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Interventional Study to Improve Adherence to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia (TAKE-IT)

Primary Purpose

Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Medication Adherence

Status
Completed
Phase
Not Applicable
Locations
Israel
Study Type
Interventional
Intervention
Adherence-encouraging interventions - Group meeting
Adherence-encouraging interventions - Individual meetings
Adherence-encouraging interventions - Monthly phone calls
Sponsored by
pia raanani
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myelogenous, Chronic, BCR-ABL Positive focused on measuring adherence, chronic myeloid leukemia, tyrosine kinase inhibitors

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with chronic phase chronic myeloid leukemia (CP-CML), aged 18 years or older

    • CP-CML defined as: Medical history of cytogenetically confirmed CP-CML defined as the presence of the Philadelphia chromosome on bone marrow aspirates (a minimum of 20 metaphases is required; FISH cannot be used). If Philadelphia chromosome was negative or if cytogenetic results were not available, BCR-ABL-positive CML patients can be included.
  • At least 3 months of TKI treatment (imatinib, dasatinib or nilotinib) before study initiation.

Exclusion Criteria:

  • Current or prior accelerated/blast phase or stem cell transplant
  • Participation in another interventional study
  • Pregnancy

Sites / Locations

  • Soroka Medical Center
  • Rambam Medical Center
  • Meir Medical Center
  • Rabin Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Run-in period

Adherence-encouraging period

Arm Description

First 3 months of study during which adherence will be measured for each consecutively included study subject, but no intervention will be performed. Patient will receive routine treatment for CML according to the physician discretion.

Months 4 to 9 of study during which adherence will be measured for each consecutively included study subject, while implementing adherence-encouraging interventions: adherence-encouraging interventions - Group meetings adherence-encouraging interventions - Individual meetings adherence-encouraging interventions - Monthly phone calls Patient will receive routine treatment for CML according to the physician discretion.

Outcomes

Primary Outcome Measures

Clinically relevant change in MEMS-measured adherence
Improvement in a patient's adherence from less than 90% during the initial 3 month run-in period, to 90% or more during the first 3 months of intervention. Definitions: Adherence above 90% was defined as clinically relevant. Adherence rate = actual calculated dose/prescribed dose. Adherence will be calculated from "medical events monitoring system" (MEMS) data which will be collected continuously throughout the first 7.5 months of the study period. MEMS is an electronic monitoring system designed to compile the dosing histories of ambulatory patients prescribed oral medications
General improvement in MEMS-measured adherence
An absolute improvement of 10% in a patient's adherence, between their adherence during the initial 3 month run-in period and their adherence during the first 3 months of intervention. See Definitions of adherence rate and measurement of adherence in the first primary outcome description.

Secondary Outcome Measures

Mean-difference in MEMS-measured adherence
Mean-difference in adherence (as measured by the MEMS) between the run-in period and the first 3 months of the intervention period (paired t-test). The aim is to evaluate whether such a difference exists and whether it has statistical significance. For more details on the MEMS system, please see the description under the primary outcome.
Mean change in The Basel Assessment of Adherence to Tyrosine Kinase Inhibitors Scale (BAATIS)
Mean-difference in BAATIS scale scores between the run-in period and the intervention period (paired t-test) The BAATIS is a clinician reported outcome which has been used to assess adherence to immunosuppressive medication in solid organ transplant patients (BAASIS; Basal assessment of adherence with the Immunosuppressive Regimen Scale). Noens et al adapted the questionnaire for use among CML patients in the ADAGIO study. We have performed a similar adaptation Regarding time frames: Each questionnaire-related secondary outcome will be evaluated at two time frames: Short term, to assess an immediate effect on adherence Long term follow up (up to one year after the end of the intervention period) in order to determine whether the intervention has a long term effect on adherence.
Effect of intervention on tyrosine kinase inhibtor related adverse events
The incidence of tyrosine kinase inhibitor related adverse events during 6 months of intervention compared to that witnessed during the initial 3 month run-in period
Adverse effects of tyrosine kinase inhibitors as a measure of MEMS-measured adherence
The incidence of tyrosine kinase inhibtor related adverse events throughout the first 6 months of the study period as a function of adherence (measured by MEMS)
Percentage of patients improving in patient self-reported non-adherence
The percentage of patients changing from a self-reported non-adherence of "yes" during the run-in period, to a self-reported non-adherence of "no" after the intervention, compared to the percentage of those who answered "yes" during the study period and remained "yes" after the intervention. Definition of the "Patient self-reported question regarding non-adherence": Each patient is asked the following question: "It is common that patients at times miss a few doses, for a whole range of reasons. Thinking of the past 7 days have you missed any doses?" If a patient answers 'yes' it will be taken as an indication that the patient has problems with adherence.
Mean change in the physician visual analogue scale (VAS) of adherence
Mean-difference in physician visual analogue scale (VAS) of adherence scores between the run-in period and the intervention period (paired t-test). The physician VAS on adherence rates patient adherence (as assessed by a physician) on a 10 cm VAS scale. A similar scale is in widespread use in several clinical disciplines, especially in assessing pain. It has also been used in assessing adherence to medication. The VAS ranges from perfect adherence (100% = 100mm) to no adherence (0% = 0mm). Regarding time frames: Each questionnaire-related secondary outcome will be evaluated at two time frames: Short term, to assess an immediate effect on adherence Long term follow up (up to one year after the end of the intervention period) in order to determine whether the intervention has a long term effect on adherence.
Mean change in the patient visual analogue scale (VAS) of adherence
Mean-difference in patient visual analogue scale (VAS) of adherence scores between the run-in period and the intervention period (paired t-test). The patient VAS on adherence rates patient adherence (as assessed by the patient) on a 10 cm VAS scale. See detailed explanation on the VAS under the outcome "Mean change in the physician visual analogue scale (VAS) of adherence" Regarding time frames: Each questionnaire-related secondary outcome will be evaluated at two time frames: Short term, to assess an immediate effect on adherence Long term follow up (up to one year after the end of the intervention period) in order to determine whether the intervention has a long term effect on adherence.

