Clinical trial NCT01768689: Interventional Study to Improve Adherence to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia
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
Overall status: COMPLETED
Phase: NA
Conditions: Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Medication Adherence
Keywords: adherence
chronic myeloid leukemia
tyrosine kinase inhibitors
Lead sponsor: Rabin Medical Center
Sponsor class: OTHER
First posted: 2013-01-15
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

1. 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.
2. To better understand non-adherence in CML and pinpoint independent risk factors for non-adherence
3. To validate questionnaires assessing adherence, and evaluate whether they could be of use in indentifying patients at risk for non-adherence
4. To compare adherence to second generation TKIs with adherence to imatinib
5. To assess the role of a clinical pharmacist in preventing potential drug interactions
6. To determine whether the intervention has a long term effect on adherence during one year of post-intervention follow up
7. To estimate long term effects of adherence on clinical, cytogenetic and molecular outcomes

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

Primary outcomes:
measure: Clinically relevant change in MEMS-measured adherence
timeFrame: From 3 months before intervention, until 3 months after starting the intervention
measure: General improvement in MEMS-measured adherence
timeFrame: 3 months prior to the intervention, until 3 months after starting the intervention
Secondary outcomes:
measure: Mean-difference in MEMS-measured adherence
timeFrame: 3 months prior to intervention until 3 months after starting the intervention
measure: Mean change in The Basel Assessment of Adherence to Tyrosine Kinase Inhibitors Scale (BAATIS)
timeFrame: 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
measure: Effect of intervention on tyrosine kinase inhibtor related adverse events
timeFrame: 3 months prior to intervention until 6 months after starting the intervention
measure: Adverse effects of tyrosine kinase inhibitors as a measure of MEMS-measured adherence
timeFrame: 3 months prior to intervention until 3 months after starting the intervention
measure: Percentage of patients improving in patient self-reported non-adherence
timeFrame: 3 months prior to intervention until 6 months after starting the intervention
measure: Mean change in the physician visual analogue scale (VAS) of adherence
timeFrame: 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
measure: Mean change in the patient visual analogue scale (VAS) of adherence
timeFrame: 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
Other outcomes:
Locations:
city: Beer Sheba
country: Israel
facility: Soroka Medical Center
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Petaẖ Tiqwa
country: Israel
facility: Rabin Medical Center
Study officials:
affiliation: Rabin Medical Center
name: Pia Raanani, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.