Clinical Trial Results:
A PHASE IV, OPEN-LABEL, MULTICENTER STUDY OF DASATINIB IN CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA (CP-CML) PATIENTS WITH CHRONIC LOW-GRADE NONHEMATOLOGIC TOXICITY TO IMATINIB
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Summary
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EudraCT number |
2011-006180-21 |
Trial protocol |
IT DE |
Global end of trial date |
01 Oct 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Oct 2016
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First version publication date |
14 Oct 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CA180-400
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01660906 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Bristol-Myers Squibb
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Sponsor organisation address |
Chausée de la Hulpe 185, Brussels, Belgium, 1170
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Public contact |
Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
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Scientific contact |
Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Oct 2015
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Oct 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to assess the frequency of reduction in grade (Grade 2 to 1) or resolution of imatinib-related chronic Grade 1 or Grade 2 non-hematologic adverse events (AEs) within 3 months after switch to dasatinib in subjects with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
Adults subjects diagnosed with CP-CML that had achieved an optimal response to imatinib (≤ 400 mg/day treatment) who had Grade 1 or 2 non-hematologic AEs persisting for at least 2 months, or recurring at least 3 times in the preceding 12 months, despite best supportive care. | ||
Evidence for comparator |
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Actual start date of recruitment |
31 Oct 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Italy: 9
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Country: Number of subjects enrolled |
Korea, Republic of: 22
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Country: Number of subjects enrolled |
United States: 3
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Worldwide total number of subjects |
39
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EEA total number of subjects |
14
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
27
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From 65 to 84 years |
12
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 22 sites in France, Germany, Italy, Republic of Korea, and the United States. | ||||||||||
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Pre-assignment
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Screening details |
A total of 39 subjects were enrolled and treated. | ||||||||||
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Period 1
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Period 1 title |
Dasatinib (100 mg) (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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Dasatinib (100 mg) | ||||||||||
Arm description |
Subjects that were previously on an imatinib therapy were treated with a 100 mg tablet of dasatinib taken orally once a day for up to 12 months while on study. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Dasatinib
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Investigational medicinal product code |
BMS-354825
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects were administered with dasatinib 100 mg tablet orally once daily for up to 12 months while on study.
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Baseline characteristics reporting groups
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Reporting group title |
Dasatinib (100 mg)
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Reporting group description |
Subjects that were previously on an imatinib therapy were treated with a 100 mg tablet of dasatinib taken orally once a day for up to 12 months while on study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dasatinib (100 mg)
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Reporting group description |
Subjects that were previously on an imatinib therapy were treated with a 100 mg tablet of dasatinib taken orally once a day for up to 12 months while on study. | ||
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End point title |
Number of Imatinib-related Adverse Events (AEs) That Were Resolved, Improved, Remained Unchanged, or Worsened After 3 Months of Dasatinib Treatment [1] | ||||||||||||||
End point description |
Prior to dasatinib treatment, subjects were on imatinib therapy and reported 121 imatinib-related Grade 1 or 2 (Grade1/2) AEs. Dasatinib treatment was administered and its impact on the imatinib-related Grade 1/2 AEs was assessed. Imatinib-related chronic AEs were defined as Grade 1 or 2 non-hematologic AEs persisting for at least 2 months or recurring at least 3 times in the preceding 12 months, despite best supportive care. The severity of an adverse event is ranked based on grades that range from 1 to 4 according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4= Potentially Life-threatening or disabling. Resolved, AE no longer present or resolution of imatinib-related chronic Grade 1 or Grade 2 non-hematologic AEs. Improved, AE grade reduced from Grade 2 to Grade 1. Unchanged, AE did not improve or worsen or no change in grade. Worsened, grade increased. All treated subjects.
