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Roflumilast TMS-EEG Plasticity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04369547
Recruitment Status : Not yet recruiting
First Posted : April 30, 2020
Last Update Posted : April 30, 2020
Information provided by (Responsible Party):
Alexander McGirr, University of Calgary

Brief Summary:
Repetitive transcranial magnetic stimulation (rTMS) uses a magnetic field to non-invasively induce electrical function within the brain. Stimulation allows brain cells to change the way that they adapt and communicate with each other, known as 'synaptic plasticity'. It is thought that alterations in these adaptive brain changes underlie the ability of rTMS to treat mental illnesses like depression. rTMS is a Health Canada approved treatment for depression, however, 2/3rds of people fail to show meaningful improvement. This highlights the need for more effective therapeutic means. The purpose of the present study is to augment the therapeutic abilities of rTMS through the conjunctive use of a medication that also increases synaptic plasticity. We will pair TMS with an electroencephalograph (EEG) to measure activity dependent changes in the frontal cortex following rTMS.

Condition or disease Intervention/treatment Phase
Synaptic Plasticity Device: Transcranial Magnetic Stimulation Drug: Roflumilast Drug: Placebo oral tablet Phase 1

Detailed Description:

This randomized, placebo-controlled, crossover trial will enroll 20 healthy participants. In one arm of the study, participants will randomly receive either 100mcg of roflumilast (a phosphodiesterase-4 inhibitor), or a placebo capsule, and participants will receive the other intervention one week later.

  1. The investigators will recruit 20 healthy participants through community advertisement, carefully screened for exclusion factors related to rTMS and roflumilast.
  2. Participants will be randomly assigned by random number sequence with allocation concealment to one of two first arms of the crossover study: a) placebo-roflumilast 100mcg and b) roflumilast 100mcg-placebo.
  3. Participants will complete the QIDS-SR (Quick Inventory of Depressive Symptoms-Self Report), the BAI (Beck Anxiety Inventory), and the STAI (State Trait Anxiety Inventory).

    Participants will report their perception of physical symptoms (potential side effects) in the 7 days before participating in the study taking the randomized capsule (Toronto Side Effects Scale - 1 Week).

  4. Participants will take their blinded capsule at least 30 minutes prior to TBS (theta-burst stimulation).
  5. The resting motor threshold of participants will be determined using electromyographic electrodes (EMG). EMG electrodes will be positioned over the first dorsal interosseous (FDI) muscle on the right hand. These electrodes are non-invasive and use an adhesive to stick to the skin.
  6. The M1 hand strip will be localized using single pulse TMS (MagPro X100) in conjunction with neuronavigation and an atlas brain.
  7. Muscle activation in response to TMS will be measured through motor evoked potentials (MEP). The strength of MEPs in response to differing strengths of single pulse TMS will be used to determine a participants resting motor threshold (RMT). The RMT is the lowest TMS setting at which the FDI muscle responds to TMS stimulus. 80% of the RMT will then be the strength at which TBS protocol will be applied to the DLPFC.
  8. Two baselines of TMS Evoked Potentials (TEPs) will be collected via one hundred single-pulse (120% RMT), 0.25Hz) over the F3 site. Each baseline will occur 10 minutes apart.
  9. TBS-rTMS will be applied to the DLPFC site. TBS consists of 2s trains every 10s. Each train is composed of 3 pulses at 50Hz, 200ms intervals given at 80% RMT. The total time for this treatment stimulus is 600 pulses over 190s.
  10. Following TBS, one hundred TEPs over the F3 site will again be acquired at 10, 20, and 30 minutes after treatment (single pulse, 120%RMT, 0.25Hz).

As this is a cross-over study, participants will return 1 week later to repeat the second arm of the protocol (steps 3-10).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: A Double-blind Placebo-controlled Crossover Study of Roflumilast Synaptic Plasticity Enhancement: a TMS-EEG Study
Estimated Study Start Date : June 1, 2020
Estimated Primary Completion Date : June 1, 2023
Estimated Study Completion Date : June 1, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Roflumilast

Arm Intervention/treatment
Experimental: Roflumilast
Participants will ingest a capsule containing 100mcg of the phosphodiesterase-4 inhibitor roflumilast. Their baseline TMS evoked potentials (TEP) will be recorded over 100 single TMS pulses prior to receiving theta-burst stimulation (TBS; a patterned stimulation) to the left dorsolateral prefrontal cortex (DLPFC). TEP will then be re-recorded at 10, 20, and 30 minutes post-stimulation.
Device: Transcranial Magnetic Stimulation
Single-pulse transcranial magnetic stimulation and theta-burst stimulation.

Drug: Roflumilast
Roflumilast 100mcg

Placebo Comparator: Placebo
Participants will ingest a capsule identical to that containing the study medication, however, this capsule will be contain a placebo. Their baseline TEP will be recorded over 100 single TMS pulses prior to receiving TBS to the left DLPFC. TEP will then be re-recorded at 10, 20, and 30 minutes post-stimulation.
Device: Transcranial Magnetic Stimulation
Single-pulse transcranial magnetic stimulation and theta-burst stimulation.

Drug: Placebo oral tablet
Placebo capsule matched to roflumilast capsule

Primary Outcome Measures :
  1. TMS Evoked Potential amplitude [ Time Frame: Baseline versus 10, 20, and 30 minutes following theta-burst stimulation. ]
    Change in the electrical response of neurons in the dorsolateral prefrontal cortex will be recorded.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  1. Healthy individuals (no chronic medical conditions).
  2. Aged 18-60 years.

Exclusion Criteria:

  1. Pregnancy
  2. Lactation
  3. Epilepsy
  4. Previous stroke
  5. Current Renal Disease
  6. Current Liver Disease
  7. Allergy to roflumilast or any of its non-medicinal ingredients
  8. Current psychiatric concerns
  9. Currently taking any medications that interact with roflumilast
  10. Intracranial metallic objects (dental hardware is not an exclusionary criterion)
  11. Substance use disorder
  12. The inability to refrain from alcohol use for 24 hours prior to stimulation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04369547

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Contact: Alexander McGirr, MD PhD 4032106410

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Canada, Alberta
University of Calgary
Calgary, Alberta, Canada, T2N1N4
Contact: Alexander McGirr, MD PhD    4032106410   
Sponsors and Collaborators
University of Calgary
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Principal Investigator: Alexander McGirr, MD PhD University of Calgary
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Responsible Party: Alexander McGirr, Assistant Professor, University of Calgary Identifier: NCT04369547    
Other Study ID Numbers: REB20-0196
First Posted: April 30, 2020    Key Record Dates
Last Update Posted: April 30, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There will be no sharing of individual participant data.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Alexander McGirr, University of Calgary:
Augmented Plasticity