Clinical trial NCT03077919
Conditions: PostTraumatic Stress Disorder
Keywords: Posttraumatic Stress Disorder Generalized Anxiety Disorder Depression Distress Alcohol Use Pain
Sponsor: RTI International
Start date: 2016-05-25; Completion date: 2018-06-09
Enrollment: 113 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multisite, randomized, blinded, sham-procedure-controlled study to evaluate the efficacy of right-sided stellate ganglion block (SGB) on the acute symptomatology of Post traumatic Stress Disorder (PTSD), evaluated by the Clinician-Administered PTSD Scale (CAPS-5) clinical interview at pre-treatment and at 8 weeks. This entry describes the effectiveness study.The acceptability study is described in a separate entry.

Detailed description:
Study intervention will be administered at week 0 and at week 2. Injections will be performed under ultrasound visualization. The study medication will be either 7-10 mL 0.5% ropivacaine injected ventral to the right longus coli muscle (around and into the ventral fascia) and into the longus coli immediately dorsal to the presumed ventral fascia at the level of the C6 anterior tubercle (landmarks for the stellate ganglion) (active study medication) or 1-2 mL preservative free normal saline injected anterolateral to the anterior tubercle of C6 (sham procedure). The participant will not be informed which treatment he or she has received and the interaction of the participant and treating physician will be scripted as much as possible. Following the intervention, the treating physician should have no further contact with the participant except as required for participant safety.

Participants will be evaluated for posttraumatic stress disorder (PTSD) symptomatology prior to week 0 and at 8 weeks using the Diagnostic and Statistical Manual (DSM-5) Clinician-Administered PTSD Scale (CAPS-5). They will complete the PTSD Checklist for DSM-5 (PCL-5), the PTSD Checklist - Civilian Version (PCL-C), and the Mini-international Neuropsychiatric Interview (M.I.N.I.-Plus) Suicidality Items at 0, 2, 4, 6, and 8 weeks; they also will complete the M.I.N.I.-Plus items at screening. The 12 item short form survey (SF-12), generalized anxiety disorder 7-item (GAD-7), patient health questionnaire (PHQ-9), K6, Alcohol Use Disorder Identification Test (AUDIT-C/AUDIT), and a short pain scale will be completed at weeks 0, 4, and 8.

Data collected at baseline and 8 weeks will be the primary focus of data analysis. Data collected at other time points will be analyzed as appropriate.

Arms: arm 1: 7-10 mL 0.5% ropivacaine injected under ultrasound visualization ventral to right longus coli muscle (around and into the ventral fascia) and into the longus coli immediately dorsal to the presumed ventral fascia, at the level of the C6 anterior tubercle (landmarks for stellate ganglion). arm 2: 1-2 mL preservative-free normal saline, injected under ultrasound visualization anterolateral to right anterior tubercle of C6.
Interventions: intervention 1: Ropivacaine intervention 2: Sham treatment
Intervention descriptions: intervention 1: 0.5% ropivacaine intervention 2: preservative-free normal saline

Protocol documents:
Prot_000.pdf: 
 
416632-2.0_SGB_Bartoszek_v 3 Mar 2018 
CONFIDENTIAL 
Page 1 
 
March 3, 2018 
 
USAMRAA W81XWH-15-2-0015 
 
CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
A Randomized, Sham-procedure-controlled, Blinded Study 
to Evaluate the Effectiveness and Acceptability of Right-
sided Stellate Ganglion Block for Treatment of Posttraumatic 
Stress Disorder Symptoms 
 
  
Sponsor: 
RTI International 
3040 Cornwallis Road 
Research Triangle Park, NC 
27709 
 
 
 
 
 
 
 
Protocol ID: 
SGB-201 
Amendment 2.0 (Eisenhower Regional IRB) 
 
 
 
 
Principal Investigator: 
 
 
 
 
Co-Investigator: 
Bradford B. Walters, MD, PhD 
Telephone: 
(919) 316-3509 
Fax: 
 
(919) 541-1275 
Cell: 
 
(919) 614-6273 
 
Kristine Rae Olmsted 
Telephone:   (919) 541-8035 
Fax:         (919) 485-5555 
Cell:        (919) 632-4079 
 
 
Research Monitor: 
MAJ Samuel Blacker, MD 
Telephone: 
(910) 907-7318 
Fax: 
 
(910) 907-8570 
Pager:  
(301) 957-0958 
 
 
Protocol Version/Date: 
 
 
Clinical Trial ID: 
Version #: 
Amendment 2.0 
 
 
March 3, 2018  
 
NCT03077919 
 
 
 
 
 
 
 


  
Protocol SGB-201 
Amendment 2.0 
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REVISION HISTORY 
Protocol 
version 
Protocol 
Date 
Section(s) 
revised 
Description of revision(s) 
Original 
Protocol 
11 November, 2010 Not applicable 
Not applicable 
Amendment 1 
 
October 2, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Study 
Locations 
Text revision. 
Protocol 
Additional Co-
Investigators 
Text revision. 
Protocol Table of 
Contents 
Deleted 6.2.3.12; Deleted Joggle items; 
6.2.3.13 changed to 6.2.3.12; Deleted 
Appendix 17; re-numbered subsequent 
appendices accordingly. 
Protocol Synopsis Deleted Joggle text. Added CAPS-5 change. 
Clarified acceptability target population. 
Protocol Glossary 
of Abbreviations 
and Definitions 
Deleted Joggle text. 
Protocol 1.1.1 
Specified use of DSM-5. 
Protocol 1.2 
Clarified frequency of SGB for PTSD. 
Protocol 2.1 
Deleted Joggle text. Clarified timeline for 
assessments. 
Protocol 3.1 
Added PCL-C to screener. Deleted Joggle 
text. Deleted Joggle assessments. Clarified 
that participants remain blinded. Clarified 
intent of MEDCOM 40-54. Added details 
regarding study incentives. Clarified 
participants will remain blinded to 
intervention. Changed “treatment” to 
“intervention.” 
Protocol 3.2 
Corrected time for subjective assessment of 
change (4-week assessment). Revised 
participant-spouse eligibility criteria. Added 
text explaining scheduling of focus 
groups/individual interviews and clarified 
eligibility for incentive and the amount and 
delivery method. 
Protocol 4.1.2 
 
  
Revised inclusion criterion. Clarified A-level 
modalities. 
 
 
 


  
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Protocol 
version 
Protocol 
Date 
Section(s) 
revised 
Description of revision(s) 
 
 
 
 
Protocol 4.1.3 
Revised final exclusion criterion and added 
exclusion criterion (PCL-C). Clarified 
assessment of psychiatric and TBI history. 
Protocol 4.2.2 
Changed Appendix numbering. Changed 
spouse dyad language. 
Protocol 5.3 
Changed “ultrasound-guided” to “ultrasound-
visualized.” 
Protocol 6.1 
Clarified possibility of randomization to a 
sham study group. Added language to clarify 
recruiting process. 
Protocol 6.2.2 
Specified no AHLA encounter entered. 
Protocol 6.2.2.4 
Clarified DRP. 
Protocol 6.2.3 
Deleted Joggle text. 
Protocol 6.2.3.2 
Clarified use of PCL-5 and PCL-C. 
Protocol 6.2.3.5 
Deleted AUDIT scoring range. 
Protocol 6.2.3.6 
Deleted K6 scoring range. 
Protocol 6.2.3.7 
Deleted PHQ-9 scoring range. 
Protocol 6.2.3.8 
Deleted GAD-7 scoring range. 
Protocol 6.2.3.10 
Inserted references. 
Protocol 6.2.3.12 
Deleted Joggle text. 
Protocol 6.2.3.13 
Changed to 6.2.3.12. Changed Appendix 
numbering. 
Protocol 6.3 
Deleted Joggle text. Changed Appendix 
numbering. Clarified MEDCOM 40-54. 
Protocol 6.4 
Changed Appendix numbering. 
Protocol 6.4.13 
Clarified command contact information to be 
listed and text of messages. 
Protocol 6.5.1.1 
Changed Appendix numbering. 
Protocol 6.5.1.2 
Changed Appendix numbering. 
Protocol 6.5.1.3 
Changed Appendix numbering. 
Protocol 6.5.2 
Changed Appendix numbering. Clarified 
burden for qualitative data collection. 
Clarified purpose of audio recordings. 
Protocol 7.2 
Clarified Research Monitor notification. 
Protocol 8.2 
Deleted Joggle text. 
Protocol 9.1.3.1 
Changed Appendix numbering. 


  
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Protocol 
version 
Protocol 
Date 
Section(s) 
revised 
Description of revision(s) 
Protocol 9.1.3.2 
Changed Appendix numbering. 
Protocol 9.1.4 
Clarified confidentiality of participants in 
group settings. 
Protocol 9.3.1 
Deleted “routine.” 
Protocol Table 1 
Deleted Joggle. Added PCL-C to screener. 
Protocol Table 3 
Added NVivo 9 citation. 
Protocol 
References 
Added References from protocol section 
6.2.3.10. 
Appendix 1 
Added PCL-C to screening. 
Appendix 3 
Language clarifications. Revised questions 4 
and 10. Added PCL-C.  
Appendix 10 
Language clarifications. 
Appendix 17 
Deleted; Joggle items. 
Appendix 18 
Re-numbered to Appendix 17. 
Appendix 19 
Re-numbered to Appendix 18. 
Appendix 20-1 
Re-numbered to Appendix 19-1. 
Appendix 20-2 
Re-numbered to Appendix 19-2. Updated 
dates. 
Appendix 20-3 
Re-numbered to Appendix 19-3. 
Appendix 20-4 
Clarifications. Re-numbered to Appendix 19-
4. 
Appendix 20-5 
Re-numbered to Appendix 19-5. 
Appendix 20-6 
Re-numbered to Appendix 19-6. 
Appendix 20-7 
Re-numbered to Appendix 19-7. 
Appendix 20-8 
Re-numbered to Appendix 19-8. 
Appendix 20-9 
Re-numbered to Appendix 19-9. 
Appendix 20-10 
Re-numbered to Appendix 19-10. 
Appendix 20-11 
Re-numbered to Appendix 19-11. 
Appendix 21-1 
Language clarifications. Deleted Joggle text. 
Simplified language. Re-numbered to 
Appendix 20-1.  
Appendix 21-2 
Provided contact number. Re-numbered to 
Appendix 20-2. 
Appendix 21-3 
 
 
 
Provided contact number. Re-numbered to 
Appendix 20-3. 


  
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Protocol 
version 
Protocol 
Date 
Section(s) 
revised 
Description of revision(s) 
 
Appendix 21-4 
Provided contact number. Re-numbered to 
Appendix 20-4. 
Appendix 21-5 
Re-numbered to Appendix 20-5. 
HIPAA Waiver 
Clarified intent of waiver.  
Addendum 
Section 2 
(Effectiveness 
Trial Recruitment) 
Described recruitment strategy. 
Addendum 
Section 2 
(Acceptability 
Study 
Recruitment) 
Described recruitment strategy and group 
assignment. Revised Spouse Dyad eligibility. 
Addendum 
Section 3 
(Consenting for 
Initial Screening) 
Described consenting process for initial 
effectiveness study screening.  
Addendum 
Section 3 
(Effectiveness 
Trial Consenting) 
Described consenting process for 
effectiveness trial.  
Addendum 
Section 3 
(Acceptability 
Study Consenting) 
Described consenting process for acceptability 
study.  
Addendum  
Section 4 
Clarified need for participant referral. 
Addendum  
Section 6 
Clarified terms of records retention. 
Addendum  
Section 8 
Clarified standard behavioral health care 
requirements. 
 
 
 
 
 
Amendment 2 
 
October 23, 2015 
Protocol 4.1.3 
Deleted pre-existing Horner’s syndrome as 
study exclusion criterion. 
Protocol 6.2.1 
Deleted pre-existing Horner’s syndrome as 
study exclusion criterion. Clarified role of 
clinician in determining whether an individual 
with pre-existing Horner’s syndrome should 
be excluded from the study.  


  
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Protocol 6.4.13 
Text addition regarding participant messaging 
when suicidal ideation is identified during 
online assessments. 
Protocol 7.2 
Text addition to address potential risk to 
subjects in the event that they learn they were 
randomized to sham.  
Protocol 9.1.3 
Text addition regarding suicidal/homicidal 
ideation and command notification.  
Protocol 
References 
Deleted references associated with Joggle.  
Appendix 1 
Deleted Joggle. 
Appendix 2 
Text revisions regarding diagnosis of PTSD 
and additions regarding eligibility for gift 
cards. Clarification that those deemed 
ineligible for the study may still be able to get 
an SGB outside the study. 
Appendix 19-1 
Text revisions.  
Appendix 19-3 
Text revisions. 
Appendix 19-6 
Text revisions.  
Appendix 20-1 
Text revisions re: AHLTA and beneficiaries. 
Addition of text regarding the assigning of 
“quarters” following procedures.  
 
 
 
 
 
Amendment 3 
 
November 19, 2015 
Protocol 
Additional Co-
Investigators 
Text revision.  
Protocol Synopsis Text additions and revisions. 
Protocol 4.1.3 
Text revision. 
Protocol 4.2.2 
Text revision. 
Protocol 6.1 
Text revision. 
Protocol 6.2.2 
Text revision. 
Protocol 9.1.3 
Highlighted text addition regarding 
suicidal/homicidal ideation and command 
notification.  
Appendix 2 
Text revisions, primarily to clarify the remote 
consent and screening process. 
Appendix 19-1 
Text revision. 
Appendix 19-3 
Text addition. 
Appendix 19-4 
Text addition. 
Appendix 19-5 
Text addition. 


  
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Appendix 19-6 
Text addition. 
Appendix 20-1 
Text additions to clarify that no diagnosis of 
PTSD will be placed in the participant’s 
medical record.  
Appendix 20-3 
Text revision. 
Appendix 20-4 
Text additions. 
Appendix 20-5 
Text revisions. 
Commander 
Letter 
Text revision. 
WAMC 
Addendum 
Personnel addition and text revision.  
 
 
Amendment 4 
 
December 1, 2015 
Protocol 6.5.1.2 
Text revisions.  
Appendix 10 
Text deletions regarding scenario 5.  
WAMC 
Addendum 
Text revision.  
Amendment 5 
 
January 8, 2016 
Protocol 7.1, 7.2, 
7.4, 7.6, 7.7  
Revisions regarding HRPO reporting 
requirements; deletion of text regarding 
HSRRB. 
Protocol 7.10 
Text additions summarizing HRPO reporting 
requirements. 
Protocol 9.1.2 
Deletion of text regarding HSRRB. 
Appendix 18 
Text revisions. 
Appendix 20-1 
Text revisions. 
 
 
Amendment 6 
 
March 23, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 3.1 
Text revision.  
Protocol 6.2.1 
Text revisions. 
Protocol 6.2.3 
Text revision.  
Protocol 6.4.13 
Text deletion.  
Protocol 6.5.1.1 
Text revision.  
Protocol 7.1, 7.2, 
7.4, 7.6.1, 7.6.3, 
7.7 
Text revisions and additions per HRPO 
specification.  
Protocol 7.5  
Text deletion. 
Protocol 7.10 
Text additions per HRPO specification.  
Protocol 9.1.2 
Text deletion per HRPO specification.  
Appendix 2 
Text addition.  
Appendix 18 
Text addition regarding the importance of not 
discussing information about the study with 
other service members.  


  
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Appendix 19-1 
Text revisions.  
Appendix 20-1 
Text addition elaborating on request that study 
participants not discuss study information 
with others.  
Amendment 7 
 
July 21, 2016 
Protocol Study 
Locations Page 
Text addition. 
Protocol Table of 
Contents 
Added Appendix 19-12. Qualitative Study 
Telephone Script and Reminder Emails. 
Protocol 6.5.1.1 
Text addition regarding Appendix 19-12. 
Appendix 9 
Text additions.  
Appendix 19-12 
Added.  
WAMC Site 
Specific 
Addendum 
Text additions.  
Amendment 8 (Disapproved) 
August 25, 2016 
Protocol 6.1 
Text addition.  
Renumbering of Amendments 
Beginning Below 
 
 
Amendment 12 
August 29, 2016 
 
Protocol Synopsis Replaced CAPS eligibility criterion with PCL-
C criterion. 
Table 1 
Clarification. 
Protocol 4.1.2 
Replaced CAPS eligibility criterion with PCL-
C criterion. 
Protocol 4.1.3 
Removed concurrent psychological treatment 
from exclusion criteria; removed PCL-C. 
Protocol 6.2.1 
Corrected CAPS text. 
Protocol 6.2.2 
Removed CAPS eligibility, corrected text. 
Protocol 6.2.2.3 
Corrected text. 
Protocol 6.2.3.3 
Added PCL-C as eligibility criterion. 
 
 
Amendment 13 (LRMC) 
August 12, 2016 
WAMC Site 
Specific 
Addendum 
Text revisions.  
Amendment 14 
October 11, 2016 
Protocol Study 
Locations 
Text revisions.  
WAMC Site 
Specific 
Addendum 
Text additions regarding recruitment activities 
and revisions.  
Study Poster 
Text revisions.  


  
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Amendment 15 
Protocol 
Deviation 
WAMC 
Amendment 16 
November 29, 2016 
LRMC Site 
Specific 
Addendum 
Text revisions regarding the expansion of Dr. 
Ryan Young’s role and recruitment activities 
 
TAMC Site 
Specific 
Addendum 
Text revisions regarding the expansion of Dr. 
Cuong Nguyen’s role and recruitment 
activities 
Amendment 17 
January 23, 2017 
 
Amendment retracted 
Amendment 18 
March 24, 2017 
LRMC Site 
Specific 
Addendum 
Text revisions regarding coordinator 
personnel change at LRMC 
Amendment 19 
April 12, 2017 
Protocol 
Additional 
Investigators 
Deletion of COL James Lynch as Co-
Investigator 
Protocol 6.1 
Text deletion regarding PTSD diagnosis; text 
additions regarding recruitment activities, role 
of the PI, use of POAs and mass e-mail for 
recruitment 
Appendix 2 
Text addition of recruitment e-mails 
Appendix 19-1 
Text addition of study closeout and thank you 
e-mail 
Appendix 19-2 
Text revisions. 
LRMC Site 
Specific 
Addendum 
Text deletion regarding PTSD diagnosis; text 
additions regarding recruitment activities, role 
of the PI, use of POAs and mass e-mail for 
recruitment 
TAMC Site 
Specific 
Addendum 
Text deletion regarding PTSD diagnosis; text 
additions regarding recruitment activities, role 
of the PI, use of POAs and mass e-mail for 
recruitment 
WAMC Site 
Specific 
Addendum 
Text deletion regarding PTSD diagnosis; text 
additions regarding recruitment activities, role 
of the PI, use of POAs and mass e-mail for 
recruitment 
Amendment 20 
June 9, 2017 
Study video 
Addition of study video  
Amendment 21 
August 4, 2017 
Protocol Study 
Locations 
Personnel title updates. 
 
Protocol 
Additional Co-
Investigators 
Personnel information updates. 


  
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Protocol Synopsis Text revision to acceptability study design to 
broaden participant pool.  
 
Protocol 2.2  
Text revision to broaden participant pool. 
 
Protocol 3.1  
Text revision to allow electronic or physical 
gift cards. 
 
Protocol 3.2 
Text revision to acceptability study design to 
broaden participant pool.  
 
Protocol 4.1.1 
Text deletion to remove site enrollment 
limitation. 
 
Protocol 4.2.1 
Text deletion to remove site enrollment 
limitation. 
 
Protocol 4.2.2 
Text revision to broaden participant pool. 
 
Protocol 4.2.3 
Text clarification. 
 
Protocol 6.1 
Text deletion to remove site enrollment 
limitation. 
 
Protocol 6.4 
Text deletion regarding in-person follow-up 
visits. 
 
Protocol 6.5.1.1 
Text addition of new acceptability study 
recruitment methods; text clarification. 
 
Protocol 6.5.1.2 
Text clarification. 
 
Protocol 6.5.1.3 
Text revision to broaden participant pool. 
 
Appendix 19-1 
Addition of KRO and RVP. 
 
Appendix 19-3 
Text clarification and addition to broaden 
participant pool.  
 
Appendix 19-4 
Text clarification and revision to broaden 
participant pool. 
 
Appendix 19-5 
Text clarification and revision to broaden 
participant pool. 
 
Appendix 19-6 
Text revision to broaden participant pool. 
 
Appendix 19-7 
Text revision to broaden participant pool. 
 
Appendix 19-8 
Text revision to broaden participant pool. 
 
Appendix 19-9 
Text revision to broaden participant pool. 
 
Appendix 19-10 
Text revision to broaden participant pool. 
 
Appendix 19-11 
Text correction and revision to broaden 
participant pool. 
 
Appendix 19-12 
Text revision regarding gift card and addition 
to broaden participant pool. 
 
Appendix 20-1 
Increased checkbox size. 
 
Appendix 20-2 
Text clarification and addition.  


  
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Appendix 20-3 
Text clarification and addition.  
 
Appendix 20-4 
Text clarification and addition.  
 
Appendix 20-5 
Text clarification and addition. 
 
HIPAA Waivers 
Text revision and addition for acceptability 
study recruitment. 
 
LRMC Site 
Specific 
Addendum 
Removal of site enrollment limitation, 
inclusion of AFN for recruitment, and 
addition for acceptability study recruitment. 
 
TAMC Site 
Specific 
Addendum 
Personnel information update, removal of site 
enrollment limitation and addition for 
acceptability study recruitment. 
 
WAMC Site 
Specific 
Addendum 
Personnel information update, removal of site 
enrollment limitation, and addition for 
acceptability study recruitment. 
 
Data collection 
form 
Addition of data collection form for 
acceptability study recruitment. 
 
Provider Fact 
sheet 
Addition of a provider fact sheet as 
recruitment material to answer common 
questions. 
 
Patient Fact sheet Addition of a patient fact sheet as recruitment 
material to answer common questions. 
 
Radio ad text 
Addition of text for an AFN radio 
advertisement. 
Amendment 22 
August 2017 
Continuing 
Review 
 
Amendment 23 
September 22, 2017 
Protocol 6.1 
Addition of text regarding Facebook page and 
advertising for recruitment 
 
LRMC Site 
Specific 
Addendum 
Addition of text regarding Facebook page and 
advertising for recruitment 
 
TAMC Site 
Specific 
Addendum 
Addition of text regarding Facebook page and 
advertising for recruitment 
 
WAMC Site 
Specific 
Addendum 
Addition of text regarding Facebook page and 
advertising for recruitment 
 
Facebook ad  
Addition of Facebook advertisement 
 
AFN TV ad 
Addition of AFN TV advertisement 
Amendment 2.0 (numbering restarts 
in eIRB) 
March 3, 2018 
Throughout 
protocol 
 
Protocol 8.3  
Revise CAPS change from 15 to 10 
Clarification of enrollment estimates 
 
Justification for CAPS change from 15 to 10 


  
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Protocol 10 
 
Addition of references 
 
 
 
 
 
 


  
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STUDY LOCATIONS 
Womack Army Medical Center (WAMC) 
4-2817 Reilly Street 
Fort Bragg NC 28310 
Site PI/Co-Investigator:  Michael Bartoszek, MD 
 
Chief Anesthesiologist, Department of Anesthesia 
Co-Investigator: Anthony Plunkett, MD 
Consultant: COL Marla R. Hemphill, MD 
Federalwide/DOD Assurance #: 00012834 
 
 
Tripler Army Medical Center (TAMC) 
1 Jarrett White Road 
Honolulu HI 96859 
Site PI/Co-Investigator: LTC Brian McLean, MD 
Co-Investigator: Cuong Nguyen, MD 
Federalwide/DOD Assurance #: 00003575 
 
 
Landstuhl Regional Medical Center (LRMC) 
Geb. 3765 
66849 Landstuhl, Germany 
Site PI/Co-Investigator: MAJ Ali Turabi, MD 
Co-Investigator: Octav Constantinescu, MD 
Co-Investigator: Ryan Young, MD 
Federalwide/DOD Assurance #: 00019005 
 


  
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ADDITIONAL CO-INVESTIGATORS 
COL Shawn F. Kane, MD, FAAFP, FACSM 
U.S. Army Special Operations Command 
Commander, Special Warfare Medical Group (Airborne) 
USAJFK SWCS 
ATTN:  AOJK-MED 
3004 Ardennes St, Stop A 
Ft Bragg NC 28310 
 
LTC Eugene Kim, MD 
Chief, Specialty Behavioral Health 
Womack Army Medical Center 
4-2817 Reilly Street 
Fort Bragg NC 28310 
 
 
 
COL Sean Mulvaney, MD 
Consortium for Health and Military Performance 
Uniformed Services University, 4201 Jones Bridge Road  
Bethesda, MD 20814 
 
 
 


  
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INVESTIGATOR’S AGREEMENT AND SIGNATURE PAGE 
Efficacy and Patient Acceptability of Stellate Ganglion Block for Treatment of PTSD Symptoms 
Protocol Issue Date:  
I have read the protocol and agree: 
• 
That the protocol contains all necessary details for carrying out the study and that I will complete the study 
within the time designated by RTI International. 
• 
To assume responsibility for the proper conduct of the study according to the protocol and any other study-
conduct procedures and requirements provided by RTI International. 
• 
To read, understand, and provide the protocol to all physicians, nurses, and other study personnel 
accountable to me and participating in the conduct of this study. 
• 
To ensure that all study personnel assisting me with the study are fully informed of their study-related 
duties and responsibilities as described in the protocol and other procedures/requirements provided by RTI 
International. 
• 
That the participants will be under my personal supervision or under the supervision of an investigator 
responsible to me. 
• 
Not to implement or initiate the study or make any changes to the protocol without agreement from RTI 
International and prior submission to and written approval from the institutional review board (IRB), except 
when necessary to eliminate the immediate hazard to the participants, or for administrative aspects of the 
study (where permitted by all applicable regulatory requirements). 
• 
To comply with all applicable regulatory requirements in the conduct and reporting of the study. 
• 
To keep the conduct and results of this study confidential until it and all study analyses are complete. 
• 
That RTI International and its designees shall have access to any source documents from which Case 
Report Form data have been collected. 
 
______________________________ 
______________________________ 
Principal Investigator’s Signature  
Date 
 
______________________________                        ______________________________ 
Principal Investigator’s Printed Name                        Site 


  
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TABLE OF CONTENTS 
1. 
INTRODUCTION ....................................................................................................................................... 25 
1.1. 
Background ..................................................................................................................................... 25 
1.1.1. 
PTSD ............................................................................................................................. 25 
1.1.2. 
PTSD Treatment ............................................................................................................ 25 
1.1.3. 
Stellate Ganglion Block................................................................................................. 26 
1.1.4. 
Theoretical Models ........................................................................................................ 27 
1.2. 
Rationale for the Current Study ...................................................................................................... 28 
2. 
OBJECTIVES .............................................................................................................................................. 30 
2.1. 
Clinical Effectiveness Trial ............................................................................................................. 30 
2.2. 
Acceptability Study ......................................................................................................................... 30 
3. 
STUDY DESIGN ......................................................................................................................................... 31 
3.1. 
Clinical Effectiveness Trial Treatment Plan and Regimen ............................................................. 31 
3.2. 
Acceptability Study Design ............................................................................................................. 33 
4. 
PARTICIPANT POPULATION .................................................................................................................. 35 
4.1. 
Clinical Effectiveness Trial ............................................................................................................. 35 
4.1.1. 
Number of Participants .................................................................................................. 35 
4.1.2. 
Inclusion Criteria ........................................................................................................... 35 
4.1.3. 
Exclusion Criteria .......................................................................................................... 35 
4.2. 
Acceptability Study ......................................................................................................................... 36 
4.2.1. 
Number of Participants .................................................................................................. 36 
4.2.2. 
Inclusion Criteria ........................................................................................................... 37 
4.2.3. 
Exclusion Criteria .......................................................................................................... 37 
5. 
STUDY DRUGS .......................................................................................................................................... 38 
5.1. 
Randomization and Blinding ........................................................................................................... 38 
5.2. 
Description and Handling of Study Drug ........................................................................................ 38 
5.2.1. 
Formulation ................................................................................................................... 38 
5.2.2. 
Packaging and Labeling ................................................................................................ 38 
5.2.3. 
Storage and Handling .................................................................................................... 38 
5.3. 
Dosage and Administration of Study Drug ..................................................................................... 38 
6. 
STUDY PROCEDURES (APPENDIX 1) ................................................................................................... 39 
6.1. 
Participant Enrollment and Treatment Assignment......................................................................... 39 
6.2. 
Pre-Treatment Assessments ............................................................................................................ 40 
6.2.1. 
Screening Visit .............................................................................................................. 40 
6.2.2. 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5;  Appendix 9) .................... 41 
6.2.2.1. 
CAPS-5 Administration .............................................................................................. 42 
6.2.2.2. 
Field Preparations: Clinical Interviewer Recruiting and Training .............................. 42 
6.2.2.3. 
Clinical Quality Control ............................................................................................. 42 
6.2.2.4. 
Managing Distressed Respondents During CAPS-5 Administration .......................... 42 
6.2.3. 
Baseline Assessments (Week 0, immediately before SGB) .......................................... 43 
6.2.3.1. 
Urine Pregnancy Test for Females of Child-bearing Potential ................................... 43 
6.2.3.2. 
PTSD Checklist for DSM-5 (PCL-5; Appendix 5) .................................................... 43 
6.2.3.3. 
PTSD Checklist - Civilian Version (PCL-C; Appendix 6) ........................................ 44 
6.2.3.4. 
Mini-International Neuropsychiatric Interview (M.I.N.I.)-Plus Suicidality Items 
(Appendix 7) ............................................................................................................. 44 
6.2.3.5. 
AUDIT-C/AUDIT (Appendix 8) ............................................................................... 44 
6.2.3.6. 
K6 (Appendix 11) ...................................................................................................... 45 
6.2.3.7. 
PHQ-9 (Appendix 12) ................................................................................................ 45 


  
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6.2.3.8. 
GAD-7 (Appendix 13) ............................................................................................... 45 
6.2.3.9. 
SF-12 (Version 2.0) (Appendix 14) ........................................................................... 45 
6.2.3.10. Short pain scale (Appendix 15) ................................................................................. 45 
6.2.3.11. Current Medications (Appendix 16) .......................................................................... 45 
6.2.3.12. Other Questions (Appendix 17) ................................................................................. 46 
6.3. 
Treatment and Treatment Assessments (Weeks 0 and 2) ................................................................ 46 
6.4. 
Post-Treatment Assessments (Weeks 4, 6, and 8) ........................................................................... 47 
6.4.1. 
CAPS-5 ......................................................................................................................... 47 
6.4.2. 
PCL-5 ............................................................................................................................ 47 
6.4.3. 
PCL-C ........................................................................................................................... 48 
6.4.4. 
M.I.N.I.-Plus Suicidality Items...................................................................................... 48 
6.4.5. 
AUDIT-C/AUDIT ......................................................................................................... 48 
6.4.6. 
K6 .................................................................................................................................. 48 
6.4.7. 
PHQ-9 ........................................................................................................................... 48 
6.4.8. 
GAD-7 ........................................................................................................................... 48 
6.4.9. 
SF-12 ............................................................................................................................. 48 
6.4.10. 
Short Pain Scale ............................................................................................................ 48 
6.4.11. 
Current Medications ...................................................................................................... 48 
6.4.12. 
Additional Questions ..................................................................................................... 48 
6.4.13. 
Managing Distressed Participants during Automated Assessments .............................. 49 
6.5. 
Acceptability Study Procedures ...................................................................................................... 49 
6.5.1. 
Participant Recruitment and Group Assignment ........................................................... 49 
6.5.1.1. 
Service Members ........................................................................................................ 49 
6.5.1.2. 
Service Member/Spouse Dyads .................................................................................. 51 
6.5.1.3. 
Providers ..................................................................................................................... 51 
6.5.2. 
Data Collection .............................................................................................................. 51 
6.5.3. 
Managing Distressed Participants During Data Collection ........................................... 52 
6.6. 
Assessments for Premature Discontinuation from Study ................................................................ 53 
6.7. 
Criteria for Suspension of Study Treatment .................................................................................... 53 
7. 
ADVERSE EVENTS AND DEVIATION MANAGEMENT ..................................................................... 54 
7.1. 
Research Monitor ............................................................................................................................ 54 
7.2. 
Adverse Events................................................................................................................................ 54 
7.3. 
Assessment of Adverse Events ....................................................................................................... 55 
7.4. 
Adverse Event Reporting Requirements ......................................................................................... 56 
7.5. 
Serious Adverse Events ................................................................................................................... 56 
7.6. 
Serious Adverse Event Reporting Requirements ............................................................................ 57 
7.6.1. 
All Serious Adverse Events ........................................................................................... 57 
7.6.2. 
Investigator Reporting Requirements for SAEs ............................................................ 58 
7.6.3. 
Post Study Reporting Requirements .............................................................................. 58 
7.7. 
Protocol Deviation Reporting Requirements................................................................................... 58 
7.8. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events ................................................................................................................... 59 
7.9. 
Risks for Women of Childbearing Potential or during Pregnancy .................................................. 59 
7.10. 
HRPO Reporting Requirements ...................................................................................................... 59 
8. 
STATISTICAL CONSIDERATIONS ......................................................................................................... 61 
8.1. 
Primary Analysis ............................................................................................................................. 61 
8.2. 
Secondary Analysis ......................................................................................................................... 61 
8.3. 
Power and Sample Size ................................................................................................................... 62 
8.4. 
Attrition ........................................................................................................................................... 62 
9. 
RESPONSIBILITIES................................................................................................................................... 64 
9.1. 
Investigator Responsibilities ........................................................................................................... 64 


  
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9.1.1. 
Good Clinical Practice................................................................................................... 64 
9.1.2. 
Institutional Review Board (IRB) Approval ................................................................. 64 
9.1.3. 
Informed Consent .......................................................................................................... 64 
9.1.3.1. 
Effectiveness Clinical Trial ........................................................................................ 64 
9.1.3.2. 
Acceptability Study .................................................................................................... 65 
9.1.4. 
Confidentiality ............................................................................................................... 65 
9.1.5. 
Case Report Forms ........................................................................................................ 66 
9.1.6. 
Drug Accountability ...................................................................................................... 66 
9.1.7. 
Inspections ..................................................................................................................... 67 
9.1.8. 
Protocol Compliance ..................................................................................................... 67 
9.2. 
Sponsor Responsibilities ................................................................................................................. 67 
9.2.1. 
Protocol Modifications .................................................................................................. 67 
9.2.2. 
Study Report and Publications ...................................................................................... 67 
9.3. 
Joint Investigator/Sponsor Responsibilities .................................................................................... 67 
9.3.1. 
Access to Information for Monitoring ........................................................................... 67 
9.3.2. 
Access to Information for Auditing or Inspections ....................................................... 68 
9.3.3. 
Study Discontinuation ................................................................................................... 68 
10. REFERENCES ............................................................................................................................................ 69 
Appendix 1. Study Procedures Table ........................................................................................................ 1-1 
Appendix 2. Phone Talking Points and Pre-Screening Questions ............................................................. 2-1 
Appendix 3. Screening Assessment ........................................................................................................... 3-1 
Appendix 4. LEC-5 Standard .................................................................................................................... 4-1 
Appendix 5. PTSD Checklist for DSM-5 (PCL-5) .................................................................................... 5-1 
Appendix 6. PTSD CheckList – Civilian Version (PCL-C) ...................................................................... 6-1 
Appendix 7. M.I.N.I.-Plus Suicidal Ideation Items ................................................................................... 7-1 
Appendix 8. Alcohol Use Disorders Identification Test (AUDIT) ............................................................ 8-1 
Appendix 9. Clinician-Administered PTSD Scale for DSM-5 .................................................................. 9-1 
Appendix 10. Distressed Respondent Protocol (DRP) ............................................................................ 10-1 
Appendix 11. K6  .................................................................................................................................... 11-1 
Appendix 12. PHQ-9 ............................................................................................................................... 12-1 
Appendix 13. GAD-7 .............................................................................................................................. 13-1 
Appendix 14. SF-12  ............................................................................................................................... 14-1 
Appendix 15. Short Pain Scale ................................................................................................................ 15-1 
Appendix 16. Current Medications .......................................................................................................... 16-1 
Appendix 17. Baseline Other Questions .................................................................................................. 17-1 
Appendix 18. Stellate Ganglion Block Scripts ........................................................................................ 18-1 
Appendix 19-1. Reminder Emails and Telephone Script......................................................................... 19-1 
Appendix 19-2. Reminder Email/Call Schedule ...................................................................................... 19-2 
Appendix 19-3. Recruitment Script: Service Members Focus Group and Interviews ............................. 19-3 
Appendix 19-4. Fact Sheet: Service Member Focus Groups and Interviews .......................................... 19-4 
Appendix 19-5. Fact Sheet: Service Member and Spouse Joint Interviews ............................................ 19-5 
Appendix 19-6. Recruitment Script: Service Member and Spouse Interviews ........................................ 19-6 
Appendix 19-7. Recruitment Script: Providers ........................................................................................ 19-7 
Appendix 19-8. Fact Sheet: Provider Focus Groups................................................................................ 19-8 
Appendix 19-9. Topic Guide: Service Member Focus Groups ................................................................ 19-9 
Appendix 19-10. Topic Guide: Service Member and Spouse Interview ............................................... 19-10 
Appendix 19-11. Topic Guide: Provider Focus Groups ........................................................................ 19-11 
Appendix 19-12. Qualitative Study Telephone Script and Reminder Emails ........................................ 19-12 
Appendix 20-1. Model Consent Form ..................................................................................................... 20-1 
Appendix 20-2. Informed Consent Form: Service Member Focus Groups ............................................. 20-2 
Appendix 20-3. Informed Consent Form: Service Member Interviews ................................................... 20-3 
Appendix 20-4. Informed Consent Form: Service Member and Spouse Interviews ............................... 20-4 
Appendix 20-5. Informed Consent Form: Provider Focus Groups .......................................................... 20-5 


  
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LIST OF IN-TEXT TABLES 
Table 1. 
Assessment Schedule .................................................................................................... 32 
Table 2. 
Number of Participants in Qualitative Study ................................................................. 36 
Table 3.  
Topics Addressed in Focus Groups and Interviews ...................................................... 51 
 


  
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PROTOCOL SYNOPSIS 
RTI International 
3040 E. Cornwallis Road 
Research Triangle Park NC 27709 
 
 
Title of Study: 
A Randomized, Sham-procedure-controlled, Blinded Study to Evaluate the 
Effectiveness and Acceptability of Right-sided Stellate Ganglion Block for 
Treatment of Posttraumatic Stress Disorder Symptoms 
IND Number: 
EudraCT Number: 
This is a non-IND study. 
This is a non-EU study 
Study Centers Planned: 
2 centers in USA 
1 center in Germany 
Effectiveness Objectives: 
The primary objective of the clinical effectiveness trial is as follows: 
• 
to evaluate whether right-sided stellate ganglion block (SGB) performed at 
0 and 2 weeks will result in a 10 point decrease in the mean Clinician 
Administered PTSD Scale for DSM-5 (CAPS-5) total symptom scores 
between baseline and 8 weeks  
The secondary objectives of the clinical effectiveness trial are as follows: 
• 
to evaluate whether right-sided SGB performed at 0 and 2 weeks will 
improve PTSD symptoms as reflected by corresponding PTSD Checklist 
for DSM-5 (PCL-5) items between baseline and 8 weeks 
• 
to explore the association between the main outcome and other potential 
confounding variables (e.g., concomitant medications, duration of 
Posttraumatic Stress Disorder [PTSD], post-block Horner’s syndrome, 
etc.) 
• 
to evaluate whether right-sided SGB performed at 0 and 2 weeks will 
reduce distress (K6), suicidality (M.I.N.I.-Plus Suicidality), anxiety 
(GAD-7), depression (PHQ-9), alcohol use (AUDIT-C/AUDIT), or pain 
(short pain scale) between baseline and 8 weeks 
• 
to evaluate whether right-sided SGB at 0 and 2 weeks will improve 
physical and mental condition (SF-12) between baseline and 8 weeks 
 
 


  
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PROTOCOL SYNOPSIS (CONTINUED) 
Effectiveness Study 
Design: 
Blinded, multi-center, randomized, sham-procedure-controlled  
Number of 
Participants Planned: 
240 
Target Population: 
active-duty service members 
Duration of Study: 
10 weeks 
Diagnosis and Main 
Eligibility Criteria: 
Participants with PCL-C score of 32 or higher 
All participants must have anticipated assignment to installation for at least 2 
months and have been offered an A-level modality PTSD treatment (see 
section 4.1.2 for definition) 
Study Procedures/ 
Frequency:  
CAPS-5 following screening (prior to week 0) and at week 8 
Stellate ganglion block at weeks 0 and 2 
PCL-5 and PCL-C at weeks 0, 2, 4, 6, and 8 
M.I.N.I.-Plus Suicidality Items at screening and weeks 0, 2, 4, 6, and 8 
K6 Scale at weeks 0, 2, 4, 6, and 8 
SF-12, GAD-7, PHQ-9, AUDIT-C/AUDIT, pain scale at weeks 0, 4, and 8 
Acceptability Objectives: 
• 
to assess participants’ perceptions of stellate ganglion block in relation to 
other PTSD treatment options 
• 
to inform communication with service members before, during, and after 
the procedure 
Acceptability Study 
Design: 
Qualitative study using focus groups, small group interviews, and individual 
interviews (both in person and over the phone). 
Number of 
Participants Planned: 
193 
Target Population: 
• 
participants in effectiveness clinical trial and their spouses 
• 
service members who have received SGB for PTSD symptoms at the 
participating study sites outside of the clinical trial and their spouse 
• 
providers who have referred or could potentially refer patients for SGB for 
PTSD symptoms at the study sites 
• 
clinicians who provide SGB for PTSD  
Duration of Study: 
no individual’s participation will last more than 90 minutes 
Main Eligibility 
Criteria: 
• 
participants in effectiveness clinical trial who received at least one 
intervention and initial follow-up within the prior three months 
• 
service members who have received at least one SGB for PTSD symptoms 
at the study sites within the prior three months 
providers who have referred or could potentially refer service members for 
SGB for PTSD symptoms at the study sites 
• 
providers who perform SGB for PTSD symptoms at the study sites 


  
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PROTOCOL SYNOPSIS (CONTINUED) 
Test Product, Dose, and 
Mode of Administration: 
0.5% ropivacaine, 7-10 mL, under ultrasound visualization via needle ventral 
to right longus coli muscle (around and into the ventral fascia) and into the 
longus coli immediately dorsal to the presumed ventral fascia, at the level of 
the C6 anterior tubercle (landmarks for stellate ganglion) 
Reference Therapy, Dose, 
and Mode of 
Administration: 
Preservative-free normal saline, 1-2 mL, under ultrasound visualization via 
needle anterolateral to right anterior tubercle of C6 
Study intervention: 
Participants will be randomized 2:1 to either active (0.5% ropivacaine 
injection) or sham (normal saline injection).  
Primary outcome: 
CAPS-5 total symptom score 
Criteria for Evaluation: 
 
Safety:    
adverse events 
Efficacy: 
A 10 point decrease in mean CAPS-5 scores pre-treatment (prior to week 0) to 
8 weeks post-treatment 
Acceptability: 
service members’ and providers’ decision-making processes and information 
needs related to stellate ganglion block 
Statistical Methods: 
Estimates of CAPS-5 total symptom score change between week 8 and pre-
week 0 will be compared between the two treatment arms (active and sham) 
using a linear model that also accounts for study site, the initial (prior to week 
0) CAPS-5 score, as well as potential confounding variables (e.g., 
concomitant medications, duration of PTSD, post-block Horner’s syndrome, 
etc.) depending on availability. Output from the model will include adjusted 
point estimates of the average 8-week change in CAPS-5 symptom score for 
each treatment arm, the estimated average difference in the change between 
the two treatment arms, and corresponding 95% confidence intervals for each 
of these estimates, as well as a formal test of hypothesis of the difference in 
the scores between the two treatment arms. 
We will analyze the effect of SGB on clinical criteria of PTSD as measured by 
the PCL-5 over time. We will assess differential treatment effects at weeks 2, 
4, 6, and 8. The outcome variable in each model will be the binary outcome of 
diagnosis and the models will account for arm classification, week and study 
site; two-way and three-way interactions of treatment will also be included in 
the model. 
Other secondary outcomes similarly will be assessed using linear mixed models 
or generalized models, as appropriate for the structure of the outcome measure. 
 
 
All essential documents are being archived as required  
by the study contractual agreements or protocol. 


  
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
AHRQ 
Agency for Healthcare Research and Quality 
AUDIT 
Alcohol Use Disorders Identification Test 
AUDIT-C 
Alcohol Use Disorders Identification Test Alcohol Consumption Questions 
BHP 
behavioral health provider 
CAPS 
Clinician-Administered PTSD Scale 
CAPS-4 
Clinician-Administered PTSD Scale for DSM-IV 
CAPS-5 
Clinician-Administered PTSD Scale for DSM-5 
CBC 
complete blood count 
CITI 
Collaborative Institutional Training Initiative 
CRF 
Case Report Form(s) 
CRO 
Contract Research Organization 
CRPS 
complex regional pain syndrome 
CS 
Clinical Supervisor 
DOD 
Department of Defense 
DRP 
Distressed Respondent Protocol 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
ECG 
electrocardiogram 
ED 
emergency department 
EEG 
electroencephalogram 
FDA 
(U.S.) Food and Drug Administration 
GAD-7 
Generalized Anxiety Disorder 7-item Scale 
GCP 
Good Clinical Practice (Guidelines) 
HCT 
hematocrit 
HGB 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HPA 
Human Protections Administrator 
HRB 
Survey of Health Related Behaviors among Active Duty Service Members 
HRPO 
USAMRMC Office of Research Protections Human Research Protections Office 
ICD-10 
International Statistical Classification of Diseases and Related Health Problems, 10th edition 
ICF 
International Classification of Functioning, Disability and Health 
ICH 
International Conference on Harmonisation 
ICH-GCP 
International Conference on Harmonisation Good Clinical Practice 
ID 
identification 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
IOM 
Institute of Medicine 
IRB 
Institutional Review Board 
ITT 
intent-to-treat (population) 
IUD 
intrauterine device 
IV 
intravenous 
 
 


  
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (Continued) 
JAMA 
Journal of the American Medical Association 
K6 
Kessler Psychological Distress Scale 
LEC 
Life Events Checklist 
LRMC 
Landstuhl Regional Medical Center 
mL 
milliliter(s) 
MP 
Military Police 
MRI 
magnetic resonance imaging 
NCS-R 
National Comorbidity Survey Replication 
NHIS 
U.S. National Health Interview Survey 
NSDUH 
National Survey on Drug Use and Health 
ORP 
USAMRMC Office of Research Protections 
PAPI 
paper-and-pencil interviewing 
PCL-5 
PTSD Checklist for DSM-5 
PCL-C 
PTSD Checklist - Civilian 
PCL-M 
PTSD Checklist - Military 
PE 
physical examination 
PHI 
protected health information 
PHQ 
Patient Health Questionnaire 
PHQ-9 
Patient Health Questionnaire - 9 
PTSD 
Posttraumatic Stress Disorder 
PVN 
paraventricular nucleus of the thalamus 
RC 
Research Coordinator 
RCT 
randomized, controlled trial 
RSD 
reflex sympathetic dystrophy 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SF-12 
Short Form (12) Health Survey 
SF-36 
Short Form (36) Health Survey 
SG 
stellate ganglion 
SGB 
stellate ganglion block 
SOP 
Standard Operating Procedure 
SPN 
sympathetic preganglionic neuron 
TAMC 
Tripler Army Medical Center 
TBI 
traumatic brain injury 
TV 
television 
UCMJ 
Uniform Code of Military Justice 
ULN 
upper limit of the normal range 
USAMRAA 
US Army Medical Research Acquisition Activity 
USAMRMC 
U.S. Army Medical Research and Materiel Command 
USASOC 
U.S. Army Special Operation Command 
VA 
Veterans Administration 
WAMC 
Womack Army Medical Center 


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1. INTRODUCTION 
1.1. 
Background 
1.1.1. PTSD 
Posttraumatic stress disorder (PTSD) is a reaction to a traumatic event in which an 
individual perceives threat of death or significant injury, resulting in acute fear that is 
experienced over an extended period of time following the event(s). According to the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), symptoms are 
generally categorized in terms of intrusive symptoms (diagnostic criterion B), avoidance 
(diagnostic criterion C), negative alterations in cognitions and mood (diagnostic criterion D), 
and alterations in arousal and reactivity (diagnostic criterion E) (American Psychiatric 
Association, 2013). PTSD will develop in up to a third of individuals who are exposed to a 
significant stressor (Committee on Treatment of Posttraumatic Stress Disorder, Institute of 
Medicine, 2008), and approximately 10% to 20% of those diagnosed with PTSD will become 
chronic (Fletcher, Creamer, & Forbes, 2010). According to the 2000 National Comorbidity 
Survey Replication (NCS-R), an estimated 6.8% of adults in the United States will experience 
PTSD during their lifetime (Dohrenwend et al., 2006). Certain subgroups (e.g., military service 
members) are at an increased risk because of their higher likelihood of trauma exposure (Jonas 
et al., 2013). PTSD prevalence among active duty service members ranges from approximately 
5% to 15% (Tanielian & Jaycox, 2008). Hoge and colleagues (2004) reported an estimated 
12.9% of service members returning from combat operations in Iraq fit diagnostic criteria for 
PTSD. 
There also is evidence that the prevalence of PTSD is increasing among service members. 
The 2008 Department of Defense Survey of Health Related Behaviors among Active Duty 
Service Members (HRB Survey) found that an estimated 11% met screening criteria for further 
evaluation of PTSD symptoms, up from 7% in 2005 (Bray et al., 2009). There also is a host of 
related sequelae, and comorbidity with other mental health disorders is high. In particular, work 
impairment and decreased earnings, divorce, and difficulties with child rearing are common 
(Kessler, 2000), multiplying the impact of the disorder by an untold amount. Finally, PTSD 
often occurs together with other disorders, including depression and substance use disorders 
(Brady, Killeen, Brewerton, & Lucerini, 2000), further compounding the impact. 
1.1.2. PTSD Treatment 
Treatments for PTSD include both psychotherapeutic and pharmacologic modalities, with 
little existing systematic evidence for effectiveness. A 2008 Institute of Medicine (IOM) report 
on treatment effectiveness (2008) included a systematic review of available treatments and 
divided them into pharmacotherapies and psychotherapies, with an eye toward reviewing major 
clinical practice guidelines. At the time of publication, the research regarding the effectiveness 
of pharmacotherapies in the treatment of PTSD was deemed to be inadequate for making a 
determination of a preferred treatment. Similarly, the report found that, for all but one modality 
(exposure therapy), there was insufficient evidence to support the efficacy of psychotherapeutic 
treatments. An additional report released by the Agency for Healthcare Research and Quality 
(AHRQ) (Jonas et al., 2013), found similar results regarding the effectiveness of exposure 
therapy, but also characterized a handful of pharmacologic modalities as effective, though with 
significantly smaller effect sizes than exposure therapy. 


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Currently available treatment modalities for PTSD also have some significant 
disadvantages. Pharmacotherapies frequently come with side effects including, but not limited 
to, nausea, weight gain, headache, sexual dysfunction, and agitation. Furthermore, these 
medications may take up to 6 to 8 weeks of regular use before they begin to provide symptom 
relief (Alexander, 2012), during which time it is not uncommon for patients to develop side 
effects, which may result in discontinuation of the medication(s). Psychotherapeutic modalities 
tend to take an extended period of time to show an effect, frequently 6 to 24 months before the 
patient experiences significant relief (Sharpless & Barber, 2011). Also, some of the most 
effective therapies involve exposure to traumatic stimuli which, if improperly applied, may risk 
further deterioration of the patient (Rauch, Eftekhari, & Ruzek, 2012).  
Patient adherence to and acceptability of prescribed treatments also impact treatment 
effectiveness. Health beliefs (Spoont, Sayer, & Nelson, 2005); knowledge of PTSD and its 
potential therapies (Gray, Elhai, & Frueh, 2004); and comorbid substance abuse, depression, 
and other conditions (Kronish, Edmondson, Li, & Cohen, 2012) all play a role in adherence to 
prescribed treatment regimens. Tarrier and colleagues (2006) conducted a study assessing the 
acceptability of different psychotherapeutic modalities for PTSD. They found that stigma 
associated with receiving treatment was a significant concern for study participants. Stigma has 
been shown to be a deterrent for service members to receive treatment for behavioral health 
concerns such as PTSD. In 2011, one of the key study researchers (Rae Olmsted et al., 2011) 
found that while all service members in their study reported stigma regarding treatment for 
behavioral health issues, those who had actually received behavioral health treatment perceived 
greater stigma associated with treatment. These researchers suggested that such stigma may 
result in higher likelihood of treatment failure or discontinuation (cf. Fung, Tsang, & Chan, 
2010), and that those who had previously received treatment may share their perceptions with 
other service members, in turn dissuading those service members from seeking help should they 
need it. Kim and colleagues (2011) have reported similar findings. 
1.1.3. Stellate Ganglion Block 
Given these concerns, there is a clear need for therapies for PTSD that are safe, effective, 
fast-acting, with few side effects, and with good patient acceptability and adherence. 
Sympathetic blockade, and stellate ganglion block (SGB) in particular, is hypothesized to fill 
this need. SGB is a procedure routinely performed since the 1920s to treat common conditions 
such as complex regional pain syndrome (CRPS), hot flashes, Raynaud’s syndrome, 
hyperhidrosis, and other sympathetically mediated conditions. The stellate ganglion (SG) is a 
sympathetic ganglion located at the base of the cervical spine near the C7 transverse process. 
Sensory afferent projections from the heart and thoracic cavity to cervicothoracic dorsal root 
ganglia traverse the SG (Oldfield & McLachlan, 1978); second-order neurons in the ipsilateral 
spinal cord project to the thalamus, and via third-order neurons to the somatosensory cortex 
(Nozdrachev, Fateev, Jimenez, & Morales, 2003). The neurons in the paraventricular nucleus of 
the thalamus (PVN) appear to contact sympathetic preganglionic neurons (SPN) in the 
intermediolateral column of the spinal cord; those neurons project to the SG (Ranson, Motawei, 
Pyner, & Coote, 1998). Sympathetic postganglionic neurons then project from the SG to the 
heart and thoracic cavity. Other sympathetic efferents traverse the SG (Nozdrachev et al., 2003). 
The SG thus is a major sympathetic switching and transit station for the “fight-or-flight” 
response; interrupting this complex circuitry with a local anesthetic could have observable 
effects on conditions mediated by similar responses, such as PTSD. 


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In SGB a local anesthetic is injected into the SG to “block” its function. To date, only a 
small number of case reports and series have been published about the effectiveness of SGB in 
treating PTSD, but the findings are intriguing and warrant further scientific investigation. In 
1990, Lebovits and colleagues (1990) described an adolescent female who had suffered multiple 
gunshot wounds and developed both reflex sympathetic dystrophy (RSD) and PTSD. The 
patient received 13 SGBs (for RSD) over 15 weeks and reported marked PTSD symptom 
improvement, characterized by significant reductions in intrusive memories and calmer mood. 
Nearly 20 years later, Lipov et al. (2008) reported a patient with insufficient reduction in PTSD 
symptoms from pharmacotherapy who underwent SGB 55 days post-trauma. The individual 
reported immediate resolution of his symptoms (80% to 90% reduction) as well as improved 
appetite and sleep. The symptoms, however, returned 32 days later, at which time pulsed 
radiofrequency energy was applied to the SG. Three months later, the patient reported a 
continued 90% improvement in all symptoms of PTSD. Mulvaney and colleagues (2010), 
including two of the co-investigators of the current study (Mulvaney and McLean), described 
two patients diagnosed with PTSD and treated with SGB. In both, post-treatment PTSD 
Checklist (PCL) scores were sub-threshold for PTSD diagnosis. One of the patients requested 
retreatment 3 months later; their symptoms remained diminished for an additional 7 months of 
follow up. Hicky et al. (2012) described 9 military service members with chronic PTSD who 
were treated with SGB. Each of the participants had more than 1 year of unsuccessful treatment 
via pharmacotherapeutic and/or psychotherapeutic modalities. Following a single SGB, 
Clinician-Administered PTSD Scale (CAPS) assessments showed that 5 of the 9 patients 
experienced a clinically significant reduction in symptoms 1 week post-procedure. The effects 
of the procedure seemed to decrease within 1 to 2 months, though symptoms that did return 
were not always as severe as they had been before the procedure. Of note, they also performed 
two repeat SGB treatments. One individual with no initial benefit also saw no improvement 
following a second block, whereas another who had seen the greatest reduction in symptoms 
experienced full remission after the second procedure. 
Mulvaney et al. (2014) (including two other authors involved in this trial, Lynch and Kane) 
recently reported a case series of 166 patients, by far the largest in the literature. The PTSD 
Checklist – Military (PCL-M) was administered a day before treatment and repeated at 1 week 
and 1, 2, and 3-6 months post-SGB. An improvement in PCL-M scores of ≥10 was observed in 
73.5% of the 132 patients evaluated at 3-6 months. 24 subjects who had a positive response for 
at least 3 months and then had the return of symptoms were treated with a second SGB; their 
PCL-M response trends were similar to those with their first SGB. 
These findings support the need for a randomized, blinded, sham-procedure-controlled trial 
to rigorously study the efficacy of SGB for treatment of PTSD symptoms. 
1.1.4. Theoretical Models 
There are few published theoretical models that seek to explain the effectiveness of SGB 
for PTSD. Lipov and colleagues (2009) proposed that the procedure causes its effect via an 
interaction between the SG and key brain areas known to modulate PTSD, including the insular 
cortex (Liberzon & Martis, 2006) and the amygdala (Rauch et al., 2000). This hypothesis has 
been challenged, however, as being based on faulty understanding of some of the explanatory 
research cited by the authors (Alino, 2011). In another theoretical model, Uchida, Tateda, and 
Hino (2002) proposed that SGB effects are through the involvement of the pineal gland and the 


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regulation of melatonin secretion. The authors note that their hypothesized mechanism of action 
is based on foundations of Oriental medicine, as opposed to Western medicine. Nonetheless, the 
case report and series literature provide support for the evaluation of SGB as a procedure to help 
ameliorate the symptoms of PTSD.  
1.2. 
Rationale for the Current Study 
Because SGB is routinely done in the military for indications such as complex regional 
pain syndrome, and occasionally for treatment of PTSD symptoms (i.e., approximately 25 per 
month at WAMC), there is an unequalled opportunity to collect data and assess the 
effectiveness and patient acceptability of the procedure for a relatively low cost. Though there is 
not compelling supporting evidence, currently SGBs are performed as treatment for PTSD at the 
request and referral from a behavioral health provider (BHP) or other provider. Efficacy of the 
treatment should be established now, before its use becomes more widespread and “accepted,” 
and thus the conduct of a randomized, sham-procedure-controlled study becomes significantly 
less feasible. 
In its original formulation, this study was envisioned to be fully double blinded, with the 
physicians performing the intervention administering 5-7 mL of study drug (either 0.5% 
ropivacaine or saline) at the stellate ganglion. However, in a recently presented randomized, 
controlled trial of SGB for treatment of PTSD (McLay et al., 2015), no differences in CAPS 
scores were observed between subjects who received a 7 mL 0.5% ropivacaine injection at the 
stellate ganglion and those who received 7 ml of normal saline superficial to the anterior 
tubercle of C6. The trial was smaller (42 subjects), only one of up to three SGB was placebo 
controlled and blinded (the first), and selection criteria were broad and included subjects with 
potential secondary gain. Nevertheless, it failed to meet a lower bar than afforded by a fully 
blinded study design. Given these data and also the fact that the injection of 5-7 mL of saline 
around and/or into the stellate ganglion could itself have significant (though likely brief) 
functional effects, addressing the question “does application of a long-acting anesthetic at the 
stellate ganglion have a different effect than that of an equal volume of saline on PTSD 
symptoms assessed by the CAPS?” seems to the Investigators a less practical and relevant 
question to address than “does interruption of function of the stellate ganglion with a 
standardized approach using a long-acting anesthetic have a different effect than a nearby sham 
injection (without any theoretically relevant mechanism of action) on PTSD symptoms as 
assessed by the CAPS?” Only the physicians administering the intervention and their immediate 
team will be unblinded; all other study personnel and the participants themselves will not be 
informed of treatment arm assignment. 
In order for the benefits of SGB and other treatment to be realized, service members must 
be willing to initiate and engage in treatment. Individual understanding of treatment options, 
mechanisms, and effectiveness is a key determinant of treatment acceptability (Sayers et al., 
2009; Shiner et al., 2013). However, individuals filter information about treatment options 
through values and beliefs that impact how information is processed and understood (Charles, 
Gafni, & Whelan, 1999; Charles et al., 2006). Extensive evidence supports the premise that 
service members’ beliefs and values related to mental health treatment are powerfully 
influenced by military culture including their perceptions of stigma associated with mental 
health issues and treatment (Vogt, 2011). Therefore, we have integrated a concurrent qualitative 


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study into the clinical trial to examine the benefits and drawbacks of SGB in comparison to 
other treatment options for PTSD.  
Should SGB be demonstrated to be effective, findings from the qualitative study will 
inform communication about the procedure between providers and service members. Our 
findings will also contribute to efforts to encourage utilization of other evidence based PTSD 
treatments.  


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2. OBJECTIVES 
2.1. 
Clinical Effectiveness Trial  
The primary objective of the effectiveness study is: 
• to evaluate whether right-sided SGB performed at 0 and 2 weeks will improve the 
CAPS-5 total symptom scores between baseline and 8 weeks  
The secondary objectives of this study are: 
• to evaluate whether right-sided SGB performed at 0 and 2 weeks will improve PTSD 
symptoms as reflected by corresponding PCL-5 items between baseline and 8 weeks 
• to explore the association between the main outcome and potential confounding 
variables (e.g., concomitant medications, duration of PTSD, post-block Horner’s 
syndrome, etc.) 
• to evaluate whether right-sided SGB performed at 0 and 2 weeks will reduce distress 
(K6), suicidality (M.I.N.I.-Plus Suicidality), anxiety (GAD-7), depression (PHQ-9), 
alcohol use (AUDIT-C/AUDIT) or pain (short pain scale) between baseline and 8 
weeks 
• to evaluate whether right-sided SGB performed at 0 and 2 weeks will improve physical 
and mental (SF-12) condition between baseline and 8 weeks 
2.2. 
Acceptability Study 
• to assess  perceptions of SGB in relation to other PTSD treatment options among 
service members who have received the procedure and inform communication with 
service members before, during, and after the procedure.  
 
 


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3. STUDY DESIGN 
3.1. 
Clinical Effectiveness Trial Treatment Plan and Regimen 
This will be a multisite, randomized, blinded, sham-procedure-controlled study to evaluate 
the efficacy of unilateral right-sided stellate ganglion block (SGB) on the acute symptomatology 
of PTSD, evaluated by the CAPS-5 pre-treatment and at 8 weeks. Participants will be centrally 
randomized to 2:1 active:sham SGB and will be evaluated at Womack Army Medical Center in 
North Carolina, Tripler Army Medical Center in Hawaii, and Landstuhl Regional Medical 
Center in Germany. Randomization will be stratified by site so that each will have a 2:1 
active:sham ratio. 
On the day of the procedure, clinic nursing staff will perform standard nursing intake to 
include brief interim history, review of systems, vital signs, and placement of intravenous 
catheter. The attending physician will perform a targeted history and physical, paying attention 
to potential contraindications to SGB (e.g., infection at the site of injection, current 
anticoagulated state, presence of mass distorting the tissues, recent myocardial infarction, 
contralateral phrenic nerve palsy, glaucoma). The physician will also give a brief explanation of 
the procedure as well as a review of risks and potential benefits, though these will have been 
described to the participants beforehand.  
Injections will be performed under ultrasound visualization. The study medication will be 
either 7-10 mL 0.5% ropivacaine injected ventral to the right longus coli muscle (around and 
into the ventral fascia) and into the longus coli immediately dorsal to the presumed ventral 
fascia at the level of the C6 anterior tubercle (landmarks for the stellate ganglion) (active study 
medication) or 1-2 mL preservative free normal saline injected anterolateral to the anterior 
tubercle of C6 (sham procedure). The participant will not be informed which treatment he or she 
has received; the interaction of the participant and treating physician will be scripted as much as 
possible. Customary vital signs will be recorded. MEDCOM 40-54 dated Feb 09 provides “a 
standard process and procedure for surgical and procedural site verification of patients 
undergoing operative or other invasive procedures”. In accordance with this regulation, the 
participant’s identity, the procedure to be performed, and the specific site of the procedure will 
be verified. A separate paper Case Report Form (CRF) will be created for the procedure; this 
information will not be shared with anyone outside the treatment suite (Research Coordinator 
(RC), participant, other members of the RTI project team, etc.). It is critical that only the 
physician administering the treatment (and his immediate team) be aware of the participant’s 
assignment to active or sham intervention. Following the intervention, the treating physician 
should have no further contact with the participant except as required for participant safety. At 
no point in time during the conduct of the trial should the physician or treatment team disclose 
by verbal or non-verbal communication the intervention received by the participant.  Once an 
individual participant completes their participation in the trial, they may be offered an unblinded 
standard SGB as clinically indicated, but they will remain blinded to their treatment arm. After 
an individual participant completes their portion of the study (i.e., after completion of the Week 
8 instruments and their second CAPS-5), if an independent clinician providing care to the 
participant needs to know the intervention assignment of that particular participant in order to 
make clinical treatment decisions, a request may be made to the study PI (Dr. Walters) for 
unblinding. Dr. Walters (blinded) will evaluate the request and, if granted, will notify an 
unblinded RTI colleague to provide the intervention information to the clinician for use in 


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clinical decision-making; the clinician, however, is not to disclose the participant’s intervention 
information to anyone else.  
Immediately following the procedure, the participant will be observed in the procedure 
suite prior to transport to the recovery area for assessment of potential complications that could 
require immediate intervention, according to local clinic policy. They then will be taken to the 
post-procedure recovery area, where monitoring of vital signs will continue under the 
supervision of the recovery nurse for 20 minutes or longer, as dictated by clinic policy and 
participant condition. The study RC will use metrics to assess for a Horner’s syndrome (Section 
6.3). A successful block will be recognized by the RC and perhaps by the participant (although 
we are unaware of data pertaining to possible signs and symptoms from saline injection near the 
SG). The RC will not share outcome information with the physician or the participant. While we 
cannot completely prevent the possibility of inadvertent un-blinding of study participants who 
may be familiar with the significance of developing signs and symptoms of SGB, no implicit or 
explicit confirmation will be given to the participants by the research team. This is a limitation 
of the proposed study and indeed any study with participant-accessible outcomes following an 
intervention. 
Study intervention will be administered at week 0 and at week 2. 
Participants will be evaluated for PTSD symptomatology prior to week 0 and at 8 weeks 
using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). They will complete the 
PTSD Checklist for DSM-5 (PCL-5), the PTSD Checklist – Civilian Version (PCL-C), and the 
M.I.N.I.-Plus Suicidality Items at 0, 2, 4, 6, and 8 weeks; they also will complete the M.I.N.I.-
Plus items at screening. The SF-12, GAD-7, PHQ-9, K6, AUDIT-C/AUDIT, and a short pain 
scale will be completed at weeks 0, 4, and 8. 
Table 1. 
Assessment Schedule 
Screener 
Baseline 
2  
Weeks 
4  
Weeks 
6  
Weeks 
8  
Weeks 
CAPS-5 and LEC-5 
X* 
 
 
 
 
X 
PCL-5  
 
X 
X 
X 
X 
X 
PCL-C 
X 
X 
X 
X 
X 
X 
M.I.N.I.-Plus SI Items 
X 
X 
X 
X 
X 
X 
AUDIT-C/AUDIT 
X 
X 
 
X 
 
X 
K6 
 
X 
X 
X 
X 
X 
PHQ-9 
 
X 
 
X 
 
X 
GAD-7 
 
X 
 
X 
 
X 
SF-12 
 
X 
 
X 
 
X 
Short pain scale 
 
X 
 
X 
 
X 
Current medications 
 
X 
 
X 
 
X 
*Not an inclusion/exclusion criterion despite being administered before baseline.  
Individuals who participate in study assessments during off-duty hours will be eligible for 
payments as follows:  
1st CAPS interview:  $15 
Week 0 assessment:  $10 


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Week 2 assessment:  $10 
Week 4 assessment: $15 
Week 6 assessment: $15 
Week 8 assessment: $15 
2nd CAPS interview:  $15 
Qualitative Interview: $20 
 
Payment will be in the form of Amazon or Visa gift cards. 
 
3.2. 
Acceptability Study Design 
The qualitative study will use focus groups, small group interviews, and individual 
interviews to compile a range of perspectives on service members’ decision-making processes 
and information needs related to SGB. Participants will include service members, spouses, and 
providers. Data collection will occur at each study site because attitudes conveyed by leadership 
and chain of command may vary across installation. Scheduling will be based on the 
accumulation of ample service members indicating an interest in participating.   
Participating service members will have received at least one SGB and/or study procedure 
within the prior 3 months, although this interval may be expanded if necessary for recruitment 
into focus groups. Because all study staff (with the exception of the physicians administering 
the study intervention) are blind with respect to treatment status, participants will include 
participants from both active and sham procedure arms. To increase homogeneity within focus 
groups and avoid potential distress among participants who do not experience symptom relief, 
groups will be stratified based on positive versus neutral or negative subjective assessment of 
change at the 4-week assessment (see Section 6.4.12) or at the time of screening for the 
qualitative study. Because beliefs and attitudes related to behavioral health treatment are likely 
to vary according to pay grade, separate groups will be held for lower enlisted service members 
and NCOs. Officers, if available as participants, will be interviewed individually. Data 
collection will address perceived benefits and drawbacks of SGB and other treatment options 
for PTSD; information needs before, and during the procedure; and participants’ description of 
the effects of the procedure.  
Spouses may have questions and concerns regarding SGB and other treatment options that 
differ from those of their service members. Spouses can also provide input that may vary from 
that which is perceived or reported by service members. All married service members and their 
spouses will be eligible to participate in a participant-spouse interview. Data collection with 
spouses will be conducted in joint interviews, in which both members of the couple are 
interviewed at the same time by one interviewer. Interview topics will parallel those used in the 
service member focus groups. Joint interviews will avoid the risk of inadvertent breach of 
confidentiality among spouses. They will also allow comparison of the perspectives of the 
spouse and the service member.  
Providers will include physicians who administer SGBs, and both Behavioral Health 
providers and other (e.g., Family Medicine) physicians who have or could potentially refer 
service members for the procedure. Data collection with providers will consist of small focus 
groups, addressing provider views of how SGB complements or adds to available modalities, 
and how the procedure should be communicated to service members. If scheduling small focus 


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groups with providers is unfeasible, we will conduct individual interviews with providers 
according to their availability.  
Focus groups, small group interviews, and individual interviews will be scheduled to best 
accommodate the participants. This will include evenings and weekends if these are deemed to 
be the most appropriate time. Active duty participants will be reminded that in order for them to 
be given an incentive for taking part in this component of the study, their participation must be 
on their own time. Those who participate in the acceptability study on their own time will 
receive a $20 Amazon or Visa gift card following the completion of their participation. 
 
 


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4. PARTICIPANT POPULATION 
4.1. 
Clinical Effectiveness Trial  
4.1.1. Number of Participants  
A total of up to 240 participants will be enrolled at the three sites.  
4.1.2. Inclusion Criteria 
Participants must meet all of the following inclusion criteria to be eligible for participation 
in this study. 
• Active duty status  
• Personal access to Internet  
• Anticipated stable assignment to installation for at least 2 months  
• Stable dosing for ≥3 months, if receiving psychotropic medications  
• Prior to enrollment, offered PTSD treatment using A-level modality (as defined by 
MEDCOM policy 14-094; 18 Dec 2014). A-level psychotherapies are defined as 
individually provided “trauma-focused psychotherapy that includes components of 
exposure and/or cognitive restructuring; or stress inoculation training” 
(Narration/imaginal exposure; cognitive restructuring; in-vivo exposure; relaxation or 
stress modulation skills; psychoeducation). Relevant manualized treatments include 
Prolonged Exposure Therapy, Cognitive Processing Therapy, and Eye Movement 
Desensitization and Reprocessing. A-level pharmacotherapies include Selective 
Serotonin Reuptake Inhibitors and Serotonin Norepinephrine Reuptake Inhibitors, as 
well as adjunctive prazosin.  
• PCL-C score of 32 or greater at screening 
• Acceptable clinically indicated preoperative laboratory studies, per standard site-
specific protocols 
4.1.3. Exclusion Criteria 
Potential participants who meet any of the following exclusion criteria are not to be 
enrolled in this study. 
• Prior SGB 
• Allergy to amide local anesthetics (e.g., ropivacaine, bupivacaine)  
• Pregnancy (evaluated by urine test pre-procedure) 
• Current anticoagulant use  
• History of a bleeding disorder 
• Infection or mass at injection site  
• Myocardial infarction within 6 months of procedure  
• Phrenic or laryngeal nerve palsy (hoarseness) 


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• History of glaucoma  
• History of schizophrenia, other psychotic disorder, bipolar disorder, or personality 
disorder (axis 2) as verified by medical record review by an Army Co-Investigator with 
access to medical records 
• Moderate or severe traumatic brain injury as verified by medical record review by an 
Army Co-Investigator with access to medical records 
• Symptoms of moderate to severe substance use disorder in past 30 days 
• Suicidal ideation in the past 2 months, documented by the M.I.N.I.-Plus Suicidality 
Items 
• Any ongoing other major life stressor or condition not listed here that the site 
Investigator believes clearly would place the participant at risk for injury or a poor 
outcome (including anniversary of the inciting event, pending divorce, undergoing 
medical board/retirement, undergoing UCMJ or pending legal administrative actions, 
significant illness in participant or family)  
4.2. 
Acceptability Study  
4.2.1. Number of Participants 
A total of up to 193 participants across the 3 sites will be enrolled in the qualitative study. 
Participants will include up to 131 service members, up to 14 spouses of service members, and 
up to 48 providers. The expected allocation of participants by pay grade and subjective 
assessment of change is shown in Table 2. These numbers will be adjusted to proportionally 
reflect study participants.  
Table 2. 
Number of Participants in Qualitative Study 
Total 
Reporting 
Improvement 
No Improvement 
Total 
Groups 
Individuals 
Groups 
Individuals 
Groups 
Individuals 
Service members 
Lower enlisted  
8 
48 
4 
24 
12 
72 
NCOs 
3 
18 
3 
18 
6 
36 
Officers 
6 
3 
9 
  
  
Service member/ 
spouse interviews 
  
  
Lower enlisted  
6 
12 
6 
12 
12 
24 
NCOs 
1 
2 
1 
2 
2 
4 
Providers  
Family Medicine 
4 
16 
Behavioral Health 
4 
16 
 SGB Physicians 
 
 
 
 
4 
16 
Total 
18 
86 
14 
59 
44 
193 
Service members  
131 


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Total 
Reporting 
Improvement 
No Improvement 
Total 
Groups 
Individuals 
Groups 
Individuals 
Groups 
Individuals 
Spouses  
14 
Providers 
48 
4.2.2. Inclusion Criteria 
The following inclusion criteria apply to the qualitative study:  
• Service members must have received at least one SGB and/or study procedure during 
the past three months at a participating study site (as a participant in the clinical 
effectiveness trial or outside of the study) 
• For clinical trial participants, they must have indicated willingness to participate in the 
qualitative study when asked by the RC at baseline data collection 
• For non-clinical trial participants, they must be active-duty status 
• A service member/spouse dyad will consist of a service member meeting the above 
criterion and his/her spouse, when the spouse has responded to the fact sheet describing 
the study (Appendix 19-5, given to the service member at screening) 
• Providers will be Behavioral Health or other (e.g., Family Medicine) clinicians who 
have referred orcould potentially refer service members to the study, and physicians 
who administer SGBs.  
4.2.3. Exclusion Criteria 
Service members will be excluded from the qualitative study if participation would cause 
them undue distress, in the opinion of the RC or treating clinician.  
 
 


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5. STUDY DRUGS  
5.1. 
Randomization and Blinding 
Participants eligible for the study will be randomized to either the sham or active treatment. 
Randomization will be conducted using a permuted block design and stratified by site to ensure 
that the 2:1 active:sham ratio is achieved at each center. 
The control will be a sham injection of saline near the SG. The physicians administering 
the intervention will perforce be unblinded. However, all others involved in the trial (RC, 
participants, RTI study personnel, etc.) will be blind to the administered treatment, and the sole 
interaction of the participants with the treating physicians will be in the treatment suite (except 
as required for participant safety). Also, the RC will not discuss the post-procedure presence or 
absence of a Horner’s syndrome with the Investigator or participant. 
5.2. 
Description and Handling of Study Drug 
Ropivacaine hydrochloride 0.5% for injection is FDA approved for use in SGB. Sterile 
normal saline for injection also is commercially available. There will be site-specific protocols 
for drawing up the study drug; these will produce sufficient documentation to identify which 
participants received active or sham intervention. 
5.2.1. Formulation 
The sterile saline for injection and ropivacaine will be used as commercially formulated 
and approved. 
5.2.2. Packaging and Labeling 
Packaging and labeling of ropivacaine and saline will be per site procedure and protocols. 
The syringes used to administer the active and sham interventions will be indistinguishable by 
the participants. 
5.2.3. Storage and Handling 
The storage and handling of the agents will be per site procedures and protocols. 
5.3. 
Dosage and Administration of Study Drug 
The study drug (7-10 mL 0.5% ropivacaine or 1-2 mL saline) will be administered by the 
site Investigator per the ultrasound-visualized protocol used at the site. 


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6. STUDY PROCEDURES (APPENDIX 1) 
6.1. 
Participant Enrollment and Treatment Assignment 
Participants will be active duty service members who meet inclusion criteria (as described 
above). Based on our power calculations, we anticipate enrolling approximately 240 participants 
(80 per site) into the trial, with 160 being randomized into the active arm and 80 into the control 
arm. Assignment to active or sham will be stratified per site.  
At each of the three study sites, a qualified Research Coordinator (RC) will be staffed by 
the project to oversee all recruiting, screening, enrollment, and assessment activities. While 
these activities will generally be considered the RC’s responsibility and will primarily be 
completed by the RC, the site PI and approved RTI staff may also complete all recruiting, 
screening, enrollment, and assessment activities. For conventional forces, the primary 
mechanism for recruitment will be through Behavioral Health providers (BHP) or Family 
Medicine or other physicians within the installation referral area. They will identify individuals 
whom they think are good candidates for participation in the clinical trial and then briefly 
explain the study. If the service member is interested in participating, then the provider will give 
the individual an interest card on which contact information can be written (Name, email 
address, phone number). These interest cards will be kept by the providers and the RC will 
collect them periodically. The interest card also will have the email address of the RC. If the 
individual prefers he/she can simply email the RC to indicate interest rather than filling out the 
interest card.  
We will also post the study’s approved poster at appropriate locations and send both 
approved poster and e-mail (Appendix 2) through the study sites’ social media outlets, as well 
as in bulletins, newsletters, listservs, mass e-mail, an Armed Forces Network (AFN) 
advertisement, and other electronic means. We will go through proper approval channels for 
official military outlets. RCs may disseminate approved study materials at various locations 
where approval to do so has been obtained. Examples may include but are not limited to on-post 
events where service members, spouses, or others may be present; presentations to Family 
Readiness Groups and similar organizations; and distribution of study materials at locations 
within the facilities where large numbers of people are known to pass. We will post approved 
material on a study Facebook page and ads including only approved materials via Facebook 
advertising. Additionally, we will engage Public Affairs Officers (PAO) at each study site to 
promote the study via approved news/press and other electronic means.  
We also anticipate that some individuals may “self-refer” to the study as a result of having 
seen one of the posters or interest cards that may be displayed at the clinics or simply by word 
of mouth. If these “self-referrers” contact either the local RC or other study staff, they will be 
thanked for their interest and then informed that in order to take part in the study, they need to 
be referred by a mental health or medical provider. For USASOC, there are two potential 
referral routes. First, currently there are WAMC Behavioral Health assets embedded within 
USASOC; that is, when Dr. Bartoszek briefs the WAMC Behavioral Health providers, the 
USASOC-embedded assets will be included. Second, unit assets within USASOC will be made 
familiar with the study’s protocols and will refer appropriate individuals to the study RC.  
The RC will contact by telephone (Appendix 2) those who have expressed interest in the 
study, to explain the study, including the possibility of being randomized to a sham group, and 


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invite them to participate. The RC will provide a study overview and answer any questions that 
individuals may have about participation. Once individuals have agreed to take part in the study, 
they will be asked a few pre-screening questions over the telephone to determine basic 
eligibility (i.e., lack of prior SGB procedure, currently on active duty, with access to the 
Internet, no plans to transfer to a different installation in the coming 2 months, not undergoing 
medical board/retirement, and not undergoing UCMJ or pending legal administrative actions; 
also Appendix 2). Those who pre-screen by phone as ineligible will be thanked for their time 
and will not be contacted again for the study. Participants who pre-screen as eligible and are 
located geographically close to the study site will be asked to come to the RC’s office to 
complete the consenting process in person, and to complete computer-based screening which 
will assess our other study inclusion and exclusion criteria.  We expect this to be the majority of 
our participants.  
However, because our study sites provide coverage for large geographic areas, we also 
likely will encounter some potential participants who are located a considerable distance from 
the study site, to the degree that it is impractical for them to physically come to the RC’s office 
for the screening assessment, only to return home to wait for their CAPS phone interview. 
Consent will be obtained and documented as described below, and then these participants will 
be asked to complete the screening questions on-line or via telephone.   
• An electronic copy of the ICF will be made available to the potential participant via the 
study website or email. 
• The potential participant will be asked to print out a copy of the ICF. 
• The RC will contact the potential participant and go through the consent form in detail 
to insure that the potential participant has read it. The RC will answer any questions. 
• The RC will ask for a verbal consent from the potential participant and have that verbal 
consent confirmed by a witness who is with the participant. 
• The RC will ask the participant and the witness to sign the ICF and return the signed 
signature page of the ICF to RTI in one of the following ways: 1) scan the page and 
upload it via RTI’s secure web system, 2) fax the ICF to the RC, 3) take a photograph 
of the page with a mobile phone or digital camera and upload it via RTI’s secure web 
system, or 4) return the page via mail.  
• If the participant is deemed eligible and comes into the RC’s office for the baseline 
interview, he/she will be asked to initial and sign a new (and newly witnessed) copy of 
the consent form before beginning the assessment.  
6.2. 
Pre-Treatment Assessments 
6.2.1. Screening Visit  
Participants will be screened within 4 weeks prior to randomization to determine eligibility 
for participation in the study. The following will be performed and documented at screening in 
the RC’s office, or over the phone if the participant is unable to make a dedicated screening trip 
to the RC’s office (Appendix 3): 
• Obtain written informed consent (see below for subjects unable to come to RC’s office) 


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• Assessment of eligibility (see inclusion criteria [4.1.3] and exclusion criteria [4.1.4]) 
• Demographics and screening medical history performed by participant on RC laptop 
(Appendix 3)  
• Life Events Checklist-5 (LEC-5; Appendix 4), PCL-C (Appendix 6), M.I.N.I.-Plus 
Suicidality Items (Appendix 7), AUDIT-C/Audit (Appendix 8) – performed by 
participant on RC laptop 
Participants meeting all of the inclusion criteria and none of the exclusion criteria will be 
scheduled for a baseline CAPS-5. Following administration of the CAPS-5, the RC will contact 
RTI to randomize the participant and will schedule the participant’s return to the clinic within 4 
weeks at week 0, their treatments in the clinic at weeks 0 and 2, their Web follow-ups at weeks 
4, 6, and 8, and their post-treatment CAPS-5 at week 8. 
Participants who are not eligible for the study will be so informed, and if they choose this 
information will be provided back to their referring healthcare provider. 
Because some study participants are physically located at a distance from the study site, it 
is possible that some may need to complete their screening remotely. In these instances, the 
prospective participant will receive the same screening content as those who are located locally 
and can complete the assessment in the RC’s office; however, they will provide their consent 
over the phone and then the screening will be performed by the RC. In addition, pre-existing 
Horner’s syndrome will be assessed at the first study visit (i.e., week 0) when they present for 
their initial study condition. At that time, intervening physicians will use their clinical judgment 
to determine whether an individual with a pre-existing Horner’s syndrome would be at 
increased risk from participating in the study. (Note that we expect presentation with a pre-
existing Horner’s syndrome to be very rare - Dr. Bartoszek has indicated that he has never seen 
this in a patient.) If it is determined by the intervening physician that the reason for the Horner’s 
syndrome represents a risk to a study participant, the physician will inform that individual that 
they are ineligible and will answer any questions the individual might have.  
6.2.2. Clinician-Administered PTSD Scale for DSM-5 (CAPS-5;  
Appendix 9) 
The primary outcome measure will be the Clinician-Administered PTSD Scale, or CAPS-5 
(Weathers et al., 2013) (Appendix 9), which is the gold standard in clinical PTSD assessment. 
The CAPS-5 clinical interview is a 30-item structured interview that corresponds to the DSM-5 
criteria for PTSD. For each item, standardized questions and probes are provided; total scores 
range from 0 to 80. CAPS-5 requires the identification of a single index trauma to serve as the 
basis of symptom inquiry. 
As part of the trauma assessment, the CAPS-5 includes the Life Events Checklist, or LEC-
5 (Weathers et al., 2013). The LEC-5 is a 17-item self-administered checklist of potential 
traumatic events. The CAPS-5 is our central outcome measure in support of primary objective 
1. No notes will be added to a participant’s medical records record regarding the CAPS-5 
assessment, as the clinicians administering the CAPS-5 will be subcontractors to RTI and will 
not have access to medical records.  


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6.2.2.1. CAPS-5 Administration  
The LEC-5 will be administered at the time of initial screening by the RC. These data will 
be uploaded to a secure website accessible by the clinical interviewer (CI) in preparation for the 
CAPS-5 interview. The CAPS-5 was designed to be administered by clinicians and clinical 
researchers who have a working knowledge of PTSD, and will be conducted over the telephone 
by trained CIs, who will record all notes and clinical information on hardcopy CAPS-5 forms. 
6.2.2.2. Field Preparations: Clinical Interviewer Recruiting and Training  
Necessary CI credentials will include having completed doctoral coursework in clinical 
psychology, a willingness to participate in study training, and a willingness to meet specific 
scheduling requirements for the position. Study CIs will be recruited from a pool of 
approximately 100 seasoned veteran CIs located throughout the United States who meet these 
criteria. These CIs have completed hundreds of diagnostic interviews over the telephone for 
both the NSDUH Mental Health Surveillance Study (2008-2012) and the Group Project for 
Holocaust Survivors and Their Children (2013). Based on experience hiring CIs of this caliber 
for the NSDUH Mental Health Study, the NSDUH Clinical Validation Study, and the National 
Vietnam Veterans Longitudinal Study, we anticipate between 20% and 30% CI attrition; 
therefore, we will train two more CIs than our goal of four for data collection. 
6.2.2.3. Clinical Quality Control  
CAPS-5 training and clinical quality control will be led by a credentialed, licensed, and 
experienced clinical supervisor (CS) with expertise in PTSD and the CAPS-5. The CS will 
review 100% of hard-copy study clinical interview notes, item-by-item, comparing the notes 
provided by the CI and the scoring, and listening to the accompanying audio files as needed to 
ensure data accuracy. The CS will also review the full audio recordings for a randomly selected 
10% of the clinical interviews. 
6.2.2.4. Managing Distressed Respondents During CAPS-5 Administration  
A number of measures will be taken to enhance the safety of potentially distressed 
participants during telephone CAPS-5 administration. First, we will provide explicit protocols 
for CIs to follow if they encounter either passive or active suicidal or homicidal thoughts. 
Training and supervision will be provided for managing respondents who express sadness, 
agitation, frustration, or any other strong emotion during the course of the clinical interview. A 
detailed Distressed Respondent Protocol (DRP) (Appendix 10), which has been successfully 
used for the NSDUH Mental Health Surveillance Study, will be employed for this study. The 
DRP provides definitions and examples of five types of distressed respondents, along the 
continuum of no risk of harm (i.e., respondent is agitated or upset) to imminent danger (e.g., 
respondent reports active suicidal thoughts, a plan, and a means to carry out that plan). The DRP 
then gives step-by-step instructions for handling each of the five types of distressed 
respondents. CIs will be thoroughly trained in the use of the DRP.  
The DRP will be very similar to the system described in Section 6.4.13 regarding 
management of distressed participants during automated assessments. Clinical interviewers will 
inform individuals at the beginning of the CAPS-5 that they need to obtain the individual’s 
physical location (address) for the purposes of safety, that such information will not be stored, 
and that it will only be used in the case of an emergency. In the event that a respondent indicates 
active suicidal or homicidal ideation during their CAPS-5, the clinician administering the 


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CAPS-5 will call or (in the event that keeping the respondent on the phone is advisable) send a 
text message to study co-investigator Kristine Rae Olmsted and study logistics director Russ 
Vandermaas-Peeler indicating the nature of the ideation, physical location of the respondent (if 
known), and contact information for the respondent. Ms. Rae Olmsted or Mr. Vandermaas-
Peeler will immediately call the respondent’s CQ/duty phone number, CO, or 1SG to report the 
incident. Given the emergent nature of active suicidal or homicidal ideation, we believe that 
using text messaging and/or telephone communications is justified.  
A second measure taken to enhance participant safety relates to the credentials of our CIs 
and the CS. Our study CIs will be seasoned clinicians with experience assessing risk and 
providing direct care for distressed individuals. Similarly, the CS will be a licensed clinical 
psychologist and certified health care provider. This supervisor will be integrally involved in 
supervising the CIs so that if a distressed respondent is encountered, his/her level of risk can be 
verified, and consultation and debriefing can be provided. After each encounter with a 
distressed respondent, the CI will immediately contact the supervisor to review the details of the 
incident, the assessment of risk, and the application of the DRP. If unusual circumstances arise, 
the supervisor will contact the study director and IRB. 
Together, these methods have been effective and allowed us to properly handle 201 
incidents of distressed respondents in the NSDUH Mental Health Surveillance Study, which 
included cases involving suicidal ideation (n=155), homicidal ideation (n=4), and respondents 
who were agitated or upset (n=42). 
6.2.3. Baseline Assessments (Week 0, immediately before SGB) 
All instrument assessments in the following section will be administered via secure 
computer. Paper-and-pencil (PAPI) versions of the assessments will be available in the event 
that Internet services should be interrupted at a study site. If use of PAPI assessments becomes 
necessary, the RC will hand-key the participant’s data upon restoration of Internet services; the 
original forms will be sent to RTI via a secure FTP site so that a second person can review the 
RC’s data entry for accuracy.  
6.2.3.1. Urine Pregnancy Test for Females of Child-bearing Potential 
A urine pregnancy test will be performed on all females of child-bearing potential. A 
positive test will end participation in this study. 
6.2.3.2. PTSD Checklist for DSM-5 (PCL-5; Appendix 5) 
The PCL-5 is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of 
PTSD. Its purposes include screening for PTSD and/or provisional diagnosis, and monitoring 
symptom change before, during, and after treatment. A total symptom severity score ranging 
from 0 to 80 is possible (Weathers et al., 2013). Data on a clinically meaningful change are not 
yet available, nor are full psychometrics. We will administer the PCL-5 at baseline in order to 
be consistent with our use of the CAPS-5, and in order to establish a baseline score in support of 
secondary objective 1. (Note that we are including the instrument in this study at all assessment 
time points, despite its current lack of psychometric testing and clinically meaningful change 
data, because it represents the most up-to-date standard of self-administered PTSD assessment.) 
We anticipate that full psychometrics will be available for our final data analysis in 2017.  


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6.2.3.3. PTSD Checklist - Civilian Version (PCL-C; Appendix 6) 
There are three versions of the PCL for DSM-IV, including the PCL-C for civilians. This 
standardized assessment comprises 17 items corresponding to the key symptoms of PTSD from 
the DSM-IV. The total symptom severity score ranges from 17 to 85. The PCL-C has been 
thoroughly validated and deemed reliable (Convbeare, Behar, Solomon, Newman, Borkovec, 
2012; Weathers et al., 1993). Because data regarding clinically meaningful change are 
unavailable for the PCL-5, and because full psychometrics for the PCL-5 are not yet available, 
we will be administering the PCL-C at baseline in order to establish study eligibility as well as a 
baseline score in support of secondary objective 1.  
6.2.3.4. Mini-International Neuropsychiatric Interview (M.I.N.I.)-Plus Suicidality Items 
(Appendix 7) 
The M.I.N.I.-Plus is a structured interview for diagnosing DSM-IV and ICD-10 psychiatric 
disorders (Sheehan et al., 1998). This study will use a subset of items from the full instrument 
geared toward identifying individuals experiencing suicidal ideation in the past 2 months. 
Response options are dichotomous (yes/no) and questions ask about desire, thoughts, planning, 
taking steps toward, and attempting suicide as well as deliberate injury without intent to kill 
oneself. Individuals answering affirmatively to any of the first 7 items regarding suicidal 
ideation in the previous 2 months will be asked to complete an additional 4 questions regarding 
any current desire to harm themselves, thoughts about suicide, plans for suicide, and active 
steps they may be taking.  
The suicidal ideation assessment will be administered at initial screening so as to identify 
(and exclude) individuals deemed to be at elevated risk for suicide attempt. Those who screen 
positive on the M.I.N.I.-Plus items, who are then asked the follow-up items regarding current 
ideation, will be excluded from the study; they will be evaluated and managed per the 
appropriate site-specific Standard Operating Procedure (SOP). The assessment will also be 
administered on weeks 0, 2, 4, 6, and 8. Because screening will already have taken place, these 
enrolled participants will still be included in the study. This instrument will enhance participant 
safety and support secondary objective 3. 
6.2.3.5. AUDIT-C/AUDIT (Appendix 8) 
The Alcohol Use Disorders Identification Test (AUDIT; Babor, Higgins-Biddle, Saunders, 
& Monteiro, 2001) will be used to assess potential alcohol abuse symptoms. The instrument was 
developed as a means of brief assessment and screening for excessive drinking. This 10-item 
scale is widely used and has been shown to be consistent with ICD-10 definitions for alcohol 
dependence and harmful alcohol use (Allen, Litten, Fertig, & Babor, 1997; Saunders, Aasland, 
Amundsen, & Grant, 1993).  
The AUDIT-C (AUDIT alcohol consumption questions) consists of the first 3 items of the 
full AUDIT and assess frequency of drinking, typical quantity, and frequency of heavy 
drinking. In order to decrease participant burden, we will administer the AUDIT-C first; only 
those screening positive on these items will receive the remaining 7 items of the full AUDIT. It 
is administered in support of secondary objective 3. 


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6.2.3.6. K6 (Appendix 11) 
The K6 was developed for use in the U.S. National Health Interview Survey (NHIS) as a 
means of assessing nonspecific psychological distress. While this study’s active duty military 
population with PTSD may not be representative of the U.S. general population (Kessler et al., 
2003; Kessler et al. 2002), we are including the K6 so as to assess any changes in serious 
psychological distress over time among study participants (secondary objective 3).  
6.2.3.7. PHQ-9 (Appendix 12) 
Depression symptoms will be assessed using the validated PHQ-9 (Kroenke, Spitzer, & 
Williams, 2002) in support of secondary objective 3. The PHQ-9 was developed as a short form 
of the full Patient Health Questionnaire, which was a self-administered version of the PRIME-
MD instrument (Kroenke, Spitzer, & Williams, 2001; Kroenke & Spitzer, 2002; Löwe, Unutzer, 
Callahan, Perkins, & Kroenke, 2004).  
 
6.2.3.8. GAD-7 (Appendix 13) 
Generalized anxiety symptoms will be assessed via the GAD-7 (Spitzer, Kroenke, 
Williams, & Löwe, 2006) in support of secondary objective 3. The instrument was designed to 
be administered in general health settings as part of the Primary Care Evaluation of Mental 
Disorders (PRIME-MD) assessment (Spitzer et al., 1994), and has been validated by a number 
of studies (Spitzer et al., 2006; Kroenke, Spitzer, Williams, Monahan, & Löwe, 2007).  
6.2.3.9. SF-12 (Version 2.0) (Appendix 14) 
The SF-12 is a shortened version of the SF-36, which was designed as a general health 
utility index. Consisting of 12 items, the SF-12v2 improves on the original SF-12 and includes 
simplified wording, better usability, and multi-level response options. The twelve items provide 
an estimate for eight domains of functional health and well-being: physical functioning, role-
physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental 
health. Together, the first four domains constitute a Physical Health summary measure, and the 
second 4 constitute a Mental Health summary measure (Ware, Kosinski, & Keller, 1996; SF-
36.org, n.d.). This assessment will be used as a measure of general functioning in support of 
secondary objective 4.  
6.2.3.10. Short pain scale (Appendix 15) 
Because pain frequently presents with PTSD and may play a confounding role in treatment 
effectiveness (Beck & Clapp, 2011; Kulich, Mencher, Bertrand, & Maciewicz, 2000; Moeller-
Bertram, Keltner, & Strigo, 2012), we will administer a 0-10 Likert-type numeric pain scale 
where 0 represents “No pain,” 5 represents “Moderate pain,” and 10 represents “Worst possible 
pain.” While Visual Analog Scales, Verbal Rating Scales, and Numeric Rating Scales have all 
been deemed valid and reliable (Williamson & Hoggart, 2005), we opted for a numeric scale 
due to prospective study participants’ likelihood of being familiar with the scale, which is 
commonly used in clinical practice at the three participating study sites. The pain scale will be 
administered in support of secondary objective 3. 
6.2.3.11. Current Medications (Appendix 16) 
In order to assess the potential impact of medication use concurrent with study participation, 
we will ask study participants about their use of prescription psychotropics (including stimulants, 


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anxiolytics, and depressants), anticonvulsants, anticholinergic drugs, and 
sympathomimetics/sympatholytics. Given that the mechanism of action of SGB is unknown but 
likely involves some combination of central, peripheral, and autonomic pathways, use of these 
medications could be confounding. These data will be collected to support secondary objective 2. 
6.2.3.12. Other Questions (Appendix 17) 
Additional questions will be asked at week 0 that are not part of an established, 
standardized assessment. In order to determine whether duration of PTSD symptoms moderate 
any treatment effects that may be seen in our study, we will ask study participants whether they 
have been diagnosed with posttraumatic stress (PTS) or posttraumatic stress disorder (PTSD), 
and if so, the month and year when they received this diagnosis. For those who indicate that 
they have not been diagnosed, we will ask for the approximate month and year when their 
symptoms started. 
Similarly, because nicotine has a direct impact on the sympathetic nervous system, we will 
ask study participants four items that will allow for calculation of estimated pack years for 
cigarette smoking. These items will establish age at initiation of regular smoking, smoking 
longevity (whether they have smoked at least 100 cigarettes in their lifetime), recency of regular 
smoking, and number of cigarettes typically smoked. The resulting pack-year estimate will be 
assessed for any moderation of treatment effects among study participants. A similar estimate 
will be computed for chewing tobacco, snuff, or other smokeless tobacco exposure.  
6.3. 
Treatment and Treatment Assessments (Weeks 0 and 2) 
The PCL-5, PCL-C, K6, and the M.I.N.I.-Plus Suicidality Items will be administered prior 
to the procedure at week 2. 
Standard right-sided SGBs will be performed in accordance with this protocol (Section 
3.1). On the day of the procedure, clinic nursing staff will perform standard nursing intake to 
include brief interim history, review of systems, vital signs, and placement of intravenous 
catheter. Females of child-bearing potential will have a urine pregnancy test. The treating 
physician will perform a targeted history and physical, paying attention to potential 
contraindications to SGB. At week 0, the physician will also give a brief explanation of the 
procedure as well as a review of risks and potential benefits, though these will have been 
described to them beforehand.  
Injections will be performed under ultrasound visualization. The study medication will be 
either 7-10 mL 0.5% ropivacaine injected ventral to the right longus coli muscle (around and 
into the ventral fascia) and into the longus coli immediately dorsal to the presumed ventral 
fascia, at the level of the C6 anterior tubercle (landmarks for the stellate ganglion; active study 
medication) or 1-2 mL preservative free normal saline injected anterolateral to the anterior 
tubercle of C6 (sham procedure). The treating physician will access participant assignment 
(performed at RTI per protocol) via email from RTI’s central office. The participant will not be 
informed which treatment he or she is receiving; for blinding purposes, the same type of 
syringes will be used for both injections. Similarly, the same number and types of syringes and 
other supplies should be placed on the sterile procedure table regardless to which intervention 
(SGB or sham) the participant has been randomized. The interaction of the treating physician 
with the participant will be scripted as much as possible (Appendix 18). Customary vital signs 
will be recorded. MEDCOM 40-54 dated Feb 09 provides “a standard process and procedure for 


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surgical and procedural site verification of patients undergoing operative or other invasive 
procedures”. In accordance with this regulation, the participant’s identity, the procedure to be 
performed, and the specific site of the procedure will be verified.  A separate paper CRF will be 
created for the procedure; this information will not be shared with anyone outside the treatment 
suite (RC, participant, other members of the RTI Project Team, etc.). It is critical that only the 
physician administering the treatment (and his immediate team) be aware of the participant’s 
assignment to active or sham intervention. Following the intervention, the treating physician 
should have no further contact with the participant except as required for participant safety. 
Immediately following each SGB procedure, the subject will be observed in the procedure 
suite prior to transport to the recovery area for assessment of potential complications that could 
require immediate intervention, according to local clinic policy. The participant then will be 
taken to the post-procedure recovery area, where monitoring of vital signs will continue under 
the supervision of the recovery nurse for 20 minutes or longer, again per local clinic policy and 
participant condition. 
The RC will assess the participant at 30 minutes post-procedure for his/her Horner’s 
syndrome, recording the time post-SGB and using the following metrics (0 for absent, 1 for 
slight, 2 for obvious) when the participant is sitting up straight and not facing a bright light: 
ptosis 
scleral injection 
miosis  
Assuming the absence of complications requiring further evaluation or treatment, the 
participant will be given discharge instructions, and will be required to verbally indicate 
understanding of signs and symptoms that would require emergency care (e.g., shortness of 
breath or difficulty breathing, increasing neck pain). In addition, the clinic nurse will remind the 
participant that soreness at the injection site, a full sensation of the throat, and Horner’s 
symptomology may occur for 6-18 hours (the duration of effect of the local anesthetic); if the 
recurrent laryngeal nerve has been blocked, there may also be hoarseness and difficulty 
swallowing. The participant then will be allowed to leave the clinic per local site policy. 
6.4. 
Post-Treatment Assessments (Weeks 4, 6, and 8) 
With the exception of the final CAPS-5, it is expected that these instruments will be 
completed by the participants on their own devices using a secure Web-based platform. For 
analytical purposes, each follow-up period will begin 2 days before the exact date of the follow-
up and will end 11 days after the exact date of the follow-up. For example, the 2-week follow-
up period will begin on day 12 and will end on day 25, the 4-week follow-up period will begin 
on day 26 and will end on day 38, etc. See Appendix 19-1 and 19-2 for email communications, 
phone reminder script and contacting schedule. 
6.4.1. CAPS-5 
The CAPS-5 will be repeated, again via phone interview, at approximately 8 weeks 
following the first SGB, in support of the primary objective. 
6.4.2. PCL-5 
The PCL-5 will be repeated at weeks 4, 6, and 8 in support of secondary objective 1. 


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6.4.3. PCL-C 
The PCL-C will be repeated at weeks 4, 6, and 8 in support of secondary objective 1. 
6.4.4. M.I.N.I.-Plus Suicidality Items 
The M.I.N.I.-Plus Suicidality Items will be repeated at weeks 4, 6, and 8, and is intended to 
enhance participant safety and support secondary objective 3. In most cases these assessments 
will take place via a secure web portal on the participant’s device of choice (i.e., there will be no 
interaction between the participant and the RC at these times). If an individual affirmatively on 
any of the first seven M.I.N.I.-Plus items regarding suicidal ideation in the previous 2 months, 
they will be asked an additional 4 questions regarding current suicidal ideation or plans. If a 
participant answers affirmatively to currently wanting to harm themselves, thinking about 
committing suicide, having a plan, or planning to act on a plan, an automated participant safety 
system will be triggered (see Section 6.4.13). 
6.4.5. AUDIT-C/AUDIT 
The AUDIT-C and, if the participant screens positive, the full AUDIT, will be repeated at 
weeks 4 and 8 in support of secondary objective 3. 
6.4.6. K6 
The K6 will be repeated at weeks 4, 6, and 8 in support of secondary objective 3. 
6.4.7. PHQ-9 
The PHQ-9 will be repeated at weeks 4 and 8 in support of secondary objective 3. 
6.4.8. GAD-7 
The GAD-7 will be repeated at weeks 4 and 8 in support of secondary objective 3. 
6.4.9. SF-12 
The SF-12 will be repeated at weeks 4 and 8 in support of secondary objective 4. 
6.4.10. Short Pain Scale 
The short pain scale will be repeated at weeks 4 and 8 in support of secondary objective 3. 
6.4.11. Current Medications 
Current medications will be reassessed at weeks 4 and 8 in support of secondary objective 2. 
6.4.12. Additional Questions 
Additional questions will be asked of study participants at follow-up time points as follows. 
Subjective Assessment of Change. For purposes of stratifying participants for qualitative 
analysis (see Section 3.2), we will ask participants overall how they are feeling at 2, 4, 6, and 8 
weeks post initial treatment compared to how they were feeling before having the procedure. 
Response options will be categorical.  
Subjective Assessment of Treatment Group. At week 4, in order to analyze participants’ 
beliefs regarding whether they were randomized to the study’s active or sham treatment arm (in 
support of secondary objective 2), we will ask participants whether they believe they received 
an “active” procedure or an “imitation” procedure.  


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6.4.13. Managing Distressed Participants during Automated Assessments 
Ensuring the well-being of study participants is of paramount importance, particularly when 
utilizing web-based self-assessments to monitor PTSD symptoms and suicidal ideation. Our 
web-based system will have the capability to send messages to the participant and to key study 
staff in the event that a participant indicates a clinically significant risk of suicide.  If an 
individual answers “yes” to any of the initial seven questions concerning suicidal ideation in the 
past two months, they then will be asked an additional 4 questions regarding current suicidal 
ideation or plans. If a participant answers affirmatively to currently wanting to harm themselves, 
thinking about committing suicide, have a plan, or are planning to act on a plan, an automated 
system will be triggered with the following results: 
• A message will be displayed on the participant’s screen that says the following: 
“Given your responses to some of these questions, we are concerned about your safety. 
As you were told when you signed your consent form to participate in this study, we are 
contacting your Command in an effort to make sure that you are safe. We would like 
for you to please go to your nearest Emergency Room for assistance. In addition, please 
click below to indicate that you agree not to harm yourself before you get to the 
Emergency Room.”  
• A text message providing the service member’s name and his/her command contact 
information (name, telephone number, and email) will be generated and sent to the 
following RTI staff: 
‒ The RC at the site 
‒ Kristine Rae Olmsted (KRO) 
‒ Russ Vandermass-Peeler (RVP) 
• RTI staff will contact the participant’s command by first calling the CQ/duty phone 
number. If that is unsuccessful, they will contact the participant’s First Sergeant or 
Commanding Officer. 
‒ The RC will be the first level responder, since he/she is local 
‒ If the RC doesn’t respond in 2 hours, KRO and RVP will respond. 
• Per site policy, Behavioral Health will be notified by the following business day. 
6.5. 
Acceptability Study Procedures 
6.5.1. Participant Recruitment and Group Assignment 
6.5.1.1. Service Members 
Clinical Effectiveness Trial Participants 
All service members enrolled in the trial will be eligible for the qualitative study if they 
have received at least one SGB study procedure during the three months prior to qualitative data 
collection and if participation would not cause undue distress, as described below.  During 
Baseline Assessment, the RC will describe the qualitative study, following the recruitment 
script included in Appendix 19-3 and providing the Fact Sheet included as Appendix 19-4. The 
RC will keep a list of all service members who indicate willingness to participate in the 
qualitative study. Recruitment for actual qualitative data collection will be determined by the 


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pace of accrual into the clinical trial. When qualitative data collection is scheduled, the RC will 
draw on this list to invite service members to participate in the qualitative study, either in the 
course of a follow-up visit or by email, following the scripts included as Appendix 19-12. 
Service members will not be contacted for qualitative study participation if the RC or treating 
provider considers that participation would cause undue distress based on their most recent 
contact with the individual.  
Other Service Members 
 
Service members who did not participate in the clinical trial are eligible for the 
qualitative study if they have received at least one SGB for PTSD symptoms at a study site in 
the 3 months prior to qualitative data collection and if participation would not cause undue 
distress as described above. These participants will be recruited in the clinic as well as through a 
medical record search conducted by the Site PI or other clinical staff. 
The RCs or clinic staff will identify individuals coming into the clinic for an SGB who may 
be good candidates for participation in the qualitative study. Once at the clinic, the RC or 
clinical staff will briefly explain the study to patients using the scripts included in Appendix 19-
3. If the service member is interested in participating, then the RC will screen the individual at 
that time or contact them later and provide the Fact Sheet included as Appendix 19-4. If the 
individual prefers, he/she can also email the RC later to indicate interest.  
Additionally, site PI or clinic staff at the three study sites will review clinic records to 
identify those patients who have come in for an SGB in the three months prior to qualitative 
data collection. This list will be securely stored in a locked cabinet and securely shredded when 
recruitment for the qualitative has been completed. The PI, clinic staff, or RCs will contact 
potentially eligible individuals by phone or e-mail to see if they are interested in the qualitative 
study following the recruitment script included in Appendix 19-3. Potentially eligible 
individuals will receive up to 2 e-mails and 2 phone calls regarding the study. E-mail contact 
will refer only to SGB and will not mention PTSD symptoms. This will ensure confidentiality 
of the potential participant in the event that the contact is seen by someone other than the 
intended recipient. Phone contacts will confirm potential participant identity prior to providing 
any information regarding the study. 
If the service member is interested in participating, then the RC will speak with the 
individual at that time or contact them later and provide the Fact Sheet included as Appendix 
19-4. If the individual prefers, he/she can also contact the RC later to indicate interest.  
Group Assignment 
Assignment to specific focus groups will be based on pay grade and subjective assessment 
of change as reported at the 4 Week assessment or at the time of screening for the qualitative 
study. In order to maximize homogeneity, lower enlisted service members and NCOs will be 
assigned to different groups. These groups will be further divided so that those reporting 
positive change since the procedure will be assigned to a different group than those reporting no 
change or feeling worse than at the time of the procedure. Depending on the number of eligible 
participants by pay grade, officers may be interviewed individually. 


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6.5.1.2. Service Member/Spouse Dyads 
Eligible participants will be service members who meet the above criteria and whose 
spouse has expressed interest in participating in the qualitative study. Joint interview 
participants will not be allowed to also participate in focus groups. For service members who 
have indicated an interest in participating in focus groups, the RC will identify marital status 
from participants’ demographic data or by asking the participant and inquire whether the service 
member’s spouse is currently living with him/her. If so, the RC will offer these service members 
a recruitment Fact Sheet (Appendix 19-5) for the joint interviews. Interested spouses will 
contact the RC, who will use the recruitment script (Appendix 19-6) to describe the study and 
confirm interest. The RC will invite service members and spouses by email (again including the 
Fact Sheet) or phone to participate in a dyadic interview. 
Participants in joint interviews will include lower enlisted and NCOs, and service members 
will be stratified by whether they report positive versus neutral or negative change since the 
procedure.  
6.5.1.3. Providers 
Eligible participants for the provider focus groups will be Behavioral Health or other (e.g., 
Family Medicine) clinicians who have referred or could potentially refer service members for 
SGB for PTSD symptoms, as well as physicians who provide SGBs. The RC will identify 
eligible clinicians in consultation with the site PIs and study records. These individuals will be 
invited to participate in a small focus group through an email sent by the site PI or RC. Sample 
text for this email is included in Appendix 19-7. A Fact Sheet describing the study will be 
attached to this email, included as Appendix 19-8.  
6.5.2. Data Collection 
Focus group interviews are planned; these are structured discussions on a particular topic 
involving a small number of people under the direction of a moderator (Krueger & Casey, 
2000). The method relies on both the interactive social context of the discussion and on the 
individual experiences of each of the group members to produce a rich discussion in which 
shared experiences stimulate individual contributions. A methodological review by Polak and 
Green (2015) notes that joint interviews in which couples who are interviewed together offer 
similar advantages, with the opportunity for individuals to support and prompt each other, and 
offer contrasting perspectives on shared events. The authors further note that interviews have 
been found particularly useful in describing health-related decision-making.  
The qualitative study will explore participants’ perceptions of SGB in relation to other 
options for treatment of PTSD, from the perspectives of service members, service 
member/spouse couples, and providers. Broad topics covered in service member focus groups, 
service members/spouse interviews, and provider focus group are compared in in Table 3. The 
topic guide for service member focus groups is included as Appendix 19-9, for service member 
and spouse interviews as Appendix 19-10, and for provider focus groups as Appendix 19-11. If 
it is necessary to interview officers individually, questions will follow those in the service 
members topic guide. We anticipate that focus groups and small group interviews will take 
approximately 90 minutes, service member-significant other interviews will take approximately 
60 minutes, and individual interviews will take approximately 45 minutes.  
Table 3.  
Topics Addressed in Focus Groups and Interviews 


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Topic 
Service Members 
Service Member/ 
Spouse Couple 
Provider 
Context for mental health and 
treatment 
• 
 
• 
 
 
Advantages and drawbacks of 
treatment options 
• 
 
• 
 
• 
 
Information and decision-making 
• 
 
• 
 
• 
 
Experience and expectations 
• 
 
• 
 
 
 
All focus groups and interviews will be led by a study team member with prior experience 
in qualitative data collection with clinicians and service members engaged in mental health 
treatment. Real-time notes will be collected by a second team member. We will also audio-
record each focus group or interview, if all participants give permission to do so. The purpose of 
the audio recordings is to augment any notes taken by the second team member (for instance, if 
the note-taker misses something said by a group participant, they may need to consult the audio 
recordings to clarify). We will use a digital recorder for this purpose, with each session’s file 
transferred to an encrypted laptop immediately after the session, then deleted from the digital 
recorder. Participants will not be personally identified in these notes, but will instead be 
indicated generically, such as “Respondent 1” or “Respondent 2.”  
Data from focus groups and interviews will be summarized in topline notes as soon as 
feasible after data collection. In-depth analysis will employ standard qualitative methods. All 
notes will be entered into qualitative data base software such as NVivo 9 (QSR International Pty 
Ltd. Version 9, 2010) to facilitate coding and retrieval. Analysis will be both deductive, 
following a hierarchical coding structure based on topic guide questions, and inductive, creating 
queries to assess patterns observed in the data and hypotheses emerging from preliminary 
analyses. We will also construct analytic matrixes to compare responses across respondent 
types. Comparisons of interest include:  
• Enlisted, NCO, officer 
• Service member, spouse 
• Service member, provider 
• Self-assessed improvement, no self-assessed improvement 
• Behavioral Health clinicians, Family Medicine physicians 
• Study sites  
6.5.3. Managing Distressed Participants During Data Collection 
Discussion of PTSD treatment experiences may be distressing to participants. We will 
remind all participants of counseling resources available to them if they wish to discuss further 
any issue addressed or suggested by the focus group. Contact information for the installation’s 
chaplain services, Behavioral Health services, and substance abuse services, as well as Military 
OneSource, will be attached to each participant’s copy of the informed consent forms. In 
addition, research team members will have contact information for the clinical staff available 
during and immediately after each of the focus groups. These providers will be contacted 
immediately if any participants’ behavior raises concerns that they will harm themselves or 


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another person. Study staff will also have contact information for installation Military Police to 
be used in the event of any urgent threat to safety. 
6.6. 
Assessments for Premature Discontinuation from Study 
The study is designed as intention-to-treat, and therefore participants will not be excluded 
after randomization. If a participant discontinues further treatment or participation in the study, 
for example as a result of an adverse event (AE, Section 7), every attempt should be made to 
continue to perform the required study-related follow-up and procedures (see Section 6.7, 
Criteria for Suspension of Study Treatment). If this is not possible or acceptable to the 
participant or Investigator, the participant may be withdrawn from the study.  
6.7. 
Criteria for Suspension of Study Treatment 
Study intervention may be discontinued in the following instances: 
• Intercurrent illness that would, in the judgment of the Investigator, affect assessments 
of clinical status to a significant degree.  
• Unacceptable toxicity that compromises the ability to continue study-specific 
procedures, or is considered to not be in the participant’s best interest. 
• Participant request to discontinue for any reason. 
• Participant non-compliance. 
• Pregnancy during the first two weeks of the study, when study-related treatment 
procedures (either active or sham) are being conducted. 
• Discontinuation of the study at the request of the relevant IRB. 


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7. ADVERSE EVENTS AND DEVIATION MANAGEMENT 
7.1. 
Research Monitor 
This trial is not a safety study; SGB is a well-studied procedure with a low probability of 
serious adverse events (Wulf & Maier, 1992), and a smaller volume of saline injected 
superficially to the region of the SG would be expected to result in even fewer serious adverse 
events. Nevertheless, reports of adverse events will be collected during the trial, and the 
Research Monitor is required to review all unanticipated problems involving risk to volunteers 
or others, Serious Adverse Events (SAE) and all volunteer deaths associated with the protocol 
and provide an unbiased written report of the event. At a minimum the Research Monitor should 
comment on the outcomes of the event or problem and in the case of a SAE or death comment 
on the relationship to participation in the study. The Research Monitor should also indicate 
whether he/she concurs with the details of the report provided by the Study Investigator. All 
unanticipated problems involving risk to subjects or others will be promptly reported to the 
USAMRMC Office of Research Protection (ORP) Human Research Protection Office (HRPO) 
by telephone (301-619-2165), by email (usarmy.detrick.medcom-
usamrmc.other.hrpo@mail.mil), or by facsimile (301-619-7803) or mail to the US Army 
Medical Research and Materiel Command, ATTN: MCMR-RP, 810 Schreider Street, Fort 
Detrick, Maryland 21702-5000.  
At a minimum, the Research Monitor may discuss the research protocol with the 
Investigators, interview the participants, observe study interventions, and consult with others 
outside of the study about the research. The Research Monitor has the authority to stop this trial, 
remove individual participants from the protocol, and take whatever steps are necessary to 
protect the safety and well-being of human subjects until the IRB can assess the Monitor’s 
report. It is the Research Monitor’s responsibility to promptly report their observations and 
finding to the IRB. There should be no conflict of interest for the Monitor, and the Monitor 
cannot be under the supervision of the PI or other Investigators or research staff. If the duties of 
the Research Monitor could require disclosure of participants’ Protected Health Information 
outside a covered entity (i.e., the Monitor is not an agent of the covered entity), the institution 
responsible for the protection of human subjects may require the identity and location of the 
Research Monitor to be described in the study Health Information Portability and 
Accountability Act authorization. 
7.2. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. AEs may also include pre- or post-treatment 
complications that occur as a result of protocol-mandated procedures (e.g. invasive procedures 
such as venipuncture, biopsy, etc.). Pre-existing events which increase in severity or change in 
nature during or as a consequence of use of a medicinal product in human clinical trials will also 
be considered AEs. 


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Any reported medical condition or clinically significant laboratory abnormality with an 
onset date before the screening visit and not related to study procedures is considered to be pre-
existing, and should be documented in the case report form.  
Any AE (i.e., a new event or an exacerbation of a pre-existing condition) with an onset date 
after the screening visit up to the last day on study (including the follow-up, off study 
medication period of the study), should be recorded as an AE on the appropriate CRF page(s).  
An AE does not include: 
• Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an adverse event. 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected prior 
to the screening visit that do not worsen. 
• Situations where an untoward medical occurrence has not occurred (e.g. hospitalization 
for elective surgery, social and/or convenience admissions). 
• Overdose of either study drug or concomitant medication without any signs or 
symptoms unless the participant is hospitalized for observation. 
The risks attributable to the trial itself originate from the sham procedure arm and include 
those associated with the sham saline injection itself. These would be expected to be 
significantly lower than those associated with the “active” SGB, for which “severe 
complications” (e.g., seizures, epidural and subarachnoid blocks, pneumothorax, allergic 
reactions) have been reported to be 0.17% (Wulf & Maier, 1992). It is also possible that 
participants may learn inadvertently the intervention group to which they were randomized, and 
that those who learn they were randomized to a sham procedure may react negatively to this 
information. These individuals may present to their regular health care provider(s), the 
Department of Behavioral Health, their local emergency department, or other relevant resources 
should they wish. 
Unanticipated problems involving risk to volunteers or others, SAE related to participation 
in the study and all volunteer deaths related to participation in the study should be promptly 
reported to the HRPO by telephone (301-619-2165), by e-mail (usarmy.detrick.medcom-
usamrmc.other.hrpo@mail.mil), by facsimile (301-619-7803), or by mail to the U.S. Army 
Medical Research and Materiel Command, ATTN: MCMR-RP, 810 Schreider Street, Fort 
Detrick, Maryland 21702-5000. The Research Monitor also should be promptly informed.   
7.3. 
Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded on the appropriate CRF page, 
including the date of onset and resolution, severity, relationship to study drug or study 
procedures, outcome and action taken with study medication.  
The relationship to study drug therapy or study procedures should be assessed using the 
following definitions: 
• Definitely Not Related: The participant did not receive the study drug and/or study 
procedure, the temporal sequence of the AE/SAE onset relative to administration of the 
study drug or performance of the procedure is not reasonable, or there is another 
obvious cause of the AE/SAE. 


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• Possibly Related: There is evidence of exposure to the study drug and/or study 
procedure, the temporal sequence of the AE/SAE onset relative to administration of the 
study drug or performance of the procedure is reasonable, but the AE/SAE could have 
been due to another cause. 
• Definitely Related: There is evidence of exposure to the study drug and/or study 
procedure, the temporal sequence of the AE/SAE onset relative to administration of the 
study drug and/or study procedure is reasonable, the AE/SAE is more likely explained 
by the study drug and/or study procedure than by any other cause, and the AE/SAE 
shows a pattern consistent with previous knowledge of the study drug or study drug 
class and/or the study procedure. 
These criteria in addition to good clinical judgment should be used as a guide for 
determining the causal assessment. If it is felt that the event is not related to study drug therapy, 
then an alternative explanation should be provided. 
7.4. 
Adverse Event Reporting Requirements 
AE reports (including SAE reports, Section 7.5) will be included in the continuing review 
reports and in the regularly scheduled re-approval applications to the IRB of record. 
7.5. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as follows:  
• Any adverse drug experience occurring at any dose that results in any of the following 
outcomes:  
o Death;  
o Life-threatening situation (subject is at immediate risk of death); 
o In-patient hospitalization or prolongation of existing hospitalization (excluding 
those for study therapy or placement of an indwelling catheter, unless associated 
with other serious events);  
o Persistent or significant disability/incapacity; 
o Congenital anomaly/birth defect in the offspring of a subject who received study 
drug; 
o Other: medically significant events that may not result in death, be immediately 
life-threatening, or require hospitalization, may be considered a SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
Examples of such events are: 
• Intensive treatment in an emergency room or at home for allergic bronchospasm 
• Blood dyscrasias or convulsions that do not result in hospitalization 
• Development of drug dependency or drug abuse 
Clarification of Serious Adverse Events 


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• Death is an outcome of an adverse event, and not an adverse event in itself. In reports 
of death due to “Disease Progression,” where no other information is provided, the 
death will be assumed to have resulted from progression of the disease being treated 
with the study drug(s). 
• All deaths, regardless of cause or relationship, must be reported for subjects on study 
and for deaths occurring within 30 days of last study drug dose or within 30 days of last 
study evaluation, whichever is longer. 
• “Occurring at any dose” does not imply that the subject is receiving study drug at the 
time of the event. Dosing may have been given as treatment cycles or interrupted 
temporarily prior to the onset of the SAE, but may have contributed to the event. 
• “Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death, if it had 
occurred with greater severity. 
• Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is a SAE. 
• “In-patient hospitalization” means the subject has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It does 
not include presentation and care within an emergency department. 
• The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
A distinction should be drawn between serious and severe AEs. An AE that is assessed as 
grade 4 (potentially life-threatening) should not be confused with a SAE. Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as grade 4. 
An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described 
above. 
7.6. 
Serious Adverse Event Reporting Requirements 
7.6.1. All Serious Adverse Events 
RTI International, the Research Monitor, and HRPO must be notified immediately 
regarding the occurrence of any unanticipated and/or serious adverse event that occurs after the 
screening visit, including serious adverse events resulting from study procedures performed 
from screening onwards. The procedures for reporting all serious adverse events, regardless of 
causal relationship, are as follows: 
• Record the unanticipated and/or SAE on the AE CRF and complete the “Serious 
Adverse Event Report” form.  
‒ Fax and email the serious adverse event report to the attention of RTI International 
and HRPO within 24 hours of the investigator’s knowledge of the event. Contact 
information is below. 
‒ For fatal or life-threatening events, also fax and email copies of hospital case 
reports, autopsy reports, and other documents when requested and applicable.  


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RTI International Principal 
Investigator: 
Name: Bradford B. Walters MD, PhD  
Title   Chief Medical Officer 
Phone: 919-316-3509  
Mobile Phone: 919-614-6273 
Email:  bwalters@rti.org 
RTI International Co-
Investigator: 
Name: Kristine Rae Olmsted 
Phone: 919-541-8035  
Mobile Phone: 919-632-4079 
Fax: 
919-485-5555  
Email:  krolmsted@rti.org 
HRPO: 
 
 
Research Monitor: 
Phone: 301-619-2165 
Fax :  301-619-7803 
Email: usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil  
 
Name: MAJ Samuel Blacker MD 
Phone : 910-907-7318 
Fax : 910-907-8570 
Pager : 301-957-0958 
Email : samuel.n.blacker.mil@mail.mil 
RTI International may request additional information from the Investigator to ensure the 
timely completion of accurate safety reports. 
The Investigator must take all therapeutic measures necessary for resolution of the SAE. 
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the participant’s CRF. 
Follow-up of adverse events will continue through the last day on study (including the 
follow-up, off study medication period of the study), until the Investigator and/or RTI 
International determine that the participant’s condition is stable, or up to 30 days after the last 
dose of study drug, whichever is longer. RTI International may request that certain adverse 
events be followed until resolution. 
7.6.2. Investigator Reporting Requirements for SAEs 
The Investigator should notify the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) as soon as is practical of serious events in writing where this is required by 
local regulatory authorities, and in accordance with the local institutional policy. 
7.6.3. Post Study Reporting Requirements 
All deaths, regardless of cause or relationship, must be reported to RTI for 
participants on study and for all deaths occurring within 30 days of last study drug 
dose. Protocol Deviation Reporting Requirements 
Any deviation from this protocol that may have an effect on the safety or rights of the 
volunteer or the integrity of the study must be promptly reported to RTI and the IRB. Any 
corrective actions taken to avoid future such deviations should be included in the report. 
Documentation of any actions taken by the IRB related to the deviation report should be 
provided when available. 


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7.7. 
   Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities are usually not recorded as adverse events or serious adverse 
events unless they are associated with clinical signs and/or symptoms. However, laboratory 
abnormalities (e.g. clinical chemistry, hematology, urinalysis, etc.) independent from the 
underlying medical condition, that require medical or surgical intervention, or lead to study drug 
interruption or discontinuation must be recorded as an AE, as well as an SAE, if applicable. In 
addition, laboratory or other abnormal assessments (e.g. electrocardiogram, X-rays, vital signs) 
that are associated with signs and/or symptoms must be recorded as an AE or SAE if they meet 
the definition of an adverse event (or serious adverse event) as described in Sections 7.1 and 
7.3. If the laboratory abnormality is part of a syndrome, record the syndrome or diagnosis. 
Severity should be recorded and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. For adverse events associated with laboratory 
abnormalities, the event should be graded based on the clinical severity in the context of the 
underlying conditions, which may or may not be in agreement with the grading of the laboratory 
abnormality. 
7.8. 
Risks for Women of Childbearing Potential or during Pregnancy 
The FDA classes ropivacaine as Pregnancy Category B, and pregnant women are not to be 
enrolled in this trial. The participant must be instructed to discontinue all study drugs and 
inform the investigator immediately if she becomes pregnant during the study. 
The investigator should report all pregnancies to RTI International within 24 hours of 
becoming aware of the pregnancy. The investigator should counsel the participant regarding the 
possible effects of prior study drug exposure on the fetus and the need to inform the study site 
of the outcome of the pregnancy.  
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or a SAE.  
A spontaneous abortion is always considered to be a SAE and will be reported as described 
in the adverse and Serious Adverse Events section. Furthermore, any SAE occurring as an 
adverse pregnancy outcome post-study must be reported to RTI International. 
7.9. 
HRPO Reporting Requirements 
a. Substantive modifications to the research protocol and any modifications that could 
potentially increase risk to subjects must be submitted to the HRPO for approval prior to 
implementation. The USAMRMC ORP HRPO defines a substantive modification as a change in 
Principal Investigator, change or addition of an institution, change to the IRB of Record, 
elimination or alteration of the consent process, change to the study population that has 
regulatory implications (e.g. adding children, adding active duty population, etc.), significant 
change in study design (i.e. would prompt additional scientific review), or a change that could 
potentially increase risks to subjects.  
b. A copy of the IRB continuing review approval letter must be submitted to the HRPO as 
soon as possible after receipt of approval.  


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c. The final study report submitted to the IRB, including a copy of any acknowledgement 
documentation and any supporting documents, must be submitted to the HRPO as soon as all 
documents become available. 
d. The following study events must be promptly reported to the HRPO by telephone 
(301-619-2165), by email (usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil), or by 
facsimile (301-619-7803) or mail to the US Army Medical Research and Materiel Command, 
ATTN: MCMR-RP, 810 Schreider Street, Fort Detrick, Maryland 21702-5000. 
(1) All unanticipated problems involving risk to subjects or others. 
(2) Suspensions, clinical holds (voluntary or involuntary), or terminations of this 
research by the IRB, the institution, the sponsor, or regulatory agencies. 
(3) Any instances of serious or continuing noncompliance with the federal regulations or 
IRB requirements. 
(4) The knowledge of any pending compliance inspection/visit by the Food and Drug 
Administration (FDA), Office for Human Research Protections, or other government agency 
concerning this clinical investigation or research. 
(5) The issuance of inspection reports, FDA Form 483, warning letters, or actions taken 
by any government regulatory agencies. 
(6) Change in subject status when a previously enrolled human subject becomes a 
prisoner must be promptly reported to the USAMRMC ORP HRPO. The report must include 
actions taken by the institution and the IRB. 
e. Events or protocol reports received by the HRPO that do not meet reporting requirements 
identified within this memorandum will be included in the HRPO study file but will not be 
acknowledged  


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8. STATISTICAL CONSIDERATIONS 
8.1. 
Primary Analysis 
Data analysis will be performed according to the intent-to-treat principle. The primary 
outcome of this study (difference in CAPS-5 total syndrome score from baseline) will be tested 
for differences between arms. The primary outcome will be analyzed using a linear model for 
continuous variable that accounts for treatment assignment, site and other factors. Adjusted 
estimates of the difference in the change between the two arms and corresponding 95% 
confidence intervals will be produced. 
8.2. 
Secondary Analysis 
The treatment effect on the clinical criteria of PTSD as measured by the PCL-5 over time 
will be assessed at weeks 2, 4, 6 and 8 using a generalized-linear mixed model to account for 
temporal correlation between weekly measures and the clustering of the data; this model will 
control for treatment, week, site, baseline PCL-5 score and the two way interaction between 
treatment and time. The outcome variable will be a binary variable denoting positive diagnosis. 
Because the psychometric properties of this instrument are still under development, details of 
the cut point definitions will be described more fully in the Statistical Analysis Plan (SAP), 
based on either published results of those psychometric studies currently ongoing, or 
preliminary psychometric analyses of data from this study, as deemed most appropriate when 
the SAP is developed. Adjusted and unadjusted probabilities of benefit of treatment at each time 
point will be produced using contingency table analysis (log-likelihood chi-square) and 
generalized-mixed models, correspondingly. 
Effects of treatment on individual items from the PCL-5 through time will be evaluated 
descriptively using shift tables and shift frames. Details of these descriptive analyses will be 
included in the SAP. 
Treatment effect in the improvement or reduction of relevant health and psychological 
status information such as suicidal thoughts (M.I.N.I.-Plus Suicidality), psychological distress 
(K6), anxiety disorders (GAD-7), depression (PHQ-9) and pain (short pain scale) will be 
analyzed using similar modeling techniques with either linear mixed models or generalized 
models used appropriately for the structure of the outcome measure (continuous, binary, ordinal, 
nominal). Each model will incorporate treatment, baseline measure, site, and time as categorical 
variables and two-way interactions between treatment and time and appropriate confounding 
variables. Models exploring change through time will account for the repeated measures 
(longitudinal) and clustering effects (participants). Models evaluating the different scores at 
different time points will account for the site effect, baseline measure and concomitant variables 
and comorbidities relevant to the different outcomes. 
Similarly, improvement in physical and mental composite measures (SF-12) due to 
treatment effect will be analyzed using linear mixed models at each time point, or comparing 
the scores at different time points. As before, the effects will be adjusted by corresponding 
baseline measure, site, and concomitant variables and comorbidities relevant to these measures. 
Another secondary analysis of interest is to determine the efficacy of the SGB among the 
participants for whom the stellate ganglion was anesthetized effectively. The population that 
will be utilized for this analysis will be defined as the “Horner’s responder population.” The 


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analytic approach will mirror that for the primary analysis but will utilize only Horner’s 
responders from the active treatment arm, with propensity scores as described in the SAP to 
select the appropriate sub-population among the control arm participants. 
8.3. 
Power and Sample Size 
Because the proposal for the current study was written before the publication of the DSM-
5, we initially based sample size estimates on known characteristics of the CAPS related to the 
DSM-IV. Weathers et al. (2001) indicate that a minimum clinically significant change in the 
prior version of CAPS total symptom score was 15, and data available from multiple PTSD 
trials in both civilian and military populations indicate that a reasonable conservative estimate 
of post-treatment standard deviation in CAPS-IV total symptom score was 25. Based on these 
assumptions, a study of 240 participants randomized at a 2:1 ratio of active treatment to sham 
will provide a power of 0.99 to detect a minimal clinically important difference of 15 in the 
CAPS-IV total symptom score between active and sham intervention participants with a Type I 
error rate of 0.05. Because this effect size doesn’t account for a placebo effect, we also 
examined the power of a study of this size to detect a 10-point difference in the two arms, and 
the proposed study will have a power of 0.83 to detect that effect, indicating that the study is 
statistically feasible across the three study sites.  
As of February 2017, new psychometric data have become available regarding the CAPS-5. 
Although initial psychometric properties are still being analyzed (Weathers et al., 2017), 
consultants from the National Center for PTSD have suggested that 8-10 points are indicative of 
clinically significant or meaningful change. We have recently communicated with Frank 
Weathers, co-author of the CAPS, and he conveyed the following:  
 
“There isn't a well-validated change score, but most people are using somewhere 
around 8 to 10 points for the CAPS-5. They also use loss of diagnosis or moving into a 
lower severity range as alternative indicators. In case you don't have them, here are the 
rationally derived CAPS-5 severity score ranges.” 
 
Additionally, Paula Schnurr at the National Center for PTSD told us: 
“We have not finalized a number but I am suggesting somewhere between 8 and 10.  I 
think 10 is probably better given the larger number of sxs in the criteria, despite the 0-4 
scoring on the CAPS. In our prior work with the CAPS-IV, we had defined 10 points as 
response…” 
 
Given this “new” information, we are establishing a 10-point (rather than 15-point) change 
in CAPS score from baseline to follow-up eight weeks after stellate ganglion block as our 
primary outcome measure to indicate clinically significant and meaningful decrease in PTSD 
symptoms.  
 
8.4. 
Attrition 
Loss to follow-up is always a concern where statistical power is necessary for rigorous 
research. In the event that we see as high as 25% attrition between our baseline and 8-week 
follow-up assessment, we will still have power of more than 0.88 to detect a treatment 
difference of 15 in CAPS-5 total symptom score between active and sham procedure 


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participants with a Type I error rate of 0.05. We believe this rate of attrition is unlikely, 
however, given our success in implementing similar recruitment and retention methods for a 
multisite RCT regarding treatment of PTSD and depression in Army primary care, where we 
have seen a greater than 80% follow-up rate at 3 months, whereas the current study entails only 
2 months of participation. 


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9. RESPONSIBILITIES 
9.1. 
Investigator Responsibilities 
9.1.1. Good Clinical Practice 
The Investigator will ensure that this study is conducted in full compliance with the 
principles of the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong 
Kong, and South Africa), ICH guidelines, or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the study 
participant. Each study Investigator, as well as staff charged with the handling of confidential 
study data, will be required to maintain current human subjects training affiliated with their 
respective institution through the Collaborative Institutional Training Initiative (CITI).  
9.1.2. Institutional Review Board (IRB) Approval 
This protocol and any accompanying material to be provided to the participant (such as 
advertisements, participant information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted, by the Investigator, to an IRB. Approval from the 
committee must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, documents reviewed, and date 
on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB approval must also be 
submitted to the committee for approval prior to implementation. 
9.1.3. After local IRB approval, the Protocol then must be submitted to 
HRPO for approval, which also must be documented before enrolling of 
participants may begin. ’ Informed Consent 
9.1.3.1. Effectiveness Clinical Trial 
For the effectiveness clinical trial, it is the responsibility of the Investigator or his designee 
(e.g., the Research Coordinator) to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and prior to undertaking any study-related procedures. The 
discussion must take place in a private setting. The Investigator must utilize an IRB-approved 
consent form for documenting written informed consent. A model consent form is provided in 
Appendix 20-1. Each informed consent will be appropriately signed and dated by the 
participant and the person obtaining consent; all other pages of the consent are to be initialed by 
the participant, also. The informed consent form does not explicitly describe the Horner’s 
syndrome evaluations to be performed by the RC; they add no risk, and we do not wish to draw 
attention to this participant-observable phenomenon which may unblind the participant. 
During the consent process it will be made clear to potential participants that if they 
indicate an intention to harm themselves or somebody else during the trial, their command will 
be notified. This includes verbal indications as well as those during online assessments, should 
relevant items be answered in such a way as to indicate emergent suicidal ideation. Those 
indicating emergent suicidal ideation during an online assessment (Section 6.4.13) will see a 
message on their screen recommending that they go to their nearest Emergency Department 


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(ED) for assistance. These individuals will also be asked to confirm (via checking a box on the 
screen) that they will not act on any suicidal thoughts before presenting to the ED. 
There may be potential participants referred to the study who are unable to travel to one of 
the three trial sites prior to a scheduled intervention (given TAMC’s catchment area is the 
Pacific Basin and LRMC provides care for active duty service members throughout Europe, 
Africa, and the Middle East). In those instances, an initial informed consent will be obtained via 
telephone and secure digital communication (see Section 6.1) prior to the screening evaluation. 
In such cases, a second physical informed consent document will be signed when the participant 
comes for his or her baseline evaluation. 
9.1.3.2. Acceptability Study 
The Fact Sheet provided to service members at baseline data collection will describe the 
voluntary and confidential nature of the qualitative acceptability study. A second copy of this 
document will be provided to participants when they are scheduled to take part in a focus group 
or interview.  
At each focus group or interview, the study team will review the Informed Consent Form 
with participants. The consent form for service member focus groups is included as Appendix 
20-2; for service members who are interviewed individually as Appendix 20-3; for service 
member and spouse interviews is included as Appendix 20-4; and for provider focus groups as 
Appendix 20-5. Consent forms explain who we are, how participants were selected, the 
voluntary nature of participation in the qualitative study, including the right not to participate, 
the right to not answer specific questions, and the right to withdraw from the focus group at any 
time with no consequences. The consent form also explains the time required to complete the 
focus group, the nature of the topics to be discussed, the purpose of the focus group, and the 
protection of confidentiality of participants. Additionally, the consent form provides contact 
information for the RTI project director and RTI’s Office of Research Protection in case a 
respondent has any questions about the study or his or her rights as a participant.  
To protect confidentiality of participants who have been diagnosed with a serious mental 
health condition, we are requesting a waiver of signed consent for service members. All 
participants will be given a copy of the consent form to take with them if they choose. A list of 
counseling resources (on-installation and Military OneSource) will be attached to participant’s 
copy of the consent form.  
9.1.4. Confidentiality 
The Investigator must assure that participants’ anonymity will be strictly maintained and 
that their identities are protected from unauthorized parties regarding the randomized controlled 
trial portion of the study. Only participant initials and an identification code (i.e., not names) 
should be recorded on any form submitted to the sponsor and IRB. The Investigator must keep a 
screening log showing codes, names, and addresses for all participants screened and for all 
participants enrolled in the trial. Regarding the qualitative acceptability study, participants in 
group settings will be provided the same assurances of anonymity and data protection from the 
study staff’s perspective, and we will request that those participating in group settings not reveal 
the identities of any other participants. Study staff, however, cannot guarantee that participants 
will keep their own participation (or that of others) confidential.  
Study Files and Retention of Records. 


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The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 
should be classified into 2 separate categories (although not limited to) the following: (1) 
Investigator’s study file, and (2) participant clinical source documents. 
The Investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence. 
Participant clinical source documents (usually defined by the project in advance to record 
key efficacy/safety parameters independent of the CRFs) would include (although not be limited 
to) the following: participant hospital/clinic records, physician’s and nurse’s notes, appointment 
book, original laboratory reports, electrocardiogram (ECG), electroencephalogram (EEG), X-
ray, pathology and special assessment reports, consultant letters, screening and enrollment log, 
etc.  
All clinical study documents must be retained by the Investigator and/or RTI until seven 
years from the date when the financial status report is submitted. Investigators may be required 
to retain documents longer if required by applicable regulatory requirements or an agreement 
with RTI International. The Investigator must notify RTI International prior to destroying any 
clinical study records. 
Should the Investigator wish to assign the study records to another party or move them to 
another location, RTI International must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or 
all of the documents, special arrangements must be made between the investigator and RTI 
International to store these in sealed containers outside of the site so that they can be returned 
sealed to the Investigator in case of an audit. Where source documents are required for the 
continued care of the participant, appropriate copies should be made for storage outside of the 
site. 
9.1.5. Case Report Forms 
For each participant enrolled in the clinical trial, a CRF must be completed and signed by 
the site Principal Investigator or sub-Investigator within a reasonable time period after data 
collection. This also applies to records for those participants who fail to complete the study 
(even during a pre-randomization screening period if a CRF was initiated). If a participant 
withdraws from the study, the reason must be noted on the CRF. If a participant is withdrawn 
from the study because of a treatment-limiting adverse event, thorough efforts should be made 
to clearly document the outcome. 
9.1.6. Drug Accountability 
The Investigator or designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability of administered study drug (ropivacaine or saline). This includes participant 
dispensing records. The intervention CRF will document quantities administered to participants, 
including lot number, date dispensed, participant identifier number, participant initials, and the 
initials of the person administering the medication. 
All drug-associated documentation will be periodically reviewed and verified by the study 
monitor over the course of the study. 


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9.1.7. Inspections 
The Investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from RTI International or its representatives, to 
IRBs, or to regulatory authority or health authority inspectors. 
9.1.8. Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
9.2. 
Sponsor Responsibilities 
9.2.1. Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study 
participants, may be made only by RTI International. All protocol modifications must be 
submitted to the IRB in accordance with local requirements. Approval must be obtained before 
changes can be implemented. 
9.2.2. Study Report and Publications 
The final study report, including any acknowledgement documentation and supporting 
documents, must be submitted to HRPO when available. 
With prior RTI approval, Investigators may communicate, orally present, or publish in 
scientific or other scholarly media at any time. After conclusion of the study and without prior 
written approval from RTI International, Investigators in this study may communicate, 
orally present, or publish in scientific journals or other scholarly media only after the following 
conditions have been met: 
• the results of the study in their entirety have been publicly disclosed by or with the 
consent of RTI International in an abstract, manuscript, or presentation form; or 
• the study has been completed at all study sites for at least 2 years. 
No such communication, presentation, or publication will include confidential information 
(see Section 9.1.4).  
The Investigator will submit for RTI approval any proposed publication or presentation 
along with the respective scientific journal or presentation forum at least 30 days prior to 
submission of the publication or presentation. The Investigator will comply with RTI 
International’s request to delete references to its confidential information (other than the study 
results) in any paper or presentation. All publications will follow appropriate industry guidelines 
for determining authorship. 
9.3. 
Joint Investigator/Sponsor Responsibilities 
9.3.1. Access to Information for Monitoring 
In accordance with International Conference on Harmonisation Good Clinical Practice 
(ICH-GCP) guidelines, the study monitor must have direct access to the Investigator’s source 
documentation in order to verify the data recorded in the CRFs for consistency. 
The monitor is responsible for review of the CRFs at regular intervals throughout the study, 
to verify adherence to the protocol, and the completeness, consistency and accuracy of the data 


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being entered on them. The monitor should have access to any participant records needed to 
verify the entries on the CRFs. The Investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
9.3.2. Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of RTI International may conduct inspections 
or audits of the clinical study. If the Investigator is notified of an inspection by a regulatory 
authority the investigator agrees to notify RTI International immediately. The Investigator 
agrees to provide to representatives of a regulatory agency or RTI International access to 
records, facilities, and personnel for the effective conduct of any inspection or audit. 
9.3.3. Study Discontinuation 
Both RTI International and the Investigator reserve the right to terminate the study at any 
time. Should this be necessary, both parties will arrange discontinuation procedures and notify 
the appropriate regulatory authority(ies) and IRBs. In terminating the study, RTI International 
and the Investigator will assure that adequate consideration is given to the protection of the 
participants’ interests. 


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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
A Randomized, Sham-procedure-controlled, Blinded Study to Evaluate the Effectiveness and 
Acceptability of Right-sided Stellate Ganglion Block for Treatment of Posttraumatic Stress 
Disorder Symptoms 
 
 
SAP VERSION: 
10.0 
SAP DATE: 
July 12, 2018 
SPONSOR: RTI International 
3040 Cornwallis Road 
Research Triangle Park, NC 27709 
PREPARED BY: 
RTI International 
 
3040 East Cornwallis Rd. 
 
Post Office Box 12194 
 
Research Triangle Park, NC 27709-2194 
AUTHOR (S): 
Breda Munoz, PhD 
 
Dennis Wallace, PhD 
 
Shawn Hirsch, MPH 
 
CLINICAL TRIAL ID: NCT03077919 
 
 


ABBREVIATIONS 
AE 
Adverse Event 
AHRQ 
Agency for Healthcare Research and Quality 
AUDIT 
Alcohol Use Disorders Identification Test 
AUDIT-C 
Alcohol Use Disorders Identification Test Alcohol Consumption Questions 
BHP 
behavioral health provider 
CAPS 
Clinician-Administered PTSD Scale 
CAPS-4 
Clinician-Administered PTSD Scale for DSM-IV 
CAPS-5 
Clinician-Administered PTSD Scale for DSM-5 
CBC 
complete blood count 
CITI 
Collaborative Institutional Training Initiative 
CRF 
Case Report Form(s) 
CRO 
Contract Research Organization 
CRPS 
complex regional pain syndrome 
CS 
Clinical Supervisor 
DOD 
Department of Defense 
DRP 
Distressed Respondent Protocol 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
ECG 
electrocardiogram 
ED 
emergency department 
EEG 
electroencephalogram 
FDA 
(U.S.) Food and Drug Administration 
GAD-7 
Generalized Anxiety Disorder 7-item Scale 
GCP 
Good Clinical Practice (Guidelines) 
HCT 
hematocrit 
HGB 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HPA 
Human Protections Administrator 
HRB 
Survey of Health Related Behaviors among Active Duty Service Members 
HRPO 
USAMRMC Office of Research Protections Human Research Protections Office 
HSRRB 
USAMRMC Office of Research Protections Human Subjects Research Review Board 
ICD-10 
 International Statistical Classification of Diseases and Related Health Problems, 10th edition 
ICF 
 International Classification of Functioning, Disability and Health 
ICH 
International Conference on Harmonisation 
ICH-GCP 
International Conference on Harmonisation Good Clinical Practice 
ID 
identification 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
IOM 
Institute of Medicine 
IRB 
Institutional Review Board 
ITT 
intent-to-treat (population) 
IUD 
intrauterine device 
IV 
intravenous 


 
JAMA 
Journal of the American Medical Association 
K6 
Kessler Psychological Distress Scale 
LEC 
Life Events Checklist 
LRMC 
Landstuhl Regional Medical Center 
mL 
milliliter(s) 
MP 
Military Police 
MRI 
magnetic resonance imaging 
NCS-R 
National Comorbidity Survey Replication 
NHIS 
U.S. National Health Interview Survey 
NSDUH 
National Survey on Drug Use and Health 
ORP 
USAMRMC Office of Research Protections 
PAPI 
paper-and-pencil interviewing 
PCL-5 
PTSD Checklist for DSM-5 
PCL-C 
PTSD Checklist - Civilian 
PCL-M 
PTSD Checklist - Military 
PE 
physical examination 
PHI 
protected health information 
PHQ 
Patient Health Questionnaire 
PHQ-9 
Patient Health Questionnaire - 9 
PTSD 
Posttraumatic Stress Disorder 
PVN 
paraventricular nucleus of the thalamus 
RC 
Research Coordinator 
RCT 
randomized, controlled trial 
RSD 
reflex sympathetic dystrophy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SF-12 
Short Form (12) Health Survey 
SF-36 
Short Form (36) Health Survey 
SG 
stellate ganglion 
SGB 
stellate ganglion block 
SOP 
Standard Operating Procedure 
SPN 
sympathetic preganglionic neuron 
TAMC 
Tripler Army Medical Center 
TBI 
traumatic brain injury 
TV 
television 
UCMJ 
Uniform Code of Military Justice 
ULN 
upper limit of the normal range 
USAMRAA 
US Army Medical Research Acquisition Activity 
USAMRMC 
U.S. Army Medical Research and Materiel Command 
USASOC 
U.S. Army Special Operation Command 
VA 
Veterans Administration 
WAMC 
Womack Army Medical Center 
 
 


BACKGROUND 
Posttraumatic stress disorder (PTSD) is a reaction to a traumatic event in which an individual 
perceives threat of death or significant injury, resulting in acute fear that is experienced over an 
extended period of time following the event(s). Symptoms are generally categorized in terms of 
intrusive symptoms, avoidance, negative alterations in cognitions and mood and alterations in 
arousal and reactivity (American Psychiatric Association, 2013). PTSD will develop in up to a 
third of individuals who are exposed to a significant stressor (Committee on Treatment of 
Posttraumatic Stress Disorder, Institute of Medicine, 2008), and approximately 10% to 20% of 
those diagnosed with PTSD will become chronic (Fletcher, Creamer, & Forbes, 2010). 
According to the 2000 National Comorbidity Survey Replication (NCS-R), an estimated 6.8% 
of adults in the United States will experience PTSD during their lifetime (Dohrenwend et al., 
2006). Certain subgroups (e.g., military service members) are at an increased risk because of 
their higher likelihood of trauma exposure (Jonas et al., 2013). PTSD prevalence among active 
duty service members ranges from approximately 5% to 15% (Tanielian & Jaycox, 2008). Hoge 
and colleagues (2004) reported an estimated 12.9% of service members returning from combat 
operations in Iraq fit diagnostic criteria for PTSD. 
There is evidence that the prevalence of PTSD is increasing among service members. The 2008 
Department of Defense Survey of Health Related Behaviors among Active Duty Service 
Members (HRB Survey) found that an estimated 11% met screening criteria for further 
evaluation of PTSD symptoms, up from 7% in 2005 (Bray et al., 2009). PTSD is also associated 
with certain mental health disorders, work impairment and decreased earnings, divorce, 
difficulties with child rearing (R. C. Kessler, 2000), depression and substance use disorders 
(Brady, Killeen, Brewerton, & Lucerini, 2000). 
 
A. PTSD Treatment 
Treatments for PTSD include both psychotherapeutic and pharmacologic modalities, with little 
existing systematic evidence for effectiveness (Institute of Medicine, 2008). Jonas et al. (2013) 
found similar results regarding the effectiveness of exposure therapy, and characterized a 
handful of pharmacologic modalities marginally effective when compared to exposure therapy. 
Currently available treatments for PTSD have side effects and varying onset of action (the time 
required after administration for the treatment for the effect to be observed). Pharmacotherapies 
side effects include, but are not limited to, nausea, weight gain, headache, sexual dysfunction, 
and agitation. Symptom relief for this medication take between 6 to 8 weeks of regular use 
(Alexander, 2012), during which time side effects may develop and discontinuation of the 
medication(s) may occur. Psychotherapeutic modalities tend to take between 6 to 24 months 
before the patient experiences significant relief (Sharpless & Barber, 2011). Also, some of the 
most effective therapies involve exposure to traumatic stimuli which, if improperly applied, 
may risk further deterioration of the patient (Rauch, Eftekhari, & Ruzek, 2012).  


Patient adherence to and acceptability of prescribed treatments also impact treatment 
effectiveness. Health beliefs (Spoont, Sayer, & Nelson, 2005); knowledge of PTSD and its 
potential therapies (Gray, Elhai, & Frueh, 2004); and comorbid substance abuse, depression, 
and other conditions (Kronish, Edmondson, Li, & Cohen, 2012) all play a role in adherence to 
prescribed treatment regimens.  
Several studies demonstrated that stigma associated with receiving treatment is a significant 
concern for study participants (Rae Olmsted et al., 2011; Tarrier, Liversidge, & Gregg, 2006) 
and may result in higher likelihood of treatment failure or discontinuation (Fung, Tsang, & 
Chan, 2010; Kim, Britt, Klocko, Riviere, & Adler, 2011). 
B. Stellate Ganglion Block 
Sympathetic blockade, and stellate ganglion block (SGB) in particular, are PTSD treatments 
that are considered safe, effective, fast-acting, with few side effects, and with good patient 
acceptability and adherence. SGB is a procedure routinely performed since the 1920s to treat 
common conditions such as complex regional pain syndrome (CRPS), hot flashes, Raynaud’s 
syndrome, hyperhidrosis, and other sympathetically mediated conditions. The stellate ganglion 
(SG) is a sympathetic ganglion located at the base of the cervical spine near the C7 transverse 
process. The SG thus is a major sympathetic switching and transit station for the “fight-or-
flight” response; interrupting this complex circuitry with a local anesthetic could have 
observable effects on conditions mediated by similar responses, such as PTSD. 
In SGB a local anesthetic is injected into the SG to “block” its function. To date, only a small 
number of studies have been published about the effectiveness of SGB in treating PTSD, but the 
findings are intriguing and warrant further scientific investigation (Lebovits, Yarmush, & 
Lefkowitz, 1990; Lipov, Joshi, Lipov, Sanders, & Siroko, 2008; Mulvaney, McLean, & De 
Leeuw, 2010) reported a patient with insufficient reduction in PTSD symptoms from 
pharmacotherapy who underwent SGB 55 days post-trauma. The individual reported immediate 
resolution of his symptoms (80% to 90% reduction) as well as improved appetite and sleep. The 
symptoms, however, returned 32 days later, at which time pulsed radiofrequency energy was 
applied to the SG. Three months later, the patient reported a continued 90% improvement in all 
symptoms of PTSD. Mulvaney and colleagues (2010), including two of the co-investigators of 
the current study (Mulvaney and McLean), described two patients diagnosed with PTSD and 
treated with SGB. In both, post-treatment PTSD Checklist (PCL) scores were sub-threshold for 
PTSD diagnosis. One of the patients requested retreatment 3 months later; their symptoms 
remained diminished for an additional 7 months of follow up. Hicky et al. (2012) described 9 
military service members with chronic PTSD who were treated with SGB. Each of the 
participants had more than 1 year of unsuccessful treatment via pharmacotherapeutic and/or 
psychotherapeutic modalities. Following a single SGB, Clinician-Administered PTSD Scale 
(CAPS) assessments showed that 5 of the 9 patients experienced a clinically significant 
reduction in symptoms 1 week post-procedure. The effects of the procedure seemed to decrease 


within 1 to 2 months, though symptoms that did return were not always as severe as they had 
been before the procedure. Of note, they also performed two repeat SGB treatments. One 
individual with no initial benefit also saw no improvement following a second block, whereas 
another who had seen the greatest reduction in symptoms experienced full remission after the 
second procedure. 
Mulvaney et al. (2014) (including two other authors involved in this trial, Lynch and Kane) 
recently reported a case series of 166 patients, by far the largest in the literature. The PTSD 
Checklist – Military (PCL-M) was administered a day before treatment and repeated at 1 week 
and 1, 2, and 3-6 months post-SGB.  An improvement in PCL-M scores of ≥10 was observed in 
73.5% of the 132 patients evaluated at 3-6 months.  24 subjects who had a positive response for 
at least 3 months and then had the return of symptoms were treated with a second SGB; their 
PCL-M response trends were similar to those with their first SGB. 
These findings support the need for a randomized, blinded, sham-procedure-controlled trial to 
rigorously study the effectiveness of SGB for treatment of PTSD symptoms. 
1. PURPOSE OF THE ANALYSIS PLAN 
This statistical analysis plan (SAP) contains detailed information about statistical analyses to be 
performed to evaluate the effectiveness of SGB applied at weeks 0 and 2 for treatment of PTSD 
symptoms. This study also includes an acceptability portion, which focuses on participants’ 
perception of SGB in relation to other PTSD treatments. This SAP does not include statistical 
analysis for the acceptability portion of this study. Additional statistical analyses not included 
here may be done to support manuscript preparation but these will not require an update to the 
SAP. 
2. STUDY OBJECTIVE AND OUTCOMES 
2.1. STUDY OBJECTIVES 
The primary study objective of the effectiveness study is to evaluate whether right-sided SGB 
performed at 0 and 2 weeks will reduce PTSD symptoms which will be reflected in the 
improvement of the CAPS-5 total symptom scores between baseline and 8 weeks.  Data analysis 
will be performed according to the intent-to-treat principle. The primary outcome of this study 
(difference in CAPS-5 total syndrome score from baseline) will be tested for differences 
between arms. 
Secondary objectives include: 
1. to evaluate whether right-sided SGB performed at 0 and 2 weeks will improve PTSD 
symptoms as reflected by corresponding PCL-5 items across time  
2. to explore the association between the main outcome and potential confounding variables 
(e.g., concomitant medications, duration of PTSD, post-block Horner’s syndrome, etc.) 


3. to evaluate whether right-sided SGB performed at 0 and 2 weeks will reduce distress (K6), 
suicidality (M.I.N.I.-Plus Suicidality), anxiety (GAD-7, PHQ-9) and pain (short pain scale) 
across time 
4. to evaluate whether right-sided SGB performed at 0 and 2 weeks will improve physical and 
mental (SF-12) condition across time 
2.2. PRIMARY OUTCOME MEASURES 
The primary outcome of the study will be changes in the CAPS-5 total symptom scores between 
baseline and 8 weeks. The CAPS-5 is the gold standard in clinical PTSD assessment, and it is a 
30-item structured interview that corresponds to the DSM-5 criteria for PTSD. For each item, 
standardized questions and probes are provided; total scores range from 0 to 80. CAPS-5 
requires the identification of a single index trauma to serve as the basis of symptom inquiry. 
2.3. SECONDARY OUTCOME MEASURES 
2.3.1.  PCL-5. 
The PCL-5 is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. 
Its purposes include screening for PTSD and/or provisional diagnosis, and monitoring 
symptom change before, during, and after treatment. A total symptom severity score ranging 
from 0 to 80 is possible (Weathers et al., 2013).  The PCL-5 will be administered at baseline to 
establish a baseline score in support of secondary objective 1.  
 
2.3.2. PCL-C (PTSD symptoms) 
This standardized assessment comprised 17 items corresponding to the key symptoms of 
PTSD from the DSM-IV. The total symptom severity score ranges from 17 to 85. The PCL-C 
has been thoroughly validated and deemed reliable (Weathers, Litz, Herman, Huska, & Keane, 
1994). The PCL-C will be administered at baseline in order to establish a baseline score in 
support of secondary objective 1. 
2.3.3. MINI-INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW (M.I.N.I.)-
PLUS SUICIDALITY MODULE    
The M.I.N.I.-Plus is a structured interview for diagnosing DSM-IV and ICD-10 psychiatric 
disorders (Sheehan et al., 1998). This assessment will be administered at each follow-up 
(weeks 2, 4, 6, and 8). Response options are dichotomous (yes/no) and questions ask about 
desire, thoughts, planning, taking steps toward, and attempting suicide as well as deliberate 
injury without intent to kill oneself. The set of 7 items employs a complex automated scoring 
algorithm, with each item representing a different point value. For example, an affirmative 
response to the question about wanting to harm oneself carries a value of 2 points, while a 
positive response to the question about taking active steps toward preparing to injure or kill 
oneself carries a value of 9 points. Individuals scoring nine points or greater will be asked to 
complete an additional 4 questions regarding any current desire to harm themselves, thoughts 


about suicide, plans for suicide, and active steps they may be taking. These four items will be 
used only for clinical purposes by a behavioral health clinician on call, as discussed below.  
The suicidal ideation items from the M.I.N.I.-Plus serves to monitor participant safety during 
the course of their participation in the study, particularly since the 4-, 6-, and 8-week follow-up 
assessments will be administered online and completed by participants on their own (i.e., not 
in the study RC’s office). If an individual should score 9 or greater on the M.I.N.I.-Plus items, 
they will be asked an additional 4 questions regarding current suicidal ideation or plans.  
2.3.4. AUDIT-C/AUDIT. 
The Alcohol Use Disorders Identification Test (AUDIT; Babor, Higgins-Biddle, Saunders, & 
Monteiro, 2001) will be used to assess potential alcohol abuse symptoms. The instrument was 
developed as a means of brief assessment and screening for excessive drinking. This 10-item 
scale is widely used and has been shown to be consistent with ICD-10 definitions for alcohol 
dependence and harmful alcohol use (Allen, Litten, Fertig, & Babor, 1997; Saunders, Aasland, 
Amundsen, & Grant, 1993). Scores range from 0 to 40, with scores between 8 and 15 
(inclusive) suggest a medium level of alcohol problems, scores ranging from 16 to 19 represent 
a high risk of alcohol problems, and scores of 20 or greater warrant further diagnostic 
evaluation for alcohol dependence.  
The AUDIT-C (AUDIT alcohol consumption questions) consists of the first 3 items of the full 
AUDIT and assess frequency of drinking, typical quantity, and frequency of heavy drinking. 
Based on a scale of 0 to 12, a score of 4 or greater is considered positive in males, while a score 
of 3 or more is positive among females.  
2.3.5. K6  
The K6 was developed for use in the U.S. National Health Interview Survey (NHIS) as a means 
of assessing nonspecific psychological distress. Scores range from 0 to 24 resulting from 6 
items administered on a scale of 0 to 4, with a score of 13 or greater are indicative of serious 
psychological distress in the U.S. general population (Kessler et al., 2003).  
2.3.6. PHQ-9 
Depression symptoms will be assessed using the validated PHQ-9 (Kroenke, Spitzer, & 
Williams, 2001) in support of secondary objective 2. The PHQ-9 was developed as a short form 
of the full Patient Health Questionnaire (which was a self-administered version of the PRIME-
MD instrument). Severity scores range from 0 to 27, with a score of 5 to 9 representing mild 
depression, a score of 10 to 14 representing moderate depression, and a score of 15 or greater 
representing a severe level of depression. Scores of 10 or greater are considered a “yellow flag” 
indicating possibly clinically significant depression (Kroenke et al., 2001; Löwe, Unützer, 
Callahan, Perkins, & Kroenke, 2004). 


2.3.7. GAD-7 
 
Generalized anxiety symptoms will be assessed via the GAD-7 (Spitzer, Kroenke, Williams, & 
Löwe, 2006) in support of secondary objective 2. Scores range from 0 to 21, with a score of 5 to 
9 representing mild anxiety, a score of 10 to 14 representing moderate anxiety, and a score of 15 
or greater representing a severe level of anxiety. Scores of 10 or greater are considered a 
“yellow flag” indicating possibly clinically significant anxiety 
(http://www.phqscreeners.com/instructions/instructions.pdf ) 
2.3.8. SF-12 (Version 2.0) 
 
The SF-12 is a shortened version of the SF-36, which was designed as a general health utility 
index. The twelve items provide an estimate for eight domains of functional health and well-
being: physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional, and mental health. Together, the first four domains constitute a 
Physical Health summary measure, and the second 4 constitute a Mental Health summary 
measure (Ware, Kosinski, & Keller, 1996). This assessment will be used as a measure of 
general functioning in support of secondary objective 2.  
2.3.9. Short pain scale 
Because pain frequently presents with PTSD and may play a confounding role in treatment 
effectiveness (Asmundson, Coons, Taylor, & Katz, 2002; McGeary, Moore, Vriend, Peterson, 
& Gatchel, 2011), a 0-10 Likert-type numeric pain scale where 0 represents “No pain,” 5 
represents “Moderate pain,” and 10 represents “Worst possible pain” will be administered. The 
pain scale will be administered in support of secondary objective 2. 
Other information that will be collected include:  
2.3.10. Current Medications 
In order to assess the potential impact of medication use concurrent with study participation, 
information on prescription psychotropics (including stimulants, anxiolytics, and 
antidepressants), anticonvulsants, antipsychotics, anticholinergic drugs, opioids, nicotine, 
sleeping medications, antihypertensives, and sympathomimetics/sympatholytics will be 
collected. 
   
3. STUDY METHOD 
This is a multisite, randomized, blinded, sham-procedure-controlled study to evaluate the 
effectiveness of unilateral right-sided stellate ganglion block (SGB) on the acute 
symptomatology of PTSD, evaluated by the CAPS-5 pre-treatment and at 8 weeks.  Participants 


will be centrally randomized to 2:1 active:sham SGB and will be evaluated at Womack Army 
Medical Center in North Carolina, Tripler Army Medical Center in Hawaii, and Landstuhl 
Regional Medical Center in Germany.  A total of up to 240 participants will be enrolled at the 
three sites (up to 80 per site).  No single site will enroll more than half the participants and each 
will have a 2:1 active:sham ratio.  
Study intervention will be administered at week 0 and at week 2. Participants will be evaluated 
for PTSD symptomatology at 0 weeks (pre-treatment) and at 8 weeks using the Clinician-
Administered PTSD Scale for DSM-5 (CAPS-5).  They will complete the PTSD Checklist for 
DSM-5 (PCL-5) and the M.I.N.I.-Plus Suicidality Module at 0, 2, 4, 6, and 8 weeks; they also 
will complete the M.I.N.I.-Plus module at screening.  The SF-12, GAD-7, PHQ-9, K6, AUDIT-
C/AUDIT, and a short pain scale will be completed at weeks 0, 4, and 8.  
4. STUDY POPULATION AND INCLUSION CRITERIA 
Participants will be active duty service members who meet inclusion criteria (as described 
below): 
• Active duty status  
• Personal access to Internet  
• Anticipated stable assignment to installation for at least 2 months  
• Stable dosing for ≥3 months, if receiving psychotropic medications  
• Prior to enrollment, offered PTSD treatment using A-level modality (as defined by 
MEDCOM policy 14-094; 18 Dec 2014) 
• PCL-C score of 32 or greater at screening 
• Acceptable clinically indicated preoperative laboratory studies, per standard site-specific 
protocols 
  
EXCLUSION CRITERIA 
Enrolled subjects must not meet any of the following criteria: 
• Prior SGB 
• Allergy to amide local anesthetics (e.g., ropivacaine, bupivacaine)  
• Pre-existing Horner’s syndrome 
• Pregnancy  


• Current anticoagulant use  
• History of a bleeding disorder 
• Infection or mass at injection site  
• Myocardial infarction within 6 months of procedure  
• Phrenic or laryngeal nerve palsy (hoarseness) 
• History of glaucoma  
• History of schizophrenia, other psychotic disorder, bipolar disorder, or personality disorder 
(axis 2), as verified by medical record review by an Army Co-Investigator with access to 
medical records 
• Moderate or severe traumatic brain injury as verified by medical record review by an Army 
Co-Investigator with access to medical records  
• Symptoms of moderate to severe substance use disorder in past 30 days 
• Suicidal ideation in the past 2 months, documented by the M.I.N.I.-Plus Suicidality Module  
• Any ongoing other major life stressor or condition not listed here that the site Investigator 
believes clearly would place the participant at risk for injury or a poor outcome (including 
anniversary of the inciting event, pending divorce, undergoing medical board/retirement, 
undergoing UCMJ or pending legal administrative actions, recent significant illness in 
participant or family)  
 
5. RECRUITMENT 
For recruitment, behavioral health providers (BHP) or family or other physicians within the 
medical center referral area will identify potential participants and obtain their permission to 
pass contact information on to the site Research Coordinator (RC). The RC will contact by 
telephone those who have expressed interest in the study, to explain the study and invite them to 
participate. The RC will provide a study overview and answer any questions that individuals 
may have about participation. Once individuals have agreed to take part in the study, they will 
be asked a few pre-screening questions over the telephone to determine eligibility. Those who 
pre-screen as eligible will be asked to come to the RC’s office to complete the consenting 
process in person and to complete a computer-based screening, which will assess the study 
inclusion and exclusion criteria. 
 
6. DISCONTINUATION OF INTERVENTION 


Study intervention may be discontinued in the following instances: 
• Intercurrent illness that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant degree.  
• Unacceptable toxicity that compromises the ability to continue study-specific procedures, or 
is considered to not be in the participant’s best interest. 
• Participant request to discontinue for any reason. 
• Participant non-compliance. 
• Pregnancy during the first two weeks of the study, when study-related treatment procedures 
(either active or sham) are being conducted. 
• Discontinuation of the study at the request of the relevant IRB. 
 
7. DATA LOCK AND UNMASKING 
Data lock and unmasking will occur after enrollment is completed. The study is designed as 
intention-to-treat (ITT), and therefore participants will not be excluded after randomization.  If a 
participant discontinues further treatment or participation in the study, for example as a result of 
an adverse event, every attempt should be made to continue to perform the required study-
related follow-up and procedures.  If this is not possible or acceptable to the participant or 
Investigator, the participant may be withdrawn from the study. 
8. STATISTICAL / ANALYTICAL ISSUES 
 
8.1  Analysis Populations 
This study will have two analysis populations, and intention-to-treat (ITT) population and a per 
protocol (PP) population. 
The primary analysis will be based on the intention-to-treat principle. All participants who were 
enrolled and randomly allocated to a treatment arm will be included in the analysis in the group 
to which they were randomized (not to which treatment they actually received). This approach 
ignores noncompliance, protocol deviations, withdrawal and lost-to-follow-ups. Analysis of the 
ITT population avoids overoptimistic estimates of the efficacy of an intervention resulting from 
the removal of non-compliers, accepting that protocol deviations occur in actual clinical practice 
(Heritier, Gebski, & Keech, 2003).   


Analyses will be replicated on the per-protocol population. The per-protocol population will 
consist of those participants who strictly adhered to the protocol (i.e., will exclude participants 
that withdrew or were lost-to-follow-up prior to completion of the study, received treatment 
they were not randomized to, completed visits outside of the prespecified window, participants 
known to the intervening anesthesiologist, baseline CAPS < 10, screening to baseline interval 
>32 days, or any other protocol deviation). The per-protocol analysis provides an estimate of the 
true efficacy of an intervention (i.e., among those who completed the treatment as planned) 
(Ranganathan, Pramesh, & Aggarwal, 2016).  
A sensitivity analysis also will be performed, excluding subjects with final CAPS scores 
obtained more than 12 weeks post initial intervention and assigning discordant interventions to 
the one actually delivered. 
 
8.2 General Considerations 
Data will be summarized by treatment group. For summaries of study data, categorical measures 
will be summarized in tables listing the frequency and the percentage of subjects in each 
treatment; continuous data will be summarized by presenting mean, standard deviation, median 
and range; and ordinal data will be summarized by only presenting median and range. 
Most statistical computations will be performed and data summaries will be created using SAS 
9.4. If additional statistical software is required, this will be discussed in the study report. All 
statistical analyses will be conducted using the intent to treat principle, unless explicitly 
specified otherwise (e.g., the per-protocol protocol, or for certain secondary and/or post-hoc 
analyses).   
Demographic and all baseline characteristics will be compared between treatment groups. If 
analyses of these characteristics suggest that substantial differences exist for some of these 
characteristics between treatments at baseline, their use as covariates will be explored in the 
model-based secondary analyses.  
8.3 Missing Data Approaches 
The primary analysis will be conducted using the available data without any statistical 
imputation for missing data for data lost to follow up or otherwise unavailable. Accordingly, it 
is assumed for the primary analyses that missing primary outcomes are missing completely at 
random. We will examine the proportion of missing primary outcome data to ensure that the 
missing rate is comparable across the two treatments.  
Analysis of the secondary objectives will generally include available data such that no data 
obtained within the study assessments windows will be discarded and no imputation for missing 
data will be done.  


8.4 Other Analysis 
All other analyses of outcomes not described in the primary or secondary outcomes are 
exploratory in nature; therefore, resulting p-values and confidence intervals will generally be 
provided for descriptive purposes only. All p-values provided for any baseline and demographic 
characteristics will be for descriptive purposes only. As such, unless otherwise specified, p-
values presented will be on a per analysis basis, with no further control for multiple tests.  
For model building activities, p-values will be used to identify the best fitting model as well as 
covariates to be included in the final models. For these model building activities, p-values <0.05 
will generally determine significance. However, due to the exploratory nature of these models, 
less rigid standards may be considered and would be described fully in the final clinical study 
report and study manuscript.  
8.5 Primary Analysis 
Data analysis for the primary outcome will be performed according to the intent-to-treat 
principle with an analogous secondary analysis conducted with the per-protocol population. The 
primary outcome of this study (difference in CAPS-5 total syndrome score from baseline) will 
be tested for differences between arms. The primary outcome will be analyzed using a linear 
model for continuous variable that accounts for treatment assignment, site and baseline CAPs 
score (see proposed initial model below).  95% confidence intervals will be produced for each 
of the arms. 
𝒀𝒀𝒊𝒊= 𝜷𝜷𝟎𝟎+ 𝜷𝜷𝟏𝟏𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝑻𝒊𝒊+ 𝜷𝜷𝟐𝟐𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝒊𝒊+ 𝜷𝜷𝟑𝟑𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩𝑩 𝑪𝑪𝑪𝑪𝑪𝑪𝑪𝑪𝒊𝒊+𝝐𝝐𝒊𝒊 
Where Yi is the primary outcome measure (Week 8 CAPs score minus the Baseline CAPs 
score), β0 is the intercept, β1 through β3 are coefficients, and εi is the error term which is 
assumed normally distributed. 
Statistical analysis modeling will be carried out utilizing SAS/STAT PROC GLM (SAS 
Institute Inc., 2009) with the general structure of the SAS code for this model shown below. 
Adjusted estimates of the difference in the change between the two arms and within each 
treatment arm and corresponding 95% confidence intervals will be produced. 
proc glm data=Primanaly_sgb; 
class Treat site; 
model CAPS5_Differ = Treat site BL_CAPS/ solution clparm; 
estimate 'Stellate Ganglion Block (SGB)' intercept 1 Treat 
1 0 site 1 0 0 BL_CAPS 38.56; 
estimate 'Placebo' intercept 1 Treat 0 1 site 1 0 0 BL_CAPS 
38.11; 
estimate 'Intervention Effect of SGB' Treat 1 -1; 
lsmeans Treat / cl; /*Confirm est. means for Tx group*/ 
ods output Estimates = SGB_Estimates ParameterEstimates = 
SGB_overallEstimates FitStatistics = SGB_fitstats; 
run; 


As of February 2017, new psychometric data have become available regarding the CAPS-5. 
Although initial psychometric properties are still being analyzed (Weathers et al., 2017), 
consultants from the National Center for PTSD have suggested that 8-10 points are indicative of 
clinically significant or meaningful change. We have recently communicated with Frank 
Weathers, co-author of the CAPS, and he conveyed the following:  
“There isn't a well-validated change score, but most people are using somewhere 
around 8 to 10 points for the CAPS-5. They also use loss of diagnosis or moving into a 
lower severity range as alternative indicators. In case you don't have them, here are the 
rationally derived CAPS-5 severity score ranges.” 
 
Additionally, Paula Schnurr at the National Center for PTSD told us: 
“We have not finalized a number but I am suggesting somewhere between 8 and 10.  I 
think 10 is probably better given the larger number of sxs in the criteria, despite the 0-4 
scoring on the CAPS. In our prior work with the CAPS-IV, we had defined 10 points as 
response…” 
Given this “new” information, we are establishing a 10-point change in CAPS score from 
baseline to follow-up eight weeks after stellate ganglion block as a clinically meaningful 
change.  Consequently, as a part of the primary outcome analyses, point and interval estimates 
of the change will be generated for each treatment arm to evaluate whether one or both arms 
reach the level of clinically meaningful change.  
8.6 Secondary Analyses 
All secondary analyses will be performed according to both the intent-to-treat and per-protocol 
principle. 
8.6.1 Explore the Association between the Main Outcome and Other Potential 
Confounding Variables 
An analogous model to the one described in section 8.5 will be run as a sensitivity analysis; 
however, additional covariates (e.g. effect modification or confounder) may be included in the 
model. Covariates to be examined will include: 
• Taking specific concomitant mediations (stimulant, sleeping medication, 
anticonvulsant, antidepressant, anxiolytic, nicotine, antihypertensive, antipsychotic, and 
opioid), 
• Concurrent behavioral health therapy (defined as an affirmative response to 
PTSDTx30DCONT), 
• Participant self-assessment of intervention (SGB vs. Sham), 
• Post-block Horner’s (HRNRSCOR_POST), and 


• Duration of PTSD (derived from DxMonth and DxYear for formal diagnoses or 
SxMonth and SxYear for symptom presence) 
Other additional covariates may be considered for inclusion into the model based on a 
univariate analysis to investigate if any other measures are significantly associated with change 
in baseline to week 8 CAPs (where the p-value is less than 0.05). The study team will identify 
the list of potential covariates to include in the base model. 
Each covariate will be included in the ‘full’ model as a confounder or effect modifier (an 
interaction term of the covariate with treatment arm will be included in the model). To simplify 
the full model, non-significant (p > 0.05) covariates will be removed and reduced models will 
be run and compared against the full model. A final parsimonious model will be selected via 
two model fit indices: Akaike information criterion (AIC) and Bayesian information criterion (BIC). 
8.6.2 Evaluate Treatment Effects on PTSD symptoms (via PCL-5 score) Across Time 
The treatment effect on the clinical criteria of PTSD as measured by the PCL-5 over time will 
be assessed at weeks 2, 4, 6 and 8 using a generalized-linear mixed model to account for 
temporal correlation between weekly measures and the clustering of the data; this model will 
control for treatment, week, site, baseline PCL-5 score and the two way interaction between 
treatment and time (see below for proposed model). The outcome variable will be the 
continuous PCL-5 score obtained at each visit. A sensitivity analysis will also be run by treating 
the outcome variable as a binary indicator of positive PTSD diagnosis (score of 33 or greater 
suggests positive screening for PTSD) (National Center for PTSD, 2017).  
Yij=α+β1Timeij+β2Siteij+β3Treatmentij+β4BaselinePCL5iji+β5(TimeXTreatment)i+ si + εij 
Where Yij is the jth measure of PCL-5 in subject i, α is the intercept, β1 through β5 are coefficients, 
si is a random subject effect and εij is the residual error term. Statistical analysis modeling will 
be carried out utilizing SAS/STAT PROC MIXED (Littell, Milliken, Stroup, Wolfinger, & 
Schabenberger, 2006) with the general structure of the SAS code for this model shown below. 
Adjusted estimates of the PCL-5 scores at each visit between the two arms and corresponding 
95% confidence intervals will be produced. 
proc mixed data = Secanaly_sgb; 
class Unique_ID timepointN Treat site; 
model PCL5_TotalScore = timepointN Treat BL_Score timepointN*Treat/s; 
 
random int / subject= Unique_ID; 
 
repeated timepointN / type=cs subject=Unique_ID;  
 
estimate 'Intervention Effect of SGB' Treat 1 -1; 
 
lsmeans timepointN* Treat;  
run; 
8.6.3 Evaluate Treatment Effects on Suicidal Thoughts (via M.I.N.I.-Plus Suicidality), 
Psychological Distress (via the K6), Anxiety Disorders (via GAD-7), Depression (via 
PHQ-9), Physical and Mental Composite Measures (via SF-12), and Pain (via Short 
Pain Scale) Across Time 


Treatment effect in the improvement or reduction of relevant health and psychological status 
information such as suicidal thoughts (M.I.N.I.-Plus Suicidality), psychological distress (K6), 
anxiety disorders (GAD-7), depression (PHQ-9), physical and mental composite measures (SF-
12), and pain (short pain scale) will be analyzed using similar modeling techniques as 
mentioned in section 8.6.2. Modeling techniques with either linear mixed models or generalized 
mixed models will account for the structure of the outcome measure (continuous, binary, 
ordinal, nominal). Each model will incorporate treatment, baseline measure, site, time (as 
categorical variable) and two-way interactions between treatment and time. Other potential 
covariates or effect modification variables may be included in the model based on a univariate 
analysis of baseline measures with the specific outcome measure of interest. 
Another secondary analysis of interest is to determine the effectiveness of the SGB among the 
participants for whom the stellate ganglion was anesthetized effectively.  The population that 
will be utilized for this analysis will be defined as the “Horner’s responder population.”  This 
population will be defined as those participants who showed a maximum density of Horner’s 
syndrome, reflected by scleral injection, meiosis, and ptosis, following the procedure. For 
analytic purposes, this will include all participants with a Post-Horner’s total score of 12. The 
analytic approach will mirror that for the primary analysis but will utilize only Horner’s 
responders from the active treatment arm, with propensity scores based on baseline 
demographic and clinical characteristics used to define a comparator control population.   
 
9. SUBJECT CHARACTERIZATION 
 
9.1 Subject Disposition 
Subject eligibility status will be summarized and listed by treatment group. The number of 
subjects screened; eligible; randomized; completing or discontinuing treatment; and completing 
follow up will be summarized by treatment group as well. Study withdrawals and reasons 
thereof will also be listed in a similar manner.  
9.2 Protocol Deviations 
Protocol deviations are identified by site staff and via automated checks of the database. 
Protocol deviations will be listed by site with information such as type of deviation, time of 
occurrence, and reason. Incidence rate of protocol deviations will also be summarized overall 
and for each protocol deviation category by site. 
 
10. ADVERSE EVENTS 
Reports of adverse events will be collected during the trial, and the Research Monitor is 
required to review all unanticipated problems involving risk to volunteers or others, Serious 
Adverse Events (SAE) and all volunteer deaths associated with the protocol and provide an 
unbiased written report of the event to the USAMRMC Office of Research Protections (ORP) 
Human Research Protection Office (HRPO). 


An adverse event (AE) is any untoward medical occurrence in a clinical investigation 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. AEs may also include pre- or post-treatment 
complications that occur as a result of protocol-mandated procedures (e.g. invasive procedures 
such as venipuncture, biopsy, etc.). Pre-existing events, which increase in severity or change in 
nature during or as a consequence of use of a medicinal product in human clinical trials, will 
also be considered AEs. 
An AE does not include: 
• Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an adverse event. 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected prior 
to the screening visit, that do not worsen. 
• Situations where an untoward medical occurrence has not occurred (e.g. hospitalization 
for elective surgery, social and/or convenience admissions). 
• Overdose of either study drug or concomitant medication without any signs or 
symptoms unless the participant is hospitalized for observation. 
 
10.1 Assessment of Adverse Events 
All AEs will be assessed by the investigator and recorded on the appropriate CRF page, 
including the date of onset and resolution, severity, relationship to study drug or study 
procedures, outcome and action taken with study medication.  
The relationship to study drug therapy or study procedures should be assessed using the 
following definitions: 
• Definitely Not Related: The participant did not receive the study drug and/or study 
procedure, the temporal sequence of the AE/SAE onset relative to administration of the 
study drug or performance of the procedure is not reasonable, or there is another obvious 
cause of the AE/SAE. 
• Possibly Related:  There is evidence of exposure to the study drug and/or study procedure, 
the temporal sequence of the AE/SAE onset relative to administration of the study drug or 
performance of the procedure is reasonable, but the AE/SAE could have been due to another 
cause. 
• Definitely Related: There is evidence of exposure to the study drug and/or study procedure, 
the temporal sequence of the AE/SAE onset relative to administration of the study drug 
and/or study procedure is reasonable, the AE/SAE is more likely explained by the study 
drug and/or study procedure than by any other cause, and the AE/SAE shows a pattern 


consistent with previous knowledge of the study drug or study drug class and/or the study 
procedure. 
10.2 Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as follows:   
Any adverse drug experience occurring at any dose that results in any of the following 
outcomes:  
• Death;  
• Life-threatening situation (subject is at immediate risk of death); 
• In-patient hospitalization or prolongation of existing hospitalization (excluding those for 
study therapy or placement of an indwelling catheter, unless associated with other serious 
events);  
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect in the offspring of a subject who received study drug; 
• Other: medically significant events that may not result in death, be immediately life-
threatening, or require hospitalization, may be considered a SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Clarification of Serious Adverse Events 
• Death is an outcome of an adverse event, and not an adverse event in itself. In reports of 
death due to “Disease Progression”, where no other information is provided, the death will 
be assumed to have resulted from progression of the disease being treated with the study 
drug(s). 
• All deaths, regardless of cause or relationship, must be reported for subjects on study and for 
deaths occurring within 30 days of last study drug dose or within 30 days of last study 
evaluation, whichever is longer. 
• “Occurring at any dose” does not imply that the subject is receiving study drug at the time of 
the event.  Dosing may have been given as treatment cycles or interrupted temporarily prior 
to the onset of the SAE, but may have contributed to the event. 
• “Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death, if it had occurred with 
greater severity. 


• Complications that occur during hospitalizations are AEs. If a complication prolongs 
hospitalization, it is a SAE. 
• “In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not 
include presentation and care within an emergency department. 
• The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
 
 


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ADDENDUM NUMBER 1 TO STATISTICAL ANALYSIS PLAN 
FOR PROTOCOL SGB-201 
 
A Randomized, Sham-procedure-controlled, Blinded Study to Evaluate the Effectiveness and 
Acceptability of Right-sided Stellate Ganglion Block for Treatment of Posttraumatic Stress 
Disorder Symptoms 
 
SAP VERSION: 
10.0 
SAP DATE: 
July 12, 2018 
 
Sponsor: 
RTI International 
3040 Cornwallis Road 
Research Triangle Park, NC 
27709 
 
 
 
 
 
PREPARED BY: 
RTI International 
 
3040 East Cornwallis Rd. 
 
Post Office Box 12194 
 
Research Triangle Park, NC 27709-2194 
AUTHOR (S): 
Breda Munoz, PhD 
 
Dennis Wallace, PhD 
 
Shawn Hirsch, MPH 
 
 
 


Timing of Addendum:  ___ Before unblinding    _X_ After unblinding 
Reason for addendum: 
After the approval of this clinical study plan and the analysis plan contained within it, clinical 
colleagues suggested that study results should include two additional efficacy outcome 
measures: the proportion of participants in each treatment arm who achieved a 10 point or 
greater improvement in the total symptom severity score (TSSS) on the CAPS-5 from baseline 
to week 8, and the proportion of participants in each treatment group who met CAPS-5 criteria 
for a PTSD diagnosis at baseline but no longer met criteria at 8-week follow-up. Additionally, 
clinical colleagues also suggested conducting a subgroup analysis on the primary outcome 
based on presence or absence of a clinical baseline PTSD diagnosis (based on the CAPS-5). The 
rationale for these investigative analyses was to provide additional information to increase 
interpretability and usability of results by clinicians. This addendum to the statistical analysis 
plan (SAP) details the investigative analyses that were performed, and hence this should be 
considered as post-hoc analyses that were determined post unblinding, and post approval of the 
original statistical analysis plan. 
Addendum: 
Section 2.3.11. Decrease in Total Symptom Severity Score (TSSS) exceeded by 10 or more 
points. 
The proportion of participants in each treatment group who achieved a 10 point or greater 
improvement (reduction) in TSSS from baseline to week 8 was calculated. Contingency table 
analysis was used to compare both proportions descriptively. 
Section 2.3.12. Change in PTSD diagnosis status based on CAPS-5. 
The proportion of participants in each treatment group who met CAPS-5 criteria for a PTSD 
diagnosis at baseline but no longer met criteria at 8-week follow-up was calculated. 
Contingency table analysis was used to compare both proportions descriptively. 
Section 8.5.1. Subgroup Analysis on the Primary Outcome based on Baseline PTSD 
Diagnosis. 
The model specified in the SAP (section 8.5) will be re-run but will also include baseline PTSD 
diagnosis and its interaction with treatment group. Full subgroup analyses will be reported if 
there is evidence of a subgroup by treatment interaction (a p-value of ≤ 0.1). However, if there 
is no evidence of a subgroup by treatment interaction, then a sensitivity analysis will be 


conducted by re-running the primary analysis only among participants that had a baseline PTSD 
diagnosis. 
 
 
 


ADDENDUM NUMBER 2 TO STATISTICAL ANALYSIS PLAN 
FOR PROTOCOL SGB-201 
 
A Randomized, Sham-procedure-controlled, Blinded Study to Evaluate the Effectiveness and 
Acceptability of Right-sided Stellate Ganglion Block for Treatment of Posttraumatic Stress 
Disorder Symptoms 
 
SAP VERSION: 
10.0 
SAP DATE: 
June 23, 2019 
 
Sponsor: 
RTI International 
3040 Cornwallis Road 
Research Triangle Park, NC 
27709 
 
 
 
 
 
PREPARED BY: 
RTI International 
 
3040 East Cornwallis Rd. 
 
Post Office Box 12194 
 
Research Triangle Park, NC 27709-2194 
AUTHOR (S): 
Breda Munoz, PhD 
 
Dennis Wallace, PhD 
 
Shawn Hirsch, MPH 
 
 
 


Timing of Addendum:  ___ Before unblinding    _X_ After unblinding 
Reason for addendum: 
This addendum to the statistical analysis plan (SAP) is to document the methods to determine if 
the missingness observed in CAPS-5 week 8 data is random, and to describe the methods to 
impute the missing week 8 CAPS-5 values and the approach used to produce the final analysis.  
The rationale for imputation of missing data for the primary outcome under the intention to treat 
(ITT) principle is that when the randomization process is disrupted by dropout or missing data 
outcomes, bias may be introduced that compromises the results.  
The changes were made to provide additional clarification of the results in response to questions 
from journal reviewers. 
Addendum: 
Section 8.3 Missing Data Approaches. 
The primary outcome analysis will be conducted using the intention-to-treat principle, and 
imputation will be used to adjust for the presence of missing data on the week 8 CAPS-5 
assessment. We will compare baseline measurements between those with and without week 8 
CAPS-5 scores to assess whether the data appear to be missing at random. Multiple imputation 
(via PROC MI, SAS) will be used to impute missing CAPS-5 values at week 8 based on 
information collected at the baseline visit. Five replicates of the imputed dataset will be generated, 
analyzed as specified in section 8.5 of the SAP, and PROC MIANALYZE will be used to generate 
final estimates and uncertainty measures (e.g. treatment effects and corresponding standard 
errors). 
Analysis of secondary outcomes will generally include available data such that no data obtained 
within the study assessments windows will be discarded and no imputation for missing data will 
be done. Because these analyses were conducted with mixed model approaches, they are analyzed 
in a manner that is consistent with both the ITT principle and the missing at random assumption.