Full Information

First Posted
January 8, 2013
Last Updated
June 5, 2017
Sponsor
pia raanani
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1. Study Identification

Unique Protocol Identification Number
NCT01768689
Brief Title
Interventional Study to Improve Adherence to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
Acronym
TAKE-IT
Official Title
The Effect of Active Adherence-Encouraging Interventions on Adherence to Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia - A Prospective Observational Multicenter Study (TAKE-IT)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
October 2013 (Actual)
Primary Completion Date
June 2015 (Actual)
Study Completion Date
June 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
pia raanani

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Adherence to tyrosine kinase inhibitors is associated with improved outcomes in chronic myeloid leukemia patients. Hence, improved adherence might improve CML patients' prognosis. Decreased adherence is a common problem in such patients, with non-adherence in up to 30% of patients in several studies. Recently, an emphasis has been placed on improving patient's adherence to tyrosine kinase inhibitors in these patients. However, there is no prospective high-quality evidence showing that adherence can be improved in these patients. Therefore, the investigators hypothesize that adherence-encouraging interventions improve adherence to tyrosine kinase inhibitors in chronic myeloid leukemia patients.
Detailed Description
The cytogenetic hallmark of chronic myeloid leukemia (CML) is the reciprocal translocation between chromosomes 9 and 22 creating the Philadelphia (Ph(1)) chromosome. The BCRABL1 fusion gene is the result of this translocation and encodes for a constitutively active tyrosine kinase responsible for the development of CML. Tyrosine kinase inhibitors (TKIs) targeting the protein product of this aberrant gene, the BCRABL-1 protein, have revolutionized the therapeutic approach to chronic myeloid leukemia (CML). Treatment with the first FDA approved TKI, imatinib mesylate (Gleevec, Novartis), in chronic phase CML results in a projected 8 year overall survival of 85%. Recently, two second generation TKIs, Dasatinib and Nilotinib, have been approved for use in newly diagnosed chronic phase CML, as a result of studies showing improved molecular and cytogenetic outcomes. Importantly, in each of the above studies there was a substantial number of dropouts due to drug intolerance and resistance, among other reasons. In a prospective observational study of 169 CML patients, only 14% of patients were fully adherent with prescribed imatinib. Moreover, one third of patients were considered to be non-adherent, which is similar to the proportion of dropouts in the landmark studies on TKIs in CML. Thus, it is clear that there is a subgroup of patients who do not properly adhere to treatment. This is especially significant because the contemporary approach to CML in complete cytogenetic remission (CCyR) and major molecular remission (MMR) necessitates long-term, chronic treatment with TKIs. Therefore, although hematologists have the luxury of an armamentarium of highly effective drugs, one of the most challenging aspects of treating CML is the management of non-compliance to TKI treatment. TKI-induced adverse effects are only one of a wide spectrum of reasons for non-adherence to TKI treatment. Recently several studies have demonstrated the prognostic importance of adhering to imatinib treatment. In a pivotal study of 87 chronic phase CML (CP-CML) patients in CCyR, an adherence rate of > 90% strongly correlated with the 6 year probability of achieving MMR (94.5% vs. 28.4% when adherence rates were ≤ 90%). Non-adherence to imatinib treatment also adversely affects event free survival and is associated with loss of CCyR in patients on long term treatment. These data support the intuitive concept that CML can be effectively treated with the drugs currently available, as long as patients adhere to treatment. Moreover, non-adherence to imatinib treatment has been associated with increased economic burden and healthcare costs. Consequently, TKI adherence is an attractive potential target for intervention. Non-adherence to medication is an intricate problem that is influenced by the physician, the healthcare system, and economic and social factors. Other medical disciplines have assessed various modes of improving adherence to therapeutic regimens, with varying success. A recent study assessing adherence-related behavior among CML patients, demonstrated that among a multitude of reasons for non-adherence, patient forgetfulness and drug side effects were the most common causes of unintentional and intentional non-adherence, respectively. Several methods of improving adherence among patients with CML were retrospectively assessed by Moon et al. Subjects in the intervention arm were more likely to receive prescriptions for imatinib than those receiving standard care (98.2 ± 0.03% vs. 79.3 ± 0.16%). Although there was no difference in adherence to prescribed treatment between the two groups, the overall compliance, a composite endpoint of the above two outcomes, was markedly improved in the intervention group ((93.0 ± 2.3% vs. 76.2 ± 7.4%, P = 0.001). Recently, Gater et al conceived a conceptual model aimed at improving adherence in CML patients treated with 1st and 2nd generation TKIs, based on a systematic review of the literature. However, there are currently no prospective data evaluating whether adherence in CML can be influenced by active intervention. Study Hypothesis: Adherence to tyrosine kinase inhibitors (TKIs) is associated with improved outcomes in chronic myeloid leukemia (CML) patients. Hence, improved adherence might improve CML patients' prognosis. The investigators hypothesize that adherence-encouraging interventions improve adherence to TKIs in CML patients. Study Objective: Primary Objective: By means of a prospective before-after study, the investigators aim to assess whether specific adherence-encouraging interventions improve TKI adherence in patients with CP-CML treated by these agents. The investigators will target previously documented reasons for non-adherence 11 with interventions that were selected based on prior experience in other medical disciplines and will evaluate their contribution to patients' adherence to treatment. To better understand non-adherence in CML and pinpoint independent risk factors for non-adherence To validate questionnaires assessing adherence, and evaluate whether they could be of use in indentifying patients at risk for non-adherence To compare adherence to second generation TKIs with adherence to imatinib To assess the role of a clinical pharmacist in preventing potential drug interactions To determine whether the intervention has a long term effect on adherence during one year of post-intervention follow up To estimate long term effects of adherence on clinical, cytogenetic and molecular outcomes

