Trial Outcomes & Findings for NOLAN: Naproxen or Loratadine and Neulasta (NCT NCT01712009)

NCT ID: NCT01712009

Last Updated: 2018-01-30

Results Overview

Bone pain data were captured as part of standard adverse event (AE) reporting.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

600 participants

Primary outcome timeframe

Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval)

Results posted on

2018-01-30

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	No Prophylaxis Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	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.	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.
Overall Study STARTED	198	200	202
Overall Study Received Pegfilgrastim	191	196	200
Overall Study Received Naproxen / Loratadine	0	193	198
Overall Study COMPLETED	160	171	181
Overall Study NOT COMPLETED	38	29	21

Reasons for withdrawal

Reasons for withdrawal
Measure	No Prophylaxis Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	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.	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.
Overall Study Withdrawal by Subject	24	15	8
Overall Study Lost to Follow-up	2	0	1
Overall Study Decision by Sponsor	12	14	12

Baseline Characteristics

NOLAN: Naproxen or Loratadine and Neulasta

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	No Prophylaxis n=191 Participants Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	Naproxen 500 mg BID n=196 Participants 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.	Loratadine 10 mg QD n=200 Participants 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.	Total n=587 Participants Total of all reporting groups
Age, Continuous	54.8 years STANDARD_DEVIATION 10.7 • n=5 Participants	53.2 years STANDARD_DEVIATION 11.7 • n=7 Participants	54.6 years STANDARD_DEVIATION 10.9 • n=5 Participants	54.2 years STANDARD_DEVIATION 11.1 • n=4 Participants
Sex: Female, Male Female	191 Participants n=5 Participants	196 Participants n=7 Participants	200 Participants n=5 Participants	587 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized Hispanic/Latino	13 participants n=5 Participants	15 participants n=7 Participants	9 participants n=5 Participants	37 participants n=4 Participants
Race/Ethnicity, Customized Not Hispanic/Latino	178 participants n=5 Participants	181 participants n=7 Participants	191 participants n=5 Participants	550 participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized Asian	3 participants n=5 Participants	3 participants n=7 Participants	1 participants n=5 Participants	7 participants n=4 Participants
Race/Ethnicity, Customized Black (or African American)	33 participants n=5 Participants	27 participants n=7 Participants	23 participants n=5 Participants	83 participants n=4 Participants
Race/Ethnicity, Customized Multiple	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized White	148 participants n=5 Participants	166 participants n=7 Participants	173 participants n=5 Participants	487 participants n=4 Participants
Race/Ethnicity, Customized Other	5 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	7 participants n=4 Participants

PRIMARY outcome

Timeframe: Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval)

Population: Full anlysis set

Bone pain data were captured as part of standard adverse event (AE) reporting.

Outcome measures

Outcome measures
Measure	No Prophylaxis n=191 Participants Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	Naproxen 500 mg BID n=196 Participants 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.	Loratadine 10 mg QD n=200 Participants 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.
Percentage of Participants With Bone Pain (All Grades) in Cycle 1	46.6 percentage of participants Interval 39.4 to 53.9	40.3 percentage of participants Interval 33.4 to 47.5	42.5 percentage of participants Interval 35.6 to 49.7

SECONDARY outcome

Timeframe: 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.

Bone pain data were captured as part of standard adverse event (AE) reporting.

Outcome measures

Outcome measures
Measure	No Prophylaxis n=191 Participants Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	Naproxen 500 mg BID n=196 Participants 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.	Loratadine 10 mg QD n=200 Participants 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.
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 Interval 27.3 to 41.7	34.4 percentage of participants Interval 27.5 to 41.9	34.7 percentage of participants Interval 28.0 to 41.9
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 Interval 26.8 to 41.7	34.1 percentage of participants Interval 27.1 to 41.6	36.2 percentage of participants Interval 29.3 to 43.5
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 Interval 33.1 to 48.7	40.2 percentage of participants Interval 32.8 to 48.0	38.0 percentage of participants Interval 30.9 to 45.5
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 Interval 56.1 to 70.2	59.2 percentage of participants Interval 52.0 to 66.1	61.0 percentage of participants Interval 53.9 to 67.8

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	No Prophylaxis n=191 Participants Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	Naproxen 500 mg BID n=196 Participants 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.	Loratadine 10 mg QD n=200 Participants 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.
Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles Across All Cycles (n=191, 196, 200)	5.8 percentage of participants Interval 2.9 to 10.1	4.1 percentage of participants Interval 1.8 to 7.9	4.5 percentage of participants Interval 2.1 to 8.4
Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles Cycle 1 (n=191, 196, 200)	4.7 percentage of participants Interval 2.2 to 8.8	3.1 percentage of participants Interval 1.1 to 6.5	4.5 percentage of participants Interval 2.1 to 8.4
Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles Cycle 2 (n=178, 180, 193)	1.1 percentage of participants Interval 0.1 to 4.0	1.7 percentage of participants Interval 0.3 to 4.8	0.0 percentage of participants Interval 0.0 to 1.9
Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles Cycle 3 (n=165, 176, 188)	1.8 percentage of participants Interval 0.4 to 5.2	1.1 percentage of participants Interval 0.1 to 4.0	0.0 percentage of participants Interval 0.0 to 1.9
Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles Cycle 4 (n=162, 169, 179)	1.9 percentage of participants Interval 0.4 to 5.3	0.6 percentage of participants Interval 0.0 to 3.3	0.0 percentage of participants Interval 0.0 to 2.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	No Prophylaxis n=191 Participants Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	Naproxen 500 mg BID n=196 Participants 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.	Loratadine 10 mg QD n=200 Participants 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.
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	1.8 units on a scale Standard Error 0.2	1.7 units on a scale Standard Error 0.1
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	1.3 units on a scale Standard Error 0.1	1.4 units on a scale Standard Error 0.1
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	1.3 units on a scale Standard Error 0.1	1.4 units on a scale Standard Error 0.1
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	1.2 units on a scale Standard Error 0.1	1.3 units on a scale Standard Error 0.1
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	1.5 units on a scale Standard Error 0.1	1.5 units on a scale Standard Error 0.1

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	No Prophylaxis n=191 Participants Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	Naproxen 500 mg BID n=196 Participants 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.	Loratadine 10 mg QD n=200 Participants 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.
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	3.3 units on a scale Standard Error 0.2	3.0 units on a scale Standard Error 0.2
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	2.4 units on a scale Standard Error 0.2	2.6 units on a scale Standard Error 0.2
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	2.2 units on a scale Standard Error 0.2	2.5 units on a scale Standard Error 0.2
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	2.1 units on a scale Standard Error 0.2	2.1 units on a scale Standard Error 0.2
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	4.2 units on a scale Standard Error 0.2	4.1 units on a scale Standard Error 0.2

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	No Prophylaxis n=191 Participants Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	Naproxen 500 mg BID n=196 Participants 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.	Loratadine 10 mg QD n=200 Participants 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.
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	7.7 units on a scale * days Standard Error 0.6	7.0 units on a scale * days Standard Error 0.6
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	5.6 units on a scale * days Standard Error 0.6	5.9 units on a scale * days Standard Error 0.5
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	5.5 units on a scale * days Standard Error 0.6	6.1 units on a scale * days Standard Error 0.6
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	5.2 units on a scale * days Standard Error 0.6	5.6 units on a scale * days Standard Error 0.6
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	6.6 units on a scale * days Standard Error 0.5	6.3 units on a scale * days Standard Error 0.5

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	No Prophylaxis n=196 Participants Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.	Naproxen 500 mg BID n=193 Participants 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.	Loratadine 10 mg QD n=198 Participants 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.
Number of Participants With Adverse Events (AEs) SAE related to pegfilgrastim	4 participants	0 participants	1 participants
Number of Participants With Adverse Events (AEs) Any adverse event	188 participants	192 participants	194 participants
Number of Participants With Adverse Events (AEs) Worst grade of ≥ 2	164 participants	169 participants	168 participants
Number of Participants With Adverse Events (AEs) Worst grade of ≥ 3	74 participants	73 participants	63 participants
Number of Participants With Adverse Events (AEs) Worst grade of ≥ 4	18 participants	30 participants	20 participants
Number of Participants With Adverse Events (AEs) Serious adverse events	34 participants	30 participants	14 participants
Number of Participants With Adverse Events (AEs) Fatal adverse events	0 participants	0 participants	0 participants
Number of Participants With Adverse Events (AEs) AE leading to discontinuation from study	3 participants	5 participants	3 participants
Number of Participants With Adverse Events (AEs) SAE leading to discontinuation from study	1 participants	3 participants	2 participants
Number of Participants With Adverse Events (AEs) Any adverse event related to IP	0 participants	30 participants	7 participants
Number of Participants With Adverse Events (AEs) SAE related to IP	0 participants	1 participants	0 participants
Number of Participants With Adverse Events (AEs) AE related to IP leading to discontinuation of IP	0 participants	9 participants	0 participants
Number of Participants With Adverse Events (AEs) SAE related to IP leading to discontinuation of IP	0 participants	1 participants	0 participants
Number of Participants With Adverse Events (AEs) Any adverse event related to pegfilgrastim	87 participants	96 participants	105 participants
Number of Participants With Adverse Events (AEs) AE related to / leading to discontinuation of Peg	6 participants	3 participants	6 participants
Number of Participants With Adverse Events (AEs) SAE related to / leading to discontinuation of Peg	1 participants	0 participants	0 participants

Adverse Events

No Prophylactic Intervention

Serious events: 34 serious events

Other events: 184 other events

Deaths: 0 deaths

Naproxen 500mg BID

Serious events: 30 serious events

Other events: 190 other events

Deaths: 0 deaths

Loratadine 10mg QD

Serious events: 14 serious events

Other events: 193 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER