MODAFIMS: A Trial to Evaluate Predictors of Response to MODAFinil in Patients With Multiple Sclerosis

This is a phase II/exploratory clinical trial with a single-center, open-label design to evaluate the effect of modafinil on cognitive deficits in adult patients with multiple sclerosis and identify predictors of response using functional Magnetic Resonance Imaging (fMRI).

Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system. There are no commercially authorized therapeutic options available for the treatment of cognitive impairment in patients with multiple sclerosis. It is then necessary to conduct robust clinical trials to select better therapies.

Modafinil is a drug approved by INFARMED and European Medicines Agency (EMA) for the treatment of excessive sleepiness associated with narcolepsy. Modafinil has been tested in 5 clinical trials in patients with multiple sclerosis and the results indicated a potential improvement in cognitive deficits in tasks that measure executive function, verbal memory, and/or working memory performance.

Despite encouraging results, there is a huge variation in its effect in individual patients and a significant proportion of sub-optimal/non-responders. Therefore, it is important to identify personalized predictors of response to best tailor the treatment to each patient.

This is a phase II/exploratory clinical trial with a single-center, open-label design to evaluate the effect of modafinil on cognitive deficits in adult patients with multiple sclerosis and identify predictors of response using functional Magnetic Resonance Imaging (fMRI).

The primary objective of the clinical trial is to identify fMRI markers of response to modafinil. In other words, our aim is to analyse brain activity (using fMRI) before and after modafinil intake and select the features that can better differentiate between responders and non-responders. These patient groups will be determined according to the improvement rate in the Symbol digit modalities test (SDMT) - which will be evaluated at screening, baseline and at the end of treatment.

The clinical trial will be conducted at Centro Clínico Académico - Braga, Associação (2CA-Braga), Unidade Local de Saúde de Braga (ULS Braga), E.P.E.. Participants will be recruited at the outpatient unit of the Neurology department of ULS de Braga.

A total of 64 eligible patients will be enrolled to receive modafinil at a dose 200 mg (2 tablets of 100 mg) once per day in the morning for 3 months.

Eligibility Criteria:
Inclusion Criteria:

* Participant is willing and able to give informed consent for the participation in the trial.
* Patients that are able to read and write.
* Male or female, aged between 18 and 64 years old at the time of signing the ICF.
* Diagnosed with Relapsing-Remitting MS or Clinically Isolated Syndrome, according to McDonald 2017 diagnostic criteria (Thompson et al., 2018).
* Expanded disability status score (EDSS) less than 6.5.
* Presence of subjective cognitive complaints.
* SDMT score (number of correct responses within 90 seconds) at Screening ≤ 55 (Benedict et al., 2016; Parmenter et al., 2007).
* Female participants of childbearing potential and male participants whose partner is of childbearing potential must be willing to ensure that they or their partner use protocol's recommended effective contraception methods, which is not based only on hormonal methods, during all the 6 months of the trial (3 months of treatment plus 3 months of safety follow-up).
* Male participants must agree to refrain from donation of semen from first study treatment administration up to at least 90 days after last administration.
* Participants, that in the medical investigator's opinion, are able and willing to comply with all trial requirements.

Exclusion Criteria:

* Female participant who is pregnant, breastfeeding or planning pregnancy during the trial.
* Participants who have participated in another research trial involving an investigational product within the past 5 half-lives of the other investigational product.
* Participants who have any disability that, in the opinion of the investigator, significantly interferes with the neuropsychological testing and/or the tasks in the functional MRI.
* Participants not able to undergo MRI scanning.
* Participants who have any contra-indication for taking modafinil, according to the prescribing information and SmPC, such as hypersensitivity to the active substance and any excipient present in the modafinil or any documented adverse reaction after modafinil intake.
* Participants with known hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
* Participants with a history of left ventricular hypertrophy or cor pulmonale and patients with mitral valve prolapse who developed mitral valve prolapse syndrome when previously treated with central nervous system stimulants.
* Current use of modafinil, armodafinil.
* Current use of other psychostimulants, including amphetamines, cocaine, bupropion, gingko biloba, among others, and beverages or food containing methylxanthines (e.g., coffee, tea, cola, caffeine, chocolate, sodas) exceeding 500 mg methylxanthines per day (for example, consumption of more than 5 espresso coffees or 100 mg of dark chocolate per day; Sanchez, 2017).
* Significant neurological history aside from MS (e.g., Epilepsy).
* Significant psychiatric history (e.g., Schizophrenia, Bipolar Disorder, Major Depression, severe anxiety disorder, aggressive or hostile behaviour).
* A documented history of attempted suicide in the last 2 years OR suicidal ideation with intent, with or without a plan or method (e.g., positive response to items 4 or 5 in the assessment of suicidal ideation on the C-SSRS) over the 6 months prior to the Screening Visit.
* Significant insomnia (grade \&gt; 1 according to Common Terminology Criteria for Adverse Events, CTCAE v5)
* History of severe hypersensitivity reactions to any medicine.
* Presence of any clinically significant abnormality in ECG morphology or ECG parameters.
* Known immunodeficiency syndrome.
* Have serum alanine aminotransferase (ALT) values greater than 3 times the upper limit of normal at screening.
* Positive test for anti-Human Immunodeficiency virus 1 or 2 antibodies, Hepatitis B surface antigen (HBsAg) or anti Hepatitis C virus antibodies.
* Creatinine clearance \&lt; 20 ml/min determined by Cockcroft-Gault equation.
* History of alcoholism or drug abuse.
* Average daily consumption of more than 20 cigarettes.
* Participants with disability that interferes with the performance of the CT procedures (for example, motor deficit in upper limb, decreased visual acuity even with correction).
* Participants with increased risk of epileptic seizures, history of cardiac arrhythmias, or uncontrolled moderate to severe hypertension.
* Participants taking warfarin or any other prohibited medication.
* Sleep complaints confirmed by Epworth Sleepiness Scale (ESS) scale score \&gt;10 at screening visit OR known sleep disorder.
* Any other condition that, in the opinion of the investigator, contra-indicates the participation of the patient.