Clinical trial NCT05386394: Transcranial Direct Current Stimulation in the Treatment of Primary Progressive Aphasia
Official title: Phase II Clinical Trial of Transcranial Direct Current Stimulation in the Treatment of Primary Progressive Aphasia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Primary Progressive Aphasia
Logopenic Progressive Aphasia
Non-Fluent Primary Progressive Aphasia
Keywords: transcranial direct current stimulation
language treatment
primary progressive aphasia
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2022-05-23
Enrollment: 180
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a crossover design of tDCS + behavioral language therapy that crossovers to sham + behavioral language therapy in Arm 1, and sham + behavioral language therapy that crossovers to tDCS + behavioral language therapy in Arm 2.
Primary purpose: TREATMENT

Brief summary: While many have strongly suggested that transcranial direct current stimulation (tDCS) may represent a beneficial intervention for patients with primary progressive aphasia (PPA), this promising technology has not yet been applied widely in clinical settings. This treatment gap is underscored by the absence of any neurally-focused standard-of-care treatments to mitigate the devastating impact of aphasia on patients' family, work, and social lives. Given that tDCS is inexpensive, easy to use (it is potentially amenable to home use by patients and caregivers), minimally invasive, and safe there is great promise to advance this intervention toward clinical use. The principal reason that tDCS has not found wide clinical application yet is that its efficacy has not been tested in large, multi-center, clinical trials. In this study, scientists in the three sites that have conducted tDCS clinical trials in North America-Johns Hopkins University and the University of Pennsylvania in the US, and the University of Toronto in Canada, will collaborate to conduct a multi-site, Phase II clinical trial of tDCS a population in dire need of better treatments.

Detailed description: Aim 1: To determine whether tDCS over the left perisylvian language areas paired with naming treatment will improve oral and written naming outcomes in two variants of PPA (nfvPPA and lvPPA).

The investigators will use a double-blind, sham-controlled, within-subject, cross-over design. Participants will receive Naming and Spelling (NASP) treatment + tDCS condition or NASP treatment + sham condition, in Period 1 or 2, randomized for the Period 1 stimulation condition. Each treatment period will last 3 weeks, with 5 language therapy sessions/week, for 15 sessions in total, and a 3-month (stimulation-free) wash-out time between the two periods of stimulation to evaluate clinically meaningful effects.

Language therapy (NASP treatment) will be delivered by a speech-language pathologist or a trained research associate. The participant will be shown a picture on the screen, asked to orally name it, and subsequently write the name. If the participant cannot, the participant will be asked to provide 3 semantic attributes to reinforce semantic representations, as in Semantic Feature Analysis treatment (Boyle, 2010). If the word still cannot be named or written, the clinician will provide the correct name and spelling and the participant will be asked to repeat or copy it 3 times, in a spell-study-spell procedure (Rapp \& Glucroft, 2009). There will be two word-sets: trained (targeted during therapy) and untrained (not targeted during therapy), both individually tailored to the participant based on severity of spelling deficit. Treatment stimuli will consist of 10-30 words depending on individual severity. General procedures and the outcome measure (letter accuracy) will be maintained across all participants. Consistent with the investigators previous work, the NASP treatment will be conducted in English, which, for most participants, will be the participant's first language.

To deliver tDCS, the investigators will use the Soterix 1x1 platform. The anode will be placed over the left frontal lobe, centered on F7 in the 10-20 electrode placement system (Homan, 1988), and cathode will be placed over the right cheek. Non-metallic, conductive rubber electrodes (5 cm x 5 cm), fitted with saline-soaked sponges to limit skin-electrode reactions will be used so the full left inferior frontal gyrus (IFG) will be covered. Current will be delivered with an intensity of 2 mA (estimated current density 0.08 milliamps (mA)/cm2) for a total of 20 minutes each tDCS session. Delivery of tDCS will be simultaneous with the start of language therapy, which will continue for an additional 25 minutes beyond the cessation of tDCS in each session. In contrast to actual tDCS, sham stimulation involves the delivery of 30 seconds of current ramping up to 2 mA and back down to 0 mA simultaneous with the start of language therapy.

Behavioral/language assessments will involve: oral and written naming, spelling, connected speech/discourse, sentence comprehension and production, verbal fluency, short-term/working memory tasks, etc. Other global cognitive assessments will be conducted, as well as quality of life assessments. Bilingual assessments will be conducted for those who bilingual or multilingual.

Aim 2: To identify clinical, neural, cognitive, biological, and demographic predictors of tDCS vs sham effects on primary outcomes.

Imaging will be performed at before Period 1, before Period 2 and 3-months post Period 2 for a total of 3 scans per participant. Scans will be done on a 3T Philips system and will consist of magnetization prepared rapid gradient echoresting state (MPRAGE), resting state functional MRI (rsfMRI), and diffusion tensor imaging (DTI). Each scanning session will last approximately 1 hour.

Saliva samples will be collected for exploratory analysis and DNA will be extracted using standard methodology. Genotyping will be carried out by the Johns Hopkins DNA Diagnostic Laboratory using standard methods.

Eligibility criteria: Inclusion Criteria:

* Presence of aphasia attributable to non-fluent PPA or logopenic PPA
* High school education (or more)
* Between the ages of 50 and 80
* Must be able to understand the nature of the study and give informed consent

Exclusion Criteria:

* Cognitive impairment of sufficient severity to preclude giving informed consent (Mini Mental State Examination \[MMSE\] less than 15 or Montreal Cognitive Assessment \[MOCA\] less than 10; Frontotemporal Dementia - Modified Clinical Dementia Rating \[FTD-CDR\] Scale score =3)
* Any unrelated neurologic of physical condition that impairs communication ability
* History of unrelated neurological conditions, including but not limited to traumatic brain injury (TBI), stroke, or small vessel disease, that has resulted in a neurologic deficit
* Any additional neurological condition that would likely reduce the safety of study participation, including central nervous system (CNS) vasculitis, intracranial tumor, intracranial aneurysm, multiple sclerosis or arteriovenous malformations
* A medically unstable cardiopulmonary or metabolic disorder
* Individuals with pacemakers or implantable cardiac defibrillators
* Terminal illness associated with survival of less than 12 months
* Major active psychiatric illness that may interfere with required study procedures or treatments, as determined by enrolling physician
* Current abuse of alcohol or drugs, prescription or otherwise
* Participant in another drug, device or biologics trial within 30 days prior to enrollment
* Nursing a child, pregnant or intent to become pregnant during the study
* Left-handedness

Exclusion for tDCS, specifically:

* History of spontaneous or partial complex seizures or unexplained loss of consciousness within 6 months of enrollment
* Subjects with metallic objects in the face or head other than dental apparatus, such as braces, fillings or implants
* Subjects with previous craniotomy or any breach in the skull

Exclusion for MRI, specifically:

* Presence of any of the following devices: cardiac pacemaker, other pacemakers (for carotid sinus, insulin pumps, nerve stimulators, lead wires or similar wires), optic implant, implanted cardiac defibrillator, aneurysm clip, any electronically/magnetically/mechanically activated implant, ferromagnetic implants (coils, filters, stents; metal sutures or staples)
* Presence of any of the following: pregnancy, claustrophobic, metal in eye or orbit, tattooed eyeliner

Primary outcomes:
measure: Immediate Change in Phonemic Accuracy
timeFrame: Baseline and Immediate follow-up of 3-week intervention period
measure: Immediate Change in Letter Accuracy
timeFrame: Baseline and Immediate follow-up of 3-week intervention period
measure: Change in Phonemic Accuracy at 3-month follow-up visit
timeFrame: Baseline and 3 months post intervention
measure: Change in Letter Accuracy at 3-month follow-up visit
timeFrame: Baseline and 3 months post intervention
Secondary outcomes:
measure: Change in Untrained Naming Items (phonemic accuracy)
timeFrame: Baseline and 3 months post intervention
measure: Change in Untrained Naming Items (letter accuracy)
timeFrame: Baseline and 3 months post intervention
measure: Change in functional connectivity of select brain regions (z-correlations)
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
Other outcomes:
measure: Change in volumetric measurements of select brain regions
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in location of white matter tracts of select brain regions
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in anisotropy of white matter tracts of select brain regions
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Bilingualism as assessed by the Language Experience and Proficiency Questionnaire
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in oral naming Boston Naming Test score
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in oral naming Philadelphia Naming Test Short Form A score
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in oral naming of action as assessed by Hopkins Assessment of Naming Actions (HANA)
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in spelling as assessed by the Johns Hopkins Dysgraphia battery
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in semantic content of connected speech
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in syntactic comprehension as assessed by Subject-relative, Object-relative, Active, Passive (S.O.A.P.) Syntactic Battery
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in verbal fluency task score
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in digit span forward score
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in digit span backward score
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in spatial span forward score
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in spatial span backward score
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in attention and manipulation of information scores
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
measure: Change in Rey Auditory-Verbal Learning Test (RAVLT) score
timeFrame: Immediate follow-up of 3-week intervention period and 3-month follow-up
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Toronto
country: Canada
facility: Baycrest Centre for Geriatric Care
state: Ontario
Study officials:
affiliation: Johns Hopkins University
name: Kyrana Tsapkini, PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tsapkini K, Frangakis C, Gomez Y, Davis C, Hillis AE. Augmentation of spelling therapy with transcranial direct current stimulation in primary progressive aphasia: Preliminary results and challenges. Aphasiology. 2014;28(8-9):1112-1130. doi: 10.1080/02687038.2014.930410.
citation: Roncero C, Kniefel H, Service E, Thiel A, Probst S, Chertkow H. Inferior parietal transcranial direct current stimulation with training improves cognition in anomic Alzheimer's disease and frontotemporal dementia. Alzheimers Dement (N Y). 2017 Mar 24;3(2):247-253. doi: 10.1016/j.trci.2017.03.003. eCollection 2017 Jun.
citation: McConathey EM, White NC, Gervits F, Ash S, Coslett HB, Grossman M, Hamilton RH. Baseline Performance Predicts tDCS-Mediated Improvements in Language Symptoms in Primary Progressive Aphasia. Front Hum Neurosci. 2017 Jun 30;11:347. doi: 10.3389/fnhum.2017.00347. eCollection 2017.
citation: Gervits F, Ash S, Coslett HB, Rascovsky K, Grossman M, Hamilton R. Transcranial direct current stimulation for the treatment of primary progressive aphasia: An open-label pilot study. Brain Lang. 2016 Nov;162:35-41. doi: 10.1016/j.bandl.2016.05.007. Epub 2016 Aug 12.
citation: Roncero C, Service E, De Caro M, Popov A, Thiel A, Probst S, Chertkow H. Maximizing the Treatment Benefit of tDCS in Neurodegenerative Anomia. Front Neurosci. 2019 Nov 22;13:1231. doi: 10.3389/fnins.2019.01231. eCollection 2019.
citation: Tsapkini K, Webster KT, Ficek BN, Desmond JE, Onyike CU, Rapp B, Frangakis CE, Hillis AE. Electrical brain stimulation in different variants of primary progressive aphasia: A randomized clinical trial. Alzheimers Dement (N Y). 2018 Sep 5;4:461-472. doi: 10.1016/j.trci.2018.08.002. eCollection 2018.
citation: Boyle M. Semantic feature analysis treatment for aphasic word retrieval impairments: what's in a name? Top Stroke Rehabil. 2010 Nov-Dec;17(6):411-22. doi: 10.1310/tsr1706-411.
citation: Rapp B, Glucroft B. The benefits and protective effects of behavioural treatment for dysgraphia in a case of primary progressive aphasia. Aphasiology. 2009 Feb 1;23(2):236-265. doi: 10.1080/02687030801943054.
citation: Homan RW. The 10-20 electrode system and cerebral location. American Journal of EEG Technology. 1988;28(4):269-279.