iTBS-DCS in Fibromyalgia

University of Calgary

Status and phase: Active, not recruiting; Phase 2

Conditions: Fibromyalgia

Treatments: Drug: Placebo oral tablet; Drug: D-Cycloserine; Device: iTBS repetitive Transcranial Magnetic Stimulation (rTMS)

Study type: Interventional

Funder types: Other

Identifiers

NCT05395494

REB21-1916

Details and patient eligibility

About

Background & Rationale: Fibromyalgia is characterized by widespread pain, fatigue, mood and anxiety as well as cognitive complaints. For an unacceptable proportion of patients, depressive symptoms remain impairing despite multiple treatments.

For such patients, novel treatments include non-invasive brain stimulation. Transcranial Magnetic Stimulation (TMS) targeting the dorsolateral prefrontal cortex (DLPFC) or the primary motor cortex (M1) is the non-invasive neurostimulation method with the largest evidence base in fibromyalgia. It involves generating magnetic fields outside of the body to change the firing of neurons in the brain, and has a very favorable tolerability profile. Recent meta-analyses indicate that both the DLPFC and M1 targets are associated with improvements in pain, mood and anxiety, however the benefits are more persistent when the DLPFC is targeted (Su et al, 2021 - J Clin Med). The DLPFC is important in fibromyalgia through its implication in several symptoms domains in fibromyalgia, as well as pain catastrophization.

The researchers neurophysiological data and clinical data in depression suggests that the researchers can enhance the effects of TMS by using an adjunctive medication called D-Cycloserine (DCS, 100mg) in conjunction with a protocol called intermittent theta-burst stimulation (iTBS). Specifically, this data indicated that several converging features of fibromyalgia improve with augmented iTBS, specifically depressive symptoms, anxiety symptoms, fatigue, and cognitive function. The researchers therefore hypothesize that the combination of D-cycloserine and TMS will lead to greater improvements in fibromyalgia symptoms than TMS alone.

Although iTBS has not yet been studied in fibromyalgia, it has a well characterized neurophysiological effect and been shown to be non-inferior to conventional TMS protocols in conditions such as depression. More importantly, its physiological basis can be manipulated with D-Cycloserine whereas this has not been convincingly demonstrated with rTMS (see Brown et al, 2019, 2021 Brain Stim).

Research Question and Objectives: To conduct a randomized placebo-controlled trial of DCS in adjunct with rTMS in Fibromyalgia. Participants will be randomized to receive 100mg of DCS or placebo together with TMS.

Full description

Methods: 90participants (males and females aged aged 18-65, with a diagnosis of fibromyalgia of at least moderate moderate impact as defined by a FIQR score of ≥39, stable psychotropic medication for 4 weeks) will be recruited. Patients will be randomized 1:1 to TMS+DCS or TMS+Placebo. Participants who do not have recent bloodwork will have laboratory tests to rule out haematological, hepatic, and renal disease, and participants will be screened for suicidal ideation. The dose of DCS will be 100mg, taken daily for four weeks. Clinical outcomes will be quantified using the Revised Fibromyalgia Impact Questionnaire (FIQR), as well as clinical and self reported measures of depression, anxiety, and quality of life done at baseline, halfway through TMS treatment (week 2), and after TMS treatment (week 4). Participants clinical symptoms will be evaluated again one-month after treatment (week 8). Quantitative sensory testing done at baseline and week 4 will characterize sensory perception. Blood samples at baseline and week 4 will be used to analyze changes in pro-inflammatory markers. Changes in cognition will be assessed by cognitive testing at baseline, week 4, and week 8. MRI scans completed at baseline and week 4. MRI scans at baseline and week 4 will be used to assess the following neuroimaging outcomes: single voxel magnetic resonance spectroscopy, locus coeruleus neuromelanin, and functional MRI resting state connectivity.

In parallel, a matched sample of 90 healthy participants will be cross-sectionally characterized for normative comparison, and these participants will not go on to receive any TMS or other interventions. Having this sample of healthy participants will allow the researchers to determine the clinical, cognitive, sensory, and imaging characteristics that characterize fibromyalgia. They will also allow the researchers to determine whether treatment effects restore clinical, cognitive, sensory, and imaging characteristics to the level of healthy controls.

Enrollment: 90 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

1. Males and females aged 18 to 65 years
2. are competent to consent to treatment
3. have a diagnosis of fibromyalgia as per the American College of Rheumatology 2016 fibromyalgia criteria.
4. have failed to achieve a clinical response to an adequate trial of a serotonin reuptake inhibitor, a norepinephrine reuptake inhibitor, cognitive behavioral therapy or have been unable to tolerate these medications/access psychotherapy.
5. have a score ≥ 41 on the FIQR.
6. have had no change in dose, or initiation of any psychotropic medication in the 4 weeks prior to randomization
7. are able to adhere to the treatment schedule
8. pass the TMS adult safety screening (TASS) and MRI screening questionnaire
9. have had blood work within the last month (complete blood count, electrolytes, BUN, creatinine, eGFR, AST, ALT and GGT) within the reference range.

Exclusion criteria

1. Allergy to cycloserine or any excipients.
2. have an alcohol or substance use disorder within the last 3 months
3. have suicidal ideation (score of 4 ≥ on item 10 of MADRS or positive response to item 4 on the CSSRS-screen)
4. are at a significant risk of harm to themselves or others
5. current symptoms of psychosis
6. history of psychosis
7. are currently pregnant, breast feeding or plan to become pregnant. Health Canada requires that women of reproductive potential utilize either highly effective birth control or double barrier method of contraception. Abstinence is only acceptable when it is the usual and preferred lifestyle of the participant.
8. history of non-response to rTMS treatment.
9. have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space occupying brain lesion, any history of epilepsy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than or equal to 5 minutes
10. have concomitant major unstable medical illness, cardiac pacemaker, or implanted medication pump
11. have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed
12. If participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study
13. are currently (or in the last 4 weeks) not taking any benzodiazepine, cyclopyrrolone, gabapentin/pregabalin or anticonvulsant due to the potential to limit iTBS efficacy
14. are being currently treated with ethionamide or isoniazid

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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90 participants in 2 patient groups, including a placebo group

D-Cycloserine

Experimental group

Description:

Participants will orally ingest a capsule containing 100mg of the antibiotic d-cycloserine daily (Monday-Friday) during 4 weeks of rTMS treatment (20 sessions) 60-120 minutes prior to rTMS treatment.

Treatment:

Device: iTBS repetitive Transcranial Magnetic Stimulation (rTMS)

Drug: D-Cycloserine

Placebo

Placebo Comparator group

Description:

Participants will orally ingest a capsule identical to that containing the study medication, however this capsule will contain a placebo. They will ingest this capsule daily (Monday-Friday) for 4 weeks of rTMS treatment (20 sessions) 60 - 120 minutes prior to rTMS treatment.

Treatment:

Drug: Placebo oral tablet

Device: iTBS repetitive Transcranial Magnetic Stimulation (rTMS)