Clinical trial NCT06457191: Roflumilast and TMS Motor Plasticity
Official title: PDE4 Inhibition and Theta-burst Stimulation Transcranial Magnetic Stimulation Motor Plasticity: a Randomized Placebo-controlled Single-blind Crossover Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Other Conditions of Brain
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2024-06-13
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Motor evoked potential amplitude
timeFrame: -5 minutes, -10minutes, -5 minutes, and immediately prior to theta-burst stimulation, then +5 minutes, +10 minutes, +15 minutes, +20 minutes, +25 minutes, +30 minutes, +45 minutes and +60 minutes after theta-burst stimulation.
Secondary outcomes:
measure: Motor evoked potential stimulus response curve
timeFrame: Baseline, 30 minutes following theta-burst stimulation, 60 minutes following theta-burst stimulation.
measure: Cortical silent period
timeFrame: Baseline, 30 minutes following theta-burst stimulation, 60 minutes following theta-burst stimulation.
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
Study officials:
References: