or spinal cord compression.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Percentage of Participants Who Experienced Surgery to Bone Year 1	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.	0.02 percentage of participants Interval 0.0 to 0.07
Percentage of Participants Who Experienced Surgery to Bone Year 2	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.

SECONDARY outcome

Timeframe: Years 1 and 2

Population: ITT analysis set includes all participants who were enrolled in this study. Number analyzed signifies the number of participants with data available for analysis at given time point.

HCM is defined as corrected serum calcium ≥ 12.0 milligrams per deciliter (mg/dL) (3.00 millimoles per liter \[mmol/L\]), or a lower level of hypercalcemia that was symptomatic and required active treatment other than rehydration.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Percentage of Participants Who Experienced HCM Year 1	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.	0.02 percentage of participants Interval 0.0 to 0.07
Percentage of Participants Who Experienced HCM Year 2	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.	0.00 percentage of participants Upper and lower limits of 95% CI was not estimable due to smaller number of participants with the event.

SECONDARY outcome

Timeframe: Years 1 and 2

Population: ITT analysis set includes all participants who were enrolled in this study. Number analyzed signifies the number of participants with data available for analysis at given time point.

The SRE rate for each participant was calculated as the number of SREs/total follow-up time. SRE included pathological bone fracture, initiation of radiotherapy or surgery on bone, spinal cord compression, or HCM.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Skeletal Related Event (SRE) Rate Year 1	0.00 number of SRE/total follow-up time Standard Deviation 0.00	0.03 number of SRE/total follow-up time Standard Deviation 0.080
Skeletal Related Event (SRE) Rate Year 2	0.00 number of SRE/total follow-up time Standard Deviation 0.00	0.02 number of SRE/total follow-up time Standard Deviation 0.049

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 24, 36, 48, 60, 72, 84 and 100/End of Study (EOS)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of zoledronic acid. Number analyzed signifies the number of participants with data available for analysis at given time point.

uNTx is a biomarker used to measure the rate of bone turnover found in urine.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Change from Baseline to Week 60	-2.5 nmol/mmol creatinine Standard Deviation 12.30	-0.8 nmol/mmol creatinine Standard Deviation 17.54
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Baseline	19.8 nmol/mmol creatinine Standard Deviation 8.82	24.1 nmol/mmol creatinine Standard Deviation 15.63
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Change from Baseline to Week 12	0.2 nmol/mmol creatinine Standard Deviation 11.50	4.3 nmol/mmol creatinine Standard Deviation 19.47
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Change from Baseline to Week 24	-1.4 nmol/mmol creatinine Standard Deviation 8.72	-0.5 nmol/mmol creatinine Standard Deviation 15.66
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Change from Baseline to Week 36	-2.0 nmol/mmol creatinine Standard Deviation 9.77	-0.9 nmol/mmol creatinine Standard Deviation 13.92
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Change from Baseline to Week 48	-2.3 nmol/mmol creatinine Standard Deviation 9.24	1.7 nmol/mmol creatinine Standard Deviation 18.39
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Change from Baseline to Week 72	-3.5 nmol/mmol creatinine Standard Deviation 10.99	-6.7 nmol/mmol creatinine Standard Deviation 15.50
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Change from Baseline to Week 84	-3.0 nmol/mmol creatinine Standard Deviation 10.73	-7.6 nmol/mmol creatinine Standard Deviation 18.51
Change From Baseline in Urinary N-telopeptide of Type 1 Collagen (uNTx) Change from Baseline to Week 100	-5.2 nmol/mmol creatinine Standard Deviation 9.25	-7.4 nmol/mmol creatinine Standard Deviation 17.68

SECONDARY outcome

Timeframe: Up to 2 years

Population: ITT analysis set included all participants who were enrolled in this study.

Time to death was defined as the time from the date of enrollment to the date of death. Participants who dropped out or completed the study were considered censored observations. Time to death was assessed by Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Zoledronic Acid Every 12 Weeks n=79 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement ( \<50 nmol/mmol creatinine).	Zoledronic Acid Every 4 Weeks or 12 Weeks n=42 Participants Participants received 4 mg or a reduced dose, i.e., 3.5 mg, or 3.3 mg or 3.0 mg of Zoledronic acid as an IV infusion over a minimum of 15 minutes every 4 weeks or every 12 weeks for up to 96 weeks based on the participants most recent urine NTx measurement (≥ 50 nmol/mmol creatinine or \<50 nmol/mmol creatinine, respectively).
Time to Death	NA years The median and 95% CI was not estimable because there were too few events (low incidence of observed deaths) to calculate the median and 95% CI.	NA years The median and 95% CI was not estimable because there were too few events (low incidence of observed deaths) to calculate the median and 95% CI.

Adverse Events

Zoledronic Acid Every 12 Weeks

Serious events: 23 serious events

Other events: 70 other events

Deaths: 2 deaths

Zoledronic Acid Every 4 Weeks or 12 Weeks

Serious events: 25 serious events

Other events: 41 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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 (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER