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Trial registered on ANZCTR


Registration number
ACTRN12611000765921
Ethics application status
Approved
Date submitted
21/07/2011
Date registered
21/07/2011
Date last updated
23/09/2022
Date data sharing statement initially provided
6/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of Methylphenidate Treatment in Children with Neurofibromatosis type 1 (NF1): A randomised, placebo controlled, cross over trial
Scientific title
A placebo controlled trial of methylphenidate for treatment of cognitive and behavioural impairment in children and adolescents with neurofibromatosis type 1.
Secondary ID [1] 262669 0
2011/0282 TGA CTN scheme
Universal Trial Number (UTN)
U1111-1123-0940
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neurofibromatosis type 1 268375 0
Condition category
Condition code
Human Genetics and Inherited Disorders 268510 268510 0 0
Other human genetics and inherited disorders
Neurological 268519 268519 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1
Methylphenidate will be the active substance in the first phase of this trial. This part of the trial will be a randomised placebo controlled cross over trial with a duration of 12 weeks (6 weeks of active substance, 6 weeks of placebo). Methylphenidate dose level will be up to 1.5mg/kg a day. Dose level will not exceed 60mg/day. The appropriate dose level for each subject will be determined during a 2 week titration phase. Methylphenidate powder will be presented as a crushed powder in opaque gelatin capsules containing either 5mg methylphendiate or 10mg methylphenidate. Treatment phase duration is 4 weeks. Capsules will need to be taken orally three times a day. No washout period between the active arm and the placebo arm exists.

Part 2 (open label)
Methylphenidate (Ritalin LA capsules) 10mg/20mg/30mg/40mg.
If a participant demonstrates a significant reliable improvement in any of the primary outcome measures after they have completed Part 1 of the trial (i.e. completed both 6 weeks of methylphenidate and 6 weeks of placebo) he/she will be invited to immediately continue on methylphenidate (Ritalin long acting) for 13 weeks (or until 6 months after her/his baseline assessment). The dose level of Ritalin long acting will be different for each participant and will be equivalent to his/her dose level of active substance in Part 1 of the trial. Participants will be required to take this dose level once in the morning on daily basis.
Intervention code [1] 267015 0
Treatment: Drugs
Comparator / control treatment
Part 1

The placebo will be presented in identical form as treatment as crushed powder in opaque gelatin capsules. The placebo capsules will contain a negligible amount of lactose. Participants on the placebo arm will undergo an identical 2 week mimic titration phase in which they will take placebo. Participants must take the placebo 3 times a day for 4 weeks after the 2 week mimic titration phase.
Control group
Placebo

Outcomes
Primary outcome [1] 269258 0
Cambridge Neuropsychological Testing Automated Battery (CANTAB) Spatial Working Memory Task. The number of between errors will be the outcome measure for this subtest.
Timepoint [1] 269258 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Primary outcome [2] 269259 0
The Conners Continous Performance Test-II (CPT-II) Omission errors will be the outcome measure for this subtest
Timepoint [2] 269259 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Primary outcome [3] 269260 0
The Conners 3 parent questionnaire. The outcome measures will be inattentive and hyperactive/impulsivity scale (T scores).
Timepoint [3] 269260 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [1] 279229 0
Test of Everyday Attention for Children will be used in this study to assess selective attention (Sky Search), sustained attention (Score!) divided attention (Sky Search Dual Task) and attentional control/switching (Creature Counting). Raw scores will be used.
Timepoint [1] 279229 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [2] 279230 0
The Social Skills Improvement System Rating Scales (parent version) (SSIS: Gresham & Elliott, 2008). Communication, cooperation, assertion, responsibility, empathy, engagement and self-control scales will be used.
Timepoint [2] 279230 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [3] 279231 0
The Conners 3 (teacher version) will be used to assess ADHD behavioural symptoms. Outcome will be the inattentive and hyperactive/impulsivity scale (T scores)
Timepoint [3] 279231 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [4] 279232 0
Planning/Problem solving will be assessed with the CANTAB Stockings of Cambridge Raw score: Problems solved in minimum moves.
Timepoint [4] 279232 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [5] 279233 0
Behavior Rating Inventory of Executive Function-Parent Report Forms (BRIEF; Gioia, Isquith, Guy & Kenworthy, 2000; Guy, Isquith & Gioia, 2004). The eight clinical scales including: initiate, inhibit, shift, plan, organize, self-monitor, emotional control, and working memory as well as Behavioural Regulation, Metacognition and a Global Executive Composite score will be outcome. T scores will be used.
Timepoint [5] 279233 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [6] 279234 0
Tasks of Executive Control (TEC: Isquith, Roth,. and. Gioia, 2010)
Timepoint [6] 279234 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [7] 279235 0
Child Behaviour Checklist (CBCL 6-18: Achenbach, 2001).
The following indexes will be outcome measure: Anxious/Depressed, Withdrawn/Depressed, Somatic Complaints, Social Problem, Thought Problems, Attention Problems, Rule-Breaking Behavior, Aggressive Behavior.
Timepoint [7] 279235 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [8] 279236 0
The Paediatric Quality of Life Scale (PedsQL: Varni, Seid & Kurtin, 2001)self-report and parent proxy-report scales. Four core scales: physical, emotional, social, and school.
Timepoint [8] 279236 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [9] 279237 0
Visuospatial Skills will be assessed with the Judgment of Line Orientation (JLO: Benton, Varney & Hamsher, 1976) Version V. Total correct.
Timepoint [9] 279237 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [10] 279238 0
Fine Motor Skills will be assessed with The Grooved Pegboard (Lafayette Instrument Co, 2002).
Measures recorderd will be the length of time required to perform each trial, the number of drops made during each trial and finally the number of pegs correctly placed in the holes for each trial.
Timepoint [10] 279238 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [11] 279239 0
Expressive language will be briefly assessed with The Formulated Sentences subtest- Australian version (CELF-4: Semel, Wiig, Secord 2003).
Timepoint [11] 279239 0
Baseline (before treatment)
After 6 weeks of treatment
After 6 weeks of placebo
6 months from baseline
Secondary outcome [12] 279240 0
Academic Achievement will be assessed with the Wechsler Individual Achievement Test- Second Edition (WIAT-II: Wechsler, 2001) Single word reading, spelling and numerical operations.
Timepoint [12] 279240 0
Baseline (before treatment)
6 months from baseline
Secondary outcome [13] 279241 0
The Wechsler Intelligence Scale for Children-version 4 Australian (WISC-IV; Wechsler, 2003;).
Timepoint [13] 279241 0
Baseline (before treatment)
6 months from baseline.
Secondary outcome [14] 335561 0
CANTAB Paired Associate learning (PAL)
Timepoint [14] 335561 0
Baseline line, Week 6 and week 12
Secondary outcome [15] 335562 0
Conners CPT-II commission errors
Timepoint [15] 335562 0
Baseline, week 6 and week 12

Eligibility
Key inclusion criteria
1. All participants must fulfil the diagnosis of NF1 based on NIH criteria (NIH, 2000);

2. Participants must have a full scale IQ greater than or equal to 70 or if a significant discrepancy is present between PRI and VCI the higher will be used. This index used must be 70 or above;

3. Participants’ behaviour must be rated as abnormal by their parent on the Conners 3. An abnormal score is defined as a T score equal to or greater than 65 on the following scales inattention, hyperactivity/impulsivity.

4. Participants must have a cognitive impairment defined as having a score of at least one standard deviation or more below the population mean on at least one of the primary objective outcome measures:
a) Conner’s Continuous Performance Test –II (CPT II Omissions)
b) CANTAB Spatial Working Memory (SWM) (between errors total).
Minimum age
7 Years
Maximum age
16 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participants who have intracranial pathology such as epilepsy, hydrocephalus, diagnosed traumatic brain injury, or progressive intracranial tumours (children with asymptomatic or static lesions will be eligible);

2. Children who have significant visual and/or hearing problems;

3. Children who have contraindications to stimulant medication. These include those with glaucoma, hypertension, previous insensitivity to stimulant medication or are on contraindicated medication such as monoamine oxidase (MAO) inhibitors;

4. Children with Tourette’s syndrome, tics, or other major psychiatric disorders;

5. Female participants of childbearing age should not be pregnant, must have a negative urine pregnancy test before initiation of treatment;

6. Children who have received any investigational drugs of any type within 30 days of initiation of study;

7. Children with a co-existing medical condition that is likely to interfere or who are taking any concomitant medication that is likely to interfere with safe administration of methylphenidate in the investigators opinion.

8. Children who are requiring any of the following medications: clonidine or other alpha2 adrenergic receptor agonists, tricyclic antidepressants, selective serotonin reuptake inhibitors, theophylline, coumarin, or anticonvulsants.

9. Children who have blood pressure measurements (systolic or diastolic) equal to or greater than 95th percentile for age, sex and height at screening.

