Osteoporosis
Conditions
Keywords
zoledronic acid, post dose symptoms, transient, acetaminophen, fluvastatin
Brief summary
This study will evaluate the efficacy of acetaminophen or fluvastatin in reducing the rate of occurrence and the severity of post dose symptoms that may occur during the 3 day period following a zoledronic acid infusion in post menopausal women with low bone mass.
Interventions
DRUGPlacebo
DRUGAcetaminophen
DRUGFluvastatin
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
1. Postmenopausal women greater than or equal to 45 and less than or equal to 79 years of age at randomization 2. Women who are clinically indicated for treatment with Bisphosphonates for osteopenia or osteoporosis with a documented central (spine or hip) Bone Mineral Density T Score less than or equal to 1.5
Exclusion criteria
1. Any prior treatment with intravenous Bisphosphonates 2. Oral treatment with Bisphosphonates for more than 8 weeks or within 6 months prior to the screening visit 3. Patients who are taking, and are unwilling or unable to stop taking, certain medications 4. Patients who require anticoagulant therapy 5. Patients with a known hypersensitivity to ibuprofen, ACET, bisphosphonates, statins or with allergies manifested by attacks of asthma, urticaria or acute rhinitis following 6. Proteinuria (protein detected on a urine dipstick) greater than or equal to 2+ at screening 7. Protocol specific laboratory values that fall out of range for this study 8. Ongoing infection (oral body temperature greater than or equal to 37.5C (99.5°F),chronic febrile disease or fever of unknown origin at screening or randomization 9. Active dental infection, unhealed dental extraction or planned oral surgery within 3 months after randomization 10. History of iritis, uveitis or chronic conjunctivitis 11. History of hypoparathyroidism, hyperparathyroidism or Paget's Disease 12. Partial or total removal of parathyroid or thyroid gland 13. History of malignancy of any organ system, treated or untreated, within the past 1 year whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin 14. Treatment with an investigational drug within the previous 30 days of screening 15. Patients with any medical or psychiatric condition which, in the opinion of the Principal Investigator, would preclude the participant from adhering to the protocol or completing the trial per protocol, or any patient who the Principal Investigator thinks should not participate in the study for any reason, including current drug or alcohol abuse Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature or Use of Rescue Medication. | 0 - 3 days | Clinically significant increase in oral body temperature or used rescue medication ibuprofen \>= 1 time during the 3-day period after i.v. infusion of zoledronic acid 5 mg. A clinically significant increase in body temperature was defined as an increase of at least 1 degree Celsius from baseline and a mean oral body temperature reading of at least 38.5 degrees Celsius occurring at least once during the 3-day treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Used Rescue Medication. | 0 - 3 days | Patients that took rescue medication \>= 1 time during the 3-day period after i.v. infusion of zoledronic acid 5 mg. Patients who experienced severe discomfort after their first home measurements and self-administration of study medication were allowed to take ibuprofen (200 mg tablets every 4-6 hours as needed) as rescue medication while continuing to take their study medication. |
| Number of Rescue Medication Tablets Taken | 0 - 3 days | Patients who experienced severe discomfort after their first home measurements and self-administration of study medication were allowed to take ibuprofen (200 mg tablets every 4-6 hours as needed) as rescue medication while continuing to take their study medication. |
| Time to First Rescue Medication After Infusion of Zoledronic Acid 5 mg. | 0 - 3 days | Patients who experienced severe discomfort after their first home measurements and self-administration of study medication were allowed to take ibuprofen (200 mg tablets every 4-6 hours as needed) as rescue medication while continuing to take their study medication. |
| Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature. | 0 - 3 days | Clinically significant increase in oral body temperature \>= 1 time during the 3-day period after i.v. infusion of zoledronic acid 5 mg. A clinically significant increase in body temperature was defined as an increase of at least 1 degree Celsius from baseline and a mean oral body temperature reading of at least 38.5 degrees Celsius occurring at least once during the 3-day treatment period. |
| Proportion of Patients Reporting Severe Questionnaire Symptoms. | 0 - 3 days | A severe questionnaire symptom was defined as experiencing a severe specified symptom (feeling feverish, experiencing headaches, having aches and pains of muscles and joints) at least once post-baseline. |
| Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | 0 - 3 days | Effect on severity of symptoms following i.v. infusion of zoledronic acid 5 mg. The VAS is a 100-mm linear visual analog scale (0 = no symptoms to 100 = severe symptoms). The baseline VAS measurement was defined as the VAS measurement recorded prior to the infusion. |
| Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | 0 - 3 days | A major increase (worsening) in severity was defined as an increase in severity of 2 units or more from baseline at least once during the 3 days immediately following i.v. infusion of zoledronic acid 5 mg. The severity of the symptom was evaluated using a 4-point categorical scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo 2 capsules of placebo (matching fluvastatin) and 2 capsules of placebo (matching acetaminophen) administered 45 +/- 15 minutes prior to intravenous (i.v.) infusion of zoledronic acid 5 mg, then 2 capsules of placebo (matching acetaminophen) 4 times per day (including medication taken at study site at visit 2/day 1) over the next 3 days (not exceeding 8 capsules in a 24-hour period). | 267 |
| Acetaminophen 2 capsules of acetaminophen 325 mg and 2 capsules of placebo (matching fluvastatin) administered 45 +/- 15 minutes prior to i.v. infusion of zoledronic acid 5 mg, then 2 capsules of acetaminophen 325 mg 4 times per day (including medication taken at study site at visit 2/day 1) over the next 3 days (not exceeding 8 capsules in a 24-hour period). | 264 |
| Fluvastatin 2 capsules of fluvastatin 40 mg and 2 capsules of placebo (matching acetaminophen) administered 45 +/- 15 minutes prior to i.v. infusion of zoledronic acid 5 mg, then 2 capsules of placebo (matching acetaminophen) 4 times per day (including medication taken at study site at visit 2/day 1) over the next 3 days (not exceeding 8 capsules in a 24-hour period). | 262 |
| Total | 793 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative problems | 0 | 2 | 1 |
| Overall Study | Adverse Event | 3 | 3 | 4 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Fluvastatin | Acetaminophen | Placebo |
|---|---|---|---|---|
| Age, Customized >=65 years | 301 participants | 103 participants | 97 participants | 101 participants |
| Age, Customized Between 45 and 55 years | 200 participants | 67 participants | 69 participants | 64 participants |
| Age, Customized Between 56 and 64 years | 292 participants | 92 participants | 98 participants | 102 participants |
| Sex/Gender, Customized Female | 793 participants | 262 participants | 264 participants | 267 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 | 34 / 267 | 39 / 264 | 36 / 262 |
| serious Total, serious adverse events | 1 / 267 | 2 / 264 | 2 / 262 |
Outcome results
Primary
Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature or Use of Rescue Medication.
Clinically significant increase in oral body temperature or used rescue medication ibuprofen \>= 1 time during the 3-day period after i.v. infusion of zoledronic acid 5 mg. A clinically significant increase in body temperature was defined as an increase of at least 1 degree Celsius from baseline and a mean oral body temperature reading of at least 38.5 degrees Celsius occurring at least once during the 3-day treatment period.
Time frame: 0 - 3 days
Population: Intent to Treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature or Use of Rescue Medication. | Increase in oral body temperature:Yes | 0.607 proportion of patients |
| Placebo | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature or Use of Rescue Medication. | Increase in oral body temperature:No | 0.39 proportion of patients |
| Acetaminophen | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature or Use of Rescue Medication. | Increase in oral body temperature:Yes | 0.398 proportion of patients |
| Acetaminophen | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature or Use of Rescue Medication. | Increase in oral body temperature:No | 0.602 proportion of patients |
| Fluvastatin | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature or Use of Rescue Medication. | Increase in oral body temperature:No | 0.382 proportion of patients |
| Fluvastatin | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature or Use of Rescue Medication. | Increase in oral body temperature:Yes | 0.618 proportion of patients |
Secondary
Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity
Effect on severity of symptoms following i.v. infusion of zoledronic acid 5 mg. The VAS is a 100-mm linear visual analog scale (0 = no symptoms to 100 = severe symptoms). The baseline VAS measurement was defined as the VAS measurement recorded prior to the infusion.
