Clinical trial NCT05395494: iTBS-DCS in Fibromyalgia
Official title: A Randomized Controlled Trial of Adjunctive D-Cycloserine to Intermittent Theta-burst Stimulation Transcranial Magnetic Stimulation in Fibromyalgia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Fibromyalgia
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2022-05-27
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Revised Fibromyalgia Impact Questionnaire (FIQR)
timeFrame: Administered at baseline, at the halfway point (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Sustained changes in Revised Fibromyalgia Impact Questionnaire (FIQR)
timeFrame: Administered at baseline, at the halfway point (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Differential change in the primary outcome will be mediated by D-Cycloserine plasma level
timeFrame: Single timepoint. First day of TMS treatment, 90 minutes after ingestion of blinded oral capsule.
measure: Differential change in the primary outcome will be mediated by fidelity to the protocol
timeFrame: Daily Monday-Friday throughout study (4 weeks)
Secondary outcomes:
measure: Change in Physical Function as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Anxiety as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Depression as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Fatigue as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Sleep Disturbances as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Social Function as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Pain Interference as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Pain Intensity as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in self-reported pain as measured by the Short-Form McGill Pain Questionnaire (SF-MPQ)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in self-reported pain as measured by the painDETECT scale.
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Central Sensitization Pain as measured by the The Central Sensitization Inventory (CSI)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in fibromyalgia severity as measured by the Polysymptomatic Distress Scale (PDS).
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Montgomery-Asberg Depression Rating Scale (MADRS)
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Number of participants with clinical depression remission
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Number of participants with clinical depression response
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Clinical Global Impression- Severity
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Clinical Global Impression- Improvement
timeFrame: Administered at baseline, halfway (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in self-reported depression as measured by the Quick Inventory of Depressive Symptoms (QIDS-SR)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in self-reported anxiety as measured by the Generalized Anxiety Disorder (GAD-7) questionnaire
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in self-reported depression and anxiety as measured by the The Hospital Anxiety and Depression Scale (HADS)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in sleep quality as measured by the The Insomnia Severity Index (ISI)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in general health as measured by a visual analog scale (VAS)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in quality of Life as measured by the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in fatigue symptoms as measured by the Chalder Fatigue Questionnaire
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in catastrophic thinking related to pain using the Pain Catastrophizing Questionnaire (PCQ)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in self-reported personality traits as measured by the Big Five Inventory (BFI)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in pain medication usage
timeFrame: Data will be collected at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in self reported cognitive failures as measured by The Cognitive Failures Questionnaire (CFQ)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in self reported cognitive function as measured by The Multidimensional Inventory of Subjective Cognitive Impairment (MISCI)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Perceived Deficits Questionnaire - 5 item scale (PDQ-5)
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Choice Reaction Time
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Working Memory
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Digit Symbol Substitution
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Change in Cognitive Function - THINC-integrated tool (THINC-it)- Trail Making Test part B
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Implicit Suicidality
timeFrame: Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)
measure: Changes in inflammatory markers
timeFrame: Participants will provide a blood sample prior to TMS treatment (baseline) and after TMS treatment (Week 4)
measure: Change in functional Magnetic Resonance Imaging
timeFrame: MRI scan will be completed at baseline and week 4
measure: Fibro vs Healthy Control functional Magnetic Resonance Imaging
timeFrame: MRI scan will be completed at baseline
measure: Change in Magnetic Resonance (MR) spectroscopy
timeFrame: MRI scan will be completed at baseline and week 4
measure: Fibro vs Healthy Control Magnetic Resonance (MR) spectroscopy
timeFrame: MRI scan will be completed at baseline
measure: Neuromelanin
timeFrame: MRI scan will be completed at baseline
measure: Quantitative Sensory Testing (QST) - Pain pressure thresholds via Algometry
timeFrame: QST will be completed at baseline and week 4
measure: Quantitative Sensory Testing (QST) - Central sensitization via Temporal summation
timeFrame: QST will be completed at baseline and week 4
measure: Quantitative Sensory Testing (QST) - Conditioned pain modulation via cold-pressor conditioning
timeFrame: QST will be completed at baseline and week 4
measure: Quantitative Sensory Testing (QST) - cold-pressor tolerance testing
timeFrame: QST will be completed at baseline and week 4
Other outcomes:
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: Daily Monday-Friday throughout study (4 weeks) and at one month follow up
measure: Side Effects
timeFrame: The TSES will be administered at baseline, Week 2, Week 4, and at follow up (week 8)
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
Study officials:
affiliation: University of Calgary
name: Alexander McGirr, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: