Bone Pain in Stage I - III Breast Cancer
Conditions
Keywords
Breast cancer, Chemotherapy, Neulasta, Pegfilgrastim, Naproxen, Loratadine, Non-steroidal antiinflammatory drug (NSAID), Anti-histamine, Bone Pain
Brief summary
The primary objective of the study is to estimate the difference in bone pain between breast cancer patients receiving chemotherapy and pegfilgrastim and either no prophylactic intervention, prophylactic naproxen, or prophylactic loratadine.
Detailed description
In this study, the investigational products are naproxen, a non-steroidal antiinflammatory drug (NSAID), and loratadine, an anti-histamine. Both agents are being investigated as prophylactic medications to reduce the incidence and/or severity of bone pain in breast cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy and pegfilgrastim prophylaxis. Pegfilgrastim treatment is used to stimulate bone marrow to produce more neutrophils to help fight infections in patients undergoing chemotherapy.
Interventions
DRUGNaproxen
DRUGLoratadine
BIOLOGICALPegfilgrastim
Commercially available pegfilgrastim (Neulasta®) will be used in the study, and is considered background therapy. Pegfilgrastim is administered as a single 6 mg subcutaneous injection 24 hours to 72 hours after completion of chemotherapy.
DRUGChemotherapy
The choice of chemotherapy regimen (agent, dose, and schedule) is at the discretion of the treating physician.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Age 18 years or over * Eastern cooperative oncology group (ECOG) performance status 0-2 * Female with newly diagnosed, not previously treated with chemotherapy, stage I-III breast cancer * Medically eligible to safely receive adjuvant or neoadjuvant chemotherapy, pegfilgrastim, naproxen and loratadine as determined by the investigator * Creatinine ≤ 1.5 X upper limit of normal (ULN) * Planning to receive at least 4 cycles of adjuvant or neoadjuvant chemotherapy * Planning to receive prophylaxis with pegfilgrastim starting in the first cycle and continuing throughout each chemotherapy cycle of the treatment period * Subject has provided informed consent
Exclusion criteria
* History of other malignancy within the past 5 years, with the following exceptions: * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated cervical carcinoma in situ without evidence of disease * Planning to receive weekly chemotherapy * Ongoing chronic pain, or other painful conditions requiring treatment (including immediate post-operative treatment of surgical or procedural-associated pain) as determined by the investigator * Chronic oral steroid use. Premedication related to the administration of chemotherapy, and use of anti-emetics is allowed, per usual clinical practice * Chronic use of oral non-steroidal anti-inflammatory drug (NSAIDs) or oral antihistamines outside of those dictated by the randomization groups outlined in the protocol, with the following exception: \- Chronic oral aspirin use for cardiovascular-related indications * Prior chemotherapy treatment for cancer within 5 years of current breast cancer diagnosis * Prior use of granulocyte colony stimulating factor (G-CSF) * History of clinically significant gastrointestinal (GI) bleeding, history of GI ulcers or active GI bleeding within 6 months prior to randomization * History of clinically significant bleeding disorders, thromboembolism within 6 months prior to randomization * Currently enrolled in, or less than 30 days since ending, another clinical trial which includes language directing G-CSF (filgrastim, pegfilgrastim, other) or granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim) use * Currently enrolled in, or less than 30 days since ending, another interventional clinical trial which includes a blinded treatment or blinded treatment arm (whether or not the subject is randomized to the blinded arm) * Currently enrolled in, or less than 30 days since ending, another interventional clinical trial which includes the use of any agent not currently considered to be standard therapy for the adjuvant or neoadjuvant treatment of stage I-III breast cancer based on National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Breast Cancer * Currently enrolled in, or less than 30 days since ending, any pain intervention study * Female subjects who are pregnant or lactating or of reproductive potential not willing to employ an effective method of birth control during treatment and for 17 days after discontinuing study treatment * History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Amgen, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Bone Pain (All Grades) in Cycle 1 | Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval) | Bone pain data were captured as part of standard adverse event (AE) reporting. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval) | Bone pain data were captured as part of standard adverse event reporting. Severe bone pain is defined as grade 3 or 4 according to common terminology criteria for adverse events (CTCAE) version 3 grading criteria: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening or disabling. |