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End point type |
Primary
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End point timeframe |
From screening up to 3 months after switch to dasatinib
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive statistics was planned for this safety end-point. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in Subject Reported CML Symptom Severity and Interference by MD Anderson Symptom Inventory (MDASI) CML Score After Switching to Dasatinib | ||||||||||||||||||||||||||||||||||||||
End point description |
The MDASI-CML is a validated questionnaire completed by study subjects to assess symptom severity and symptom interference on daily function. These categories are divided into 5 domain summary scores: Core Symptom Severity Score, Interference Score, Symptom Severity Score, CML-Specific Symptom Severity Score, and 5 Most Severe Symptom Score. Scores were evaluated at baseline and after switching to dasatinib on a range from 1 to 10; 1=not present/did not interfere, 10=as bad as you can imagine/interfered completely. All treated subjects. Small "n" refers to the total number of subjects that responded to the survey at the specified interval.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 3, 6, and 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Subject Reported Quality of Life Measurements by The European Organization for Research and Treatment of Cancer - Quality of Life (QoL) Questionnaire (EORTC QLQ) Score After Switching to Dasatinib at Month 6 and 12 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The EORTC QLQ-C30 questionnaire was completed by study subjects to assess quality of life through nine multi-item scales: five functional scales (physical, role, cognitive, emotional and social functioning); three symptom scales (fatigue, pain and nausea/vomiting); and a global health status/QoL scale. Six single-item scales were included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All scales and single-item measures were evaluated at baseline and after switching to Dasatinib as an average raw score that was standardized by transformation, so that final scores were on a range in score from 0 to 100. A high score for a functional scale represented a healthy level of functioning, a high score for the global health status/QoL represented a high QoL, but a high score for a symptom scale represented a high level of problematic symptomatology. All treated subjects. Small "n" refers to total number of subjects that responded to the questionnaire.
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End point type |
Secondary
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End point timeframe |
Baseline, Month 6 , Month 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects With at least One AE, Discontinuations Due to AE, Treatment-related AE, Serious Adverse Event (SAE), Treatment-related SAE, or Death as an Outcome | ||||||||||||||||||
End point description |
SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Treatment-related=having certain, probable, possible, or missing relationship to study drug, dasatinib. All treated subjects.
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End point type |
Secondary
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End point timeframe |
SAEs: From screening period and within 30 days of discontinuation of dosing.
AEs: From first-treatment dose to 12 months
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Percentage of Subjects With at Least 1 Imatinib-related Grade 1 or Grade 2 Chronic Adverse Events (AEs) That Improved Without Worsening Within 3 Months of Switching to Dasatinib | ||||||||
End point description |
The percentage of subjects is based on the number that had pre-existing Imatinib-related AEs. Subjects with reduction or improvement of at least 1 Imatinib-related Grade 1 or Grade 2 chronic AE, without a worsening of any Imatinib-related, chronic adverse events after dasatinib treatment were assessed. The severity of an adverse event is ranked based on grades that range from 1 to 4. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4= Potentially Life-threatening or disabling. Improved, AE grade reduced from Grade 2 to Grade 1. Worsened, Grade Increased. Confidence interval from Clopper-Pearson method. All treated subjects.
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End point type |
Secondary
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End point timeframe |
3 months
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| Notes [2] - All treated subjects. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects With a Major Molecular Response (MMR) and MR 4.5 After Switching to Dasatinib | ||||||||||||||
End point description |
Molecular responses were assessed at 6 and 12 months after switching to dasatinib to determine if these baseline responses could be maintained. All treated subjects.
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End point type |
Other pre-specified
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End point timeframe |
Month 6, Month 12
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Date of fist dose of study drug to 30 days post discontinuation of the last dose, up to October 2015
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.0
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Reporting groups
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Reporting group title |
Dasatinib (100 mg)
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Reporting group description |
Subjects that were previously on an imatinib therapy were treated with a 100 mg tablet of dasatinib taken orally once a day for up to 12 months while on study | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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31 Aug 2012 |
This protocol required subject to have the ability to complete patient reported outcome measure; the changes to this protocol in the Informed Consent and Inclusion/Exclusion Criteria sections reflected this requirement. Parameters regarding fluorescence in situ hybridization (FISH) testing were clarified and added to ensure accurate and feasible testing procedures for this study. The differences between disease progression and treatment failure were differentiated. |
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21 Nov 2012 |
The Purpose of this amendment was to:
Chest x-rays are not considered to be standard of care in Germany. Therefore, this Amendment is designed to remove the requirement of pre-specified chest x-rays and allow the testing to be completed as clinically indicated. The exclusion criterion of pleural effusion is also changed to known pleural effusion as a result of this change. These changes will immediately affect all patients in the study sites located in Germany. Also, added the address in Belgium on the cover page. |
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09 Oct 2013 |
Based on an analysis of the BMS Dasatinib safety database (CARES) and a revision to an internal BMS directive related to “Women of Childbearing Potential (WOCBP) in clinical trials”, this protocol was amended to adjust the frequency of pregnancy testing for sexually active female subjects of childbearing potential to monthly pregnancy testing.
Additional changes related to this initiative were:
• updated language related to WOCBP to harmonize with the new BMS directive including requiring 2 highly effective forms of birth control
• defined highly effective forms of birth control
• adjusted language related to sexually active fertile men with WOCBP partners and adapt the length of birth control to be used after the last dose of investigational product (90 days).
Finally, an appendix was added to specify criteria for response required for study enrollment and clarifications were added to the time and events schedule.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
