A Phase 2 interventional study of Naproxen and Loratadine in Bone Pain in Stage I - III Breast Cancer, sponsored by Amgen. Completed at 83 sites in United States. Open to female participants aged 18 Years to 100 Years. Per ClinicalTrials.gov, last updated 2018-01-30.
Sponsored by Amgen · Phase 2, Interventional, and Treatment
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.
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.
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Age 18 years or over
Exclusion Criteria
History of other malignancy within the past 5 years, with the following exceptions:
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:
Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis 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.
Drug: Naproxen · Biological: Pegfilgrastim · Drug: Chemotherapy
Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis 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.
Drug: Loratadine · Biological: Pegfilgrastim · Drug: Chemotherapy
Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis.
Biological: Pegfilgrastim · Drug: Chemotherapy
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.
Also known as: Neulasta®
The choice of chemotherapy regimen (agent, dose, and schedule) is at the discretion of the treating physician.
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)
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)
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)
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)
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)
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)
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.
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.
| Milestone | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD |
|---|---|---|---|
| Started | 198 | 200 | 202 |
| Received pegfilgrastim | 191 | 196 | 200 |
| Received naproxen / loratadine | 0 | 193 | 198 |
| Completed | 160 | 171 | 181 |
| Not completed | 38 | 29 | 21 |
| Withdrew: Withdrawal by subject | 24 | 15 | 8 |
| Withdrew: Lost to follow-up | 2 | 0 | 1 |
| Withdrew: Decision by sponsor | 12 | 14 | 12 |
Bone pain data were captured as part of standard adverse event (AE) reporting.
| percentage of participants | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD |
|---|---|---|---|
| Percentage of Participants With Bone Pain (All Grades) in Cycle 1 | 46.6 (39.4 to 53.9) | 40.3 (33.4 to 47.5) | 42.5 (35.6 to 49.7) |
Bone pain data were captured as part of standard adverse event (AE) reporting.
| percentage of participants | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD |
|---|---|---|---|
| Cycle 2 (n=178, 180, 193) | 34.3 (27.3 to 41.7) | 34.4 (27.5 to 41.9) | 34.7 (28.0 to 41.9) |
| Cycle 3 (n=165, 176, 188) | 33.9 (26.8 to 41.7) | 34.1 (27.1 to 41.6) | 36.2 (29.3 to 43.5) |
| Cycle 4 (n=162, 169, 179) | 40.7 (33.1 to 48.7) | 40.2 (32.8 to 48.0) | 38.0 (30.9 to 45.5) |
| Across All Cycles (n=191, 196, 200) | 63.4 (56.1 to 70.2) | 59.2 (52.0 to 66.1) | 61.0 (53.9 to 67.8) |
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.
| percentage of participants | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD |
|---|---|---|---|
| Cycle 1 (n=191, 196, 200) | 4.7 (2.2 to 8.8) | 3.1 (1.1 to 6.5) | 4.5 (2.1 to 8.4) |
| Cycle 2 (n=178, 180, 193) | 1.1 (0.1 to 4.0) | 1.7 (0.3 to 4.8) | 0.0 (0.0 to 1.9) |
| Cycle 3 (n=165, 176, 188) | 1.8 (0.4 to 5.2) | 1.1 (0.1 to 4.0) | 0.0 (0.0 to 1.9) |
| Cycle 4 (n=162, 169, 179) | 1.9 (0.4 to 5.3) | 0.6 (0.0 to 3.3) | 0.0 (0.0 to 2.0) |
| Across All Cycles (n=191, 196, 200) | 5.8 (2.9 to 10.1) | 4.1 (1.8 to 7.9) | 4.5 (2.1 to 8.4) |
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.
| units on a scale | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD |
|---|---|---|---|
| Cycle 1 (n=191, 196, 200) | 2.2 ± 0.2 | 1.8 ± 0.2 | 1.7 ± 0.1 |
| Cycle 2 (n=178, 180, 193) | 1.7 ± 0.2 | 1.3 ± 0.1 | 1.4 ± 0.1 |
| Cycle 3 (n=165, 176, 188) | 1.6 ± 0.2 | 1.3 ± 0.1 | 1.4 ± 0.1 |
| Cycle 4 (n=162, 169, 179) | 1.7 ± 0.2 | 1.2 ± 0.1 | 1.3 ± 0.1 |
| Across all Cycles (n=191, 196, 200) | 1.9 ± 0.1 | 1.5 ± 0.1 | 1.5 ± 0.1 |
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.
| units on a scale | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD |
|---|---|---|---|
| Cycle 1 (n=191, 196, 200) | 3.9 ± 0.2 | 3.3 ± 0.2 | 3.0 ± 0.2 |
| Cycle 2 (n=178, 180, 193) | 3.0 ± 0.2 | 2.4 ± 0.2 | 2.6 ± 0.2 |
| Cycle 3 (n=165, 176, 188) | 2.7 ± 0.2 | 2.2 ± 0.2 | 2.5 ± 0.2 |
| Cycle 4 (n=162, 169, 179) | 2.8 ± 0.2 | 2.1 ± 0.2 | 2.1 ± 0.2 |
| Across All Cycles (n=191, 196, 200) | 4.7 ± 0.2 | 4.2 ± 0.2 | 4.1 ± 0.2 |
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.