| Mean Patient-reported Bone Pain by Cycle and Across Cycles | Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle) | Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Mean patient-reported bone pain values are the average of each participant's bone pain values across survey days 1-5 within each cycle. Across all cycles the mean is the average of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An analysis of variance (ANOVA) model with treatment as explanatory term was used. |
| Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval) | Bone pain data were captured as part of standard adverse event (AE) reporting. |
| Area Under the Curve (AUC) for Patient-reported Bone Pain | Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle) | Patient-reported bone pain AUC was calculated using the trapezoidal rule with bone pain scores from day 1 to 5 for each cycle. The AUC across cycles is the average of AUCs across the cycle. |
| Number of Participants With Adverse Events (AEs) | From first dose of investigational product (IP, naproxen or loratidine) or first dose of pegfilgrastim (Peg), whichever occurred first, until 30 days after last dose, up to 24 weeks. | Severity was graded using CTCAE version 3. A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal; • life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • congenital anomaly/birth defect; • other medically important serious event. The investigator assessed each adverse event for relatedness to investigational product(s) or other protocol-required therapies. |
| Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle) | Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Maximum patient-reported bone pain is the maximum of each participant's bone pain values across survey Days 1-5 within each cycle. Across all cycles the maximum is the maximum of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An ANOVA model with treatment as explanatory term was used. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 83 centers in the United States. The first participant enrolled on 01 November 2012 and the last participant enrolled on 20 November 2014.
Pre-assignment details
Participants were randomized in a 1:1:1 ratio to receive no prophylactic intervention, prophylactic naproxen, or prophylactic loratadine. Randomization was stratified by age group (\< 65 years vs ≥ 65 years) and planned chemotherapy type (taxane vs non-taxane). Participants remained on study for the first 4 chemotherapy cycles.
Participants by arm
| Arm | Count |
|---|---|
| No Prophylaxis Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim. | 191 |
| Naproxen 500 mg BID Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration. | 196 |
| Loratadine 10 mg QD Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration. | 200 |
| Total | 587 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Decision by Sponsor | 12 | 14 | 12 |
| Overall Study | Lost to Follow-up | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 24 | 15 | 8 |
Baseline characteristics
| Characteristic | Total | Loratadine 10 mg QD | Naproxen 500 mg BID | No Prophylaxis |
|---|---|---|---|---|
| Age, Continuous | 54.2 years STANDARD_DEVIATION 11.1 | 54.6 years STANDARD_DEVIATION 10.9 | 53.2 years STANDARD_DEVIATION 11.7 | 54.8 years STANDARD_DEVIATION 10.7 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 7 participants | 1 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Black (or African American) | 83 participants | 23 participants | 27 participants | 33 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 37 participants | 9 participants | 15 participants | 13 participants |
| Race/Ethnicity, Customized Multiple | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 550 participants | 191 participants | 181 participants | 178 participants |
| Race/Ethnicity, Customized Other | 7 participants | 2 participants | 0 participants | 5 participants |
| Race/Ethnicity, Customized White | 487 participants | 173 participants | 166 participants | 148 participants |
| Sex: Female, Male Female | 587 Participants | 200 Participants | 196 Participants | 191 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 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 | 184 / 196 | 190 / 193 | 193 / 198 |
| serious Total, serious adverse events | 34 / 196 | 30 / 193 | 14 / 198 |
Outcome results
Primary
Percentage of Participants With Bone Pain (All Grades) in Cycle 1
Bone pain data were captured as part of standard adverse event (AE) reporting.
Time frame: Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval)
Population: Full anlysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| No Prophylaxis | Percentage of Participants With Bone Pain (All Grades) in Cycle 1 | 46.6 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Bone Pain (All Grades) in Cycle 1 | 40.3 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Bone Pain (All Grades) in Cycle 1 | 42.5 percentage of participants |
95% CI: [-16.7, 4.1]
95% CI: [-14.5, 6.3]
95% CI: [-8, 12.4]
Secondary
Area Under the Curve (AUC) for Patient-reported Bone Pain
Patient-reported bone pain AUC was calculated using the trapezoidal rule with bone pain scores from day 1 to 5 for each cycle. The AUC across cycles is the average of AUCs across the cycle.
Time frame: Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)
Population: Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. n indicates the number of participants who entered each cycle.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| No Prophylaxis | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 1 (n=191, 196, 200) | 9.3 units on a scale * days | Standard Error 0.7 |
| No Prophylaxis | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 4 (n=162, 169, 179) | 7.2 units on a scale * days | Standard Error 0.7 |
| No Prophylaxis | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 3 (n=165, 176, 188) | 6.8 units on a scale * days | Standard Error 0.7 |
| No Prophylaxis | Area Under the Curve (AUC) for Patient-reported Bone Pain | Across All Cycles (n=191, 196, 200) | 8.0 units on a scale * days | Standard Error 0.6 |
| No Prophylaxis | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 2 (n=178, 180, 193) | 7.3 units on a scale * days | Standard Error 0.7 |
| Naproxen 500 mg BID | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 3 (n=165, 176, 188) | 5.5 units on a scale * days | Standard Error 0.6 |
| Naproxen 500 mg BID | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 1 (n=191, 196, 200) | 7.7 units on a scale * days | Standard Error 0.6 |
| Naproxen 500 mg BID | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 2 (n=178, 180, 193) | 5.6 units on a scale * days | Standard Error 0.6 |
| Naproxen 500 mg BID | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 4 (n=162, 169, 179) | 5.2 units on a scale * days | Standard Error 0.6 |
| Naproxen 500 mg BID | Area Under the Curve (AUC) for Patient-reported Bone Pain | Across All Cycles (n=191, 196, 200) | 6.6 units on a scale * days | Standard Error 0.5 |
| Loratadine 10 mg QD | Area Under the Curve (AUC) for Patient-reported Bone Pain | Across All Cycles (n=191, 196, 200) | 6.3 units on a scale * days | Standard Error 0.5 |
| Loratadine 10 mg QD | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 4 (n=162, 169, 179) | 5.6 units on a scale * days | Standard Error 0.6 |
| Loratadine 10 mg QD | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 1 (n=191, 196, 200) | 7.0 units on a scale * days | Standard Error 0.6 |
| Loratadine 10 mg QD | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 3 (n=165, 176, 188) | 6.1 units on a scale * days | Standard Error 0.6 |
| Loratadine 10 mg QD | Area Under the Curve (AUC) for Patient-reported Bone Pain | Cycle 2 (n=178, 180, 193) | 5.9 units on a scale * days | Standard Error 0.5 |
Comparison: Difference across all treatment cyclesp-value: 0.077595% CI: [-3, 0.2]ANOVA
Comparison: Difference across all treatment cyclesp-value: 0.032995% CI: [-3.1, -0.1]ANCOVA
Comparison: Difference across all treatment groupsp-value: 0.757295% CI: [-1.7, 1.2]ANOVA
Secondary
Maximum Patient-reported Bone Pain by Cycle and Across Cycles
Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Maximum patient-reported bone pain is the maximum of each participant's bone pain values across survey Days 1-5 within each cycle. Across all cycles the maximum is the maximum of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An ANOVA model with treatment as explanatory term was used.
Time frame: Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)
Population: Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. n indicates the number of participants who entered each cycle.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| No Prophylaxis | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 2.8 units on a scale | Standard Error 0.2 |
| No Prophylaxis | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 2.7 units on a scale | Standard Error 0.2 |
| No Prophylaxis | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 3.9 units on a scale | Standard Error 0.2 |
| No Prophylaxis | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 3.0 units on a scale | Standard Error 0.2 |
| No Prophylaxis | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Across All Cycles (n=191, 196, 200) | 4.7 units on a scale | Standard Error 0.2 |
| Naproxen 500 mg BID | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 2.2 units on a scale | Standard Error 0.2 |
| Naproxen 500 mg BID | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 3.3 units on a scale | Standard Error 0.2 |
| Naproxen 500 mg BID | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 2.4 units on a scale | Standard Error 0.2 |
| Naproxen 500 mg BID | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 2.1 units on a scale | Standard Error 0.2 |
| Naproxen 500 mg BID | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Across All Cycles (n=191, 196, 200) | 4.2 units on a scale | Standard Error 0.2 |
| Loratadine 10 mg QD | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Across All Cycles (n=191, 196, 200) | 4.1 units on a scale | Standard Error 0.2 |
| Loratadine 10 mg QD | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 2.1 units on a scale | Standard Error 0.2 |
| Loratadine 10 mg QD | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 3.0 units on a scale | Standard Error 0.2 |
| Loratadine 10 mg QD | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 2.5 units on a scale | Standard Error 0.2 |
| Loratadine 10 mg QD | Maximum Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 2.6 units on a scale | Standard Error 0.2 |
Comparison: Difference across all treatment cyclesp-value: 0.146695% CI: [-1.1, 0.2]ANOVA
Comparison: Difference across all treatment cyclesp-value: 0.041195% CI: [-1.3, 0]ANOVA
Comparison: Difference across all treatment cyclesp-value: 0.568995% CI: [-0.8, 0.5]ANOVA
Secondary
Mean Patient-reported Bone Pain by Cycle and Across Cycles
Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Mean patient-reported bone pain values are the average of each participant's bone pain values across survey days 1-5 within each cycle. Across all cycles the mean is the average of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An analysis of variance (ANOVA) model with treatment as explanatory term was used.
