Clinical trial NCT00576472: Learning Impairments Among Survivors of Childhood Cancer
Official title: Learning Impairments Among Survivors of Childhood Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Acute Lymphoblastic Leukemia
Brain Tumors
Keywords: Brain Tumor, Acute Lymphoblastic Leukemia, Methylphenidate, Cognitive Late Effects
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-12-19
Enrollment: 469
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Intervention model: CROSSOVER
Primary purpose: SUPPORTIVE_CARE

Brief summary: Children surviving some types of cancer have a higher risk of developing learning problems after cancer treatment than do children who have not had cancer or its treatment. Cancer treatment may cause problems with learning, attention, and memory. The purpose of this study is to identify brain changes that may underlie learning problems in cancer survivors and investigate whether methylphenidate (a stimulant medication) may reduce these problems.

Subjects who have had treatment for acute lymphoblastic leukemia (ALL) or a brain tumor will be asked to take part in this research study. Siblings of some subjects will also be asked to take part, so that their results can be compared with those of children who have had cancer treatment. We hypothesize that children receiving more aggressive therapy will have lower white matter brain volumes and these volumes will be significantly lower than age-matched siblings. We also hypothesize that children who take methylphenidate will show improvements on teacher and parent report measures of attention and social skills.

Detailed description: This study is a multi-phase, multi-site methylphenidate (MPH) trial in childhood cancer survivors. Study participants that meet inclusion and exclusion criteria are screened to ensure that they have adequate global cognitive functioning (IQ \> 50) and have academic and attention difficulties that might be managed with MPH. Following the screening phase, qualifying participants take part in a two-day, in-clinic, double-blind, cross-over trial during which they receive MPH (0.6 mg/kg; maximum dose, 20 mg) and placebo (inert substance) in a randomly assigned order. Patients who do not have a significant adverse reaction during the two-day trial go on to participate in a randomized, double-blind, placebo-controlled, three-week home cross-over trial consisting of placebo, low-dose MPH (0.3 mg/kg; maximum dose, 10 mg bid), and moderate-dose MPH (0.6 mg/kg; maximum dose, 20 mg bid). Patients are then selected for participation in a 12-month open-label MPH trial if they show improvement over placebo on a parent and/or teacher rating of attention during the three-week home cross-over trial. The 12-month open-label MPH trial includes individually titrated MPH dosing to maximize clinical benefit, monthly monitoring of side effects and regular acquisition of parent and teacher ratings of attention and behavior. Laboratory measures of intellectual function, attention and memory are conducted at the end of the 12-month trial.

Eligibility criteria: Inclusion Criteria:

* Age: 6 to 18 years old.
* Active subject at St. Jude Children's Research Hospital, or is an age-matched sibling control subject.
* If a subject, received treatment for brain tumor or ALL with either radiation therapy and/or chemotherapy directed at the brain.
* If a subject, at least 12 months post-completion of antineoplastic therapies
* If a subject, no evidence of malignancy, or continuously stable disease since completion of therapy
* English as a primary language
* Informed consent

Exclusion Criteria:

* Glaucoma
* Patient or immediate family member with a history of Tourette's syndrome
* Current antidepressant, anxiolytic, antipsychotic or stimulant therapy
* History of substance abuse
* Recent history of uncontrolled seizures
* Uncorrected hypothyroidism
* Previously or currently randomized on COGRM1 intervention arm
* Previously diagnosed with ADHD, or, if a patient, diagnosed with ADHD prior to diagnosis of malignancy

