iTBS-DCS in Fibromyalgia

NCT05395494 | Terminated Phase 2 FDA Drug FDA Device

• 1 other identifier: REB21-1916
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

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.

Conditions

Fibromyalgia

Outcome Measures

Primary Outcomes (4)

• Revised Fibromyalgia Impact Questionnaire (FIQR)

  Change in severity of the impact of fibromyalgia as measured by the Revised Fibromyalgia Impact Questionnaire (FIQR). The FIQR is a self-administered questionnaire commonly used to evaluate fibromyalgia across 3 domains: function, overall impact and symptoms. The FIQR consists of 21 individual questions, each with a rating scale of 0 (no impact) -10 (maximum impact).

  Administered at baseline, at the halfway point (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)

• Sustained changes in Revised Fibromyalgia Impact Questionnaire (FIQR)

  Differences in sustained treatment effects between iTBS+cycloserine and iTBS+placebo groups as measured by Revised Fibromyalgia Impact Questionnaire (FIQR) changes one month after treatment end. The FIQR is a self-administered questionnaire commonly used to evaluate fibromyalgia across 3 domains: function, overall impact and symptoms. The FIQR consists of 21 individual questions, each with a rating scale of 0 (no impact) -10 (maximum impact).

  Administered at baseline, at the halfway point (week 2), after rTMS treatment (week 4), and at one month follow up (week 8)

• Differential change in the primary outcome will be mediated by D-Cycloserine plasma level

  Participants will provide a blood sample prior to the first TMS treatment (90 minutes after ingestion of blinded oral capsule) to characterize D-Cycloserine plasma levels. The primary efficacy measures will be examined in relation to drug blood levels.

  Single timepoint. First day of TMS treatment, 90 minutes after ingestion of blinded oral capsule.

• Differential change in the primary outcome will be mediated by fidelity to the protocol

  All participants will be instructed to take the blinded capsule 60 - 120 minutes prior to TMS treatment, ensuring adequate time for drug absorption. Daily logs will be kept by the study staff to confirm time of capsule ingestion and TMS treatment. Any TMS sessions missed, capsule doses missed and/or capsule doses taken at the incorrect time will be tracked. The primary efficacy measures will be examined in relation to adherence to the protocol (20/20 TMS session completed with oral capsule taken between 60 - 120 minutes prior).

  Daily Monday-Friday throughout study (4 weeks)

Secondary Outcomes (45)

• Change in Physical Function as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)

  Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)

• Change in Anxiety as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)

  Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)

• Change in Depression as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)

  Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)

• Change in Fatigue as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)

  Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)

• Change in Sleep Disturbances as measured by the Patient Reported Outcomes Measurement Information System (PROMIS-29)

  Administered at baseline, after rTMS treatment (week 4), and at one month follow up (week 8)

Other Outcomes (2)

• Incidence of Treatment-Emergent Adverse Events

  Daily Monday-Friday throughout study (4 weeks) and at one month follow up

• Side Effects

  The TSES will be administered at baseline, Week 2, Week 4, and at follow up (week 8)

Study Arms (2)

D-Cycloserine

EXPERIMENTAL

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.

Drug: D-Cycloserine; Device: iTBS repetitive Transcranial Magnetic Stimulation (rTMS)

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo oral tablet; Device: iTBS repetitive Transcranial Magnetic Stimulation (rTMS)

Interventions

D-Cycloserine DRUG

Daily oral D-cycloserine 100mg during TMS treatments (20 days). Other Names: Seromycin

Also known as: Seromycin

D-Cycloserine

Placebo oral tablet DRUG

Daily oral placebo during the TMS treatments (20 days).

Placebo

iTBS repetitive Transcranial Magnetic Stimulation (rTMS) DEVICE

Repetitive Transcranial magnetic stimulation (rTMS) will be delivered using a MagPro X100 device with B70 coil and the intermittent theta burst (iTBS) protocol to the left dorsolateral prefrontal cortex. Participants will receive daily treatments (Monday-Friday) over four weeks.

D-Cycloserine; Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females aged 18 to 65 years
• are competent to consent to treatment
• have a diagnosis of fibromyalgia as per the American College of Rheumatology 2016 fibromyalgia criteria.
• 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.
• have a score ≥ 41 on the FIQR.
• have had no change in dose, or initiation of any psychotropic medication in the 4 weeks prior to randomization
• are able to adhere to the treatment schedule
• pass the TMS adult safety screening (TASS) and MRI screening questionnaire
• have had blood work within the last month (complete blood count, electrolytes, BUN, creatinine, eGFR, AST, ALT and GGT) within the reference range.

You may not qualify if:

• Allergy to cycloserine or any excipients.
• have an alcohol or substance use disorder within the last 3 months
• have suicidal ideation (score of 4 ≥ on item 10 of MADRS or positive response to item 4 on the CSSRS-screen)
• are at a significant risk of harm to themselves or others
• current symptoms of psychosis
• history of psychosis
• 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.
• history of non-response to rTMS treatment.
• 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
• have concomitant major unstable medical illness, cardiac pacemaker, or implanted medication pump
• 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
• 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
• 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
• are being currently treated with ethionamide or isoniazid

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

University of Calgary

Calgary, Alberta, T2N 1N4, Canada

Location

MeSH Terms

Conditions

Fibromyalgia

Interventions

Cycloserine

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Alexander McGirr, MD, PhD

  University of Calgary

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2022
• First Posted: May 27, 2022
• Study Start: August 29, 2022
• Primary Completion: July 31, 2025
• Study Completion: July 31, 2025
• Last Updated: August 17, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)