Naturalistic Study of Alpha-Stim in Patients With a Primary Working Diagnosis of Moderate-to-severe Generalised Anxiety Disorder Who Did Not Improve With Low Intensity Psychological Therapy Intervention
Phase: NA
Conditions: Anxiety
Sponsor: Electromedical Products International, Inc.

 
 
 
 
Full Study Title: 
Clinical and cost effectiveness of Alpha-Stim AID Cranial Electrotherapy 
Stimulations (CES); a naturalistic study in patients with a primary working 
diagnosis of moderate-to-severe generalised anxiety disorder who did not 
improve with low intensity psychological therapy intervention 
 
 
Short Study Title: 
Clinical and cost effectiveness of Alpha-Stim AID CES 
 
Lay Study Title: 
Using a safe electronic device to help patients with anxiety disorder who did not improve with low intensity 
psychological therapy intervention 
 
 
 
IRAS REFERENCE:  
206555 
 
PROTOCOL VERSION NUMBER AND DATE:  
Version 2.0; 28 July 2016 
 
 
SPONSOR: 
Electromedical Products International, Inc. 
2201 Garrett Morris Parkway 
Mineral Wells 
Texas 
76067 
United States of America 
 
 
 
 
 
 
This protocol has regard for the Health Research Authority guidance and order of content. 
 
 
 
 

 
 
 
 
Page 2. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
VERSION CONTROL 
 
 
Amendment 
no. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1.0 
2.0 
28 July 2016 
Mark Terry 
Throughout: Correction of typographical 
mistakes. 
6.1: Addition to inclusion criterion 3 of “OR 
deemed unsuitable for step two within an 
IAPT service”. 
7: Revised wording to clarity that 6 – 8 week 
waiting list is a minimum. 
7.1: Revised identification process to 
remove follow up letter for non-responders. 
7.4: Clarification of expectation of morning 
device use. 
9.2/3: Clarification that AEs and SAEs must 
be recorded in the CRF. 
11.2: Clarification that recruitment window 
if 6 months and not 12 months. 
12.1: Clarification of anticipation that CRF 
will act as source documentation. 
12.2: Clarification of email data transfer 
within 3 working days. 
Appendix B: Revised structure of CSRI but 
no change to content. 
Appendix 
C: 
Inclusion 
of 
EQ-5D-5L 
assessment tool. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Page 3. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KEY STUDY CONTACTS 
 
Chief Investigator 
Professor Richard Morriss 
University of Nottingham 
C20 Institute of Mental Health 
Jubilee Campus 
Wollaton Road 
Nottingham 
NG8 1BB 
United Kingdom 
Tel: 0115 823 0427 
Email: Richard.Morriss@nottingham.ac.uk  
 
Trial Co-ordinator 
 
AND 
 
Sponsor Legal Representative under 
Research Governance Framework for 
Health and Social Care 2005 
 
AND 
 
Funder 
 
Steve Hutchinson 
The Microcurrent Site Limited 
1st Floor, Unit 3 
Brookside 
Sawtry 
Cambridgeshire 
PE28 5SB 
United Kingdom 
Tel: 01487 208041 
Email: Steve@themicrocurrentsite.co.uk  
 
Sponsor Representative 
Jeff Marksberry 
Electromedical Products International, Inc 

 
 
 
 
Page 4. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
2201 Garrett Morris Parkway 
Mineral Wells 
Texas 
76967 
United States of America 
Tel: 940 328 0788 
Email: Jeff@epii.com  
 
Key Protocol Contributors 
Dr Jennifer Martin 
NIHR MindTech Healthcare Technology Co-operative 
The Institute of Mental Health 
University of Nottingham 
Innovation Park 
Triumph Road 
Nottingham  
NG7 2TU 
United Kingdom 
Tel: 0115 748 4339 
Email: Jennifer.Martin@nottingham.ac.uk 
 
Dr Peter Caunt 
Nottinghamshire Healthcare NHS Foundation Trust 
Let’s Talk Wellbeing – Leicestershire & Rutland 
2 Bank Court 
Weldon Road 
Loughborough 
LE11 5RF 
United Kingdom 
Tel: 0115 8760174 
Email: Peter.Caunt@nottshc.nhs.uk  
 
Mark Terry 
Research Applications Limited 
Unit 209 
Pell Street 
Surrey Quays 
London 
SE8 5EN 
United Kingdom 
Tel: 07809 337 115 
Email: Mark@researchapplications.co.uk  
 
NIHR MindTech Healthcare Technology Co-operative is 
acknowledged as having kindly facilitated the service user review. 
 
 
 
 
 
 

 
 
 
 
Page 5. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY SUMMARY 
 
Full Study Title 
Clinical and cost effectiveness of Alpha-Stim AID Cranial 
Electrotherapy Stimulations (CES); a naturalistic study in patients 
with a primary working diagnosis of moderate-to-severe 
generalised anxiety disorder (GAD) who did not improve with low 
intensity psychological therapy intervention. 
 
Short Study Title 
Clinical and cost effectiveness of Alpha-Stim AID CES. 
Lay Study Title 
Using a safe electronic device to help patients with anxiety 
disorder who did not improve with low intensity psychological 
therapy intervention. 
 
Study Design 
Single-centre, naturalistic post-market clinical study of one CE 
marked device within intended purpose over 24 week follow up 
period. 
 
Study Participants 
Patients seen within the three teams comprising Leicestershire and 
Rutland Improving Access to Psychological Therapies (IAPT) service 
(part of Nottinghamshire Healthcare NHS Foundation Trust) with a 
primary working diagnosis of moderate-to-severe generalised 
anxiety disorder (GAD) who did not improve (continued to have a 
primary working diagnosis of moderate-to-severe GAD) with 
previous low intensity psychological therapy intervention. 
 
Planned Sample Size 
120  

 
 
 
 
Page 6. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
Study Duration Per Participant 
24 weeks 
 
Planned Enrolment Period 
6 months from 01 September 2016 to 01 March 2017 
 
Planned Study End Date  
01 September 2017 
 
Study End Definition 
Last Participant Last Visit 
 
 
Objectives 
Outcome Measures 
Primary 
 
The primary objective of this 
study is to evaluate the clinical 
effectiveness of treatment with 
Alpha-Stim AID Cranial 
Electrotherapy Stimulations 
(CES) for participants with a 
primary working diagnosis of 
generalised anxiety disorder 
(GAD), as defined by the NHS 
IAPT service in terms of reliable 
improvement, clinically 
significant improvement, and 
recovery, from baseline to week 
24, following previous 
treatment with low intensity 
psychological therapy 
intervention. 
 
 
GAD-7 
 
See Appendix A 
 
The GAD-7 is a participant-
reported screening tool and 
severity measure for 
generalised anxiety disorder 
(GAD).  
 
Reliable improvement is defined 
as participants who reach a 
score reduction of 5 or more 
from baseline to week 24. Such 
a reduction amounts to a 
clinically important change.  
 
Some reliable improvement is 
defined as participants who 
reach a score reduction of 1 – 4 
from baseline to week 24.  
 
No reliable improvement is 
defined as participants who 
reach no score reduction from 
baseline to week 24. 
 
Clinically significant 
improvement is defined as 
participants with a score of 10 
or more at baseline, who reach 
9 or fewer by week 24.  
 
Recovery is defined as 
participants with a score of 10 
or more at baseline, who reach 
7 or fewer by week 24. 
 
Secondary 
 
The secondary objective of this 
study is to evaluate the cost 
effectiveness of treatment with 
Client Service Receipt Inventory 
(CSRI) 
 

 
 
 
 
Page 7. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
Alpha-Stim AID Cranial 
Electrotherapy Stimulations 
(CES) for participants with a 
primary working diagnosis of 
generalised anxiety disorder 
(GAD), in terms of health and 
social care service cost, and 
patient cost, from baseline to 
week 24, following previous 
treatment with low intensity 
psychological therapy 
intervention. 
 
See Appendix B 
 
The CSRI, adapted for use for 
anxiety disorders in primary 
care and community settings, is 
a measure of the full health and 
social care cost and patient cost 
of treatment. 
 
The endpoint will be the cost 
impact from baseline to week 
24. 
 
EQ-5D-5L 
 
See Appendix C 
 
The EQ-5D-5L is a participant-
reported measure of health 
utility and quality of life used by 
NICE to generate QALYs for cost 
effectiveness assessments. The 
EQ-5D-5L uses 6 items.  
 
The endpoint will be the change 
in EQ-5D-5L for participants 
from baseline to week 24.  
 
Work and Social Adjustment 
Scale (WASA) 
 
See Appendix D 
 
The WASA scale is a participant-
reported measure of work and 
social function. The WASA scale 
uses 5 items. 
 
The endpoint will be the change 
in WASA scale score for 
participants from baseline to 
week 24. 
 
Tertiary 
The tertiary objective of this 
study is to evaluate the clinical 
effectiveness of treatment with 
Alpha-Stim AID Cranial 
Electrotherapy Stimulations 
(CES) for depression and 
insomnia in participants with a 
PHQ-9 
 
See Appendix E 
 
The PHQ-9 is a participant-
reported measure of depressive 
symptomatology.  

 
 
 
 
Page 8. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
primary working diagnosis of 
generalised anxiety disorder 
(GAD), in terms of reliable 
improvement, clinically 
significant improvement, and 
recovery, from baseline to week 
24, following previous 
treatment with low intensity 
psychological therapy 
intervention. 
 
Reliable improvement is defined 
as participants who reach a 
score reduction of 6 or more 
from baseline to week 24.  
 
Clinically significant 
improvement is defined as 
participants with a score of 10 
or more at baseline, who reach 
9 or fewer by week 24.  
 
Recovery is defined as 
participants with a score of 11 
or more at baseline, who reach 
8 or fewer by week 24. 
 
Athens Insomnia Scale 
 
See Appendix F 
 
 
The Athens Insomnia Scale is a 
participant-reported measure of 
sleep difficulty.  
 
Reliable improvement has no 
current, standardised definition, 
and so in this study, will be 
defined as participants who 
reach a score reduction of 50% 
or more from baseline to week 
24. 
  
Clinically significant 
improvement is defined as 
participants with a score of 6 or 
more at baseline, who reach 5 
or fewer by week 24. 
 
Recovery is defined as 
participants with a score of 6 or 
more at baseline, who reach 4 
or fewer by week 24. 
 
Medical Device 
Alpha-Stim AID Cranial Electrotherapy Stimulations (CES) medical 
device, used within intended purpose (for the treatment of 
anxiety, depression and insomnia), under CE marking valid 12 April 
2016 – 12 September 2020.  
 

 
 
 
 
Page 9. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
See Appendix H 
 
Treatment Procedure 
60-minute self-directed Alpha-Stim AID CES treatment sessions 
undertaken at participant’s home, on a daily basis for 6 weeks for 
all participants.  During this 6-week period, participants will be on 
the waiting list for high intensity psychological therapy 
intervention. 
 
Following 6 weeks of Alpha-Stim AID CES treatment, participants 
have the option to receive a further 6 weeks of treatment, which is 
likely to coincide with start of high intensity psychological therapy 
intervention as clinically indicated. 
 
Following a maximum of 12 weeks’ treatment with Alpha-Stim AID 
CES, all participants will cease to receive treatment on study.  
 
Participants will have 1x additional visit in clinic at baseline, 
followed by 5 additional visits via telephone at week 4, 6, 8, 12 and 
24. 
 
All participants will continue to receive standard care assessment, 
as undertaken by the NHS IAPT service, standard care high 
intensity psychological therapy intervention as clinically indicated 
and provided by the NHS IAPT service, and standard care 
pharmacological treatment as prescribed by the participant’s GP. 
Participation in this study will not influence nor compromise 
standard care treatment – all study procedures are additional to 
standard care. Participation in the study will have no impact upon 
the duration of the waiting time for high intensity psychological 
therapy intervention. 
 
 
 
 
 
 

 
 
 
 
Page 10. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
FUNDING AND SUPPORT IN KIND 
 
FUNDER 
FINANCIAL AND NON FINANCIAL SUPPORT GIVEN 
The Microcurrent Site Limited 
60 Alpha-Stim AID CES devices loaned to 
Nottinghamshire Healthcare NHS Foundation Trust 
for duration of study. Should all 60 devices be in use 
by participants concurrently, additional devices may 
be loaned to the Trust.  
 
Consumables will be provided to the Trust, including 
AAA batteries, pregnancy testing kits, cleaning 
materials, conduction fluid and electrode pads.  
 
Total funding of approximately £38,000.00 to 
Nottinghamshire Healthcare NHS Foundation Trust 
for study delivery costs. 
 
 
 
 
 

 
 
 
 
Page 11. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
ROLE DELEGATION 
 
SPONSOR: Electromedical Products International, Inc 
Under the Research Governance Framework for Health and Social Care 2005, Electromedical Products 
International Inc is the legal sponsor of this research study. Electromedical Products International Inc retains 
responsibility for all legally mandated roles of a sponsor of clinical research, but has delegated a number of roles 
to the organisations listed below. 
 
LEGAL REPRESENTATIVE AND CONTRACT RESEARCH ORGANISATION: The Microcurrent Site Limited 
Under the Research Governance Framework for Health and Social Care 2005, a sponsor incorporated outside of 
the United Kingdom must appoint a legal representative incorporated in the United Kingdom for service of 
documents. Given that Electromedical Products International Inc is incorporated in the United States of America, 
The Microcurrent Site Limited will fulfil the role of legal representative. 
 
In this role as legal representative, The Microcurrent Site Limited is also undertaking the following roles on behalf 
of the sponsor: 
• 
Point of conduct for study conduct queries 
• 
Upload of accrual data to the NIHR CRN Portfolio database (CPMS) 
• 
Oversight of conduct and delivery 
• 
Archiving 
• 
Manuscript writing 
• 
Dissemination of results 
FUNDER: The Microcurrent Site Limited 
The Microcurrent Site Limited is responsible for the provision of funding and will process and pay invoices from 
the NHS research site, and is also responsible for the provision of loaned medical devices and consumables.  
 
CONTRACTED ORGANISATION: Research Applications Limited 
Research Applications Limited is responsible for creation and submission of study documents to the Health 
Research Authority (HRA) for Research Ethics Committee (REC) favourable opinion, HRA Approval; submission 
to the National Institute for Health Research Clinical Research Network (NIHR CRN) Portfolio; and submission to 
the NHS R&D department of Nottinghamshire Healthcare NHS Foundation Trust for confirmation of capacity 
and capability. No application to the Competent Authority is required.  
 
 
 
 
 

 
 
 
 
Page 12. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
LIST OF CONTENTS 
 
LIST OF ABBREVIATIONS 
STUDY FLOW CHART 
1 
BACKGROUND 
2 
RATIONALE  
3 
OBJECTIVES AND OUTCOME MEASURES 
3.1 
Primary objective 
3.2 
Secondary objectives 
3.3 
Tertiary objective 
3.4 
Primary outcome measures 
3.5 
Secondary outcome measures 
3.6 
Tertiary outcome measures 
4 
STUDY DESIGN 
5 
STUDY SETTING 
6 
ELIGIBILITY CRITERIA 
6.1 
Inclusion criteria 
6.2 
Exclusion criteria 
7 
STUDY PROCEDURES  
7.1 
Participant Identification 
7.2         Consent 
7.3 
Screening 
7.4 
Baseline assessments 
7.5 
Study assessments 
7.6 
Assessment summary 
7.7 
Follow up 
7.8 
Withdrawal 
7.9 
End of study 
8 
STUDY DEVICE 
8.1 
Nature of device 
8.2  
End of study provision 
8.3  
Storage and handling on device 
8.4  
Safety profile 
9 
SAFETY REPORTING 
9.1 
Definitions 
9.2 
AE reporting 
9.3 
SAE reporting 
9.4 
Urgent safety measures 
9.5 
Pregnancy reporting 
10 
PROGRESS REPORTING 
10.1 
Progress reports 
10.2 
Declaration of conclusion 
10.3 
Summary of final report 
11 
STATISTICS AND DATA ANALYSIS 
11.1 
Sample size calculation 
11.2 
Planned recruitment rate 
11.3 
Statistical analysis plan 
12 
DATA HANDLING 
12.1 
Data collection tools and source document identification 
12.2 
Data handling and record keeping 
14 
15 
16 
18 
19 
19 
19 
19 
19 
19 
20 
21 
21 
21 
21 
22 
22 
22 
23 
23 
24 
26 
29 
29 
30 
30 
30 
30 
30 
30 
30 
31 
31 
31 
31 
31 
32 
32 
32 
32 
32 
32 
32 
33 
33 
33 
33 
34 

 
 
 
 
Page 13. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
12.3 
Archiving 
13 
AUDIT 
14  
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1  
Approvals 
14.2  
Peer review 
14.3  
Public and patient involvement 
14.4  
Protocol compliance 
14.5  
Notification of serious breaches to GCP and/or the protocol  
14.6  
Data protection and patient confidentiality  
14.7  
Financial and other competing interests  
14.8  
Indemnity 
14.9  
Amendments  
15 
REFERENCES 
16  
APPENDIX A: GAD-7 
17  
APPENDIX B: CSRI 
18  
APPENDIX C: EQ-5D-5L 
19  
APPENDIX D: WASA 
20  
APPENDIX E: PHQ-9  
21  
APPENDIX F: ATHENS INSOMNIA SCALE 
22  
APPENDIX G: ANXIETY LOG BOOK 
23  
APPENDIX H: CE MARK 
24  
APPENDIX I: INSURANCE CERTIFICATE 
 
34 
34 
35 
35 
35 
35 
35 
35 
35 
36 
36 
36 
37 
40 
41 
46 
47 
48 
49 
50 
51 
52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Page 14. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
CA 
Competent Authority (MHRA) 
CBT 
Cognitive Behavioural Therapy 
CI 
Chief Investigator 
CE  
Conformitee Europeenee 
CES 
Cranial Electrotherapy Stimulations 
CPMS 
Central Portfolio Management System 
CRF 
Case Report Form 
CRN 
Clinical Research Network 
CRO 
Contract Research Organisation 
CSRI 
Client Services Receipt Inventory 
EU 
European Union 
FDA 
Food and Drug Administration 
GAD 
Generalised Anxiety Disorder 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HRA 
Health Research Authority 
IAPT 
Improving Access to Psychological Therapies 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
ISF 
Investigator Site File 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS R&D 
National Health Service Research & Development   
NIHR 
National Institute for Health Research 
PCMIS 
Trust electronic patient record 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
PWP 
Psychological Wellbeing Practitioner 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
TMF  
Trial Master File 
WASA 
Work and Social Adjustment Scale 
WHO 
World Health Organisation 
 
 
 
 
 

 
 
 
 
Page 15. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1: Day 1 
Baseline in clinic visit comprising informed 
consent, training in use of Alpha-Stim AID CES 
device, GAD-7, WASA, PHQ-9, EQ-5D-5L, Athens 
and CSRI.  
Visit 2: Week 4 
Telephone visit comprising GAD-7, WASA, PHQ-
9, EQ-5D-5L, Athens and treatment compliance 
and adverse events. 
Visit 3: Week 6 
Telephone visit comprising GAD-7, WASA, PHQ-
9, EQ-5D-5L, Athens, CSRI and treatment 
compliance and adverse events. 
End of treatment for participants as requested. 
Visit 4: Week 8 
Telephone visit comprising GAD-7, WASA, PHQ-
9, EQ-5D-5L, Athens and treatment compliance 
and adverse events. 
 
Visit 5: Week 12 
Telephone visit comprising GAD-7, WASA, PHQ-
9, EQ-5D-5L, Athens and treatment compliance 
and adverse events. 
End of treatment for all participants. 
Visit 6: Week 24 
Telephone visit comprising GAD-7, WASA, PHQ-
9, EQ-5D-5L, Athens and CSRI. 
End of study for all participants. 
Day 1 – Week 6 
Initial Alpha-Stim 
AID CES treatment 
period with daily 60 
minute sessions 
and pre and post 
anxiety scale 
completion. 
 
Week 6 – Week 12 
Optional additional 
Alpha-Stim AID CES 
treatment period 
with daily 60 
minute sessions 
and pre and post 
anxiety scale 
completion. 
 
Standard care 
Participant on 
waiting list (at least 
6 - 8 weeks) for 
step three high 
intensity 
psychological 
therapy 
intervention, 
followed by 
assessment and at 
least two individual 
CBT sessions as 
required. 
 

 
 
 
 
Page 16. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
1 
BACKGROUND 
 
Generalised anxiety disorder (GAD) is a common mental disorder with an annual prevalence of 2.1% to 4.4% in 
English speaking countries (Grant et al, 2005; Hunt et al, 2002; Kessler and Wang, 2008). Patients with a primary 
working diagnosis of GAD incur a significant clinical burden, and a significant cost burden upon the health and 
social care system. According to the World Health Organisation (WHO), anxiety disorders in general are the 
seventh leading cause of disability lost years in the world (Vos et al, 2012), and an economic case for the 
management of GAD, and other anxiety and depression disorders in working-age adults, was made by Lord 
Layard (Layard, 2006).  
 