Time frame: Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)
Population: Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. n indicates the number of participants who entered each cycle.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| No Prophylaxis | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 1.7 units on a scale | Standard Error 0.2 |
| No Prophylaxis | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 1.6 units on a scale | Standard Error 0.2 |
| No Prophylaxis | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 2.2 units on a scale | Standard Error 0.2 |
| No Prophylaxis | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 1.7 units on a scale | Standard Error 0.2 |
| No Prophylaxis | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Across all Cycles (n=191, 196, 200) | 1.9 units on a scale | Standard Error 0.1 |
| Naproxen 500 mg BID | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 1.3 units on a scale | Standard Error 0.1 |
| Naproxen 500 mg BID | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 1.8 units on a scale | Standard Error 0.2 |
| Naproxen 500 mg BID | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 1.3 units on a scale | Standard Error 0.1 |
| Naproxen 500 mg BID | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 1.2 units on a scale | Standard Error 0.1 |
| Naproxen 500 mg BID | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Across all Cycles (n=191, 196, 200) | 1.5 units on a scale | Standard Error 0.1 |
| Loratadine 10 mg QD | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Across all Cycles (n=191, 196, 200) | 1.5 units on a scale | Standard Error 0.1 |
| Loratadine 10 mg QD | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 1.3 units on a scale | Standard Error 0.1 |
| Loratadine 10 mg QD | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 1.7 units on a scale | Standard Error 0.1 |
| Loratadine 10 mg QD | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 1.4 units on a scale | Standard Error 0.1 |
| Loratadine 10 mg QD | Mean Patient-reported Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 1.4 units on a scale | Standard Error 0.1 |
Comparison: Difference across all treatment cyclesp-value: 0.088195% CI: [-0.7, 0]ANOVA
Comparison: Difference across all treatment cyclesp-value: 0.044395% CI: [-0.7, 0]ANOVA
Comparison: Difference across all treatment cyclesp-value: 0.800795% CI: [-0.4, 0.3]ANOVA
Secondary
Number of Participants With Adverse Events (AEs)
Severity was graded using CTCAE version 3. A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal; • life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • congenital anomaly/birth defect; • other medically important serious event. The investigator assessed each adverse event for relatedness to investigational product(s) or other protocol-required therapies.
Time frame: From first dose of investigational product (IP, naproxen or loratidine) or first dose of pegfilgrastim (Peg), whichever occurred first, until 30 days after last dose, up to 24 weeks.
