Brain and Central Nervous System Tumors, Cognitive/Functional Effects, Fatigue, Neurotoxicity, Psychosocial Effects of Cancer and Its Treatment
Conditions
Keywords
childhood brain tumor, neurotoxicity, fatigue, cognitive/functional effects, psychosocial effects of cancer and its treatment
Brief summary
RATIONALE: Modafinil may help improve memory, attention, and fatigue caused by cancer treatment. PURPOSE: This phase II randomized trial studies how well modafinil works in treating children with memory and attention problems caused by cancer treatment for a brain tumor.
Detailed description
OBJECTIVES: Primary * Determine whether a 6-week drug trial of modafinil, compared to placebo, is associated with improvement in neurocognitive function as defined by direct assessment of attention in children with cognitive impairment after treatment for a primary brain tumor. Secondary * Determine whether modafinil, compared to placebo, is associated with improved executive function, as assessed using the BRIEF executive function and hippocampal learning and executive function tasks from the CogState battery. Determine whether modafinil, compared to placebo, is associated with improved attention, as assessed by the Conners' (3rd Edition) 3 Parent Rating Scale (CPRS-3) - Short Form. * Determine whether modafinil, compared to placebo, is associated with reduced fatigue as assessed using the PedsQL Multidimensional Fatigue Scale. * Evaluate the safety of modafinil in this population. OUTLINE: This is a multicenter study. Participants are randomized to 1 of 2 treatment arms. * Arm I: Participants receive modafinil orally (PO) once daily (QD) on days 1-42. * Arm II: Participants receive placebo PO QD on days 1-42. Participants complete a semi-automated, computerized cognitive-testing system (CogState) designed to assess psychomotor, attention/vigilance, memory, and other components of executive function by presenting different tasks, each with its own set of rules, at baseline and after completion of study therapy. Participants also complete the PedsQL Multidimensional Fatigue Scale (Peds QL-MFS). Parents or legal guardians complete the PedsQL-MFS, the Conners Parent Reported Scale (CPR-3), and the Behavior Rating Inventory of Executive Function (BRIEF) at baseline and after completion of study therapy. Clinical and/or research staff administer the Systematic Assessment for Treatment Emergency Events (SAFTEE), a semi-structured interview designed to elicit adverse events, at baseline and periodically during study. After completion of study therapy, participants are followed up for 30 days.
Interventions
DRUGmodafinil
Given PO
OTHERplacebo
Given PO
Sponsors
National Cancer Institute (NCI)
University of South Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 19 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 6 years and ≤ 18 years 10 months at the time of study entry (so that participants will be \< 19 at the 6 week evaluation, which is the upper age limit for which the included instruments are valid). * Diagnosis of a primary brain tumor treated with at least one of the following: 1. neurosurgical resection of the brain tumor; 2. cranial irradiation; or 3. any chemotherapy to treat the brain tumor. * Off-treatment and progression-free for at least 12 months and ≤ 14 years. Treatment cessation is defined as the final dose of chemotherapy, the last dose (fraction) of radiation or date of surgery, whichever occurred last. * Parent/Legal Guardian and child able to read English or Spanish. * Vision and hearing (eyeglasses and/or hearing aid permissible) sufficient for valid test administration and cooperation with examinations. * Availability of a reliable parent or legal guardian who is willing and able to complete all of the outcome measures and fulfill the requirements of the study, including administration of medications and accompanying the participant to all study visits. * Females of childbearing potential must have a negative pregnancy test result and must agree to use a medically acceptable method of contraception throughout the entire study period and for 30 days after the last dose of study drug. * Childbearing potential is defined as girls who are \>Tanner stage 2, except for those who have documented pan pituitary insufficiency or other hormonal state incompatible with pregnancy. * Urine pregnancy tests are acceptable.
Exclusion criteria
* Off treatment \> 14 years * Inability to perform the testing procedure (for example, because of aphasia, motor deficits affecting the dominant hand, or IQ \< 70) * Known cardiac disorders including arrhythmias, hypertension requiring treatment or structural heart disease * Diagnosis of narcolepsy, sick sinus syndrome, arrhythmia or prolonged QTc * History of stroke or head injury associated with loss of consciousness within 12 months of registration * History of grade 2 depression or anxiety or treatment with antidepressants, antipsychotics or MAO inhibitors within 30 days of registration * Concurrent treatment with any medications or substances that are potent inhibitors or inducers of CYP3A4, hepatic enzyme inducing antiepileptic drugs (EIAEDs),or other drugs known to affect the metabolism of modafinil. Examples include but are not limited to itraconazole, ketoconazole, doxycycline, rifampin, St. John's wort, phenytoin, phenobarbital, diazepam, tricyclic antidepressants. * If patients were previously taking, EIAEDs, they must be off for \> 2 weeks prior to study enrollment. * Treatment with other stimulant medications within 14 days of registration; however, a diagnosis of ADHD does NOT exclude a child from participation * Participants with known hypersensitivity to modafinil, armodafinil or any of its components
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Age-Adjusted Scores at Week Six From Baseline in the Attention Task of the CogState Battery | Baseline and 6 weeks | CogState Battery. CogState is a semi-automated, computerized cognitive testing system that was developed as a rapid and accurate test of cognitive function specifically for repeated assessment that is sensitive to the effects of medication in children over the age of 5 years and in adults from different language, cultural and socio-economic backgrounds. The CogState tasks to assess processing speed, visual attention, working memory and executive function were used. The CogState battery was administered in the following order: Detection Task, Identification Task, One Card Learning Task, One Back Task, and lastly, the Modified Groton Maze Learning Task. It was administered at baseline and 6 weeks. A positive change from baseline is an improvement. There is not a minimum or maximum since the value is reported as a z-score, but with the mean = 0 and the SD = 1, the range should be between -3 and 3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Reported Adverse Events (AEs) | 30 days post intervention | AEs gathered using SAFTEE (Systematic Assessment for Treatment Emergent Effects) and participant report on daily log. |
| Change in Working Memory Score at 6 Weeks From Baseline as Assessed on BRIEF | Baseline and 6 weeks | Behavior Rating Inventory of Executive Function (BRIEF). The BRIEF is a behavior rating scale designed to assess executive functions in the home and school environments. The measure was selected to provide parent-reported outcomes of problems related to attention, memory and executive function that occur in everyday life. The instrument was utilized to measure the change in working memory, according to the parent's perspective only, from baseline to 6 weeks. Scores are linear transformations of raw scores into T scores (mean = 50, SD = 10); higher scores indicate greater difficulties. The baseline score was subtracted from the 6 week score. Positive change from baseline is an improvement. The total scale ranges from 0 to 172. A T score \>60 on the BRIEF working memory subscale indicates cognitive impairment. |
| Change in PedsQL Score at 6 Weeks From Baseline | Baseline and 6 weeks | PedsQL is Pediatric Quality of Life Inventory Multi-dimensional Fatigue Scale. This scale is designed as a generic symptom-specific instrument to measure fatigue. Higher scores indicate fewer symptoms of fatigue. It was administered at baseline and 6 weeks. The score is the sum of the answers. The baseline score was subtracted from the 6 week score. A positive change indicates worsening. The scale total score range is from 0-72 for both the parent and patient reported instruments. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I - Modafanil Participants receive modafinil orally (PO) once daily (QD) on days 1-42.
modafinil: Given PO | 56 |
| Arm II - Placebo Participants receive placebo PO QD on days 1-42.
placebo: Given PO | 56 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Toxicity, side effects or complications related to study | 0 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 5 |
Baseline characteristics
| Characteristic | Arm I - Modafanil | Total | Arm II - Placebo |
|---|---|---|---|
| Age, Continuous | 12.12 Years STANDARD_DEVIATION 2.92 | 12.41 Years STANDARD_DEVIATION 3.02 | 12.7 Years STANDARD_DEVIATION 3.12 |
| BMI | 22.66 kg/m^2 STANDARD_DEVIATION 7.53 | 22.08 kg/m^2 STANDARD_DEVIATION 7.05 | 21.5 kg/m^2 STANDARD_DEVIATION 6.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 16 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 91 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Height in cm | 143.93 cm STANDARD_DEVIATION 17.34 | 146.84 cm STANDARD_DEVIATION 30.21 | 149.74 cm STANDARD_DEVIATION 39.03 |
| Primary Cancer Diagnosis Astrocytoma (Grade 2) | 3 Participants | 6 Participants | 3 Participants |
| Primary Cancer Diagnosis Choroid plexus tumor (all grades) | 1 Participants | 1 Participants | 0 Participants |
| Primary Cancer Diagnosis Craniopharygioma | 3 Participants | 4 Participants | 1 Participants |
| Primary Cancer Diagnosis Ependymoma | 7 Participants | 10 Participants | 3 Participants |
| Primary Cancer Diagnosis Germinoma or non-germinomatous germ | 4 Participants | 7 Participants | 3 Participants |
| Primary Cancer Diagnosis Medulloblastoma PNET or ATRT | 22 Participants | 51 Participants | 29 Participants |
| Primary Cancer Diagnosis Missing | 0 Participants | 1 Participants | 1 Participants |
| Primary Cancer Diagnosis Oligodendroglioma | 0 Participants | 1 Participants | 1 Participants |
| Primary Cancer Diagnosis Optic Pathway Tumor (optic nerve, chiasmatic optic tract) | 1 Participants | 2 Participants | 1 Participants |
| Primary Cancer Diagnosis Other | 4 Participants | 8 Participants | 4 Participants |
| Primary Cancer Diagnosis Pilocytic Astrocytoma (Grade 1) | 10 Participants | 20 Participants | 10 Participants |
| Primary Cancer Diagnosis Pinealoma (all grades) | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) White | 47 Participants | 90 Participants | 43 Participants |
| Sex: Female, Male Female | 27 Participants | 58 Participants | 31 Participants |
| Sex: Female, Male Male | 29 Participants | 54 Participants | 25 Participants |
| Weight in kg | 49.68 Kg STANDARD_DEVIATION 25.72 | 48.7 Kg STANDARD_DEVIATION 23.38 | 47.72 Kg STANDARD_DEVIATION 20.96 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 56 |
| other Total, other adverse events | 34 / 56 | 12 / 56 |
| serious Total, serious adverse events | 0 / 56 | 1 / 56 |
Outcome results
Primary
Change in Age-Adjusted Scores at Week Six From Baseline in the Attention Task of the CogState Battery
CogState Battery. CogState is a semi-automated, computerized cognitive testing system that was developed as a rapid and accurate test of cognitive function specifically for repeated assessment that is sensitive to the effects of medication in children over the age of 5 years and in adults from different language, cultural and socio-economic backgrounds. The CogState tasks to assess processing speed, visual attention, working memory and executive function were used. The CogState battery was administered in the following order: Detection Task, Identification Task, One Card Learning Task, One Back Task, and lastly, the Modified Groton Maze Learning Task. It was administered at baseline and 6 weeks. A positive change from baseline is an improvement. There is not a minimum or maximum since the value is reported as a z-score, but with the mean = 0 and the SD = 1, the range should be between -3 and 3.
Time frame: Baseline and 6 weeks
Population: Decreased number of participants analyzed is because not all participants had a CogState score at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I - Modafinil | Change in Age-Adjusted Scores at Week Six From Baseline in the Attention Task of the CogState Battery | -0.16 Z Score | Standard Deviation 0.71 |
| Arm II - Placebo | Change in Age-Adjusted Scores at Week Six From Baseline in the Attention Task of the CogState Battery | 0.14 Z Score | Standard Deviation 1.06 |
Secondary
Change in PedsQL Score at 6 Weeks From Baseline
PedsQL is Pediatric Quality of Life Inventory Multi-dimensional Fatigue Scale. This scale is designed as a generic symptom-specific instrument to measure fatigue. Higher scores indicate fewer symptoms of fatigue. It was administered at baseline and 6 weeks. The score is the sum of the answers. The baseline score was subtracted from the 6 week score. A positive change indicates worsening. The scale total score range is from 0-72 for both the parent and patient reported instruments.
Time frame: Baseline and 6 weeks
Population: Not all participants had a completed PedsQL at Week 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I - Modafinil | Change in PedsQL Score at 6 Weeks From Baseline | Parent Rating | 11.3 Scores on a scale | Standard Deviation 17.6 |
| Arm I - Modafinil | Change in PedsQL Score at 6 Weeks From Baseline | Patient Rating | 9.3 Scores on a scale | Standard Deviation 16.5 |
| Arm II - Placebo | Change in PedsQL Score at 6 Weeks From Baseline | Parent Rating | 11.4 Scores on a scale | Standard Deviation 15.9 |
| Arm II - Placebo | Change in PedsQL Score at 6 Weeks From Baseline | Patient Rating | 6.9 Scores on a scale | Standard Deviation 16.6 |
Secondary
Change in Working Memory Score at 6 Weeks From Baseline as Assessed on BRIEF
Behavior Rating Inventory of Executive Function (BRIEF). The BRIEF is a behavior rating scale designed to assess executive functions in the home and school environments. The measure was selected to provide parent-reported outcomes of problems related to attention, memory and executive function that occur in everyday life. The instrument was utilized to measure the change in working memory, according to the parent's perspective only, from baseline to 6 weeks. Scores are linear transformations of raw scores into T scores (mean = 50, SD = 10); higher scores indicate greater difficulties. The baseline score was subtracted from the 6 week score. Positive change from baseline is an improvement. The total scale ranges from 0 to 172. A T score \>60 on the BRIEF working memory subscale indicates cognitive impairment.
Time frame: Baseline and 6 weeks
Population: Not all participants had a BRIEF score at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I - Modafinil | Change in Working Memory Score at 6 Weeks From Baseline as Assessed on BRIEF | -4.1 T Score | Standard Deviation 7.4 |
| Arm II - Placebo | Change in Working Memory Score at 6 Weeks From Baseline as Assessed on BRIEF | -4.5 T Score | Standard Deviation 9.2 |
Secondary
Number of Reported Adverse Events (AEs)
AEs gathered using SAFTEE (Systematic Assessment for Treatment Emergent Effects) and participant report on daily log.
Time frame: 30 days post intervention
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I - Modafinil | Number of Reported Adverse Events (AEs) | 76 Adverse Events |
| Arm II - Placebo | Number of Reported Adverse Events (AEs) | 26 Adverse Events |