Patients with a primary working diagnosis of GAD often present with other mental disorder such as depression 
and insomnia, and there is strong evidence that comorbidity among anxiety, insomnia and depression is the rule, 
rather than the exception (Alvaro et al., 2013; Chapman et al., 2010; Soehner & Harvey, 2012; LeBlanc et al., 
2009; Jansson-Frojmark & Lindblom, 2008; Buysse et al., 2008; Franzen & Buysse, 2008; Riemann, 2007; Johnson 
et al., 2006; Taylor et al., 2005).  Comorbid anxiety and depression or insomnia can start a negative spiral in which 
one enhances the other (Jansson-Frojmark & Lindblom, 2008). Given that these disorders may also have a 
physical cause, or the symptoms of these disorders may initially be perceived as having a physical cause, the 
treatment of GAD and associated comorbidities can lead to considerable expenditure within a health and social 
care system. 
 
NICE guidelines for the treatment of patients with a primary working diagnosis of GAD, published in England in 
2011 (Nice; 2011), recommend a three step approach in the care pathway: 
 
• 
Step one: Upon patient recognition of a psychological problem, and discussion with a General 
Practitioner (GP), the patient will receive, within primary care, an assessment/referral/active monitoring, 
which includes careful monitoring of symptoms, psychoeducation about the disorder, and sleep hygiene 
advice.  
 
• 
Step two: Upon failure to improve as a result of step one treatment, the patient will be referred by a GP 
to an Improving Access to Psychological Therapies (IAPT) service. Alternatively, a patient may self-refer 
directly to an IAPT service without having undertaken step one treatment in primary care. Upon referral 
or self-referral, all patients will receive an assessment to diagnose their problem. If indicated, patients 
will receive step two treatment - the basis of step two is low intensity psychological therapy intervention, 
which includes individual non-facilitated self-help, individual guided self-help and psychoeducation 
groups. Patients are assessed throughout step two. 
 
• 
Step three: Upon failure to improve as a result of step two treatments, patients will be indicated to 
receive from the IAPT service, as a minimum, an assessment and two individual Cognitive Behavioural 
Therapy (CBT) treatment sessions focussed on long-term coping strategies. Dependent upon 
improvement, patients will receive further CBT sessions and support as required. Pharmacological 
treatment, initially with selective serotonin re-uptake inhibitor anti-depressants, and subsequently drugs 
such as pregabalin, may be prescribed by the GP independently of the IAPT service, for which 
pharmacological treatment are not part of the care pathway. 
 
Step one and two treatment are relatively inexpensive, but are often ineffective. Step three treatment, both 
psychological and pharmacological, are relatively expensive, requiring frequent contacts with highly qualified 
health professionals within the IAPT service, and prescription of expensive drugs in primary care (for example, a 
28-day treatment course of pregabalin is approximately £80.00). GAD is a relatively persistent clinical problem 
and therefore pharmacological treatment can extend for many months and years, whilst there are frequently 
substantial delays in offering access to high intensity psychological treatment intervention.  

 
 
 
 
Page 17. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
Alpha-Stim AID is a CE marked medical device which has been registered as an approved product since 11 May 
1998. Alpha-Stim AID is marketed for the alleviation of psychological conditions including anxiety, insomnia and 
depression, through using cranial electrotherapy stimulations (CES) which are tiny electric currents applied 
through ear clips. The treatment provided by the device is non-invasive, non-pharmacological, and can be used 
as adjunctive treatment to step one, two and three treatment intervention. Pregnancy, implantation with a pace 
maker and implantation with an implantable cardioverter device (ICD) are contraindications.  
 
Alpha-Stim AID CES could therefore compliment psychological treatment in the IAPT care pathway, through 
acting as an effective maintenance treatment, and to act as adjunctive treatment to improve the clinical 
effectiveness of step three high intensity psychological therapy intervention. Improved effectiveness could 
reduce the requirement for additional psychological and pharmacological treatment, thus reducing cost within 
the health and social care system (primarily within the IAPT services but also within primary care), thus enabling 
the IAPT service to maintain capacity to deliver high intensity psychological therapy intervention. 
 
This study will recruit 120 participants from Leicestershire and Rutland IAPT service (under the organisation of 
Nottinghamshire Healthcare NHS Foundation Trust). These participants will have a primary working diagnosis of 
moderate-to-severe GAD, and will have received step two low intensity psychological therapy intervention within 
an IAPT service but received no improvement (continued to be classified as moderate-to-severe GAD) from these 
interventions.  
 
So as to place the study in the context of a systematic review of relevant studies, the following information 
provides background to the clinical effectiveness of CES treatment generally, and then specifically for anxiety, 
depression and insomnia.  
 
Clinical effectiveness in general 
 
Most early CES studies between the 1970s to early 1990s were small, had limitations and used research designs 
that do not meet current research standards. However, the findings from these studies were consistently positive 
showing that CES effectively decreased anxiety, depression and insomnia. Anxiety was the most common 
condition studied. A dramatic increase in the quality of CES research occurred during 1995 to 2008. The first 
study to use a double-blind, randomised, sham-controlled Alpha-Stim CES device protocol research design was 
conducted by Voris in 1995 that investigated the effectiveness of CES on anxiety in outpatient psychiatric 
patients. This study included 105 participants who were randomised to an active CES group (n=40) or sham CES 
group (n=35) 20-minute treatment, or to a control group (n=30). There was no difference among groups on the 
measure of anxiety at baseline, using the State Anxiety Inventory (SAI).  The active CES group had significantly 
lower scores (indicating less state anxiety) on SAI than the sham and control groups at end point of study (p = 
0.0001, d = -1.60). The active CES group had significantly higher finger temperature scores (p = 0001, d = 0.50) 
and significantly lower EMG scores (p = 0.0001, d = -1.08), indicating less anxiety than sham group as measured 
by objective physiological tests. Bystritsky et al (2008), in an open-label study was the only study in the group of 
CES anxiety studies that specifically looked at the efficacy of CES in participants with GAD. Anxiety scores 
decreased significantly from baseline to the endpoint of the study as measured by the HAMA-A (p = 0.01, d = 
1.52). and the FDADS (p = 0.01, d = -0.75). A score on the CGI-I at the endpoint of the study (6 weeks), was used 
to determine if a participant was a responder or non-responder to treatment. At the end of the study, 6 patients 
(50% of the intent to treat sample and 67% of the completers) had a 50% decrease on HAMA-A and a score of 1 
or 2 on the CGI-I and were therefore considered responders to treatment.  
 
Clinical effectiveness for anxiety 
 
There are human studies using Alpha-Stim CES technology that support the efficacy of CES for treatment of 
anxiety: 

 
 
 
 
Page 18. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
• 
7 double-blind, sham-controlled, randomised controlled trials on anxiety using the Alpha-Stim CES 
technology had significant findings in favour of the treatment group (Barclay & Barclay, 2014; Kolesos, 
2013; Strentzsch, 2008; Cork, 2004; Lichtbroun, 2001; Winick, 1999; and Voris 1995).  
• 
5 of the double-blind, sham controlled, randomised controlled trials (Barclay, 2004; Strentzsch, 2008; 
Cork, 2004; Lichtbroun, 2001; Winick, 1999) were replications of the Voris (1995) study using different 
patient populations. All of these studies found significant differences in favour of the active CES group; 
CES significantly decreased anxiety.  
• 
3 additional randomised controlled trials on anxiety found significant findings in favour of the 
treatment group (Lee, 2013; Kim, 2008; and Chen, 2007).  
• 
3 open label studies also reported that CES significantly decreased anxiety (Bystritsky, 2008; Lu, 2005 
and Overcash, 1999).  
Clinical effectiveness for depression 
 
• 
Barclay and Barclay (2014) in a double-blind, sham-controlled, randomised controlled trial (n=115) 
using Alpha-Stim CES technology found that depression was significantly decreased in favour of the 
treatment group.  
• 
Bystritsky et al. (2008) also reported that CES significantly decreased depression from baseline to the 
endpoint of the study.   
Clinical effectiveness for insomnia 
 
• 
2 double-blind, sham-controlled, randomised controlled trials using Alpha-Stim CES technology found 
that CES significantly decreased insomnia in favour of the treatment (Taylor et al., 2013; Lichtbroun et 
al., 2001).  
• 
1 United States of America army study by Lande (2013) found Alpha-Stim CES treatment to increase 
sleep by 43 minutes in patients in a partial hospitalisation program after 5 days of treatment, while the 
sham treated group in this double-blind study reported 19 minutes less sleep. 
 
2 
RATIONALE  
 
The purpose of this study is not demonstrate clinical effectiveness of Alpha-Stim AID CES – the device has a CE 
marking and there are sufficient clinical trials to demonstrate effectiveness. The purpose of this study is to 
address the paucity of data on the clinical effectiveness and cost effectiveness in an NHS setting. For Alpha-Stim 
AID CES treatment to be available as standard care within the IAPT service, the treatment must be appraised by 
NICE, which will require evidence of clinical effectiveness in the NHS, and an assessment of the economic impact.  
 
The study will also be published to demonstrate to an international audience of how Alpha-Stim AID CES can 
complement psychological therapy intervention within a care pathway, which may then be commissioned in 
other health and social care systems. However, the study is primarily designed to obtain sufficient evidence for 
NICE and NHS England. 
 
 
 

 
 
 
 
Page 19. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
3 
OBJECTIVES AND OUTCOME MEASURES 
 
3.1 
Primary objective 
 
The primary objective of this study is to evaluate the clinical effectiveness of treatment with Alpha-Stim AID 
cranial electrotherapy stimulations (CES) for participants with a primary working diagnosis of generalised anxiety 
disorder (GAD), as defined by the NHS IAPT service in terms of reliable improvement, clinically significant 
improvement, and recovery, from baseline to week 24, following previous treatment with low intensity 
psychological therapy intervention. 
 
3.2 
Secondary objectives 
 
The secondary objective of this study is to evaluate the cost effectiveness of treatment with Alpha-Stim AID 
cranial electrotherapy stimulations (CES) for participants with a primary working diagnosis of generalised anxiety 
disorder (GAD), in terms of health and social care service cost, and patient cost, over the previous 12 weeks, 
from baseline to week 24, following previous treatment with low intensity psychological therapy intervention. 
 
3.3 
Tertiary objective 
 
The tertiary objective of this study is to evaluate the clinical effectiveness of treatment with Alpha-Stim AID 
cranial electrotherapy stimulations (CES) for depression and insomnia in participants with a primary working 
diagnosis of Generalised Anxiety Disorder (GAD), in terms of reliable improvement, clinically significant 
improvement, and recovery, from baseline to week 24, following previous treatment with low intensity 
psychological therapy intervention. 
 
3.4 
Primary outcome measures 
 
The primary objective will be measured using GAD-7 scores, which is a participant-reported screening tool and 
severity measure for generalised anxiety disorder (GAD).  
 
• 
The outcome measure for reliable improvement of GAD is defined as participants who reach a score 
reduction of 5 or more from baseline to week 24. Such a reduction amounts to a clinically important 
change. Some reliable improvement is defined as participants who reach a score reduction of 1 – 4 from 
baseline to week 24. No reliable improvement is defined as participants who reach no score reduction 
from baseline to week 24. 
• 
The outcome measure for clinically significant improvement of GAD is defined as participants with a 
score of 10 or more at baseline, who reach 9 or fewer by week 24.  
• 
The outcome measure for recovery of GAD is defined as participants with a score of 10 or more at 
baseline, who reach 7 or fewer by week 24. 
3.5 
Secondary outcome measures 
 
The secondary objective will be measured using the Client Service Receipt Inventory (CSRI), adapted for use for 
anxiety disorders in primary care and community settings, which is a measure of the full health and social care 
cost and patient cost of treatment. Additionally, the objective will be measured using the EQ-5D-5L, which is a 
participant-reported measure of health utility and quality of life used by NICE to generate QALYs for cost 
effectiveness assessments, and uses 6 items. Finally, the objective will be measured using the Work and Social 
Adjustment Scale (WASA) which is a participant-reported measure of work and social function, and uses 8 items. 
 

 
 
 
 
Page 20. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
• 
The outcome measure for CSRQ is the change in cost impact for previous 12 weeks from baseline to 
week 24.  
• 
The outcome measure for EQ-5D-5L is the change for participants from baseline to week 24.  
• 
The outcome measure for WASA is the change for participants from baseline to week 24. 
3.6 
Tertiary outcome measures 
  
The tertiary objectives will be measured using the PHQ-9, which is a participant-reported measure of depressive 
symptomatology. Additionally, the objective will be measured using the Athens Insomnia Scale, which is 
participant-reported measure of sleep difficulty. 
 
• 
The outcome measure for reliable improvement of depressive symptomology is defined as participants 
who reach a score reduction of 6 or more from baseline to week 24.  
• 
The outcome measure for clinically significant improvement of depressive symptomology is defined as 
participants with a score of 10 or more at baseline, who reach 9 or fewer by week 24.  
• 
The outcome measure for recovery of depressive symptomology is defined as participants with a score 
of 11 or more at baseline, who reach 8 or fewer by week 24. 
 
• 
The outcome measure for reliable improvement of insomnia has no current, standardised definition, 
and so in this study, will be defined as participants who reach a score reduction of 50% or more from 
baseline to week 24. 
• 
The outcome measure for clinically significant improvement of insomnia is defined as participants with 
a score of 6 or more at baseline, who reach 5 or fewer by week 24 
• 
The outcome measure for recovery of insomnia is defined as participants with a score of 6 or more at 
baseline, who reach 4 or fewer by week 24. 
 
4 
STUDY DESIGN 
This is a single-centre, naturalistic post-market clinical study of one CE marked device within intended purpose 
over 24-week follow-up period. The study will enrol patients with a primary working diagnosis of moderate-to-
severe GAD who did not improve (continued to have a primary working diagnosis of moderate-to-severe GAD) 
with previous low intensity psychological therapy intervention.  
 
Participants indicated for high intensity psychological therapy intervention will be approached by their routine 
care provider (either a Psychological Wellbeing Practitioner (PWP) or Cognitive Behavioural Therapist) with 
information about this study when they are contacted to discuss a step-up to step 3 high intensity therapy. From 
this initial approach, the current minimum waiting time for access to such therapy interventions is at least 6 - 8 
weeks.  
 
Participants who consent to enrolment will undertake 60 minute self-directed Alpha-Stim AID CES treatment 
sessions in their own homes on a daily basis for 6 weeks. During this 6-week period, participants will be on the 
waiting list for high intensity psychological therapy intervention. 
 
Following 6 weeks of Alpha-Stim AID device treatment, participants have the option to receive a further 6 weeks 
of treatment, which may coincide with start of high intensity psychological therapy interventions as clinically 
indicated. This option is available to make the study design more comparable to real-world scenarios. 

 
 
 
 
Page 21. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
Participants wishing to discontinue use of the Alpha-Stim AID device will return the device and any unused 
electrode pads to the research nurse via pre postage paid envelope. 
 
Following a maximum of 12 weeks’ treatment with Alpha-Stim AID device, all participants will cease to receive 
treatment on study. At this time-point, all participants will return the device and any unused electrode pads to 
the research nurse via pre postage paid envelope. 
 
Participants will have 1x additional visit in clinic at baseline, followed by 5 additional visits via telephone at week 
4, 6, 8, 12 and 24. 
 
All participants will continue to receive standard care assessment, as undertaken by the NHS IAPT service, 
standard care high intensity psychological therapy intervention as clinically indicated and provided by the NHS 
IAPT service, and standard care pharmacological treatment as prescribed by the participant’s GP. Participation 
in this study will not influence nor compromise standard care treatment – all study procedures are additional to 
standard care. Participation in the study will have no impact upon the duration of the waiting time for high 
intensity psychological therapy intervention. 
 
 
5 
STUDY SETTING 
Participants will be enrolled from the clinical caseload of the three teams comprising Leicestershire and Rutland 
Improving Access to Psychological Therapies (IAPT) service (part of Nottinghamshire Healthcare NHS Foundation 
Trust). These participants will have 1x additional baseline visit in clinic (which will be the routine facilities of the 
IAPT service, comprising a GP clinic room or community venue) in addition to 5x additional visits via telephone 
at week 4, 6, 8, 12 and 24.  
 
Participants will continue to receive standard of care assessments and interventions as routine, which will take 
place in routine facilities. 
 
Study delivery will be undertaken by staff within the IAPT service, in addition to staff from NIHR CRN East 
Midlands. 
 
 
6 
ELIGIBILITY CRITERIA 
 
6.1 
Inclusion criteria 
 
• 
Primary working diagnosis of moderate-to-severe GAD indicated via a GAD-7 score of 10 or more at 
baseline visit 
• 
Previous treatment within an IAPT service with step two low intensity psychological therapy 
intervention 
• 
Indicated for step three high intensity psychological therapy intervention and on the waiting list OR 
deemed unsuitable for step two within an IAPT service 
• 
Capable of giving informed consent 
• 
Female participants of child-bearing potential must have a negative urine human chorionic 
gonadotropin dipstick pregnancy test 
• 
Female participants of child-bearing potential must be practising a highly effective method of 
contraception (failure rate of less than 1% per year when used consistently and correctly and agree to 
remain on a highly effective method throughout the 6 or 12 week treatment period. Examples of highly 
effective contraceptives include: barrier condoms, intrauterine device (IUD), intrauterine hormone-

 
 
 
 
Page 22. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
releasing system (IUS), vasectomised partner, sexual abstinence (refraining from heterosexual 
intercourse), and oestrogen and progestogen containing hormonal contraception associated with 
ovulation. 
• 
18 years of age or above at baseline visit 
• 
Able to understand written and verbal English 
 
6.2 
Exclusion criteria 
 
• 
Primary working diagnosis of a mental disorder other than moderate-to-severe GAD (but other mental 
and anxiety disorders as secondary comorbidities is not an exclusion criteria) 
• 
No previous treatment within an IAPT service with step two low intensity psychological therapy 
intervention 
• 
Not indicated for step three high intensity psychological therapy intervention and not on the waiting 
list 
• 
Requiring urgent clinical care 
• 
Female participants of child-bearing potential with a positive urine human chorionic gonadotropin 
dipstick pregnancy test 
• 
Female participants of child-bearing potential not willing to practice a highly effective method of 
contraception during the treatment period 
• 
Implantation with a pace maker 
• 
Implantation with an implantable cardioverter defibrillator (ICD) 
• 
Incapable of giving informed consent 
• 
17 years of age or less at baseline visit 
• 
Unable to understand written and verbal English 
 
7 
STUDY PROCEDURES  
Participants will have study specific assessments, undertaken at additional visits at day 1, week 4, week 6, week 
8, week 12 and week 24, in addition to self-directed treatment with Alpha-Stim AID CES for a minimum of 6 
weeks and a maximum of 12 weeks. 
 
Whilst enrolled in the study, participants will be on the waiting list for high intensity psychological therapy 
intervention, and may begin to receive such interventions if clinically indicated following the minimum 6 - 8 week 
waiting period. Scores from assessments undertaken for the purposes of this study will be available to the IAPT 
service and may be used to inform treatment plans.  
 
7.1 
Participant Identification 
Eligible participants will be known to the IAPT service, as these patients will have been indicated for step three 
high intensity psychological therapy intervention, and will be on the waiting list. As per standard care, during 
step two low intensity psychological therapy intervention, as provided by the PWP or Cognitive Behavioural 
Therapist within the IAPT service, patients will be assessed. Those who have not improved as a result of 
treatment (due to a GAD-7 score remaining at 10 or above and therefore remaining to be moderate-to-severe) 
will be contacted by the routine PWP or Cognitive Behavioural Therapist at a face-to-face visit, via telephone, via 
email and/or via letter to discuss a step-up to step three therapy intervention.  
As such, all PWPs and Cognitive Behavioural Therapists in the IAPT service will screen their patient lists pro-
actively to maintain an awareness of those patients who are eligible. Concurrently to receiving information about 
a step-up to step three therapy intervention, patients will receive a Participant Information Sheet (PIS) to 
introduce and explain the study. As such, the initial approach will be from a member of the patient’s routine 
healthcare team. Patients must respond to the PWP or Cognitive Behavioural Therapist to advise that they do 

 
 
 
 
Page 23. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
not wish to be placed on to the waiting list for step three. For any patients that are currently on the waiting list, 
the PWP or Cognitive Behavioural Therapist will contact the patient with a Participant Information Sheet (PIS) to 
introduce and explain the study. 
The PIS will encourage patients that are interested in learning more about this study to contact the research 
nurse assigned to study delivery, by telephone, email or post. The research nurse will be employed by NIHR CRN 
East Midlands to assist with study delivery. Patients that do not respond will be deemed uninterested in study 
participation. The PWP or Cognitive Behavioural Therapist will maintain a screening log to record those patients 
who have been approached about study participation. The research nurse will therefore have no contact with 
any patient who has not indicated consent to discuss the study, and as such, no access to personal identifiable 
information prior to the patient themselves making contact.  
No participants will be identified at any other services other than via the three teams comprising Leicestershire 
and Rutland IAPT service. No participants will be identifiers via Participant Identification Centres (PICs) and no 
participants will have the opportunity to self-refer as none will be recruited by publicity.  
 
7.2 Consent 
Following the initial approach, and once a patient has contacted the research nurse to learn more about the 
study, a baseline visit will be arranged for the patient to further discuss the study and consent. The baseline visit 
will be an additional visit, and will take place at routine facilities used by the IAPT service (either a GP clinic room 
or community venue).  
Patients will have the opportunity to discuss the details of the study with the research nurse, and if happy to 
proceed, will sign the Informed Consent Form (ICF). If a patient would not like to participate following a discussion 
of the study with the research nurse, their involvement will terminate at this time point and they will continue 
to receive routine care. The research nurse will evaluate the capacity of the patient to consent at this time point. 
Should the research nurse not be content that the patient fully understands the study, and is therefore able to 
make an informed decision regarding participation, then the patient will not be enrolled.  
One copy of the ICF will be received by the participant, one copy will be stored in the Investigator Site File (ISF) 
and one copy will be scanned into PCMIS - the electronic patient record system used locally. 
It will be made clear that all participants will continue to receive standard care assessment, as undertaken by the 
NHS IAPT service, standard care high intensity psychological therapy intervention as clinically indicated and 
provided by the NHS IAPT service, and standard care pharmacological treatment as prescribed by the 
participant’s GP. Participation in this study will not influence nor compromise standard care treatment – all study 
procedures are additional to standard care. Participation in the study will have no impact upon the duration of 
the waiting time for high intensity psychological therapy intervention. 
 
7.3 
Screening 
Participants will have a confirmed working diagnosis of moderate-to-severe GAD via a GAD-7 score of 10 or more 
upon identification by the PWP or Cognitive Behavioural Therapist as potentially eligible for the study. 
Once the ICF has been signed, the research nurse will take a urine pregnancy dipstick test for any female 
participant of child-bearing potential. Should the result be positive, their involvement will terminate at this time-
point and they will continue to receive routine care.  
It is possible that, over the timeframe of having been identified and provided consent to participate, the GAD-7 
score of the participant may have changed. As such, once the ICF has been signed, the research nurse, trained in 
the administration of the GAD-7, will undertake a GAD-7 assessment with the participant. Should the participant, 
at this baseline visit, have a score of 9 or less, their involvement will terminate at this time point and they will 

 
 
 
 
Page 24. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
continue to receive routine care. The research nurse will also re-confirm full eligibility in accordance with the 
inclusion/exclusion criteria. 
This baseline visit will be the sole additional in-clinic visit, with all other study visits undertaken via telephone. 
Patients that attend this baseline visit will have their travel expenses reimbursed up to a maximum of £10.00 and 
must submit their receipt(s) or indication of miles driven (reimbursement up to £0.45 per mile in accordance 
with HMRC guidance). Patients will receive this reimbursement in cash at the baseline visit.  
 
7.4 
Baseline assessments 
Baseline visit 1: Day 1 
Having provided consent for participation, the research nurse will notify the participant’s GP via a notification 
letter unless the participant expressly requests that the GP is not notified, and the research nurse will undertake 
the following assessments: 
Urine pregnancy test 
 
The first assessment will be a urine pregnancy dipstick human chorionic gonadotropin test will be used to assess 
pregnancy in all females of child-bearing potential. The urine and dipstick will be disposed of in accordance with 
the Human Tissue Authority code of conduct.  
 
GAD-7 
 
See Appendix A 
 
The second assessment will be the GAD-7, which is a participant-reported screening tool and severity measure 
for generalised anxiety disorder (GAD). The GAD-7 score is calculated by assigning scores of 0, 1, 2 and 3, to the 
responses categories of “not at all”, “several days”, “more than half the days” and “nearly every day”, 
respectively to 7 problems over the last 2 weeks, and adding together the scores for the 7 problems. The 
maximum score is 21. Scores of 5, 10 and 15 are taken as the cut-off points for mild, moderate and severe anxiety.  
 
The research nurse will administer the GAD-7 and record the data either directly into the electronic patient 
record (PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form 
(CRF) if not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or 
scan the CRF into the electronic file. 
 
It is anticipated that this assessment will take approximately 5 minutes. 
 
Client Service Receipt Inventory (CSRI) 
 
See Appendix B 
 
The CSRI, for use for anxiety disorders in primary care and community settings, is a measure of the full health 
and social care cost and patient cost of treatment. 
 
The research nurse will administer the CSRI and record the data either directly into the electronic patient record 
(PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form (CRF) if 
not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or scan the 
CRF into the electronic file. 
 
It is anticipated that this assessment will take approximately 15 minutes. 

 
 
 
 
Page 25. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
EQ-5D-5L 
 
See Appendix C 
 
The EQ-5D-5L is a participant-reported measure of health utility and quality of life used by NICE to generate 
QALYs for cost effectiveness assessments. The EQ-5D-5L uses 6 items, covering the categories of mobility, self-
care, usual activities, pain/discomfort, anxiety/depression and a visual analogue score of health state.  
 
The research nurse will administer the EQ-5D-5L and record the data either directly into the electronic patient 
record (PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form 
(CRF) if not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or 
scan the CRF into the electronic file.  
 
It is anticipated that this assessment will take approximately 5 minutes. 
 
Work and Social Adjustment Scale (WASA) 
 
See Appendix D 
 
WASA scale is a participant-reported measure of work and social function. The WASA scale uses 5 items, covering 
the categories of work, home management, social leisure activities, private leisure activities, and family and 
relationships, to the response categories of “not at all”, “slightly”, “definitely”, “markedly”, “very severely”. The 
maximum score is 40.  
 
The research nurse will administer the WASA and record the data either directly into the electronic patient record 
(PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form (CRF) if 
not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or scan the 
CRF into the electronic file.  
 
It is anticipated that this assessment will take approximately 5 minutes. 
 
PHQ-9 
 
See Appendix E 
 
The PHQ-9 is a participant-reported measure of depressive symptomatology. The PHQ-9 uses 9 items, to the 
response categories of “not at all”, “several days”, “more than half the days”, and “nearly every day”. The 
maximum score is 27. 
 
The research nurse will administer the PHQ-9 and record the data either directly into the electronic patient 
record (PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form 
(CRF) if not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or 
scan the CRF into the electronic file.  
 
It is anticipated that this assessment will take approximately 5 minutes. 
 
Athens Insomnia Scale 
 
See Appendix F 
 

 
 
 
 
Page 26. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
The Athens Insomnia Scale is a participant-reported measure of sleep difficulty. Athens scale used 8 items, 
covering the categories of sleep induction, awakening during the night, final awakening earlier than desired, total 
sleep duration, overall quality of sleep, sense of well-being during the day, functioning (physical and mental) 
during the day, and sleepiness during the day, to 5 response categories. The maximum score is 24. 
 
The research nurse will administer the Athens scale and record the data either directly into the electronic patient 
record (PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form 
(CRF) if not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or 
scan the CRF into the electronic file.  
 
It is anticipated that this assessment will take approximately 5 minutes. 
 
Alpha-Stim AID CES treatment 
 
Participants will be trained in the use of the Alpha-STIM AID medical device by the research nurse, and will be 
informed that they are expected to undertake 60-minute self-directed Alpha-Stim AID CES treatment sessions 
undertaken at their home, on a daily basis for 6 weeks. It is expected that participants will use the device in the 
morning if possible. Participants will receive a written instruction sheet and will be advised to contact the 
research nurse if they have any queries. Participants will use ear clip electrodes with the current set at their level 
of comfort.  
 
Participants will undertake all sessions at home, and none in-clinic. Immediately prior to treatment, and post 
treatment, participants will record their level of anxiety of a scale of 0 – 10 (with 0 indicating no anxiety and 10 
maximum anxiety). Participants will record these measurements in a log, which will act as source data.  
 
See Appendix G. 
 
The first treatment session should be completed after the baseline assessments undertaken by the research 
nurse. 
 
During this 6-week period, participants will be on the waiting list for high intensity psychological therapy 
intervention. 
 
Following 6 weeks of Alpha-Stim AID CES treatment, participants have the option to receive a further 6 weeks of 
treatment, which is likely to coincide with start of high intensity psychological therapy intervention as clinically 
indicated. 
 
Following a maximum of 12 weeks’ treatment with Alpha-Stim AID CES, all participants will cease to receive 
treatment on study.  
 
7.5 
Study assessments 
At baseline, participants will agree with the research nurse a convenient time and date for the visits undertaken 
via telephone. Visits should be undertaken within 5 calendar days of the exact date. 
 
Additional visits are undertaken at 4 weeks post baseline, 6 weeks post baseline, 8 weeks post baseline, 12 weeks 
post baseline and 24 weeks post baseline.  
 
Visit 2: Week 4 (plus or minus 5 calendar days) 
 
The research nurse will telephone call the participant and undertake the following assessments: 

 
 
 
 
Page 27. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
• 
GAD-7 
• 
EQ-5D-5L 
• 
WASA 
• 
PHQ-9 
• 
Athens Insomnia Scale 
• 
Check treatment compliance and anxiety log completion 
• 
Check adverse events 
The research nurse will administer these and record the data either directly into the electronic patient record 
(PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form (CRF) if 
not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or scan the 
CRF into the electronic file.  
 
It is anticipated that these assessments will take approximately 30 minutes in total.  
 
Visit 3: Week 6 (plus or minus 5 calendar days) 
 
The research nurse will telephone call the participant and undertake the following assessments: 
• 
GAD-7 
• 
EQ-5D-5L 
• 
WASA 
• 
PHQ-9 
• 
Athens Insomnia Scale 
• 
Check treatment compliance and anxiety log completion 
• 
Check adverse events 
The research nurse will administer these and record the data either directly into the electronic patient record 
(PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form (CRF) if 
not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or scan the 
CRF into the electronic file.  
 
It is anticipated that these assessments will take approximately 30 minutes in total.  
 
At this visit, the research nurse will discuss whether the participant wishes to continue with Alpha-Stim AID CES 
treatment in the same manner for an additional 6 weeks. If the participant does wish to do so, they will be 
advised that they must continue to complete the anxiety log book. The decision to continue or end treatment 
with Alpha-Stim AID CES will not impact upon access to stand care therapy interventions, and participants will 
be contacted by the IAPT service regardless of their decision at this time point. If the participant does not wish 
to continue with Alpha-Stim AID CES treatment, the research nurse will ask that they return the medical device 
via post.  
 
The final treatment session should be completed immediately prior to the visit 3 assessments undertaken by the 
research nurse. 
 
Visit 4: Week 8 (plus or minus 5 calendar days) 
 
The research nurse will telephone call the participant and undertake the following assessments: 
• 
GAD-7 

 
 
 
 
Page 28. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
• 
EQ-5D-5L 
• 
WASA 
• 
PHQ-9 
• 
Athens Insomnia Scale 
• 
Check treatment compliance and anxiety log completion (if continuing with Alpha-Stim AID CES 
treatment) 
• 
Check adverse events (if continuing with Alpha-Stim AID CES treatment) 
The research nurse will administer these and record the data either directly into the electronic patient record 
(PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form (CRF) if 
not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or scan the 
CRF into the electronic file.  
 
It is anticipated that these assessments will take approximately 30 minutes in total.  
 
Visit 5: Week 12 (plus or minus 5 calendar days) 
 
The research nurse will telephone call the participant and undertake the following assessments: 
• 
GAD-7 
• 
EQ-5D-5L 
• 
WASA 
• 
PHQ-9 
• 
Athens Insomnia Scale 
• 
CSRI 
• 
Check treatment compliance and anxiety log completion (if continuing with Alpha-Stim AID CES 
treatment) 
• 
Check adverse events (if continuing with Alpha-Stim AID CES treatment) 
The research nurse will administer these and record the data either directly into the electronic patient record 
(PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form (CRF) if 
not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or scan the 
CRF into the electronic file.  
 
It is anticipated that these assessments will take approximately 45 minutes in total.  
 
At this visit, the participant will end treatment with Alpha-Stim AID CES and the research nurse will ask that they 
return the medical device via post.  
 
The final treatment session should be completed immediately prior to the visit 5 assessments undertaken by the 
research nurse. 
 
Visit 6: Week 24 (plus or minus 5 calendar days) 
 
The research nurse will telephone call the participant and undertake the following assessments: 
• 
GAD-7 
• 
EQ-5D-5L 
• 
CSRI 

 
 
 
 
Page 29. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
• 
WASA 
• 
PHQ-9 
• 
Athens Insomnia Scale 
The research nurse will administer these and record the data either directly into the electronic patient record 
(PCMIS) if available (and therefore the PCMIS record will act as source data), or into a Case Report Form (CRF) if 
not available (and therefore the CRF will act as source data) and then transpose the data into PCMIS or scan the 
CRF into the electronic file.  
 
It is anticipated that these assessments will take approximately 30 minutes in total.  
 
This is the end of study visit, after which the participant will cease communication with the research nurse. 
 
7.6 
Assessment summary 
 
ASSESSMENT 
VISIT 1 
DAY 1 
VISIT 2 
WEEK 4 
VISIT 3 
WEEK 6 
VISIT 4 
WEEK 8 
VISIT 5 
WEEK 12 
VISIT 6 
WEEK 24 
CONSENT 
X 
 
 
 
 
 
TRAINING IN 
USE 
OF 
ALPHA STIM 
AID 
X 
 
 
 
 
 
PREGNANCY 
TEST 
X (*) 
 
 
 
 
 
GAD-7 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
X 
X 
CSRI 
X 
 
 
 
X 
X 
WASA 
X 
X 
X 
X 
X 
X 
PHQ-9 
X 
X 
X 
X 
X 
X 
ATHENS 
X 
X 
X 
X 
X 
X 
ALPHA-STIM 
AID 
CES 
TREATMENT 
Ongoing 
Ongoing 
Ongoing (**) 
Ongoing (**) 
Ongoing (**) 
 
COMPLIANCE  
X 
X 
X (**) 
X (**) 
 
ADVERSE 
EVENTS 
 
X 
X 
X (**) 
X (**) 
 
 
(*) If a female of child-bearing potential 
(**) If continuing with Alpha-Stim AID CES treatment between week 6 – week 12. 
 
 
7.7 
Follow up 
If a participant is unavailable for the pre-arranged telephone call visit, and the visit is likely to fall outside of the 
5 calendar day window, the sponsor legal representative must be informed.  
 
If a participant is lost to follow up during the Alpha-Stim AID CES treatment period, or during the follow up period, 
best efforts should be made to re-establish contact by the research nurse, in conjunction with the IAPT service, 
to ensure return of the medical device and full data collection.  

 
 
 
 
Page 30. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
 
7.8 
Withdrawal 
Participants will be made aware that they are free to withdraw from the study at any time point, without giving 
reason. If participants withdraw during the Alpha-Stim AID CES treatment period, the participant should return 
the medical device and any unused electrodes to the research nurse. Participants will be informed that the data 
collected prior to their withdrawal will be retained for analysis unless a specific request is made for their data to 
be removed from analysis.  
 
Participants may be withdrawn from the study, if it is in the best interests of the participant, in the view of the 
Principal Investigator.  
 
7.9 
End of study 
Participants will be enrolled in the study for 24 weeks from baseline, with the recruitment window anticipated to 
open 01 September 2016 and close 01 March 2017. The end of study is defined as last participant last visit, and this 
is anticipated at 01 September 2017. The REC will be notified of the end of study.  
 
8 
STUDY DEVICE 
8.1 
Nature of device 
The medical device is the Alpha-Stim AID CES device, which will be used within intended purpose (for the 
treatment of anxiety, depression and insomnia), under CE marking valid 12 April 2016 – 12 September 2020. 
 
See Appendix H. 
 
8.2  
End of study provision 
The device is marketed and sold in the UK by the sponsor legal representative, and are available from private 
purchase at a cost of £499.00. Participants will be fully informed that participation in the study will result in a 
maximum of 12 weeks of Alpha-Stim AID device treatment, after which time point the device must be returned 
to the research nurse. Participants will not be encouraged to purchase a device, but will be advised by the 
research nurse if an interest is expressed. Participants will not receive a discount on the purchase of a device. 
 
8.3  
Storage and handling on device 
60 Alpha-Stim AID CES medical devices will be provided to site in one single bulk dispatch, and will be loaned for 
the period of the study. All 60 medical devices are expected to be returned to the sponsor legal representative 
by the end of the study. The devices should be kept in secure location until given to participants, for use in their 
homes, for the 6 or 12 week treatment period. Should all 60 devices be in use by participants concurrently, 
additional devices may be loaned. 
 
The sponsor is not listed on the NHS Master Indemnity Agreement register, and therefore a Form of Indemnity 
will be signed between the sponsor as the device supplier and the site to provide confirmation that there is 
adequate public and product liability insurance in place for £1,000,000.00. 
See Appendix I 
The site will not be held liable for maintenance and cleaning costs, wear-and-tear, accidental damage and loss 
of these devices. 
 
8.4  
Safety profile 

 
 
 
 
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CES is the application of a pulsed, mild electrical current to the head using ear clip electrodes (0.5 Hz, 50% duty 
cycle, and 100 to 500 µA). The U.S. Food and Drug Administration (FDA) cleared CES for the treatment of anxiety, 
depression and insomnia in 1979. CES is non-invasive and has an excellent safety profile.  A FDA commissioned 
review of the safety of CES by the National Research Council (1974) stated, “significant side effects or 
complications attributable” to the application of electric current of approximately one milliampere or less for 
“therapeutic effect to the head” (i.e., cranial electrotherapy stimulation) were “virtually non-existent”. The 
Alpha-Stim AID uses 50% of this amount of current at the highest CES setting. A review of 14 Alpha-Stim CES 
studies using human subjects revealed that incidence of adverse events was < 1% and all were mild and self-
limiting. Between 2007 and 2011, there was a total of 8,248,920 Alpha-Stim CES treatments (1,982,520 individual 
users treatments plus 6,266,400 in-office treatments by practitioners) based on the sales figures for 2007 - 2011 
of 58,030 minus returns (there were 75 returns in 2011), an individual home Alpha-Stim post-marketing user 
survey  (EPI, 2011a)  and an Alpha-Stim practitioner survey (EPI, 2011b).   
 
14 adverse events were reported 2007 – 2011, comprising skin irritation at electrode site (11), tinnitus (2) and 
panic attack (1). 
 
No serious adverse events have been reported during the 33 years that Alpha-Stim CES had been on the market.  
 
 
9 
SAFETY REPORTING 
 
9.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant receiving treatment with 
Alpha-Stim AID CES, including occurrences which are not necessarily caused 
by or related to that product. 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
 
9.2 
AE reporting 
The purpose of this study is not demonstrate clinical effectiveness of Alpha-Stim AID CES, which has been 
established. However, AEs should be recorded in PCMIS and reported to the CI or sponsor legal representative 
via completion of the CRF upon the research nurse becoming aware of these.   
 
9.3 
SAE reporting 
SAEs should be recorded in PCMIS and the CRF, and reported to the CI or sponsor legal representative via 
telephone and email upon the research nurse becoming aware of these.  The CI or sponsor legal representative 
will notify the REC which issued favourable opinion within 15 days of becoming aware of the event using the HRA 
SAE report form for non-CTIMPs.  
 
9.4 
Urgent safety measures 

 
 
 
 
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The CI or sponsor legal representative will notify the REC which issued favourable opinion immediately by 
telephone or within 3 days in writing of the implementation of an urgent safety measure and the plan for further 
action.   
9.5 
Pregnancy reporting 
A urine pregnancy dipstick human chorionic gonadotropin test will be used to assess pregnancy in all females of 
child-bearing potential at baseline. Pregnancy should be recorded in PCMIS and reported to the CI or sponsor 
legal representative via email upon the research nurse becoming aware of these and a decision will be made 
regarding continued participation.  
 
Pregnancy is an exclusion criterion and reportable as a precautionary measure as research has not been 
undertaken on the safety and efficacy of Alpha-Stim AID CES treatment in pregnant patients. 
 
10 
PROGRESS REPORTING 
 
10.1 
Progress reports 
The CI or sponsor legal representative will submit, annually, starting at 12 months’ post-date of favourable 
opinion, a progress report to the REC which issued favourable opinion, using the HRA progress report from for 
non-CTIMPs.  
 
10.2 
Declaration of conclusion 
The CI or sponsor legal representative will submit, within 90 days of study end, a declaration of study conclusion, 
to the REC which issued favourable opinion, using the HRA standard form.  
 
10.3 
Summary of final report 
The CI or sponsor legal representative will submit, within one year of study end, a summary of final report, to 
the REC which issued favourable opinion. The summary will be posted online by the HRA. It is intended that the 
final report will be presented at conference and published, but will primarily be used to obtain sufficient evidence 
for NICE and NHS England approval.  
 
11 
STATISTICS AND DATA ANALYSIS 
 
11.1 
Sample size calculation 
If Alpha-Stim AID CES has a comparable effect to IAPT high intensity psychological therapy interventions in 
patients with a primary working diagnosis of GAD, it will achieve an effect size of 1.04 (95% CI 0.88 to 1.23) in an 
intention to treat sample of 4,183 participants with pre-treatment GAD-7 score of 14.06 (s.d. 5.11) and post 
treatment GAD-7 score of 8.10 (s.d. 6.37) (Richards and Borglin, 2011). Reliable improvement was obtained after 
IAPT treatment for generalised anxiety disorder in 54.7%, reliable improvement plus clinically significant change 
in 40.1% and recovery in 46.0%.  
 
However, to make a meaningful economic impact on NHS care, then Alpha-Stim AID CES does not need to be as 
effective as IAPT high intensity psychological therapy interventions. In a previous randomised controlled trial 
(Barclay and Barclay 2014), Alpha Stim CES reduced the mean Hamilton Anxiety score from 29.5 to 13.4 while 
sham Alpha Stim CES reduced it from 27.6 to 20.0 over 5 weeks p=0.001, d=0.94, with 83% patients showing a 
drop of 50% in HAM-A score.   

 
 
 
 
Page 33. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
A meta-analysis of 14 Alpha Stim CES randomised controlled trials estimates an average effect size of 0.60. On 
this basis reliable improvement may be seen in 33%, reliable improvement plus clinically significant change in 
24% and recovery in 28% cases.  
 
The cost of IAPT high intensity psychological therapy intervention is estimated to be £2,895.00 per participant 
and £2,914.00 if stepped care was involved (Radhakrishnan et al, 2013). On a cost offset basis if Alpha-Stim AID 
CES cost £465.00, then reliable improvement plus clinically significant change (which would not necessitate high 
intensity treatment) in only 20% would be clinically and cost effective.  
 
Taking all data into account, 60 patients would be required to complete Alpha Stim AID CES treatment and all 
assessments. However, to allow for drop-out from assessments, drop-out from Alpha-Stim AID CES, and choice 
in relation to IAPT high intensity psychological therapy intervention ,120 patients will be recruited. 
 
It is anticipated from a sample size of 120, then at least 40 (33%) would show reliable improvement, 29 (24%) 
plus clinically significant improvement, and 34 (28%) recovery at 6 months. Since a repeat course of Alpha-Stim 
from 6 to 12 weeks can result in further improvement in those who have made some improvement in symptoms, 
we estimate that a further 20 (17%) will make a reliable improvement in their symptoms. Therefore, it is 
anticipated that 60 (50%) will make a reliable improvement in their GAD-7 symptoms requiring no additional 
psychological treatment or a minimal psychological treatment intervention (in those with other symptoms or do 
not make a reliable improvement plus clinically significant change). 
 
11.2 
Planned recruitment rate 
 
According to IAPT service data, 11.7% cases referred to IAPT meet criteria to establish a primary working 
diagnosis GAD. Of these 39.1% make no clinical improvement and are still clinical cases with a primary working 
diagnosis of GAD upon completion of low intensity psychological therapy intervention (Richards and Borglin, 
2011). On this basis 4.6% of all referrals to the three teams within the single IAPT service should be eligible so a 
conservative estimate is that 2.0% of all referrals may be recruited to this study, allowing for exclusions and 50% 
consent to participation. The IAPT service receives 11,000 referrals per year each leading to 440 potential 
participants.  
 
It is planned that recruitment will be complete within 6 months. 
 
11.3 
Statistical analysis plan 
 
Mean and standard deviation scores will be reported for each visit time-point. The statistician who will deliver 
the analysis is: 
 
Larry R. Price, Ph.D., PStat 
Professor – Psychometrics & Statistics 
Accredited Professional Statistician - American Statistical Association 
Director – Initiative for Interdisciplinary Research Design & Analysis (IIRDA) 
Texas State University 
San Marcos, Texas 78666 
Email: lprice@txstate.edu 
 
 
12 
DATA HANDLING 

 
 
 
 
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12.1 
Data collection tools and source document identification 
The data collection tools are: 
• 
GAD-7 
• 
EQ-5D-5L 
• 
CSRI 
• 
WASA 
• 
PHQ-9 
• 
Athens Insomnia Scale 
• 
Anxiety log 
The research nurse will administer these and record the data as follows: 
 
• 
Enter the data directly into the electronic patient record (PCMIS) – GAD-7, WASA and PHQ-9 are currently 
established within PCMIS. In this scenario, PCMIS record acts as the source document. A copy of the 
anonymised PCMIS data will then be emailed to the sponsor. 
OR 
• 
Enter the data into a CRF – EQ-5D-5L, CSRI, and Athens are not currently established within PCMIS. In 
this scenario, the CRF acts as the source document. The source document will be scanned into PCMIS, 
and a copy will then be emailed to the sponsor. It is anticipated that the CRF will act as source 
documentation for all assessments, regardless of establishment within PCMIS. 
OR 
• 
Participant will enter data into the anxiety log, and send this to the research nurse at week 6 or week 12. 
The anxiety log will act as the source document, and will be scanned into PCMIS, and a copy will then be 
emailed to the sponsor. 
 
12.2 
Data handling and record keeping 
 
Participant in the study will be confidential. Only IAPT staff who are part of the patient’s routine care team will 
have access to personal information prior to the patient indicating interest in the study and arranging a baseline 
visit with the research nurse.  
 
When consent is received, participants will ask to agree for IAPT staff, host institution, authorised representatives 
of the Sponsor and regulatory authorities to have access to participant’s medical records for the purpose of 
monitoring and audit.  
 
Source data will be retained at site, and copies will be sent in hard copy via email to the Sponsor, whereby data 
will be inserted into the study database. Study database will be maintained by the Sponsor, and will be stored 
anonymously at all times. It will not be possible to identify participants from the information stored, and no 
identifiable information will be used in any publications. Data will be emailed within 3 working days of the 
participant visit.  
 
12.3 
Archiving 

 
 
 
 
Page 35. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
The TMF will be retained by the sponsor legal representative, and the ISF will be retained by the host site. Both 
the TMF and ISF must be archived for a minimum of five years post study end date. Sponsor legal representative 
will notify the host site when essential documents may be destroyed. 
 
13 
AUDIT 
Data will be monitored for quality by the sponsor, sponsor legal representative or delegated representative 
throughout the study to ensure consistent data collection. 
 
 
14  
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1  
Approvals 
Prior to enrolling participants, the study will be submitted to the HRA for REC and legislation compliance reviews. 
The study will not enrol participants until receipt of REC favourable opinion, HRA Approval, and local confirmation 
of capacity and capability from Nottinghamshire Healthcare NHS Foundation Trust. Competent Authority approval 
is not required. 
The study will comply with all approval requirements, including the requirement for registration to a publically 
accessible database. The study will be registered to clinicaltrials.gov within 6 weeks of recruitment of the first 
participant. 
 
14.2  
Peer review 
The study has been subject to expert peer review within the sponsor organisation. The review has been undertaken 
by a member of the organisation who is independent of the research team and independent of the financial team. 
The review indicates that the aims and objectives are achievable based upon the design and methodology. 
 
14.3  
Public and patient involvement 
Sponsor recognises the value of patient and public involvement, and therefore service users have been involved in 
the design of the research, to review and improve the protocol design and participant information sheet design. This 
involvement was kindly facilitated by NIHR MindTech Healthcare Technology Co-operative. 
 
14.4  
Protocol compliance 
Prospective, planned deviations or waivers to the protocol are not allowed. Accidental protocol deviations can 
happen, and the research nurse should adequately document these and report to the CI and sponsor legal 
representative immediately.  
 
Deviations from the protocol which are found to frequently recur are not acceptable, will require immediate 
action and could potentially be classified as a serious breach. 
 
14.5  
Notification of serious breaches to GCP and/or the protocol  
A serious breach is a breach which is likely to effect to a significant degree: 
• 
The safety or physical or mental integrity of the participants  
• 
The scientific value of the study 

 
 
 
 
Page 36. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
The CI and sponsor legal representative will be notified immediately of any case where the above definition 
applies during the study, and immediate action will be undertaken. 
 
14.6  
Data protection and patient confidentiality  
All investigators and host site staff must comply with the requirements of the Data Protection Act 1998 with 
regards to the collection, storage, processing and disclosure of personal information and will uphold the Act’s 
core principles.  
 
Participants will be assigned a coded, depersonalised study ID upon consent. The study ID will be used on all 
documentation emailed to the sponsor. The sponsor will never receive personally identifiable data. The linking 
document between the code and the participant’s identifying information will be retained at the host site. The 
custodian of the data remains the Caldicott Guardian within Nottinghamshire Healthcare NHS Foundation Trust. 
 
14.7  
Financial and other competing interests  
Host site (Nottinghamshire Healthcare NHS Foundation Trust) will receive payment for enrollment of participants 
in the study, in accordance with the negotiated fee outlined in the NIHR CRN Industry Costing Template. 
Neither the CI, PI nor host site staff have any commercial ties to the Sponsor nor Sponsor’s Legal Representative.  
 
14.8  
Indemnity 
Sponsor has sufficient indemnity in place for the management and design of the study, and NHS indemnity will be in 
place for the conduct of the study at the host site. 
 
14.9  
Amendments  
Amendments will be notified to the HRA, REC and host site as per requirements under UK procedures.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Page 37. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
 
 
15 
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Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental disorders in the United 
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Klawansky S, Yeung A, Berkey C, Shah N, Phan H, Chalmers TC. Meta-analysis of randomized controlled trials of 
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Kolesos ON., Osionwo H O, Akkhigbe KO.  The role of relaxation therapy and cranial electrotherapy stimulation 
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16 
APPENDIX A: GAD-7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Page 41. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
 
 
 
 
17 
APPENDIX B: CSRI 
Ethnicity 
 
Indicate participant’s ethnicity, by marking with a cross (X) in the relevant box. 
  
 
White 
1 
English/Welsh/Scottish/Northern Irish/British 
 
2 
Irish 
 
3 
Gypsy or Irish traveler 
 
4 
Any other White background, please describe: 
 
 
 
 
Mixed/multiple ethnic groups 
5 
White and Black Caribbean 
 
6 
White and Black African 
 
7 
White and Asian 
 
8 
Any other Mixed/multiple ethnic background, please describe: 
 
 
 
 
Other Ethnic group 
9 
Arab 
 
10 
Any other Ethnic group, please describe: 
 
 
 
 
Asian/British 
11 
Indian 
 
12 
Pakistani 
 
13 
Bangladeshi 
 
14 
Chinese 
 
15 
Any other Asian background, please describe: 
 
 
 
 
Black/African/Caribbean/Black British 
16 
Black Caribbean 
 
17 
Black African 
 
18 
Black other 
 
19 
Any other Black/African/Caribbean background, please describe: 
 
 
 
 
 
Highest qualification 
 
Indicate participant’s highest qualification, by marking with a cross (X) in the relevant box. 
 
1 
Higher degree 
 
2 
First degree 
 

 
 
 
 
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3 
Other higher qualification 
 
4 
A-level 
 
5 
O-level / GCSE 
 
6 
Other qualification 
 
7 
No qualification 
 
 
 
Marital status 
 
Indicate participant’s marital status, by marking with a cross (X) in the relevant box. 
 
1 
Married 
 
2 
Single 
 
3 
Partner 
 
4 
Divorced  
 
5 
Widowed 
 
 
 
Occupational status 
 
Indicate participant’s occupational status, by marking with a cross (X) in the relevant box. 
 
1 
Employed 
 
2 
Self-employed 
 
3 
Voluntary employment 
 
4 
Student / training 
 
5 
House wife / husband 
 
6 
Unemployed 
 
7 
Retired 
 
 
 
Indicate participant’s number of hours worked each week, in hours and minutes. 
 
Number of hours worked each week (XX:XX) 
 
 
 
 
If participant is employed, indicate the participant’s occupational group, by marking with a cross (X) in 
the relevant box. 
 
1 
Manager / administrator 
 
2 
Professional (eg, health, teaching, legal) 
 
3 
Clerical worker / secretary 
 
4 
Services / sales 
 
5 
Skilled labour / craftsmen (eg, building, electrical) 
 
6 
Factory worker 
 
7 
Other, please specify: 
 
 
 
 
 
Costs 
 

 
 
 
 
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The following questions relate to the various costs associated with participant health care to do with 
participant health problems.  Where the participant is unsure of exact numbers, please ask participant 
to provide best estimate or average. 
 
 
Monthly net income 
 
Indicate participant’s monthly net income, by marking with a cross (X) in the relevant box. 
 
1 
£0.00 - £500.00 
 
2 
£500.00 - £1000.00 
 
3 
£1000.00 + 
 
 
 
 
Indicate duration of time participant has taken off work because of ill-health in the last 3 months, by 
indicating numerical values in each box. 
 
1 
Months (XX) 
 
2 
Weeks (XX) 
 
3 
Days (XX) 
 
 
 
If participant is unemployed, indicate the primary reason, by marking with a cross (X) in the relevant 
box. 
 
1 
Mental illness 
 
2 
Physical disability 
 
3 
General employment situation 
 
4 
Redundancy 
 
5 
Other, please specify: 
 
 
 
 
 
If participant receives social security benefits, indicate by marking with a cross (X) in the relevant box. 
 
 
Yes 
No 
Participant receives social security benefits 
 
 
 
 
If participant does receive social security benefits, indicate which by marking with a cross (X) in the 
relevant box(es). 
 
1 
Income support 
 
2 
Incapacity benefit (pre January 2011 / ESA (post January 2011) 
 
3 
Jobseekers allowance (previously unemployment benefit) 
 
4 
Statutory sick pay 
 
5 
Housing benefit 
 
6 
Severe disablement allowance 
 
7 
Mobility allowance 
 
8 
Family (child tax) credit 
 
9 
Lone parent benefit 
 

 
 
 
 
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10 
Attendance allowance  
 
11 
Other, please specify: 
 
 
 
 
 
Indicate participant’s total amount of benefit received each week. 
 
Total amount of benefit received per week (£XX.XX) 
 
 
 
 
Indicate participant’s main source of income, by marking with a cross (X) in the relevant box. 
 
1 
Salary / wage 
 
2 
State benefits 
 
3 
Pension 
 
4 
Family support (ie, from spouse) 
 
5 
Other, please specify: 
 
 
 
 
 
 
Use of outpatient hospital services over the last 3 months 
 
Indicate yes or no, by marking with a cross (X) in the relevant box. 
 
 
Yes 
No 
Participant has made any outpatient hospital visits in the last 3 months 
 
 
 
If yes, provide further detail below. 
 
 
Service 
Total number of appointments in 
last 3 months 
1 
Accident and Emergency department 
 
 
2 
Radiology department 
 
 
3 
Physiotherapist 
 
 
4 
Occupational Therapist 
 
 
5 
Psychiatric outpatient visit 
 
 
6 
Other, please specify: 
 
 
 
 
 
 
 
Use of inpatient hospital services over the last 3 months 

 
 
 
 
Page 45. Protocol. IRAS: 206555. Version 2.0. 28 July 2016. 
 
Indicate yes or no, by marking with a cross (X) in the relevant box. 
 
 
Yes 
No 
Participant has made any inpatient hospital visits in the last 3 months 
 
 
 
If yes, provide further detail below. 
 
 
Service 
Total number 
of admissions 
in last 3 
months 
Total 
number of 
inpatient 
days 
1 
General medical ward 
 
 
 
2 
Psychiatric rehabilitation ward 
 
 
 
3 
Acute psychiatric ward 
 
 
 
4 
Other, please specify: 
 
 
 
 
 
 
Any primary and community care contacts over the last 3 months 
 
Indicate yes or no, by marking with a cross (X) in the relevant box. 
 
 
Yes 
No 
Participant has used any primary and community care services in the 
last 3 months 
 
 
 
If yes, provide further detail below. 
 
 
Service 
Total 
number of 
contacts in 
last 3 
months 
Average 
duration of 
each 
attendance 
(minutes) 
1 
GP surgery 
 
 
 
2 
GP home visit 
 
 
 
3 
Practice nurse 
 
 
 
4 
Community psychiatric nurse 
 
 
 
5 
Walk-in centre 
 
 
 
6 
Out-of-hours care 
 
 
 
7 
Occupational therapist 
 
 
 
8 
Social worker 
 
 

 
 
 
 
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9 
Advocate (eg, creative support) 
 
 
 
10 
Home-help / home care worker 
 
 
 
11 
Community support worker 
 
 
 
12 
Psychiatrist  
 
 
 
13 
Psychologist 
 
 
 
14 
Other, please specify: 
 
 
 
 
 
 
 
Travel costs 
 
Indicate yes or no, by marking with a cross (X) in the relevant box. 
 
 
Yes 
No 
Participant has incurred any travel costs associated with use of services 
in the last 3 months 
 
 
 
If yes, provide further detail below. 
 
Location 
Main method 
of travel (eg, 
private car, 
bus) 
Cost of return 
trip if public 
transport 
(£XX.XX) 
Number of 
miles round 
trip if private 
car (XX.X) 
Total parking 
fees (£XX.XX) 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
 
 
Other costs 
 
Indicate yes or no, by marking with a cross (X) in the relevant box. 
 
 
Yes 
No 
Participant has purchased any over-the-counter medicines or attended 
any private therapy sessions as a result of symptoms during the last 3 
months (including herbal or complementary remedies (eg, crystals and 
visits to alternative practitioners) 
 
 

 
 
 
 
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If yes, provide further detail below. 
 
 
Medicine / preparation / herbal remedy 
bought or appointment with private 
practitioner 
Total number of 
purchases or 
visits in last 3 
months 
Cost of each 
remedy or 
private session 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
Additional care costs 
 
Indicate yes or no, by marking with a cross (X) in the relevant box. 
 
 
Yes 
No 
Participant has not incurred any additional costs as a result of 
symptoms such as requiring informal care 
 
 
 
If yes, provide further detail below. 
 
 
Type of help 
Total 
number of 
visits in last 
3 months 
Average 
cost of each 
visit 
1 
Personal care (eg, washing, dressing, etc) 
 
 
2 
Help in / around house (eg, cooking, cleaning) 
 
 
3 
Help outside the home (eg, shopping, transport) 
 
 
4 
Child care 
 
 
5 
Other, please specify: 
 
 
 
 
6 
Other, please specify: 
 
 
 
 

 
 
 
 
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7 
Other, please specify: 
 
 
 
 
 
 
 
Informal care 
 
Indicate yes or no, by marking with a cross (X) in the relevant box. 
 
 
Yes 
No 
Participant has someone (other than nurses or home helps), such as a 
family member, relative, or friend, who provides help (eg, cleaning, 
cooking, shopping, accompanying to appointments and social events) 
because of the distress caused by the participant’s symptoms 
 
 
 
If yes, provide further detail below. 
 
The relationship of the person to the 
participant  
 
 
 
 
 
Yes 
No 
Person is in paid employment 
 
 
 
If person is in paid employment, indicate the participant’s occupational group, by marking with a cross 
(X) in the relevant box. 
 
1 
Manager / administrator 
 
2 
Professional (eg, health, teaching, legal) 
 
3 
Clerical worker / secretary 
 
4 
Services / sales 
 
5 
Skilled labour / craftsmen (eg, building, electrical) 
 
6 
Factory worker 
 
7 
Other, please specify: 
 
 
 
 
Indicate persons’ number of hours worked each week, in hours and minutes. 
 
Number of hours worked each week (XX:XX) 
 
 
 
Indicate duration of time person has taken off work because of ill-health of the participant in the last 3 
months, by indicating numerical values in each box. 
 
1 
Months (XX) 
 
2 
Weeks (XX) 
 
3 
Days (XX) 
 
 
 
Indicate the length of time, on average, that the person spends each week looking after / helping the 
participant, by marking with a cross (X) in the relevant box. 

 
 
 
 
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1 
1 -5 hours per week 
 
2 
6 – 10 hours per week 
 
3 
11 – 20 hours per week 
 
4 
21 – 35 hours per week 
 
5 
36 – 50 hours per week 
 
6 
50 or more hours per week 
 
7 
Varies: under 20 per week 
 
8 
Varies: more than 20 per week 
 
9 
Other, please specify: 
 
 
 
 
 
18 
APPENDIX C: EQ-5D-5L 
 
 
 

 
 
 
 
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19 
APPENDIX D: WASA 
 

 
 
 
 
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20 
APPENDIX E: PHQ-9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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21 
APPENDIX F: ATHENS INSOMNIA SCALE 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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22 
APPENDIX G: ANXIETY LOG BOOK 
 
Date 
Current setting 
 
Length of treatment 
(minutes) 
 
 
Time of score (before 
treatment) 
 
Anxiety score 
 
Time of score (after 
treatment) 
 
Anxiety score 
 
 
Date 
Current setting 
 
Length of treatment 
(minutes) 
 
 
Time of score (before 
treatment) 
 
Anxiety score 
 
Time of score (after 
treatment) 
 
Anxiety score 
 
 
Date 
Current setting 
 
Length of treatment 
(minutes) 
 
 
Time of score (before 
treatment) 
 
Anxiety score 
 
Time of score (after 
treatment) 
 
Anxiety score 
 
 
Date 
Current setting 
 
Length of treatment 
(minutes) 
 
 
Time of score (before 
treatment) 
 
Anxiety score 
 
Time of score (after 
treatment) 
 
Anxiety score 
 
 
Date 
Current setting 
 
Length of treatment 
(minutes) 
 
 
Time of score (before 
treatment) 
 
Anxiety score 
 
Time of score (after 
treatment) 
 
Anxiety score 
 
 
Date 
Current setting 
 
Length of treatment 
(minutes) 
 
 
Time of score (before 
treatment) 
 
Anxiety score 
 
Time of score (after 
treatment) 
 
Anxiety score 
 
 
Date 
Current setting 
 
Length of treatment 
(minutes) 
 
 
Time of score (before 
treatment) 
 
Anxiety score 
 
Time of score (after 
treatment) 
 
Anxiety score 
 
 
 
 
 

 
 
 
 
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23 
APPENDIX H: CE MARK 
 
 

 
 
 
 
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24 
APPENDIX A: INSURANCE CERTIFICATE