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

This study has been terminated.

(This study was prematurely discontinued because no improvement was observed in the 800mg dose compared to 400mg dose)

Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

ClinicalTrials.gov Identifier:

NCT00124748

First received: July 27, 2005

Last updated: January 5, 2012

Last verified: January 2012

History of Changes

Results First Received: November 2, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Leukemia, Myeloid, Chronic Phase
Intervention:	Drug: Imatinib mesylate

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Imatinib 400 mg	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.
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.

Participant Flow: Overall Study

	Imatinib 400 mg	Imatinib 800 mg
STARTED	157	319
Safety Population	157	316
COMPLETED	14	35
NOT COMPLETED	143	284
Adverse Event	8	39
Abnormal laboratory Value	2	2
Abnormal Procedure	0	1
Lack of Efficacy	20	41
No longer requires study drug	1	1
Protocol Violation	3	1
Withdrawal by Subject	5	15
Lost to Follow-up	2	7
Administrative Problem(Study Terminated)	101	174
Death	1	3

Baseline Characteristics

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Reporting Groups

	Description
Imatinib 400 mg	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.
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.
Total	Total of all reporting groups

Baseline Measures

	Imatinib 400 mg	Imatinib 800 mg	Total
Number of Participants [units: participants]	157	319	476
Age [units: years] Mean ± Standard Deviation	46.2 ± 14.90	48.2 ± 13.89	47.6 ± 14.25
Gender [units: participants]
Female	73	136	209
Male	84	183	267

Outcome Measures

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1. Primary:

Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months [ Time Frame: 12 months ]

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2. Secondary:

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

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3. Secondary:

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

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4. Secondary:

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

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5. Secondary:

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 [ Time Frame: 12 , 24, 36 and 42 months ]

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6. Secondary:

Time to First Major Molecular Response [ Time Frame: 42 months overall ]

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7. Secondary:

Time to First Complete Cytogenetic Response [ Time Frame: 60 months overall ]

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8. Secondary:

Time to First Complete Hematological Response (CHR)] [ Time Frame: 60 months overall ]

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9. Secondary:

Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms [ Time Frame: 60 months over all ]

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10. Secondary:

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

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11. Secondary:

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

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12. Secondary:

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

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13. Secondary:

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

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14. Secondary:

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

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15. Secondary:

Mean Actual Dose Intensity Per Day [ Time Frame: start of treatment to Month 36 ]

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Measure Type	Secondary
Measure Title	Mean Actual Dose Intensity Per Day
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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).

Reporting Groups

	Description
Imatinib 400 mg	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.
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.

Measured Values

	Imatinib 400 mg	Imatinib 800 mg
Number of Participants Analyzed [units: participants]	157	316
Mean Actual Dose Intensity Per Day [units: mg/day] Mean ± Standard Deviation	399.3 ± 83.84	643.3 ± 158.63

No statistical analysis provided for Mean Actual Dose Intensity Per Day

16. Secondary:

Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12 [ Time Frame: Month 12 ]

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17. Secondary:

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

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18. Secondary:

Time to First Complete Molecular Response (CMR)] [ Time Frame: 48 months overall ]

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19. Secondary:

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

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Study Director
Organization: Novartis Pharmaceuticals
phone: 862-778-8300

No publications provided by Novartis

Publications automatically indexed to this study:

Guilhot F, Hughes TP, Cortes J, Druker BJ, Baccarani M, Gathmann I, Hayes M, Granvil C, Wang Y. Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial. Haematologica. 2012 May;97(5):731-8. Epub 2012 Feb 7.

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT00124748 History of Changes
Obsolete Identifiers:	NCT00324636
Other Study ID Numbers:	CSTI571K2301
Study First Received:	July 27, 2005
Results First Received:	November 2, 2011
Last Updated:	January 5, 2012
Health Authority:	United States: Food and Drug Administration

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