10. Children who require drug therapy or hospitalisation for treatment of a mood disorder or anxiety disorder.

11. Children with ECG abnormalities that are deemed clinically significant

12. Children with drug or alcohol abuse or dependence within the prior six months

13. Children who are currently on stimulant medication for ADHD before the trial will be required to undergo a 3 week washout period prior to the screening assessment to minimise any potential carry over effects of the drug and allow the parents and teachers to complete the behavioural questionnaire based on the child's off medication behaviour.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
After informed assent has been obtained, a screening assessment will be performed. The screening assessment will include a medical history, a physical examination, ECG, and a urine sample test (to screen for pregnancy for females). Height, weight, blood pressure and pulse will be recorded. Participants will also be administered the MINI-KID & the Disruptive Behavioural Disorders Structured Interview to identify child psychopathology or other excluding disorders such as oppositional defiant disorder, conduct disorder, major depressive disorder, dysthymic disorder and anxiety disorders. The site psychologist will administer the primary outcome measures and a test of general intelligence which are estimated to take around 1.5-2 hours to complete. Parents will be required to complete the Conner 3 questionnaire during this time.

After a successful screening period, the participant will be randomised to one of two conditions: Treatment or placebo. Randomisation will be managed by the chief site biostatistician (who is independent to study). Allocation will be concealed to the person who determines eligibility.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/07/2011
Actual
30/07/2011
Date of last participant enrolment
Anticipated
30/10/2023
Actual
Date of last data collection
Anticipated
30/12/2023
Actual
Sample size
Target
36
Accrual to date
25
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 8236 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 8237 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 16294 0
2145 - Westmead
Recruitment postcode(s) [2] 16295 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 267495 0
Hospital
Name [1] 267495 0
The Children's Hospital at Westmead
Country [1] 267495 0
Australia
Funding source category [2] 296643 0
Charities/Societies/Foundations
Name [2] 296643 0
The Children's Tumor Foundation
Country [2] 296643 0
United States of America
Primary sponsor type
Hospital
Name
The Children's Hospital at Westmead
Address
Corner of Hawkesbury Road and Hainsworth Street Westmead NSW 2145
Country
Australia
Secondary sponsor category [1] 266539 0
None
Name [1] 266539 0
Address [1] 266539 0
Country [1] 266539 0
Other collaborator category [1] 279592 0
Hospital
Name [1] 279592 0
The Royal Children's Hospital Melbourne
Address [1] 279592 0
The Royal Children’s Hospital
Flemington Rd Parkville, Victoria 3052 AUS
Country [1] 279592 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269463 0
Children's Hospital at Westmead Human Research Ethics Commitee
Ethics committee address [1] 269463 0
Corner of Hawkesbury Road and Hainsworth Street Westmead NSW 2145
Ethics committee country [1] 269463 0
Australia
Date submitted for ethics approval [1] 269463 0
10/12/2010
Approval date [1] 269463 0
04/03/2011
Ethics approval number [1] 269463 0
10/CHW/121

Summary
Brief summary
The specific aim of this study is to determine whether methylphenidate significantly reduces deficits in attention and/or executive function in children with NF1. This study also aims to establish whether MPH reduces ADHD related behaviours in neurofibromatosis.
It is hypothesised that methylphenidate will improve attention and executive function deficits in children with NF1 and reduce the ADHD like behavioural characteristics in children with NF1.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32902 0
Dr Dr Natalie Pride
Address 32902 0
The Children's Hospital at Westmead Locked bag 4001 Westmead NSW 2145
Country 32902 0
Australia
Phone 32902 0
61 2 9845 3714
Fax 32902 0
Email 32902 0
[email protected]
Contact person for public queries
Name 16149 0
Dr Natalie Pride
Address 16149 0
The Children's Hospital at Westmead
Corner of Hawkesbury Road and Hainsworth Sreet
Westmead NSW 2145
Country 16149 0
Australia
Phone 16149 0
61 2 98453714
Fax 16149 0
61 02 9845 3945
Email 16149 0
[email protected]
Contact person for scientific queries
Name 7077 0
Dr Natalie Pride
Address 7077 0
The Children's Hospital at Westmead
Corner of Hawkesbury Road and Hainsworth Sreet
Westmead NSW 2145
Country 7077 0
Australia
Phone 7077 0
61 02 9845 3714
Fax 7077 0
61-2-9845-3389
Email 7077 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not approved


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1: A study protocol for a randomised placebo-controlled crossover trial.2018https://dx.doi.org/10.1136/bmjopen-2018-021800
N.B. These documents automatically identified may not have been verified by the study sponsor.