Modafinil in Treating Children With Memory and Attention Problems Caused by Cancer Treatment for a Brain Tumor

• Sponsor: University of South Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT01381718
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 112
• Locations: 60
• Arms: 2
• Duration (Months): 60
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors; Cognitive/Functional Effects; Fatigue; Neurotoxicity; Psychosocial Effects of Cancer and Its Treatment	Drug: modafinil; Other: placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 112 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: A Phase II Placebo-Controlled Trial of Modafinil to Improve Neurocognitive Deficits in Children Treated for a Primary Brain Tumor
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Participants receive modafinil orally (PO) once daily (QD) on days 1-42.	Drug: modafinil; Given PO
Placebo Comparator: Arm II Participants receive placebo PO QD on days 1-42.	Other: placebo; Given PO

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 19 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Miller Children's Hospital	Long Beach	California	United States	90806
3	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
4	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
5	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
6	Children's Hospital of Colorado; Saint Joseph Hospital	Denver	Colorado	United States	80218
7	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
8	A. I. duPont Hospital for Children	Wilmington	Delaware	United States	19803
9	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
10	Lee Memorial Health System	Fort Myers	Florida	United States	33908
11	University of Florida	Gainesville	Florida	United States	32610
12	Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
13	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
14	Nemours Children's Hospital	Orlando	Florida	United States	32827
15	Nemours Children's Clinic- Pensacola	Pensacola	Florida	United States	32207
16	All Children's Hospital	Saint Petersburg	Florida	United States	33701
17	Tampa General Hospital	Tampa	Florida	United States	33606
18	SunCoast CCOP Research Base at the University of South Florida	Tampa	Florida	United States	33612
19	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
20	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96813
21	St. Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
22	University of Illinois at Chicago	Chicago	Illinois	United States	60612
23	Riley Hospital for Children- Indiana University	Indianapolis	Indiana	United States	46163
24	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
25	Johns Hopkins University	Baltimore	Maryland	United States	21287
26	Children's Hospital Boston	Boston	Massachusetts	United States	02115
27	CS Mott/University of Michigan	Ann Arbor	Michigan	United States	48109
28	Wayne State University	Detroit	Michigan	United States	48201
29	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota	United States	55404
30	Mayo Clinic	Rochester	Minnesota	United States	55905
31	University of Mississippi	Jackson	Mississippi	United States	39216
32	Children's Mercy Hospital and Clinics	Kansas City	Missouri	United States	64108
33	Saint Louis University / Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
34	Saint Louis University Cancer Center	Saint Louis	Missouri	United States	63110
35	Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
36	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
37	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
38	University of New Mexico	Albuquerque	New Mexico	United States	87131
39	Montefiore Medical Center	Bronx	New York	United States	10467
40	New York University Langone Medical Center	New York	New York	United States	10016
41	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York	United States	10032
42	SUNY Upstate Medical University	Syracuse	New York	United States	13210
43	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
44	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
45	Dayton Children's Hospital	Dayton	Ohio	United States	45404
46	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
47	Doernbecher Children's Hospital/ Oregoon Health Science University	Portland	Oregon	United States	97329
48	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
49	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19320
50	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
51	East Tennessee Children's Hospital	Knoxville	Tennessee	United States	37916
52	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
53	Vanderbilt Children's Hospital	Nashville	Tennessee	United States	37232
54	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
55	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390
56	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
57	University of Virginia	Charlottesville	Virginia	United States	22908
58	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
59	St. Vincent Hospital	Green Bay	Wisconsin	United States	54301
60	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• University of South Florida
• National Cancer Institute (NCI)

Investigators

• Study Chair: Jeffrey P. Krischer, MD, PhD, University of South Florida
• Study Chair: Nicole J. Ullrich, MD, PhD, Boston Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of South Florida
• ClinicalTrials.gov Identifier: NCT01381718
• Other Study ID Numbers: SCUSF 0901; SCUSF-0901; ACCL0922; 5U10CA081920-11
• First Posted: Jun 27, 2011
• Last Update Posted: Aug 13, 2021
• Last Verified: Sep 1, 2018

• Keywords provided by University of South Florida: childhood brain tumor; neurotoxicity; fatigue; cognitive/functional effects; psychosocial effects of cancer and its treatment
• Additional relevant MeSH terms: Brain Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Neurotoxicity Syndromes; Fatigue; Modafinil

Study Results

Participant Flow

Arm/Group Title	Arm I - Modafinil	Arm II - Placebo
Arm/Group Description	Participants receive modafinil orally (PO) once daily (QD) on days 1-42. modafinil: Given PO	Participants receive placebo PO QD on days 1-42. placebo: Given PO
Period Title: Overall Study
STARTED	56	56
COMPLETED	51	43
NOT COMPLETED	5	13

Baseline Characteristics

Arm/Group Title	Arm I - Modafanil	Arm II - Placebo	Total
Arm/Group Description	Participants receive modafinil orally (PO) once daily (QD) on days 1-42. modafinil: Given PO	Participants receive placebo PO QD on days 1-42. placebo: Given PO	Total of all reporting groups
Overall Participants	56	56	112
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	12.12 (2.92)	12.7 (3.12)	12.41 (3.02)
Sex: Female, Male (Count of Participants)
Female	27 48.2%	31 55.4%	58 51.8%
Male	29 51.8%	25 44.6%	54 48.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 14.3%	8 14.3%	16 14.3%
Not Hispanic or Latino	45 80.4%	46 82.1%	91 81.3%
Unknown or Not Reported	3 5.4%	2 3.6%	5 4.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.8%	3 5.4%	4 3.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 10.7%	7 12.5%	13 11.6%
White	47 83.9%	43 76.8%	90 80.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 3.6%	3 5.4%	5 4.5%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.66 (7.53)	21.5 (6.55)	22.08 (7.05)
Weight in kg (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	49.68 (25.72)	47.72 (20.96)	48.7 (23.38)
Height in cm (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	143.93 (17.34)	149.74 (39.03)	146.84 (30.21)
Primary Cancer Diagnosis (Count of Participants)
Medulloblastoma PNET or ATRT	22 39.3%	29 51.8%	51 45.5%
Pilocytic Astrocytoma (Grade 1)	10 17.9%	10 17.9%	20 17.9%
Ependymoma	7 12.5%	3 5.4%	10 8.9%
Germinoma or non-germinomatous germ	4 7.1%	3 5.4%	7 6.3%
Astrocytoma (Grade 2)	3 5.4%	3 5.4%	6 5.4%
Other	4 7.1%	4 7.1%	8 7.1%
Craniopharygioma	3 5.4%	1 1.8%	4 3.6%
Optic Pathway Tumor (optic nerve, chiasmatic optic tract)	1 1.8%	1 1.8%	2 1.8%
Choroid plexus tumor (all grades)	1 1.8%	0 0%	1 0.9%
Oligodendroglioma	0 0%	1 1.8%	1 0.9%
Pinealoma (all grades)	1 1.8%	0 0%	1 0.9%
Missing	0 0%	1 1.8%	1 0.9%

Outcome Measures

1. Primary Outcome

Title	Change in Age-Adjusted Scores at Week Six From Baseline in the Attention Task of the CogState Battery
Description	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

Outcome Measure Data

Analysis Population Description

Decreased number of participants analyzed is because not all participants had a CogState score at 6 weeks

Arm/Group Title	Arm I - Modafinil	Arm II - Placebo
Arm/Group Description	Participants receive modafinil orally (PO) once daily (QD) on days 1-42. modafinil: Given PO	Participants receive placebo PO QD on days 1-42. placebo: Given PO
Measure Participants	50	42
Mean (Standard Deviation) [Z Score]	-0.16 (0.71)	0.14 (1.06)

2. Secondary Outcome

Title	Number of Reported Adverse Events (AEs)
Description	AEs gathered using SAFTEE (Systematic Assessment for Treatment Emergent Effects) and participant report on daily log.
Time Frame	30 days post intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I - Modafinil	Arm II - Placebo
Arm/Group Description	Participants receive modafinil orally (PO) once daily (QD) on days 1-42. modafinil: Given PO	Participants receive placebo PO QD on days 1-42. placebo: Given PO
Measure Participants	56	56
Number [Adverse Events]	76	26

3. Secondary Outcome

Title	Change in Working Memory Score at 6 Weeks From Baseline as Assessed on BRIEF
Description	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

Outcome Measure Data

Analysis Population Description

Not all participants had a BRIEF score at 6 weeks

Arm/Group Title	Arm I - Modafinil	Arm II - Placebo
Arm/Group Description	Participants receive modafinil orally (PO) once daily (QD) on days 1-42. modafinil: Given PO	Participants receive placebo PO QD on days 1-42. placebo: Given PO
Measure Participants	51	43
Mean (Standard Deviation) [T Score]	-4.1 (7.4)	-4.5 (9.2)

4. Secondary Outcome

Title	Change in PedsQL Score at 6 Weeks From Baseline
Description	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

Outcome Measure Data

Analysis Population Description

Not all participants had a completed PedsQL at Week 6

Arm/Group Title	Arm I - Modafinil	Arm II - Placebo
Arm/Group Description	Participants receive modafinil orally (PO) once daily (QD) on days 1-42. modafinil: Given PO	Participants receive placebo PO QD on days 1-42. placebo: Given PO
Measure Participants	51	43
Parent Rating	11.3 (17.6)	11.4 (15.9)
Patient Rating	9.3 (16.5)	6.9 (16.6)

Adverse Events

Time Frame	6 weeks
Adverse Event Reporting Description	Complete and frequent monitoring for AEs was incorporated into the study using SAFTEE (Systematic Assessment for Treatment Emergent Effects developed by the National Institute of Mental Health. The final SAFTEE assessment will take place 30 days after the last dose of study agent. Participants will use the Study Medication Log, completed daily, to document any adverse events. Staff will review logs and compare to SAFTEE report.
Arm/Group Title	Arm I - Modafanil		Arm II - Placebo
Arm/Group Description	Participants receive modafinil orally (PO) once daily (QD) on days 1-42. modafinil: Given PO		Participants receive placebo PO QD on days 1-42. placebo: Given PO
All Cause Mortality
	Arm I - Modafanil		Arm II - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/56 (0%)		0/56 (0%)
Serious Adverse Events
	Arm I - Modafanil		Arm II - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/56 (0%)		1/56 (1.8%)
Injury, poisoning and procedural complications
Fracture	0/56 (0%)	0	1/56 (1.8%)	1
Other (Not Including Serious) Adverse Events
	Arm I - Modafanil		Arm II - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/56 (60.7%)		12/56 (21.4%)
Nervous system disorders
Headache	12/56 (21.4%)	18	7/56 (12.5%)	9
Psychiatric disorders
Insomnia	13/56 (23.2%)	16	3/56 (5.4%)	3
Agitation	4/56 (7.1%)	4	2/56 (3.6%)	2
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	5/56 (8.9%)	5	0/56 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.