Population: Safety analysis set included all participants who received primary prophylaxis with pegfilgrastim according to the prophylactic medication actually received. Participants in the Naproxen or Loratadine groups who did not receive naproxen or loratadine are analyzed in the No Prophylaxis group for safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 3 | 74 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 4 | 18 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | SAE related to IP | 0 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | Serious adverse events | 34 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | Any adverse event related to pegfilgrastim | 87 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 0 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | AE leading to discontinuation from study | 3 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | SAE leading to discontinuation from study | 1 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | SAE related to pegfilgrastim | 4 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | AE related to / leading to discontinuation of Peg | 6 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | AE related to IP leading to discontinuation of IP | 0 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | SAE related to / leading to discontinuation of Peg | 1 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | Any adverse event | 188 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | Any adverse event related to IP | 0 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 2 | 164 participants |
| No Prophylaxis | Number of Participants With Adverse Events (AEs) | SAE related to IP leading to discontinuation of IP | 0 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | AE related to IP leading to discontinuation of IP | 9 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | SAE related to IP leading to discontinuation of IP | 1 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | SAE related to pegfilgrastim | 0 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 4 | 30 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | Any adverse event related to IP | 30 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 3 | 73 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | Serious adverse events | 30 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | AE related to / leading to discontinuation of Peg | 3 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | Any adverse event | 192 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 0 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | Any adverse event related to pegfilgrastim | 96 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 2 | 169 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | AE leading to discontinuation from study | 5 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | SAE related to IP | 1 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | SAE related to / leading to discontinuation of Peg | 0 participants |
| Naproxen 500 mg BID | Number of Participants With Adverse Events (AEs) | SAE leading to discontinuation from study | 3 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 2 | 168 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | Any adverse event related to IP | 7 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | SAE related to IP | 0 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | AE related to IP leading to discontinuation of IP | 0 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | SAE related to IP leading to discontinuation of IP | 0 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | Any adverse event related to pegfilgrastim | 105 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | SAE related to pegfilgrastim | 1 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | AE related to / leading to discontinuation of Peg | 6 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | SAE related to / leading to discontinuation of Peg | 0 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | Any adverse event | 194 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | SAE leading to discontinuation from study | 2 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 3 | 63 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | Worst grade of ≥ 4 | 20 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | Serious adverse events | 14 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 0 participants |
| Loratadine 10 mg QD | Number of Participants With Adverse Events (AEs) | AE leading to discontinuation from study | 3 participants |
Secondary
Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles
Bone pain data were captured as part of standard adverse event (AE) reporting.
Time frame: Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval)
Population: Full analysis set; n indicates the number of participants who entered each cycle.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| No Prophylaxis | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 2 (n=178, 180, 193) | 34.3 percentage of participants |
| No Prophylaxis | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 3 (n=165, 176, 188) | 33.9 percentage of participants |
| No Prophylaxis | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 4 (n=162, 169, 179) | 40.7 percentage of participants |
| No Prophylaxis | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Across All Cycles (n=191, 196, 200) | 63.4 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Across All Cycles (n=191, 196, 200) | 59.2 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 2 (n=178, 180, 193) | 34.4 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 4 (n=162, 169, 179) | 40.2 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 3 (n=165, 176, 188) | 34.1 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Across All Cycles (n=191, 196, 200) | 61.0 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 3 (n=165, 176, 188) | 36.2 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 4 (n=162, 169, 179) | 38.0 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles | Cycle 2 (n=178, 180, 193) | 34.7 percentage of participants |
Comparison: Difference across all treatment cycles95% CI: [-14.4, 6]
Comparison: Difference across all treatment cyces95% CI: [-12.5, 7.8]
Comparison: Dfference across all treatment cycles95% CI: [-8.3, 12]
Secondary
Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles
Bone pain data were captured as part of standard adverse event reporting. Severe bone pain is defined as grade 3 or 4 according to common terminology criteria for adverse events (CTCAE) version 3 grading criteria: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening or disabling.
Time frame: Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval)
Population: Full analysis set; n indicates the number of participants who entered each cycle.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| No Prophylaxis | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 1.9 percentage of participants |
| No Prophylaxis | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 1.8 percentage of participants |
| No Prophylaxis | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 4.7 percentage of participants |
| No Prophylaxis | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 1.1 percentage of participants |
| No Prophylaxis | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Across All Cycles (n=191, 196, 200) | 5.8 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 1.1 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 3.1 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 1.7 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 0.6 percentage of participants |
| Naproxen 500 mg BID | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Across All Cycles (n=191, 196, 200) | 4.1 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Across All Cycles (n=191, 196, 200) | 4.5 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 4 (n=162, 169, 179) | 0.0 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 1 (n=191, 196, 200) | 4.5 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 3 (n=165, 176, 188) | 0.0 percentage of participants |
| Loratadine 10 mg QD | Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles | Cycle 2 (n=178, 180, 193) | 0.0 percentage of participants |
Comparison: Difference across all treatment cycles95% CI: [-6.5, 3.2]
Comparison: Difference across all cycles95% CI: [-6.1, 3.6]
Comparison: Difference across all cycles95% CI: [-4.1, 4.9]