Clinical trial NCT04937452: Dopaminergic Therapy for Frontotemporal Dementia Patients
Official title: Dopaminergic Therapy for Frontotemporal Dementia Patients: an Interventional, Multi-site, Randomized, Double-blind, Placebo-controlled Study on the Efficacy and Safety of RTG Treatment in Patients with Behavioral FTD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Frontotemporal Dementia
Dementia
Aphasia, Primary Progressive
Pick Disease of the Brain
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Neurodegenerative Diseases
Frontotemporal Lobar Degeneration
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Disease
Aphasia
Speech Disorders
Language Disorders
Communication Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Keywords: dopamine
frontal cortex
FTD
Rotigotine
Lead sponsor: I.R.C.C.S. Fondazione Santa Lucia
Sponsor class: OTHER
Collaborators: name: Alzheimer's Drug Discovery Foundation
First posted: 2021-06-24
Enrollment: 75
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase IIa 24-week randomized, double-blind, placebo-controlled study. The study is designed to evaluate the efficacy and safety of Rotigotine (RTG) transdermal administration at the dosage of 4 mg or 6 mg per day versus Placebo (PLC) in newly diagnosed behavioural Frontotemporal Dementia (bvFTD) patients. 75 patients with a diagnosis of probable bvFTD will be randomly allocated to the 3 treatment arms (RTG 4mg/day, RTG 6mg/day or PLC), with 25 patients per group. Clinical and neurophysiological measurements and brain metabolism via FDG-PET will be collected before and after drug administration.

Detailed description: The current study has the ambition to provide the first-time evidence of the clinical impact, at cognitive and behavioral level, of a dopamine-based treatment in newly diagnosed bvFTD patients.

To evaluate the cognitive and behavioral effects of RTG administration, the investigators will employ a battery of tests assessing global cognition, executive functions, language and behavior.

The battery will include: Neuropsychiatric Inventory (NPI) and Frontal Behavioral Inventory (FBI) to evaluate behavior, Clinical Dementia Rating Scale-Frontotemporal Dementia Sum Of Boxes (CDR-FTD SOB) to evaluate global disease severity, Frontal Assessment Battery (FAB) to evaluate frontal functions, Screening for aphasia in Neurodegeneration (SAND) to evaluate language functions, Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) to evaluate activities of daily living, the Addenbrooke's Cognitive Examination Revised (ACE-R) to evaluate global cognition.

To evaluate changes in brain metabolism the investigators will perform 2 FDG-PET scans before starting the treatment and at the end of week 24.

Neurophysiological investigations will be performed to identify quantifiable biomarkers underlying the effects induced by dopamine agonist on the bvFTD brain. In particular, the investigators will use multimodal neurophysiological tools based on TMS-EMG and TMS-EEG. More specifically, different paired-pulse TMS protocols will be used to evaluate in vivo the activity of different intracortical circuits, such as short intracortical inhibition (SICI), reflecting GABA(A)-ergic neurotransmission; long intracortical inhibition (LICI), evaluating GABA(B)-ergic neurotransmission; short afferent inhibition (SAI) evaluating cholinergic neurotransmission and intermittent theta burst stimulation (iTBS) probing cortical plasticity mechanisms, such as long- term potentiation (LTP). The effects of these protocols will be evaluated by means of motor-evoked potentials, recordable with EMG. TMS-EEG will be used to measure the effects of RTG on frontal and parieto-temporal cortical activity, in terms of cortical excitability, oscillatory activity and connectivity. The investigators will evaluate the effects of the DA drug on brain activity and plasticity by analyzing MEPs and TEPs before and after the treatment. The investigators expect to find modulations in the high EEG frequencies (beta and gamma oscillatory activities) and/or in the indexes of cortical reactivity and plasticity (amplitude of TEPs and MEPs) that correlate with improvement in clinical assessment.

Eligibility criteria: Inclusion Criteria:

1. The patient has a diagnosis of probable Frontotemporal dementia behavioural variant (bv-FTD) based on the International consensus clinical diagnostic criteria described by Rascovsky et al., 2011.
2. The patient is a man or a woman, aged from 40 to 80 years.
3. The patient has a Clinical Dementia Rating-FTD (CDR-FTD) total score of ≤2 at Screening.
4. The patient has not been treated with acetylcholinesterase inhibitor (AChEI), i.e., donepezil, galantamine, or rivastigmine, at the time of screening.
5. The patient is able to comply with the study procedures in the view of the investigator.
6. Evidence of frontotemporal hypometabolism at PET imaging.
7. Evidence of amyloid markers excluding Alzheimer's disease (cerebrospinal fluid Abeta/Tau dosages or amyloid PET imaging).
8. Signature and date of written ICF prior to entering in the study
9. Female patient must be neither pregnant nor breastfeeding. Women of childbearing potential should be willing to use contraception while receiving Rotigotine and for six months after its last assumption

Exclusion Criteria:

1. Significant neurodegenerative disorder of the central nervous system other than FTD e.g., Alzheimer's disease, Lewy body dementia, Parkinson's disease, multiple sclerosis, progressive supranuclear palsy, normal pressure hydrocephalus, Huntington's disease, any condition directly or indirectly caused by Transmissible Spongiform Encephalopathy (TSE), Creutzfeldt-Jakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), or new variant Creutzfeldt-Jakob Disease (nvCJD)
2. Significant intracranial focal or vascular pathology seen on brain MRI scan within a maximum of 6 months before Baseline leading to a diagnosis other than probable FTD.
3. The patients has history of seizure (with the exception of febrile seizures in childhood).
4. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that are contraindications to MR imaging.
5. Treatment currently or within 3 months before Baseline with any of the following medications: Typical and Atypical antipsychotics (i.e., Clozapine, Olanzapine); Antiepileptics drugs (i.e., Carbamazepine, Primidone, Pregabalin, Gabapentin); Antidepressants (i.e., Citalopram, Duolxetine, Paroxetine).

Primary outcomes:
measure: Frontal Assessment Battery (FAB)
timeFrame: 24 weeks
Secondary outcomes:
measure: Neuropsychiatric Inventory (NPI) scale
timeFrame: 24 weeks
measure: Frontal Behavioural Inventory (FBI)
timeFrame: 24 weeks
measure: Clinical Dementia Rating scale-Frontotemporal dementia Sum Of Boxes (CDR-FTDSOB)
timeFrame: 24 weeks
measure: Screening for aphasia in Neurodegeneration (SAND) scale
timeFrame: 24 weeks
measure: Mini Mental State Examination (MMSE)
timeFrame: 24 weeks
measure: Addenbrooke's Cognitive Examination Revised (ACE-R)
timeFrame: 24 weeks
measure: Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
timeFrame: 24 weeks
measure: CGIC questionnaire
timeFrame: 24 weeks
measure: 18F-FDG CT/PET
timeFrame: 24 weeks
measure: Long intracortical inhibition (LICI)
timeFrame: 24 weeks
measure: Short intracortical inhibition (SICI)
timeFrame: 24 weeks
measure: Short-Latency Afferent Inhibition (SAI)
timeFrame: 24 weeks
measure: Intermittent Theta Burst Stimulation (iTBS)
timeFrame: 24 weeks
measure: TMS-EEG
timeFrame: 24 weeks
measure: Nature, frequency and severity of adverse events (AEs)
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Giacomo Koch
state: <None>
city: Brescia
country: Italy
facility: Department of Neurology, University of Brescia
city: Rome
country: Italy
facility: Santa Lucia Foundation
Study officials:
affiliation: Santa Lucia Foundation IRCCS
name: Giacomo Koch, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Santa Lucia Foundation IRCCS
name: Martina Assogna, MD
role: STUDY_DIRECTOR
affiliation: University of Tor Vergata
name: Alessandro Martorana, MD, PhD
role: STUDY_CHAIR
References: