Clinical Trials Register

Summary
EudraCT Number:	2015-004444-19
Sponsor's Protocol Code Number:	CRIT124D2201
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-04-05
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2015-004444-19

A.3

Full title of the trial

An open-label, behavioral-treatment-controlled evaluation of the effects of extended release methylphenidate (Ritalin® LA) on the frequency of cytogenetic abnormalities in children 6 - 12 years of age with attention deficit hyperactivity disorder (ADHD) followed by an observation phase up to 24-months

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Effects of Methylphenidate on Chromosomal Abnormalities in Children With Attention Deficit Hyperactivity
Disorder (ADHD)

A.4.1

Sponsor's protocol code number

CRIT124D2201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00409708

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharmaceutical corporation
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharmaceutical corporation
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma AG
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Forum 1, Novartis Campus
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4056
B.5.3.4	Country	Switzerland
B.5.6	E-mail	clinicaltrial.enquiries@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ritalin® LA
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharmaceutical corporation
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ritalin® LA
D.3.2	Product code	RIT124
D.3.4	Pharmaceutical form	Modified-release capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METHYLPHENIDATE HYDROCHLORIDE
D.3.9.1	CAS number	298-59-9
D.3.9.2	Current sponsor code	RIT124
D.3.9.3	Other descriptive name	Ritalin
D.3.9.4	EV Substance Code	SUB03254MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	10 to 30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

To determine whether the administration of extended-release methylphenidate in treatment-naïve children with ADHD affects the frequency of chromosomal abnormalities.

E.1.1.1

Medical condition in easily understood language

Frequency of chromosomal abnormalities in Attention Deficit Hyperactivity Disorder (ADHD)

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10003736
E.1.2	Term	Attention deficit/hyperactivity disorder
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective was to compare the frequency of chromosomal abnormalities (chromosomal aberrations per 100 cells excluding gaps and micronuclei per 1000 binucleated cells) before and after three months of treatment with Ritalin® LA (extended release MPH) and behavioral treatment, compared to behavioral treatment alone.

E.2.2

Secondary objectives of the trial

To compare the frequency of chromosomal abnormalities in sister chromatid exchange before and after treatment with Ritalin® LA (extended release MPH) and behavioral treatment, compared to behavioral treatment alone.
To compare the frequency of persistent chromosomal changes (stable translocations) before and after treatment of ADHD with Ritalin® LA (extended release MPH) and behavioral treatment, compared to behavioral treatment alone. This evaluation is contingent on the outcome of the primary objective.
To evaluate plasma concentrations of MPH, using sparse sampling, for exploration of the PK/PD relationship to cytogenetic changes, if relevant cytogenetic changes are present.
To assess the efficacy, safety and tolerability of Ritalin® LA treatment in children with ADHD, 6-12 years of
age.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients were included who met the following criteria:
1. Children of both genders, 6-12 years old.
2. Written informed consent had to be obtained from the parent or legal guardian of the child to
participate in the core study. Assent had also be obtained from all pediatric patients and
documented by the child’s signature for all patients over the age of seven years (or children who
have an appropriate level of intellectual maturity to understand the implication of the study), or as
per local requirements. Additional written consent/assent had to be obtained after the patient had
her/his final visit in the core study and before she/he entered the observation phase.
3. Diagnosis of ADHD of any type according to DSM-IV criteria, as established by a psychiatric
examination and a semi-structured diagnostic interview [the ADHD module of the Kiddie Schedule
for Affective Disorders and Schizophrenia-Present and Lifetime Version, (K-SADS-PL)], as well as
the DSM-IV diagnostic criteria for ADHD, which are listed in Post-text Supplement 1.
4. Age-appropriate cognitive functioning, as determined by the investigator, who had to take into
account any prior cognitive or academic testing.
5. All patients who had at least one post-baseline cytogenetic assessment in the core study can
enter the observation phase.

E.4

Principal exclusion criteria

1. Prior exposure to MPH or any amphetamine-based medication (dextroamphetamine salts
or amphetamine salts)
2. A positive urine drug screen at Screening
3. Any abnormality in the Screening assessments (physical examination, vital signs,
laboratory tests) which was judged by the investigator to be clinically significant.
4. Any history of malignant neoplasm
5. Known family history of long QT syndrome or QTc > 450 (males) or >470 (females) ms
6. Previous and current (at screening) QTc prolongation of QTc > 449 ms
7. History of structural cardiac abnormality
8. History of seizures (except childhood febrile seizures), hypertension or cardiac arrhythmia
or increased heart rate for age
9. History or current diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder,
severe form of conduct disorder, obsessive-compulsive disorder, autism, tic disorder
(including Tourette’s disorder).
10. Current and past diagnosis of any mood disorder or anxiety disorder according to DSM-IV
11. Any concurrent medical condition which had not been stabilized for at least 3 months
prior to the Screening visit, or which in the judgment of the investigator may interfere
with study participation and/or study assessments, and for which treatment with
methylphenidate may have posed a risk to the patient.
12. Current or past diagnosis of hyperthyroidism
13. ASAT, ALAT, GGT or serum creatinine above the upper normal limit at Screening
14. Positive HIV test result at Screening
15. A positive hepatitis serology for hepatitis B or C at Screening
16. Treatment with potentially nephrotoxic drugs within 2 weeks prior to Screening (e.g.,
aminoglycosides, amphotericin B, colchicine).
17. Current or past treatment with medications known to have cytogenetic effects: all anticancer
drugs, all nucleoside analogs, haloperidol, metronidazole and pyrimethamine
18. Concomitant psychotropic medication. The minimum discontinuation period for previous
psychotropic medication varied according to drug class, as follows:
• One week prior to randomization: antidepressants other than fluoxetine;
antipsychotics; atomoxetine and herbal preparations with psychotropic effects.
• Two weeks prior to randomization: benzodiazepines, barbiturates, all other sedatives
or hypnotics; monoamine oxidase inhibitors (MAOIs).
• Four weeks prior to randomization: fluoxetine
19. Any use of nicotine-containing products (cigarettes, chewing tobacco, etc.).
20. Patients who were pregnant or nursing.
21. Female patients who had a positive serum pregnancy test at screening or a positive urine
pregnancy test at Baseline.
22. Sexually active, female patients who were not using adequate and reliable contraception
(e.g. double-barrier method) throughout the course of the study.
23. Patients or parents, who were judged by the investigator as likely to be non-compliant
with study procedures, including those patients with a suspected history of substance
abuse, or patients living with a person diagnosed with a substance abuse disorder.
24. Parent or guardian who were unable or unwilling to complete the Conners ADHD/DSMIV
Scale (CADS-P) and/or the Strengths and Difficulties Questionnaire (SDQ) for parents.
25. Patients who had taken any other investigational drug during the 30 days prior to entry in
the study.

E.5 End points

E.5.1

Primary end point(s)

• The Number of Chromosomal Aberrations Per 100 Cells Excluding Gaps at Baseline and at the End of treatment i.e Day 84 (Week 12) [ Time Frame: baseline and at end of treatment (Week 12) ]

The number of chromosomal aberrations per 100 cells excluding gaps at Baseline (n=33, n=32) and at Week 12 (n=33, n=32) was counted in blood samples cultured for 48 hours using a standard protocol. The types of abnormalities included translocations (reciprocal and nonreciprocal), insertions, dicentrics, fragments, inversions, chromatid exchanges (quadriradials and triradials), breaks, and other unusual observations, eg, aneuploidy, tetraploidy or endoreduplication.

• The Number of Micronuclei Per 1000 Binucleated Cells Endpoints at Baseline and at the End of Treatment i.e Day 84 (Week 12) [ Time Frame: baseline and at end of treatment (Week 12) ]

The number of micronuclei per 1000 binucleated cells was measured at Baseline ( n=34 , n=29 ) and at the end of treatment, Week 12 (n =34,
n= 29), in blood cultured for 48 hours using a standard protocol.

E.5.1.1

Timepoint(s) of evaluation of this end point

Time Frame: baseline and at end of treatment (Week 12)

E.5.2

Secondary end point(s)

• Number of Sister Chromatoid Exchanges Per Cell [ Time Frame: baseline and at end of treatment (Week 12) ]
• Pharmacokinetic/Pharmacodynamic Relationship of Methylphenidate Blood Levels and Cytogenetic Changes [ Time Frame: End of treatment (Week 12) ]
• Change From Baseline to End of Treatment (Week 12) on the Conners' ADHD/DSM-IV Scale for Parents (CADS-P) [ Time Frame: Baseline to end of treatment (Week 12) ]
• Change From Baseline to the End of Treatment (Week 12) on the Global Improvement Rating of the Clinical Global Impression Scale (CGI-I) [ Time Frame: From baseline to the end of treatment (Week 12) ]
• Change From Baseline to the End of Treatment (Week 12) on the Severity of Illness Rating of the Clinical Global Impression Scale (CGI-S) [ Time Frame: From baseline to the end of treatment (Week 12) ]

E.5.2.1

Timepoint(s) of evaluation of this end point

Time Frame: baseline and at end of treatment (Week 12)
Time Frame: End of treatment (Week 12)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

behavioral-treatment controlled

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS (=LPLV)

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

109

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

104

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Below the age of seven years (or children who do not have an appropriate level of intellectual maturity to understand the implication of the study), or as per local requirements.

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Children 6 - 12 years

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

109

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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