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Medication Adherence
Keywords
adherence, chronic myeloid leukemia, tyrosine kinase inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare Provider
Masking Description
The adherence assessed per study protocol was masked to participants and care providers during the preintervention and post intervention phases. At the time of intervention participants were notified once of their adherence as part of the feedback-based intervention
Allocation
Non-Randomized
Enrollment
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Run-in period
Arm Type
No Intervention
Arm Description
First 3 months of study during which adherence will be measured for each consecutively included study subject, but no intervention will be performed. Patient will receive routine treatment for CML according to the physician discretion.
Arm Title
Adherence-encouraging period
Arm Type
Experimental
Arm Description
Months 4 to 9 of study during which adherence will be measured for each consecutively included study subject, while implementing adherence-encouraging interventions: adherence-encouraging interventions - Group meetings adherence-encouraging interventions - Individual meetings adherence-encouraging interventions - Monthly phone calls Patient will receive routine treatment for CML according to the physician discretion.
Intervention Type
Behavioral
Intervention Name(s)
Adherence-encouraging interventions - Group meeting
Intervention Description
One Group meeting (at the beginning of the intervention period) for all participants, focusing on issues relevant to adherence improvement
Intervention Type
Behavioral
Intervention Name(s)
Adherence-encouraging interventions - Individual meetings
Intervention Description
Individual meetings focusing on adherence issues with a multidiscilinary team
Intervention Type
Behavioral
Intervention Name(s)
Adherence-encouraging interventions - Monthly phone calls
Intervention Description
Monthly phone calls to detect urgent adherence-related issues
Primary Outcome Measure Information:
Title
Clinically relevant change in MEMS-measured adherence
Description
Improvement in a patient's adherence from less than 90% during the initial 3 month run-in period, to 90% or more during the first 3 months of intervention. Definitions: Adherence above 90% was defined as clinically relevant. Adherence rate = actual calculated dose/prescribed dose. Adherence will be calculated from "medical events monitoring system" (MEMS) data which will be collected continuously throughout the first 7.5 months of the study period. MEMS is an electronic monitoring system designed to compile the dosing histories of ambulatory patients prescribed oral medications
Time Frame
From 3 months before intervention, until 3 months after starting the intervention
Title
General improvement in MEMS-measured adherence
Description
An absolute improvement of 10% in a patient's adherence, between their adherence during the initial 3 month run-in period and their adherence during the first 3 months of intervention. See Definitions of adherence rate and measurement of adherence in the first primary outcome description.
Time Frame
3 months prior to the intervention, until 3 months after starting the intervention
Secondary Outcome Measure Information:
Title
Mean-difference in MEMS-measured adherence
Description
Mean-difference in adherence (as measured by the MEMS) between the run-in period and the first 3 months of the intervention period (paired t-test). The aim is to evaluate whether such a difference exists and whether it has statistical significance. For more details on the MEMS system, please see the description under the primary outcome.
Time Frame
3 months prior to intervention until 3 months after starting the intervention
Title
Mean change in The Basel Assessment of Adherence to Tyrosine Kinase Inhibitors Scale (BAATIS)
Description
