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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Every 3 months | Experimental | 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. |
|
| Every 4 weeks | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Zoledronic acid | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Annual Overall Skeletal Morbidity Rate (SMR) | 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. | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Skeletal Related Events (SREs) are defined as a:
|
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Inclusion criteria:
Exclusion criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Forlì | Italy |
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Total enrollment was 430; five participants were screened but not treated.
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| ID | Title | Description |
|---|---|---|
| FG000 | Zoledronic Acid Every 3 Months | Zoledronic acid given as a 15-minute (at least) i.v. infusion every three months. The dose of study drug was the same as administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Randomized participants received a maximum of 4 infusions in this group. |
| FG001 | Zoledronic Acid Every 4 Weeks | Zoledronic acid given as a 15-minute (at least) i.v. infusion every 4 weeks. The dose of study drug was the as same administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Participants randomized to this group received up to 12 infusions. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Zoledronic Acid Every 3 Months | Zoledronic acid given as a 15-minute (at least) i.v. infusion every three months. The dose of study drug was the same as administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Randomized participants received a maximum of 4 infusions in this group. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Annual Overall Skeletal Morbidity Rate (SMR) | 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. | Intent-to-treat (ITT) population will include all randomized patients. | Posted | Mean | Standard Deviation | Number of Skeletal Events per Year | 12 months |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Zoledronic Acid Every 3 Months | Zoledronic acid given as a 15-minute (at least) i.v. infusion every three months. The dose of study drug was the same as administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Randomized participants received a maximum of 4 infusions in this group. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 |
Not provided
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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| ID | Term |
|---|---|
| D000077211 | Zoledronic Acid |
| ID | Term |
|---|---|
| D004164 | Diphosphonates |
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
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|
| 12 month |
| Annual Incidence of Any Skeletal Related Events (SREs) | Skeletal Related Events (SREs) are defined as a:
| 12 months |
| Median Time to First Skeletal Related Event(s) (SRE) | 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. | 12 month |
| Percentage of Participants Skeletal Related Event (SRE) Free | 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:
| 12 months |
| Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | 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 | At Baseline, Month 3, Month 6, Month 9 and Month 12 |
| Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | 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. | At Baseline, Month 3, Month 6, Month 9 and Month 12 |
| Use Of Analgesic Medications According to the Analgesic Score Scale | 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
| At Baseline, Month 3, Month 6, Month 9 and Month 12 |
| Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | 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 | At Baseline, Month 3, Month 6, Month 9 and Month 12 |
| Abnormal laboratory value(s) |
|
| Unsatisfactory therapeutic effect |
|
| Patient no longer requires study drug |
|
| Protocol Violation |
|
| Withdrawal by Subject |
|
| Lost to Follow-up |
|
| Administrative reasons |
|
| Death |
|
| Zoledronic Acid Every 4 Weeks |
Zoledronic acid given as a 15-minute (at least) i.v. infusion every 4 weeks. The dose of study drug was the as same administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Participants randomized to this group received up to 12 infusions. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | Zoledronic Acid Every 4 Weeks | Zoledronic acid given as a 15-minute (at least) i.v. infusion every 4 weeks. The dose of study drug was the as same administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Participants randomized to this group received up to 12 infusions. |
|
|
| Secondary | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Skeletal Related Events (SREs) are defined as a:
| Intent-to-treat (ITT) population will include all randomized patients. | Posted | Number | Percentage of Participants | 12 month |
|
|
|
| Secondary | Annual Incidence of Any Skeletal Related Events (SREs) | Skeletal Related Events (SREs) are defined as a:
| Intent-to-treat (ITT) population will include all randomized patients. | Posted | Mean | Standard Deviation | Number of SRE per Year | 12 months |
|
|
|
| Secondary | Median Time to First Skeletal Related Event(s) (SRE) | 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. | Posted | Number | Day | 12 month |
|
|
|
| Secondary | Percentage of Participants Skeletal Related Event (SRE) Free | 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:
| Intent-to-treat (ITT) population will include all randomized patients. | Posted | Number | 95% Confidence Interval | Percentage of participants | 12 months |
|
|
|
| Secondary | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | 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 | Intent-to-treat (ITT) population will include all randomized patients. All ITT patients with BPI questionnaire filled up at baseline were included. | Posted | Mean | Standard Deviation | score on a scale | At Baseline, Month 3, Month 6, Month 9 and Month 12 |
|
|
|
| Secondary | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | 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. | Intent-to-treat (ITT) population will include all randomized patients. | Posted | Median | Full Range | score on a scale | At Baseline, Month 3, Month 6, Month 9 and Month 12 |
|
|
|
| Secondary | Use Of Analgesic Medications According to the Analgesic Score Scale | 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
| Intent-to-treat (ITT) population will include all randomized patients. | Posted | Median | Full Range | score on a scale | At Baseline, Month 3, Month 6, Month 9 and Month 12 |
|
|
|
| Secondary | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | 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 | Intent-to-treat (ITT) population will include all randomized patients. | Posted | Median | Full Range | score on a scale | At Baseline, Month 3, Month 6, Month 9 and Month 12 |
|
|
|
| 21 |
| 209 |
| 133 |
| 209 |
| EG001 | Zoledronic Acid Every 4 Weeks | Zoledronic acid given as a 15-minute (at least) i.v. infusion every 4 weeks. The dose of study drug was the as same administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Participants randomized to this group received up to 12 infusions | 29 | 216 | 161 | 216 |
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Acute myocardial infarction | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Cardiac failure | Cardiac disorders | MedDRA | Systematic Assessment |
|
| Diplopia | Eye disorders | MedDRA | Systematic Assessment |
|
| Gastric haemorrhage | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Oral pain | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Mucosal inflammation | General disorders | MedDRA | Systematic Assessment |
|
| Pain | General disorders | MedDRA | Systematic Assessment |
|
| Jaundice | Hepatobiliary disorders | MedDRA | Systematic Assessment |
|
| Acute sinusitis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA | Systematic Assessment |
|
| Skin infection | Infections and infestations | MedDRA | Systematic Assessment |
|
| Femur fracture | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Humerus fracture | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
|
| Cachexia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Jaw disorder | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Osteitis | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Osteonecrosis | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Malignant neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
|
| Metastases to central nervous system | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
|
| Cranial nerve paralysis | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Epilepsy | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Ischaemic cerebral infarction | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Paraparesis | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Sopor | Psychiatric disorders | MedDRA | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Breast operation | Surgical and medical procedures | MedDRA | Systematic Assessment |
|
| Laparoscopic surgery | Surgical and medical procedures | MedDRA | Systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | MedDRA | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA | Systematic Assessment |
|
| Pain | General disorders | MedDRA | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
|
| Malignant neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
|
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.
| D017437 |
| Skin and Connective Tissue Diseases |
| D007093 |
| Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Non vertebral pathological fracture |
|
| Spinal cord compression |
|
| Radiation to bone |
|
| Surgery to bone |
|
| Hypercalcemia of malignancy |
|
| Spinal cord compression rate |
|
| Radiation to bone rate |
|
| Surgery to bone rate |
|
| Hypercalcemia of malignancy rate |
|
| At Month 3 |
|
| At Month 4 |
|
| At Month 5 |
|
| At Month 6 |
|
| At Month 7 |
|
| At Month 8 |
|
| At Month 9 |
|
| At Month 10 |
|
| At Month 11 |
|
| At Month 12 |
|
| Month 6 (N= 143, 160) |
|
| Month 9 (N= 131, 130) |
|
| Month 12 (N= 135, 124) |
|
| At Rest: Month 6 |
|
| At Rest: Month 9 |
|
| At Rest: Month 12 |
|
| At Movement : Baseline |
|
| At Movement : Month 3 |
|
| At Movement : Month 6 |
|
| At Movement : Month 9 |
|
| At Movement : Month 12 |
|
| Month 6 |
|
| Month 9 |
|
| Month 12 |
|
| Month 6 |
|
| Month 9 |
|
| Month 12 |
|