EEG-MRI Study of the Effect of Methylphenidate on Neural Mechanisms in Adult Patients With ADHD With or Without Mood Disorders: a Randomized Controlled Trial Versus Placebo

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Les Hopitaux Universitaires De Strasbourg

Participant type

Healthy volunteers, Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04]

Trial duration

19 Sep 2024 → ongoing

Decision date (initial)

2024-09-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516902-46-00

EudraCT number

2019-003049-13

ClinicalTrials.gov

NCT05832489

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

To determine whether methylphenidate has a different impact on the brain circuits associated with cognitive functions in the two clinical populations studied (adult ADHD patients and patients with attention deficit post-mood disorder) and compared to controls.

Secondary objectives 4

1. To determine the effect of methylphenidate on the basal cerebral flow in the two clinical populations and in the controls (healthy subjects).
2. To determine if methylphenidate has a different impact on cognitive performance in the two clinical populations studied and compared to controls (healthy subjects).
3. To confirm the effect of methylphenidate on the maintenance of cortical awakening.
4. To distinguish the brain networks impacted by methylphenidate (maintenance of attention or inhibition) with MRI and EEG.

Conditions and MedDRA coding

Attention Deficit Hyperactivity Disorder (ADHD)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Common criteria for all groups: - Subject (male or female) aged 18 to 60 years - Subject affiliated to a social health insurance plan, or beneficiary / beneficiary of such a plan - Able to understand the objectives and risks of the research and to give dated and signed informed consent - Subject who has been informed of the results of the prior medical examination - Subject with a "health pass" in relation to the SARS-Cov2 pandemic as defined by current legislation, if applicable - Subject agreeing not to consume narcotics during the study (except tobacco and alcohol) - For a woman of childbearing age: *blood pregnancy test prescribed at inclusion, the result of which must be negative before taking the study treatment *effective contraception throughout the study *and agreement to perform a urine pregnancy test before each MRI
2. Group A: ADHD patients without associated mood disorder (ADHD-P) - Diagnosis of ADHD according to DSM-5 (in particular criterion B: presence of symptoms before the age of 12 years) NB: the diagnosis was not necessarily made at this age. - Subjects benefiting or not from a methylphenidate treatment
3. Group B: patients with attention deficit due to/accentuated by mood disorders (ADHD-HD) - Association of ADHD symptoms with attentional disorders according to the combination of the following criteria: * DSM-5 diagnosis of recurrent depressive disorder or bipolar disorder *Currently euthymic, i.e., a QIDS-16 depression score < 6 (Appendix 1) and a YRMS mania score < 6 (Appendix 2), and clinically stabilized for at least 6 weeks prior to inclusion (stable treatment and out of acute phase). NB: for QIDS item 10 (concentration/decision making, score only decision making) *Criterion A of adult ADHD according to DSM-5 (at least 5 symptoms of inattention and/or hyperactivity/impulsivity) *Absence of Criterion D in childhood, adolescence and prior to mood disorders (i.e., absence of significant impact with reduced social, academic or occupational functioning) *Criterion D present (symptoms have a significant impact with reduced social, academic or occupational functioning) - Whether or not the subject is receiving treatment for mood disorders that is approved for: *mood stabilizers (lithium, valproate, lamotrigine, oxcarbazepine), *antidepressants (SSRIs, SNRIs ≤150mg/d venlafaxine and ≤60mg/d duloxetine), benzodiazepines at stable doses for more than one month (maximum daily dose of 10mg diazepam equivalent). - Subjects with or without methylphenidate treatment
4. Group C: healthy control subjects - Subjects with no psychiatric or neurological history

