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Safety and Efficacy of Zoledronic Acid in Patients With Breast Cancer With Metastatic Bone Lesions

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ClinicalTrials.gov Identifier: NCT00375427
Recruitment Status : Completed
First Posted : September 13, 2006
Results First Posted : August 4, 2011
Last Update Posted : April 11, 2012
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE September 12, 2006
First Posted Date  ICMJE September 13, 2006
Results First Submitted Date  ICMJE February 28, 2011
Results First Posted Date  ICMJE August 4, 2011
Last Update Posted Date April 11, 2012
Study Start Date  ICMJE February 2006
Actual Primary Completion Date February 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 11, 2011)
Annual Overall Skeletal Morbidity Rate (SMR) [ Time Frame: 12 months ]
The SMR was computed by summing all Skeletal Related Event(s) (SREs)which occurred during the observation period and dividing it by the ratio "days of observation period / 365.25", for each participant. SRE was defined as: pathologic bone fracture, spinal cord compression, surgery to bone both curative and prophylactic, radiation therapy to bone, or hypercalcemia of malignancy. SMR (years) = 365.25 x SMR(days) where SMR (days) = total number of SREs / total SRE risk period (days). Risk period for SMR was computed as the days from randomization date to the date of last visit.
Original Primary Outcome Measures  ICMJE
 (submitted: September 12, 2006)
Annual Overall Skeletal Morbidity Rate (SMR)
Change History Complete list of historical versions of study NCT00375427 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 11, 2011)
  • Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) [ Time Frame: 12 month ]
    Skeletal Related Events (SREs) are defined as a:
    • pathologic bone fracture such as non-vertebral and vertebral compression fractures
    • spinal cord compression identified by positive diagnosis documented by X-ray evidence
    • surgery to bone both curative and prophylactic
    • radiation therapy to bone including palliative, therapeutic or prophylactic
    • hypercalcemia of malignancy, defined as a corrected serum calcium > 12 mg/dl (3.00 mmol/l) or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration.
  • Annual Incidence of Any Skeletal Related Events (SREs) [ Time Frame: 12 months ]
    Skeletal Related Events (SREs) are defined as a:
    • pathologic bone fracture such as non-vertebral and vertebral
    • spinal cord compression identified by X-rays evidence
    • surgery to bone both curative and prophylactic
    • radiation therapy to bone including palliative, therapeutic or prophylactic
    • hypercalcemia of malignancy, defined as a corrected serum calcium > 12 mg/dl (3.00 mmol/l) or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration. Annual incidence for each SRE was computed in the same way as annual overall SMR.
  • Median Time to First Skeletal Related Event(s) (SRE) [ Time Frame: 12 month ]
    Median Time to first skeletal related event (SRE) is defined as the time from randomization to the date of first occurrence of any SRE which includes at least one of the following: radiation therapy to bone, pathologic bone fracture, spinal cord compression, surgery to bone, and hypercalcemia of malignancy (HCM). Due to the few numbers of SRE, Kaplan-Meier estimate never reaches a failure probability >=25%; so median time, 25th and 75th percentiles are not determined.For this reason only the estimated percentage of patient SRE free are reported at each time point.
  • Percentage of Participants Skeletal Related Event (SRE) Free [ Time Frame: 12 months ]
    Percentage of participants SRE free is defined as the Kaplan-Meier estimate of participants free of any Skeletal Related Events(SRE) at each time point. Skeletal Related Events (SREs) are:
    • pathologic bone fracture; non-vertebral and vertebral
    • spinal cord compression identified by X-rays
    • surgery to bone both curative and prophylactic
    • radiation therapy to bone (palliative, therapeutic or prophylactic)
    • hypercalcemia of malignancy, defined as a corrected serum calcium > 12 mg/dl (3.00 mmol/l) or a lower level which is symptomatic and requires treatment other than rehydration.
  • Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire [ Time Frame: At Baseline, Month 3, Month 6, Month 9 and Month 12 ]
    Bone pain was assessed by means of a pain score obtained using the Brief Pain Inventory (BPI) questionnaire. The BPI can produce three pain scores: worst pain, a composite pain score, and a pain interference score. The composite pain score, which is the average of questions 3, 4, 5 and 6 of the questionnaire was used in this study. Pain was rated on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The outcome is given as the median score for participants at baseline, and 3, 6, 9 and 12 months of treatment
  • Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value [ Time Frame: At Baseline, Month 3, Month 6, Month 9 and Month 12 ]
    Pain intensity at rest and on movement is rated by the patient by means of a validated 6-point Verbal Rating Scale (VRS) and refers to the pain which occurred during the last week before the assessment. Median score value is the median of all the observed scores (none=0, very mild=1, mild=2, moderate=3, severe=5 and very severe=6) at each time point.
  • Use Of Analgesic Medications According to the Analgesic Score Scale [ Time Frame: At Baseline, Month 3, Month 6, Month 9 and Month 12 ]
    The analgesic score used for this study is modified from the Radiation Therapy Oncology Group (RTOG) analgesic score scale. The scale represents type of medication administered from 0 to 4 where: 0 = None
    1. = Minor analgesics (aspirin, NSAID, acetaminophen, propoxyphene, etc.)
    2. = Tranquilisers, antidepressants, muscle relaxants, and steroids
    3. = Mild narcotics (oxycodone, meperidine, codeine, etc.)
    4. = Strong narcotics (morphine, hydromorphone, etc.) The outcome is given a the median score for the participants at Baseline and 3, 6, 9 and 12 months of treatment
  • Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score [ Time Frame: At Baseline, Month 3, Month 6, Month 9 and Month 12 ]
    ECOG Performance Score has 4 grades. 0 = Fully active, able to carry out all pre-disease activities; 1 = Restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Active about 50% of waking hours; 3 = Capable of limited self-care, confined to bed/chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on self-care. Totally confined to bed/chair. Outcome is given as median score for participants at Baseline and 3, 6 , 9 and 12 months of treatment
Original Secondary Outcome Measures  ICMJE
 (submitted: September 12, 2006)
  • Proportion of patients experiencing SREs (overall and by event)
  • Time to first SRE
  • Annual incidence of any SREs (by event SMR)
  • Composite bone pain score according to the Brief Pain inventory/BPI questionnaire and VRS (verbal rating scale)
  • Use of analgesic medications according to the analgesic score
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Zoledronic Acid in Patients With Breast Cancer With Metastatic Bone Lesions
Official Title  ICMJE A Prospective, Randomized, Multi-center Comparative 2-arm Trial of Efficacy and Safety of Zoledronic Acid (Every 3-months vs. Every 4 Weeks) Beyond Approximately 1 Year of Treatment With Zoledronic Acid in Patients With Bone Lesions From Breast Cancer
Brief Summary The objective of this study is to assess the clinical benefit of two different dosing schedules of zoledronic acid in patients with metastatic bone lesions from breast cancer who have already been treated with zoledronic acid for about one year.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer With Bone Metastasis
Intervention  ICMJE Drug: Zoledronic acid
Zoledronic acid as a 15-minute (at least) intravenous (i.v.) infusion. The dose of study drug will be the same administered before the study entry, that is 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg.
Other Names:
  • ZOL446
  • Zometa®
Study Arms  ICMJE
  • Experimental: Every 3 months
    Zoledronic acid as a 15-minute (at least) intravenous (i.v.) infusion every three months. The dose of study drug will be the same administered before the study entry, that is 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Randomized patients will receive a maximum of 4 infusions in this group.
    Intervention: Drug: Zoledronic acid
  • Experimental: Every 4 weeks
    Zoledronic acid as a 15-minute (at least) intravenous (i.v.) infusion every 4 weeks. The dose of study drug will be the same administered before the study entry, that is 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Patients randomized to this group will receive up to 12 infusions.
    Intervention: Drug: Zoledronic acid
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 5, 2010)
430
Original Enrollment  ICMJE
 (submitted: September 12, 2006)
420
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date February 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • Female patients ≥ 18 years of age.
  • Written informed consent given.
  • Histologically confirmed Stage IV breast cancer with at least one bone metastasis radiologically confirmed.
  • Previous treatment with zoledronic acid every 3-4 weeks, for 9-12 infusions over no more than 15 months.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤2 .
  • Life expectancy ≥ 1 year.

Exclusion criteria:

  • More than 3 months since last infusion of Zoledronic Acid (Zometa®).
  • Treatments with other bisphosphonate than Zoledronic Acid (Zometa®) at any time prior to study entry.
  • Serum creatinine > 3 mg/dL (265 μmol/L) or calculated (Cockcroft-Gault formula) creatinine clearance (CLCr) < 30 mL/min CrCl = ({[140-age (years)] x weight(kg)}/ [72 x serum creatinine (mg/dL)])x 0.85
  • Corrected (adjusted for serum albumin) serum calcium < 8 mg/dl (2 mmol/L) or > 12 mg/dL ( 3.0 mmol/L).
  • Current active dental problem including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a recurrent or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.
  • Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants).
  • Pregnant patients (with a positive pregnancy test prior to study entry) or lactating patients. Women of childbearing potential not using effective methods of birth control (e.g. abstinence, oral contraceptives or implants, IUD, vaginal diaphragm or sponge, or condom with spermicide).
  • History of non-compliance to medical regimens or potential unreliable behavior.
  • Known sensitivity to study drug(s) or class of study drug(s).
  • Patients with severe medical condition(s) that in the view of the investigator prohibits participation in the study
  • Use of any other investigational agent in the last 30 days.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00375427
Other Study ID Numbers  ICMJE CZOL446EIT14
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date July 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP