Trial Outcomes & Findings for A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) (NCT NCT00471497)

Last Updated: 2020-11-18

Results Overview

MMR is defined as the percentage of participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR)) at 12 months.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

846 participants

Primary outcome timeframe

Baseline, 12 months

Results posted on

2020-11-18

Participant Flow

The study over-enrolled, and 846 patients (283 in the imatinib 400 mg arm, 282 in the nilotinib 300 mg arm and 281 in the nilotinib 400 mg arm) were randomized. DP = disease progression, SOR/TF = Suboptimal response or treatment failure

Randomization was planned for a total of 771 patients.

Participant milestones

Participant milestones
Measure	Imatinib 400 mg QD Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Core Treatment Phase STARTED	283	282	281
Core Treatment Phase Safety Analysis Set	280	279	277
Core Treatment Phase Discon. Core/Did Not Enter Ext.	235	256	278
Core Treatment Phase Discontinued Core/Entered Ext.	48	26	3
Core Treatment Phase COMPLETED	99	107	99
Core Treatment Phase NOT COMPLETED	184	175	182
Extension Phase STARTED	48	26	3
Extension Phase COMPLETED	21	12	2
Extension Phase NOT COMPLETED	27	14	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Imatinib 400 mg QD Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Core Treatment Phase Abnormal Laboratory Values	3	9	9
Core Treatment Phase Abnormal Test Procedures	1	0	1
Core Treatment Phase Condition no longer requires study drug	0	1	0
Core Treatment Phase Withdrawal by Subject	31	29	34
Core Treatment Phase Lost to Follow-up	6	6	3
Core Treatment Phase Death	3	9	3
Core Treatment Phase Disease Progression	10	2	4
Core Treatment Phase Protocol Violation	6	15	11
Core Treatment Phase Sub optimal response or treat. failure	19	11	13
Core Treatment Phase Administrative problems	14	14	12
Core Treatment Phase Adverse Event	43	53	89
Core Treatment Phase Disc. Core/Entered Ext. - DP progression	2	0	0
Core Treatment Phase Disc. Core/Entered Ext.- SOR/TF	46	26	3
Extension Phase Adverse Event	9	5	1
Extension Phase Unsatisfactory therapeutic effect	8	6	0
Extension Phase Withdrawal by Subject	3	1	0
Extension Phase Lost to Follow-up	2	0	0
Extension Phase Death	1	0	0
Extension Phase Disease progression	2	0	0
Extension Phase Protocol Violation	2	2	0

Baseline Characteristics

Missing patient that cannot be identified

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Total n=846 Participants Total of all reporting groups
Age, Customized <35 years	63 Participants n=283 Participants	67 Participants n=282 Participants	65 Participants n=281 Participants	195 Participants n=846 Participants
Age, Customized >= 35 - <45 years	67 Participants n=283 Participants	50 Participants n=282 Participants	59 Participants n=281 Participants	176 Participants n=846 Participants
Age, Customized >=45 - <55 years	63 Participants n=283 Participants	72 Participants n=282 Participants	65 Participants n=281 Participants	200 Participants n=846 Participants
Age, Customized >=55 - < 65 years	55 Participants n=283 Participants	57 Participants n=282 Participants	65 Participants n=281 Participants	177 Participants n=846 Participants
Age, Customized >=65 years	35 Participants n=283 Participants	36 Participants n=282 Participants	27 Participants n=281 Participants	98 Participants n=846 Participants
Sex: Female, Male Female	125 Participants n=283 Participants	124 Participants n=282 Participants	106 Participants n=281 Participants	355 Participants n=846 Participants
Sex: Female, Male Male	158 Participants n=283 Participants	158 Participants n=282 Participants	175 Participants n=281 Participants	491 Participants n=846 Participants
Race/Ethnicity, Customized Caucasian	187 Participants n=283 Participants • Missing patient that cannot be identified	170 Participants n=282 Participants • Missing patient that cannot be identified	185 Participants n=281 Participants • Missing patient that cannot be identified	542 Participants n=846 Participants • Missing patient that cannot be identified
Race/Ethnicity, Customized Black	7 Participants n=282 Participants • Missing patient that cannot be identified	12 Participants n=281 Participants • Missing patient that cannot be identified	11 Participants n=280 Participants • Missing patient that cannot be identified	30 Participants n=843 Participants • Missing patient that cannot be identified
Race/Ethnicity, Customized Asian	71 Participants n=283 Participants • Missing patient that cannot be identified	76 Participants n=282 Participants • Missing patient that cannot be identified	66 Participants n=281 Participants • Missing patient that cannot be identified	213 Participants n=846 Participants • Missing patient that cannot be identified
Race/Ethnicity, Customized Native American	1 Participants n=283 Participants • Missing patient that cannot be identified	0 Participants n=282 Participants • Missing patient that cannot be identified	2 Participants n=281 Participants • Missing patient that cannot be identified	3 Participants n=846 Participants • Missing patient that cannot be identified
Race/Ethnicity, Customized Other	17 Participants n=283 Participants • Missing patient that cannot be identified	24 Participants n=282 Participants • Missing patient that cannot be identified	17 Participants n=281 Participants • Missing patient that cannot be identified	58 Participants n=846 Participants • Missing patient that cannot be identified

PRIMARY outcome

Timeframe: Baseline, 12 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Major Molecular Response Rate (MMR) at 12 Months Between All 3 Arms - With Imputation	22.3 Percentage of participants Interval 17.6 to 27.6	44.3 Percentage of participants Interval 38.4 to 50.3	42.7 Percentage of participants Interval 36.8 to 48.7

PRIMARY outcome

Timeframe: 12 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation Sokal risk group = Low	26.0 Percentage of participants Interval 17.9 to 35.5	40.8 Percentage of participants Interval 31.2 to 50.9	53.4 Percentage of participants Interval 43.3 to 63.3
Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation Sokal risk group = Interm.	22.8 Percentage of participants Interval 15.0 to 32.2	50.5 Percentage of participants Interval 40.4 to 60.6	40.0 Percentage of participants Interval 30.3 to 50.3
Percentage of Participants With MMR at 12 Months Between All 3 Arms by Sokal Risk Group With Imputation Sokal risk group = High	16.7 Percentage of participants Interval 9.2 to 26.8	41.0 Percentage of participants Interval 30.0 to 52.7	32.1 Percentage of participants Interval 21.9 to 43.6

SECONDARY outcome

Timeframe: 24 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Durable MMR at 24 months is defined as having MMR both at 12 months and at 24 months, and with no documented loss of MMR between these 12 month and 24 month time points.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rates of Durable MMR at 24 Months Between All 3 Arms	20.5 Percentage of participants Interval 15.9 to 25.7	41.8 Percentage of participants Interval 36.0 to 47.8	39.1 Percentage of participants Interval 33.4 to 45.1

SECONDARY outcome

Timeframe: 12, 24, 36, 48, 60, 72 months (M)

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Patients with no CCyR as the best response by any specific time point, all missing cytogenetic evaluations by that time point or Ph- at baseline are combined as "Nocomplete cytogenetic response".

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months CCyR at M12	55.5 Percentage of participants	70.2 Percentage of participants	68.7 Percentage of participants
Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months CCyR at M24	61.5 Percentage of participants	66.0 Percentage of participants	66.2 Percentage of participants
Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months CCyR at M36	14.1 Percentage of participants	9.2 Percentage of participants	12.8 Percentage of participants
Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months CCyR at M48	11.3 Percentage of participants	8.9 Percentage of participants	13.5 Percentage of participants
Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months CCyR at M60	2.5 Percentage of participants	2.8 Percentage of participants	2.8 Percentage of participants
Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months and Beyond 12 Months CCyR at M72	1.8 Percentage of participants	1.8 Percentage of participants	2.8 Percentage of participants

SECONDARY outcome

Timeframe: 12 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=282 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of Major Molecular Response (MMR) at 12 Months Between Two Nilotinib Arms	44.3 Percentage of participants Interval 38.4 to 50.3	42.7 Percentage of participants Interval 36.8 to 48.7	—