Time frame: 0 - 3 days
Population: Intent to Treat (ITT) population. Number of participants analyzed may vary from ITT population due to some patients not reporting baseline or post baseline VAS measurement. Calculating change requires both baseline and post baseline values to be present.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 3 - late evening | 6.2 units on a scale | Standard Deviation 19.66 |
| Placebo | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 2 - late evening | 18.9 units on a scale | Standard Deviation 25.86 |
| Placebo | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 1 - late evening | 7.6 units on a scale | Standard Deviation 22.74 |
| Acetaminophen | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 3 - late evening | 3.9 units on a scale | Standard Deviation 17.59 |
| Acetaminophen | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 1 - late evening | 4.4 units on a scale | Standard Deviation 18 |
| Acetaminophen | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 2 - late evening | 11.8 units on a scale | Standard Deviation 23.22 |
| Fluvastatin | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 3 - late evening | 6.6 units on a scale | Standard Deviation 20.4 |
| Fluvastatin | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 2 - late evening | 20.8 units on a scale | Standard Deviation 27.18 |
| Fluvastatin | Change From Baseline in Visual Analog Scale (VAS) Measurement of Symptom Severity | Change from baseline to Day 1 - late evening | 6.0 units on a scale | Standard Deviation 18.89 |
Secondary
Number of Rescue Medication Tablets Taken
Patients who experienced severe discomfort after their first home measurements and self-administration of study medication were allowed to take ibuprofen (200 mg tablets every 4-6 hours as needed) as rescue medication while continuing to take their study medication.
Time frame: 0 - 3 days
Population: Number of patients who took rescue medication at least once. One patient in acetaminophen arm was not included in analysis since the number of tablets taken was not recorded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Number of Rescue Medication Tablets Taken | 6.3 tablets | Standard Deviation 4.41 |
| Acetaminophen | Number of Rescue Medication Tablets Taken | 5.7 tablets | Standard Deviation 4.73 |
| Fluvastatin | Number of Rescue Medication Tablets Taken | 6.5 tablets | Standard Deviation 4.78 |
Secondary
Proportion of Patients Reporting Severe Questionnaire Symptoms.
A severe questionnaire symptom was defined as experiencing a severe specified symptom (feeling feverish, experiencing headaches, having aches and pains of muscles and joints) at least once post-baseline.
Time frame: 0 - 3 days
Population: Intent to Treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Aches and pains of muscles/joints | 0.303 proportion of patients |
| Placebo | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Headache | 0.157 proportion of patients |
| Placebo | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Feeling feverish | 0.135 proportion of patients |
| Acetaminophen | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Aches and pains of muscles/joints | 0.212 proportion of patients |
| Acetaminophen | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Headache | 0.068 proportion of patients |
| Acetaminophen | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Feeling feverish | 0.076 proportion of patients |
| Fluvastatin | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Aches and pains of muscles/joints | 0.302 proportion of patients |
| Fluvastatin | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Headache | 0.160 proportion of patients |
| Fluvastatin | Proportion of Patients Reporting Severe Questionnaire Symptoms. | Feeling feverish | 0.145 proportion of patients |
Secondary
Proportion of Patients Who Used Rescue Medication.
Patients that took rescue medication \>= 1 time during the 3-day period after i.v. infusion of zoledronic acid 5 mg. Patients who experienced severe discomfort after their first home measurements and self-administration of study medication were allowed to take ibuprofen (200 mg tablets every 4-6 hours as needed) as rescue medication while continuing to take their study medication.
Time frame: 0 - 3 days
Population: Intent to Treat (ITT) population. One patient who used rescue medication in acetaminophen arm and two patients in fluvastatin arm were not included in analysis due to lack of documentation regarding use and exposure of rescue medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Proportion of Patients Who Used Rescue Medication. | Took rescue medication >= 1 time: Yes | 0.573 proportion of patients |
| Placebo | Proportion of Patients Who Used Rescue Medication. | Took rescue medication >= 1 time: No | 0.423 proportion of patients |
| Acetaminophen | Proportion of Patients Who Used Rescue Medication. | Took rescue medication >= 1 time: Yes | 0.386 proportion of patients |
| Acetaminophen | Proportion of Patients Who Used Rescue Medication. | Took rescue medication >= 1 time: No | 0.614 proportion of patients |
| Fluvastatin | Proportion of Patients Who Used Rescue Medication. | Took rescue medication >= 1 time: Yes | 0.595 proportion of patients |
| Fluvastatin | Proportion of Patients Who Used Rescue Medication. | Took rescue medication >= 1 time: No | 0.405 proportion of patients |
Secondary
Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature.
Clinically significant increase in oral body temperature \>= 1 time during the 3-day period after i.v. infusion of zoledronic acid 5 mg. A clinically significant increase in body temperature was defined as an increase of at least 1 degree Celsius from baseline and a mean oral body temperature reading of at least 38.5 degrees Celsius occurring at least once during the 3-day treatment period.
Time frame: 0 - 3 days
Population: Intent to Treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature. | Increase in oral body temperature: Yes | 0.105 proportion of patients |
| Placebo | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature. | Increase in oral body temperature: No | 0.891 proportion of patients |
| Acetaminophen | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature. | Increase in oral body temperature: Yes | 0.049 proportion of patients |
| Acetaminophen | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature. | Increase in oral body temperature: No | 0.951 proportion of patients |
| Fluvastatin | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature. | Increase in oral body temperature: No | 0.885 proportion of patients |
| Fluvastatin | Proportion of Patients With a Clinically Significant Increase in Oral Body Temperature. | Increase in oral body temperature: Yes | 0.115 proportion of patients |
Secondary
Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms.
A major increase (worsening) in severity was defined as an increase in severity of 2 units or more from baseline at least once during the 3 days immediately following i.v. infusion of zoledronic acid 5 mg. The severity of the symptom was evaluated using a 4-point categorical scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe).
Time frame: 0 - 3 days
Population: Intent to Treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Aches and pains of muscles/joints | 0.477 proportion of patients |
| Placebo | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Headache | 0.391 proportion of patients |
| Placebo | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Feeling feverish | 0.395 proportion of patients |
| Acetaminophen | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Aches and pains of muscles/joints | 0.337 proportion of patients |
| Acetaminophen | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Headache | 0.254 proportion of patients |
| Acetaminophen | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Feeling feverish | 0.235 proportion of patients |
| Fluvastatin | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Headache | 0.439 proportion of patients |
| Fluvastatin | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Feeling feverish | 0.397 proportion of patients |
| Fluvastatin | Proportion of Patients With a Major Increase (Worsening) in Severity of Questionnaire Symptoms. | Aches and pains of muscles/joints | 0.462 proportion of patients |
Secondary
Time to First Rescue Medication After Infusion of Zoledronic Acid 5 mg.
Patients who experienced severe discomfort after their first home measurements and self-administration of study medication were allowed to take ibuprofen (200 mg tablets every 4-6 hours as needed) as rescue medication while continuing to take their study medication.
Time frame: 0 - 3 days
Population: Number of patients who took rescue medication at least once. Two patients who took rescue medication in fluvastatin arm were not included in analysis since the time rescue medication was taken was not recorded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time to First Rescue Medication After Infusion of Zoledronic Acid 5 mg. | 21.9 hours | Standard Deviation 12.21 |
| Acetaminophen | Time to First Rescue Medication After Infusion of Zoledronic Acid 5 mg. | 28.2 hours | Standard Deviation 18.15 |
| Fluvastatin | Time to First Rescue Medication After Infusion of Zoledronic Acid 5 mg. | 19.9 hours | Standard Deviation 40.95 |