Mean-difference in BAATIS scale scores between the run-in period and the intervention period (paired t-test) The BAATIS is a clinician reported outcome which has been used to assess adherence to immunosuppressive medication in solid organ transplant patients (BAASIS; Basal assessment of adherence with the Immunosuppressive Regimen Scale). Noens et al adapted the questionnaire for use among CML patients in the ADAGIO study. We have performed a similar adaptation Regarding time frames: Each questionnaire-related secondary outcome will be evaluated at two time frames: Short term, to assess an immediate effect on adherence Long term follow up (up to one year after the end of the intervention period) in order to determine whether the intervention has a long term effect on adherence.
Time Frame
1) Short term: 3 months prior to intervention until 6 months after starting the intervention; 2) Long term: 3 months prior to intervention until 18 months after starting the intervention
Title
Effect of intervention on tyrosine kinase inhibtor related adverse events
Description
The incidence of tyrosine kinase inhibitor related adverse events during 6 months of intervention compared to that witnessed during the initial 3 month run-in period
Time Frame
3 months prior to intervention until 6 months after starting the intervention
Title
Adverse effects of tyrosine kinase inhibitors as a measure of MEMS-measured adherence
Description
The incidence of tyrosine kinase inhibtor related adverse events throughout the first 6 months of the study period as a function of adherence (measured by MEMS)
Time Frame
3 months prior to intervention until 3 months after starting the intervention
Title
Percentage of patients improving in patient self-reported non-adherence
Description
The percentage of patients changing from a self-reported non-adherence of "yes" during the run-in period, to a self-reported non-adherence of "no" after the intervention, compared to the percentage of those who answered "yes" during the study period and remained "yes" after the intervention. Definition of the "Patient self-reported question regarding non-adherence": Each patient is asked the following question: "It is common that patients at times miss a few doses, for a whole range of reasons. Thinking of the past 7 days have you missed any doses?" If a patient answers 'yes' it will be taken as an indication that the patient has problems with adherence.
Time Frame
3 months prior to intervention until 6 months after starting the intervention
Title
Mean change in the physician visual analogue scale (VAS) of adherence
Description
Mean-difference in physician visual analogue scale (VAS) of adherence scores between the run-in period and the intervention period (paired t-test). The physician VAS on adherence rates patient adherence (as assessed by a physician) on a 10 cm VAS scale. A similar scale is in widespread use in several clinical disciplines, especially in assessing pain. It has also been used in assessing adherence to medication. The VAS ranges from perfect adherence (100% = 100mm) to no adherence (0% = 0mm). Regarding time frames: Each questionnaire-related secondary outcome will be evaluated at two time frames: Short term, to assess an immediate effect on adherence Long term follow up (up to one year after the end of the intervention period) in order to determine whether the intervention has a long term effect on adherence.
Time Frame
1) Short term: 3 months prior to intervention until 6 months after starting the intervention; 2) Long term: 3 months prior to intervention until 18 months after starting the intervention
Title
Mean change in the patient visual analogue scale (VAS) of adherence
Description
Mean-difference in patient visual analogue scale (VAS) of adherence scores between the run-in period and the intervention period (paired t-test). The patient VAS on adherence rates patient adherence (as assessed by the patient) on a 10 cm VAS scale. See detailed explanation on the VAS under the outcome "Mean change in the physician visual analogue scale (VAS) of adherence" Regarding time frames: Each questionnaire-related secondary outcome will be evaluated at two time frames: Short term, to assess an immediate effect on adherence Long term follow up (up to one year after the end of the intervention period) in order to determine whether the intervention has a long term effect on adherence.
Time Frame
1) Short term: 3 months prior to intervention until 6 months after starting the intervention; 2) Long term: 3 months prior to intervention until 18 months after starting the intervention

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with chronic phase chronic myeloid leukemia (CP-CML), aged 18 years or older CP-CML defined as: Medical history of cytogenetically confirmed CP-CML defined as the presence of the Philadelphia chromosome on bone marrow aspirates (a minimum of 20 metaphases is required; FISH cannot be used). If Philadelphia chromosome was negative or if cytogenetic results were not available, BCR-ABL-positive CML patients can be included. At least 3 months of TKI treatment (imatinib, dasatinib or nilotinib) before study initiation. Exclusion Criteria: Current or prior accelerated/blast phase or stem cell transplant Participation in another interventional study Pregnancy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pia Raanani, MD
Organizational Affiliation
Rabin Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Soroka Medical Center
City
Beer Sheba
ZIP/Postal Code
84101
Country
Israel
Facility Name
Rambam Medical Center
City
Haifa
Country
Israel
Facility Name
Meir Medical Center
City
Kfar Saba
ZIP/Postal Code
44281
Country
Israel
Facility Name
Rabin Medical Center
City
Petaẖ Tiqwa
ZIP/Postal Code
49100
Country
Israel

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
19349618
Citation
Noens L, van Lierde MA, De Bock R, Verhoef G, Zachee P, Berneman Z, Martiat P, Mineur P, Van Eygen K, MacDonald K, De Geest S, Albrecht T, Abraham I. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009 May 28;113(22):5401-11. doi: 10.1182/blood-2008-12-196543. Epub 2009 Apr 6.
Results Reference
background
PubMed Identifier
21095002
Citation
Eliasson L, Clifford S, Barber N, Marin D. Exploring chronic myeloid leukemia patients' reasons for not adhering to the oral anticancer drug imatinib as prescribed. Leuk Res. 2011 May;35(5):626-30. doi: 10.1016/j.leukres.2010.10.017. Epub 2010 Nov 20.
Results Reference
background
PubMed Identifier
22364811
Citation
Gater A, Heron L, Abetz-Webb L, Coombs J, Simmons J, Guilhot F, Rea D. Adherence to oral tyrosine kinase inhibitor therapies in chronic myeloid leukemia. Leuk Res. 2012 Jul;36(7):817-25. doi: 10.1016/j.leukres.2012.01.021. Epub 2012 Feb 23.
Results Reference
background
PubMed Identifier
20385986
Citation
Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, Apperley JF, Szydlo R, Desai R, Kozlowski K, Paliompeis C, Latham V, Foroni L, Molimard M, Reid A, Rezvani K, de Lavallade H, Guallar C, Goldman J, Khorashad JS. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010 May 10;28(14):2381-8. doi: 10.1200/JCO.2009.26.3087. Epub 2010 Apr 12.
Results Reference
background
PubMed Identifier
16079372
Citation
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005 Aug 4;353(5):487-97. doi: 10.1056/NEJMra050100. No abstract available.
Results Reference
background
PubMed Identifier
21472487
Citation
Moon JH, Sohn SK, Kim SN, Park SY, Yoon SS, Kim IH, Kim HJ, Kim YK, Min YH, Cheong JW, Kim JS, Jung CW, Kim DH. Patient counseling program to improve the compliance to imatinib in chronic myeloid leukemia patients. Med Oncol. 2012 Jun;29(2):1179-85. doi: 10.1007/s12032-011-9926-8. Epub 2011 Apr 7.
Results Reference
background
PubMed Identifier
22048790
Citation
Jonsson S, Olsson B, Soderberg J, Wadenvik H. Good adherence to imatinib therapy among patients with chronic myeloid leukemia--a single-center observational study. Ann Hematol. 2012 May;91(5):679-685. doi: 10.1007/s00277-011-1359-0. Epub 2011 Nov 3. Erratum In: Ann Hematol. 2017 Jun 9;:
Results Reference
background

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Interventional Study to Improve Adherence to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

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