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

Study Overview
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Brief Summary
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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
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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

Official Title
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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)

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

Intervention / Treatment
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* Behavioral: Adherence-encouraging interventions - Group meeting
* Behavioral: Adherence-encouraging interventions - Individual meetings
* Behavioral: Adherence-encouraging interventions - Monthly phone calls


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Run-in period<br>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. | |
| Experimental: Adherence-encouraging period<br>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. | Behavioral: Adherence-encouraging interventions - Group meeting<br>* One Group meeting (at the beginning of the intervention period) for all participants, focusing on issues relevant to adherence improvement<br>Behavioral: Adherence-encouraging interventions - Individual meetings<br>* Individual meetings focusing on adherence issues with a multidiscilinary team<br>Behavioral: Adherence-encouraging interventions - Monthly phone calls<br>* Monthly phone calls to detect urgent adherence-related issues<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From 3 months before intervention, until 3 months after starting the intervention | 
| 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. | 3 months prior to the intervention, until 3 months after starting the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 months prior to intervention until 3 months after starting the intervention | 
| 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. | 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 | 
| 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 | 3 months prior to intervention until 6 months after starting the intervention | 
| 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) | 3 months prior to intervention until 3 months after starting the intervention | 
| 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. | 3 months prior to intervention until 6 months after starting the intervention | 
| 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. | 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 | 
| 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adherence, chronic myeloid leukemia, tyrosine kinase inhibitors