| units on a scale * days | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD |
|---|---|---|---|
| Cycle 1 (n=191, 196, 200) | 9.3 ± 0.7 | 7.7 ± 0.6 | 7.0 ± 0.6 |
| Cycle 2 (n=178, 180, 193) | 7.3 ± 0.7 | 5.6 ± 0.6 | 5.9 ± 0.5 |
| Cycle 3 (n=165, 176, 188) | 6.8 ± 0.7 | 5.5 ± 0.6 | 6.1 ± 0.6 |
| Cycle 4 (n=162, 169, 179) | 7.2 ± 0.7 | 5.2 ± 0.6 | 5.6 ± 0.6 |
| Across All Cycles (n=191, 196, 200) | 8.0 ± 0.6 | 6.6 ± 0.5 | 6.3 ± 0.5 |
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.
| participants | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD |
|---|---|---|---|
| Any adverse event | 188 | 192 | 194 |
| Worst grade of ≥ 2 | 164 | 169 | 168 |
| Worst grade of ≥ 3 | 74 | 73 | 63 |
| Worst grade of ≥ 4 | 18 | 30 | 20 |
| Serious adverse events | 34 | 30 | 14 |
| Fatal adverse events | 0 | 0 | 0 |
| AE leading to discontinuation from study | 3 | 5 | 3 |
| SAE leading to discontinuation from study | 1 | 3 | 2 |
| Any adverse event related to IP | 0 | 30 | 7 |
| SAE related to IP | 0 | 1 | 0 |
| AE related to IP leading to discontinuation of IP | 0 | 9 | 0 |
| SAE related to IP leading to discontinuation of IP | 0 | 1 | 0 |
| Any adverse event related to pegfilgrastim | 87 | 96 | 105 |
| SAE related to pegfilgrastim | 4 | 0 | 1 |
| AE related to / leading to discontinuation of Peg | 6 | 3 | 6 |
| SAE related to / leading to discontinuation of Peg | 1 | 0 | 0 |
Collected over From first dose of investigational product (naproxen or loratidine) or first dose of pegfilgrastim, whichever occurred first, until 30 days after last dose, up to 24 weeks.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| No Prophylactic Intervention | — | 34/196 (17.3%) | 184/196 (93.9%) |
| Naproxen 500mg BID | — | 30/193 (15.5%) | 190/193 (98.4%) |
| Loratadine 10mg QD | — | 14/198 (7.1%) | 193/198 (97.5%) |
| Event | No Prophylactic Intervention | Naproxen 500mg BID | Loratadine 10mg QD |
|---|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 7/196 | 6/193 | 3/198 |
| DehydrationMetabolism and nutrition disorders | 6/196 | 3/193 | 1/198 |
| SyncopeNervous system disorders | 1/196 | 4/193 | 0/198 |
| PyrexiaGeneral disorders | 3/196 | 3/193 | 2/198 |
| NauseaGastrointestinal disorders | 3/196 | 2/193 | 0/198 |
| VomitingGastrointestinal disorders | 3/196 | 2/193 | 0/198 |
| DiarrhoeaGastrointestinal disorders | 2/196 | 2/193 | 0/198 |
| SepsisInfections and infestations | 1/196 | 2/193 | 0/198 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 0/196 | 2/193 | 0/198 |
| NeutropeniaBlood and lymphatic system disorders | 2/196 | 0/193 | 2/198 |
| Event | No Prophylactic Intervention | Naproxen 500mg BID | Loratadine 10mg QD |
|---|---|---|---|
| FatigueGeneral disorders | 120/196 | 110/193 | 128/198 |
| NauseaGastrointestinal disorders | 98/196 | 118/193 | 100/198 |
| AlopeciaSkin and subcutaneous tissue disorders | 68/196 | 85/193 | 106/198 |
| ConstipationGastrointestinal disorders | 60/196 | 77/193 | 66/198 |
| DiarrhoeaGastrointestinal disorders | 67/196 | 75/193 | 71/198 |
| Bone painMusculoskeletal and connective tissue disorders | 56/196 | 55/193 | 63/198 |
| AnaemiaBlood and lymphatic system disorders | 42/196 | 60/193 | 40/198 |
| HeadacheNervous system disorders | 49/196 | 54/193 | 48/198 |
| VomitingGastrointestinal disorders | 32/196 | 43/193 | 29/198 |
| Decreased appetiteMetabolism and nutrition disorders | 36/196 | 34/193 | 39/198 |
Full analysis set included all participants based on the randomization treatment group who received primary prophylaxis with pegfilgrastim.
| Age, Continuous(years) | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD | Total |
|---|---|---|---|---|
| Mean | 54.8 ± 10.7 | 53.2 ± 11.7 | 54.6 ± 10.9 | 54.2 ± 11.1 |
| Sex: Female, Male(Participants) | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD | Total |
|---|---|---|---|---|
| Female | 191 | 196 | 200 | 587 |
| Male | 0 | 0 | 0 | 0 |
| Race/Ethnicity, Customized(participants) | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD | Total |
|---|---|---|---|---|
| Hispanic/Latino | 13 | 15 | 9 | 37 |
| Not Hispanic/Latino | 178 | 181 | 191 | 550 |
| Race/Ethnicity, Customized(participants) | No Prophylaxis | Naproxen 500 mg BID | Loratadine 10 mg QD | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 0 | 1 |
| Asian | 3 | 3 | 1 | 7 |
| Black (or African American) | 33 | 27 | 23 | 83 |
| Multiple | 0 | 0 | 1 | 1 |
| Native Hawaiian or Other Pacific Islander | 1 | 0 | 0 | 1 |
| White | 148 | 166 | 173 | 487 |
| Other | 5 | 0 | 2 | 7 |
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