Efficacy of 400 Mg Versus 800 Mg Imatinib in Chronic Myeloid Leukemia in Chronic Phase Patients - TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity)

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00124748
• Collaborator: (none)
• Enrollment: 476
• Locations: 75
• Arms: 2
• Duration (Months): 65
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study investigated the safety and efficacy of 400mg Versus 800mg imatinib in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Chronic Phase	Drug: Imatinib mesylate	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 476 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Open-label Study of 400 mg Versus 800 mg of Imatinib Mesylate in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Using Molecular Endpoints.
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Imatinib 400 mg Oral dose of 400mg Imatinib once daily. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Drug: Imatinib mesylate; Imatinib is packaged in bottles as 100mg and 400mg tablets; Other Names: STI571 Gleevec Glivec
Experimental: imatinib 800 mg Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.	Drug: Imatinib mesylate; Imatinib is packaged in bottles as 100mg and 400mg tablets; Other Names: STI571 Gleevec Glivec

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months [12 months]

   MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally).

Secondary Outcome Measures

1. Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months [24, 36 and 42 months]

   MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally).

2. Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months [12, 24, 36, 42 months]

   Cytogenetic response (CyR)is the percentage of Philadelphia chromosome positive metaphases (among at least 20 metaphase cells in bone marrow (BM)) with Complete Cytogenetic Response (CCyR) being 0 percent.

3. Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months [12, 24, 36, and 42 months]

   Complete Hematologic Response (CHR) is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) < 5% in PB and No evidence of extramedullary involvement.

4. Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts [12 , 24, 36 and 42 months]

   "Undetectable levels" or Complete molecular response is defined as Bcr-Abl ratio (%) on international scale (IS) <= 0.0032% (≥ 4.5 log reduction of BCR-Abl transcripts from a standardized baseline).

5. Time to First Major Molecular Response [42 months overall]

   MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally). Time to MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375. Time to first MMR was evaluated using the Kaplan-Meier method

6. Time to First Complete Cytogenetic Response [60 months overall]

   Cytogenetic response (CyR) is the percentage of Philadelphia positive metaphases (among at least 20 metaphase cells in Bone Marrow) with Complete Cytogenetic Response (CCyR) being 0 percent. Time to CCyR (months) = (date of first CCyR or censoring - date of randomization + 1) / 30.4375. Time to first CCyR was evaluated using the Kaplan-Meier method.

7. Time to First Complete Hematological Response (CHR)] [60 months overall]

   Complete Hematological Response (CHR) is defined is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) < 5% in PB and No evidence of extramedullary involvement. Time to CHR (months) = (date of first CHR or censoring - date of randomization + 1) / 30.4375. Time to first CHR was evaluated using the Kaplan-Meier method.

8. Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms [60 months over all]

   EFS on treatment was defined as time between randomization and either (1) death due to any cause during study treatment, (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment, (3) loss of complete hematological response (CHR), or (4) loss of major cytogenic response (MCyR) while on treatment. Estimated rate of EFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

9. Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms [60 months over all and follow up period]

   PFS on study which was defined as time between randomization and either (1) death due to any cause on treatment of during follow-up after discontinuation of treatment or (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment during follow-up after discontinuation of study treatment. Estimated rate of PFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

10. Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms [60 months over all and follow up period]

    (Accelerated Phase/Blast Crisis) AP/BC was defined as time between randomization and either (1) (Chronic Myeloid Leukemia) CML-related death (if death was primary reason for discontinuation) or (2) progression to AP or BC (during treatment). Estimated rate of AC/BC was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

11. Estimated Rate of Overall Survival (OS) in Two Treatment Arms [60 months over all and follow up period]

    OS was defined as time between randomization and death due to any cause during study treatment or during follow-up after discontinuation of treatment. Estimated rate of OS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

12. Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss [From First major molecular response to first confirmed loss or censoring]

    Duration of MMR (months) = (date of first confirmed loss or censoring - date of MMR + 1 ) / 30.4375. Estimated rate of duration of first MMR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

13. Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) [From first complete cytogenetic response to first confirmed loss or censoring]

    Duration of CCyR was defined as the time between date of CCyR and the earliest of either (1) loss of CCyR OR (2) (Chronic Myeloid Leukemia) CML-related death or progression to (Accelerated Phase/Blast Crisis) AP/BC during study treatment. Estimated rate of duration of first CCyR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).

14. Mean Actual Dose Intensity Per Day [start of treatment to Month 36]

    The mean actual dose intensity per day from start of treatment up to last dose or discontinuation was evaluated up to Month 36. Actual dose intensity (mg/day) = total dose/time on treatment (periods of zero dose are included)

15. Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12 [Month 12]

    Imatinib PK trough plasma concentration (Cmin) was defined as any pre-dose Imatinib plasma concentration

16. Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) [42 months]

    A Landmark Kaplan-Meier analysis was performed for PFS at 42 months by MMR status at 6, 12, and 18 months to investigate their prognostic value.

17. Time to First Complete Molecular Response (CMR)] [48 months overall]

    Complete Molecular Response is defined as a Bcr-Abl (a fusion of gene of Bcr and ABl genes) ratio ≤0.0032% on the International Scale Bcr = breakpoint cluster gene Abl = abelson proto-oncogene.

18. Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes [12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis)

• Diagnosis of chronic myelogenous leukemia (CML) in chronic phase with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations and presence of Breakpoint cluster region gene-abelson proto-oncogene (Bcr-Abl)

• Documented chronic phase CML

• Adequate end organ function as defined by:

• total bilirubin < 1.5 x Upper Limit of Normal (ULN)

• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 2.5 x ULN

• creatinine < 1.5 x ULN

Exclusion Criteria:

• Patients in late chronic phase, accelerated phase, or blastic phase are excluded

• Patients who have received other investigational agents

• Patients who received Gleevec/Glivec for any duration prior to study entry, with the exception of those patients successfully completing [CSTI571A2107 (NCT00428909)] study immediately prior to the participation in this study

• Patient received any treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide

• Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention

• Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use barrier contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential).

• Patient with a severe or uncontrolled medical condition (i.e., uncontrolled diabetes,chronic renal disease)

• Patient previously received radiotherapy to ≥ 25% of the bone marrow

• Patient had major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery

• Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status Score ≥ 3

• Patients with International normalized ratio (INR) or partial thromboplastin time (PTT) > 1.5 x ULN, with the exception of patients on treatment with oral anticoagulants

• Patients with known positivity for human immunodeficiency virus (HIV); baseline testing for HIV is not required

• Patients with identified sibling donors where allogeneic bone marrow transplant is elected as first line treatment

Other protocol-defined inclusion/exclusion criteria applied.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Alabama	Mobile	Alabama	United States	36693
2	Alta Bates Comprehsenive Cancer Center	Berkeley	California	United States	94704
3	University of Miami	Berkeley	California	United States	94704
4	South Bay Oncology Hematology Partners	Campbell	California	United States	95008
5	UCLA Medical Center	Los Angeles	California	United States	90095
6	Rocky Mountain Cancer Center	Denver	Colorado	United States	80218
7	Osler Medical Inc.	Melbourne	Florida	United States	32901
8	Advanced Medical Specialists	Miami	Florida	United States	33176
9	Integrated Community Oncology Network	Orange Park	Florida	United States	32073
10	Hematology-Oncology Associates, P.A.	Pensacola	Florida	United States	32501
11	Palm Beach Cancer Institute	West Palm Beach	Florida	United States	233401
12	Palm Beach Cancer Institute	West Palm Beach	Florida	United States	33401
13	Cancer Research Center of Hawaii	Honolulu	Hawaii	United States	96813
14	Rush University Medical Center	Chicago	Illinois	United States	60612
15	Indiana Blood and Marrow Institutw	Beech Grove	Indiana	United States	46107
16	Indiana Blood and Marrow Transplant	Beech Grove	Indiana	United States	46107
17	University of Iowa Hospitals & Clinic	Iowa City	Iowa	United States	52242
18	University of Kentucky - C201 Clinic	Lexington	Kentucky	United States	40536
19	University of Kentucky	Lexington	Kentucky	United States	40536
20	Lousville Oncology, Clinical Research Program M-25	Louisville	Kentucky	United States	40202
21	Jayne S. Gurtler, MD, Laura A. Brinz, MD & Angelo Russo, MD	Metairie	Louisiana	United States	70006
22	Hematology and Oncology Specialists	New Orleans	Louisiana	United States	70115
23	LSU Health Science Center	Shreveport	Louisiana	United States	71103
24	LSU Health Scine Center	Shreveport	Louisiana	United States	71130
25	St. Agnes Hospital	Baltimore	Maryland	United States	21229
26	Great Lakes Cancer Institute	Lansing	Michigan	United States	48910
27	U of Minnesota	Minneapolis	Minnesota	United States	55455
28	University of Minnesota	Minneapolis	Minnesota	United States	55455
29	Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
30	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
31	San Juan Oncology Associates	Farmington	New Mexico	United States	87401
32	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
33	Duke University Medical Center	Durham	North Carolina	United States	27710
34	Cancer Center of the Carolinas	Greenville	North Carolina	United States	29615
35	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
36	University Hospitals of Cleveland, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106
37	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
38	Kaiser Permanente Northwest Region Oncology/Hemacology	Portland	Oregon	United States	97227
39	Kaiser Permanente Northwest Region	Portland	Oregon	United States	97227
40	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania	United States	15224
41	University of Pittsburg, Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232
42	MUSC Hollings Cancer Center	Charleston	South Carolina	United States	29425
43	Cancer Center of the Carolinas	Greenville	South Carolina	United States	29615
44	Cancer Centers of the Carolinas	Greenville	South Carolina	United States	29615
45	The Jones Clinic	Germantown	Tennessee	United States	38138
46	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
47	UT Southwestern Harold C. Simmons Comprehensive Cancer Center	Dallas	Texas	United States	75390
48	University of Texas / MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
49	MD Anderson Cancer Center	Houston	Texas	United States	77030
50	University of Virgina Cancer Center, UVA Division of Hematology & Oncology	Charlottesville	Virginia	United States	22908
51	Novartis Investigative Site	Buenos Aires		Argentina
52	Novartis Investigative Site	La Plata		Argentina
53	Novartis Investigative Site	St. Leonards	New South Wales	Australia
54	Novartis Investigative Site	Waratah	New South Wales	Australia
55	Novartis Investigative Site	Westmead	New South Wales	Australia
56	Novartis Investigative Site	Herston	Queensland	Australia
57	Novartis Investigative Site	Woolloongabba	Queensland	Australia
58	Novartis Investigative Site	Adelaide	South Australia	Australia
59	Novartis Investigative Site	East Melbourne	Victoria	Australia
60	Novartis Investigative Site	Fitzroy	Victoria	Australia
61	Novartis Investigative Site	Frankston	Victoria	Australia
62	Novartis Investigative Site	Parkville	Victoria	Australia
63	Novartis Investigative Site	Prahran	Victoria	Australia
64	Novartis Investigative Site	South Brisbane		Australia
65	Novartis Investigative Site	Campinas		Brazil
66	Novartis Investigative Site	Calgary		Canada
67	Novartis Investigative Site	Montreal		Canada
68	Novartis Investigative Site	Ottawa		Canada
69	Novartis Investigative Site	Quebec		Canada
70	Novartis Investigative Site	Bologna		Italy
71	Novartis Investigative Site	Firenze		Italy
72	Novartis Investigative Site	Milano		Italy
73	Novartis Investigative Site	Napoli		Italy
74	Novartis Investigative Site	Orbassano		Italy
75	Novartis Investigative Site	Roma		Italy

