Breast Cancer
Conditions
Keywords
Breast cancer, zoledronic acid, bone metastases
Brief summary
Clinical trial in breast cancer patients with bone metastases pretreated for approximately 1 year with a standard zoledronic acid regimen. Looking at the continued effectiveness and safety of giving zoledronic acid every 4 weeks versus every 12 weeks given over 1 year. This study is prospective, double-blind, stratified, multi-center, and two-arm.
Interventions
DRUGZoledronic acid
4mg IV
DRUGPlacebo
Placebo to zoledronic acid
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Female patients ≥ 18 years of age. Confirmed breast cancer with bone metastasis. Pretreated with Zometa®, or Aredia (pamidronate) or all sequential regimens of both, for a minimum of 9 doses;
Exclusion criteria
Abnormal kidney function determined by serum creatinine levels. Current active dental problems including: ongoing infection of the teeth or jawbone; current exposed bone in the mouth; and current or prior diagnosis of osteonecrosis of the jaw. Recent (within 8 weeks) or planned dental or jaw surgery (e.g., extraction, implants). Diagnosis of metabolic bone disease other than osteoporosis (e.g., Paget's disease of bone). Known hypersensitivity to Zometa. Treatment with other investigational drugs within 30 days prior to randomization. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Experienced at Least One Skeletal Related Event (SRE) | 52 weeks | An SRE was defined as a pathologic fracture (vertebral and non-vertebral), spinal cord compression, radiation to bone or surgery to bone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Individual Type of SRE | 52 weeks | Types of SREs analyzed were pathologic fractures (vertebral and non-vertebral), spinal cord compression, radiation to bone and surgery to bone. The time to first indvidual SRE was defined as the date of randomization to the date of the first occurrence of any individual SRE. |
| Change From Baseline in Mean Composite Brief Pain Inventory (BPI) Score | baseline, 52 weeks | Participants completed a BPI short form which is a 9 item self-administered questionnaire used to evaluate the severity of a participant's pain and the impact of this pain on the participant's daily functioning. The participant rates his or her worst, least, average, and current pain intensity, lists current treatments and perceived effectiveness, and rates the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a 10 point scale. The BPI composite score, which was calculated as the average of items 3, 4, 5 and 6 (worst pain, least pain, average pain and pain right now), ranged from 0 (best possible outcome, no pain) to 10 (worst possible outcome, pain as bad as you can imagine). A positive change from baseline indicates worsening. |
| Change From Baseline in Mean Analgesic Score | baseline, 52 weeks | The analgesic score indicates the types of pain medication used. The scores range as follows: 0 = none medication; 1 = minor analgesics (aspirin, NSAID, acetaminophen, propoxyphene, etc.); 2 = Tranquilizers, antidepressants, muscle relaxants, and steroids; 3 = Mild narcotics (oxycodone, meperidine, codeine, etc.); and 4 = Strong narcotics (morphine, hydromorphone, etc.). A positive change from baseline indicates worsening. |
| Time to First SRE | 52 weeks | An SRE was defined as a pathologic bone fracture (vertebral and non-vertebral), spinal cord compression, radiation to bone, or surgery to bone. The time to first individual SRE was defined as the date of randomization to the date of first occurrence of any SRE. |
| Change From Baseline in Serum Bone Specific Alkaline Phosphatase | baseline, 48 weeks | Serum samples were collected to obtain bone specific alkaline phosphatase values. |
| Skeletal Morbidity Rate | 52 weeks | An SMR for a patient was defined as the number of occurrences of any (or a particular) SRE allowing for only 1 event in any 3-week interval, divided by the time at risk in years. The number of occurrences and the time at risk were counts of SRE and the time from the randomization date. Counting began from randomization in the way that every counted event was followed by a 20-day period during which no SRE was counted, nor was the time counted as at risk. For example, if a patient had 1 SRE during the study, the time at risk was calculated as the total number of days in the study minus the 20-day follow-up period for that SRE. If a patient had no SRE events, the entire study period was counted as time at risk. This SMR calculation method had the advantage of avoiding multiple counts of possibly interdependent SREs (e.g. having 1 fracture increases the probability of having a subsequent SRE). |
| Change From Baseline in Urinary N-telopeptide / Creatinine Ratio | baseline, 48 weeks | Urine samples were collected to obtain n-telopeptide and creatinine values. |
Countries
United States
Participant flow
Recruitment details
