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This is a double-blind, sham-controlled, crossover study in which subjects with the non-fluent/agrammatic and semantic variants of primary progressive aphasia (naPPA and svPPA, respectively) will undergo language testing and structural and functional brain imaging before and after receiving 10 semi-consecutive daily sessions of real or sham transcranial direct current stimulation (tDCS) paired with modified constraint-induced language therapy (mCILT). Language testing and brain imaging will be repeated immediately after completion of and up-to 24 weeks following completion of treatment. The investigators will examine changes in language performance induced by tDCS + mCILT compared to sham tDCS + mCILT. The investigators will also use network science to analyze brain imaging (fMRI) data to identify network properties associated with baseline PPA severity and tDCS-induced changes in performance. This study will combine knowledge gained from our behavioral, imaging, and network data in order to determine the relative degrees to which these properties predict whether persons with PPA will respond to intervention.
The central framework for the project is a double-blind, sham-controlled, crossover study in which subjects with the non-fluent/agrammatic and semantic variants of primary progressive aphasia (naPPA and svPPA, respectively) will undergo language testing and structural and functional brain imaging before and after receiving 10 semi-consecutive daily sessions of real or sham transcranial direct current stimulation (tDCS) paired with modified constraint-induced language therapy (mCILT). Language testing and brain imaging will be repeated immediately after completion of and up-to 24 weeks following completion of treatment.
Subjects with naPPA and svPPA will be randomized to one of two study arms: tDCS+mCILT or sham stimulation+mCILT paired with pre- and post-stimulation imaging and behavioral measures. Equal numbers of subjects with naPPA and svPPA will be randomized to the tDCS + mCILT and sham + mCILT study arms. The study is double-blinded, in that neither the subject nor the study personnel administering tDCS or sham stimulation will know which arm of the study the subject has been randomized into. Study coordinators will administer tDCS by entering a pre-determined code that has been programmed into the device by another member of the study team. Data will be digitally audio-recorded and analyzed off-line, such that study team members performing data coding and analysis will likewise be blinded to the treatment condition of each subject.
Subject participation in this protocol will occur during 36 planned visits that will span approximately 12 months. The events of the study visits are described below:
VISIT 1:
Informed consent and screening
VISIT 2:
Baseline MRI
VISIT 3 & 4:
Baseline language assessment
VISITS 5-14:
tDCS+mCILT OR sham stimulation+mCILT, depending on the study arm to which they had been randomized.
VISIT 15 & 16:
Follow-up language assessment Follow-up MRI
VISIT 17:
6-Week follow-up language assessment
VISIT 18 & 19:
12-week follow-up language assessment 12-week follow-up MRI
**CROSSOVER**
VISIT 20:
Crossover baseline language assessment
VISITS 21-30:
tDCS+mCILT or sham stimulation+mCILT
VISIT 31 & 32:
Follow-up language assessment Follow-up MRI
VISIT 33:
6 Week follow-up language assessment
VISIT 34 & 35:
12-week follow-up language assessment 12-week follow-up MRI
VISIT 36:
24 week follow-up language assessment
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| tDCS + CILT | Active Comparator | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of tDCS for 20 minutes using a montage in which an anode (1.5 mA) is placed over F7 (left frontotemporal lobe) and the cathode will be place on O1 (left occipital) using the 10-20 EEG mapping system. Subjects will participate in a modified constraint-induced language therapy. |
|
| Sham tDCS + CILT | Sham Comparator | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of sham tDCS for 20 minutes using a montage in which an anode is placed of F7 and cathose is placed over O1. Subjects will participate in a modified constraint-induced language therapy, |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Transcranial Direct Current Stimulation (tDCS) | Device | tDCS is a type of non-invasive brain stimulation in which small electrical currents are applied to the scalp via 2 electrodes. The current, 1.5 mA, is approximately of the same intensity as the current provided by a 9-volt battery. To deliver the current, electrodes that are placed in saline soaked sponges. They will be attached to the left side of your head; they will be held in place with an elastic cap. For both real and sham stimulation the electrodes will be placed on the scalp. |
| Measure | Description | Time Frame |
|---|---|---|
| Western Aphasia Battery Aphasia Quotient (WAB-AQ) | The primary outcome measure will be the change in score on the Western Aphasia Battery Aphasia Quotient (WAB-AQ), a score assessing overall aphasia recovery. Scores can range from 0-100, with higher scores representing better outcomes. 0-25 is very severe, 26-50 is severe, 51-75 is moderate, and 76-above is mild. A score of 93 or higher is considered recovered. | Baseline to 12 weeks; baseline to 24 weeks when available |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Roy Hamilton, MS | University of Pennsylvania | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pennsylvania | Philadelphia | Pennsylvania | 19104 | United States |
A total of 3 participants did not qualify at the time of enrollment due to low MMSE scores (2) and diagnosis change that no longer met our PPA criteria (1).
A total of 2 participants dropped out of the study before they were randomized due to travel concerns.
Participants were recruited from July 2020-July 2024 from the Hospital of the University of Pennsylvania and surrounding Philadelphia area medical centers.
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| ID | Title | Description |
|---|---|---|
| FG000 | tDCS + CILT First, Then Sham tDCS + CILT | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of tDCS for 20 minutes using a montage in which an anode (1.5 mA) is placed over F7 (left frontotemporal lobe) and the cathode will be place on O1 (left occipital) using the 10-20 EEG mapping system. Subjects will simultaneously participate in a modified constraint-induced language therapy. Follow-up language assessments will be completed immediately, 6 weeks and 12 weeks after tDCS + CILT treatment. After a 12 week washout period, participants will then crossover to the Sham tDCS condition. Follow-up language assessments will be completed immediately, 6 weeks,12 weeks and 24 weeks after Sham tDCS + CILT treatment. |
| FG001 | Sham tDCS + CILT First, Then tDCS + CILT | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of sham tDCS for 20 minutes using a montage in which an anode is placed of F7 and cathode is placed over O1. During sham stimulation, the current, 1.5 mA, will be delivered for a short amount of time (about 30 seconds) and then turn-off. Most people cannot tell the difference between real and sham stimulation. Subjects will simultaneously participate in a modified constraint-induced language therapy. Follow-up language assessments will be completed immediately, 6 weeks and 12 weeks after Sham tDCS + CILT treatment. After a 12 week washout period, participants will then crossover to the tDCS condition. Follow-up language assessments will be completed immediately, 6 weeks,12 weeks and 24 weeks after tDCS + CILT treatment. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | tDCS + CILT First, Then Sham + CILT | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of tDCS for 20 minutes using a montage in which an anode (1.5 mA) is placed over F7 (left frontotemporal lobe) and the cathode will be place on O1 (left occipital) using the 10-20 EEG mapping system. Subjects will simultaneously participate in a modified constraint-induced language therapy. Participants will then crossover to the Sham tDCS condition. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Western Aphasia Battery Aphasia Quotient (WAB-AQ) | The primary outcome measure will be the change in score on the Western Aphasia Battery Aphasia Quotient (WAB-AQ), a score assessing overall aphasia recovery. Scores can range from 0-100, with higher scores representing better outcomes. 0-25 is very severe, 26-50 is severe, 51-75 is moderate, and 76-above is mild. A score of 93 or higher is considered recovered. | 24 week follow-up data are not available for individuals randomized to the tDCS + CILT first, then Sham tDCS + CILT group because there is no 24 week follow-up for the first arm. 24 week follow-up data are not available for individuals randomized to the Sham tDCS + CILT first, then tDCS + CILT group because there is no 24 week follow-up for the first arm. | Posted | Mean | Standard Deviation | scores on a scale | Baseline to 12 weeks; baseline to 24 weeks when available |
|
From baseline, adverse event data were collected over a period of time consisting of 36 weeks (12 weeks for arm 1 and 24 weeks for arm 2).
Adverse event (AEs) information was collected daily during treatment sessions, as well as each follow-up visit.
This is a crossover study, meaning all participants received the real intervention at some point during their participation.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | tDCS + CILT | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of tDCS for 20 minutes using a montage in which an anode (1.5 mA) is placed over F7 (left frontotemporal lobe) and the cathode will be place on O1 (left occipital) using the 10-20 EEG mapping system. Subjects will simultaneously participate in a modified constraint-induced language therapy. Follow-up language assessments will be completed immediately, 6 weeks and 12 weeks after treatment. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hip replacement | Surgical and medical procedures | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| skin irritation | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Daniela Sacchetti, MS | Clinical Research Coordinator | 215-573-4336 | danielas@pennmedicine.upenn.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 7, 2022 | Jun 28, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D018888 | Aphasia, Primary Progressive |
| D003147 | Communication Disorders |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
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Crossover assignment
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|
| Sham tDCS | Device | tDCS is a type of non-invasive brain stimulation in which small electrical currents are applied to the scalp via 2 electrodes. During sham stimulation, the current, 1.5 mA, will be delivered for a short amount of time and then turn-off. To deliver the current, electrodes that are placed in saline soaked sponges. They will be attached to the left side of your head; they will be held in place with an elastic cap. For both real and sham stimulation the electrodes will be placed on the scalp. Most people cannot tell the difference between real and sham stimulation. |
|
| Modified Contraint-Induced Language Therapy (mCILT) | Behavioral | Modified constraint-induced language therapy (mCILT) is a behavioral language therapy that invokes use-dependent learning in communicative interactions by requiring spoken output and restricting use of alternative forms of communication, such as gestures, as a substitute for spoken output. Other key elements of CILT include massed practice of goal-directed speech and shaping of desired responses by increasing response demands as participants improve. MCILT differs from traditional constraint-induced language therapy (CILT) in three ways: 1) it will be done as an individual therapy with the examiner in the role of a communication partner; 2) treatment will be delivered in short sessions (1 hour rather than a more typical 3-4 hour session); 3) targeting nouns + semantically related verbs to generate noun + verb phrases in treatment, a modification that may be better suited to addressing syntactic structure. |
|
| BG001 | Sham tDCS + CILT First, Then tDCS + CILT | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of sham tDCS for 20 minutes using a montage in which an anode is placed of F7 and cathode is placed over O1. During sham stimulation, the current, 1.5 mA, will be delivered for a short amount of time (about 30 seconds) and then turn-off. Most people cannot tell the difference between real and sham stimulation. Subjects will simultaneously participate in a modified constraint-induced language therapy. Participants will then crossover into the tDCS condition. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Western Aphasia Battery (WAB-AQ) Score | Mean | Standard Deviation | scores on a scale |
|
Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of tDCS for 20 minutes using a montage in which an anode (1.5 mA) is placed over F7 (left frontotemporal lobe) and the cathode will be place on O1 (left occipital) using the 10-20 EEG mapping system. Subjects will simultaneously participate in a modified constraint-induced language therapy.
Participants will then crossover to the Sham tDCS condition.
| OG001 | Sham tDCS + CILT First, Then tDCS + CILT | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of sham tDCS for 20 minutes using a montage in which an anode is placed of F7 and cathode is placed over O1. During sham stimulation, the current, 1.5 mA, will be delivered for a short amount of time (about 30 seconds) and then turn-off. Most people cannot tell the difference between real and sham stimulation. Subjects will simultaneously participate in a modified constraint-induced language therapy. Participants will then crossover into the tDCS condition. |
|
|
|
| 0 |
| 18 |
| 1 |
| 18 |
| 4 |
| 18 |
| EG001 | Sham tDCS + CILT | Participants will undergo 10 daily sessions (Monday-Friday, x2 weeks) of sham tDCS for 20 minutes using a montage in which an anode is placed of F7 and cathode is placed over O1. During sham stimulation, the current, 1.5 mA, will be delivered for a short amount of time (about 30 seconds) and then turn-off. Most people cannot tell the difference between real and sham stimulation. Subjects will simultaneously participate in a modified constraint-induced language therapy. Follow-up language assessments will be completed immediately, 6 weeks and 12 weeks after treatment. | 0 | 18 | 1 | 18 | 3 | 18 |
| Chest pain | Cardiac disorders | Systematic Assessment |
|
| Fall | General disorders | Systematic Assessment |
|
| Headache | General disorders | Systematic Assessment |
|
| ear biopsy | Surgical and medical procedures | Systematic Assessment |
|
| Macular Degeneration | Eye disorders | Systematic Assessment |
|
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| D001037 |
| Aphasia |
| D013064 | Speech Disorders |
| D007806 | Language Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D065886 | Neurodevelopmental Disorders |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |