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Study to Assess Compliance With Long-Term Mercaptopurine Treatment in Young Patients With Acute Lymphoblastic Leukemia in Remission

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ClinicalTrials.gov Identifier: NCT00268528
Recruitment Status : Active, not recruiting
First Posted : December 22, 2005
Last Update Posted : October 15, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:
This clinical trial is assessing compliance with long-term mercaptopurine treatment in young patients with acute lymphoblastic leukemia in remission. Assessing why young patients who have acute lymphoblastic leukemia may not take their medications as prescribed may help identify ways to assist them in taking their medications more consistently and may improve long-term treatment outcomes.

Condition or disease Intervention/treatment
Childhood Acute Lymphoblastic Leukemia in Remission Behavioral: Compliance Monitoring Other: Laboratory Biomarker Analysis Drug: Mercaptopurine Drug: Methotrexate Other: Questionnaire Administration Other: Study of Socioeconomic and Demographic Variables

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine and compare adherence to maintenance mercaptopurine (6-MP) in a cohort of children with acute lymphoblastic leukemia (ALL) from four different ethnic and racial groups (Caucasians, African-Americans, Hispanics, and Asians) receiving maintenance/continuation chemotherapy, using the following assessments: serial red cell 6-MP metabolites (6-thioguanine [6TGN] and methyl thioinosine monophosphate [TIMP]); frequency of 6-MP dosing using an electronic pill monitoring system (Microelectromechanical Systems [MEMS]?); self-report of adherence to 6-MP by questionnaire.

II. To determine the impact of adherence to 6-MP (measured using 6TGN, methyl [Me]TIMP, MEMS? and self-report data independently) on event-free-survival (EFS) in the entire cohort, after adjusting for known predictors of disease outcome.

III. Define a critical level of adherence (measured independently by 6TGN, MeTIMP, MEMS?, self-report) that has a significant impact on EFS for the entire cohort.

IV. Describe prevalence of adherence to 6-MP by ethnicity (6TGN, MeTIMP, MEMS?, Self-report).

V. Describe behavioral and socio-demographic predictors of adherence using the questionnaire data.

VI. Describe the pill-taking practices in this cohort using the MEMS? data. VII. To evaluate the impact of adherence on ethnic/racial difference in EFS.

SECONDARY OBJECTIVES:

I. To assess the concordance among 6TGN and MeTIMP levels, electronic pill monitoring, and self-reported adherence in the ethnic/racial groups.

OUTLINE:

Patients receive an electronic pill monitoring system comprising an empty MEMS? medication bottle with TrackCap? child resistant (CR). The mercaptopurine prescription is filled using this system. Beginning on day 1 of the third or later course of maintenance therapy, patients take all doses of mercaptopurine from the MEMS? medication bottle with TrackCap? CR for at least 169 days. The MEMS? TrackCap? CR is mailed to the Coordinating Center at the end of study. Patients also receive methotrexate orally (PO) as indicated by their individual chemotherapy regimen.

NOTE: *Study closed to accrual for Caucasian and Hispanic patients as of 8/14/2009.

After completion of study, patients are followed up every 6 months for 5 years and then annually for up to 10 years.


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Study Type : Observational
Estimated Enrollment : 720 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Understanding the Ethnic and Racial Differences in Survival in Children With Acute Lymphoblastic Leukemia
Actual Study Start Date : May 30, 2005


Group/Cohort Intervention/treatment
Health service research (electronic pill monitoring system)
Patients receive an electronic pill monitoring system comprising an empty MEMS^? medication bottle with TrackCap? CR. The mercaptopurine prescription is filled using this system. Beginning on day 1 of the third or later course of maintenance therapy, patients take all doses of mercaptopurine from the MEMS^? medication bottle with TrackCap? CR for at least 169 days. The MEMS^? TrackCap? CR is mailed to the Coordinating Center at the end of study. Patients also receive methotrexate PO as indicated by their individual chemotherapy regimen.
Behavioral: Compliance Monitoring
Receive an electronic pill monitoring system comprising an empty MEMS medication bottle with TrackCap

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Mercaptopurine
Given PO
Other Names:
  • 3H-Purine-6-thiol
  • 6 MP
  • 6 Thiohypoxanthine
  • 6 Thiopurine
  • 6-Mercaptopurine
  • 6-Mercaptopurine Monohydrate
  • 6-MP
  • 6-Purinethiol
  • 6-Thiopurine
  • 6-Thioxopurine
  • 6H-Purine-6-thione, 1,7-dihydro- (9CI)
  • 7-Mercapto-1,3,4,6-tetrazaindene
  • Alti-Mercaptopurine
  • Azathiopurine
  • BW 57-323H
  • Flocofil
  • Ismipur
  • Leukerin
  • Leupurin
  • Mercaleukim
  • Mercaleukin
  • Mercaptina
  • Mercaptopurinum
  • Mercapurin
  • Mern
  • NCI-C04886
  • Puri-Nethol
  • Purimethol
  • Purine, 6-mercapto-
  • Purine-6-thiol (8CI)
  • Purine-6-thiol, monohydrate
  • Purinethiol
  • Purinethol
  • U-4748
  • WR-2785