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00124748
• Other Study ID Numbers: CSTI571K2301; NCT00324636
• First Posted: Jul 28, 2005
• Last Update Posted: Feb 3, 2012
• Last Verified: Jan 1, 2012

• Keywords provided by Novartis Pharmaceuticals: CML; Philadelphia positive; Bcr-abl; imatinib mesylate; Chronic myeloid leukemia (CML) in chronic phase
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Imatinib Mesylate

Study Results

Participant Flow

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Period Title: Overall Study
STARTED	157	319
Safety Population	157	316
COMPLETED	14	35
NOT COMPLETED	143	284

Baseline Characteristics

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg	Total
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.	Total of all reporting groups
Overall Participants	157	319	476
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.2 (14.90)	48.2 (13.89)	47.6 (14.25)
Sex: Female, Male (Count of Participants)
Female	73 46.5%	136 42.6%	209 43.9%
Male	84 53.5%	183 57.4%	267 56.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months
Description	MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
Number [Percentage of participants]	38.9 24.8%	45.1 14.1%

2. Secondary Outcome

Title	Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months
Description	MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally).
Time Frame	24, 36 and 42 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
24 months	53.5 34.1%	50.8 15.9%
36 months	52.2 33.2%	49.8 15.6%
42 months	51.6 32.9%	50.2 15.7%

3. Secondary Outcome

Title	Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months
Description	Cytogenetic response (CyR)is the percentage of Philadelphia chromosome positive metaphases (among at least 20 metaphase cells in bone marrow (BM)) with Complete Cytogenetic Response (CCyR) being 0 percent.
Time Frame	12, 24, 36, 42 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
12 months	66.9 42.6%	70.2 22%
24 months	76.4 48.7%	76.8 24.1%
36 months	79.0 50.3%	80.6 25.3%
42 months	80.3 51.1%	81.5 25.5%

4. Secondary Outcome

Title	Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months
Description	Complete Hematologic Response (CHR) is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) < 5% in PB and No evidence of extramedullary involvement.
Time Frame	12, 24, 36, and 42 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
12 months	94.9 60.4%	93.7 29.4%
24 months	94.9 60.4%	93.7 29.4%
36 months	96.2 61.3%	94.4 29.6%
42 months	96.2 61.3%	94.4 29.6%

5. Secondary Outcome

Title	Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts
Description	"Undetectable levels" or Complete molecular response is defined as Bcr-Abl ratio (%) on international scale (IS) <= 0.0032% (≥ 4.5 log reduction of BCR-Abl transcripts from a standardized baseline).
Time Frame	12 , 24, 36 and 42 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who were randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
12 Months	4.5	4.7
24 Months	11.5	10.3
36 Months	12.7	13.2
42 Months	14.6	12.5

6. Secondary Outcome

Title	Time to First Major Molecular Response
Description	MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally). Time to MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375. Time to first MMR was evaluated using the Kaplan-Meier method
Time Frame	42 months overall

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who were randomized to the study treatment.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
Median (95% Confidence Interval) [Months]	13.6	8.4

7. Secondary Outcome

Title	Time to First Complete Cytogenetic Response
Description	Cytogenetic response (CyR) is the percentage of Philadelphia positive metaphases (among at least 20 metaphase cells in Bone Marrow) with Complete Cytogenetic Response (CCyR) being 0 percent. Time to CCyR (months) = (date of first CCyR or censoring - date of randomization + 1) / 30.4375. Time to first CCyR was evaluated using the Kaplan-Meier method.
Time Frame	60 months overall

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
Median (95% Confidence Interval) [Months]	10.8	5.8

8. Secondary Outcome

Title	Time to First Complete Hematological Response (CHR)]
Description	Complete Hematological Response (CHR) is defined is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) < 5% in PB and No evidence of extramedullary involvement. Time to CHR (months) = (date of first CHR or censoring - date of randomization + 1) / 30.4375. Time to first CHR was evaluated using the Kaplan-Meier method.
Time Frame	60 months overall

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
Median (95% Confidence Interval) [Months]	1.0	1.0

9. Secondary Outcome

Title	Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms
Description	EFS on treatment was defined as time between randomization and either (1) death due to any cause during study treatment, (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment, (3) loss of complete hematological response (CHR), or (4) loss of major cytogenic response (MCyR) while on treatment. Estimated rate of EFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time Frame	60 months over all

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
12 Months	95.3	98.0
24 Months	94.6	95.3
36 Months	92.3	94.5
42 Months	92.3	94.1
48 Months	92.3	93.6
60 Months	90.3	93.6

10. Secondary Outcome

Title	Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms
Description	PFS on study which was defined as time between randomization and either (1) death due to any cause on treatment of during follow-up after discontinuation of treatment or (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment during follow-up after discontinuation of study treatment. Estimated rate of PFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time Frame	60 months over all and follow up period

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
12 Months	97.4	98.7
24 Months	95.9	97.5
36 Months	94.4	96.7
42 Months	94.4	96.3
48 Months	94.4	95.8
60 Months	94.4	95.8

11. Secondary Outcome

Title	Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms
Description	(Accelerated Phase/Blast Crisis) AP/BC was defined as time between randomization and either (1) (Chronic Myeloid Leukemia) CML-related death (if death was primary reason for discontinuation) or (2) progression to AP or BC (during treatment). Estimated rate of AC/BC was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time Frame	60 months over all and follow up period

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
12 Months	97.4	99.0
24 Months	95.9	97.9
36 Months	95.2	97.5
42 Months	95.2	97.0
48 Months	95.2	97.0
60 Months	95.2	97.0

12. Secondary Outcome

Title	Estimated Rate of Overall Survival (OS) in Two Treatment Arms
Description	OS was defined as time between randomization and death due to any cause during study treatment or during follow-up after discontinuation of treatment. Estimated rate of OS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time Frame	60 months over all and follow up period

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
12 Months	98.7	99.0
24 Months	97.4	97.8
36 Months	96.1	95.5
42 Months	94.7	94.8
48 Months	94.0	93.4
60 Months	94.0	93.4

13. Secondary Outcome

Title	Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss
Description	Duration of MMR (months) = (date of first confirmed loss or censoring - date of MMR + 1 ) / 30.4375. Estimated rate of duration of first MMR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time Frame	From First major molecular response to first confirmed loss or censoring

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
3 Months	100	96.3
6 Months	98.3	90.7
9 Months	97.4	90.2
12 Months	95.6	88.4
15 Months	93.8	87.5
18 Months	92.8	86.1
21 Months	90.9	85.1
24 Months	89.9	83.6
30 Months	88.5	82.5
36 Months	85.1	81.1
42 Months	85.1	77.9

14. Secondary Outcome

Title	Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR)
Description	Duration of CCyR was defined as the time between date of CCyR and the earliest of either (1) loss of CCyR OR (2) (Chronic Myeloid Leukemia) CML-related death or progression to (Accelerated Phase/Blast Crisis) AP/BC during study treatment. Estimated rate of duration of first CCyR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time Frame	From first complete cytogenetic response to first confirmed loss or censoring

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	319
6 Months	99.1	99.2
12 Months	98.2	97.8
18 Months	98.2	97.3
24 Months	98.2	96.8
30 Months	98.2	96.8
36 Months	98.2	95.9
42 Months	98.2	95.9

15. Secondary Outcome

Title	Mean Actual Dose Intensity Per Day
Description	The mean actual dose intensity per day from start of treatment up to last dose or discontinuation was evaluated up to Month 36. Actual dose intensity (mg/day) = total dose/time on treatment (periods of zero dose are included)
Time Frame	start of treatment to Month 36

Outcome Measure Data

Analysis Population Description

Safety analysis population (SAP): consisted of all patients who received at least one dose of study medication.Subjects are summarized according to the safety treatment allocation (the dose they actually received).

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	157	316
Mean (Standard Deviation) [mg/day]	399.3 (83.84)	643.3 (158.63)

16. Secondary Outcome

Title	Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12
Description	Imatinib PK trough plasma concentration (Cmin) was defined as any pre-dose Imatinib plasma concentration
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Pharmakokinetic (PK) population consisted of number of patients with a pre-dose PK sample at Month 12

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	86	150
Mean (Standard Deviation) [mg/mL]	1458.2 (2259.5)	739.58 (1321.09)

17. Secondary Outcome

Title	Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR)
Description	A Landmark Kaplan-Meier analysis was performed for PFS at 42 months by MMR status at 6, 12, and 18 months to investigate their prognostic value.
Time Frame	42 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population consisted of all patients who were randomized to the study treatment. Patients without a valid polymerase chain reaction (PCR) assessment or those who had experienced an event before the landmark were excluded from analysis

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	134	274
No MMR at 6 Months	94.8	95.6
MMR at 6 Months	100	99.0
No MMR at 12 Months	93.2	94.6
MMR at 12 Months	100	99.3
No MMR at 18 Months	96.7	97.0
MMR at 18 Months	98.7	99.3

18. Secondary Outcome

Title	Time to First Complete Molecular Response (CMR)]
Description	Complete Molecular Response is defined as a Bcr-Abl (a fusion of gene of Bcr and ABl genes) ratio ≤0.0032% on the International Scale Bcr = breakpoint cluster gene Abl = abelson proto-oncogene.
Time Frame	48 months overall

Outcome Measure Data

Analysis Population Description

This analysis was not done because no major molecular improvement was observed in the 800mg dose compared to 400mg dose. Hence, analysis for complete molecular response was not necessary.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	0	0

19. Secondary Outcome

Title	Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Due to the small number of diabetic patients enrolled into the study, the analysis was never done.

Arm/Group Title	Imatinib 400 mg	Imatinib 800 mg
Arm/Group Description	Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
Measure Participants	0	0

Adverse Events

Arm/Group Title	Imatinib 400mg		Imatinib 800mg
Arm/Group Description	Oral dose of 400mg imatinib once daily. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.		Patients randomized to receive 800 mg imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.
All Cause Mortality
	Imatinib 400mg		Imatinib 800mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Imatinib 400mg		Imatinib 800mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/157 (26.8%)		121/316 (38.3%)
Blood and lymphatic system disorders
Anaemia	3/157 (1.9%)		6/316 (1.9%)
Febrile neutropenia	2/157 (1.3%)		5/316 (1.6%)
Granulocytopenia	0/157 (0%)		1/316 (0.3%)
Leukopenia	0/157 (0%)		2/316 (0.6%)
Neutropenia	5/157 (3.2%)		12/316 (3.8%)
Pancytopenia	1/157 (0.6%)		1/316 (0.3%)
Splenic cyst	0/157 (0%)		1/316 (0.3%)
Thrombocytopenia	4/157 (2.5%)		9/316 (2.8%)
Cardiac disorders
Angina pectoris	2/157 (1.3%)		0/316 (0%)
Arrhythmia supraventricular	0/157 (0%)		1/316 (0.3%)
Atrial fibrillation	1/157 (0.6%)		3/316 (0.9%)
Cardiac arrest	0/157 (0%)		1/316 (0.3%)
Cardiac discomfort	0/157 (0%)		1/316 (0.3%)
Cardiac failure congestive	1/157 (0.6%)		1/316 (0.3%)
Coronary artery disease	0/157 (0%)		1/316 (0.3%)
Coronary artery occlusion	1/157 (0.6%)		0/316 (0%)
Myocardial infarction	1/157 (0.6%)		1/316 (0.3%)
Palpitations	0/157 (0%)		1/316 (0.3%)
Congenital, familial and genetic disorders
Phimosis	1/157 (0.6%)		0/316 (0%)
Ear and labyrinth disorders
Deafness	0/157 (0%)		1/316 (0.3%)
Hearing impaired	0/157 (0%)		1/316 (0.3%)
Sudden hearing loss	0/157 (0%)		1/316 (0.3%)
Vertigo	1/157 (0.6%)		0/316 (0%)
Endocrine disorders
Hypothyroidism	0/157 (0%)		1/316 (0.3%)
Eye disorders
Amaurosis	0/157 (0%)		1/316 (0.3%)
Conjunctivitis	0/157 (0%)		1/316 (0.3%)
Glaucoma	0/157 (0%)		2/316 (0.6%)
Retinal detachment	0/157 (0%)		2/316 (0.6%)
Retinal haemorrhage	0/157 (0%)		1/316 (0.3%)
Retinal vein occlusion	0/157 (0%)		1/316 (0.3%)
Uveitis	0/157 (0%)		1/316 (0.3%)
Vitreous haemorrhage	0/157 (0%)		1/316 (0.3%)
Gastrointestinal disorders
Abdominal pain	1/157 (0.6%)		3/316 (0.9%)
Abdominal pain lower	0/157 (0%)		3/316 (0.9%)
Abdominal pain upper	0/157 (0%)		1/316 (0.3%)
Anal polyp	0/157 (0%)		1/316 (0.3%)
Caecitis	0/157 (0%)		1/316 (0.3%)
Colitis	0/157 (0%)		3/316 (0.9%)
Diarrhoea	1/157 (0.6%)		4/316 (1.3%)
Diverticulum	0/157 (0%)		1/316 (0.3%)
Duodenal ulcer	0/157 (0%)		1/316 (0.3%)
Enteritis	0/157 (0%)		1/316 (0.3%)
Enterovesical fistula	0/157 (0%)		1/316 (0.3%)
Gastritis	0/157 (0%)		2/316 (0.6%)
Gastritis alcoholic	0/157 (0%)		1/316 (0.3%)
Gastrointestinal haemorrhage	0/157 (0%)		3/316 (0.9%)
Haematemesis	0/157 (0%)		1/316 (0.3%)
Haemorrhoids	0/157 (0%)		2/316 (0.6%)
Hiatus hernia	0/157 (0%)		1/316 (0.3%)
Inguinal hernia	0/157 (0%)		1/316 (0.3%)
Lower gastrointestinal haemorrhage	0/157 (0%)		1/316 (0.3%)
Melaena	0/157 (0%)		1/316 (0.3%)
Nausea	0/157 (0%)		3/316 (0.9%)
Reflux gastritis	0/157 (0%)		1/316 (0.3%)
Small intestinal haemorrhage	0/157 (0%)		1/316 (0.3%)
Small intestinal obstruction	0/157 (0%)		2/316 (0.6%)
Upper gastrointestinal haemorrhage	0/157 (0%)		1/316 (0.3%)
Vomiting	1/157 (0.6%)		4/316 (1.3%)
General disorders
Adverse drug reaction	1/157 (0.6%)		0/316 (0%)
Asthenia	0/157 (0%)		2/316 (0.6%)
Chest discomfort	0/157 (0%)		1/316 (0.3%)
Chest pain	2/157 (1.3%)		0/316 (0%)
Concomitant disease progression	0/157 (0%)		1/316 (0.3%)
Death	0/157 (0%)		1/316 (0.3%)
Device ineffective	0/157 (0%)		1/316 (0.3%)
Mucosal inflammation	0/157 (0%)		1/316 (0.3%)
Non-cardiac chest pain	0/157 (0%)		1/316 (0.3%)
Polyp	0/157 (0%)		1/316 (0.3%)
Polyserositis	0/157 (0%)		1/316 (0.3%)
Pyrexia	3/157 (1.9%)		13/316 (4.1%)
Hepatobiliary disorders
Bile duct stone	1/157 (0.6%)		0/316 (0%)
Cholecystitis	0/157 (0%)		1/316 (0.3%)
Cholecystitis acute	0/157 (0%)		1/316 (0.3%)
Cholelithiasis	1/157 (0.6%)		2/316 (0.6%)
Hepatotoxicity	0/157 (0%)		2/316 (0.6%)
Liver disorder	1/157 (0.6%)		1/316 (0.3%)
Infections and infestations
Appendicitis	0/157 (0%)		5/316 (1.6%)
Bacterial infection	1/157 (0.6%)		0/316 (0%)
Bacterial sepsis	0/157 (0%)		1/316 (0.3%)
Cellulitis	0/157 (0%)		2/316 (0.6%)
Diverticulitis	0/157 (0%)		3/316 (0.9%)
Escherichia bacteraemia	0/157 (0%)		1/316 (0.3%)
Febrile infection	0/157 (0%)		1/316 (0.3%)
Gastroenteritis	2/157 (1.3%)		5/316 (1.6%)
Gastroenteritis viral	1/157 (0.6%)		0/316 (0%)
Gastrointestinal infection	0/157 (0%)		1/316 (0.3%)
HIV infection	1/157 (0.6%)		0/316 (0%)
Haematoma infection	0/157 (0%)		1/316 (0.3%)
Herpes zoster	0/157 (0%)		1/316 (0.3%)
Infection	0/157 (0%)		1/316 (0.3%)
Influenza	1/157 (0.6%)		0/316 (0%)
Meningitis	1/157 (0.6%)		0/316 (0%)
Pharyngotonsillitis	0/157 (0%)		1/316 (0.3%)
Pneumonia	2/157 (1.3%)		5/316 (1.6%)
Pneumonia pneumococcal	1/157 (0.6%)		0/316 (0%)
Pulmonary tuberculosis	0/157 (0%)		1/316 (0.3%)
Pyelonephritis	1/157 (0.6%)		1/316 (0.3%)
Pyelonephritis acute	0/157 (0%)		1/316 (0.3%)
Retroperitoneal abscess	0/157 (0%)		1/316 (0.3%)
Salmonellosis	0/157 (0%)		2/316 (0.6%)
Sepsis	0/157 (0%)		1/316 (0.3%)
Septic shock	0/157 (0%)		1/316 (0.3%)
Sinusitis	1/157 (0.6%)		0/316 (0%)
Tooth infection	0/157 (0%)		1/316 (0.3%)
Upper respiratory tract infection	1/157 (0.6%)		2/316 (0.6%)
Urinary tract infection	1/157 (0.6%)		1/316 (0.3%)
Injury, poisoning and procedural complications
Alcohol poisoning	0/157 (0%)		1/316 (0.3%)
Ankle fracture	2/157 (1.3%)		0/316 (0%)
Drug exposure during pregnancy	1/157 (0.6%)		1/316 (0.3%)
Fall	2/157 (1.3%)		2/316 (0.6%)
Hip fracture	0/157 (0%)		1/316 (0.3%)
Injury	0/157 (0%)		1/316 (0.3%)
Joint dislocation	1/157 (0.6%)		0/316 (0%)
Joint injury	1/157 (0.6%)		0/316 (0%)
Lower limb fracture	0/157 (0%)		1/316 (0.3%)
Multiple fractures	0/157 (0%)		1/316 (0.3%)
Subdural haematoma	0/157 (0%)		1/316 (0.3%)
Tendon rupture	0/157 (0%)		1/316 (0.3%)
Investigations
Alanine aminotransferase increased	1/157 (0.6%)		1/316 (0.3%)
Aspartate aminotransferase increased	1/157 (0.6%)		1/316 (0.3%)
Electrocardiogram T wave abnormal	0/157 (0%)		1/316 (0.3%)
Metabolism and nutrition disorders
Decreased appetite	0/157 (0%)		1/316 (0.3%)
Dehydration	0/157 (0%)		2/316 (0.6%)
Gout	0/157 (0%)		1/316 (0.3%)
Hypocalcaemia	0/157 (0%)		1/316 (0.3%)
Hypokalaemia	0/157 (0%)		1/316 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/157 (0.6%)		3/316 (0.9%)
Back pain	0/157 (0%)		3/316 (0.9%)
Bone pain	0/157 (0%)		1/316 (0.3%)
Bursitis	0/157 (0%)		1/316 (0.3%)
Flank pain	0/157 (0%)		1/316 (0.3%)
Intervertebral disc protrusion	1/157 (0.6%)		2/316 (0.6%)
Musculoskeletal chest pain	1/157 (0.6%)		0/316 (0%)
Musculoskeletal pain	1/157 (0.6%)		0/316 (0%)
Myalgia	0/157 (0%)		2/316 (0.6%)
Myositis	0/157 (0%)		1/316 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	0/157 (0%)		1/316 (0.3%)
Basal cell carcinoma	0/157 (0%)		1/316 (0.3%)
Bladder cancer	0/157 (0%)		2/316 (0.6%)
Bladder transitional cell carcinoma	0/157 (0%)		1/316 (0.3%)
Blast crisis in myelogenous leukaemia	2/157 (1.3%)		2/316 (0.6%)
Breast cancer	0/157 (0%)		1/316 (0.3%)
Chronic myeloid leukaemia	0/157 (0%)		1/316 (0.3%)
Colorectal cancer	0/157 (0%)		1/316 (0.3%)
Desmoid tumour	0/157 (0%)		1/316 (0.3%)
Lung adenocarcinoma	1/157 (0.6%)		0/316 (0%)
Metastases to liver	0/157 (0%)		1/316 (0.3%)
Mycosis fungoides	0/157 (0%)		1/316 (0.3%)
Prostate cancer	0/157 (0%)		5/316 (1.6%)
Renal cell carcinoma	0/157 (0%)		1/316 (0.3%)
Sarcoma	0/157 (0%)		1/316 (0.3%)
Squamous cell carcinoma	0/157 (0%)		1/316 (0.3%)
Thyroid adenoma	0/157 (0%)		1/316 (0.3%)
Thyroid cancer	0/157 (0%)		1/316 (0.3%)
Uterine leiomyoma	1/157 (0.6%)		1/316 (0.3%)
Nervous system disorders
Cerebral infarction	1/157 (0.6%)		0/316 (0%)
Cervical myelopathy	0/157 (0%)		1/316 (0.3%)
Diabetic neuropathy	0/157 (0%)		1/316 (0.3%)
Dizziness	1/157 (0.6%)		0/316 (0%)
Encephalopathy	0/157 (0%)		1/316 (0.3%)
Epilepsy	0/157 (0%)		1/316 (0.3%)
Headache	0/157 (0%)		1/316 (0.3%)
IIIrd nerve paralysis	0/157 (0%)		1/316 (0.3%)
Migraine	1/157 (0.6%)		1/316 (0.3%)
Nerve root compression	0/157 (0%)		1/316 (0.3%)
Paraesthesia	0/157 (0%)		3/316 (0.9%)
Parkinsonism	0/157 (0%)		1/316 (0.3%)
Radiculopathy	0/157 (0%)		1/316 (0.3%)
Spinal cord compression	0/157 (0%)		1/316 (0.3%)
Subarachnoid haemorrhage	0/157 (0%)		1/316 (0.3%)
Syncope	0/157 (0%)		3/316 (0.9%)
Transient ischaemic attack	0/157 (0%)		1/316 (0.3%)
VIIth nerve paralysis	1/157 (0.6%)		0/316 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion incomplete	0/157 (0%)		1/316 (0.3%)
Neonatal disorder	0/157 (0%)		1/316 (0.3%)
Placental disorder	0/157 (0%)		1/316 (0.3%)
Pregnancy	0/157 (0%)		2/316 (0.6%)
Premature labour	1/157 (0.6%)		0/316 (0%)
Psychiatric disorders
Confusional state	1/157 (0.6%)		0/316 (0%)
Depression	0/157 (0%)		2/316 (0.6%)
Renal and urinary disorders
Calculus ureteric	0/157 (0%)		3/316 (0.9%)
Calculus urinary	0/157 (0%)		1/316 (0.3%)
Haematuria	0/157 (0%)		1/316 (0.3%)
Nephrolithiasis	0/157 (0%)		1/316 (0.3%)
Paroxysmal nocturnal haemoglobinuria	0/157 (0%)		1/316 (0.3%)
Renal colic	0/157 (0%)		1/316 (0.3%)
Renal failure	0/157 (0%)		1/316 (0.3%)
Renal failure acute	0/157 (0%)		1/316 (0.3%)
Urethral disorder	1/157 (0.6%)		0/316 (0%)
Reproductive system and breast disorders
Cervical dysplasia	0/157 (0%)		1/316 (0.3%)
Endometriosis	1/157 (0.6%)		0/316 (0%)
Haemorrhagic ovarian cyst	1/157 (0.6%)		0/316 (0%)
Ovarian cyst ruptured	1/157 (0.6%)		0/316 (0%)
Prostatitis	0/157 (0%)		1/316 (0.3%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/157 (0%)		1/316 (0.3%)
Cough	1/157 (0.6%)		1/316 (0.3%)
Dyspnoea	1/157 (0.6%)		4/316 (1.3%)
Epistaxis	1/157 (0.6%)		0/316 (0%)
Haemoptysis	0/157 (0%)		1/316 (0.3%)
Lung consolidation	0/157 (0%)		1/316 (0.3%)
Oropharyngeal pain	0/157 (0%)		1/316 (0.3%)
Pleural effusion	1/157 (0.6%)		0/316 (0%)
Pneumonitis	0/157 (0%)		1/316 (0.3%)
Pulmonary embolism	0/157 (0%)		1/316 (0.3%)
Respiratory failure	0/157 (0%)		1/316 (0.3%)
Skin and subcutaneous tissue disorders
Angioedema	0/157 (0%)		2/316 (0.6%)
Dermatitis allergic	1/157 (0.6%)		0/316 (0%)
Rash	0/157 (0%)		4/316 (1.3%)
Rash pruritic	0/157 (0%)		1/316 (0.3%)
Skin lesion	0/157 (0%)		1/316 (0.3%)
Toxic skin eruption	0/157 (0%)		1/316 (0.3%)
Social circumstances
Pregnancy of partner	2/157 (1.3%)		2/316 (0.6%)
Vascular disorders
Circulatory collapse	0/157 (0%)		1/316 (0.3%)
Extremity necrosis	1/157 (0.6%)		0/316 (0%)
Haematoma	1/157 (0.6%)		0/316 (0%)
Hypertensive crisis	0/157 (0%)		1/316 (0.3%)
Hypotension	0/157 (0%)		1/316 (0.3%)
Orthostatic hypotension	0/157 (0%)		1/316 (0.3%)
Peripheral ischaemia	0/157 (0%)		1/316 (0.3%)
Peripheral vascular disorder	1/157 (0.6%)		0/316 (0%)
Vasculitis	0/157 (0%)		1/316 (0.3%)
Other (Not Including Serious) Adverse Events
	Imatinib 400mg		Imatinib 800mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	157/157 (100%)		315/316 (99.7%)
Blood and lymphatic system disorders
Anaemia	41/157 (26.1%)		120/316 (38%)
Leukopenia	20/157 (12.7%)		51/316 (16.1%)
Neutropenia	38/157 (24.2%)		107/316 (33.9%)
Thrombocytopenia	36/157 (22.9%)		111/316 (35.1%)
Eye disorders
Conjunctival haemorrhage	8/157 (5.1%)		19/316 (6%)
Conjunctivitis	9/157 (5.7%)		19/316 (6%)
Eye swelling	3/157 (1.9%)		19/316 (6%)
Eyelid oedema	21/157 (13.4%)		45/316 (14.2%)
Lacrimation increased	8/157 (5.1%)		30/316 (9.5%)
Periorbital oedema	46/157 (29.3%)		132/316 (41.8%)
Gastrointestinal disorders
Abdominal discomfort	13/157 (8.3%)		17/316 (5.4%)
Abdominal distension	9/157 (5.7%)		15/316 (4.7%)
Abdominal pain	36/157 (22.9%)		76/316 (24.1%)
Abdominal pain upper	38/157 (24.2%)		54/316 (17.1%)
Constipation	19/157 (12.1%)		36/316 (11.4%)
Diarrhoea	71/157 (45.2%)		184/316 (58.2%)
Dyspepsia	21/157 (13.4%)		57/316 (18%)
Flatulence	7/157 (4.5%)		20/316 (6.3%)
Gastritis	6/157 (3.8%)		20/316 (6.3%)
Gastrooesophageal reflux disease	5/157 (3.2%)		28/316 (8.9%)
Haemorrhoids	6/157 (3.8%)		25/316 (7.9%)
Nausea	78/157 (49.7%)		205/316 (64.9%)
Toothache	14/157 (8.9%)		21/316 (6.6%)
Vomiting	54/157 (34.4%)		140/316 (44.3%)
General disorders
Asthenia	22/157 (14%)		48/316 (15.2%)
Chest pain	9/157 (5.7%)		7/316 (2.2%)
Chills	9/157 (5.7%)		18/316 (5.7%)
Face oedema	13/157 (8.3%)		64/316 (20.3%)
Fatigue	51/157 (32.5%)		131/316 (41.5%)
Influenza like illness	12/157 (7.6%)		35/316 (11.1%)
Oedema	10/157 (6.4%)		35/316 (11.1%)
Oedema peripheral	43/157 (27.4%)		135/316 (42.7%)
Pyrexia	31/157 (19.7%)		75/316 (23.7%)
Infections and infestations
Bronchitis	10/157 (6.4%)		26/316 (8.2%)
Gastroenteritis	8/157 (5.1%)		26/316 (8.2%)
Influenza	17/157 (10.8%)		18/316 (5.7%)
Nasopharyngitis	19/157 (12.1%)		30/316 (9.5%)
Pharyngitis	5/157 (3.2%)		17/316 (5.4%)
Sinusitis	13/157 (8.3%)		33/316 (10.4%)
Upper respiratory tract infection	44/157 (28%)		88/316 (27.8%)
Urinary tract infection	17/157 (10.8%)		26/316 (8.2%)
Injury, poisoning and procedural complications
Contusion	6/157 (3.8%)		18/316 (5.7%)
Procedural pain	7/157 (4.5%)		16/316 (5.1%)
Investigations
Alanine aminotransferase increased	11/157 (7%)		25/316 (7.9%)
Aspartate aminotransferase increased	11/157 (7%)		26/316 (8.2%)
Platelet count decreased	1/157 (0.6%)		18/316 (5.7%)
Weight decreased	6/157 (3.8%)		26/316 (8.2%)
Weight increased	26/157 (16.6%)		54/316 (17.1%)
Metabolism and nutrition disorders
Decreased appetite	22/157 (14%)		54/316 (17.1%)
Fluid retention	3/157 (1.9%)		21/316 (6.6%)
Hypocalcaemia	8/157 (5.1%)		28/316 (8.9%)
Hypokalaemia	8/157 (5.1%)		33/316 (10.4%)
Hypophosphataemia	30/157 (19.1%)		43/316 (13.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	48/157 (30.6%)		107/316 (33.9%)
Back pain	29/157 (18.5%)		71/316 (22.5%)
Bone pain	17/157 (10.8%)		39/316 (12.3%)
Flank pain	2/157 (1.3%)		16/316 (5.1%)
Muscle spasms	69/157 (43.9%)		141/316 (44.6%)
Musculoskeletal chest pain	10/157 (6.4%)		14/316 (4.4%)
Musculoskeletal pain	22/157 (14%)		29/316 (9.2%)
Myalgia	37/157 (23.6%)		83/316 (26.3%)
Neck pain	10/157 (6.4%)		16/316 (5.1%)
Pain in extremity	33/157 (21%)		79/316 (25%)
Nervous system disorders
Dizziness	38/157 (24.2%)		47/316 (14.9%)
Dysgeusia	8/157 (5.1%)		37/316 (11.7%)
Headache	46/157 (29.3%)		98/316 (31%)
Paraesthesia	11/157 (7%)		16/316 (5.1%)
Psychiatric disorders
Anxiety	12/157 (7.6%)		24/316 (7.6%)
Depression	20/157 (12.7%)		32/316 (10.1%)
Insomnia	21/157 (13.4%)		53/316 (16.8%)
Respiratory, thoracic and mediastinal disorders
Cough	34/157 (21.7%)		74/316 (23.4%)
Dyspnoea	10/157 (6.4%)		44/316 (13.9%)
Epistaxis	8/157 (5.1%)		21/316 (6.6%)
Oropharyngeal pain	13/157 (8.3%)		27/316 (8.5%)
Skin and subcutaneous tissue disorders
Alopecia	9/157 (5.7%)		38/316 (12%)
Dry skin	4/157 (2.5%)		18/316 (5.7%)
Night sweats	18/157 (11.5%)		25/316 (7.9%)
Pruritus	15/157 (9.6%)		41/316 (13%)
Rash	32/157 (20.4%)		119/316 (37.7%)
Vascular disorders
Hypertension	12/157 (7.6%)		18/316 (5.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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 the pooled data (i.e., data from all sites) in the clinical trial.