Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT02733224 |
| Other study ID # |
0336-15 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
April 5, 2016 |
| Last updated |
June 1, 2016 |
| Start date |
June 2016 |
| Est. completion date |
August 2018 |
Study information
| Verified date |
June 2016 |
| Source |
Rabin Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Israel: Ethics Commission |
| Study type |
Observational
|
Clinical Trial Summary
we intend to evaluate the association between non-adherence to Lenalidomide in Multiple
Myeloma (MM) patients and overall response rates and time to progression (TTP).
Adherence will be measured in several ways, including by electronic monitoring, which is the
gold standard method.
Description:
Study Hypothesis: We hypothesize that non-adherence to lenalidomide in MM patients is
associated with decreased overall response rates and shorter time to progression (TTP).
Study Objectives:
Primary Objective: To evaluate the association between non-adherence to lenalidomide in MM
patients and the overall response rate at 6 months.
Secondary Objectives: 1) To evaluate the prevalence of non-adherence to lenalidomide in MM
patients, and independent risk factors thereof. 2) To validate the utility of questionnaires
assessing adherence in identifying MM patients at risk for lenalidomide non-adherence.3) To
assess the association between non-adherence to lenalidomide and long-term response,
measured as time to progression (TTP) at 18 months.
Background: Lenalidomide-based regimens are a key component of the armamentarium for initial
treatment in newly diagnosed multiple myeloma patients. Real-life data shows CR rates that
are comparable to or slightly higher 1than those seen in prospective clinical trials. This
variable response is a result of differences in clinical settings and patient and disease
characteristics, but in theory, also may be due to variable adherence to lenalidomide. The
development of oral anticancer therapies, such as lenalidomide, represents a significant
step forward in oncology care by providing patients with convenient treatment of proven
clinical efficacy, but also presents healthcare professionals with the challenge of
monitoring and maintaining patients' adherence to this therapy.
Non-adherence may be defined, for example, as non-perfect adherence (i.e. less than 100%),
another cutoff with proven clinical significance, or simply as a numerical value
representing the percentage of medication taken, relative to that recommended. This
definition, together with the method used to measure adherence, can greatly influence
reported rates of non-adherence in any given clinical setting. Taking all these limitations
into account, reported rates of non-adherence to oral anti-cancer regimens across empirical
studies average approximately 25% 2,3.Accordingly, using pharmacy refill data, a recent
retrospective study demonstrated that 33% of newly diagnosed MM patients were non-adherent
to lenalidomide treatment (defined as adherence < 80%)4. This is the only study, assessing
adherence to lenalidomide in MM patients, which we are aware of.
Using electronic monitoring (EM), Marin et al prospectively demonstrated that poor adherence
to the tyrosine kinase inhibitor (TKI), imatinib, in CML, adversely impacts molecular and
cytogenetic response 5,6.This landmark study provided proof of concept that non-adherence to
oral anti-cancer in hematological malignancies may be associated with poor responses and
decreased survival. Our study group is currently analyzing data from our prospective
interventional study aimed at improving adherence to TKIs in CML (NCT01768689).
In light of this evidence, in an era that has witnessed the advent of effective oral agents
for MM, understanding the prevalence, characteristics and clinical implications of
non-adherence to these agents is key to providing high-quality care for these patients.
Nevertheless, research regarding adherence to oral agents in MM (e.g. thalidomide,
lenalidomide, pomalidomide) is still in its infancy, and there are no data indicating
whether a similar association between adherence and treatment response exists in this field.
Moreover, there is a paucity of data regarding the prevalence of non-adherence and risk
factors thereof, in the above context.
Study design:
Prospective multi-center observational (non-interventional) cohort study.Patients will be
managed routinely according to the local protocol at each center for the treatment of
multiple myeloma. Study period: From initiation of lenalidomide therapy for a period of 18
months. Setting and location: Institute of hematology, Sheba medical center and Hematology
Institute at the Davidoff cancer center, Rabin medical center, Israel.
Inclusion criteria: Patients diagnosed with active MM starting induction treatment with the
lenalidomide with or without dexamethasone, as any line of therapy.
Key exclusion criteria: Treatment with any additional anti-myeloma drugs, during study
period.
Patient characteristics and confounders: Patient characteristics (demographics,
comorbidities); Disease-related characteristics (duration, myeloma stage and risk, details
regarding previous therapy and response, functional status, quality of life); Other drugs
(Number of drugs, pills and potential interactions with lenalidomide). We will use an
adaptation of the questionnaire from the "BRIGHT" study (which assesses barriers to
immunosuppressive medication adherence in heart transplant recipients) to assess barriers to
adherence in this patient cohort.
Measurement of adherence: Adherence to lenalidomide treatment will be measured continuously
throughout the study period, by several means: 1) Electronic monitoring (EM) will be used
throughout the first 5 months of the study period. This is considered the gold standard for
measuring adherence, reflecting adherence more objectively than questionnaires and
pill-counting. The microelectronic monitoring system (MEMS), a specific type of EM, consists
of an electronic device fitted in the cap of a normal-looking medication bottle that
automatically records each time the bottle is opened. Adherence measured with this device
was associated with treatment response in the landmark study in CML by Marin et al. 2) Pill
counting for first five months. 3) Questionnaires: The physician visual analogue scale
(physician VAS) and an adaptation of the "Basel assessment of adherence with the
Immunosuppressive Regimen Scale" (BAASIS), will be assessed at predefined time points
throughout the 18 months of the study period.
Outcome Measures: Primary outcome measure: Response to treatment (Overall response) 4 weeks
after finishing five months of electronic adherence monitoring (i.e. at 6 months).
Analysis: Primary analysis: Incidence of the primary outcome measure in patients with
electronically measured adherence of above 90% versus those below 90%, as measured for 5
consecutive months after study initiation.
Secondary analysis: 1) Analyze the association of each of the baseline characteristics /
confounders and adherence-barriers questionnaire to electronically-measured adherence and
look for independent risk factors for non-adherence. This will be stratified to line of
treatment. 2) Validation of study questionnaires compared to electronically measured
adherence.
3) A long-term analysis which will look at an association between TTP at 18 months and both
initial adherence measure electronically (first 5 months) and long term overall adherence
measured by BAASIS questionnaire (18months).
Sample size:
In a prior study7, the ORR (i.e. PR and better) was 68% in the Rd arm, after 4 cycles. A
prior study in CML showed a profound effect of adherence above 90% on optimal treatment
response (RR=11) 5. As no data exists regarding the effect of adherence on outcome in our
study population we utilized a RR which was conservative (<2), relative to the data from
CML. We assumed an 80% ORR at 6 months in the adherent group and 45% ORR at 6 months in the
non-adherent group (defined by a cutoff of 90% adherence). Prior data8 suggested the
adherent/non-adherent ratio in patients receiving lenalidomide induction for myeloma is 7:3,
and we assumed a similar ratio of 2:1.
Based on the above data, we calculated that 43 patients in the adherent arm and 22 patients
in the non-adherent arm will have a power of 0.8 (with a type I error of 0.05) to reject the
null hypothesis that there is no difference in ORR between these groups.
Therefore the required sample size is 67.