Exclusion criteria 4

1. Common criteria for all groups - Subject with a contraindication to methylphenidate: * hypersensitivity to the active substance, * glaucoma * pheochromocytoma, * treatment with other indirect sympathomimetics or alpha sympathomimetics (oral and/or nasal), irreversible MAOIs * Hyperthyroidism or thyrotoxicosis, * Pre-existing cardiovascular disorders including severe hypertension, XML File Identifier: 0Vmd7NrSRK8JeP+9ISLPaO9Oq+U= Page 12/26 heart failure, arterial occlusive disease, angina pectoris, congenital heart disease with hemodynamic impact, cardiomyopathy, myocardial infarction, arrhythmias and potentially life-threatening channelopathies (disorders caused by ion channel dysfunction), * Pre-existing cerebrovascular disorders, cerebral aneurysms, vascular abnormalities including vasculitis or stroke, * wheat allergy (other than celiac disease) - Unstabilized psychiatric disorders: severe depression, anorexia nervosa or anorexic disorder, suicidal tendencies, psychotic symptoms, severe mood disorders, mania, schizophrenia, psychopathic or borderline personality disorder - Family history of ventricular arrhythmia, sudden death, particularly of cardiac origin, or unexplained death - Subjects with a contraindication to MRI: presence of a non-removable ferromagnetic body, prosthesis, pacemaker, medication delivered by an implanted pump, vascular clip or stent, heart valve or ventricular bypass - History that may affect brain anatomy or be related to an abnormality (neonatal distress, neurosurgical operation, comitiveness, stroke, head injury with loss of consciousness of more than 15 minutes and mental retardation) - History that may affect brain function (general anesthesia or electroconvulsive therapy within 3 months prior to inclusion) - Substance use disorder, according to DSM-5 criteria (excluding tobacco) - Pregnant women or, in women of childbearing age and capacity (not infertile), lack of effective contraception - Subjects participating in other research involving an investigational product - Nursing women - Serious or unstabilized somatic pathology. - Subject deprived of liberty, or under forced care - Incapacitated subject (subject to a legal protection measure: curatorship, guardianship, future protection mandate, family habilitation) - Impossibility to give the subject informed information (subject in an emergency situation, difficulties in understanding the subject, ...) - Subject in a period of exclusion defined by another protocol in progress
2. Group A: ADHD patients without associated mood disorder (ADHD-P) • Current Mood Disorder • History of bipolar disorder in a first-degree relative • Taking unauthorized psychotropic drugs: all antidepressants, antipsychotics, sedative antihistamines, regular hypnotics, benzodiazepines in unstable doses.
3. Group B: Patients with attention deficit disorder due to/ accentuated by mood disorders (ADHD-MD) • Acute phase of mood disorder defined by scores a depression score in the QIDS-16SC ≥ 6 and a mania score in the YRMS ≥ 6. NB: for ISQ item 10 (concentration/decision making, score decision making only). • Use of unauthorized psychotropic drugs including antipsychotics, sedative antihistamines, high-dose IRSNa (>150mg/d venlafaxine and >60mg/d duloxetine), MAOIs, tricyclic antidepressants, benzodiazepines in unstable doses.
4. Group C: healthy subjects control - Taking any psychotropic medication (seasonal allergy treatments permitted)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Effect of methylphenidate on the task vs. rest in a region defined by its involvement in the cognitive task and its reactivity to methylphenidate. ROI (Region of Interest) analysis to maximize power.

Secondary endpoints 5

1. Decrease in rCBF (regional Cerebral Blood Flow) in the methylphenidate condition vs. placebo, in the different groups.
2. Improved cognitive performance on tests of sustained attention, working memory and flexibility following the administration of methylphenidate, in the different groups.
3. Stabilization of the power of the EEG spectrum in the low frequencies (delta (1-4Hz) and theta (4-8Hz)) in the methylphenidate condition vs. placebo.
4. MRI: Interaction group x treatment x task on cerebral activation linked to sustained attention and linked to the inhibition corresponding to each of these tasks.
5. EEG: Group x treatment x task interaction on the amplitude of the XML File Identifier: 0Vmd7NrSRK8JeP+9ISLPaO9Oq+U= Page 14/26 P300 wave linked to sustained attention (P300b) and linked to inhibition (P300a) corresponding to each of these tasks.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Les Hopitaux Universitaires De Strasbourg

Sponsor organisation

Les Hopitaux Universitaires De Strasbourg

Address

1 Place De L Hopital, Cs 80426 Cs 80426

City

Strasbourg Cedex

Postcode

67091

Country

France

Scientific contact point

Organisation

Les Hopitaux Universitaires De Strasbourg

Contact name

Sébastien WEIBEL

Public contact point

Organisation

Les Hopitaux Universitaires De Strasbourg

Contact name

Sébastien WEIBEL

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications