Double-Blind, Proof-of-Concept (POC) Trial of Low Field Magnetic Stimulation (LFMS) Augmentation of Antidepressant Therapy in Treatment-Resistant Depression (TRD)
This is a six-site, double-blind, sham-controlled, sequential parallel comparison design (SCPD) study of the acute efficacy of LFMS in the treatment of adults with MDD with TRD, to be carried in the six proposed core RaPiD sites. eligible subjects will be randomly assigned to double-blind treatment with LFMS 20 min/day for four days, sham treatment 20 min/day for four days, or sham 20 min/day for 2 days followed by LFMS treatment 20 min/day for two days, using the SPCD (randomization 1:1:1). SPCD reduces the detrimental impact of high placebo response. Therefore, in comparison to a conventional trial design with a specified sample size n, use of SPCD with the same n can increase the power of a trial, by approximately 10-25 percentage points.
Study participants will be consented prior to the administration of any procedure or wash-out. Following a washout period for those subjects on concomitant medications that are not allowed in the study, under the close supervision and monitoring of the study clinicians, for patients on psychotropic drugs except for antidepressants and stable hypnotic therapy, baseline assessment, and re-confirmation that they meet all criteria for entry into the study, eligible subjects will be randomly assigned to receive LFMS or sham treatment.
in accordance with the SCPD, the 5-day, double-blind treatment will be divided into two phases of 48 hours each, with assessments performed every day to assess the safety and efficacy of LFMS compared to sham therapy in depressed patients who have demonstrated an inadequate response from one to three antidepressant Therapies (aDTs).
The study will consist of a screening period and a randomization period. Patients who meet eligibility during the screening period will be randomized according to the SCPD to double-blind treatment with LFMS 20 min/day for 4 consecutive days (n[?]20) (active-active sequence or aa), with sham therapy 20 min/day for 2 consecutive days and with LFMS 20 min/day for the following 2 consecutive days (n[?]20) (sham-active sequence or Sa), or with sham therapy 20 min/day for 4 consecutive days (n[?]20) (sham-sham sequence or SS). The design will involve a 1:1:1 ratio for random assignment to the treatment sequences active/active (aa), sham/active (Sa), and sham/sham (SS).
active or sham (according to the randomization sequence) Low-Field Magnetic Stimulation (LFMS) treatment will be delivered to the study subjects through a device (see below) requiring the subject to lay flat on a bed for 20 minutes during each treatment session. The devices are provided at no cost to the study by Tal Medical. Training and calibration of each device will be provided by Tal Medical.
The device software currently enables double blind randomization so that the person performing the treatment simply presses the start button and is not aware if sham or active treatment is being performed, in order to create a true double-blind study. There is no physical sensation, and only a low volume noise created by the coil itself. This audible noise is recreated by an audio speaker inside of the coil housing in the sham condition to effectively blind the patient and operator (although the operator will likely not be able to hear the noise at all depending on the background noise). The operator puts in a unique patient code and the software has a randomization table (loaded prior to study initiation) which then outputs either an active or sham treatment signal. Following the administration of the treatment on Day 0, the operator will be asked to guess whether the treatment delivered was active or sham.
in the event of a medical emergency, study clinicians at the site will have access to the randomization code for the patient involved.
1. Male or female, 18 to 65 years of age, inclusive, at screening.
2. Participants are able to read, understand, and provide written, dated informed consent prior to screening. Participants will be deemed likely to comply with study protocol and communicate with study personnel about adverse events and other clinically important information.
3. A participant must be diagnosed with MDD, single or recurrent, and currently experiencing a Major Depressive Episode (MDE) of at least eight weeks in duration, prior to screening, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, fourth Edition, Text Revision (DSM-IV-TR(TM)). The diagnosis of MDD will be made by a site psychiatrist and supported by the Structured Clinical Interview for DSM-IV Axis I Disorders - Patient Edition (SCID-I/P).The diagnosis will be confirmed by remote, independent MGH CTNI raters who will administer the mood disorder module of the SCID-I/P, via teleconference, between the screen visit and the baseline visit.
4. A participant has TRD of the current MDE, as assessed by the investigator and remote, independent MGH CTNI rater using the MGH Antidepressant Treatment Response Questionnaire (ATRQ). TRD is defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms), as perceived by the participant, to at least one
* treatment course
* of a therapeutic dose of an antidepressant therapy of at least 8 weeks duration. The adequacy of dose and duration of the antidepressant therapy will be determined as per the MGH ATRQ criteria. The TRD status will be confirmed by remote, independent MGH CTNI raters who will administer the MGH ATRQ, via teleconference, between the screen visit and the baseline visit. Participants must be currently on a stable (for at least 4 weeks) dose of ongoing antidepressant therapy, whose total duration must be at least 8 weeks.
5. Participants will meet the threshold on the total MADRS score of >20 for moderate to severe depression at both the screen visit and the baseline visit (Day -7/14 and Day 0), as confirmed by the remote, independent MGH CTNI rater between the screen visit and the baseline visit.
6. Good general health as ascertained by medical history, physical examination (PE) (including measurement of supine and standing vital signs), clinical laboratory evaluations, and 12-lead electrocardiogram (ECG).
7. For female participants, status of non-childbearing potential or use of an acceptable form of birth control per the following specific criteria:
a. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant, i.e., permanently sterilized (status post hysterectomy, bilateral tubal ligation), or is post-menopausal with her last menses at least one year prior to screening); or
b. Childbearing potential, and meets the following criteria:
i. Childbearing potential, including women using any form of hormonal birth control, on hormone replacement therapy started prior to 12 months of amenorrhea, having a monogamous relationship with a partner who has had a vasectomy, or is sexually abstinent.
ii. Negative urinary pregnancy test at screening, confirmed by a negative urinary pregnancy test at randomization prior to receiving study treatment.
iii. Willing and able to continuously use one of the following methods of birth control during the course of the study, defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectable or patch hormonal contraception, oral contraceptives, double-barrier contraception, sexual abstinence. Form of birth control will be documented at screening and baseline.
8. Body mass index between 18-40 kg/m2.
9. Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive behavioral, insight-oriented) and frequency (e.g., weekly, monthly) of the therapy has been stable for at least three months prior to screening and if the type and frequency of the therapy is expected to remain stable during the course of the subject[Single Quote]s participation in the study.
10. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, eszopiclone, benzodiazepine hypnotics, and low-dose trazodone) will be allowed if the therapy has been stable for at least 4 weeks prior to screening and if it is expected to remain stable during the course of the subject[Single Quote]s participation in the study.