Drug: Methotrexate
Given PO
Other Names:
  • Abitrexate
  • Alpha-Methopterin
  • Amethopterin
  • Brimexate
  • CL 14377
  • CL-14377
  • Emtexate
  • Emthexat
  • Emthexate
  • Farmitrexat
  • Fauldexato
  • Folex
  • Folex PFS
  • Lantarel
  • Ledertrexate
  • Lumexon
  • Maxtrex
  • Medsatrexate
  • Metex
  • Methoblastin
  • Methotrexate LPF
  • Methotrexate Methylaminopterin
  • Methotrexatum
  • Metotrexato
  • Metrotex
  • Mexate
  • Mexate-AQ
  • MTX
  • Novatrex
  • Rheumatrex
  • Texate
  • Tremetex
  • Trexeron
  • Trixilem
  • WR-19039

Other: Questionnaire Administration
Ancillary studies

Other: Study of Socioeconomic and Demographic Variables
Receive an electronic pill monitoring system comprising an empty MEMS medication bottle with TrackCap




Primary Outcome Measures :
  1. Adherence to 6-MP as measured by 6TGN and MethylTIMP levels [ Time Frame: 169 days ]
    Will initially perform an exploratory data analysis on distributions across the four groups using side-by-side boxplots, histograms, and summary quantities (mean, median, quartiles, standard deviations, inter-quartile-range, etc.). If central values summarize across-group differences well, then mean and median of the distribution will be compared between 6 pairs of the four ethnic groups using the two-sample t-test and the Mann-Whitney U-test. Will perform these tests adjusting for 6 pairwise multiple comparisons among the four groups using the Bonferroni?s correction method.

  2. Adherence as measured by frequency of 6-MP dosing as a continuous variable using MEMS? defined as the number of days the MEMS? Cap openings are recorded, taken as a percentage of days doses were prescribed during the study period [ Time Frame: Up to 169 days ]
    Will initially perform an exploratory data analysis on distributions across the four groups using side-by-side boxplots, histograms, and summary quantities (mean, median, quartiles, standard deviations, inter-quartile-range, etc.). If central values summarize across-group differences well, then mean and median of the distribution will be compared between 6 pairs of the four ethnic groups using the two-sample t-test and the Mann-Whitney U-test. Will perform these tests adjusting for 6 pairwise multiple comparisons among the four groups using the Bonferroni?s correction method.

  3. Self-report of adherence to 6-MP by questionnaire, defined as the number of days doses of 6-MP are reported to being taken, as a percentage of days doses were prescribed during the study period [ Time Frame: 169 days ]
    Will initially perform an exploratory data analysis on distributions across the four groups using side-by-side boxplots, histograms, and summary quantities (mean, median, quartiles, standard deviations, inter-quartile-range, etc.). If central values summarize across-group differences well, then mean and median of the distribution will be compared between 6 pairs of the four ethnic groups using the two-sample t-test and the Mann-Whitney U-test. Will perform these tests adjusting for 6 pairwise multiple comparisons among the four groups using the Bonferroni?s correction method.

  4. EFS [ Time Frame: Up to 10 years ]
    For each of the three types of adherence measures, will fit independent Cox?s proportional-hazard models to assess the prognostic significance of the adherence measure on EFS, after adjusting for known predictors of disease outcome, including the National Cancer Institute risk group (based on the age at diagnosis and presenting white cell count) and chromosomal abnormalities.

  5. Critical level of adherence (measured independently by 6TGN/MethylTIMP, MEMS?, self-report) that has a significant impact on EFS [ Time Frame: Up to 10 years ]
    Will fit a separate Cox regression model to each of the three adherence measures (i.e., 6TGN, MeTIMP, MEMS, and self-report). Using no more than several knots, the natural spline (a special type of cubic splines) fits a very wide range of smoothly changing adherence effects. The adherence effects on EFS will be visualized graphically. This will be the primary approach for defining the critical level of adherence. To confirm the spline analysis results, will categorize the continuous adherence measures into multiple levels and estimate the effect of each adherence level.

  6. Prevalence of adherence to 6-MP by ethnicity (measured independently by 6TGN/MethylTIMP, MEMS?, Self-report) that has a significant impact on EFS [ Time Frame: Up to 10 years ]
    Will describe the prevalence of non-adherence by race/ethnicity and compare the prevalence by using two-tailed chi-squared test (with a Yates' correction).

  7. Behavioral, socio-demographic predictors of adherence using the questionnaire data [ Time Frame: Up to 10 years ]
    The reasons for non-adherence will be assessed. The relationship between adherence to 6-MP as reported by the patients/parents and the independent behavioral variables knowledge of medications, understanding of treatment regimen, extent of treatment side effects, length of treatment, and beliefs about the efficacy of the regimen, beliefs and attitudes towards health and medical care will be evaluated descriptively first using standard parametric or non-parametric tests, and then analytically by logistic regression (dichotomous adherence) or linear regression (continuous adherence).

