Roflumilast and TMS Motor Plasticity

University of Calgary

Status and phase: Active, not recruiting; Phase 1

Conditions: Other Conditions of Brain

Treatments: Drug: Roflumilast; Drug: Placebo; Device: Intermittent theta-burst stimulation transcranial magnetic stimulation; Device: Continuous theta-burst stimulation transcranial magnetic stimulation

Study type: Interventional

Funder types: Other

Identifiers

NCT06457191

REB23-1506

Details and patient eligibility

About

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.

The regulation of synaptic plasticity is complex, and involves multiple interacting factors and redundant systems to ensure that plasticity is carefully regulated. To date, studies attempting to alter impact synaptic plasticity have done so using pharmacological adjuncts that target extracellular contributions to plasticity. Here, we propose the first proof of principle study targeting intracellular regulation of plasticity by using a pharmacological adjunct targeting Phosphodiesterase 4 (PDE4), a key regulator a cyclic AMP gradients in brain cells.

We will pair TMS with electromyography (EMG) to measure activity dependent changes in the motor cortex following rTMS to test the ability of a PDE4 inhibition to enhance synaptic plasticity after rTMS.

Full description

This study will employ a randomized, placebo-controlled single-blind crossover trial of adjunctive roflumilast with intermittent or continuous theta burst (iTBS/cTBS) TMS to the primary motor cortex. Participants will complete a screen visit to determine eligibility based on the inclusion/exclusion criteria. If the participants are not eligible, no further study procedures will be conducted.

Randomization with allocation concealment of eligible patients to begin with either the study medication or placebo arm of the study will involve a random number sequence generated a priori with atmospheric noise, with single-blind random condition assignment and allocation concealment.

Baseline corticospinal excitability will be quantified. One hour following ingestion of the blinded capsule iTBS/cTBS will be applied to the primary motor cortex, and the response will be quantified through a combination of motor evoked potentials (MEPs) at a fixed stimulus intensity, cortical silent period, and a range of stimuli to generate stimulus response curves (SRCs).

The duration of each arm is up to 2.5 hours, and they will be separated by at least 1 week.

All participants will complete a questionnaire to assess any side effects (emotional and physical) following each rTMS session.

Enrollment: 20 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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 with known serious interactions with roflumilast (abametapir, apalutamide, dabrafenifb, enzalutamide, fexinidazole, idelalisib, ivosidenib, lonadarnib, ritonavir, secobarbital, tucatinib, and voxelotor).Intracranial metallic objects (dental hardware is not an exclusionary criterion)
10. Substance use disorder
11. The inability to refrain from alcohol use for 24 hours prior to stimulation

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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20 participants in 4 patient groups, including a placebo group

Intermittent Theta-Burst Stimulation with Placebo

Placebo Comparator group

Description:

Intermittent theta-burst stimulation delivered to the left primary motor cortex after the participant has ingested a placebo.

Treatment:

Device: Intermittent theta-burst stimulation transcranial magnetic stimulation

Drug: Placebo

Intermittent Theta-Burst Stimulation with Roflumilast

Experimental group

Description:

Intermittent theta-burst stimulation delivered to the left primary motor cortex after the participant has ingested roflumilast 500mcg.

Treatment:

Device: Intermittent theta-burst stimulation transcranial magnetic stimulation

Drug: Roflumilast

Continuous Theta-Burst Stimulation with Placebo

Placebo Comparator group

Description:

Continuous theta-burst stimulation delivered to the left primary motor cortex after the participant has ingested a placebo.

Treatment:

Device: Continuous theta-burst stimulation transcranial magnetic stimulation

Drug: Placebo

Continuous Theta-Burst Stimulation with Roflumilast

Experimental group

Description:

Continuous theta-burst stimulation delivered to the left primary motor cortex after the participant has ingested roflumilast 500mcg.

Treatment:

Device: Continuous theta-burst stimulation transcranial magnetic stimulation

Drug: Roflumilast