SECONDARY outcome

Timeframe: 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M6	12.0 Percentage of participants Interval 8.5 to 16.4	33.0 Percentage of participants Interval 27.5 to 38.8	29.5 Percentage of participants Interval 24.3 to 35.2
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M12	22.3 Percentage of participants Interval 17.6 to 27.6	44.7 Percentage of participants Interval 38.8 to 50.7	43.1 Percentage of participants Interval 37.2 to 49.1
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M24	37.5 Percentage of participants Interval 31.8 to 43.4	61.7 Percentage of participants Interval 55.8 to 67.4	59.1 Percentage of participants Interval 53.1 to 64.9
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M36	38.5 Percentage of participants Interval 32.8 to 44.5	59.2 Percentage of participants Interval 53.2 to 65.0	57.3 Percentage of participants Interval 51.3 to 63.2
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M48	43.8 Percentage of participants Interval 38.0 to 49.8	59.9 Percentage of participants Interval 54.0 to 65.7	55.2 Percentage of participants Interval 49.1 to 61.1
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M60	49.1 Percentage of participants Interval 43.2 to 55.1	62.8 Percentage of participants Interval 56.8 to 68.4	61.2 Percentage of participants Interval 55.2 to 66.9
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M72	41.7 Percentage of participants Interval 35.9 to 47.7	52.5 Percentage of participants Interval 46.5 to 58.4	57.7 Percentage of participants Interval 51.6 to 63.5
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M84	40.3 Percentage of participants Interval 34.5 to 46.3	50.0 Percentage of participants Interval 44.0 to 56.0	50.9 Percentage of participants Interval 44.9 to 56.9
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M96	37.5 Percentage of participants Interval 31.8 to 43.4	46.1 Percentage of participants Interval 40.2 to 52.1	46.3 Percentage of participants Interval 40.3 to 52.3
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M108	37.5 Percentage of participants Interval 31.8 to 43.4	43.3 Percentage of participants Interval 37.4 to 49.3	40.2 Percentage of participants Interval 34.4 to 46.2
Rate of MMR at 6 Months and Beyond in All 3 Treatment Arms MMR at M120	36.4 Percentage of participants Interval 30.8 to 42.3	37.9 Percentage of participants Interval 32.3 to 43.9	39.1 Percentage of participants Interval 33.4 to 45.1

SECONDARY outcome

Timeframe: at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Molecular response of \<=0.01% is defined as BCR-ABL ratio (%) on IS \<= 0.01% (corresponds to \>=4 log reduction of BCR-ABL transcripts from standardized baseline value)

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 6 months	1.1 Percentage of participants Interval 0.2 to 3.1	8.9 Percentage of participants Interval 5.8 to 12.8	5.7 Percentage of participants Interval 3.3 to 9.1
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 12 months	3.9 Percentage of participants Interval 2.0 to 6.8	12.1 Percentage of participants Interval 8.5 to 16.4	8.9 Percentage of participants Interval 5.8 to 12.9
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 24 months	10.2 Percentage of participants Interval 7.0 to 14.4	24.5 Percentage of participants Interval 19.6 to 29.9	22.1 Percentage of participants Interval 17.4 to 27.4
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 36 months	14.1 Percentage of participants Interval 10.3 to 18.7	29.4 Percentage of participants Interval 24.2 to 35.1	23.8 Percentage of participants Interval 19.0 to 29.3
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 48 months	19.8 Percentage of participants Interval 15.3 to 24.9	33.0 Percentage of participants Interval 27.5 to 38.8	29.9 Percentage of participants Interval 24.6 to 35.6
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 60 months	31.1 Percentage of participants Interval 25.7 to 36.8	47.9 Percentage of participants Interval 41.9 to 53.9	43.4 Percentage of participants Interval 37.5 to 49.4
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 72 months	27.2 Percentage of participants Interval 22.1 to 32.8	44.3 Percentage of participants Interval 38.4 to 50.3	45.2 Percentage of participants Interval 39.3 to 51.2
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 84 months	29.0 Percentage of participants Interval 23.8 to 34.6	42.9 Percentage of participants Interval 37.1 to 48.9	40.6 Percentage of participants Interval 34.8 to 46.6
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 96 months	28.3 Percentage of participants Interval 23.1 to 33.9	39.7 Percentage of participants Interval 34.0 to 45.7	38.1 Percentage of participants Interval 32.4 to 44.0
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 108 months	32.2 Percentage of participants Interval 26.7 to 37.9	40.4 Percentage of participants Interval 34.6 to 46.4	34.9 Percentage of participants Interval 29.3 to 40.8
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 120 months	28.3 Percentage of participants Interval 23.1 to 33.9	35.5 Percentage of participants Interval 29.9 to 41.4	33.8 Percentage of participants Interval 28.3 to 39.7

SECONDARY outcome

Timeframe: at 6, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

This is the molecular response of \<=0.0032% is defined as BCR-ABL ratio (%) on IS \<= 0.0032% (corresponds to \>=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 6 months	0.0 Percentage of participants Interval 0.0 to 1.3	3.5 Percentage of participants Interval 1.7 to 6.4	1.4 Percentage of participants Interval 0.4 to 3.6
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 12 months	0.4 Percentage of participants Interval 0.0 to 2.0	4.6 Percentage of participants Interval 2.5 to 7.8	5.0 Percentage of participants Interval 2.8 to 8.2
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 24 months	2.8 Percentage of participants Interval 1.2 to 5.5	12.4 Percentage of participants Interval 8.8 to 16.8	7.8 Percentage of participants Interval 5.0 to 11.6
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 36 months	8.1 Percentage of participants Interval 5.2 to 11.9	13.8 Percentage of participants Interval 10.0 to 18.4	12.1 Percentage of participants Interval 8.5 to 16.5
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01032 at 48 months	10.2 Percentage of participants Interval 7.0 to 14.4	16.3 Percentage of participants Interval 12.2 to 21.2	17.1 Percentage of participants Interval 12.9 to 22.0
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 60 months	19.8 Percentage of participants Interval 15.3 to 24.9	32.3 Percentage of participants Interval 26.8 to 38.1	29.5 Percentage of participants Interval 24.3 to 35.2
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 72 months	18.0 Percentage of participants Interval 13.7 to 23.0	31.2 Percentage of participants Interval 25.8 to 37.0	28.8 Percentage of participants Interval 23.6 to 34.5
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 84 months	19.1 Percentage of participants Interval 14.7 to 24.2	31.6 Percentage of participants Interval 26.2 to 37.3	28.8 Percentage of participants Interval 23.6 to 34.5
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.01% at 96 months	23.3 Percentage of participants Interval 18.5 to 28.7	31.9 Percentage of participants Interval 26.5 to 37.7	32.4 Percentage of participants Interval 26.9 to 38.2
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 108 months	24.0 Percentage of participants Interval 19.2 to 29.4	31.9 Percentage of participants Interval 26.5 to 37.7	28.1 Percentage of participants Interval 22.9 to 33.8
Rate of a ≥ 4.5 Log Reduction in BCR-ABL Transcripts in Nilotinib Treatment Arms With Imatinib Molecular response of <=0.0032% at 120 months	21.2 Percentage of participants Interval 16.6 to 26.4	27.0 Percentage of participants Interval 21.9 to 32.5	25.6 Percentage of participants Interval 20.6 to 31.1

SECONDARY outcome

Timeframe: up to 84 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Time to MMR is defined as time from date of randomization to the date of the first documented MMR in nilotinib treatment arms, compared to imatinib in adult patients with Ph+ CML in CP.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Time to First MMR	14.13 Months Interval 11.6 to 17.31	8.31 Months Interval 6.21 to 8.48	8.53 Months Interval 8.31 to 11.07

SECONDARY outcome

Timeframe: approx. 11 years

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Duration of MMR for patients with MMR is defined as the time between date of MMR and the earliest of the following: loss of MMR, CML-related death or progression to AP/BC during study treatment The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Duration of MMR	NA Months NA = not enough events to calculate median and CI of duration MMR	NA Months NA = not enough events to calculate median and CI of duration MMR	NA Months NA = not enough events to calculate median and CI of duration MMR