  8. Pill-taking practices using the MEMS? data [ Time Frame: Up to 169 days ]
    Using the MEMS? output data, the adherence report will be analyzed for: i) longest and shortest interval between doses in hours; ii) percent prescribed doses taken, and iii) percent prescribed doses taken on schedule.

  9. Impact of adherence (measured independently by 6TGN/MethylTIMP, MEMS, self-report) on ethnic/racial differences in EFS [ Time Frame: Up to 10 years ]
    Will fit independent Cox?s proportional-hazard models to assess the impact of adherence measure on EFS, after adjusting for known predictors of disease outcome, including the National Cancer Institute risk group (based on the age at diagnosis and presenting white cell count) and chromosomal abnormalities.


Secondary Outcome Measures :
  1. Concordance among red cell thiopurine metabolite levels, electronic pill monitoring, and self-reported adherence among the ethnic/racial groups [ Time Frame: Up to 168 days ]
    Correlations between mean dosage- and TPMT-normalized serial red cell 6-MP metabolites and mean adherence by electronic pill monitoring system and self-report will be assessed for statistical significance by Spearman's rank correlation coefficient.


Biospecimen Retention:   Samples With DNA
Blood


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Children with ALL from four different ethnic and racial groups (Caucasians, African-Americans, Hispanics, and Asians) receiving maintenance/continuation chemotherapy.
Criteria

Inclusion Criteria:

  • Diagnosis of ALL in first remission, irrespective of risk stratification; enrollment on a Children's Oncology Group (COG) therapeutic study for ALL is not required, but the treatment plan must meet the criteria in this protocol
  • Belongs to one of the four following ethnic/racial categories: African-American, Asian, Caucasian, or Hispanic; below please find definitions for these categories

    • African-American: includes patients who are African-American or of sub-Saharan black African ancestry
    • Asian: patients of Asian ancestry, including the following: Asian Indian (subcontinent), Chinese, Japanese, Korean, Native Hawaiian, Guamanian or Chamorro, Pacific Islander, Filipino, Vietnamese, Samoan, Hmong, Cambodian, Thai, Laotian, or Other Asian races
    • Caucasian: includes White or light-skinned patients of European, North African, or Middle Eastern ancestry
    • Hispanic: patients of Hispanic ethnicity, including the following: Mexican, Mexican American, Chicano, Cuban, Puerto Rican, or Other Spanish/Hispanic/Latino ethnicity
  • Receiving self- or parent/caregiver-administered oral anti-metabolite chemotherapy during the maintenance/continuation phase of therapy; patients are eligible if their treatment plan calls for the following doses of 6-MP and methotrexate (MTX) during the maintenance/continuation phase: 6-MP ? 75 mg/m^2/day orally; MTX 20 mg/m^2/week orally;** (modification of 6-MP or MTX dosing based on laboratory or clinical parameters is acceptable)

    • For guidance regarding if and when a patient being treated on or according to a specific COG (or legacy group) protocol is eligible, please refer to ?AALL03N1 Eligibility by Protocol Tool,? available in the study data forms packet on the COG website
  • Has completed at least 24 weeks of maintenance/continuation chemotherapy, and is scheduled to receive at least 24 more weeks of maintenance/continuation chemotherapy**

    • For guidance regarding if and when a patient being treated on or according to a specific COG (or legacy group) protocol is eligible, please refer to ?AALL03N1 Eligibility by Protocol Tool,? available in the study data forms packet on the COG website
  • Written informed consent from the patient and/or the patient?s legally authorized guardian, obtained prior to registration and any study-related procedures, and in accordance with institutional policies approved by the United States (U.S) Department of Health and Human Services

Exclusion Criteria:

  • Patients of multi-ethnic/multi-racial backgrounds are not eligible for this study; while patients of multi-ethnic/multi-racial ancestry (e.g., Caucasian/Japanese, Hawaiian/Puerto Rican) are not eligible, patients of mixed ancestry within a race/ethnicity (e.g., Japanese/Chinese = Asian or Korean/Japanese/Hawaiian = Asian or Mexican/Puerto Rican = Hispanic) may participate as long as they fall under the general classification of "African-American," "Asian," "Caucasian," or "Hispanic"

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00268528


  Show 135 Study Locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Smita Bhatia Children's Oncology Group

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00268528     History of Changes
Other Study ID Numbers: AALL03N1
NCI-2009-00305 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000459748
07-462
AALL03N1 ( Other Identifier: Childrens Oncology Group )
COG-AALL03N1 ( Other Identifier: DCP )
AALL03N1 ( Other Identifier: CTEP )
R01CA096670 ( U.S. NIH Grant/Contract )
U10CA095861 ( U.S. NIH Grant/Contract )
First Posted: December 22, 2005    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: October 2019
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Methotrexate
Mercaptopurine
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors