Empower: Transcranial Direct Current Stimulation in Major Depressive Disorder: a Double-blind, Placebo-controlled, Randomized, Superiority Trial
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Flow Neuroscience AB

Clinical Study Protocol
s
1
TITLE PAGE
TRANSCRANIAL DIRECT CURRENT STIMULATION IN MAJOR DEPRESSIVE DISORDER: A DOUBLE-BLIND,
PLACEBO-CONTROLLED, RANDOMIZED, SUPERIORITY TRIAL
Protocol Number: FL001
Version: 9
Date: 10Jan2023
Sponsor:
Flow Neuroscience AB
Södra Förstadsgatan 2, 211 43 Malmö
Phone: +46736607170
Sponsor Contact:
Erik Rehn
Chief Technology Officer & Co-Founder
Email: erik@flowneuroscience.com
Phone: +46736607170
This document contains confidential information for use only by investigators participating in the clinical
investigation. This document should be maintained in a secure location and should not be copied or made
available for review by unauthorized personnel.
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2
REVISION HISTORY
Version
Date
Summary of Changes
1.0
10 Nov 2021
First Version for IDE submission
2
26 Nov 2021
-
Removed upper age limit.
-
MADRS-s of 20 or above added to inclusion criteria.
-
Improved references.
-
Clarified that the participants must be living in England,
Wales or Texas.
-
Added optional early termination visit.
2
13 Dec 2021
Incorporation of FDA comments from IDE application
SDMT baseline moved to week 0 visit.
2
05 Jan 2022
- Change to PHQ-9 form MADRS-s for the first screening
assessment after consent.
- PHQ-9 of 10 points or above added to inclusion criteria.
- MADRS-s of 20 or above removed from inclusion criteria.
3
19Feb2022
- Inclusion criteria 12 update age to ≥age 18
- Exclusion criteria 28 updated to: Are a chronic tobacco
smoker, as defined by smoking by smoking >100 cigarettes
(including hand-rolled cigarettes, cigars, cigarillos, etc.) in their
life-time and have smoked every day for the last 7 days.
4
23Feb2022
- Updated exclusion criteria 31 to: Are participating concurrently
in another clinical investigation or have participated in a clinical
investigation within the last 90 days or intend to Participate in
another clinical investigation during the study, and where the
participation in the other investigation might interfere with the
results of this trial as deemed by the PI.
- Clarified that for inclusion criteria 11 the age is 18 for UK and
22 for the US.
5
16Mar2022
- Updated device traceability (section 8.3) to reflect that UK
participants are allowed to keep the device after trial
completion.
6
04Apr2022
- Removed PHQ-9 from screening.
- Clarified which AEs will be followed-up in more detail.
Anticipated AEs will be recorded using AEQ.
- Moved some sections regarding how missing data is handled
in the statistical analysis plan to a new document (Statistical
analysis plan - FL001).
- Site staff will consent subjects not Curebase staff.
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31Aug2022
- Clarified insomnia & sleep apnea as an exclusion criteria,
added eating disorders.
- Changed some excl. criteria based comorbidities to not be
life-long.
- Clarified primary endpoint as requested by FDA IDE feedback.
8
07Dec2022
-
Added reference to adaptive design report (22.15)
-
Updated primary endpoint formulation again as
requested by the FDA.
-
EQ-5D-3L is now a secondary endpoint as requested by
the FDA.
-
Added within-patient clinically meaningful change
exploratory endpoint.
-
Added clarification of when the randomization happens
(22.4)
-
Added section 13.4 describing routines regarding video
calls, as requested by the FDA.
9
10Jan2023
-
Removed need for CRO representative to sign this
protocol since they are not involved in the development
of this protocol.
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Clinical Study Protocol
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PROTOCOL APPROVAL SIGNATURE PAGE
Protocol Number: FL001
Protocol Version: 9
Protocol Date: 10Jan2023
Protocol Name: Transcranial Direct Current Stimulation in Major Depressive Disorder: A
Double-blind, Placebo-controlled, Randomized, Superiority Trial
This protocol has been read and approved by:
SPONSOR:
Erik Rehn
Chief Technology Officer & Co-Founder
Flow Neuroscience AB
Signature & Date:
______________________________
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INVESTIGATOR PROTOCOL SIGNATURE PAGE
The signature below documents the receipt and review of the Study Protocol and any attachments and
provides the necessary assurances that this study will be conducted according to all stipulations of the
protocol, including all statements regarding confidentiality, and according to the local legal and regulatory
requirements and applicable United States Federal Regulations, ISO 14155:2020, ICH and GCP guidelines,
and the latest version of the Declaration of Helsinki.
I have read and understand this protocol and will conduct the study in accordance with this protocol, all
attachments and amendments, applicable Food and Drug Administration regulations, HIPAA, IRB/EC
requirements, and the policies of the institutions where the study will take place.
In my formal capacity as Investigator, my duties include ensuring the safety of the study subjects enrolled
under my supervision and providing Flow Neuroscience AB with complete and timely information, as outlined
in the protocol. It is understood that all information pertaining to the study will be held strictly
Protocol Number: FL001
Protocol Version: 9
Protocol Date: 10jan2023
Protocol Name: Transcranial Direct Current Stimulation in Major Depressive Disorder: A Double-blind,
Placebo-controlled, Randomized, Superiority Trial
Investigator:
(Print Name)
(Signature)
Date (dd/mmm/yyyy)
Sponsor Representative Name
_______________________________________________________________________
Sponsor Signature
Date (dd/mmm/yyyy)
Legal Representative Name
______________________________________________________________________________
Legal Representative Signature
Date (dd/mmm/yyyy)
Upon signing, send a copy of this page to Curebase and retain a copy for your files.
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TABLE OF CONTENTS
1 TITLE PAGE
1
2 REVISION HISTORY
2
3 PROTOCOL APPROVAL SIGNATURE PAGE
4
4 INVESTIGATOR PROTOCOL SIGNATURE PAGE
5
5 LIST OF ABBREVIATIONS
10
6 Study Summary
12
7 Schedule of Procedures
19
8 Introduction
21
8.1 Background
21
8.1.1 Major Depressive Disorder (MDD)
21
8.1.2 MDD Diagnosis
21
8.1.3 Other Treatment Options
21
8.1.3.1 Antidepressants
21
8.1.3.2 Psychological Treatments
23
8.1.3.3 Electroconvulsive Therapy (ECT)
23
8.1.3.4 Transcranial Magnetic Stimulation (TMS)
24
8.1.3.5 Cranial Electrotherapy Stimulation (CES)
24
8.1.3.6 Transcranial Direct Current Stimulation (tDCS)
24
8.2 Investigational Device
25
8.2.1 Flow FL-100
25
8.2.2 The Flow app
26
8.3 Device Traceability
28
8.4 Supply and Accountability of Investigational Devices
29
8.5 Device Use Experience and Training
29
9 Benefit-Risk Analysis
29
9.1 Risks
29
9.2 Risk Mitigation
30
9.2.1 Monitors
31
9.2.2 Stimulation Parameter Space
31
9.2.3 Usage Limits
31
9.3 Anticipated Benefits
31
9.4 Risk-to-Benefit Ratio
31
10 Study Objectives
31
10.1 Background
31
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10.2 Primary Objective
32
11 Study Design
32
11.1 Study Duration
32
11.2 Treatment/Control Groups
32
11.3 Blinded phase
33
11.4 Open label phase
34
11.5 Primary Endpoints
34
11.6 Secondary Endpoints
34
11.7 Exploratory Endpoints
34
12 Selection of Study Population
35
12.1 Participant Recruitment
35
12.2 Inclusion Criteria
35
12.3 Exclusion Criteria
36
12.4 Study Enrollment Procedures
38
12.4.1 Participant Enrollment
38
12.5 Screen Failures
38
12.6 Participant Treatment Assignment
39
13 Study Procedures
39
13.1 Week -3 to -1: Informed Consent (ICF)
39
13.2 Week 0
40
13.3 Weeks 1, 4 & 7
40
13.4 Week 10
41
13.5 Week 20 Follow-Up Visit - Open-Label Only
41
13.6 Video calls
42
13.7 Late and Missed Visits
42
13.8 Unscheduled Visits
43
13.9 Study Completion/Discontinuation
43
14 Description of Study Procedures
43
15 Early Discontinuation: Participants
45
15.1 Technical Failures
45
15.2 Treatment Failures
45
15.3 Lost to Follow-Up (LTFU)
46
15.4 Withdrawals
46
15.5 Documentation of Early Discontinuation and Pregnancy
47
15.6 Use of Data from Early Discontinuation Cases
47
15.7 Ongoing Treatment for Early Discontinuation Cases
47
16 Early Discontinuation: Study
47
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16.1 Procedure for Suspension or Early Termination
47
16.2 Procedure for Resuming the Clinical Investigation After Temporary Suspension
48
16.3 Routine Close-Out
48
17 Protocol Deviations
48
18 Concomitant Medications/Therapies
49
19 Adverse Event & Device Deficiency Reporting
49
19.1 Definitions
50
19.2 Classification of an AE
52
19.2.1 Severity
52
19.2.2 Assessment of Relationship to Use of the Investigational Device or Procedure
52
19.2.3 SAE Relationship Assessment
52
19.2.4 SAE Reporting
54
19.2.5 Determination and Reporting of Unanticipated Adverse Device Effects (US Sites)
55
19.3 Treatment of AEs
55
19.4 Safety Oversight: Clinical Events Committee (CEC)
55
19.5 Safety/Suicide Risk Management Plan
55
20 Stopping rules
56
21 Clinical Monitoring
56
21.1 Site Monitoring
56
21.2 Monitoring Activities
57
21.3 Frequency of Visits
58
21.4 Audit and Inspections
58
22 Statistical analysis
59
22.1 Study Hypothesis
59
22.2 Sample Size Assumptions and Calculations
59
22.3 Study Populations
59
22.3.1 Intent-to-Treat Analysis Set (ITT)
59
22.3.2 As Treated Analysis Set (AT)
59
22.3.3 Modified Intent-to-Treat Analysis Set (mITT)
59
22.3.4 Per Protocol Analysis Set (PP)
60
22.4 Randomization
60
22.5 Testing of Primary Effectiveness Hypotheses
60
22.5.1 Multiple Imputation Analysis
61
22.6 Missing Data/Sensitivity Analysis
61
22.7 Covariates/Covariate Analysis
61
22.8 Secondary Effectiveness Endpoints
61
22.9 Exploratory Endpoints
62
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22.10 Multiplicity Adjustment
62
22.11 Evaluation of Blinding
63
22.12 Device Survival
63
22.13 Poolability Analysis
63
22.14 Safety Analyses
63
22.15 Interim Analyses
64
23 Ethics & Protection of Human Subjects
64
23.1 Ethical Review
64
23.2 Regulatory Considerations
64
23.3 Study Amendments
65
23.4 Insurance
65
24 Data Handling and Recordkeeping
65
24.1 EDC and eCRFs
65
24.2 Capture of patient reported outcomes
66
24.3 Study Records Retention
66
24.4 Publication and Data Sharing Policy
67
24.5 Participant and Data Confidentiality
67
24.6 Investigator Records
68
24.7 Participant Records
68
24.8 Investigator Records and Reports
68
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5
LIST OF ABBREVIATIONS
ADE
Adverse Device Effect
AE
Adverse Event
AEQ
tDCS Adverse Events Questionnaire
ATHF
Antidepressant Treatment History Form
ATT
Average Treatment effect on the Treated
CA
Competent Authority
CABG
Coronary Artery Bypass Graft
CDC
Center for Disease Control and Prevention
CEC
Clinical Events Committee
CES
Cranial Electrotherapy Stimulation
CFR
Code of Federal Regulations
CHF
Coronary Heart Failure
CMP
Clinical Monitoring Plan
CRO
Contract Research Organization
ClinRO
C-SSRS
DBS
Clinician Reported Outcome
Columbia Suicide Severity Rating Scale
Deep Brain Stimulation
DHHS
U.S. Department of Health and Human Services
DLPFC
Dorsolateral Prefrontal Cortex
DMP
Data Management Plan
EC
Ethics Committee
eCRF
Electronic Case Report Form
ECT
Electroconvulsive Therapy
EDC
Electronic Data Capture
EOB
Explanation of Benefits
FDA
U.S. Food and Drug Administration
GCP
Good Clinical Practice
HAM-A
Hamilton Anxiety Rating Scale
HDRS-17
Hamilton Depression Rating Score
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use
IDE
Investigational Device Exemption
IFU
Instructions for Use
iOS
iPhone Operating System
IRB
Institutional Review Board
ISF
Investigator Site File
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ITT
Intent-to-Treat
LB
Lower Bound
LTFU
Lost to Follow-Up
MADRS
Montgomery–Åsberg Depression Rating Scale
MADRS-s
Montgomery–Åsberg Depression Rating Scale - Self-report
MAOIs
Monoamine oxidase inhibitors
MDD
Major Depressive Disorder
MI
Multiple Imputation
MINI
Mini International Neuropsychiatric Interview
NASSA
Noradrenaline and Specific Serotonergic Antidepressant
mITT
Modified Intent to Treat
NRS
Numeric Rating Scale
NSAIDS
Nonsteroidal anti-inflammatory drugs
OCD
Obsessive-Compulsive Disorder
OHRP
U.S. Office of Human Research Protections
PMA
Premarket Approval
PP
Per-Protocol
PRO
Patient Reported Outcome
PS
Propensity Score
QOL
Quality of Life
RAVLT
Rey Auditory Verbal Learning Test
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SDMT
Symbol-Digit Modalities Test
SDW
Source Document Worksheet
SMD
Standardized Mean Differences
SNRI
Serotonin and Noradrenaline Reuptake Inhibitor
SOC
Standard of Care
SSRI
Selective Serotonin Reuptake Inhibitor
SOP
Standard Operating Procedure
TAQ
Treatment Acceptability Questionnaire
TCA
Tricyclic Antidepressant
tDCS
Transcranial Direct Current Stimulation
TEM
Treatment-Emergent Mania/hypomania
TMS
Transcranial Magnetic Stimulation
UADE
Unanticipated Adverse Device Effect
UB
Upper Bound
WHO
World Health Organization
YMRS
Young Mania Rating Scale
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STUDY SUMMARY
Study Full Title
Transcranial Direct Current Stimulation in Major Depressive
Disorder: A Double-blind, Placebo-controlled, Randomized,
Superiority Trial
Study Sponsor
Flow Neuroscience AB
Study Number
FL001
Device Name
Flow FL-100
Protocol Date
10Jan2023
STUDY OVERVIEW
Study Design
Double-blind, placebo-controlled, randomized, superiority,
remote.
Purpose
The purpose of this trial is to investigate the use of the Flow
FL-100 device at-home to treat Unipolar Major Depressive
Disorder (MDD) in a double-blind RCT.
Expected Study Duration
10 months
Evaluation Schedule
Participants will undergo evaluations at the following study
visits. Various evaluations regarding depression severity,
suicidal ideation will be performed (see Schedule of
Evaluations for more detail):
●
Pre-Treatment Phase
-
Week -3
-
Week -2
-
Week -1
●
Blinded Phase
-
Week 0
-
Week 1
-
Week 4
-
Week 7
-
Week 10
●
Open-Label Phase
-
Week 20
At week 0, 1, 4, 7, 10, 20, participants will also complete the
MADRS-s on their personal smartphone or other device
running Android 5.0+ or iPhone Operating System (iOS) 12+.
ELIGIBILITY CRITERIA
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Intended Participant
Population
Up to 270 participants will be randomized at 2 sites, one
located in the United Kingdom and the other in the United
States. The recruitment will be capped to 155 for each of the
sites.
1:1 randomization: Flow FL-100 vs. Sham
Diagnosis and Inclusion
Criteria
To be eligible to participate in this study, participants must
meet all the following criteria:
1.
Be ≥18 years.
2.
Have a diagnosis of Unipolar MDD with a current
depressive episode as defined by the diagnostic
criteria in the Diagnostic and statistical manual of
mental disorders – 5th edition (DSM-V)
3.
Have a Hamilton Depression Rating Score (HDRS-17)
of ≥16.
4.
For 6 weeks prior to enrollment, are either:
a.
not taking antidepressant medication or:
b.
are taking a stable antidepressant regimen
with a stable medication source and agree to
continue the same regimen throughout study
participation.
5.
If in psychotherapy, have maintained stable
psychotherapy for at least 6 weeks prior to enrollment.
6.
Have access to a stable internet connection through
which the treatment will be received.
7.
Have access to a smartphone or other device running
Android 5.0+ or iPhone Operating System (iOS) 12+
(e.g., reasonably new iPhone/iPad or Android phone),
used to using the device in their everyday life, and
can capably use the study application on the device,
as determined by the investigator.
8.
Are currently living in England/Wales (UK) or Texas
(US).
9.
Subject is currently under the care of a psychiatrist or
a primary care physician, agrees to be evaluated at
regular intervals by a psychiatrist or primary care
physician for the duration of study participation, and
agrees to promptly inform the study staff of any
change of psychiatric or mental health providers
during study participation.
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10. Subject agrees to allow any and all forms of
communication between the investigators/study staff
and any healthcare provider who currently provides
and/or has provided service to the patient/subject
within at least two years of study enrollment.
11. Subject agrees to provide the name and verifiable
contact information (email and mailing addresses,
mobile and land-line phone numbers, as applicable) of
at least two persons ≥age 18 (22 in the US) who
reside within a 60-minute drive of the patient’s
residence and whom the research staff is at liberty to
contact, as they deem necessary, for the duration of
study participation.
12. Be able to give voluntary, written informed consent to
participate and have signed an Informed Consent
Form specific to this study.
13. Be willing and able to comply with all study
procedures.
14. Subject agrees to meet all of the inclusion criteria
throughout their participation in the study. Otherwise,
the subject will be discontinued from the study.
15. Subject agrees to a Safety/Suicide Risk Management
Protocol, which is intended to reduce the reduce the
risk of suicide during study participation.
Exclusion Criteria
Participants who meet any of the following criteria will be
excluded from participating in this study:
1.
Are in a current state of mania, as determined by the
YMRS or psychosis, as determined by the MINI.
2.
Are diagnosed with vitamin or hormonal deficiencies
that may mimic mood disorders, as determined by the
investigator.
3.
Are currently receiving any other interventional
therapy for MDD other than a stable regimen of
antidepressants or psychotherapy as defined in the
inclusion criteria.
4.
Considered to have treatment resistant depression as
defined by inadequate clinical response to 2 or more
trials of antidepressants at an adequate dose and
duration.
5.
Have a history of electroconvulsive therapy (ECT),
transcranial magnetic stimulation (TMS), cranial
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electrotherapy stimulation (CES), transcranial direct
current stimulation (tDCS), deep brain stimulation
(DBS), or other brain stimulation.
6.
Patient answers Yes to Questions 4, 5 or 6 on the
Columbia Suicide Severity Rating Scale (C-SSRS)
Triage and Risk Identification Screener.
7.
Any previous hospitilization for suicidal behavior.
8.
Have chronic severe insomnia (< 4 hours of sleep
each night), or depression secondary to chronic
insomnia or sleep apnea.
9.
Have any structural lesion (e.g., any structural
neurological condition, or more subcortical lesions
than would be expected for age or have had a stroke
that affects stimulated area or connected areas) or
any other clinically significant abnormality that might
affect safety, study participation, or confound
interpretation of study results, as determined by the
investigator.
10. Have any implant in the brain (e.g., DBS) or
neurocranium, or any other active implantable medical
device.
11. Have any neurocranial defect.
12. Have a history of epilepsy or seizures (including
history of withdrawal / provoked seizures).
13. Have shrapnel or any ferromagnetic material in the
head.
14. Have any disorder that would impair the ability to
complete the study questionnaires.
15. Have been diagnosed with autism spectrum disorder.
16. Are actively abusing substances (<1 week prior to
enrollment).
17. Have a cognitive impairment (including dementia).
18. Have a history of mania or psychosis.
19. Are currently using any medications that affect cortical
excitability (e.g., benzodiazepines, epileptics, etc.).
20. Are currently experiencing symptoms of withdrawal
from alcohol or benzodiazepines.
21. Have been diagnosed with Parkinsonism or other
movement disorder as determined by the investigator
to interfere with treatment.
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22. Have ever taken esketamine / ketamine for treatment
of depression.
23. Have ever been admitted to hospital for depression.
24. Have ever been diagnosed with
obsessive-compulsive disorder (OCD) or bipolar type
1 or 2 disorder.
25. Is diagnosed with an active primary anxiety disorder,
or PTSD, agoraphobia, anorexia or bulimia, panic or
personality disorder with active symptoms.
26. Have a history of psychosurgery for depression.
27. Have any history of myocardial infarction, coronary
artery bypass graft (CABG), coronary heart failure
(CHF), or history of other cardiac issues.
28. Are currently experiencing or have a history of
intractable migraines.
29. Are a chronic tobacco smoker, as defined by smoking
by smoking >100 cigarettes (including hand-rolled
cigarettes, cigars, cigarillos, etc.) in their life-time and
have smoked every day for the last 7 days.
30. If female and of child-bearing potential, currently
pregnant or breastfeeding or planning to become
pregnant or breastfeed any time during the study.
31. Are currently a prisoner.
32. Are participating concurrently in another clinical
investigation or have participated in a clinical
investigation within the last 90 days or intend to
Participate in another clinical investigation during the
study, and where the participation in the other
investigation might interfere with the results of this trial
as deemed by the PI.
33. Have any medical condition or other circumstances, in
the judgment of the investigator, that might interfere
with the ability to complete follow-up visits and the
self-reported MADRS-s in the app.
34. Have any condition which, in the judgment of the
Investigator, would preclude adequate evaluation of
the device’s safety and performance.
35. A Subject who meets any of the exclusion criteria
during study participation will be discontinued from the
study.
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FL-100 treatment sessions
FL-100 will be used by patients remotely for five sessions per
week for 3 weeks, followed by three sessions per week for 7
weeks. In total, thirty-six sessions over 10 weeks during the
blinded phase.
STUDY ENDPOINTS
Primary Endpoint
The primary effectiveness endpoint is the adjusted mean
group difference in the HDRS-17 scores at 10 weeks
compared to baseline for subjects in the Active device and
the Sham device groups.
Secondary Endpoints
●
Arm difference in HDRS-17 response and remission
rate at week 10.
●
Arm difference in MADRS average score change, and
response and remission rate at week 10.
●
Arm difference in MADRS-s average score change,
and response and remission rate at week 10.
●
Quality of life improvement as measured by EQ-5D-3L
in the active compared to sham arm at week 10.
Exploratory Endpoints
●
Young Mania Rating Scale (YMRS) at 10 weeks.
●
tDCS Adverse Events Questionnaire (AEQ) at 10 and
20 weeks
●
Hamilton Anxiety Rating Scale (HAM-A) change at
week 10.
●
HDRS-17, MADRS, MADRS-s mean decrease, and
remission and response rate at 20 weeks (after
open-label) compared to open-label start and
baseline.
●
Correlation between MADRS and MADRS-s.
●
Correlation between adherence to stimulation and
HDRS-17/MADRS decrease in the active group at 10
weeks.
●
Neuropsychological measure: verbal learning (Rey
Auditory Verbal Learning Test (RAVLT) and
information processing speed (Symbol-Digit
Modalities Test (SDMT)
●
Treatment acceptability questionnaire (TAQ) as
developed by UEL. There is one form at baseline and
another at week 10 and 20.
●
The within-patient clinically meaningful improvement
as defined as at least -3 points on the HDRS-17
scale. The percentage of subjects for each arm that
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reaches -3 points or more improvement and also the
Cumulative Distribution Function Curves of Change in
HDRS-17 Score from Baseline to Primary end-point
by arm.
STATISTICAL CONSIDERATIONS
Sample Size
270
Statistical Plan
A modified intent to treat will be used. Users who have
performed less than 10 sessions (300 minutes) during the
first 3 weeks will be excluded from the analysis.
STUDY MANAGEMENT
Principal Investigator UK
Professor of Affective Neuroscience Cynthia Fu, MD, PhD,
University East London
Principal Investigator US
Associate Professor of Psychiatry Sudhakar Selvaraj, MD,
PhD, University of Texas
Clinical Research
Organization (CRO)
Curebase, Inc.
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7
SCHEDULE OF PROCEDURES
Table 1. Schedule of Procedures. Activities in blue cells are performed by trained graduate researchers
supervised by a trained psychiatrist, and red cells are to be completed by the participant.
Activity
Pre-Treatme
nt
Blinded Phase
Open-Label
Phase
Early
termination8
Week
-3 to -1
(± 3 days)
Week
0
Week 1
(± 3
days)
Week 4
(± 3
days)
Week
7
(± 3
days)
Week 10
(± 3 days)
Final
blinded
visit1
Week 10
(± 3
days)
Open
Label
Start
Wee
k 20
(± 3
days)
Week 1-20
Informed
Consent
X
Screening and
baseline Video
Call
X
Diagnostic
Assessment for
MDD
X9
Intervention Kit
Shipped to
subject
X5
Randomization6
X
Technical
onboarding
X
Initial Visit
X
Video call
X
X
X
X
X
X
X
X
MINI
X
HDRS-17
X
X
X
X
X
X
X
MADRS
X
X
X
X
X
X
X
MADRS-s
X4
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
YMRS
X
X
X
X
X
X
X
HAM-A
X
X
X
X
EQ-5D-3L
X
X
X
X
RAVLT
X
X
X
X
SDMT
X2
X2
X2
TAQ
X
X
X
X
AEQ
X
X
X
Healthcare Visit
Survey3
X
X
X
FLOW FL-100
use7
X
X
X
X
X
X
X
Record/Review
Concomitant
Medications
X
X
X
X
X
X
X
X
Record/Review
Adverse Events
X
X
X
X
X
X
X
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1 The week 10 visit includes the study Primary end-point. This will be the final blinded visit and will be the start of the
open label phase of the study. Participants in the Sham arm will be informed of their assignment and will restart with
active stimulation for 10 weeks; participants in the Flow FL-100 arm will be allowed to continue maintenance treatment
for 10 more weeks at 3 sessions per week. The unblinding will occur after the primary end-point data has been recorded.
2 Optional
3 Participants will be surveyed about the number of times he/she has sought healthcare due to depression during the
previous 10 weeks.
4 Participants will be required to answer the nine questions of the MADRS-s form in the app to start the first stimulation
session during the technical onboarding.
5 Participants will be required to start treatment within 24 days from completing the baseline surveys.
6 Completed after eligibility is confirmed by the investigator; when the participant signs up with their email in the trial app
they will automatically be randomized to the sham or active treatment arm (with 50% probability).
7 Five sessions per week for 3 weeks, followed by three sessions per week for 7 weeks. In total, thirty-six sessions during
10 weeks during the blinded phase. Please refer to Table 2 and Table 3 below for more details.
8 In case there is an early termination the research staff can request to have an early termination interview, if the subject
agrees.
9 Diagnostic Assessment for MDD will be performed by Investigator-Psychiatrist according to the most recent APA
Practice Guideline for treatment of MDD.
Table 2. Stimulation schedule during blinded phase.
Week
1
2
3
4
5
6
7
8
9
10
Number of
sessions
5
5
5
3
3
3
3
3
3
3
Table 3. Stimulation schedule during open-label phase.
Week
Previous
assignm
ent
1
2
3
4
5
6
7
8
9
10
Number of
sessions
Active
3
3
3
3
3
3
3
3
3
3
Sham
5
5
5
3
3
3
3
3
3
3
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8
INTRODUCTION
8.1
BACKGROUND
8.1.1
MAJOR DEPRESSIVE DISORDER (MDD)
Major depressive disorder (MDD) is a common psychiatric condition, mostly treated with
antidepressant drugs, which are limited for issues such as effectiveness and adverse effects.
8.1.2
MDD DIAGNOSIS
The diagnosis of MDD is based on the diagnostic criteria in the Diagnostic and statistical manual of
mental disorders – 5th edition (DSM-V). Patients should receive a thorough diagnostic assessment
in order to establish the diagnosis of major depressive disorder, identify other psychiatric or general
medical conditions that may require attention. The psychiatrist should develop a comprehensive
plan for treatment. This evaluation generally includes a history of the present illness and current
symptoms that may trigger or exacerbate depressive symptoms. Several clinically validated
standard scales are available for the assessment of the severity of depressive symptoms. Based
on cut-offs from these scales, the severity of MDD can be classified as mild, moderate, and severe.
8.1.3
OTHER TREATMENT OPTIONS
8.1.3.1
Antidepressants
Antidepressants are psychiatric drugs used for the treatment of MDD and other conditions,
including dysthymia, anxiety disorders, OCD, eating disorders, chronic pain, neuropathic pain and,
in some cases, dysmenorrhea, attention-deficit hyperactivity disorder, addiction, and sleep
disorders. They may be prescribed alone or in combination with other medications. The Center for
Disease Control and Prevention (CDC) reported that antidepressant usage in the United States
among people aged 12 or more years rose by 400% between 1988-1994 and 2005-2008.
Antidepressants are given to improve depressive symptoms.
There are several types of antidepressants, depending to the main neurotransmitter system they
target:
●
Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Noradrenaline
Reuptake Inhibitors (SNRIs): SSRIs and SNRIs block the reuptake of serotonin or serotonin
and noradrenaline in the brain. SSRIs are more widely prescribed than SNRIs, are effective
in treating depression, and have fewer side-effects than older antidepressant classes 1.
One of the largest studies on MDD to date, the STAR*D study, showed remission rates up
1 Anderson HD, Pace WD, Libby AM, West DR, Valuck RJ. Rates of 5 common antidepressant side effects
among new adult and adolescent cases of depression: a retrospective US claims study. Clin Ther. 2012
Jan;34(1):113-23. doi: 10.1016/j.clinthera.2011.11.024.
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to 28% with SSRIs alone 2. SSRIs and SNRIs may have the following side effects:
hypoglycemia, low sodium, nausea, rash, dry mouth, constipation, diarrhea, weight loss,
sweating, tremor, sedation, sexual dysfunction, insomnia, headache, dizziness, anxiety,
agitation, and abnormal thinking.
●
Monoamine oxidase inhibitors (MAOIs): MAOIs inhibit the action of monoamine oxidase,
the enzyme that breaks down monoaminergic neurotransmitter (e.g., serotonin,
noradrenaline), thus increasing their levels in the brain. MAOIs are usually prescribed as
second-line antidepressants as they present several side effects including blurred vision,
rash, seizures, edema, weight disturbances, sexual dysfunction, diarrhea, nausea,
constipation, anxiety, insomnia, drowsiness, headache, dizziness, arrhythmia, fainting and
hypertension.
●
Noradrenaline and Specific Serotonergic Antidepressants (NASSAs): This class of
antidepressants block adrenergic and specific serotonergic receptors. NASSAs have the
following side effects: constipation, dry mouth, weight gain, drowsiness, sedation, blurred
vision, and dizziness. More serious adverse reactions include seizures, white blood cell
reduction, fainting, and allergic reactions.
●
Tricyclic Antidepressants (TCA): This is the oldest class of antidepressants which are not
typically used as first-line treatment because they have a less favorable tolerability and
safety profile than more recent antidepressants. TCAsmay have the following side effects:
seizures, insomnia, anxiety, arrhythmia, hypertension, rash, nausea, vomiting, abdominal
cramps, weight loss, constipation, urinary retention, eye pressure, and sexual dysfunction.
Current practice for selecting pharmacological antidepressant treatments are limited by low
response and remission rates in MDD. The UK National Institute for Health and Care Excellence
(NICE) CG90 guidelines3 indicate that antidepressants should not be routinely used for the initial
treatment of mild depression, because the risk-benefit ratio is poor. Antidepressant treatment
should be considered for people with a history of moderate or severe depression, and for those
with mild depression that has been present for a long period.
The guidelines further note that antidepressant treatment should be used in combination with
psychosocial interventions, should be continued for at least six months to reduce the risk of
relapse, and that SSRIs are typically better tolerated than other antidepressants4. The American
4 Depression: The treatment and Management of depression in adults (updated edition)” NICE guidelines
[CG90].
3 Depression: The treatment and Management of depression in adults (updated edition)” NICE guidelines
[CG90].
2 Sinyor M, Schaffer A, Levitt A. The sequenced treatment alternatives to relieve depression (STAR*D) trial: a
review. Can J Psychiatry. 2010 Mar;55(3):126-35. doi: 10.1177/070674371005500303.
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Psychiatric Association treatment guidelines5 recommend antidepressant medication as an initial
treatment choice in people with mild or moderate major depression and should be given to all
patients with severe depression. Moreover, treatment should be individually tailored and should
consider all available options that may include pharmacotherapy (other symptomatic treatments),
psychotherapy, ECT, TMS or tDCS.
8.1.3.2
Psychological Treatments
Many psychological treatments are available for MDD. These include but not limited to,
psychoeducation, supportive psychotherapy, various group and individual therapies. Common
components of these treatments involve (a) information about the disorder and its treatment; (b)
practical support; (c) support for improving family communication; and (d) improving social and
problem-solving skills and addressing maladaptive patterns of thinking about themselves and
others6. The two most common structured psychological interventions are cognitive-behavioral
therapy (CBT) and interpersonal therapy (IPT) that target maladaptive thoughts and behaviors
using different techniques. A further psychological approach is psychodynamic psychotherapy
(PDT) which is based on the principles of psychoanalysis. It aims to help patients increase
awareness of their internal thoughts and patterns of behavior which might be contributing to their
condition. Psychotherapy is considered a reasonable alternative to medication for mild depression
and as an adjunct treatment in more severe depression where it can enhance response and
reduce relapse 7,8,9. However, psychological interventions require the active participation of patients
as well as access to specialist therapies which might limit their real-world availability and efficacy.
8.1.3.3
Electroconvulsive Therapy (ECT)
Electroconvulsive therapy (ECT) is also referred to as electroshock or shock treatment mainly in
the lay literature. During ECT, an electrical current is passed through the brain to produce an
epileptic fit (otherwise known as convulsion or seizure). To minimize any discomfort, ECT is
administered under general anesthesia. The current strength for ECT is usually around 800mA,
which is 400 times higher than the current used for tDCS. Immediately after treatment, many
patients experience headache, muscle aches and temporary amnesia about the period just prior to
9 https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf
8 Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Third Edition, 2010.
https://www.psychiatry.org/patients-families/depression/what-is-depression
7 “Depression: The treatment and Management of depression in adults (updated edition)” Clinical guideline.
NICE guidelines [CG90]. National Institute for Health and Care Excellence (UK). Published: October 2009,
updated 2019. https://www.ncbi.nlm.nih.gov/books/NBK63748/pdf/Bookshelf_NBK63748.pdf.
6 National Alliance on Mental Illness.
https://nami.org/About-Mental-Illness/Treatments/Psychosocial-Treatments
5 Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Third Edition, 2010.
https://www.psychiatry.org/patients-families/depression/what-is-depression
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the ECT. Confusion may also occur, mostly in elderly patients, that may last for up to 3 days (ref),
and long-term memory dysfunction has been reported in patients. The ECT procedure was first
conducted in 1938 and was initially used for a variety of mental health disorders conditions.
Currently it is used mainly in patients with treatment-resistant depression. A meta-analysis on the
effectiveness of ECT in MDD and bipolar depression conducted in 2012 reported overall remission
rates of 51.5% for MDD and 50.9% bipolar depression. As of 2001, it was estimated that about one
million people received ECT annually around the world.
8.1.3.4
Transcranial Magnetic Stimulation (TMS)
Transcranial magnetic stimulation (TMS) is a noninvasive procedure approved for the treatment of
depression in Europe, Australia, and the US 10. TMS is typically reserved for patients that have
shown minimal or partial response to antidepressants and for patients for whom antidepressant
treatment is not suitable. Each treatment session involves placing a purpose-made
electromagnetic coil against the scalp in order to induce electric currents in the brain using
repetitive magnetic pulses, hence the name repetitive TMS (rTMS). The treatment requires
specialist equipment and medical supervision and is therefore not suitable for home use.
8.1.3.5
Cranial Electrotherapy Stimulation (CES)
Cranial electrotherapy stimulation (CES) (also referred to as cranial electrostimulation, electrosleep
therapy, and electronarcosis) is a non-pharmacological, non-invasive treatment in which
low-intensity electrical current is applied to the scalp. The main difference from tDCS is that CES
uses alternating current (AC) rather than direct current (DC) electricity. There is currently a wide
variety of CES devices. The Fisher Wallace Stimulator is a CES device which has FDA-approval
for the treatment of anxiety, depression, and insomnia, and sold in the EU and Canada without a
prescription, directly to consumers to be used at home.
8.1.3.6
Transcranial Direct Current Stimulation (tDCS)
Flow is based on transcranial direct current stimulation (tDCS), a non-invasive brain stimulation
technique where a weak direct current is applied on the scalp through electrodes. The current
modulates the underlying neural activity. In principle, tDCS electrodes can be placed anywhere on
the scalp. Changes in the tDCS electrode placement, also called montage, change the distribution
of the induced electrical fields in the brain. Different montages are used depending on the
indication. Empirical evidence indicates that a montage that targets the prefrontal cortex can
reduce depression symptoms (see section 3.1.3 of the IDE (Attachment 001) for clinical data).
10 Carpenter LL, Janicak PG, Aaronson ST, et al. Transcranial magnetic stimulation (TMS) for major
depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.
Depress Anxiety. 2012 Jul;29(7):587-96. doi: 10.1002/da.21969.
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8.2
INVESTIGATIONAL DEVICE
8.2.1
FLOW FL-100
Neuromodulation is a technique that alters neural activity through the targeted delivery of chemical
or electrical stimulus. In particular, brain neuromodulation may be achieved through the direct
application of stimulation via implanted deep brain stimulation (DBS) or non-invasively by TMS,
CES or tDCS. Direct and non-invasive therapies have been tested for neurologic disorders such as
Parkinson’s disease, schizophrenia, chronic pain, and MDD, with MDD being the most studied
disorder (Brunoni et al. 2010).
TMS to the dorsolateral prefrontal cortex (DLPFC) is shown in the literature to be safe and effective
in treating MDD and as a result has received FDA clearance for MDD treatment (Cole et. al.,
2019). TMS has proven to be commercially viable, however the treatment has some limitations.
The limitations of TMS include the expensive capital equipment required for the delivery of
treatment, which can only be delivered with specialist training. Patients being treated with TMS are
required to attend multiple clinic visits, sometimes daily or multiple times daily, for weeks at a time,
depending on their prescription.
Building from the understanding of the mechanisms, effects and targeting from TMS therapy, and
removing some of the logistical hurdles that prevent access to TMS therapy, it is the intent of this
study to investigate whether the area of the brain that is being modulated by TMS treatment can be
similarly modulated by a home-use tDCS device, thereby offering a more affordable, accessible
option for patients with MDD.
Flow Neuroscience has several years of experience developing and marketing tDCS devices for
depression treatment. Its device, the Flow FL-100, is a CE-marked class IIa medical device for the
treatment of Major Depressive Disorder (MDD). Flow FL-100 has been on the European market
since mid-2019 and has been used by over 3000 patients. The product is currently available over
the counter in the EU. Market approval has also been gained in Brazil.
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Figure 1. The Flow FL-100 Headset
The purpose of this trial is to investigate the use of the Flow FL-100 device to treat MDD at-home
in a double-blind RCT.
8.2.2
THE FLOW APP
The Flow app is used to control the Bluetooth connected Flow tDCS headset and acquire data
about its use. The app is connected to a server that stores all data in a secure PostgreSQL
database.
For the trial, a dedicated installation of the server and app will be used to isolate all trial data from
data collected from retail Flow users. Trial participants will be given a link to the dedicated trial app
(Google Play or Apple App store) before starting the trial. In the trial app, participants register with
their email. No other identifying information is collected in the app. Only the Flow research team
and Curebase will be able to log in to the Flow trial system and database and view the participant
emails.
During the trial, the user will answer the nine questions of the MADRS-s form in the app.
Answering the form is mandatory to continue with the stimulation. The app also continuously sends
headset usage data to the server.
The trial personnel (at Curebase and at the sites in the UK and US) will have access to an
administrative web interface where it can follow how much and when users have stimulated. This
way they can monitor the usage of each patient and contact them if they start to miss sessions.
This retention management is in addition to the normal Curebase retention management.
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Figure 2. The Flow system and its components. A dedicated app and server will be used. Trial personnel will have
access to an admin interface where they can view the activity of participants, unblind them, and move them to the
open-label phase.
Figure 3 Flow trial admin interface - List of trial participants. Participants are identified through their email.
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Figure 4 Flow trial admin interface - View of an individual unblinded participant’s data. Their MADRS-s
scores and stimulation sessions are displayed. After unbinding the user’s stimulation mode can be edited.
8.3
DEVICE TRACEABILITY
The US warehouse will maintain a Device Accountability Log to document the date of receipt,
serial number, date of use, and final disposition of each device. The log will be available for review
during monitoring visits. The Flow system also allows the trial personnel to see exactly which
device has been used by which participant, and when.
Tracking of the investigational product used in this study will be consistent with 21 CFR Part 821
and ISO 14155:2020, and in accordance with local regulations. Devices will be stored in a secure
location at the warehouses assigned for the trial (one in the US and one in Sweden).
At the end of the trial, all devices used in the US will be remotely disabled. Furthermore, a
mechanism is in place to ensure that US trial devices cannot be used in the customer-facing Flow
app. UK participants will be allowed to keep their devices.
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8.4
SUPPLY AND ACCOUNTABILITY OF INVESTIGATIONAL DEVICES
The full name and address are needed for shipping the devices to the participants’ homes. There
will be one warehouse in Sweden and one in the US. The warehouse in Sweden is the same as
used for normal Flow customers, and the warehouse in the US will be dedicated to the trial. To
ensure that only limited personnel at Flow have access to shipping information, special accounts in
the shipping partners’ software systems will be set up. This will isolate information from the normal
operations of Flow. Only the CTO from Flow Neuroscience will be able to access the shipping
information of participants.
The sponsor is:
Flow Neuroscience AB
Södra Förstadsgatan 2
211 43 Malmö
Tele: +46736607170
erik@flowneuroscience.com
8.5
DEVICE USE EXPERIENCE AND TRAINING
The study Sponsor will ensure appropriate training for each investigator prior to initiation of the
study at each investigational site. Investigators will be trained on the Flow FL-100 device by the
Sponsor, and/or qualified representatives of the Flow FL-100 device prior to their participant’s first
use. This training will address topics such as the indications and contraindications for the use of
the device, device handling, instructions for use and device instrumentation.
In addition, the Sponsor will provide training on the protocol, participant selection criteria, AE
management, and follow-up.
9
BENEFIT-RISK ANALYSIS
9.1
RISKS
The study device will deliver a maximum of 2 mA tDCS for 30 minutes at a time. Published data
has shown conventional sessions to be ≤40 minutes at ≤4mA, and the tolerability and dropout
rates between sham and active stimulation groups are equal in the literature.
As of August 2021, the most common side effects reported in the literature and from post-market
data on Flow FL-100 are:
Table 4. Common side effects from Flow FL-100
Side Effect
% of users
Skin irritation, redness
0.80%
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Strong tingling, stinging, or itching
0.14%
Headache
1.1%
Increased tinnitus
0.45%
Most people also experience skin redness at the stimulation site which passes within 30 minutes
after the stimulation. Small skin burns are also known from the literature due to the use of tap
water instead of physiological saline to wet the stimulation electrodes11. Therefore, Flow is
delivered with disposable pre-moistened sponges so that the users do not need to handle saline
themselves.
The tDCS studies in participants with MDD have reported mostly consistent adverse events with
large studies on healthy participants12. In addition to this, there have been four studies that have
published the appearance of treatment-emergent mania/hypomania (TEM) in eleven cases total13.
Most cases of TEM have been where tDCS has been combined with antidepressant drugs, which
are known to increase the risk of a manic switch14. As such, a causal relationship has not been
determined. The observed cases have also been mild and in general not required any intervention
(correspondence with authors). In the internal data from over 3,000 Flow FL-100 users, no
instance of TEM has been discovered or reported. In accordance with the recommendation from
Antal et al. (2017), participants with a history of bipolar disorder will be excluded from this study
due to their increased risk of manic switch. As an additional safety measure, the YMRS will be
administered at each follow-up visit.
9.2
RISK MITIGATION
An evaluation of the potential risks associated with use of the Flow FL-100 device has been
performed to minimize the risks associated with the device. The following are some of the ways in
which risks have been or will be minimized:
14 Patel R, Reiss P, Shetty H, Broadbent M, Stewart R, McGuire P, Taylor M. Do antidepressants increase the risk of mania and bipolar
disorder in people with depression? A retrospective electronic case register cohort study. BMJ Open. 2015 Dec 14;5(12):e008341. doi:
10.1136/bmjopen-2015-008341. PMID: 26667012; PMCID: PMC4679886.
13 André R. Brunoni, Adriano H. Moffa, Bernardo Sampaio-Júnior, Verònica Gálvez, & Colleen K. Loo (2017). Treatment-emergent
mania/hypomania during antidepressant treatment with transcranial direct current stimulation (tDCS): A systematic review and
meta-analysis. Brain Stimulation, 10(2), 260-262.
12 Antal A, Alekseichuk I, Bikson M, Brockmöller J, Brunoni AR, Chen R, Cohen LG, Dowthwaite G, Ellrich J, Flöel A, Fregni F, George
MS, Hamilton R, Haueisen J, Herrmann CS, Hummel FC, Lefaucheur JP, Liebetanz D, Loo CK, McCaig CD, Miniussi C, Miranda PC,
Moliadze V, Nitsche MA, Nowak R, Padberg F, Pascual-Leone A, Poppendieck W, Priori A, Rossi S, Rossini PM, Rothwell J, Rueger
MA, Ruffini G, Schellhorn K, Siebner HR, Ugawa Y, Wexler A, Ziemann U, Hallett M, Paulus W. Low intensity transcranial electric
stimulation: Safety, ethical, legal regulatory and application guidelines. Clin Neurophysiol. 2017 Sep;128(9):1774-1809. doi:
10.1016/j.clinph.2017.06.001. Epub 2017 Jun 19. PMID: 28709880; PMCID: PMC5985830.
11 Palm U, Keeser D, Schiller C, et al. Skin lesions after treatment with transcranial direct current stimulation. Brain Stimul
2008;1:386e7. [7] Frank E, Wilfurth S, Landgrebe M, et al. Anodal skin lesions after treatment with transcranial direct current stimulation.
Brain Stimul 2010;3:58e9.
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9.2.1
MONITORS
All Flow devices are controlled by the app and the app is connected to the Flow server over the
internet. It is possible to disable devices remotely; this feature ensures patient safety in case of
malfunction. This feature is not available for other tDCS devices. The frequency of use of each
individual Flow device is remotely monitored and therefore it is possible to assess adherence to
treatment. We expect the Flow device to enhance patient clinical care in general, given the ability
for physicians to have remote access to real-time patient data.
9.2.2
STIMULATION PARAMETER SPACE
Stimulation will always have a maximum output of 2 mA.
9.2.3
USAGE LIMITS
Since Flow is controlled by the accompanying app it limits how often the device can be used and
therefore this risk is mitigated. The treatment protocol is however the same for both devices with
up to 5 sessions per week the first 3 weeks and then 3 sessions per week. With a maximum of one
30-minute session per day.
9.3
ANTICIPATED BENEFITS
Participants may experience a clinically meaningful improvement in MDD as has been shown in
previous placebo controlled clinical studies with similar therapy. Based on the self-reporting Flow
FL-100 users complete every week, over 80% report having some improvement in their depression
and around 30% reach remission in 6 weeks. It is also possible that participants will not experience
a clinical benefit from participation, although there may be a beneficial addition to the body of
knowledge for this therapy. There may be benefits that are unforeseen at this time. Flow also gives
participants access to a type of treatment that is in general only available at clinics.
The remission rate of 30% is consistent with what has been found in the literature on tDCS for
depression treatment using other devices.
9.4
RISK-TO-BENEFIT RATIO
All applicable risks have been addressed through appropriate testing and clinical monitoring. Any
residual risks are acceptable when weighed against the potential benefits to the participant. The
device is appropriate for the intended use and is designed to protect the health and safety of the
participant, user, and environment.
Therefore, the risk/benefit profile of the Flow FL-100 in the intended use justifies the conduct of the
proposed clinical investigation.
10
STUDY OBJECTIVES
10.1 BACKGROUND
To conduct a double-blind, placebo-controlled, randomized, superiority, remote trial for individuals
with major depressive disorder.
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10.2 PRIMARY OBJECTIVE
To show that active stimulation with the Flow FL-100 device is superior to sham stimulation for the
treatment of major depressive disorder when used at-home.
11 STUDY DESIGN
The study will be lead by Professor of Affective Neuroscience Cynthia Fu, PhD, MD, University
East London (UK site) and Associate Professor of Psychiatry Sudhakar Selvaraj, PhD, MD,
University of Texas Health Sciences center at Houston (UTHealth) (US site), both with extensive
experience in managing clinical trials and treating MDD. The other co-investigators are Dr. Jair
Soares, PhD, MD, Chairman and Professor of Psychiatry at UTHealth, Houston and Dr. Marsal
Sanches, PhD, MD, Associate Professor of Psychiatry at UTHealth, Houston, both have a long
history of leading and managing clinical trials and treating MDD and Psychiatric disorders. The
other study site investigators are well trained researchers with graduate or postgraduate degrees
with training and experience in clinical studies. The study PIs and Co-Is will provide day-to-day
supervision to the study investigators and responsible for the overall conduct of the study.
11.1
STUDY DURATION
The study is expected to take approximately 10 months from first participant enrolled to the last
open-label visit.
●
5 months enrollment period (estimation)
●
5 months treatment and open-label
The follow-up period during the clinical investigation shall permit the demonstration of performance
over a period, sufficient to represent a realistic test of the performance of the investigational
device and allow any risks associated with adverse device effects over that period to be identified
and assessed.
11.2
TREATMENT/CONTROL GROUPS
For each participant, the trial will be conducted in 2 phases: blinded and open label.
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Figure 5 Participant Activity Flowchart
11.3 BLINDED PHASE
During the treatment phase, the participants will be randomized into one of the two arms: active
and sham. The participants will be divided equally between the arms and will not be informed of
their assignment. The participants will be informed during the consent process that some of them
will have sham stimulation during their initial 10-week participation, depending on their
randomization assignment.
The sham group receives sham stimulation following how sham tDCS is normally implemented in
clinical trials. At the beginning of each 30-minute stimulation session, the current is ramped up to
1mA over 30 seconds. However, when it has reached its maximum, it is again slowly ramped down
to 0 mA over 15 seconds. By the end of the session, the current is then again ramped up to 1 mA
over 30 seconds and then ramped down to 0 mA over 15 seconds.
The 1 mA current, compared to 2 mA for active stimulation, allows the user to feel the tingling of
the stimulation but while still minimizing the amount of current they are exposed to.
When in sham, the app user interface behaves exactly as if the stimulation was active. This way
the participants will be blind to the mode of stimulation. If for some reason the stimulation is
paused during stimulation the same ramp up and down procedure is done again when the
stimulation is resumed.
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Figure 6. Active vs sham stimulation current envelope.
After the trial period, all user’s devices will start working, and users who received sham stimulation
can choose to restart the treatment with active stimulation.
11.4 OPEN LABEL PHASE
After the completion of the blinded treatment phase all participants will be offered to continue the
treatment. Members of the sham group will be offered to restart the treatment with active
stimulation, while members of the active group will be offered to continue maintenance treatment
for 10 more weeks at 3 sessions per week.
11.5
PRIMARY ENDPOINTS
The primary effectiveness endpoint is the adjusted mean group difference in the HDRS-17 scores at 10
weeks compared to baseline for subjects in the Active device and the Sham device groups.
11.6
SECONDARY ENDPOINTS
●
Arm difference in HDRS-17 response and remission rate at week 10.
●
Arm difference in MADRS average score change, and response and remission rate at week
10.
●
Arm difference in MADRS-s average score change, and response and remission rate at
week 10.
●
Quality of life improvement as measured by EQ-5D-3L in the active compared to sham arm
at week 10.
11.7
EXPLORATORY ENDPOINTS
●
Young Mania Rating Scale (YMRS) at 10 weeks.
●
tDCS Adverse Events Questionnaire (AEQ) at 10 and 20 weeks
●
Hamilton Anxiety Rating Scale (HAM-A) change at week 10.
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●
HDRS-17, MADRS, MADRS-s mean decrease, and remission and response rate at 20
weeks (after open-label) compared to open-label start and baseline.
●
Correlation between MADRS and MADRS-s.
●
Correlation between adherence to stimulation and HDRS-17/MADRS decrease in the active
group at 10 weeks.
●
Neuropsychological measure: verbal learning (Rey Auditory Verbal Learning Test (RAVLT)
and information processing speed (Symbol-Digit Modalities Test (SDMT)
●
Treatment acceptability questionnaire (TAQ) as developed by UEL. There is one form at
baseline and another at week 10 and 20.
●
The within-patient clinically meaningful improvement as defined as at least -3 points on the
HDRS-17 scale. The percentage of subjects for each arm that reaches -3 points or more
improvement and also the Cumulative Distribution Function Curves of Change in HDRS-17
Score from Baseline to Primary end-point by arm.
12
SELECTION OF STUDY POPULATION
12.1 PARTICIPANT RECRUITMENT
Participants in this study will be recruited via the Flow Neuroscience website, email lists, and online
marketing. Potential participants will be directed to a pres-creening form hosted by Curebase, they
will then be required to sign up/register with the Curebase platform to complete a pre-screening
survey. This information will primarily be used to screen potential participants for eligibility. Users
will be given general information about the trial, and that is it will be blinded.
Participants who seem to meet preliminary eligibility will have a virtual pre-screening visit with a
Curebase coordinator prior to being sent to a site investigator for informed consent and further
screening procedures. Participants must meet all the following inclusion criteria and none of the
exclusion criteria. The investigator maintains exclusive responsibility for the inclusion and exclusion
of any potential study participant.
12.2 INCLUSION CRITERIA
To be eligible to participate in this study, participants must meet all the following criteria:
1.
Be ≥18 years.
2.
Have a diagnosis of Unipolar MDD with a current depressive episode as defined by the
diagnostic criteria in the Diagnostic and statistical manual of mental disorders – 5th edition
(DSM-V
3.
Have a Hamilton Depression Rating Score (HDRS-17) of ≥16.
4.
For 6 weeks prior to enrollment, are either:
a.
not taking antidepressant medication or:
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b.
are taking a stable antidepressant regimen with a stable medication source and
agree to continue the same regimen throughout study participation
5.
If in psychotherapy, have maintained stable psychotherapy for at least 6 weeks prior to
enrollment.
6.
Have access to a stable internet connection through which the treatment will be received.
7.
Have access to a smartphone or other device running Android 5.0+ or iPhone Operating
System (iOS) 12+ (e.g., reasonably new iPhone/iPad or Android phone), used to using the
device in their everyday life, and can capably use the study application on the device, as
determined by the investigator.
8.
Are currently living in England/Wales (UK) or Texas (US).
9.
Subject is currently under the care of a psychiatrist or a primary care physician, agrees to
be evaluated at regular intervals by a psychiatrist or primary care physician for the duration
of study participation, and agrees to promptly inform the study staff of any change of
psychiatric or mental health providers during study participation.
10. Subject agrees to allow any and all forms of communication between the
investigators/study staff and any healthcare provider who currently provides and/or has
provided service to the patient/subject within at least two years of study enrollment.
11. Subject agrees to provide the name and verifiable contact information (email and mailing
addresses, mobile and land-line phone numbers, as applicable) of at least two persons ≥
age 18 who reside within a 60-minute drive of the patient’s residence and whom the
research staff is at liberty to contact, as they deem necessary, for the duration of study
participation.
12. Be able to give voluntary, written informed consent to participate and have signed an
Informed Consent Form specific to this study.
13. Be willing and able to comply with all study procedures.
14. Subject agrees to meet all of the inclusion criteria throughout their participation in the study.
Otherwise, the subject will be discontinued from the study.
15. Subject agrees to a Safety/Suicide Risk Management Protocol, which is intended to reduce
the reduce the risk of suicide during study participation.
12.3 EXCLUSION CRITERIA
Participants who meet any of the following criteria will be excluded from participating in this study:
1.
Are in a current state of mania, as determined by the YMRS or psychosis, as determined by
the MINI.
2.
Are diagnosed with vitamin or hormonal deficiencies that may mimic mood disorders, as
determined by the investigator.
3.
Are currently receiving any other interventional therapy for MDD other than a stable
regimen of antidepressants or psychotherapy as defined in the inclusion criteria.
4.
Considered to have treatment resistant depression as defined by inadequate clinical
response to 2 or more trials of antidepressants at an adequate dose and duration.
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5.
Have a history of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS),
cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS),
deep brain stimulation (DBS), or other brain stimulation.
6.
Patient answers Yes to Questions 4, 5 or 6 on the Columbia Suicide Severity Rating Scale
(C-SSRS) Triage and Risk Identification Screener.
7.
Any previous hospitilization for suicidal behavior.
8.
Have chronic severe insomnia (< 4 hours of sleep each night), or depression secondary to chronic
insomnia or sleep apnea
9.
Have any structural lesion (e.g., any structural neurological condition, or more subcortical
lesions than would be expected for age or have had a stroke that affects stimulated area or
connected areas) or any other clinically significant abnormality that might affect safety,
study participation, or confound interpretation of study results, as determined by the
investigator.
10. Have any implant in the brain (e.g., DBS) or neurocranium, or any other active implantable
medical device.
11. Have any neurocranial defect.
12. Have a history of epilepsy or seizures (including history of withdrawal / provoked seizures).
13. Have shrapnel or any ferromagnetic material in the head.
14. Have any disorder that would impair the ability to complete the study questionnaires.
15. Have been diagnosed with autism spectrum disorder.
16. Are actively abusing substances (<1 week prior to enrollment).
17. Have a cognitive impairment (including dementia).
18.Have a history of mania or psychosis.
19. Are currently using any medications that affect cortical excitability (e.g., benzodiazepines,
epileptics, etc.).
20. Are currently experiencing symptoms of withdrawal from alcohol or benzodiazepines.
21. Have been diagnosed with Parkinsonism or other movement disorder as determined by the
investigator to interfere with treatment.
22. Have ever taken esketamine / ketamine for treatment of depression.
23. Have ever been admitted to hospital for depression.
24. Have ever been diagnosed with obsessive-compulsive disorder (OCD) or bipolar type 1 or
2 disorder.
25. Is diagnosed with an active primary anxiety disorder, or PTSD, agoraphobia, anorexia or
bulimia, panic or personality disorder with active symptoms.
26. Have a history of psychosurgery for depression.
27. Have any history of myocardial infarction, coronary artery bypass graft (CABG), coronary
heart failure (CHF), or history of other cardiac issues.
28. Are currently experiencing or have a history of intractable migraines.
29. Are a chronic tobacco smoker, as defined by smoking by smoking >100 cigarettes
(including hand-rolled cigarettes, cigars, cigarillos, etc.) in their life-time and have smoked
every day for the last 7 days.
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30. If female and of child-bearing potential, currently pregnant or breastfeeding or planning to
become pregnant or breastfeed any time during the study.
31. Are currently a prisoner.
32. Are participating concurrently in another clinical investigation or have participated in a
clinical investigation within the last 90 days or intend to Participate in another clinical
investigation during the study, and where the participation in the other investigation might
interfere with the results of this trial as deemed by the PI.
33. Have any medical condition or other circumstances, in the judgment of the investigator, that
might interfere with the ability to complete follow-up visits and the self-reported MADRS-s in
the app.
34. Have any condition which, in the judgment of the Investigator, would preclude adequate
evaluation of the device’s safety and performance.
35. A Subject who meets any of the exclusion criteria during study participation will be
discontinued from the study
12.4 STUDY ENROLLMENT PROCEDURES
All participants with MDD will be considered for screening into the study. Participants expressing
an interest in participation will proceed with the consent process as per section 13.1 Informed
Consent. A participant is not considered officially enrolled in the study until after signing the study
consent form.
12.4.1 PARTICIPANT ENROLLMENT
Participants who consent to participate shall be assigned a unique Participant Identification
Number to de-identify their information. This Participant Identification Number will be captured in
the Curebase platform and used to identify them on all source documents and eCRFs thereafter.
A record of all screened participants will be maintained in the Curebase platform. The date of
screening, results of screening (included or not) and, if not eligible, the primary reason for
excluding the participant, enrollment status (enrolled or not) and, if not enrolled, the primary reason
will be recorded.
Please note, for purposes of the study a participant is considered enrolled at informed consent.
NOTE: If a participant does not meet the eligibility criteria during their initial screening, the
participant cannot be re-evaluated for entry into the study later.
12.5 SCREEN FAILURES
A screen failure participant is a consented participant that did not receive the Flow FL-100
treatment due to withdrawing consent, being withdrawn from the study, or not meeting eligibility
requirements for treatment.
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If a participant signs the ICF but is found ineligible for inclusion in the study prior to receiving the
Flow FL-100, the participant will not be advanced any further in this clinical investigation. The
participant’s signed ICF and completed inclusion/exclusion criteria will be retained by the
Investigator, and the participant will be notified.
Screening data from the Screening Visit including the reason for exclusion, will be collected but
may not be complete in cases where the participant is determined to be a screen failure early in
the screening process. The participant’s exclusion from the study, and reason for ineligibility, will be
documented in the Screening & Enrollment Log.
12.6 PARTICIPANT TREATMENT ASSIGNMENT
During the technical onboarding session at Week 0, the participant will receive the link to the app
and a code to access the app. The participant will download the app and sign up in the app with
their email, password, and app access code. When the participant creates their account in the trial
app they will automatically be randomized to the sham or active treatment arm (with 50%
probability). Block randomization is used with randomly permuted block sizes of 4 and 6. This is
done by the trial server and stored in its dedicated database. No one who is working with the trial
will have access to the raw data until it has ended.
13 STUDY PROCEDURES
13.1 WEEK -3 TO -1: INFORMED CONSENT (ICF)
After passing the screener survey, prospective participants will be directed to review and sign an
electronic HIPAA, and an IRB/EC-approved consent (eConsent) form that are hosted in the
Curebase system. The eConsent form will explain the nature and scope of the study, the
procedures to be performed as part of the study, the potential risks, and benefits of participation,
expected duration of participation, possible treatment alternatives, and an overview of his/her rights
as a study participant in lay terms. Participants will have the opportunity to discuss the study with
their family or surrogates or think about it before agreeing to participate. Participants will be
informed that participation is voluntary and will be assured that they may withdraw from the study
at any time and for any reason, without repercussion.
After viewing the eConsent materials, participants will have an opportunity to email or call the
research team with any questions they may have and will be given as much time as needed to
receive answers before making a final decision regarding study participation. Participants will
receive a telephone number, email, and will have access to contact support staff as needed.
When the individual is ready to confirm their willingness to participate, an electronic signature will
be collected to complete the eConsent formalities. The participant will receive a copy of the fully
signed HIPAA, and eConsent forms via email to retain for their records, and a digital copy will be
retained within the Curebase system as part of the study records.
Upon successful documentation of informed consent, a screening video call will be performed and
will serve as a baseline evaluation to confirm patient eligibility.
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●
Clinician Reported Outcome (ClinRO)
▪
Hamilton Depression Rating Score (HDRS-17)
▪
Montgomery–Åsberg Depression Rating Scale (MADRS)
▪
Mini International Neuropsychiatric Interview (MINI)
▪
Hamilton Anxiety Rating Scale (HAM-A)
▪
Young Mania Rating Scale (YMRS)
▪
Rey Auditory Verbal Learning Test (RAVLT)
●
Patient Reported Outcome (PRO) Questionnaires
▪
EQ-5D-3L
▪
Symbol-Digit Modalities Test (SDMT)
▪
Treatment Acceptability Questionnaire (TAQ)
▪
tDCS Adverse Events Questionnaire (AEQ)
▪
Columbia Suicide Severity Rating Scale (C-SSRS)
●
Review of concomitant medications
●
Final review of inclusion/exclusion criteria
●
Intervention kit will be shipped to the participant
13.2 WEEK 0
To allow the Investigator’s assessment of the participant’s progress, the participant will complete a
video call with study staff and undergo the following:
●
Review of concomitant medications
●
Record any new or updated adverse events and device deficiencies, if applicable
●
SDMT baseline
●
Technical onboarding & device training session
●
Randomization
13.3 WEEKS 1, 4 & 7
To allow the Investigator’s assessment of the participant’s progress, the participant will complete a
video call with study staff and undergo the following:
●
ClinROs
▪
HDRS-17
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▪
MADRS
▪
YMRS
▪
C-SSRS
●
Review of concomitant medications
●
Record any new or updated adverse events and device deficiencies, if applicable
13.4 WEEK 10
To allow the Investigator’s assessment of the participant’s progress, the participant will complete a
video call with study staff and undergo the following:
●
ClinROs/PROs
▪
HDRS-17
▪
MADRS
▪
HAM-A
▪
YMRS
▪
EQ-5D-3L
▪
RAVLT
▪
SDMT
▪
TAQ
▪
AEQ
▪
C-SSRS
●
Review of concomitant medications
●
Record any new or updated adverse events and device deficiencies, if applicable
For participants in the Sham Arm:
●
Participants in the Sham arm will be informed of their assignment and will be offered to start
active, Open-Label stimulation for 10 weeks, with 5 sessions the first 3 weeks and then up
to 3 sessions per week.
For participants in the Active stimulation Arm:
●
Participants in the Active arm will be offered to continue maintenance treatment for 10 more
weeks at 3 sessions per week.
13.5 WEEK 20 FOLLOW-UP VISIT - OPEN-LABEL ONLY
To allow the Investigator’s assessment of the participant’s progress, the participant will complete a
video call with study staff and undergo the following:
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●
ClinROs/PROs
▪
HDRS-17
▪
MADRS
▪
HAM-A
▪
YMRS
▪
EQ-5D-3L
▪
RAVLT
▪
SDMT
▪
TAQ
▪
AEQ
▪
C-SSRS
●
Review of concomitant medications
●
Record any new or updated adverse events and device deficiencies, if applicable.
13.6 VIDEO CALLS
All trial visits will be conducted remotely using real-time video conferencing.
The site personnel who will conduct remote visits will be trained on how to conduct real-time video
conferencing visits (e.g., trained on the use of telemedicine for remote clinical trial visits).
Both the researcher and the trial participant should confirm their respective identities with one
another before engaging in a visit by showing a photo ID to the camera.
The date and time of a visit should be documented in the trial records.
13.7 LATE AND MISSED VISITS
If a participant fails to return for a scheduled study visit within the visit window defined in the study
protocol but completes the visit prior to the beginning of the next visit window, that visit is
considered to have been completed late. A protocol deviation should be documented on the
appropriate eCRF.
If a participant fails to return for a scheduled study visit within the visit window defined in the study
protocol and the next scheduled study visit window opens, that visit is considered to have been
missed. A protocol deviation should be documented on the appropriate eCRF.
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All attempts should be made to schedule the participant for the study visit as soon as possible so
that it is captured late rather than missed completely.
13.8 UNSCHEDULED VISITS
Participants may be seen for unscheduled visits as needed. During the unscheduled visit, the
Investigator will assess the participant’s progress and perform the following:
●
ClinROs
▪
HDRS-17
▪
MADRS
▪
YMRS
▪
C-SSRS
●
Review of concomitant medications
●
Record any new or updated adverse events and device deficiencies, if applicable
13.9 STUDY COMPLETION/DISCONTINUATION
The Primary Endpoints will be evaluated at 10 weeks. Participants will complete study participation
at 10 weeks unless consented and enrolled in an additional 10-week open-label portion of the
study. Participants enrolled in the open-label phase will complete the trial after 20-weeks.
14
DESCRIPTION OF STUDY PROCEDURES
DEMOGRAPHICS
At screening, participant baseline characteristics including, but not limited to, age and gender, will
be recorded.
PAST MEDICAL HISTORY
At screening, each participant’s past medical conditions and surgical procedures will be recorded.
PREGNANCY DETERMINATION
Prior to treatment, female participants of childbearing potential will be asked during the Screening
visit whether they are pregnant or breastfeeding or plan to become pregnant or breastfeed during
the trial.
CLINICIAN AND PATIENT REPORTED OUTCOME QUESTIONNAIRES (CLINROS/PROS)
The following Clinician or Patient Reported Outcome questionnaires will be completed and used to
compare participant outcomes at follow-up time points compared to baseline:
Montgomery–Åsberg Depression Rating Scale (MADRS) - ClinRO
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The Montgomery–Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic
questionnaire which psychiatrists use to measure the severity of depressive episodes in patients
with mood disorders.
Montgomery–Åsberg Depression Rating Scale (MADRS-s) - PRO
MADRS-s is a self-rating version of MADRS and correlates well with expert ratings. The MADRS-s
instrument has nine questions, with an overall score ranging from 0 to 54 points. During the trial,
each participant reports their MADRS-s score in the same way as normal customers would. The
MADRS-s uses cut-off points detailed below to classify the severity of depressive symptoms:
●
0-12 points: None or very mild depression
●
13-19 points: Mild depression
●
20-34 points: Moderate depression
●
≥35 points: Severe depression
Hamilton Depression Rating Score (HDRS-17)
The HDRS (also known as the Ham-D) is the most widely used clinician-administered depression
assessment scale. The original version contains 17 items pertaining to symptoms of depression
experienced over the past week. The questionnaire is designed to be used by clinicians to rate the
severity of depressive symptoms in adults by probing mood, feelings of guilt, suicide ideation,
insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms.
Mini International Neuropsychiatric Interview (MINI) - ClinRO
The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a short structured diagnostic
interview, developed jointly by psychiatrists and clinicians in the United States and Europe, for
DSM-IV and ICD-10 psychiatric disorders.
Columbia Suicide Severity Rating Scale (C-SSRS) - ClinRo
The Columbia Suicide Severity Rating Scale, or C-SSRS, is a rating scale to evaluate suicide risk.
The scale identifies specific behaviors which may be indicative of an individual's intent to kill
oneself.
Hamilton Anxiety Rating Scale (HAM-A) - ClinRo
The HAM-A was one of the first rating scales developed to measure the severity of anxiety
symptoms and is still widely used today in both clinical and research settings. The scale consists of
14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental
agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety).
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Young Mania Rating Scale (YMRS) - ClinRo
The Young Mania Rating Scale (YMRS) is one of the most frequently utilized rating scales to
assess manic symptoms. The scale has 11 items and is based on the patient’s subjective report of
his or her clinical condition over the previous 48 hours.
Rey Auditory Verbal Learning Test (RAVLT) - ClinRo
The Rey Auditory Verbal Learning Test (RAVLT) is a neuropsychological assessment designed to
evaluate verbal memory in patients, 16 years of age and older. The RAVLT can be used to
evaluate the nature and severity of memory dysfunction and to track changes in memory function
over time.
Symbol-Digit Modalities Test (SDMT) - PRO
The Symbol Digit Modalities Test (SDMT) detects cognitive impairment. It is a way for clinicians to
screen for organic cerebral dysfunction in both children (eight years and older) and adults.
The SDMT is brief, easy to administer, and has demonstrated sensitivity in detecting not only the
presence of brain damage, but also changes in cognitive functioning over time and in response to
treatment.
Treatment Acceptability Questionnaire (TAQ) - PRO
TAQ is a questionnaire for probing how acceptable participants of tDCS clinical trial think the
treatment is. At baseline it measures participant’s expectations about the trial, e.g., treatment
outcome, effort needed, ethics, etc., and then follow-up on these expectations at the end of the
trial.
tDCS Adverse Events Questionnaire (AEQ) - PRO
AEQ is a specialized questionnaire developed to capture the adverse events during tDCS trials.
EQ-5D-3L - PRO
The EQ-5D-3L is a standardized measure of health-related quality of life.
15
EARLY DISCONTINUATION: PARTICIPANTS
15.1 TECHNICAL FAILURES
In case the Flow device or the participant's smartphone breaks, and it cannot be replaced within 10
days, and the participant has not already completed 22 sessions, this will be considered a
technical failure, and the participant will be withdrawn from the trial.
15.2 TREATMENT FAILURES
The following situations will be considered treatment failures and participants will be withdrawn
from the trial:
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- 30% increase in HDRS-17 score compared to baseline.
- Suicidal attempts / completion
- Device related SAE
15.3 LOST TO FOLLOW-UP (LTFU)
Participants who miss the final, 10-week study visit will be regarded as Lost to Follow-Up. As
described in the Statistical Analysis Plan, these subjects will be included in the primary analysis
through Multiple Imputation. Therefore, this definition of LTF only applies to study operations and
not data analysis. Curebase or site staff should perform and document a minimum of three
attempts to contact them via phone to complete the final study visit prior to considering the
participant LTFU. The Curebase or site staff should document the date and type of attempted
communication.
All efforts should be made to have participants complete all follow-up visits.
15.4 WITHDRAWALS
Participants have the right to withdraw from the clinical investigation at any time and for any
reason. The Principal Investigator will ask the reason for their withdrawal and will record all
information regarding the participant discontinuation.
A Participant may be withdrawn from the clinical investigation for the following reasons:
●
Participants may choose to withdraw from the clinical investigation under the terms of the
Declaration of Helsinki and their consent documentation without having to give a reason;
●
Any unanticipated adverse event which, in the opinion of the Principal Investigator, is
related to the treatment and will endanger the well-being of the participant if treatment is
continued;
●
Development of any intercurrent illness(es), infection or condition(s) that might interfere
with the clinical investigation;
●
Non-compliance with the clinical investigation procedures deemed by the Principal
Investigator to be sufficient to cause discontinuation;
●
Any problem deemed by the Investigator to be sufficient to cause discontinuation.
Participants will be withdrawn from the trial if they do not comply with the intervention, namely if
they are unable to have a minimum of 60% of the tDCS session (22 (660 minutes) out of 36
sessions at week 10) during the blinded phase, or if they develop serious adverse effects from any
part of the study. Recording of the reasons for withdrawal will be made. Their GP will be informed
about their withdrawal, and they will have a telephone follow up at 1 month following their
withdrawal.
If a participant is withdrawn, their device is disabled to make sure they cannot continue the
treatment.
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Regardless of the reason for withdrawal, data available for the participant at the time of withdrawal,
including the reason for withdrawal, will be entered on the Case Report Forms. The research staff
will request to have an optional early termination visit to collect the same data as at the week 10
and week 20 interview. The Principal Investigator will treat all participants discontinued from the
investigation due to an unanticipated adverse event, directly related to the investigation, until the
reaction resolves. A participant that has been withdrawn from the study after treatment start will not
be replaced.
15.5 DOCUMENTATION OF EARLY DISCONTINUATION AND PREGNANCY
In every instance where a participant does not complete the study, the Investigator will document
the primary reason for discontinuation in the participant’s records.
All participants are free to withdraw from participation at any time, for any reason, specified or
unspecified, and without prejudice. However, if a participant expresses a desire to withdraw their
consent for the study, the site should attempt to obtain written documentation for their study
records.
For participants that are discontinued by the Investigator, the Investigator must notify them of their
discontinuation from the study in writing.
To ensure the safety of participants who become pregnant during the study, pregnant participants
will be withdrawn from the study.
15.6 USE OF DATA FROM EARLY DISCONTINUATION CASES
Study data collected previously for participants who withdraw from the study, are discontinued from
the study by the Investigator or LTFU will be included in the data analysis and clinical study report.
15.7 ONGOING TREATMENT FOR EARLY DISCONTINUATION CASES
Participants who withdraw voluntarily or are discontinued by the Investigator will remain eligible for
SOC treatment by the Investigator and study staff.
16
EARLY DISCONTINUATION: STUDY
16.1 PROCEDURE FOR SUSPENSION OR EARLY TERMINATION
The Sponsor may suspend or prematurely terminate this clinical investigation either at an individual
investigational site or at all sites. A Principal Investigator, IRB/EC, or regulatory authority may
suspend or prematurely terminate participation in this clinical investigation at the investigational
sites for which they are responsible.
If suspicion of an unacceptable risk to participants arises during the clinical investigation, or when
so instructed by the IRB/EC or regulatory authorities, the Sponsor will suspend the clinical
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investigation while the risk is assessed. If an unacceptable risk is confirmed, the Sponsor will
terminate the clinical investigation.
The Sponsor will consider terminating or suspending the participation of a particular investigational
site or Investigator if monitoring or auditing identifies serious or repeated deviations on the part of
an Investigator.
If suspension or premature termination occurs, the terminating party will justify its decision in
writing and promptly inform the other parties with whom they are in direct communication.
If suspension or premature termination occurs:
The Sponsor will remain responsible for providing resources to fulfill the obligations from this
protocol and existing agreements for following the participants enrolled in the clinical investigation,
and the site’s Principal Investigator or authorized designee will promptly inform the enrolled
participants at his/her investigational site
If the study is terminated, Flow Neuroscience AB must comply with all applicable government
regulations and the protocol-required participant follow-up. If discontinuation of the study should
occur, the Principal Investigator must return all clinical investigation materials (including devices) to
the Sponsor and provide a written statement to the IRB/EC explaining the reasons for the
premature termination. All applicable clinical investigation documents shall be participant to the
same retention policies, as detailed in Section 24.3.
16.2 PROCEDURE FOR RESUMING THE CLINICAL INVESTIGATION AFTER TEMPORARY SUSPENSION
When the Sponsor concludes an analysis of the reason(s) for the suspension, implements the
necessary corrective actions, and decides to lift the temporary suspension, the Sponsor will inform
the relevant parties of the rationale and provide them with the relevant data supporting this
decision. Concurrence will be obtained from the IRB/ECs and, where appropriate, regulatory
authorities before the clinical investigation resumes. If participants have been informed of the
suspension, the Principal Investigator or authorized designee will inform them of the reasons for
resumption.
16.3 ROUTINE CLOSE-OUT
Routine close-out activities will be conducted to ensure that the Principal Investigator's records are
complete, all documents needed for the Sponsor's files are retrieved, remaining clinical
investigation materials are destroyed, previously identified issues have been resolved, and all
parties are notified.
17 PROTOCOL DEVIATIONS
Conformance to the protocol is essential to the quality and integrity of the clinical study. Every effort
should be made to avoid any deviation from the clinical protocol. A protocol deviation is an event
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whereby the clinical investigator or site personnel did not conduct the study according to the
protocol.
Under emergency circumstances, deviations from the protocol to protect the rights, safety and
well-being of human subjects may proceed without prior approval of the sponsor and the IRB/EC.
Such deviations shall be documented and reported to the sponsor in the EDC within 5 days of
knowledge. The IRB/EC should be notified of the deviation as required by IRB/EC reporting
guidance.
18 CONCOMITANT MEDICATIONS/THERAPIES
For the purposes of this clinical study, only medications taken or administered for the following will
be recorded (Ensure medications reflected in incl/excl are listed here):
●
Muscle relaxation;
●
Other medications related to or given for the participant’s MDD.
19 ADVERSE EVENT & DEVICE DEFICIENCY REPORTING
Subjects will be carefully monitored during the study for possible adverse events (AEs) from the
time they sign the Informed Consent Form to the time of study completion. All medical events and
conditions prior to this time point are to be captured as medical history.
Any observed unanticipated AE will be fully investigated by the Investigator and classified in line
with the definitions of ISO 14155:2020 below. The frequency and severity of anticipated AEs will
instead be captured using the tDCS Adverse Events Questionnaire (AEQ).
All unanticipated adverse events that occur during this study will be recorded on the adverse event
eCRFs and must include the following information at minimum:
●
Event Description
●
Date of Onset
●
Date of Resolution
●
Severity
●
Seriousness
●
Relationship to Study Device/Procedure
●
Outcome
Adverse events will be reported and classified by the Investigator using the specific signs,
symptoms or abnormal laboratory values, or medical diagnosis if no signs, symptoms, or abnormal
laboratory values can be identified.
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Significant new information and updates should continue to be captured in the subject’s records
and in the EDC as they become available and the adverse event should be followed until it is
resolved or no further improvement is expected, or the subject is lost to follow-up.
Adverse events that meet the definitions of seriousness in Section 19.1 below should also be
reported to the Sponsor per the instructions provided in Section 19.2.4 below.
19.1 DEFINITIONS
The following definitions are from the ISO 14155:2020 and MDCG 2020-10:
Adverse Event (AE) – An adverse event (AE) is any untoward medical occurrence, unintended
disease or injury, or untoward clinical signs (including abnormal laboratory findings.) in subjects,
users, or other persons, whether or not related to the investigational device and whether
anticipated or unanticipated.
NOTE 1: This definition includes events related to the investigational medical device or the
comparator.
NOTE 2: This definition includes events related to the procedures involved.
NOTE 3: For users or other persons, this definition is restricted to events related to the use of
investigational medical devices.
Anticipated Adverse Events – Anticipated adverse events are adverse events that have been
identified as adverse events related to the investigational device or study procedure. The
anticipated events of this clinical investigation are outlined in tDCS Adverse Events Questionnaire
(AEQ). The frequency and severity of anticipated AEs will be captured using AEQ.
Anticipated adverse events are:
●
Headache
●
Neck pain
●
Scalp pain
●
Tingling
●
Itching
●
Burning sensation
●
Skin redness
●
Sleepiness
●
Trouble concentrating
●
Acute mood change
Adverse Device Effect (ADE) – An adverse device effect (ADE) is any adverse event related to
the use of an investigational device. This definition includes:
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●
Adverse events resulting from insufficient or inadequate instructions for use, deployment,
implantation, installation, or operation, or any malfunction of the investigational medical
device.
●
Any event resulting from use error or from intentional misuse of the investigational medical
device.
●
“Comparator” if the comparator is a medical device.
Serious Adverse Event (SAE) – A Serious Adverse Event is an AE which:
1.
Led to a death,
2.
Led to serious deterioration in the health of the subject, users, or other persons that either
resulted in:
a) A life-threatening illness or injury, or
b) A permanent impairment of a body structure or a body function including chronic
diseases, or
c)
In-patient or prolonged hospitalization, or
d) Medical or surgical intervention to prevent life threatening illness or injury or
permanent impairment to a body structure or a body function.
3.
Led to fetal distress, fetal death or a congenital abnormality or birth defect including
physical or mental impairment (not anticipated in this study as pregnant women are
excluded from the study).
NOTE: Planned hospitalization for any pre-existing condition, or a procedure required by the
Clinical Investigation Plan, without a serious deterioration in health, is not considered a serious
adverse event.
Serious Adverse Device Effect (SADE) – a Serious Adverse Device Effect is an adverse device
effect that has resulted in any of the consequences characteristic of a serious adverse event.
Anticipated Serious Adverse Device Effect (ASADE) – an Anticipated Serious Adverse Effect is
an effect which by its nature, incidence, severity, or outcome has been identified in the risk analysis
report.
Unanticipated Serious Adverse Device Effect (USADE) – this is a serious adverse device effect
which by its nature, incidence, severity, or outcome has not been identified in the current version of
the risk analysis report. This is also referred to as an Unanticipated Adverse Device Effect (UADE)
in the US. See Section 19.2.4 for details regarding determination and reporting requirements in the
US.
Device Deficiency (DD) - A device deficiency is an inadequacy of a medical device with respect to
its identity, quality, durability, reliability, safety, or performance. Device deficiencies include
malfunctions, use errors, and inadequacy in the information supplied by the manufacturer including
labelling.
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Malfunction – Failure of an investigational medical device to perform in accordance with its
intended purpose when used in accordance with the instructions for use or protocol.
Use Error – User action or lack of user action while using the medical device that leads to a
different result than that intended by the manufacturer or expected by the user.
NOTE1: Use error includes the inability of the user to complete a task.
NOTE 2: Use errors can result from a mismatch between the characteristics of the user, user
interface, task or use environment.
NOTE 3: Users might be aware or unaware that a use error has occurred.
NOTE 4: An unexpected physiological response of the patient is not by itself considered a use
error.
NOTE 5: A malfunction of a medical device that causes an unexpected result is not considered a
use error.
19.2 CLASSIFICATION OF AN AE
19.2.1 SEVERITY
Investigators will assess the severity of the adverse event and classify it according to the following
definitions:
●
Mild: Awareness of a sign or symptom that does not interfere with the patient’s usual
activity or is transient, resolved without treatment and with no sequelae.
●
Moderate: Interferes with the patient’s usual activity and/or requires symptomatic
treatment.
●
Severe: Symptom(s) causing severe discomfort and significant impact on the patient’s
usual activity and requires treatment.
These definitions are for descriptive purposes only and are independent of the judgment of
whether an event is classified as an AE or an SAE.
19.2.2 ASSESSMENT OF RELATIONSHIP TO USE OF THE INVESTIGATIONAL DEVICE OR PROCEDURE
The relationship between the use of the medical device (including the medical - surgical procedure)
or control procedure the occurrence of each unanticipated adverse event shall be assessed and
categorized. During causality assessment, clinical judgment shall be used, and the Clinical
Protocol shall be consulted, as all the foreseeable adverse events and the potential risks are listed
and assessed there. The presence of confounding factors, such as concomitant
medication/treatment, the natural history of the underlying disease, other concurrent illness or risk
factors shall also be considered.
19.2.3 SAE RELATIONSHIP ASSESSMENT
Per MDCG 2020-10/1 (May 2020), Investigators will assess the potential relationship of the SAE to
the use of the investigational device (including the surgical procedure) or control procedure and
classify the causality of the event according to the following definitions.
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●
Not Related: Relationship to the device or procedures can be excluded when:
−
the event has no temporal relationship with the use of the investigational device, or the
procedures related to application of the investigational device;
−
the serious event does not follow a known response pattern to the medical device (if the
response pattern is previously known) and is biologically implausible;
−
the discontinuation of medical device application or the reduction of the level of
activation/exposure - when clinically feasible - and reintroduction of its use (or increase
of the level of activation/exposure), do not impact on the serious adverse event;
−
the event involves a body-site or an organ that cannot be affected by the device or
procedure;
−
the serious event can be attributed to another cause (e.g., an underlying or concurrent
illness/ clinical condition, an effect of another device, drug, treatment, or other risk
factors);
−
the event does not depend on a false result given by the investigational device used for
diagnosis, when applicable;
−
harms to the subject are not clearly due to use error;
−
In order to establish the non-relatedness, not all the criteria listed above might be met at
the same time, depending on the type of device/procedures and the serious adverse
event.
●
Possible: The relationship with the use of the investigational device or the relationship with
the procedure is weak but cannot be ruled out completely. Alternative causes are also
possible (e.g., an underlying or concurrent illness/ clinical condition or/and an effect of
another device, drug, or treatment). Cases where relatedness cannot be assessed or no
information has been obtained should also be classified as possible.
●
Probable: The relationship with the use of the investigational device or the relationship with
the procedure, seems relevant and/or the event cannot reasonably be explained by another
cause.
●
Causal Relationship: The serious adverse event is associated with the investigational
device or with procedures beyond reasonable doubt when:
−
the event is a known side effect of the product category the device belongs to or of
similar devices and procedures;
−
the event has a temporal relationship with investigational device use/application or
procedures;
−
the event involves a body-site or organ that
●
the investigational device or procedures are applied to;
●
the investigational device or procedures have an effect on;
−
the serious event follows a known response pattern to the medical device (if the
response pattern is previously known);
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−
the
discontinuation of medical device application (or reduction of the level of
activation/exposure)
and
reintroduction
of
its
use (or increase of the level of
activation/exposure), impact on the serious event (when clinically feasible);
−
other possible causes (e.g., an underlying or concurrent illness/ clinical condition or/and
an effect of another device, drug, or treatment) have been adequately ruled out;
−
harm to the subject is due to error in use;
−
the event depends on a false result given by the investigational device used for
diagnosis, when applicable;
−
In order to establish the relatedness, not all the criteria listed above might be met at the
same time, depending on the type of device/procedures and the serious event.
Where the Investigator or Sponsor remains uncertain about classifying the event, it should not
exclude the relatedness and the Investigator should classify the event as “Possibly Related”.
19.2.4 SAE REPORTING
Flow Neuroscience AB is responsible for the classification and reporting of adverse events and
ongoing safety evaluation of the clinical investigation in line with ISO 14155:2020 and US/UK
regulatory requirements.
Investigator will report “to the Sponsor, without unjustified delay, all serious adverse events and
device deficiencies that could have led to a serious adverse device effect; this information shall be
promptly followed by detailed written reports” [ISO 14155:2020 § 9.8 b]. Device malfunctions and
use errors should also be reported without unjustified delay.
In the event of becoming aware of any SAE (including all device deficiencies), anticipated or
unanticipated, the Investigator will report the event to Flow Neuroscience AB and Curebase
immediately (at least within 24 hours after first knowledge of the event) by entering SAE
information in the EDC. In the event the EDC is unavailable for any reason, notification to Flow
Neuroscience AB should be made via email as follows:
Sponsor Contact: Erik Rehn
E-mail: erik@flowneuroscience.com
Phone: +46736607170
The Investigator should provide additional information on the SAE by updating the information in
the EDC as updates become available. Flow Neuroscience AB may also ask for additional clinical
reports including redacted source documents to be provided by the Investigator to assist in the
assessment of the event. Significant new information and updates should continue to be submitted
promptly to and entered in the EDC as they become available, and the Investigator should follow
the SAE until it is resolved, or no further improvement is expected.
It is the responsibility of each Investigator to report all SAEs and/or SADEs to the IRB/EC,
according to national regulations and IRB/EC requirements. A copy of the IRB/EC report should be
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forwarded to Flow Neuroscience AB. In countries that require the Sponsor to report safety events
rather than investigators, the Sponsor (Flow Neuroscience AB) will report SAEs and/or SADEs to
the EC.
Flow Neuroscience AB will ensure that all SAEs and device deficiencies that could have led to a
SAE are reported to the Competent Authorities in accordance with European Medical Devices
directives and all applicable national regulations.
Flow Neuroscience AB will ensure that all events that meet the vigilance requirements as
described in MDCG 2020-10/1 (Safety reporting in clinical investigations of medical devices under
the Regulation (EU) 2017/745) are reported to the Competent Authorities in accordance with
European Medical Devices directives and all applicable national regulations.
19.2.5 DETERMINATION AND REPORTING OF UNANTICIPATED ADVERSE DEVICE EFFECTS (US SITES)
The Sponsor shall review all reported SAEs to evaluate whether they meet the criteria for an
Unanticipated Adverse Device Effect. For adverse events that are determined to be UADEs, the
Sponsor will submit an expedited safety report to the FDA’s Center for Devices and Radiological
Health (CDRH). The expedited safety report will be submitted to the FDA as soon as possible and,
in no event, later than ten (10) business days after the Sponsor first receives notice of the UADE. A
copy of this safety report will be provided to all participating study Investigators.
If, following receipt and investigation of follow-up information regarding an adverse event that was
previously determined not to be a UADE, the Sponsor determines that the event does meet the
requirements for expedited reporting, the Sponsor will submit a report as soon as possible, but in
no event later than ten (10) business days after this is determined.
19.3 TREATMENT OF AES
The Investigator will treat all participants who experience an adverse event directly related to the
device.
19.4 SAFETY OVERSIGHT: CLINICAL EVENTS COMMITTEE (CEC)
The Clinical Events Committee (CEC) will adjudicate all AEs and protocol deviations. SAEs and
AEs deemed “definitely,” “probably,” and “possibly related” or with an “unknown relationship” to the
device or procedure, primary endpoint failure, and the following neurological AEs, including
neurologic deterioration will be reviewed.
19.5 SAFETY/SUICIDE RISK MANAGEMENT PLAN
All study participants will be provided a safety crisis action plan for suicide risk at the time of study
enrollment. The crisis action plan will include the following information;
-
Name, address, and telephone number of the closest hospital emergency
department near the study participant’s residence
-
Contact details of next of kin/friends for support
-
Study participant’s regular treating physician’s name and contact information
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-
National Suicide Prevention Lifeline 800-273-8255
-
Strategies for coping with suicidal ideation/crisis.
-
Further, subjects will be notified that study personnel will contact their psychiatrist in
the case of worsening depression/suicidality (worsening depression is defined as
30% increase in HDRS-17 score compared to baseline).
All participants will be informed about the warning signs of suicidal ideation and behavior at the
start of the study. Throughout the study, subjects will be monitored by study psychiatrists.
If the C-SSRS questions 4, 5, and 6b are positive during the study assessments, the participant will
be asked to go to the nearest emergency department or mental health crisis center.
The suicide risk management plan document (attachment “Brown_StanleySafetyPlan”) will be
completed with patients.
20
STOPPING RULES
The following events will result in the study stopping:
-
If two subjects commit suicide
-
If three subjects attempt suicide
-
If ≥2 serious adverse events (SAEs) occur that are device-related, as determined by
investigators, the IRB, the FDA, or the Clinical Events Committee (CEC)
If any of the stopping rules are reached, enrollment will be paused and the FDA will be notified in a
supplement to enable review of the information.
21 CLINICAL MONITORING
21.1 SITE MONITORING
The study will be monitored to ensure that it is conducted in conformance with the monitoring plan
by an independent CRO to assess continued compliance with the protocol, recognized Good
Clinical Practices, FDA’s 2013 guidance document “Guidance for Industry Oversight of Clinical
Investigations — A Risk-Based Approach to Monitorings, and federal regulations outlined in 21
CFR Part 812
-
Subpart A
-
Subpart B
-
Subpart C -
-
812.3 Definitions
-
812.25 Investigational Plan
-
812.28 Acceptance of data from clinical investigations conducted outside the United
States
-
812.30 FDA action on applications
-
812.35 Supplemental applications
-
812.36 Treatment use of an investigational device
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-
812.40 General responsibilities of sponsors
-
812.43 Selecting investigators and monitors
-
812.46 Monitoring investigations
-
812.47 Emergency research under 50.24 of this chapter
-
812.140 Records
-
812.150 Reports
In addition, the monitor verifies that study records are adequately maintained, that data are
reported in a satisfactory manner with respect to timeliness, adequacy, and accuracy, and that the
Investigator continues to have sufficient staff and facilities to conduct the study safely and
effectively.
The study may also be subject to a quality assurance audit by the Sponsor or its designees, as
well as inspection by appropriate regulatory authorities. It is important that the Investigator and
relevant study personnel are available during on-site monitoring visits or audits and that sufficient time is
devoted to the process.
The organization responsible for monitoring the study is:
Curebase Inc.
335 S Van Ness Ave
San Francisco, CA 94103-3627
(519)590-8490
www.curebase.com
In addition to ensuring adequate communication between the Investigators and the Sponsor, the
CRO’s duties include on-site visits and review of study documents and reported data. The CRO
study representatives will be provided with appropriate device and protocol training prior to the
study and will follow a Monitoring Plan for all study-related monitoring activities.
21.2 MONITORING ACTIVITIES
Monitoring visits include a pre-study Site Initiation Visit, periodic Interim Monitoring Visits, and a
Close-Out Visit at the end of the site’s participation in the study.
Each site’s Investigator will allocate adequate time for monitoring activities. The Investigator will
also ensure that the monitor or other compliance or quality assurance reviewer is given access to
the study-related documents and study-related facilities and has adequate space to conduct the
monitoring visit.
Monitoring visits will be documented on monitoring visit reports, and will aim to verify that:
●
Compliance with the clinical protocol and applicable regulations is being maintained
●
Source data is verified and signed-off upon as accurate
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●
Participant files are accurate and complete
●
Participant withdrawal has been documented (if applicable)
●
Participant non-compliance has been documented (if applicable)
●
The Investigator and site staff are informed and knowledgeable of all relevant document
updates concerning the clinical investigation
●
Only authorized individuals are performing study-related functions
●
The investigational device is being used according to the protocol and instructions for use
●
Adequacy of staffing and facilities
●
Signed and dated ICFs have been obtained from each participant
●
eCRFs and queries are complete
●
All adverse events are reported to the Sponsor
●
All serious and unanticipated adverse device events are reported to the Sponsor and the
IRB/EC
●
All other required IRB/EC reports, notifications, applications, submissions, and
correspondence are maintained in the Investigator’s files and are accurate
●
Corrective and preventive actions have been implemented (if applicable)
21.3 FREQUENCY OF VISITS
To ensure that the study is conducted in accordance with the terms of the clinical protocol, study
monitors must visit each investigational site at routine intervals throughout the duration of the
study. The exact frequency of visits shall be determined on an individual site basis as detailed in
the Clinical Monitoring Plan, and shall depend upon the following factors:
●
Rate of participant enrollment
●
Experience of the Investigator in conducting clinical studies
●
Record of previous site compliance
21.4 AUDIT AND INSPECTIONS
Participation as an Investigator in this study implies acceptance of potential inspection by
government regulatory authorities. The Investigator must also be prepared to permit study-related
audits and inspections by the Sponsor, CRO, IRB/EC and the site’s institutional compliance and
quality assurance groups. The Investigator will ensure the capability for inspections of applicable
study-related facilities, records, and reports.
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22 STATISTICAL ANALYSIS
22.1 STUDY HYPOTHESIS
The primary clinical outcome of the study will be to compare the adjusted mean group differencebased on
HDRS-17 scores of the two arms at 10 weeks compared to baseline.
The primary efficacy hypothesis is the change in HDRS-17 scores between 10 weeks and baseline between
subjects randomized to the study device relative to those subjects randomized to Sham. The formal
statistical hypothesis is as follows:
Ho: dflow – dsham ≤0
Ha: dflow – dsham > 0
Where dflow and dsham are the adjusted mean group difference in HDRS-17 scores in subjects
randomized to Flow and Sham groups, respectively.
22.2 SAMPLE SIZE ASSUMPTIONS AND CALCULATIONS
The sample size calculation is based on data from Brunoni et al (2017). The calculation is based
on a two- sample t-test for mean difference with the following assumptions:
●
Group difference in means = 3.2
●
Standard deviation of Investigational and Sham groups = 7.1 and 7.9, respectively
●
One-sided type I error = 0.025 
●
80% power
The resulting sample size is 176 subjects. To obtain an increase in statistical power (87.6%), 216
subjects were chosen. Accounting for 20% attrition, the overall sample size will be 270 subjects.
22.3 STUDY POPULATIONS
22.3.1 INTENT-TO-TREAT ANALYSIS SET (ITT)
All randomized subjects will be included in the “intent-to-treat” (ITT) analysis set and classified
according to their intended treatment regardless of failure to complete the required follow-up
examinations. Subjects excluded prior to randomization will be considered screening failures.
22.3.2 AS TREATED ANALYSIS SET (AT)
The As Treated Analysis Set (AT) will consist of ITT subjects who receive at least 1 treatment of
study device (Active or Sham). Subjects will be analyzed according to the study treatment
received. The As Treated Analysis Set will be used for all summaries of safety and tolerability data.
22.3.3 MODIFIED INTENT-TO-TREAT ANALYSIS SET (MITT)
The modified intent-to-treat (mITT) analysis set will include ITT subjects who receive at least 1
treatment of study device (Active or Sham) and will exclude patients who were randomized in error.
The number of exclusions from the mITT analysis set is expected to be small and will only be
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based on information that was known or could have been known prior to the first treatment.
Subjects in the mITT population will be analyzed in the group to which they were randomized.
22.3.4 PER PROTOCOL ANALYSIS SET (PP)
The Per Protocol (PP) analysis set will be comprised of the following:
●
Subjects in the mITT analysis set
●
Subjects with device failure within the 10-week follow-up period
●
Subjects with deviation from the clinical investigation plan is caused by the investigational
device or by problems with respect to tolerability
Subjects who will be excluded from the PP analysis set are as follows:
●
Subjects with major protocol violations that would be expected to confound clinical
assessment during follow-up as determined by the PIs.
●
Subjects who took new pharmaceutical substances or treatments during the clinical
investigation which are listed as an exclusion criteria;
●
Subjects who do not meet the inclusion criteria or exclusion criteria.
●
Users who have performed less than 10 sessions (300 minutes) during the first 3 weeks will
be excluded from the analysis.
Subjects in the PP population will be analyzed in the group to which they were randomized.
22.4 RANDOMIZATION
After a subject has met all inclusion criteria and none of the exclusion criteria, and creates an account in the
Flow app, the subject will be randomized. Randomization will be performed in a 1:1 ratio to the Active and
Sham groups. Randomization will be performed using randomly permuted block sizes of 4 and 6 and done
independently for the two sites.
22.5 TESTING OF PRIMARY EFFECTIVENESS HYPOTHESES
The primary effectiveness endpoint is the change in adjusted mean group difference in the HDRS-17 scores
between 10 weeks and baseline between subjects randomized to the active study device relative to those
subjects randomized to sham. The formal statistical hypothesis is as follows:
Ho: dflow – dsham ≤0
Ha: dflow – dsham > 0
Where dflow and dsham are the adjusted mean group difference in HDRS-17 scores in subjects randomized to
Active and Sham groups, respectively.
The mITT population will be the analysis population used to analyze the primary effectiveness endpoint. The
endpoint will be analyzed when all randomized subjects have completed their 10-week visit, been withdrawn
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from the trial or passed the end of their 10-week follow-up visit window. The difference in the group mean
differences will be assessed using a mixed model for repeated measures. If the p-value of the difference in
the group mean differences is less than one-sided p= 0.025, then the trial declared a success.
22.5.1 MULTIPLE IMPUTATION ANALYSIS
The mixed model for repeated measures (MMRM) allows for inclusion of patients with missing Week 10
values. If all subjects have at least one follow-up evaluation, the following MMRM will be utilized for the
primary superiority test. If there are subjects without at least one post baseline assessment, the multiple
imputation analysis summarized below will be the primary analysis method. Least squares estimated values
from the MMRM will be reported for HDRS-17 at each visit and as such these estimates include implicit
imputations of missing values.
Details of the MMRM used to evaluate the primary endpoint are described in the attached Statistical analysis
plan.
22.6 MISSING DATA/SENSITIVITY ANALYSIS
Details of the handling are in the attached Statistical analysis plan.
22.7 COVARIATES/COVARIATE ANALYSIS
The heterogeneity of treatment effects for the primary effectiveness endpoint will be examined for subgroups
using baseline variables. These will include, but are not limited to, age (split at median), and sex at birth.
Subjects on antidepressants and/or psychotherapy drugs during the course of the trial will constitute their
own subgroup and be characterized and described in the clinical study report. The mixed model for repeated
measures will be run to see the impact of the treatment effect by each subgroup of interest separately. The
results will be reported as mean differences and 95% confidence intervals for each subgroup. These results
will be graphically displayed in a forest plot.
22.8 SECONDARY EFFECTIVENESS ENDPOINTS
Secondary effectiveness endpoints will be analyzed descriptively.
For continuous variables (CONT), results will be summarized with the numbers of observations, means,
standard deviation, median, minimums and maximums. Differences between the two groups, where
specified, will be summarized with the differences of the two means, and 95% confidence intervals for the
difference between the means. These calculations will be done under the assumption that data for the two
groups are independent and approximately normally distributed. The confidence interval for the difference of
two means will be calculated under the assumption of unequal variances. If the asymptotic assumptions fail,
then nonparametric summary statistics (medians, 25th and 75th percentile) may be displayed as an
alternative.
For binary variables (BIN), results will be summarized with patient counts, percentages/rates. Differences
between the two groups, where specified, will be summarized with the difference in percent and the
Newcombe score 95% confidence interval for the difference of two percentages.
For correlation analysis, Spearman correlation will be used to assess the association between two
continuous variables. The correlation coefficient and the 95% confidence intervals will be reported.
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There are three secondary endpoints controlled multiplicity (see below):
●
The mean change in points for MADRS score from baseline to Week 10. This will be evaluated using
the same statistical methodology as the primary endpoint.
●
Clinical Response will be analyzed as a responder endpoint. Clinical Response is defined as a >50%
reduction from the baseline HDRS-17 or MADRS score, MADRS-s at Week 10.
●
Remission will be analyzed as a responder endpoint where remission is defined as an HDRS-17
score ≤7 or a MADRS score ≤10). The endpoint will be tested using a two-group large-sample
normal approximation test of proportions with a one-sided 0.025 considered significant.
●
Quality of life improvement as measured by EQ-5D-3L in the active compared to sham arm at week
10 compared to baseline.
22.9 EXPLORATORY ENDPOINTS
The following list of secondary endpoints will be analyzed using the mITT population and will be summarized
based on the type of data: Continuous (CONT), Binary (BIN) or Correlation (CORR):
●
Montgomery–Åsberg Depression Rating Scale (MADRS) response rate at all follow-up time points
(CONT)
●
Montgomery–Åsberg Depression Rating Scale - Self-report (MADRS-s) scores of the two arms
(response and remission rates) at all time points (CONT)
●
Hamilton Anxiety Rating Scale (HAM-A) at all time points (CONT)
●
Young Mania Rating Scale (YMRS) at all time points (CONT)
●
tDCS Adverse Events Questionnaire (AEQ) at 10 and 20 weeks (CONT)
●
HDRS-17 (CONT), MADRS (CONT), MADRS-s mean decrease (CONT), remission (BIN), and
response rate (BIN) at 6 weeks comparison between groups.
●
HDRS-17 (CONT), MADRS (CONT), MADRS-s (CONT) at 20 weeks (after open-label)
●
Correlation between MADRS and MADRS-s. (CORR)
●
Correlation between the percent of sessions using the FLOW FL-100 and HDRS-17/MADRS
decrease in the active group at 10 weeks.
●
The within-patient clinically meaningful improvement as defined as at least -3 points on the HDRS-17
scale. The percentage of subjects for each arm that reaches -3 points or more improvement and also
the Cumulative Distribution Function Curves of Change in HDRS-17 Score from Baseline to Primary
end-point by arm.
22.10
MULTIPLICITY ADJUSTMENT
The secondary endpoints will only be tested if the primary endpoint demonstrates superiority. By
pre-specifying the order in which the primary and conditional effectiveness hypotheses are performed, there
is no type 1 error inflation and nominal alpha levels may be used on the primary endpoint.
Should the primary endpoint be met, the clinical response endpoint (Endpoint #1 in SAP version 2) will be
tested. Should the secondary Endpoint #1 be met, the remaining endpoints will be tested using Hochberg
correction for multiplicity. Complete details for multiplicity adjustment are provided in the SAP.
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22.11 EVALUATION OF BLINDING
An evaluation of blinding will be performed. Prior to subjects unblinding through the system they will respond
to the question “Which treatment arm do you think you are in?” (answers: sham/active), followed by the
question “How certain are you of this?”, with the options 1 to 5 where 5 is very certain and 1 is very
uncertain. The counts and percentages of the subjects responding correctly will be tabulated and reported.
22.12
DEVICE SURVIVAL
Kaplan-Meier survival analysis will be used to characterize device failure time. Device failure in this study is
defined as the device not operating as intended without unexpected failure. Unexpected failure is defined as
a failure that is not related to device functionality. For example, the device accidentally falling out of a window
would be categorized as an unexpected device failure. In contrast, the device failing to turn on would be
considered an expected device failure. As the device is not expected to have any unexpected failures,
unexpected failures will only be reported if they occur. Lifetables will be tabulated indicating the number of
“failures'' and the number of “at- risk” subjects over time for all failures, unexpected failures and expected
failures. If there are more than one of each expected and unexpected failures, a log-rank test will be
performed to compare the device failure time distribution.
22.13
POOLABILITY ANALYSIS
Poolability will be assessed through stratification of the primary endpoint by Country (OUS and US). Within
country point estimates will be calculated along with nominal descriptive 95% Confidence Intervals. The
focus of this analysis will be on the similarity of the country specific point estimates. Differences will be
described in the Clinical Study Report.
Statistical evaluation of the primary endpoint will be evaluated by adding site by treatment group term to the
primary MMRM model. A p-value of <= 0.10 will be considered significant for this poolability assessment.
Should a significant site x treatment group interaction be present, the patient factors of age, gender, and
baseline scores will be assessed to understand if differences in case-mix factors explain differences
observed between sites.
22.14
SAFETY ANALYSES
Assessment of the safety of the investigational device will include an evaluation of the incidence and severity
of complications and adverse reactions associated with the treatment.
Adverse event rates will be summarized by type of AE and for specific AEs in two ways:
1.
per subject incidence of specific AEs and classes of AEs and
2.
by event, summarizing event counts by visit interval over time and in accordance with FDA Guidance
(CDRH 2004)15.
Device and procedure-related events will be summarized by severity and relatedness. Events listings that
include details such as relatedness, severity, onset, and resolution status will be provided for all events and
relevant subsets of events such as serious events and related events. Primary safety comparisons will be
performed using the AT analysis set. The summary tables will show the adverse events (in coded terms), the
total number of events, and the number and the percentage of subjects affected in each treatment group
15 CDRH. Guidance for Industry and FDA Staff: Clinical Data Presentations for Orthopedic Device Applications, December 2, 2004.
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(“subject wise evaluation”) and stratified by relation to device and severity. Data of dropouts will be presented
separately, and possible bias will be discussed in the final report.
All AEs will be summarized in listings for the AT analysis set. The following AE listings will be constructed:
●
AE Listing 1 All AEs Sorted by Group and Event Type
●
AE Listing 2 All AEs Sorted by Group and Subject
●
AE Listing 3 Serious AEs
●
AE Listing 4 Severe AEs
●
AE Listing 5 Device Related AEs
●
AE Listing 6 Serious Device Related AEs
●
AE Listing 7 Severe Device Related AEs
●
AE Listing 8 Other AEs
●
AE Listing 9 AEs among subjects discontinued early
●
AE Listing 10 AEs among subjects who died
22.15 INTERIM ANALYSES
An interim analysis testing for futility, sample size re-estimation, and claiming study success with a sample
size smaller than the maximum specified is specified. Please see the details in the Adaptive Design Report
detailing all elements of this process.
23 ETHICS & PROTECTION OF HUMAN SUBJECTS
23.1 ETHICAL REVIEW
The study will be performed in accordance with the standard guidance on clinical investigations
with medical devices on human subjects and recommendations guiding physicians in biomedical
research involving human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland,
1964 and later revisions.
The clinical investigational plan, informed consent, any other study specific study documents as
required by regulations and all amendments to these study documents will be reviewed and
approved by the FDA and appropriate IRB/EC before enrollment of any patient. In addition, the
sponsor will keep the regulatory authorities informed of any SAEs throughout the study course, if
applicable.
23.2 REGULATORY CONSIDERATIONS
This study will be conducted in accordance with the Good Clinical Practice (GCP) guidelines and
other applicable regulatory requirements including but not limited to:
●
FDA Regulations on Investigational Device Exemption (21 CFR 812)
●
FDA Regulations on research with human beings (21 CFR 50, 54 and 56)
●
Health and Human Services (DHHS) Regulations on research with human beings (45 CFR
46 Subparts A, B, C, and D)
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●
International Conference on Harmonization (ICH) Guidance for Industry-E6 Good Clinical
Practice: Consolidated Guideline
●
The Declaration of Helsinki
23.3 STUDY AMENDMENTS
All changes to the protocol that impact validity of data, scientific soundness, the rights safety, or
welfare of the participants, must be documented in the format of an amendment with justification
statements in the cover letter to the IRB/EC and FDA. All amendments must be submitted to the
IRB/EC and regulatory authority for review and approval. Following approval, the protocol
amendment will be distributed to all protocol recipients at each investigational site.
23.4 INSURANCE
The Sponsor has issued clinical trial insurance with appropriate coverage for the continuation of
the entire study.
24
DATA HANDLING AND RECORDKEEPING
24.1 EDC AND ECRFS
eCRFs will be completed in a 21 CFR Part 11 compliant electronic data capture (EDC) system for
each patient enrolled into the clinical study. The study coordinator will enter the source data onto
the eCRFs, and study monitors will verify that the source documents match the eCRFs. Once
verified, the study monitor will lock the field via a monitoring approval step so the data cannot be
changed unless requested.
All procedures for the handling and analysis of data will be conducted using good clinical data
management practices within systems meeting FDA guidelines for the handling, storage, and
analysis of data for clinical studies.
The Investigator will sign off on the Eligibility Criteria, all Adverse Event, Protocol Deviation and
Study Completion eCRFs and will sign each patient’s casebook once the patient completes the
study to attest that all data entered on the eCRFs are complete and accurate. All of the above
signatures will be completed digitally within the EDC system using the system’s Part 11 compliant
digital signature system function.
Any required data clarifications will be handled within the EDC system’s query management
system. The EDC will be programmed to automatically place data clarification queries on missing
values and values out of acceptable ranges. Study monitors and data managers will also be able to
add data clarification queries to data points within the system. Study coordinators will have the
opportunity to correct data and/or respond to the query for review by monitors and data managers.
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24.2 CAPTURE OF PATIENT REPORTED OUTCOMES
Patient reported outcomes (PROs) will be collected via the participant’s personal smartphone or
other device running Android 5.0+ or iOS 12+ and the data will be transmitted directly into the
EDC. As the data is originated in the participant’s device, it is considered to be electronic source
and the data is automatically locked as soon as it enters the EDC to ensure that it is secure.
24.3 STUDY RECORDS RETENTION
The Investigator and the Sponsor will maintain accurate, complete, and current records relating to
participation in this clinical investigation. If the Investigator wishes to assign the responsibility of
maintaining the study files to someone else or move them to another location, he/she should
consult with the study sponsor in writing regarding the change. The Investigator will take measures
to ensure that these essential documents are not accidentally damaged or destroyed.
Upon study completion, the study files must be maintained in a known location for a maximum of a
2 years following the date a marketing application is approved for the medical device for the
indication for which it is being investigated; or, if no application is to be filed or if the application is
not approved for such indication, until 2 years after the investigation is discontinued and FDA is
notified.
The Investigator and Sponsor will maintain records in accordance with 21 CFR 812, Subpart G, to
include:
●
Current and past versions of the IRB/EC-approved clinical protocol and amendments and
corresponding IRB/EC-approved consent form(s) and, if applicable, participant recruitment
advertisements
●
FDA correspondence related to the IDE application; including supplemental IDE
applications, current investigator lists, progress reports
●
IRB/EC correspondence (including submissions and approval notifications) including safety
and protocol deviation reports, and annual or interim reports
●
Signed Clinical Trial Agreement
●
Signed Investigator Agreements and financial disclosure forms for participating
Investigators
●
Curriculum vitae (Investigator and Sub-Investigators)
●
Certificates of required training for Investigators and Sub-Investigators, including human
subject protection and Good Clinical Practice
●
Instructions for handling the investigational device and other study-related materials
●
Device tracking logs
●
Signed ICFs
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●
eCRF and Source Documents
●
Monitoring visit confirmation and follow-up letters
●
Copies of relevant Sponsor-Investigator correspondence, including notifications of adverse
event information
●
Screening and Enrollment Log
●
Signed informed consent forms
●
Final clinical study report
24.4 PUBLICATION AND DATA SHARING POLICY
Data generated from the conduct of this study will be used to support an application by Flow
Neuroscience AB as an original Premarket Approval (PMA) from FDA. Publication of the results of
the study will follow Flow Neuroscience AB ’s Publication and Presentation Policy.
24.5 PARTICIPANT AND DATA CONFIDENTIALITY
Participant confidentiality will be maintained throughout the study in a way that ensures that data
can always be tracked back to the source data. For this purpose, a unique participant identification
code (two-digit site identification number and three-digit participant name identification number
code assigned sequentially) will be used that allows identification of all data reported for each
participant without traceability back to the actual participant.
The Principal Investigator or institution shall provide direct access to source data during and after
the clinical investigation for monitoring, auditing, IRB/EC review and regulatory authority
inspections.
For investigational sites within the United States, “Protected Health Information” will be treated and
maintained in compliance with the Health Insurance Portability and Accountability Act of 1996
(HIPAA) Privacy rule.
The duration of storage time of personal data at the investigational sites will be in accordance with
national regulations. Electronic Case Report Form (eCRF) data captured and maintained in
Curebase for each participant. Curebase stores all data in a secure cloud server of Amazon Web
Services (AWS) and complies with most of HIPAA and GDPR standards, including but not limited
to: password protection, platform encryption, and 2-factor verification. Curebase takes as much
action as possible to maximize the protection and security of subjects’ sensitive information. All
data pertaining to a clinical study, including protected health information (PHI), will be retained for
the duration of the study, and for 2 years thereafter, in compliance with FDA monitoring obligations.
At this point, the identifiable PHI obtained during the study will be deleted. Curebase will share
pseudonymized data collected from subjects with authorized representatives.
After 2 years have elapsed since the completion of a clinical investigation, Curebase will retain a
de-identified version of the data obtained during that study. Curebase may retain this data
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indefinitely and may use it for a variety of purposes that will include, but not be limited to, making
improvements to the Curebase product.
Information obtained while executing this study, including still and motion photography, may be
presented for regulatory, clinical, or educational purposes if no participant is identified. The data
collected is the property of Flow Neuroscience AB.
24.6 INVESTIGATOR RECORDS
The investigator is responsible for the preparation and retention of the records cited below. All
these records, except for participant’s case history records, should be filed in the Investigator Site
File.
24.7 PARTICIPANT RECORDS
●
All Source Documentation Worksheets
●
Supporting data (e.g., medical records, clinic charts)
24.8 INVESTIGATOR RECORDS AND REPORTS
The investigator is responsible for the timely preparation and submission of the reports cited below.
Table 5: Investigator Reports
Report
Sent To
Timing of Report
Unanticipated
adverse device
effect (UADE)
Flow
Neuroscience
AB, IRB/EC
UADE must be reported as soon as possible, but in no
event later than 10 business days after the investigator
first learns of the event
Withdrawal of
IRB/EC
approval
Flow
Neuroscience
AB
Reported within 5 business days
Progress
reports
Flow
Neuroscience
AB, IRB/EC
Reported as requested by Flow Neuroscience AB or the
reviewing IRB/EC, but at least yearly
Deviations
from the
investigation
plan
Flow
Neuroscience
AB, IRB/EC
(FDA)
A deviation to protect the life or physical well-being of a
participant in an emergency must be reported no later
than 5 business days after the emergency occurred.
Deviations that may affect the scientific soundness of the
investigational plan or the rights, safety, or welfare of the
participant (and are not an emergency) must receive
prior approval by Flow Neuroscience AB and be reported
to the FDA and IRB/ECs.
Device use
without
informed
consent
Flow
Neuroscience
AB, IRB/EC
This deviation must be reported within 5 business days
after the use occurs.
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Final Report
Flow
Neuroscience
AB, IRB/EC
This report must be submitted within 3 months after
termination or completion of the investigation or the
investigator’s part of the investigation.
Other
FDA, IRB/EC
Upon request, accurate, complete, and current
information about any aspect of the investigation must be
reported.
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