SECONDARY outcome

Timeframe: up to 84 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Time to BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% is defined as: date of first BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% - date of randomization +1.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts time to first molecular response of <=0.01%	30.46 Months Interval 24.11 to 36.01	19.38 Months Interval 16.62 to 22.34	22.70 Months Interval 19.48 to 27.63
Time to Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts time to first molecular response of <=0.0032%	37.29 Months Interval 33.45 to 41.63	32.46 Months Interval 23.23 to 38.67	35.94 Months Interval 30.39 to 41.0

SECONDARY outcome

Timeframe: approx. 11 years

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received

It is defined as the time from the date of first documented BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032% to the earliest of the following: Loss of BCR-ABL ratio of ≤ 0.01% and ≤ 0.0032%, respectively, CML-related death or progression to AP/BC during study treatment. The time will be censored at last molecular assessment (PCR) date for patients for whom none of the above events is reported.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts duration of first molecular response of <=0.01%	NA Months NA = not enough events to calculate median and CI of this molecular response (BCR-ABL ratio of ≤ 0.01%)	NA Months NA = not enough events to calculate median and CI of this molecular response (BCR-ABL ratio of ≤ 0.01%)	NA Months NA = not enough events to calculate median and CI of this molecular response (BCR-ABL ratio of ≤ 0.01%)
Duration of Both a ≥ 4 and ≥ 4.5 Log Reduction in BCR-ABL Transcripts duration of first molecular response of <=0.0032%	NA Months NA = not enough events to calculate median and CI of this molecular response (BCR-ABL ratio of ≤ 0.0032%)	NA Months NA = not enough events to calculate median and CI of this molecular response (BCR-ABL ratio of ≤ 0.0032%)	NA Months NA = not enough events to calculate median and CI of this molecular response (BCR-ABL ratio of ≤ 0.0032%)

SECONDARY outcome

Timeframe: 12 months, 24 months, Overall on Core study (approx. 11 years)

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received

Rate of hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes \< 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of Hematologic Response Complete hematologic response (CHR) by M12	93.3 Percentage of participants Interval 89.7 to 95.9	90.1 Percentage of participants Interval 86.0 to 93.3	89.0 Percentage of participants Interval 84.7 to 92.4
Rate of Hematologic Response CHR by M24	93.6 Percentage of participants Interval 90.1 to 96.2	90.8 Percentage of participants Interval 86.8 to 93.9	90.4 Percentage of participants Interval 86.3 to 93.6
Rate of Hematologic Response CHR Overall	94.0 Percentage of participants Interval 90.6 to 96.5	92.2 Percentage of participants Interval 88.4 to 95.0	90.7 Percentage of participants Interval 86.7 to 93.9

SECONDARY outcome

Timeframe: 24 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received

Time to CCyR is defined as the time from the date of randomization to the date of first documented CCyR

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Time to Complete Cytogenic Response (CCyR)	8.5 Months Interval 5.8 to 10.9	5.7 Months Interval 5.6 to 5.7	5.7 Months Interval 5.7 to 5.8

SECONDARY outcome

Timeframe: up to 72 months

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Duration of CCyR is defined as the time from date of first documented CCyR to the earliest date of loss of CCyR.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Duration of CCyR	NA Months NA = not enough events to calculate median and CI of duration CCyR	NA Months NA = not enough events to calculate median and CI of duration CCyR	NA Months NA = not enough events to calculate median and CI of duration CCyR

SECONDARY outcome

Timeframe: approx. 11 years

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Progression-free survival is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring in the core or extension study, or during the follow-up period after discontinuation of core or extension study

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Progression-free Survival (PFS)	NA Months NA = not enough events to calculate median or CI of PFS	NA Months NA = not enough events to calculate median or CI of PFS	NA Months NA = not enough events to calculate median or CI of PFS

SECONDARY outcome

Timeframe: approx. 11 years

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Event-free survival is defined as the time from the date of randomization to the date of first occurrence of any of the following: death due to any cause (if death is the primary reason for discontinuation), progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Event-free Survival (EFS)	NA Months NA = not enough events to calculate median and CI of EFS	NA Months NA = not enough events to calculate median and CI of EFS	NA Months NA = not enough events to calculate median and CI of EFS

SECONDARY outcome

Timeframe: approx. 11 years

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

OS is defined as the time from the date of randomization to the date death. Up to 10 calendar years of follow up from the date when the last patient randomized received the first dose of study drug in all active treatment arms of adult patients with Ph+ CML CP.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Overall Survival (OS)	NA Months NA = not enough events to calculate median and CI of OS	NA Months NA = not enough events to calculate median and CI of OS	NA Months NA = not enough events to calculate median and CI of OS

SECONDARY outcome

Timeframe: approx. 11 years

Population: Safety Set: Safety set contained 836 patients who received at least one dose of study medication.

Actual dose intensity is defined as total dose over time on treatment

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=280 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=279 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=277 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Actual Dose-intensity	400.0 mg/day Interval 206.0 to 800.0	591.1 mg/day Interval 186.0 to 699.0	758.9 mg/day Interval 232.0 to 800.0

SECONDARY outcome

Timeframe: approx. 11 years

Population: Full analysis Set (FAS): Contained 846 randomized patients. Patients were analyzed according to the treatment they were randomized to, regardless of actual treatment received.

Time to progression to AP/BC is defined as the time from the date of randomization to the date of event defined as the first documented disease progression to AP/BC or the date of CML related death.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=283 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=282 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=281 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Time to Progression to AP/BC	NA Months NA = not enough events to calculate median and CI of TTP	NA Months NA = not enough events to calculate median and CI of TTP	NA Months NA = not enough events to calculate median and CI of TTP

SECONDARY outcome

Timeframe: any day after day 8 up to cycle 12 (each cycle = 28 days) and after at least 3 consecutive days without dose interruption or dose modification at pre-dose (0 hour), 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, and 12 hours after dose administration

Population: Global Full Pharmacokinetics (PK) set: Full-PK set contained 16 patients who received nilotinib. Full PK profile was meant for nilotinib arms only and included all patients with available Full PK profile at one visit.

Cmax is defined as the maximum serum concentration after dose

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=8 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=8 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Pharmacokinetics: Cmax	1555 ng/mL Interval 1340.0 to 2300.0	1440 ng/mL Interval 1002.0 to 2125.0	—

SECONDARY outcome

Cmin is defined as the minimum serum concentration after dose

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=8 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=8 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Pharmacokinetics: Cmin	1430 ng/mL Interval 1250.0 to 1740.0	915 ng/mL Interval 752.0 to 2080.0	—

SECONDARY outcome

Tmax is defined as the sampling time when maximum measured serum concentration occurs

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=8 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=8 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Pharmacokinetics: Tmax	1.47 hour (h) Interval 0.5 to 2.04	1.50 hour (h) Interval 0.0 to 2.02	—

SECONDARY outcome

AUC0-last is defined as area under concentration-time curve from time zero to the last measurable sample, calculated by log-linear trapezoidal method

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=8 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=8 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Pharmacokinetics: AUC0-last	14446 h.ng/mL Interval 12806.0 to 17411.0	11689 h.ng/mL Interval 7925.0 to 18678.0	—

SECONDARY outcome

Timeframe: Overall for Extension study for approx. 10 years

Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=48 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=26 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=3 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of Hematologic Response on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	83.3 Percentage of participants Interval 69.8 to 92.5	84.6 Percentage of participants Interval 65.1 to 95.6	66.7 Percentage of participants Interval 9.4 to 99.2

SECONDARY outcome

Timeframe: Overall for Extension study for approx. 10 years

Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Rate of CCyR is defined as the percentage of participants in complete cytogenetic response (CCyR). CcyR is defined as 0% of Ph+ metaphases in the bone marrow.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=48 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=26 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=3 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of Complete Cytogenetic Response (CCyR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	72.9 Percentage of participants Interval 58.2 to 84.7	73.1 Percentage of participants Interval 52.2 to 88.4	66.7 Percentage of participants Interval 9.4 to 99.2

SECONDARY outcome

Timeframe: Overall for Extension study for approx. 10 years

Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Rate of MMR is defined as the percentage pf participants in MMR (reduction of ≥ 3 logs in BCR-ABL transcripts compared to the standardized baseline established in IRIS, or ≤ 0.1% BCR-ABL/ABL % by international scale and measured by real-time quantitative polymerase chain reaction (RQ-PCR))

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=48 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=26 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=3 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of Major Molecular Response (MMR) on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	64.6 Percentage of participants Interval 49.5 to 77.8	73.1 Percentage of participants Interval 52.2 to 88.4	66.7 Percentage of participants Interval 9.4 to 99.2

SECONDARY outcome

Timeframe: Overall for Extension study for approx. 10 years

Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Molecular response of \<=0.01% is defined as BCR-ABL ratio (%) on IS \<= 0.01% (corresponds to \>=4 log reduction of BCR-ABL transcripts from standardized baseline value)

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=48 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=26 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=3 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of a ≥ 4 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	43.8 Percentage of participants Interval 29.5 to 58.8	57.7 Percentage of participants Interval 36.9 to 76.6	33.3 Percentage of participants Interval 0.8 to 90.6

SECONDARY outcome

Timeframe: Overall for Extension study for approx. 10 years

Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

Molecular response of \<=0.0032% is defined as BCR-ABL ratio (%) on IS \<= 0.0032% (corresponds to \>=4.5 log reduction of BCR-ABL transcripts from standardized baseline value)

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=48 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=26 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=3 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Rate of ≥ 4.5 Log Reduction in BCR-ABL Transcripts on Nilotinib 400 mg BID Therapy After Insufficient Response During Core Treatment and Switch to Extension Phase (Extension)	35.4 Percentage of participants Interval 22.2 to 50.5	38.5 Percentage of participants Interval 20.2 to 59.4	33.3 Percentage of participants Interval 0.8 to 90.6

SECONDARY outcome

Timeframe: Overall for Extension study for approx. 10 years

Population: Extension Set: The Extension set (ES) consisted of patients who received at least one dose of treatment in the extension phase.

This is the percentage of patients with any emergent mutation on extension treatment. The mutation comprised of T315T, less sensitive to nilotinib, unknown and sensitive to nilotinib.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=48 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=26 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=3 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
Presence of Newly Observed BCR-ABL Mutations in Patients Post-baseline and Correlate With Response to Treatment With Imatinib and Nilotinib (Extension)	20.8 Percentage of participants	11.5 Percentage of participants	33.3 Percentage of participants

POST_HOC outcome

Timeframe: From FPFV up to 28 days post treatment (approx. 11 years), From FPFV to LPLV (approx. 12 years)

Population: Safety analysis set consisted of all patients who received at least one dose of study medication.

On treatment deaths were collected from first patient first visit up to 28 days after study treatment discontinuation (approx. 11 years). Patients with cancer were also followed up for overall survival until the end of the trial (to collect any deaths occurring more than 28 days after study drug discontinuation). In this study, one death was collected after randomization but before the participant received study drug.

Outcome measures

Outcome measures
Measure	Imatinib 400 mg QD n=280 Participants Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated	Nilotinb 300 mg BID n=279 Participants Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.	Nilotinib 400 mg BID n=277 Participants Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
All Collected Deaths On-treatment deaths	4 deaths	10 deaths	5 deaths
All Collected Deaths Total deaths	29 deaths	32 deaths	23 deaths

Adverse Events

Imatinib 400 mg QD

Serious events: 96 serious events

Other events: 275 other events

Deaths: 4 deaths

Nilotinib 300 mg BID

Serious events: 112 serious events

Other events: 276 other events

Deaths: 10 deaths

Nilotinib 400 mg BID

Serious events: 126 serious events

Other events: 272 other events

Deaths: 5 deaths

All Patients

Serious events: 334 serious events

Other events: 823 other events

Deaths: 19 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial.
Publication restrictions are in place

Restriction type: OTHER