The initial study design contained 3 arms: zoledronic acid q4 weeks, zoledronic acid q12 weeks and placebo q4 weeks. Due to a study amendment, the placebo arm was discontinued and participants in this treatment group were switched to the zoledronic acid q4 week group. These participants were not included in the efficacy analysis.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Every (q) 4 Weeks Participants received 4mg of zoledronic acid intravenously (IV) infusion q 4 weeks. | 200 |
| Zoledronic Acid q 12 Weeks Participants received 4 mg zoledronic acid IV q 12 weeks and received placebo to Zometa IV at the 4 week intervals between the q 12 week zoledronic acid infusions in order to maintain the blind. | 203 |
| Placebo / Zoledronic Acid Participants randomized to this arm received placebo but the arm was later dropped and participants in this arm were later switched to the zoledronic acid q 4 weeks according to a study amendment. | 13 |
| Total | 416 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 12 | 3 | 0 |
| Overall Study | Abnormal test procedure result(s) | 2 | 0 | 0 |
| Overall Study | Administrative problems | 1 | 2 | 0 |
| Overall Study | Adverse Event | 18 | 14 | 1 |
| Overall Study | Death | 10 | 7 | 1 |
| Overall Study | Disease progression | 24 | 19 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 6 | 5 | 0 |
| Overall Study | Withdrawal by Subject | 20 | 26 | 1 |
Baseline characteristics
| Characteristic | Zoledronic Acid Every (q) 4 Weeks | Zoledronic Acid q 12 Weeks | Placebo / Zoledronic Acid | Total |
|---|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 11.1 | 58.6 years STANDARD_DEVIATION 11.15 | 60.8 years STANDARD_DEVIATION 12.19 | 58.9 years STANDARD_DEVIATION 11.14 |
| Sex/Gender, Customized | 200 participants | 203 participants | 13 participants | 416 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 182 / 198 | 185 / 202 | 12 / 13 |
| serious Total, serious adverse events | 50 / 198 | 51 / 202 | 3 / 13 |
Outcome results
Primary
Proportion of Patients Who Experienced at Least One Skeletal Related Event (SRE)
An SRE was defined as a pathologic fracture (vertebral and non-vertebral), spinal cord compression, radiation to bone or surgery to bone.
Time frame: 52 weeks
Population: The population included participants who were in the zoledronic acid q4 weeks and zoledronic acid q12 weeks treatment groups.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid Every (q) 4 Weeks | Proportion of Patients Who Experienced at Least One Skeletal Related Event (SRE) | 22 Percentage of participants |
| Zoledronic Acid q 12 Weeks | Proportion of Patients Who Experienced at Least One Skeletal Related Event (SRE) | 23.2 Percentage of participants |
Secondary
Change From Baseline in Mean Analgesic Score
The analgesic score indicates the types of pain medication used. The scores range as follows: 0 = none medication; 1 = minor analgesics (aspirin, NSAID, acetaminophen, propoxyphene, etc.); 2 = Tranquilizers, antidepressants, muscle relaxants, and steroids; 3 = Mild narcotics (oxycodone, meperidine, codeine, etc.); and 4 = Strong narcotics (morphine, hydromorphone, etc.). A positive change from baseline indicates worsening.
Time frame: baseline, 52 weeks
Population: The population included participants who were in the zoledronic acid q4 weeks and zoledronic acid q12 weeks treatment groups and had both baseline and week 52 values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid Every (q) 4 Weeks | Change From Baseline in Mean Analgesic Score | 0.5 score | Standard Deviation 1.28 |
| Zoledronic Acid q 12 Weeks | Change From Baseline in Mean Analgesic Score | 0.5 score | Standard Deviation 1.13 |
Secondary
Change From Baseline in Mean Composite Brief Pain Inventory (BPI) Score
Participants completed a BPI short form which is a 9 item self-administered questionnaire used to evaluate the severity of a participant's pain and the impact of this pain on the participant's daily functioning. The participant rates his or her worst, least, average, and current pain intensity, lists current treatments and perceived effectiveness, and rates the degree that pain interferes with general activity, mood, walking ability, normal work, relations with other persons, sleep, and enjoyment of life on a 10 point scale. The BPI composite score, which was calculated as the average of items 3, 4, 5 and 6 (worst pain, least pain, average pain and pain right now), ranged from 0 (best possible outcome, no pain) to 10 (worst possible outcome, pain as bad as you can imagine). A positive change from baseline indicates worsening.
Time frame: baseline, 52 weeks
Population: The population included participants who were in the zoledronic acid q4 weeks and zoledronic acid q12 weeks treatment groups and had both baseline and week 52 values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid Every (q) 4 Weeks | Change From Baseline in Mean Composite Brief Pain Inventory (BPI) Score | 0.24 scores on a scale | Standard Deviation 1.976 |
| Zoledronic Acid q 12 Weeks | Change From Baseline in Mean Composite Brief Pain Inventory (BPI) Score | 0.31 scores on a scale | Standard Deviation 2.099 |
Secondary
Change From Baseline in Serum Bone Specific Alkaline Phosphatase
Serum samples were collected to obtain bone specific alkaline phosphatase values.
Time frame: baseline, 48 weeks
Population: The population included participants who were in the zoledronic acid q4 weeks and zoledronic acid q12 weeks treatment groups and had both baseline and week 48 values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid Every (q) 4 Weeks | Change From Baseline in Serum Bone Specific Alkaline Phosphatase | 0.797 mcg/L | Standard Deviation 27.88 |
| Zoledronic Acid q 12 Weeks | Change From Baseline in Serum Bone Specific Alkaline Phosphatase | 4.514 mcg/L | Standard Deviation 12.4509 |
Secondary
Change From Baseline in Urinary N-telopeptide / Creatinine Ratio
Urine samples were collected to obtain n-telopeptide and creatinine values.
Time frame: baseline, 48 weeks
Population: The population included participants who were in the zoledronic acid q4 weeks and zoledronic acid q12 weeks treatment groups and had both baseline and week 48 values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid Every (q) 4 Weeks | Change From Baseline in Urinary N-telopeptide / Creatinine Ratio | 10.612 ratio | Standard Deviation 40.4073 |
| Zoledronic Acid q 12 Weeks | Change From Baseline in Urinary N-telopeptide / Creatinine Ratio | 14.697 ratio | Standard Deviation 57.7315 |
Secondary
Skeletal Morbidity Rate
An SMR for a patient was defined as the number of occurrences of any (or a particular) SRE allowing for only 1 event in any 3-week interval, divided by the time at risk in years. The number of occurrences and the time at risk were counts of SRE and the time from the randomization date. Counting began from randomization in the way that every counted event was followed by a 20-day period during which no SRE was counted, nor was the time counted as at risk. For example, if a patient had 1 SRE during the study, the time at risk was calculated as the total number of days in the study minus the 20-day follow-up period for that SRE. If a patient had no SRE events, the entire study period was counted as time at risk. This SMR calculation method had the advantage of avoiding multiple counts of possibly interdependent SREs (e.g. having 1 fracture increases the probability of having a subsequent SRE).
Time frame: 52 weeks
Population: This population included all participants who were in the zoledronic acid q 4 weeks and zoledronic acid q 12 weeks treatment groups.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid Every (q) 4 Weeks | Skeletal Morbidity Rate | 0.46 Number of events per year | Standard Deviation 1.063 |
| Zoledronic Acid q 12 Weeks | Skeletal Morbidity Rate | 0.50 Number of events per year | Standard Deviation 1.5 |
Secondary
Time to First Individual Type of SRE
Types of SREs analyzed were pathologic fractures (vertebral and non-vertebral), spinal cord compression, radiation to bone and surgery to bone. The time to first indvidual SRE was defined as the date of randomization to the date of the first occurrence of any individual SRE.
Time frame: 52 weeks
Population: The population included participants who were in the zoledronic acid q4 weeks and zoledronic acid q12 weeks treatment groups.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zoledronic Acid Every (q) 4 Weeks | Time to First Individual Type of SRE | Spinal cord compression | NA Weeks |
| Zoledronic Acid Every (q) 4 Weeks | Time to First Individual Type of SRE | Radiation to bone | NA Weeks |
| Zoledronic Acid Every (q) 4 Weeks | Time to First Individual Type of SRE | Surgery to bone | NA Weeks |
| Zoledronic Acid Every (q) 4 Weeks | Time to First Individual Type of SRE | Vertebral pathologic fractures | NA Weeks |
| Zoledronic Acid Every (q) 4 Weeks | Time to First Individual Type of SRE | Non-vertebral pathologic fractures | NA Weeks |
| Zoledronic Acid q 12 Weeks | Time to First Individual Type of SRE | Non-vertebral pathologic fractures | NA Weeks |
| Zoledronic Acid q 12 Weeks | Time to First Individual Type of SRE | Spinal cord compression | NA Weeks |
| Zoledronic Acid q 12 Weeks | Time to First Individual Type of SRE | Vertebral pathologic fractures | NA Weeks |
| Zoledronic Acid q 12 Weeks | Time to First Individual Type of SRE | Radiation to bone | NA Weeks |
| Zoledronic Acid q 12 Weeks | Time to First Individual Type of SRE | Surgery to bone | NA Weeks |
Secondary
Time to First SRE
An SRE was defined as a pathologic bone fracture (vertebral and non-vertebral), spinal cord compression, radiation to bone, or surgery to bone. The time to first individual SRE was defined as the date of randomization to the date of first occurrence of any SRE.
Time frame: 52 weeks
Population: The population included participants who were in the zoledronic acid q4 weeks and zoledronic acid q12 weeks treatment groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Zoledronic Acid Every (q) 4 Weeks | Time to First SRE | NA Days |
| Zoledronic Acid q 12 Weeks | Time to First SRE | NA Days |