D-Cycloserine+iTBS PK Study

NCT05731323 | Completed Phase 1 FDA Drug FDA Device

• 1 other identifier: REB22-0547
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Background \& Rationale: Major Depressive Disorder (MDD) is a common and debilitating illness that that commonly does not respond to conventional treatments. Transcranial magnetic stimulation (TMS) and intermittent theta-burst stimulation (iTBS) are non-invasive neurostimulation treatments for depression that are Health Canada approved. These work by generating magnetic fields outside of the body to change the activity of brain cells to change how the brain works. They have a very favorable profile, with many patients experiencing improvement with minimal side effects. The investigators recently completed a study pairing iTBS with an FDA approved medication that was chosen because it might enhance iTBS improvements. This medication is called D-cycloserine, an old antibiotic that is rarely used in modern times. Years after it stopped being useful as an antibiotic, scientists recognized other properties that the molecule has, and it is some of these that make it interesting to pair with iTBS. When the investigators did so, they found that compared to iTBS with a placebo, participants who received iTBS+D-cycloserine were more likely to benefit from treatment. In this original study, all participants received a fixed dose of 100mg daily. This means that people of very different sizes could have had different drug levels, and the investigators do not know how that impacted outcomes. With this study, there will be no placebo condition because the purpose is to understand whether dosing according to weight matters. Research Question and Objectives: To describe the pharmacokinetic profile of 100mg oral D-cycloserine and weight-based oral D-cycloserine dosed 25mg/17.5kg among individuals with depression undergoing non-invasive intermittent theta-burst stimulation to the left dorsolateral prefrontal cortex (DLPFC) in Major Depressive Disorder.

Conditions

Major Depressive Disorder

Outcome Measures

Primary Outcomes (5)

• Montgomery-Asberg Depression Rating Scale (MADRS)

  Change in severity of depressive symptoms as measured by the MADRS, a clinician-rated instrument. The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes. The overall score ranges from 0 - 60. Cutoff points are 0-6 = normal, 7-9 = mild depression, 20-34 = moderate depression, \>34 = severe depression.

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

• Individual differences in D-cycloserine serum concentration will be correlated with clinical outcomes

  Examine whether differential change in clinical outcomes will be mediated by D-Cycloserine plasma levels following weight-based dosing. Participants will provide 10 blood samples to characterize plasma levels of D-Cycloserine following a weight-based dose. The primary efficacy measures will be examined in relation to drug blood levels.

  10 blood samples: PK curve over the first 2 days of TMS treatment (6 draws) and prior to ingestion and after 120 minutes on day 5 and day 6

• Individual fidelity to the protocol will be correlated with differential change in primary outcomes

  All participants will be instructed to take the blinded capsule 90 - 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 90 - 120 minutes prior).

  Daily Monday-Friday throughout study (4 weeks)

• The variance in D-cycloserine level will be greater in the 100mg dosing condition than in the weight-based dosing condition.

  The maximum serum concentration of D-cycloserine in blood serum will be measured by taking blood samples at various timepoints following oral D-cycloserine. Maximum serum concentration following 100mg oral D-cycloserine and weight-based oral D-cycloserine (dosed 25mg/17.5kg) will be compared. Blood samples will be drawn at baseline (pre-ingestion), +30 minutes, +60 minutes, +90 minutes and +24hours after a uniform dosing of 100mg of D-cycloserine and after a weight-based dosing of 25mg D-cycloserine per 17.5kg of body weight.

  PK curve done at baseline (fixed dose) and Day 1 of TMS (weight-based dose). Samples at pre-ingestion, +30 minutes, +60 minutes, +90 minutes, +120 minutes, and +24hours.

• Determine whether blood serum levels of D-cycloserine achieved by weight-based dosing is consistent across time.

  Serum concentrations of weight-based oral D-cycloserine (dosed 25mg/17.5kg body weight) will be described by collecting blood samples 120 minutes after ingestion of the first, fifth and sixth dose.

  Day 1 of TMS, Day 5 of TMS, and Day 6 of TMS.

Secondary Outcomes (14)

• Number of participants that achieve clinical remission of depression

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

• Number of participants that achieve clinical response (>=50% improvement in depression)

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

• Changes in self-reported depression as measured by the Quick Inventory of Depressive Symptoms (QIDS-SR)

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

• Changes in self-reported anxiety as measured by the Generalized Anxiety Disorder (GAD-7) questionnaire

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

• Change in suicidal intentions

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

Other Outcomes (17)

• Side Effects

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

• Incidence of Treatment-Emergent Adverse Events

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

• Safety hypothesis: There will be no clinically significant changes in bloodwork; Sodium level

  Baseline and after rTMS treatment (week 4)

Study Arms (1)

D-Cycloserine

EXPERIMENTAL

Prior to initiating TMS therapy, participants will orally ingest a capsule containing 100mg of the antibiotic d-cycloserine. During TMS therapy, participants will orally ingest a capsule containing a weight-based dose of the antibiotic d-cycloserine (dosed 25mg/17.5kg body weight) daily (Monday-Friday) for 4 weeks of rTMS treatment (20 sessions).

Drug: D-cycloserine; Device: Transcranial Magnetic Stimulator

Interventions

D-cycloserine DRUG

Daily oral D-cycloserine dosed 25mg/17.5kg body weight during TMS treatment days (20 days).

Also known as: Seromycin

D-Cycloserine

Transcranial Magnetic Stimulator 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

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• 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 confirmed diagnosis of DSM-5 criteria Major Depressive Disorder with a current episode of at least moderate severity of depression, single or recurrent
• have failed to achieve a clinical response to one adequate trial of antidepressant medication within the current episode, or been unable to tolerate antidepressant medications.
• have current episode of at least moderate severity of depression, as defined by a score ≥ 18 on the HAMD-17 item
• 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) questionnaire
• have had blood work (complete blood count, electrolytes, BUN, creatinine, eGFR, AST, ALT and GGT, and ECG) within the reference range. Female participants must have a negative pregnancy test.

You may not qualify if:

• Allergy to cycloserine.
• have failed adequate trials of ≥4 antidepressant treatments in the current episode.
• have an alcohol or substance use disorder within the last 3 months
• have suicidal ideation (score of 4 ≥ on item 10 of MADRS)
• 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 over the duration of the study
• have a diagnosis of other primary psychiatric diagnoses as assessed by a study investigator to be primary and causing greater impairment than Major Depressive Disorder.
• history of non-response to TMS 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) taking any benzodiazepine, cyclopyrrolone, gabapentin/pregabalin or anticonvulsant due to the potential to limit TMS efficacy

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

University of Calgary

Calgary, Alberta, T2N 1N4, Canada

Location

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Cycloserine

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

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 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2022
• First Posted: February 16, 2023
• Study Start: October 12, 2022
• Primary Completion: June 22, 2023
• Study Completion: June 22, 2023
• Last Updated: September 11, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)