Dopaminergic Therapy for Frontotemporal Dementia Patients

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Dementia; Language Disorders; Communication Disorders; Frontotemporal Dementia; Aphasia; Aphasia, Primary Progressive; Pick Disease of the Brain; Speech Disorders; Frontotemporal Lobar Degeneration; Metabolic Disease
• Intervention / Treatment: Drug: Rotigotine 4Mg/24Hrs Patch; Drug: Rotigotine 6Mg/24Hrs Patch; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Brescia, Italy
    • Department of Neurology, University of Brescia
  • Rome, Italy, 00179
    • Giacomo Koch
  • Rome, Italy, 00179
    • Santa Lucia foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rotigotine 4 mg; Rotigotine 4 mg/24 hours transdermal patch administration	Drug: Rotigotine 4Mg/24Hrs Patch; Rotigotine 4 mg/24Hrs administration for 24 weeks; Other Names: Neupro
Experimental: Rotigotine 6 mg; Rotigotine 6 mg/24 hours transdermal patch administration	Drug: Rotigotine 6Mg/24Hrs Patch; Rotigotine 6 mg/24Hrs administration for 24 weeks; Other Names: Neupro
Placebo Comparator: Placebo; Placebo transdermal patch administration	Drug: Placebo; Placebo administration for 24 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frontal Assessment Battery (FAB)	Battery to evaluate executive functions. The scores range from 0-18 with a higher score meaning less cognitive impairment.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long intracortical inhibition (LICI)	TMS protocol to evaluate GABA(B)ergic transmission	24 weeks
TMS-EEG	power in beta-gamma band to evaluate prefrontal cortical oscillatory activity	24 weeks
Neuropsychiatric Inventory (NPI) scale	Battery to assess behavioral changes. The scores range from 0-144 with a higher score meaning more severe behavioural disturbances.	24 weeks
Frontal Behavioural Inventory (FBI)	Battery to assess behavioral changes. The scores range from 0-72 with a higher score meaning more severe behavioural disturbances.	24 weeks
Clinical Dementia Rating scale-Frontotemporal dementia Sum Of Boxes (CDR-FTDSOB)	Battery to evaluate global disease severity. The scores range from 0-24 with a higher score meaning higher disease severity.	24 weeks
Screening for aphasia in Neurodegeneration (SAND) scale	Battery to evaluate language functions. The scores range from 0-84 with a higher score meaning less severe language deficits.	24 weeks
Mini Mental State Examination (MMSE)	battery to evaluate global cognition. The scores range from 0-30 with a higher score meaning less cognitive impairment.	24 weeks
Addenbrooke's Cognitive Examination Revised (ACE-R)	battery to evaluate global cognition. The scores range from 0-100 with a higher score meaning less cognitive impairment.	24 weeks
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)	battery to evaluate activities of daily living. The scores range from 0-78 with lower scores indicating more severe functional impairment.	24 weeks
CGIC questionnaire	questionnaire to evaluate clinically meaningful change	24 weeks
18F-FDG CT/PET	Change in brain glucose metabolism will be measured via FDG-PET	24 weeks
Short intracortical inhibition (SICI)	TMS protocol to evaluate GABA(B)ergic transmission	24 weeks
Short-Latency Afferent Inhibition (SAI)	TMS protocol to evaluate cholinergic transmission	24 weeks
Intermittent Theta Burst Stimulation (iTBS)	TMS protocol to evaluate cortical plasticity	24 weeks
Nature, frequency and severity of adverse events (AEs)	To assess the safety and tolerability	24 weeks

Collaborators and Investigators

• Sponsor: I.R.C.C.S. Fondazione Santa Lucia
• Collaborators: Alzheimer's Drug Discovery Foundation
• Investigators: Principal Investigator: Giacomo Koch, MD, Santa Lucia Foundation IRCCS; Study Director: Martina Assogna, MD, Santa Lucia Foundation IRCCS; Study Chair: Alessandro Martorana, MD, PhD, University of Tor Vergata

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2021
• Primary Completion (Anticipated): December 30, 2023
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: June 16, 2021
• First Submitted That Met QC Criteria: June 16, 2021
• First Posted (Actual): June 24, 2021

Study Record Updates

• Last Update Posted (Actual): July 11, 2022
• Last Update Submitted That Met QC Criteria: July 7, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Rotigotine; dopamine; frontal cortex; FTD
• Additional Relevant MeSH Terms: Pathologic Processes; Tauopathies; Neurodevelopmental Disorders; Disease; Mental Disorders; Dementia; Nervous System Diseases; Alzheimer Disease; Brain Diseases; Neurodegenerative Diseases; Neurobehavioral Manifestations; Aphasia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Metabolic Diseases; Language Disorders; Neurologic Manifestations; Central Nervous System Diseases; Speech Disorders; Neurocognitive Disorders; Frontotemporal Lobar Degeneration; Communication Disorders; TDP-43 Proteinopathies; Proteostasis Deficiencies; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dopamine Agonists; Dopamine Agents; Rotigotine
• Other Study ID Numbers: EudraCT 2019-002997-30

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No