Primary outcomes:
measure: Brain White Matter Volume for Patients Versus Sibling Controls
timeFrame: Enrollment to evaluation of MRI, on average 12.8 months.
measure: Brain White Matter Volume for Patients With Acute Lymphoblastic Leukemia Versus Brain Tumors
timeFrame: Enrollment to evaluation of MRI, on average 12.8 months.
measure: Brain White Matter Volume for Treatment Intensity Groups and Sibling Controls
timeFrame: Enrollment to evaluation of MRI, on average 12.8 months.
measure: Change From Methylphenidate (MPH) Home Maintenance Phase Baseline to Completion of Phase as Measured by Conners' Teacher Rating Scale (CTRS: ADHD T Score)
timeFrame: From beginning and at completion of Methylphenidate (MPH) Home Maintenance Phase, on average 16.3 months.
measure: Change From Maintenance Phase Baseline to Completion of Phase as Measured by Conners' Teacher Rating Scale (CTRS: Cognitive Problem T Score)
timeFrame: From beginning and at completion of home maintenance phase, on average 16.3 months.
measure: Change From Maintenance Phase Baseline to Completion of Phase as Measured by Conners' Parent Rating Scale (CPRS: ADHD T Score)
timeFrame: From beginning and at completion of home maintenance phase, on average 16.3 months.
measure: Change From Maintenance Phase Baseline to Completion of Phase as Measured by Conner's Parent Rating Scale (CPRS: Cognitive Problem T Score)
timeFrame: From beginning and at completion of home maintenance phase, on average 16.3 months.
measure: Change From Maintenance Phase Baseline to Completion of Phase as Measured by Social Skill Rating System (SSRS-P)
timeFrame: From beginning and at completion of home maintenance phase, on average 16.3 months.
measure: Change From Maintenance Phase Baseline to Completion of Phase as Measured by Wechsler Individual Achievement Test (WIAT) Reading: Composite Standard Score
timeFrame: From beginning and at completion of home maintenance phase, on average 16.3 months.
measure: Change From Maintenance Phase Baseline to Completion of Phase as Measured by Wechsler Individual Achievement Test (WIAT) Spelling: Standard Score
timeFrame: From beginning and after completion of home maintenance phase, on average 16.3 months.
measure: Change From Maintenance Phase Baseline to Completion of Phase as Measured by Wechsler Individual Achievement Test (WIAT) Math: Composite Standard Score
timeFrame: From beginning and after completion of home maintenance phase, on average 16.3 months.
Secondary outcomes:
measure: Best Weekly Score Measured by Conners' Parent Rating Scale (CPRS: ADHD T Score) During the 3-week Home Crossover Phase.
timeFrame: weekly during 3-week home crossover phase
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by The Conners' Parent Rating Scale (CPRS) Cognitive Problem/Inattention Scale.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by The Conners' Parent Rating Scale (CPRS) Hyperactivity Scale.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by The Conners' Parent Rating Scale (CPRS) ADHD Index.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by The Conners' Teacher Rating Scale (CTRS) Cognitive Problem/Inattention Scale.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by The Conners' Teacher Rating Scale (CTRS) Hyperactivity Scale.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by The Conners' Teacher Rating Scale (CTRS) ADHD Index.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by Social Skills Rating System - Parent (SSRS-P) - Social Skill.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by Social Skills Rating System - Parent (SSRS-P) - Problem Behavior.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by Social Skills Rating System - Teacher (SSRS-T) - Social Skill.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Effectiveness of MPH in Enhancing Classroom Attentiveness, Academic Productivity, and Social Behavior Measured by Social Skills Rating System - Teacher (SSRS-T) - Problem Behavior.
timeFrame: Evaluated at the end of each medication week during the Home Therapy Phase- placebo, low dose and moderate dose weeks.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Sustained Attention, Reaction Time, and, Impulsivity Using Conner's Continuous Performance Test (CPT) for Omission Errors.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Sustained Attention, Reaction Time, and, Impulsivity Using Conner's Continuous Performance Test (CPT) for Commission Errors.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Sustained Attention, Reaction Time, and, Impulsivity Using Conner's Continuous Performance Test (CPT) for Hit Reaction Time.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Sustained Attention, Reaction Time, and, Impulsivity Using Conner's Continuous Performance Test (CPT) for d' (Sensitivity).
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Sustained Attention, Reaction Time, and, Impulsivity Using Conner's Continuous Performance Test (CPT) for Beta (Risk Taking).
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Learning and Recall Using California Verbal Learning Test (CVLT) Over Five Learning Trials.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Learning and Recall Using California Verbal Learning Test (CVLT) for Short Delay Free Recall.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Learning and Recall Using California Verbal Learning Test (CVLT) for Long Delay Free Recall.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Interference, Impulsivity, Cognitive Flexibility, and Selective Attention Using the Stroop Word-Color Association Test (Stroop) for Word Naming Time.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Interference, Impulsivity, Cognitive Flexibility, and Selective Attention Using the Stroop Word-Color Association Test (Stroop) for Color Naming Time.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Interference, Impulsivity, Cognitive Flexibility, and Selective Attention Using the Stroop Word-Color Association Test (Stroop) for Ink Color Naming Time.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
measure: Establish the Effectiveness of MPH on Laboratory Measures of Interference, Impulsivity, Cognitive Flexibility, and Selective Attention Using the Stroop Word-Color Association Test (Stroop) for Interference Score.
timeFrame: Subjects were tested in both the drug and placebo groups before and after taking either MPH or placebo.
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Heather M Conklin
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mulhern RK, Khan RB, Kaplan S, Helton S, Christensen R, Bonner M, Brown R, Xiong X, Wu S, Gururangan S, Reddick WE. Short-term efficacy of methylphenidate: a randomized, double-blind, placebo-controlled trial among survivors of childhood cancer. J Clin Oncol. 2004 Dec 1;22(23):4795-803. doi: 10.1200/JCO.2004.04.128.
citation: Reddick WE, Shan ZY, Glass JO, Helton S, Xiong X, Wu S, Bonner MJ, Howard SC, Christensen R, Khan RB, Pui CH, Mulhern RK. Smaller white-matter volumes are associated with larger deficits in attention and learning among long-term survivors of acute lymphoblastic leukemia. Cancer. 2006 Feb 15;106(4):941-9. doi: 10.1002/cncr.21679.
citation: Conklin HM, Khan RB, Reddick WE, Helton S, Brown R, Howard SC, Bonner M, Christensen R, Wu S, Xiong X, Mulhern RK. Acute neurocognitive response to methylphenidate among survivors of childhood cancer: a randomized, double-blind, cross-over trial. J Pediatr Psychol. 2007 Oct;32(9):1127-39. doi: 10.1093/jpepsy/jsm045. Epub 2007 Jun 14.
citation: Reeves CB, Palmer S, Gross AM, Simonian SJ, Taylor L, Willingham E, Mulhern RK. Brief report: sluggish cognitive tempo among pediatric survivors of acute lymphoblastic leukemia. J Pediatr Psychol. 2007 Oct;32(9):1050-4. doi: 10.1093/jpepsy/jsm063. Epub 2007 Oct 12.
citation: Conklin HM, Lawford J, Jasper BW, Morris EB, Howard SC, Ogg SW, Wu S, Xiong X, Khan RB. Side effects of methylphenidate in childhood cancer survivors: a randomized placebo-controlled trial. Pediatrics. 2009 Jul;124(1):226-33. doi: 10.1542/peds.2008-1855.