RESCUE: A Randomized, Blinded, Placebo-controlled, Parallel Group Design to Determine the Safety of RNS60 in Large Vessel Occlusion Stroke Patients Undergoing Endovascular Thrombectomy
Phase: PHASE2
Conditions: Stroke, Ischemic
Sponsor: Revalesio Corporation

RESCUE: A Randomized, Blinded, Placebo-controlled, Parallel Group Design to Determine the 
Safety of RNS60 in Large Vessel Occlusion Stroke Patients Undergoing Endovascular 
Thrombectomy 
PROTOCOL 06.5.1.H1 
Version 2.4  
DATE: May 9, 2022 
Investigational Drug: RNS60 
Coordinating Center 
Rhode Island Hospital  
593 Eddy Street 
Providence, Rhode Island 02903  
Sponsor 
Revalesio Corporation 
1202 East D Street 
Tacoma, WA 98421 
US IND 
clinicaltrials.gov number 
152880 
NCT04693715 
CONFIDENTIAL 
This is a Revalesio document that contains confidential information.  It is intended solely for the recipient 
clinical investigator(s) and must not be disclosed to any other party.  This material may be used only for 
evaluating or conducting clinical investigations; any other proposed use requires written consent from 
Revalesio. 
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DOCUMENT HISTORY 
Document 
Date 
Original Protocol/Version 1.0 
January 07, 2021 
Protocol Revision/Version 2.0 
January 25, 2021 
Protocol Revision/Version 2.1 
April 14, 2021 
Protocol Revision/Version 2.2 
August 26, 2021 
Protocol Revision/Version 2.3 
January 26, 2022 
Protocol Revision/Version 2.4 
May 09, 2022 
 
 
 
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TABLE OF CONTENTS 
SIGNATURES OF APPROVAL .......................................................................................................................... 2 
1 PROTOCOL SUMMARY ....................................................................................................... 7 
1.1 
SYNOPSIS ............................................................................................................................................. 7 
1.2 
COORDINATING CENTER AND SPONSOR ......................................................................................... 14 
2 INTRODUCTION................................................................................................................... 16 
2.1 
BACKGROUND ................................................................................................................................... 16 
2.1.1 RNS60: AN INTRODUCTION 
16 
2.1.2 THROMBECTOMY AS A STROKE TREATMENT 
17 
2.1.3 TREATMENT OF STROKE WITH RNS60 IN MICE 
17 
2.1.4 TREATMENT OF STROKE WITH RNS60 IN NON-HUMAN PRIMATES 
17 
2.1.5 PREVIOUS CLINICAL TRIALS 
18 
2.2 
STUDY RATIONALE ........................................................................................................................... 18 
2.3 
BENEFIT/RISK ASSESSMENT ............................................................................................................ 19 
2.3.1 RISK ASSESSMENT 
19 
2.3.2 BENEFIT ASSESSMENT 
19 
2.3.3 OVERALL BENEFIT: RISK CONCLUSION 
19 
3 TRIAL OBJECTIVES............................................................................................................ 20 
3.1 
OBJECTIVES ...................................................................................................................................... 20 
3.1.1 PRIMARY OBJECTIVE 
20 
3.1.2 SECONDARY OBJECTIVES 
20 
3.1.3 TERTIARY/EXPLORATORY OBJECTIVES 
21 
3.2 
OUTCOMES........................................................................................................................................ 21 
3.2.1 PRIMARY SAFETY OUTCOMES 
21 
3.2.2 SECONDARY EFFICACY OUTCOMES 
21 
3.2.3 TERTIARY/EXPLORATORY OUTCOMES 
21 
4 TRIAL DESIGN...................................................................................................................... 22 
4.1 
OVERALL DESIGN ............................................................................................................................. 22 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ................................................................................. 22 
4.3 
JUSTIFICATION FOR THE TARGET STUDY POPULATION ............................................................... 23 
4.4 
JUSTIFICATION FOR DOSE ............................................................................................................... 23 
4.5 
END OF STUDY DEFINITION ............................................................................................................. 23 
5 STUDY POPULATION ......................................................................................................... 24 
5.1 
INCLUSION CRITERIA ....................................................................................................................... 24 
5.2 
EXCLUSION CRITERIA ...................................................................................................................... 24 
5.3 
LIFESTYLE CONSIDERATIONS ......................................................................................................... 25 
5.4 
SCREEN FAILURES ............................................................................................................................ 25 
5.5 
STUDY ENROLLMENT PROCESS ...................................................................................................... 26 
5.5.1 IMAGING 
26 
5.5.2 CONSENT PROCESS 
26 
5.5.3 REGAINED CAPACITY CONSENT 
27 
5.5.4 AMENDMENT OF THE ICF 
27 
5.5.5  PHYSICAL EXAMINATIONS 
27 
6 STUDY INTERVENTIONS AND CONCOMITANT THERAPY .................................... 28 
6.1 
STUDY INTERVENTION ADMINISTRATION ...................................................................................... 28 
6.2 
PREPARATION / HANDLING / STORAGE / ACCOUNTABILITY ......................................................... 28 
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6.2.1 STORAGE AND ACCOUNTABILITY 
29 
6.2.2 DISPOSITION OF STUDY DRUG SUPPLIES 
29 
6.3 
MEASURES TO MINIMIZE IMBALANCE: BLOCK URN RANDOMIZATION AND BLINDING ............ 29 
6.3.1 APPENDIX 1 BLOCK URN RANDOMIZATION 
30 
6.3.2  PROCEDURE FOR BREAKING THE RANDOMIZATION CODE 
30 
6.4 
STUDY DRUG COMPLIANCE ............................................................................................................. 31 
6.5 
CONTINUED ACCESS TO STUDY DRUG AFTER THE END OF THE STUDY ....................................... 31 
6.6 
PARTICIPANT INFUSION STOPPING CRITERIA ............................................................................... 31 
6.7 
CONCOMITANT THERAPY ................................................................................................................ 32 
6.8 
RESCUE MEDICINE/TREATMENT .................................................................................................... 32 
6.8.1 EARLY STUDY DRUG CESSATION 
32 
6.9 
ENDOVASCULAR INTERVENTION AND STROKE CARE ................................................................... 32 
7 DISCONTINUATION OF STUDY DRUG AND PARTICIPANT DISCONTINUATION 
/ WITHDRAWAL ................................................................................................................... 33 
7.1 
DISCONTINUATION OF STUDY DRUG .............................................................................................. 33 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE TRIAL ........................................... 33 
7.3 
LOST TO FOLLOW UP ....................................................................................................................... 33 
8 STUDY ASSESSMENTS AND PROCEDURES ................................................................. 35 
8.1 
SAFETY AND EFFICACY ASSESSMENTS ........................................................................................... 35 
8.1.1 VITAL SIGNS 
35 
8.1.2 CLINICAL SAFETY LABORATORY ASSESSMENTS 
35 
8.1.3 PREGNANCY TESTING 
36 
8.1.4 BLOOD COLLECTION FOR RNA ANALYSIS 
36 
8.1.5 BLOOD COLLECTION FOR PLASMA BIOMARKER 
37 
8.1.6 THE MODIFIED RANKIN SCALE 
37 
8.1.7 MORTALITY RATE 
37 
8.1.8 THE NATIONAL INSTITUTES OF HEALTH STROKE SCALE 
37 
8.1.9 WORSENING OF STROKE 
37 
8.1.10 VOLUME OF STROKES 
38 
8.1.11 BARTHEL INDEX 
38 
8.1.12 EQ-5D-5L 
38 
8.2 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES), AND OTHER SAFETY 
REPORTING ....................................................................................................................................... 38 
8.2.1 TIME PERIOD AND FREQUENCY FOR COLLECTING AE AND SAE INFORMATION 
39 
8.2.2 METHOD OF DETECTING AES AND SAES 
39 
8.2.3 FOLLOW-UP OF AES AND SAES 
40 
8.2.4 REGULATORY REPORTING REQUIREMENTS FOR SAES 
40 
8.2.5 PREGNANCY 
41 
9 STATISTICS ........................................................................................................................... 41 
9.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 41 
9.2 
ANALYSIS SETS ................................................................................................................................. 41 
9.3 
STATISTICAL ANALYSIS ................................................................................................................... 42 
9.3.1 GENERAL CONSIDERATIONS 
42 
9.3.2 ANALYSES OF SAFETY 
42 
9.3.3 ANALYSES OF SAFETY AND EFFICACY 
43 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .... 44 
10.1 
APPENDIX 2: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .................. 44 
10.1.1 REGULATORY AND ETHICAL CONSIDERATIONS 
44 
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10.1.2 FINANCIAL DISCLOSURE 
45 
10.1.3 INFORMED CONSENT PROCESS 
46 
10.1.4 DATA PROTECTION 
46 
10.1.5 OVERSIGHT COMMITTEES 
46 
10.1.6 DATA SAFETY MONITORING BOARD 
47 
10.1.7 DISSEMINATION OF CLINICAL STUDY DATA 
47 
10.1.8 DATA QUALITY ASSURANCE 
47 
10.1.9 SOURCE DOCUMENTS 
48 
10.1.10 
STUDY AND SITE START AND CLOSURE 
49 
10.1.11 
PUBLICATION POLICY 
50 
10.1.12 
AUDITS AND INSPECTIONS 
50 
10.2 
APPENDIX 3: CLINICAL LABORATORY TESTS AND IMAGING ....................................................... 52 
10.2.1 CLINICAL LABORATORY TESTS 
52 
10.2.2 IMAGING 
52 
10.3 
APPENDIX 4: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ................................................................................ 54 
10.3.1 DEFINITION OF SAE 
55 
10.3.2 RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
56 
10.3.3 REPORTING OF SAES 
59 
10.4 
APPENDIX 5: COLLECTION OF PREGNANCY INFORMATION ......................................................... 60 
10.5 
APPENDIX 6: ABBREVIATIONS ......................................................................................................... 61 
10.6 
APPENDIX 7: ADJUSTED QTCF CALCULATION .............................................................................. 63 
11 REFERENCES ........................................................................................................................ 64 
12 INVESTIGATOR’S AGREEMENT ..................................................................................... 67 
13 ADDENDUM ........................................................................................................................... 68 
13.1 
COVID-19 CONSIDERATIONS ......................................................................................................... 68 
13.2 
ASSESSMENT QUESTIONNAIRES ...................................................................................................... 69 
MODIFIED RANKIN SCALE (MRS) 
70 
NATIONAL INSTITUTES OF HEALTH STROKE SCALE (NIHSS) 
71 
BARTHEL INDEX (BI) 
79 
EQ-5D-5L 
81 
List of Tables 
Table 1-1:  Schedule of Activities for Randomized Participants ............................................................... 13 
Table 3-1:  Objectives and Outcomes ........................................................................................................ 20 
Table 6-1: 
Study Interventions .................................................................................................................. 28 
Table 10-1: Protocol-Required Safety Assessments ................................................................................... 52 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Title 
 
RESCUE: A Randomized, Blinded, Placebo-controlled, Parallel 
Group Design to Determine the Safety of RNS60 in Large Vessel 
Occlusion Stroke Patients Undergoing Endovascular Thrombectomy.  
Protocol Number 
06.5.1.H1 
 
Trial Design 
This study is a Phase 2, randomized, blinded assessor, placebo-
controlled, parallel group, and two-dose design. Patients with a large 
vessel occlusion and acute ischemic stroke (AIS) who meet the 
criteria for endovascular revascularization will be given a 48-h 
infusion of either 0.5 mL/kg/h RNS60 (up to a maximum of 65 
mL/h), 1 mL/kg/h RNS60 (up to a maximum of 130 mL/h), or 1 
mL/kg/h (up to a maximum of 130 mL/h) placebo (normal saline) 
starting within 30 minutes of randomization (but prior to arterial 
access closure) with the exact time to start dosing being determined 
by the timing of the informed consent. Randomization will be done 
with block urn randomization to balance age, National Institutes of 
Health Stroke Scale (NIHSS), and Alberta stroke programme early 
CT score (ASPECTS). Outcomes will be evaluated throughout a 
90-day observation period. Block urn randomization provides 
consistent imbalance control but provides greater allocation 
randomness compared with permuted block design and can be used 
for more than three arms (see Section 6.3.1). Block urn designs have 
been used in other stroke trials.   
Trial Objectives  
The primary objective is to determine the safety of the 
neuroprotectant RNS60 in patients with large vessel occlusion (LVO) 
AIS receiving a 48-h infusion of either 0.5 mL/kg/h RNS60 (up to a 
maximum of 65 mL/h) or 1 mL/kg/h RNS60 (up to a maximum of 
130 mL/h). 
The secondary objectives are to evaluate the efficacy of RNS60 in: 
1) 
Reducing global disability  
2) 
Reducing mortality rate 
3) 
Improving neurological outcome 
4) 
Reducing worsening of stroke* 
5) 
Reducing functional dependence 
* Worsening of stroke is defined as progression, or hemorrhagic 
transformation of the index stroke, as documented by brain 
imaging, and that is (a) life-threatening requiring intervention and/or 
(b) results in increased disability as gauged by a ≥ 4-point increase 
from lowest NIHSS pre decline and/or (c) results in death. 
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The tertiary objectives are to evaluate the efficacy of RNS60 in: 
• Decreasing infarct volume 
• Improving health related quality of life 
Safety Outcomes 
Safety outcomes include:  
• Serious adverse events (SAEs) to Day 90 
• 90-day mortality 
Additional Safety outcomes include: 
• Adverse events (AEs) to Day 90 
• Drug administration discontinuations due to AEs 
• Baseline and 48-h vital signs  
• Baseline and 48-h electrocardiogram 
• Baseline and 48-h chest X-ray (CXR) 
Efficacy 
Outcomes  
The efficacy outcomes (secondary) are:  
1) Mean modified Rankin Scale (mRS) at Day 90 
2) 90-day mortality 
3) Mean NIHSS at 24h and Day 90  
4) Proportion of patients exhibiting a worsening of their index 
stroke.* 
5) Mean Barthel Index (BI) at Day 90 relative to pre-stroke BI. 
*Worsening of stroke is defined as progression, or hemorrhagic 
transformation of the index stroke, as documented by brain 
imaging, and that is (a) life-threatening requiring intervention 
and/or (b) results in increased disability as gauged by a ≥ 4-point 
increase from lowest NIHSS score pre decline and/or (c) results in 
death. 
 
Tertiary/exploratory outcomes include: 
1) Infarct progression/regression as measured by MRI brain 
imaging. 
2) Health-related quality of life, as measured by the 5-level 
EuroQoL 5D index (EQ-5D-5L) at Day 90.  
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Number of 
Participants 
An initial target of 100 male and female participants with LVO AIS 
and who are selected for endovascular revascularization will be 
enrolled.    
Attrition factors include death from stroke but not treatment (10%), 
symptoms of fluid overload (20%) and early discharge (5%).   
Inclusion/ 
Exclusion 
Criteria 
Inclusion Criteria 
1) AIS patients selected for emergency endovascular treatment.
2) Age 18 years or older.
3) Stroke symptom onset or, if not known, last known well time to
randomization within 24 hours.
4) Disabling stroke defined as a baseline NIHSS score:
a.
NIHSS score NIHSS > 5 for internal carotid artery (ICA)
and M1-middle cerebral artery (MCA) occlusion or
b. NIHSS > 10 for M2-MCA occlusion.
5) Confirmed symptomatic intracranial occlusion at one or more of
the following locations: Intracranial carotid I/T/L, M1 or M2
segment MCA.  Tandem extracranial carotid and intracranial
occlusions are permitted.
6) Pre-stroke (24 hours prior to stroke onset) historical modified
Rankin Scale (mRS) ≤ 2.  Patient must be living independently
without requiring nursing care.
7) Qualifying imaging performed less than 2 hours prior to
randomization.
8) Consent process completed as per applicable laws and regulation
and the IRB requirements.
Exclusion Criteria 
1) Evidence of a large core of established infarction defined as 
ASPECTS 0-4.
2) Evidence of absence of collateral circulation on qualifying 
imaging (Collateral score of 0 or 1 if mCTA is used, or absence of 
adequate ischemic penumbra in the judgment of the Investigator if 
CTP is used).
3) Any evidence of intracranial hemorrhage or mass lesion on the 
qualifying imaging.
4) Planned use of an endovascular device not having approval or 
clearance or has been recalled by the relevant regulatory authority.
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5) Endovascular thrombectomy procedure is completed as defined 
by the presence of arterial access closure. 
6) Clinical history, past imaging or clinical judgment suggesting that 
the intracranial occlusion is chronic or there is suspected 
intracranial dissection such that there is a predicted lack of 
success with endovascular intervention. 
7) Estimated or known weight > 130 kg (287 lbs). 
8) Known pregnant/lactating female. 
9) Myocardial infarction within 6 months prior to Screening 
including non-Q wave MI; Diagnosis of congestive heart failure 
(CHF) with either:  
a) current clinical signs and symptoms of ventricular 
dysfunction (e.g., edema, shortness of breath),  
b) CHF medication adjustment within the prior 30 days or  
c) ejection fraction (if report available) of 30% or less 
measured in the 6 months prior to Screening;  
as either medically documented or reported by patient or another 
person considered by the Investigator to be reasonably reliable. 
10) Known renal impairment defined as requiring renal replacement 
therapy (hemo- or peritoneal dialysis)  
11) Inability to have MRI imaging (Non- MR compatible implants or 
any other foreseeable reason (including claustrophobia) 
12) Severe or fatal comorbid illness that will prevent improvement or 
follow up.  
13) Inability to complete follow-up treatment to Day 90. 
14) Participation in another clinical trial investigating a drug, medical 
device, or a medical procedure in the 30 days preceding trial 
inclusion and throughout the duration of the trial. 
15) Reported known seizure at time of stroke onset. 
16) Ischemic stroke within previous 30 days. 
17) Patients in normal sinus rhythm with a known QTcF > 460 ms at 
Screening.  
18) Any other symptom that in the investigator’s opinion may 
complicate or preclude the subject from participating in this trial.  
Treatment 
RNS60 0.5 mL/kg/h (up to a maximum of 65 mL/h) or RNS60 
1 mL/kg/h RNS60 (up to a maximum of 130 mL/h) intravenous 
infusion.   
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Consent 
Initial Informed Consent 
Participants or their legally authorized representative will be required 
to sign a statement of informed consent that meets the requirements 
of applicable laws and regulation and Internal Review Boards (IRBs). 
Regained Capacity Consent  
If the original consent process involved anyone other than the 
participant, and if required by local standards, consent will be sought 
for the remaining procedures from the participant once they are 
deemed to have regained capacity.  
Note: Electronic consent tools may be used for initial and regained 
capacity consent, as permitted under applicable laws and regulations 
and the applicable IRB Committee.  
Randomization 
Method 
Treatment will be assigned using 1:1:1 randomization of RNS60 0.5 
mL/kg/h: RNS60 1 mL/kg/h: placebo (normal saline) with block urn 
randomization by age, NIHSS score, and ASPECTS score (8 urns). 
Duration of 
Treatment 
Participants will receive a 48-h infusion of study drug or placebo. 
Each participant will be followed for 90 days.  At Day 30 and Day 90 
it is preferred that participants will return to clinic. If an in-clinic visit 
is not possible, the participant (or LAR) will be contacted by 
telemedicine (preferred) or by telephone (last option).  
Laboratory Tests 
If the participant is female and is of childbearing potential, a 
pregnancy test (urine or serum point-of-care pregnancy test) must be 
completed.  
In order to support the assessment of safety, pre-dose (baseline) and 
post-dose (48-h) complete blood count, electrolytes including 
magnesium, liver function test panel (LFT), blood urea nitrogen 
(BUN), creatinine, chest Xray (CXR) and cardiac electrocardiogram 
(at baseline, 24-h and 48-h) results will be reported and analysed.   
Assessment of 
Efficacy 
As the primary purpose of this trial is the assessment of safety, there 
is no power analysis for efficacy. However, the design and analyses 
of this trial will provide estimates for the powering of a subsequent 
trial for efficacy.  
The primary efficacy metric for assessment of efficacy is a lower 
mean mRS at 90 days.   
Statistical 
Assumptions 
Analyses will be examined on the intent-to-treat (ITT) sample, 
defined as all randomized participants, regardless of treatment 
actually received. The per protocol sample will also be examined 
separately. Patients who receive treatment but do not get full 48 hours 
of treatment due to fluid overload or early discharge will be included 
in the ITT analysis. Patients who complete the full 48 hours will be 
included in both per protocol and ITT analysis.  
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All analyses will be accomplished using SAS Software 9.4 (SAS Inc. 
Cary, NC). Primary: The frequency of SAEs, SAEs resulting in death, 
AEs, and discontinuations due to AEs will be summarized as counts 
and percentages between the three arms. Comparisons will be 
conducted using Fisher’s Exact tests.  
Secondary: Comparisons between conditions for mRS will be 
evaluated using generalized mixed modeling assuming a binomial 
distribution (0-6) with sandwich estimation nested by site and patient, 
when applicable. Pairwise comparisons of mRS will be conducted at 
Day 90 using a Dunnett correction. In addition, simple and interaction 
effects between pre-stroke, discharge, 30-day and 90-day mRS by 
condition will be examined.  Both NIHSS and BI at Day 90 will be 
examined in a similar fashion assuming a binomial distribution (0-42 
& 0-100) with sandwich estimation. Pairwise comparisons between 
conditions will be conducted at Day 90 using a Dunnett correction. In 
addition, simple and interaction effects between pre-treatment, 
discharge, 30-day and 90-day NIHSS and BI by condition will be 
examined. Mortality will be examined using Kaplan-Meier estimation 
with pairwise comparisons with a Dunnett correction. DWI volume 
post treatment and at 48 hours, and 90-day T2 will be modeled 
between conditions using generalized linear modeling assuming a 
normal or lognormal distribution (where appropriate), where simple 
and interaction effects will be examined.  Because superiority over 
placebo and lower dose is hypothesized, testing will reflect this 
superiority framework. Because the main aim of this trial is to 
examine safety, efficacy analysis results are intended to yield 
estimates to inform powering for a future efficacy trial. Alpha is 
established at the 0.05 level and all interval estimates will be 
calculated for 95% confidence. 
Data Safety 
Monitoring 
Board 
A Data Safety Monitoring Board (DSMB) will monitor patient safety 
and scientific integrity during the trial.  
 
 
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Table 1-1:  Schedule of Activities for Randomized Participants 
Visit/Contact 
V1 
V2 
V3 
V4 
V5 
V6/ 
End of Trial 
Day 
Day 0 
Baseline 
Day 1 
Post-EVT 
Day 2/or 
early 
discharge 
Day 61 or 
discharge 
Day 302 
Day 902 
Window 
 
(24 h+/-4h) 
(48 h±4h) 
 
(±5 d) 
(-21 to +7d) 
Informed consent 
X 
 
 
 
 
 
Regained capacity informed consent3 
 
 
X 
X 
X 
X 
History and physical examination4 
X 
X 
X 
 
 
 
Weight5 
X 
 
X 
 
 
 
Vital Signs (BP, HR, Temperature) 6 
X 
X 
X 
 
 
 
Chest radiograph 
X12 
X 
X 
 
 
 
Electrocardiogram7  
X12 
X 
X 
 
 
 
Randomization/  
Study drug administration 
X 
X 
X 
 
 
 
Continuous telemetry7 
X 
X 
X 
 
 
 
Mortality 
 
X 
X 
X 
X 
X 
NIHSS13 
X 
X 
X 
X 
X 
X 
mRS 
 X 
 
 
X 
X 
X 
Barthel Index 
X 
 
 
 
X 
X 
EQ-5D-5L 
 
 
 
 
 
X 
Imaging (NCCT & mCTA) 
X 
 
 
 
 
 
Endovascular Procedure 
X 
 
 
 
 
 
MRI head8 
 
X 
X 
 
 
X 
Laboratory Assessments 
X9 
 
X 
 
 
 
Pregnancy test10 
X 
 
 
 
 
 
Blood collection for RNA analysis11 
 
X 
X 
 
 
X 
Blood collection for Plasma Biomarker 
 
X 
X 
 
 
X 
AE  
Collected to Day 90 
SAE 
Collected to Day 90 
Prior medications 
X 
 
 
 
 
 
Concomitant medications 
Collected to Day 90 
1. Visit will occur at Day 6 or hospital discharge if prior to Day 6.  
2. At Day 30 and Day 90 it is preferred that participants will return to clinic.  If an in-clinic visit is not possible the participant can 
be contacted by telemedicine (preferred) or by telephone (last option). 
3. If the original process involved anyone other than the participant (and if required), site staff will make ongoing efforts until: (1) 
regained capacity consent is obtained from participant, (2) death, or (3) completion of the Day 90 assessment. 
4. Physical exam every 8-12 hours during Day 1 and Day 2. 
5. At baseline estimated or actual weight will be collected. If an estimated weight was collected at baseline, actual weight should 
be collected as soon as feasible and prior to discharge. 
6. Vital signs (BP, HR only) will be recorded immediately before and after completion of the study drug infusion, and every 8-12 
hours during Day 1 and Day 2, temperature will be collected at baseline only if standard of care. 
7. Abnormal electrocardiogram or continuous telemetry result that suggests clinical instability will prompt a formal cardiology 
consult. 
8. MRI head with perfusion imaging within approximately 2h post-EVT on Day 1 and at 48h +/- 4h. MRI head only at 90d.  
9. Blood should be drawn at baseline, but results are not required prior to randomization. Results from primary hospital (within 8 
hours) are accepted. 
10. If the participant is female and is of childbearing potential a pregnancy test (urine or serum point-of-care pregnancy test) must 
be collected at baseline, but result is not required prior to randomization.  
11. Day 1 collection 12-24 h (+/-4 hours) after additional consent is obtained for optional collection.  
12. Results from the baseline ECG and CXR are not required prior to randomization. 
13. NIHSS score is obtainable in-person or via telemedicine visit only (not over the phone).  
d = days; h = hours 
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was followed by neurobehavioral tests for 30 days. RNS60 achieved a significant reduction of 
infarct size and significant improvements in the neurobehavioral assessment without any notable 
signs of adverse effects.  The two proposed doses for this clinical trial (0.5 and 1 mL/kg/h) are 
comparable to the dose used in monkeys. This model has previously been successfully used to test 
another drug for clinical translation in stroke13. 
 
More detailed information on these and other non-human primate pharmacology and toxicology 
studies is provided in the Investigator’s Brochure.   
 
2.1.5 Previous Clinical Trials 
To assess clinical safety, RNS60 was administered intravenously to healthy volunteers at three 
escalating dose levels of 100 mL/h (1.2 mL/kg/h) for the first 48 hours, 150 mL/h (1.8 mL/kg/h) 
for the following 48 hours, and 200 mL/h (2.4 mL/kg/h) for the final 48 hours, for a total infusion 
volume of 21,600 mL (259 mL/kg) over 144 hours (6 days) total in a Phase I safety trial 
(ClinicalTrials.gov Identifier: NCT01264783).  There were no reported SAEs related to RNS60. 
AEs that were reported as possibly treatment related were headache and musculoskeletal pain, all 
of which were mild except for one instance of moderate abdominal pain.   
 
RNS60 has been tested in three clinical trials in disease populations: a completed clinical pilot 
study in 16 amyotrophic lateral sclerosis (ALS) patients (Clinicaltrials.gov ID #NCT02525471)14, 
an ongoing 148-patient ALS Phase II trial (Clinicaltrials.gov ID #NCT03456882), and a 
completed Phase IIa trial in 10 multiple sclerosis patients (EudraCT #2014-000221-20). In each of 
these trials, RNS60 was well tolerated. Only a single SAE was reported by investigators as 
possibly related to treatment, although it presented as an isolated, non-sustained event that did not 
result in any clinical symptoms or sequelae and did not repeat after the subject continued 
treatment (negative re-challenge)*. 
 
More detailed information on RNS60 and its previous clinical and nonclinical use is provided in 
the Investigator’s Brochure.   
 
2.2 
Study Rationale  
RNS60 has shown a significant neuroprotective effect in preclinical models of stroke as well as in 
other models of chronic neurodegenerative diseases.  There is a compelling need to develop 
neuroprotectants in order to increase the proportion of patients who may benefit from EVT and 
do not suffer from delays in care. Effective neuroprotectants could improve the outcomes of 
patients and bridge patients with AIS into candidates for endovascular or pharmacological 
recanalization treatment. The rapid progression of irreversible brain injury in most acute 
strokes implies a short window of clinical efficacy for any treatment, including RNS60.  
 
* A single SAE of elevated systolic and diastolic arterial blood pressure (~200/100 mmHg) was reported by the 
investigators of the 148-patient ALS Phase II trial as possibly related to treatment.   
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2.3 
Benefit/Risk Assessment 
More detailed information about the chemistry, pharmacology, safety, efficacy, and expected 
benefits and risks of RNS60 is provided in the Investigator’s Brochure.   
 
2.3.1 Risk Assessment 
Based on the clinical data available for RNS60 to date, the major possible risk for the proposed 
use is: 
• Circulatory volume expansion/fluid volume overload 
 
2.3.2 Benefit Assessment 
The following is a list of possible benefits to the trial participants receiving RNS60: 
• Improved functional outcome (lower mean mRS) 
• Reduced stroke mortality  
• Improved good neurologic outcome (lower mean NIHSS score)  
• Reduced chance of stroke worsening 
• Improved functional independence (higher mean BI)  
 
2.3.3 Overall Benefit: Risk Conclusion 
The potential risks identified in association with RNS60 are justified by the anticipated benefits 
that may be afforded to participants. 
 
The maximal dose of RNS60 administered over 48 hours to the subjects in this proposed trial 
equals approximately 55% of the average dose administered over 48 hours to healthy human 
subjects in the Phase I study (Protocol 11.1.1.H1, NCT01264783), and approximately 18.5% of 
the total volume administered (average dose of 1.8 mL/kg/h over 144 hours. Based on the 
nonclinical and clinical safety profile of RNS60, we submit that the proposed dose is safe for 
patients with AIS. Additionally, participants will be monitored for fluid overload by our DSMB. 
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3 
TRIAL OBJECTIVES 
3.1 
Objectives 
Table 3-1:  Objectives and Outcomes 
Objectives 
Outcomes 
Primary – Safety  
 
To determine the safety based on SAEs 
Proportion of participants with SAEs to Day 90 
90-day mortality 
Proportion of participants alive at Day 90 
Secondary – Efficacy 
 
Reducing global disability in participants with 
AIS 
Mean mRS score 
Reducing mortality rate 
Median or proportion of death on survival 
curve 
Improving neurological outcome 
Mean NIHSS score at discharge 
Reducing worsening of stroke  
See 3.1.2 
Reducing functional dependence 
Mean BI at Day 90 
Tertiary/Exploratory 
 
Decreasing infarct volume 
Volume of stroke as measured by MRI brain 
imaging 
Improving health related quality of life 
EQ-5D-5L at Day 90 
 
3.1.1 Primary Objective 
The primary objective is to determine the safety of the neuroprotectant RNS60 in patients with LVO 
AIS. Patients must have sudden onset of focal neurological symptoms or, if not known, last known 
well time within 24 hours consistent with an ischemic stroke. Symptoms must be persistent and 
present at the time of enrollment. 
 
The safety objectives are to determine the safety in participants with AIS of the 48-h infusion of 
either 0.5 mL/kg/h RNS60 (up to a maximum of 65 mL/h) or 1 mL/kg/h RNS60 (up to a maximum 
of 130 mL/h), based on serious SAEs and 90-day mortality. 
 
3.1.2 Secondary Objectives 
The secondary objectives are to evaluate the efficacy of RNS60 in: 
1) Reducing global disability  
2) Reducing mortality rate 
3) Improving neurological outcome  
4) Reducing worsening of stroke*  
5) Reducing functional dependence  
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* Worsening of stroke is defined as progression, or hemorrhagic transformation, of the index
stroke as documented by medical imaging and that is (a) life-threatening requiring
intervention and/or (b) results in increased disability as gauged by a ≥ 4-point increase from
lowest NIHSS pre decline and/or (c) results in death.
3.1.3 Tertiary/Exploratory Objectives 
The tertiary objectives are to evaluate the efficacy of RNS60 in: 
1) Decreasing infarct volume
2) Improving health related quality of life
3.2 
Outcomes 
3.2.1 Primary Safety Outcomes 
1) The safety outcomes are the frequencies and severities of SAEs and 90-day mortality
3.2.2 Secondary Efficacy Outcomes 
Secondary outcomes include: 
1) The mean mRS score at Day 90, where a lower score is better.
2) A reduction in mortality rate, as defined by a lower event rate on a Kaplan Meier survival
curve
3) The mean NIHSS score post randomization, where a lower score is better
4) The proportion of patients with worsening of stroke over the 90-day study period
5) The mean BI at Day 90
3.2.3 Tertiary/Exploratory Outcomes 
The following tertiary outcomes will be assessed descriptively: 
1) The volume of stroke as measured by MRI brain imaging
2) Health-related quality of life, as measured by the EQ-5D-5L at Day 90
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4 
TRIAL DESIGN 
4.1 
Overall Design 
This trial is a block urn randomized (by age: <80 vs. ≥80, NIHSS score: 6-10 vs. >10, and 
ASPECTS: 5-7 vs. 8-10, for a total of 8 urns), blinded assessor, placebo-controlled, parallel 
group, two-dose (full and half), longitudinal (pre-stroke, post-treatment, 48-hour, discharge, 30-
day, and 90-day) study with equal arm sample sizes (1:1:1). Although the trial’s main purpose is 
to demonstrate safety, superiority is hypothesized over placebo and lower dose for secondary and 
tertiary aims.  
AIS large vessel occlusion participants who are selected for EVT will be given a 48-h infusion of 
either 0.5 mL/kg/h RNS60 (up to a maximum of 65 mL/h), 1 mL/kg/h RNS60 (up to a maximum 
of 130 mL/h) or 1 mL/kg/h RNS60 (up to a maximum of 130 mL/h) of saline.  
The end of the trial is defined as the date that the last enrolled participant has completed their Day 
90 visit/contact.   
A target of 100 male and female participants aged 18 years and older with AIS and who are 
selected for EVT will be enrolled.  
All participants in the trial will be followed for 90 days (or until death if prior to 90 days).  At Day 
30 and Day 90 participants will return to clinic.  If an in-clinic visit is not possible the participant, 
or if participant cannot be contacted or cannot communicate well, a legally authorized 
representative can be contacted by telemedicine (preferred) or by telephone (last option).  
4.2 
Scientific Rationale for Study Design 
The RNS60 trial design rationale is based on the promising design of the recently completed 
ESCAPE-NA1 trial10. There is a compelling need to develop neuroprotectants in order to increase 
the proportion of patients who may benefit from EVT and do not suffer from delays in care. 
Effective neuroprotectants could improve the outcomes of patients and bridge patients with AIS 
into candidates for endovascular or pharmacological recanalization treatment. The rapid 
progression of irreversible brain injury in most acute strokes implies a short window of 
clinical efficacy for any treatment, including RNS60.  
The current trial is intended to demonstrate safety of RNS60 and, as a secondary aim, to provide 
first data on whether RNS60 may improve functional independence, reduce mortality, and reduce 
infarction volumes. As such, this trial is a block urn randomized (by age: <80 vs. ≥80, NIHSS 
score: <10 vs. ≥10, and ASPECTS: 5-7 vs. 8-10 for a total of 8 urns), blinded assessor, placebo-
controlled, parallel group, two-dose (full and half), longitudinal (pre-stroke, post-treatment, 48-
hour, discharge, 30-day, and 90-day) study with equal arm sample sizes (1:1:1). Although the 
trial’s main purpose is to demonstrate safety, superiority of the higher dose is hypothesized over 
placebo and the lower dose (secondary and tertiary objectives).  
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Randomized LVO stroke patients will be given a 48-h infusion of either 0.5 mL/kg/h RNS60 (up 
to a maximum of 65 mL/h), 1 mL/kg/h RNS60 (up to a maximum of 130mL/h), or 1 mL/kg/h (up 
to a maximum of 130 mL/h) placebo (normal saline) within 30 minutes of randomization but prior 
to arterial access closure (the exact time to start dosing will be determined by the timing of the 
informed consent). 
 
4.3 
Justification for the Target Study Population  
RNS60 is being developed as an emergency drug aimed at reducing global disability in patients 
with AIS.  RNS60 is intended to enhance the outcome of patients who may benefit from EVT and 
add to the existing standard of care stroke treatments including thrombolysis.   
 
4.4 
Justification for Dose 
RNS60 was selected to be infused at either a 0.5 mL/kg/h (up to a maximum of 65 mL/h) or 1 
mL/kg/h (up to a maximum of 130 mL/h) because of: 
1) The safety profile observed in the nonclinical toxicology studies and in Phase 1 clinical trials  
2) The efficacy of a similar dose of RNS60 to reduce stroke tissue damage and to improve 
neurological function in mice and non-human primates. 
 
4.5 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed to Day 90 or has 
died prior to Day 90.  The end of the study is defined as the date of the last visit of the last 
participant in the trial. 
 
 
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5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. The study population includes adults 18 years 
and older with AIS who are selected for EVT. Subjects must have sudden onset of focal 
neurological symptoms, or if not known, last known well time within 24 hours consistent with an 
ischemic stroke. Symptoms must be persistent and present at the time of enrollment. 
5.1 
Inclusion Criteria 
1)
AIS selected for emergency endovascular treatment.
2)
Age 18 years or older.
3)
Stroke symptom onset or, if not known, last known well time to randomization within 24
hours.
4)
Disabling stroke defined as a baseline NIHSS score:
a.
NIHSS > 5 for internal carotid artery (ICA) and M1-middle cerebral artery (MCA)
occlusion; or
b.
NIHSS > 10 for M2-MCA occlusion.
5)
Confirmed symptomatic intracranial occlusion at one or more of the following locations:
Intracranial carotid I/T/L, M1 or M2 segment MCA.  Tandem extracranial carotid and
intracranial occlusions are permitted.
6)
Pre-stroke (24 hours prior to stroke onset) historical modified Rankin Scale (mRS) ≤ 2.
Patient must be living independently without requiring nursing care.
7)
Qualifying imaging performed less than 2 hours prior to randomization.
8)
Consent process completed as per applicable laws and regulation and the IRB requirements.
5.2 
Exclusion Criteria 
1)
Evidence of a large core of established infarction defined as ASPECTS 0-4.
2)
Evidence of absence of collateral circulation on qualifying imaging (collateral score of
0 or 1 if mCTA is used or absence of adequate ischemic penumbra in the judgment of the 
Investigator if CTP is used).
3)
Any evidence of intracranial hemorrhage or mass lesion on the qualifying imaging.
4)
Planned use of an endovascular device not having approval or clearance or has been recalled 
by the relevant regulatory authority.
5)
Endovascular thrombectomy procedure is completed as defined by the presence of arterial 
access closure.
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6) Clinical history, past imaging or clinical judgment suggesting that the intracranial occlusion 
is chronic or there is suspected intracranial dissection such that there is a predicted lack of 
success with endovascular intervention. 
7) Estimated or known weight >130 kg (287 lbs). 
8) Known pregnant/lactating female. 
9) Myocardial infarction within 6 months prior to Screening including non-Q wave MI; 
Diagnosis of congestive heart failure (CHF) with either:  
a) current clinical signs and symptoms of ventricular dysfunction (e.g., edema, shortness 
of breath),  
b) CHF medication adjustment within the prior 30 days or  
c) ejection fraction (if report available) of 30% or less measured in the 6 months prior to 
Screening;  
as either medically documented or reported by patient or another person considered by the 
Investigator to be reasonably reliable. 
10) Known renal impairment defined as requiring renal replacement therapy (hemo- or 
peritoneal dialysis). 
11) Inability to have MRI imaging (non-MR compatible implants or any other foreseeable 
reason including claustrophobia) 
12) Severe or fatal comorbid illness that will prevent improvement or follow up.  
13)  Inability to complete follow-up treatment to Day 90.  
14) Participation in another clinical trial investigating a drug, medical device, or a medical 
procedure in the 30 days preceding trial inclusion and throughout the duration of the trial. 
15) Reported known seizure at time of stroke onset. 
16) Ischemic stroke within previous 30 days. 
17) Patients in normal sinus rhythm with a known QTcF > 460 ms at Screening. 
18) Any other symptom that in the investigator’s opinion may complicate or preclude the subject 
from participating in this trial. 
 
5.3 
Lifestyle Considerations 
No restrictions are required. 
 
5.4 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical trial but are not 
subsequently randomized to be a trial participant. The informed consent form will be maintained 
at the study site, but these participants will not be entered in the CRF. 
 
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5.5 
Study Enrollment Process 
In this AIS trial, patients should be randomized into the trial and receive study drug as soon as 
possible (within 30 minutes of randomization and before completion of EVT procedure as defined 
by completion of arterial access closure), following review of trial eligibility and the local 
informed consent process. Participants will be identified using usual standard of care screening 
methods at the acute stroke hospital. All participants will undergo an acute clinical assessment, 
blood laboratory assessment, baseline electrocardiogram, baseline chest radiograph, and baseline 
brain imaging. Due to the short time-period from arrival at the hospital to the EVT, the results of 
the baseline blood work and the results from the initial ECG and CXR are not required prior to 
randomization or start of infusion. 
 
If the participant remains eligible after completion of routine stroke screening, the patient will be 
consented (as required) and enrolled into the trial.  A participant is considered randomized the 
moment the randomization process is completed on-line.  Participants who are randomized but do 
not receive study drug will still be followed through the 90-day study period.  
 
5.5.1 Imaging 
All sites will perform an NCCT brain and CTA (CTP is allowed but not preferred) to determine 
patient eligibility.  The NCCT head will be assessed using ASPECTS prior to randomization.  
Instructions for the determination of the ASPECT score and evidence of absence of collateral 
circulation are provided at www.aspectsinstroke.com.  The CTA will be assessed for collateral 
status using a collateral scoring system if multiphase CTA is used.  If CTP is used, evidence of 
adequate penumbra must be confirmed. Confirmed symptomatic intracranial occlusion will be 
based on multiphase (preferably) CTA. Sites will only be selected to participate in the trial if they 
have established mechanisms for screening this population of participant.  This includes standard 
of care use of NCCT and CTA. 
 
5.5.2 Consent Process 
After completing a formal screening process to determine eligibility, Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of applicable laws and regulation and the ethics committee. 
 
The investigator or his/her representative will explain the nature of the trial to the participant or 
his/her legally authorized representative and answer all questions regarding the trial. 
The medical record must include a statement describing under which process consent was 
obtained, and the timing of the consent and regained capacity consent. The authorized person 
obtaining the informed consent must also sign the informed consent form (ICF). 
 
An electronic consent process is permitted for consent of subjects or their surrogate if all the 
requirements for electronic records/electronic signatures, informed consent, and IRBs as set forth 
in 21 CFR parts 11, 50, and 56 are followed. 
 
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5.5.3 Regained Capacity Consent 
If the original process involved anyone other than the participant, and if required by local 
standards, consent will be sought for the remaining procedures from the participant once they are 
deemed to have regained capacity.  Site staff will make ongoing efforts until: (1) regained 
capacity consent is obtained from participant, (2) death, or (3) completion of the Day 90 
assessment. 
 
5.5.4 Amendment of the ICF 
In the event that new information is available and the ICF is amended, and if required by local 
IRBs, participants must be re-consented to the most current version of the ICF(s) during their 
participation in the trial. A copy of each ICF must be provided to the participant or the 
participant’s legally authorized representative. 
 
Note: Electronic consent tools may be used for initial and regained capacity consent, as permitted 
under applicable laws and regulations and the IRBs.  
 
5.5.5  Physical Examinations  
To support the assessment of inclusion and exclusion criteria and medical history, a stroke 
focused physical examination at baseline will include, at a minimum, assessments of the 
Neurological, Cardiovascular, Respiratory, Genitourinary, and Gastrointestinal systems. 
Investigators should pay special attention to clinical signs related to previous strokes.  
Additionally, physical examinations will be conducted every 8-12 hours during the treatment 
phase to assess any signs of fluid overload or worsening of any clinical symptoms. Results taken 
from standard of care assessment/timepoints may be used. 
 
 
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All participants, investigators, their clinical staff, local and central laboratories, the clinical 
coordinating center, the data management group, and the sponsor staff and delegates will be 
blinded to the randomization codes. 
 
6.3.1 Appendix 1 Block Urn Randomization  
Because of the small sample size distributed among three arms, imbalance of treatment 
assignment across important baseline factors should be minimized. Block urn randomization 
provides consistent imbalance control but provides greater allocation randomness compared with 
permuted block design15. Block urn designs use blocking of balls with an active urn and inactive 
urn. A ball is randomly selected from the active urn (treatment allocation) and then placed in the 
inactive urn; this process is repeated until a minimum balance is achieved in the inactive urn at 
which point these balls are replaced in the active urn while the other balls are left in the inactive 
urn. This process is repeated until the last patient is randomized. Block urn randomization has 
been used in other stroke trials16-18.  
 
6.3.2  Procedure for Breaking the Randomization Code 
In case of an emergency, the investigator has the sole responsibility for determining whether the 
unblinding of a participant’s intervention assignment is warranted. Participant safety must always 
be the first consideration in making such a determination. If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s intervention assignment unless this could delay emergency treatment of 
the participant. If a participant’s intervention assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind†.  The date and the reason why the blind was 
broken must be recorded in the source documentation as applicable. 
 
To maintain the overall quality and legitimacy of the clinical trial, code breaks should occur only 
in exceptional circumstances when knowledge of the actual treatment is absolutely essential for 
further management of the patient to ensure their safety and well-being. 
 
In case of an emergency, a rapid unblinding procedure is available to investigators.  The 
investigator will contact the randomization provider to request unblinding of the specific 
participant. The randomization provider will respond in writing to the investigator only with the 
unblinded participant treatment allocation. 
 
Only the investigator requesting the unblinding will receive the unblinding information.  The 
investigator is requested to maintain the blind as far as possible. The actual treatment allocation 
should not be disclosed to the participant and/or other site personnel unless, in the judgment of the 
† In cases where a participant was unblinded on a Friday, where possible the investigator will aim to send the 
notification prior to the weekend.  If not possible, or if the unblinding occurs on a weekend or a holiday, notification 
will be sent on the first business day after the event.  
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investigator, this information is required for the participant’s safety. The actual treatment 
allocation must not be disclosed to study personnel on site not involved in the participant’s 
medical care, to monitors or the sponsor. 
 
In order to fulfill expedited regulatory reporting requirements, the sponsor may be required to 
unblind the participant if the SAE meets the criteria for reporting to health authorities.  The 
sponsor’s independent third party (CRO) will initiate the request that the participant’s treatment 
group be unblinded.  In this case, the code will be broken only for the participant(s) in question. 
The information resulting from code-breaking (i.e., the participant’s treatment allocation) will not 
be communicated to either the investigator or the sponsor, except as needed for determination of 
causality of a reportable SAE. 
Otherwise, randomization data will be kept strictly confidential, accessible only to authorized 
persons, until the time of unblinding after database lock at the time of interim analysis and at end 
of the study (Day 90).  
 
6.4 
Study Drug Compliance 
Study drug will be dispensed under the instructions of the investigator or designee and under 
medical supervision.  The date and time of dose administered will be recorded in the source 
documents and in the CRF.  The dose of study drug and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study drug.  The investigator may terminate study drug administration at his/her 
discretion. 
 
6.5 
Continued Access to Study Drug after the End of the Study 
Not applicable in this trial. 
 
6.6 
Participant Infusion Stopping Criteria  
Because RNS60 chemically contains only sodium chloride and oxygen, and based on the 
nonclinical and clinical safety information, the sponsor does not recommend specific treatment for 
an overdose. However, because a saline infusion of up to 130 mL/h for 48h could present a 
volume challenge the investigator should: 
 
1) Contact the PI and sponsor in case of any signs of possible fluid overload, including 
worsening dyspnea, hypoxia, or cardiac function which do not resolve with treatment. 
2) Closely monitor the participant for any AEs/SAEs and electrocardiogram (ECG), CXR, 
laboratory abnormalities for at least 1 day. (See Section 8.1.2 Clinical Safety Laboratory 
Assessments for additional infusion stopping criteria related to ECG values). 
3) Document the quantity (infusion duration) in the CRF. 
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6.7 
Concomitant Therapy 
There are no restricted medications in this trial.   
 
Any medication or vaccines (including over the counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives up to Day 90 must be recorded along 
with: 
• Dates of administration including start and end dates, medications that were ongoing at the 
last contact will be updated with a stop date or confirmed as ongoing, 
• Indication for use. 
 
6.8 
Rescue Medicine/Treatment 
6.8.1 Early Study Drug Cessation 
The intervention is 0.5 mL/kg/h RNS60 (up to a maximum of 65 mL/h) and 1 mL/kg/h RNS60 
(up to a maximum of 130 mL/h) intravenous infusion using an infusion pump, starting after 
randomization to a participant undergoing endovascular mechanical thrombolysis/thrombectomy.  
It is expected that infusion will begin prior to the completion of the procedure (defined as the time 
of arterial access closure) and complete 48h after the infusion is initiated.  
 
The infusion may be stopped if the treating investigator believes the volume of infusion can no 
longer be tolerated due to volume overload (worsening dyspnea, hypoxia, or cardiac function). As 
such, the investigator may terminate drug administration at his/her discretion. 
 
6.9 
Endovascular Intervention and Stroke Care 
EVT should be conducted as per the local protocol and in compliance with the current treatment 
guidelines such as those published by the American Heart Association (AHA)19-21. All participants 
are expected to be admitted to the hospital as part of routine standard of care.  All participants are 
expected to receive expert stroke unit care and then rehabilitation according to their clinical need 
throughout the full 90 days. 
 
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7 
DISCONTINUATION of STUDY DRUG and PARTICIPANT DISCONTINUATION / 
WITHDRAWAL 
7.1 
Discontinuation of Study Drug 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study drug. If study drug administration is discontinued, the participant will 
remain in the trial and be evaluated to Day 90. 
 
7.2 
Participant Discontinuation/Withdrawal from the Trial 
Participation in this clinical trial may be discontinued for any of the following reasons: 
• Administrative reasons (uncooperative, noncompliant, etc.) 
• Participant’s decision not to participate any further 
• If it is in the participant’s best interest, per the qualified/principal or sub-investigator 
If the participant or legally authorized representative (LAR) withdraws consent, participant data 
will be included in the analysis up to the date of the consent withdrawal and this withdrawal of 
consent will be documented in the CRF. 
 
If the LAR has originally provided consent and the participant subsequently declines consent, this 
will be deemed to be a withdrawal of consent. The investigator and sponsor would continue to 
have access to data that have already been collected. 
 
A participant may not withdraw use of his or her data that have already been collected. This is in 
alignment with the FDA guidance document “Data Retention When Participants Withdraw from 
FDA-Regulated Clinical Trials”, which is based on the importance of avoiding selection biases 
that could compromise the analysis of the overall trial. 
 
Otherwise, all randomized participants will continue to be followed according to protocol 
requirements and follow-up data will be included in the analysis.  Criteria for removal of 
participants will be recorded and reported. 
 
7.3 
Lost to Follow up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits/contacts and is unable to be contacted by the study site.  The following actions must be taken 
if a participant fails to return to the clinic or if they cannot be contacted by phone for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit/contact as 
soon as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should continue 
in the trial. 
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• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (at a minimum 3 telephone 
calls/contacts). These contact attempts should be documented in the participant’s study 
record. 
• Should the participant and/or LAR continue to be unreachable, he/she will be considered 
to have withdrawn from the trial. Every effort will be made to collect functional 
assessment and/or mortality data or any other data from the LAR if the participant is 
unreachable. 
• Site personnel will attempt to collect the vital status of the participant within legal and 
ethical boundaries for all participants randomized, including those who did not get study 
intervention. Public sources may be searched for vital status information.  If vital status is 
determined as deceased, this will be documented, and the participant will not be 
considered lost to follow-up. Sponsor personnel will not be involved in any attempts to 
collect vital status information. 
 
 
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8 
STUDY ASSESSMENTS and PROCEDURES 
Study procedures and their timing are summarized in Table 1-1: Schedule of Activities. 
Adherence to the trial design requirements is essential and required for study conduct. 
 
Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilized for baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame defined 
in Table 1-1: Schedule of Activities. 
 
8.1 
Safety and Efficacy Assessments 
Planned time points for all safety and efficacy assessments are provided in Table 1-1: Schedule of 
Activities. Further definition/description of those assessments are provided here:  
 
8.1.1 Vital Signs 
Blood pressure and heart rate will be taken at baseline (pre-dose) and per routine (every 8-12 
hours) until completion of the infusion at 48h.  Results taken from standard of care 
assessment/timepoints may be used. Temperature will be taken at baseline (if available per 
standard of care).  Clinically significant findings post-dose will be reported as AEs. 
 
8.1.2 Clinical Safety Laboratory Assessments 
Blood work will be done at baseline (within 4 hours of admission) and at Day 2 (48h +/- 4 hours), 
and include: complete blood count (hemoglobin, platelets and hematocrit), full metabolic profile 
including magnesium and other electrolytes (sodium, potassium, chloride, bicarbonate and  
magnesium), serum creatinine and serum glucose, coagulation panel: prothrombin time test (PTT) 
and international normalized ratio (INR), BUN, LFT panel: alanine transaminase (ALT), aspartate 
aminotransferase (AST) and bilirubin. All blood assessments will be done by the local laboratory.  
Results from local standard of care procedures and testing may be used. A central lab will not be 
used.  Due to the short time-period from arrival at the hospital to the EVT, the results of the 
baseline blood work and the results from the initial ECG and CXR are not required prior to 
randomization or start of infusion.  Baseline results from the primary hospital (within 8 hours) are 
accepted, if written documentation is available.  Clinically significant laboratory findings that 
follow the initiation of the infusion (post dose) will be reported as AEs. 
 
A baseline ECG and CXR will be obtained within 4 hours of admission and will represent the 
baseline measure of cardiopulmonary function. A repeat ECG and CXR will be obtained at 24h 
(+/- 4 hours), 48h (+/- 4 hours) and any new abnormality will be reported as an AE.  
 
For elevated QTcF values, the patient is not to be automatically withdrawn from the study and the 
infusion will not be automatically stopped. Determination of continuation in the study will be at 
the clinical judgment of the investigator and/or the medical monitor as detailed in the instructions 
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on repeating ECGs below. Cardiologist consultation should be used to correct and/or overread an 
ECG with elevated QTcF values. 
 
For Day 1 or Day 2 ECG: 
If a subject has a QTcF > 500 ms with at least an increase from baseline > 40 ms, or an isolated 
increase from baseline > 70 ms, then the ECG must be repeated in approximately one hour and the 
ECGs must be over-read by a cardiologist. If a QTcF > 500 ms or an increase > 70 ms is 
confirmed and not due to a new bundle branch block (QRS > 110 ms), then the medical monitor 
must be contacted, and the following steps must be completed: 
 
1) Study drug dosing must be stopped while serum electrolytes are evaluated, and it is 
determined if new medications that prolong the QTc interval were inadvertently 
initiated.  
2) If no significant hypokalemia or hypomagnesemia are identified and no new 
medications that prolong the QTc interval were initiated, study drug must be 
discontinued, not to be restarted. 
3) If significant hypokalemia or hypomagnesemia are identified, these must be corrected 
and if a new QT-prolonging medication was initiated, then the study drug must be 
stopped. 
• Study drug can be restarted after the QTcF is < 480 ms and the increase from 
baseline < 60 ms. ECGs must be repeated at approximately 2 hours and 6 
hours post resumption of the dose and on the succeeding days of dosing.  
4) If a repeat on-drug ECG’s absolute QTcF > 500 ms or an increase from baseline > 70 
ms is confirmed, study drug must be discontinued, not to be restarted. 
 
If the initial increased QTcF occurs in the setting of a new bundle branch block, calculate the 
“adjusted QTcF” (See Appendix 7: Adjusted QTcF Calculation) and contact the Medical Monitor 
to discuss the management plan. If the Adjusted QTcF is < 500 ms and the increase from baseline 
is < 70 ms, drug infusion need not be stopped while contacting the Medical Monitor. Note: The 
adjusted QTcF calculation should be done by someone qualified and experienced in making this 
calculation. 
  
8.1.3 Pregnancy Testing 
If the participant is female and is of childbearing potential, a pregnancy test (urine or serum point-
of-care pregnancy test) must be collected at baseline.  
 
8.1.4 Blood Collection for RNA Analysis 
Subjects will be asked to consent for the optional collection of blood samples for RNA biomarker 
analysis at Day 1, Day 2 and Day 90. Obtaining consent for this blood collection may occur at any 
time after randomization and is not required at the same time as the main consent for study 
participation. Subjects have the option of declining participation in this blood collection at any 
time by withdrawing their consent to have their sample used. However, it will not be possible to 
destroy samples that may have already been collected and analyzed. These samples will be used 
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for biomarker research and labeled with a deidentified subject number. Samples will be stored for 
research until they are used, damaged, decayed or otherwise unfit for analysis. All samples will be 
sent to a Revalesio-contracted lab for analysis. Sample processing and handling instructions for 
sites are provided separately. 
 
8.1.5 Blood Collection for Plasma Biomarker 
Additional blood collection (10mL EDTA tube) for plasma biomarker will occur at Day 1, Day 2 
and Day 90. All sample processing and handling instructions for sites are provided separately. 
Sites capable of collecting, processing and shipping of the biomarker samples will be confirmed 
by the Sponsor. 
  
8.1.6 The Modified Rankin Scale 
The main efficacy endpoint used in this trial will be global disability, as measured by the mRS, at 
Day 90. The mRS is a valid and reliable clinician-reported measure of global disability that has 
been widely applied for evaluating recovery from stroke. It is a scale used to measure functional 
recovery (the degree of disability or dependence in daily activities) of people who have suffered a 
stroke22, 23. The mRS scores range from 0 to 6, with 0 indicating no residual symptoms; 5 
indicating bedbound, requiring constant care; and 6 indicating death.  
 
The baseline mRS score will be used for study eligibility. The post dose mRS score will be 
obtained at Day 6 (or discharge), Day 30 and Day 90.  The mRS will only be scored by those 
trained and certified in the use of this scale.   
 
8.1.7 Mortality Rate 
Mortality status will be obtained at all visits during the 90-day study period  
 
8.1.8 The National Institutes of Health Stroke Scale 
The NIHSS is a standardized neurological examination scale that is a valid and reliable measure 
of disability and recovery after acute stroke24.  Scores range from 0 to 42, with higher scores 
indicating increasing severity. The scale includes measures of level of consciousness, extra ocular 
movements, motor and sensory tests, coordination, language and speech evaluations.  The NIHSS 
will be administered at baseline, post-EVT (2h), 24h, 48h, Day 6 (or discharge), Day 30 and Day 
90. The NIHSS will only be scored by those trained in the use of this scale.  
 
8.1.9 Worsening of Stroke  
Worsening of stroke is defined as progression, or hemorrhagic transformation, of the index stroke 
as documented by medical imaging that is (a) life-threatening requiring intervention and/or (b) 
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results in increased disability as gauged by a ≥4-point increase from lowest NIHSS score during 
hospitalization and/or (c) results in death.  
 
8.1.10 Volume of Strokes 
Prior to database lock at the end of the study, the total volume of infarct growth as measured by 
MRI brain images in RNS60 versus placebo control participants will be calculated from the Day 2 
(48h) imaging and compared to the immediate post-thrombectomy scan.  
 
In addition, the volume of injured tissue on FLAIR and T2 weighted images will be compared 
between the 90-day and post-thrombectomy time points for the RNS60 groups and placebo group, 
respectively. 
 
The plan for MRI data will be detailed in the Imaging Charter.   
 
8.1.11 Barthel Index 
The BI is an index of functional independence25 that is a valid measure of activities of daily living 
when employed in stroke trials26.  Modified BI scores range from 0 to 100, with higher scores 
indicating greater independence in activities of daily living and mobility. The BI will be scored at 
baseline (pre-morbid), Day 30 and Day 90, by those trained in the use of this scale.  Note that the 
original BI was a scale from 0-20.  The modified BI simply multiplies the original scale by 5 to 
provide a 100-point score.  
 
8.1.12 EQ-5D-5L 
The EQ-5D-5L is a generic instrument for describing and valuing health. It is based on a 
descriptive system that defines health in terms of five dimensions: Mobility, Self-Care, Usual 
Activities, Pain/Discomfort, and Anxiety/Depression27. Each dimension has five response 
categories corresponding to: no problems, slight, moderate, severe and extreme problems28. The 
version of the instrument selected for the trial is interviewer administered either in-person, or by 
telemedicine or by telephone. The respondents will also rate their overall health on the day of the 
interview on a 0–100 visual analogue scale (EQ-VAS). The EQ-5D-5L will be administered at 
Day 90. 
 
8.2 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting 
The definitions of an AE or SAE can be found in Appendix 4: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting. 
 
AEs will be reported by the participant (or, when appropriate, by a healthcare provider, caregiver, 
surrogate, or the participant’s legally authorized representative).  The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that meet the 
definition of an AE or SAE and remain responsible for following up AEs that are serious, 
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considered related to the study intervention or study procedures, or that caused the participant to 
discontinue the trial. 
 
The method of recording, evaluating, and assessing causality of AEs and SAEs, and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4: Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
 
8.2.1 Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from the start of study drug administration until Day 90, in addition 
SAE assessed as related to study drug or that have a fatal outcome will be collected to Day 90, see 
Table 1-1: Schedule of Activities. 
 
All AEs will be collected from the start of study drug administration through Day 90 at the time 
points specified in Table 1-1: Schedule of Activities. 
 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded in the Past Medical and Surgical History section of the electronic case 
report form (CRF), not in the AE section. 
 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of knowledge 
of the event, as indicated in Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting. The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available. 
 
8.2.2 Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  A consistent methodology of eliciting AEs at all participant evaluation 
timepoints will be used.  Non-directive questions include: 
• How have you felt since your last clinical visit/hospital discharge? 
• Have you had any new or changed health problems since you were last here? 
• Have you had any unusual or unexpected worsening of your underlying medical condition 
or overall health? 
• Have there been any changes in the medicines you take since your last clinical visit/hospital 
discharge? 
AE identification while the participant is admitted to the acute stroke hospital will be collected via 
acute stroke hospital patient records and verbal histories from the participant or LAR.  For follow 
up visits after discharge from the acute stroke hospital the participant (or LAR if the participant is 
not able to respond to the questions) will be asked about the occurrence of AEs since the last 
contact, and if available, from records at the acute stroke hospital. 
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Diagnosis versus signs and symptoms for the purpose of AE reporting: if known at the time of 
reporting, a diagnosis should be reported rather than individual signs and symptoms (e.g., record 
only pneumonia rather than pyrexia, coughing, shortness of breath).  However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis it is acceptable 
to report the information that is ultimately available. 
 
8.2.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 4: Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting. 
 
AEs that were ongoing at the last contact will be updated with a stop date or confirmed as 
ongoing.  AE collection will continue until Day 90, and SAE to Day 90 or the final contact. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor. 
 
8.2.4 Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety evaluation 
of the study drug under clinical investigation are met. 
 
The sponsor has a legal responsibility to notify the FDA about the safety of a study intervention 
under clinical investigation. The sponsor will comply with regulatory requirements relating to 
safety reporting to the regulatory authority, IRBs, and investigators. 
• 
Initial reporting: IND application sponsor must report any suspected adverse reaction or 
adverse reaction to study treatment that is both serious and unexpected. 
Suspected unexpected serious adverse reactions (SUSARs) and observations from animal 
studies suggesting significant risk to human subjects must be reported to FDA as soon as 
possible but no later than within 15 calendar days following the sponsor’s initial receipt 
of the information. 
Unexpected fatal or life-threatening suspected adverse reactions represent especially 
important safety information and must be reported to FDA as soon as possible but no later 
than 7 calendar days following the sponsor’s initial receipt of the information. 
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• 
Follow-up reporting: Any relevant additional information obtained by the sponsor that 
pertains to a previously submitted IND safety report must be submitted as a Follow-up 
IND Safety Report. Such report should be submitted without delay, as soon as the 
information is available but no later than 15 calendar days after the sponsor receives the 
information 
 
 
Investigator safety reports must be prepared by the sponsor for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary. 
The Sponsor will notify the Investigators in writing of the occurrence of any reportable SAEs.  The 
Investigators will be responsible for informing their local IRBs of any reportable SAEs as per their 
local requirements. 
 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB, if appropriate according to local 
requirements. 
 
8.2.5 Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until Day 90. 
 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Section 10.4 (Appendix 5: 
Collection of Pregnancy Information). Should the participant be pregnant, the infusion will be 
stopped immediately but the participant will still be monitored for safety up to 90 days.  
 
Pregnancy itself is not considered an AE, but any complications during pregnancy are to be 
considered as AEs, and in some cases, could be considered SAEs. Spontaneous abortions, fetal 
death, stillbirth, and congenital anomalies reported in the baby are always considered as SAEs, 
and the information should be provided to the sponsor regardless of when the SAE occurs (e.g., 
even after the end of the trial). 
9 
STATISTICS 
9.1 
Sample Size Determination 
As the primary aim of this study is to demonstrate safety, there was no power analysis conducted. 
Attrition factors include death from stroke but not treatment (10%), fluid overload (20%) and 
early discharge (5%). 
 
9.2 
Analysis Sets 
For purposes of analysis, the following populations are defined: 
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Population 
Description 
Intent to Treat (ITT) 
All participants randomized into the trial with grouping by randomized 
treatment, regardless of whether any treatment was actually received.  
Participant grouped according to the randomized (intended) treatment. 
(Participant who receive treatment but do not get the full 48 hours of 
treatment due to fluid overload, early discharge, or death will be included 
in the ITT analysis.) 
Per Protocol  
All participants randomized and treated, with no major protocol 
deviations including: did not meet inclusion/exclusion criteria, did not 
receive planned dose volume, incorrect study drug, consent not obtained 
(Participant who completes the full 48 hours will be included in both per 
protocol and ITT analysis.) 
Full Analysis Set / Safety 
All participants randomly assigned to study intervention and who receive 
any volume of study drug.  Participants will be analyzed according to the 
intervention they actually received. 
 
The primary efficacy analysis will be conducted in the ITT population.  The primary analysis will 
be repeated on the per protocol population.  An ITT analysis will also be conducted for the 
secondary endpoints, with participant grouped according to the randomized (intended) treatment.   
 
9.3 
Statistical Analysis 
9.3.1 General Considerations 
Mortality will be estimated using Kaplan-Meier estimation censoring on last known follow up.  
For participants missing observations, mRS, NIHSS and BI will have the last recorded value 
carried forward, when possible. Categorical data will be summarized using counts and 
percentages. Continuous data will be summarized using median and interquartile range.  
9.3.2 Analyses of Safety  
All safety analyses will be performed on the Safety Population.  The main analyses will be 
frequency of SAEs and 90-day mortality.   
Endpoint 
Analysis Methods 
SAEs 
The frequency of SAEs will be summarized using the Medical Dictionary 
for Regulatory Activities (MedDRA) Version 24.0.  
SAEs leading to 
death 
The frequency of fatal SAEs will be summarized using the MedDRA 
Version 24.0. 
AEs 
The frequency of AEs will be summarized using the MedDRA Version 24.0. 
Vital Signs 
Absolute values and changes for vital signs from pre-dose to Day 2 will be 
documented. The maximum deviation of BP from baseline between drug 
and placebo control groups (systolic and diastolic) to Day 2 will be 
analyzed. 
Laboratory 
Safety  
Absolute values for laboratory results will be summarized descriptively.    
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Prior and 
Concomitant 
Medications 
Prior and concomitant medications will be summarized using the WHO 
Drug Dictionary. 
 
9.3.3 Analyses of Safety and Efficacy 
All efficacy results will be examined using both ITT and per protocol populations. Although the 
trial’s main purpose is to demonstrate safety, several measures of efficacy will be examined in 
order to provide effect size estimates for a appropriately powered future trial demonstrating 
efficacy. As such, both pairwise comparisons at various timepoints and longitudinal data will be 
examined.  
1) Primary efficacy outcome 
2) Secondary efficacy outcomes, as specified in the order presented below 
Outcome 
Statistical Analysis Methods 
Primary 
All analyses will be accomplished using SAS Software 9.4 (SAS Inc. Cary, 
NC). Primary: The frequency of SAEs, SAEs resulting in death, AEs, and 
discontinuations due to AEs will be summarized as counts and percentages 
between conditions. Comparisons will be conducted using Fisher’s Exact tests.  
Secondary 
Secondary: Comparisons between conditions for mRS will be evaluated using 
generalized mixed modeling assuming a binomial distribution (0-6) with 
sandwich estimation nested by site and participant, when applicable. Pairwise 
comparisons of mRS will be conducted at day 90 using a Dunnett correction. 
In addition, simple and interaction effects between pre-stroke, discharge, 30 
and 90-day mRS by condition will be examined. Because superiority over 
placebo and lower dose is hypothesized, testing will reflect this superiority 
framework with one-tailed tests.  
 
Both NIHSS score and BI at Day 90 will be examined in a similar fashion 
assuming a binomial distribution (0-42 & 0-100) with sandwich estimation 
nested by site and participant (when applicable). Pairwise comparisons 
between conditions will be conducted at day 90 using a Dunnett correction. In 
addition, simple and interaction effects between pre-treatment, discharge, 30 
and 90-day NIHSS scores and BI by condition will be examined. Because 
superiority over placebo and lower dose is hypothesized, testing will reflect 
this superiority framework with one-tailed tests.  
 
Mortality will be examined using Kaplan-Meier estimation with pairwise 
comparisons with a Dunnett correction with censoring on last known follow 
up. Because superiority over placebo and lower dose is hypothesized, testing 
will reflect this superiority framework with one-tailed tests. Marginal Cox 
Hazard regression will also be used to evaluate mortality with sandwich 
estimation and nesting within site. 
 
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DWI volume and T2 will be modeled between conditions using generalized 
linear modeling assuming a normal or lognormal distribution (where 
appropriate) with sandwich estimation, where observations are nested by site 
and participant (when appropriate). Pairwise comparisons at post EVT, 48 
hours (or early discharge), and 90 days. Simple and interaction effects will be 
examined across these three timepoints. Because superiority over placebo and 
lower dose is hypothesized, testing will reflect this superiority framework with 
one-tailed tests.  
 
Because the main aim of this is trial is to examine safety, efficacy analysis 
results are intended to yield estimates to inform powering for subsequent 
efficacy trial. Alpha is established at the 0.05 level and all interval estimates 
will be calculated for 95% confidence. 
Worsening of Stroke is determined as the number of participants experiencing 
at least one worsening of stroke divided by the number of participants observed 
over the 90-day period in that treatment group, between RNS60 and placebo 
control participants. This will be modeled using generalized linear modeling 
assuming a binary distribution with sandwich estimation, where observations 
are nested by site. Because superiority over placebo and lower dose is 
hypothesized, testing will reflect this superiority framework with one-tailed 
tests. 
 
10 SUPPORTING DOCUMENTATION and OPERATIONAL CONSIDERATIONS 
10.1 Appendix 2: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations including: United States Code of Federal Regulations 
(CFR; including Title 21 Parts 50, 54, 56, and 312), where applicable. 
• Applicable guidelines issued due to the COVID-19 pandemic 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB by the investigator and reviewed and approved 
by the IRB before the study is initiated. 
 
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Any amendments to the protocol will require IRB approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
participants. 
 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB 
• Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB, and all other applicable local regulations 
 
10.1.2 Financial Disclosure 
As requested to allow the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities, investigators and sub-investigators 
may provide the sponsor with sufficient, accurate financial information. This includes information 
on financial interests during the course of the study and potentially for 1-year after completion of 
the study.  Routine care is expected to be paid for by the existing standard medical insurance 
system.  This will include but is not limited to: 
• Admission to hospital 
• Baseline laboratory testing, pregnancy test, baseline NCCT and CTA, baseline CTP 
• Endovascular procedure and angiography 
• Follow-up limited-sequence MR brain imaging at 48h 
• Follow-up laboratory testing  
• Physician fees 
• Treatment processes in the endovascular lab since they are considered standard of care 
• Stroke unit care in hospital 
• Nursing care 
• Rehabilitation and home care if relevant 
• Outpatient clinic follow-up at 90 days (routine) 
 
The study fees are designed to cover the costs of study personnel, data collection, research study 
processes and treatments, the 30-day follow up visit, the 90-day follow-up visit, CRF completion, 
adverse event reporting, concomitant medication reporting, submission of imaging to the core lab 
and support of remote monitoring, if applicable.  The study fees are inclusive of any local 
institutional overhead/indirect costs. 
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10.1.3 Informed Consent Process 
See Section 5.5.2 for further details. 
 
10.1.4 Data Protection 
Participants will be assigned a unique identifier by the CRO. Any participant records or datasets 
that are transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
 
Personal medical information may be reviewed for the purpose of verifying data recorded in the 
eCRF by the site monitors.  Other properly authorized persons, such as the regulatory authorities, 
may also have access to these records.  Personal medical information is always treated as 
confidential.  The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
 
All imaging, evaluation forms, reports, and other records that leave the site are identified only by 
the site and participant number to maintain participant confidentiality.  All records are kept in a 
locked file cabinet. Clinical information is not released without written permission of the 
participant, except as necessary for monitoring by the IRB, FDA, the sponsor, or the sponsor’s 
designee. 
 
All study investigators at the clinical sites, monitors and sponsor staff must ensure that the 
confidentiality of personal identity and all personal medical information of study participants are 
maintained at all times.  Federal legislation in the U.S. (HIPAA) and local legislations must be 
followed. 
 
10.1.5 Oversight Committees 
Safety reviews may be performed routinely by the local study site PIs and/or sponsor’s staff in the 
course of the trial. Any questions pertaining to the reported clinical data will be submitted to the 
investigator for resolution.  Each step of this process will be monitored through the 
implementation of individual passwords to maintain appropriate database access and to ensure 
database integrity. 
 
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10.1.6 Data Safety Monitoring Board 
An independent committee (composed of three individuals) will be assembled to follow the study 
charter as proposed above.  
 
10.1.7 Dissemination of Clinical Study Data 
Study information and tabular study results will be posted on the US National Institutes of 
Health’s website www.clinicaltrials.gov within one year of study completion. 
 
10.1.8 Data Quality Assurance 
All participant data relating to the study will be recorded on the electronic CRF unless transmitted 
to the sponsor or designee electronically (e.g., imaging). The investigator is responsible for 
verifying that data entries are accurate and correct signing the CRF.  The investigator must 
maintain accurate documentation (source data) that supports the information entered in the CRF. 
 
The investigator must permit study-related monitoring, audits, IRB review, and regulatory agency 
inspections and provide direct access to source data documents.  The investigator agrees to allow 
the monitor(s) direct access to all relevant documents, and to allocate his/her time and the time of 
staff to discuss findings, corrective actions and any relevant issues. In addition to contacts during 
the study, the monitor may also contact the site prior to the start of the study to discuss the 
protocol and data collection procedures with site personnel. 
 
Except for an emergency situation in which proper care for the protection, safety and well-being 
of the study participants requires medical treatment, the study will be conducted as described in 
the approved protocol, ICH GCP, SOPs and regulatory requirements.  All medical treatments will 
be recorded.  Any deviation(s) from the protocol will be recorded and presented in the final 
clinical study report. 
 
The sponsor will determine the extent, nature, and frequency of on-site visits that are needed to 
ensure that the study is being conducted in accordance with the approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements.  Monitoring details describing 
strategy (e.g., risk-based initiatives in operations and quality such as Risk Management and 
Mitigation Strategies and Analytical Risk-Based Monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the Monitoring Plan. 
 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  The sponsor assumes accountability for actions delegated to other 
individuals (e.g., Contract Research Organizations). 
 
Study monitors will perform ongoing source data verification to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being conducted 
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in accordance with the currently approved protocol and any other study agreements, ICH GCP, 
and all applicable regulatory requirements.  This review may occur at the study site or remotely.  
Any records supplied by the site for the purpose of remote monitoring and remote source 
document verification must comply with local legislation and the process approved by the local 
IRB, when required. 
 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for at least 5 years after the completion of the clinical trial, at least 2 
years after the last approved marketing application and until there are no pending or contemplated 
marketing applications, or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study drug (whichever of the above requirements is the longest) unless local 
regulations or institutional policies require a longer retention period. No records may be destroyed 
during the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
 
10.1.9 Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.  Source 
documents specification per site will be agreed prior to first participant enrolled at the site. 
Data reported in the eCRFs must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. Any records 
supplied by the site for the purpose of remote monitoring and remote source document 
verification must be de-identified using only the unique trial specific participant identifier.  This 
process will be aligned with local ethics and privacy requirements.  
 
Any investigators shall supply the sponsor, upon request, with any required background data from 
the study documentation or clinic records. This is particularly important when errors in data 
transcription are suspected.  In case of special problems and/or governmental queries or requests 
for audit inspections, it is also necessary to have access to the complete study records, provided 
that participant confidentiality is protected. 
 
Definition of what constitutes source data may include: participant hospital/clinic records, 
physician's and nurse's notes, appointment book, original laboratory reports, ECG, X-ray, 
pathology and special assessment reports, signed consent forms, consultant letters, and source 
worksheets.  
 
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 two different separate categories: (1) Investigator's Study File; and (2) Participant 
Clinical Source Documents. 
 
The Investigator's Study File will contain the Protocol/Amendments, CRFs, IRB and 
governmental approval with correspondence, all versions of IRB approved informed consent 
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forms, staff curriculum vitae and authorization forms and other appropriate documents / 
correspondence, etc. 
The investigator must keep these two categories of documents on file according to local clinical 
trial regulation.  All study documents for a regulated trial require storage for at least 5 years after 
the completion of the clinical trial, at least 2 years after the last approved marketing application and 
until there are no pending or contemplated marketing applications, or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the IMP (whichever of the above 
requirements is the longest). After that period of time the documents may be destroyed, participant 
to local regulations.  
 
The investigator and the sponsor will maintain the records of disposition of the drug and the clinic 
records in accordance with ICH GCP and each applicable regulatory agency.  Clinic records will 
be retained at the site until informed by the sponsor to destroy the documents.  If the clinical study 
must be terminated for any reason, the investigator will return all study materials to the sponsor 
and provide a written statement as to why the termination has taken place and notify the IRB. 
 
10.1.10 Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of patients.  
 
The first act of recruitment is the first site open and will be the study start date. 
 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion at 90 days. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
 
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
 
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
 
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10.1.11 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
 
The sponsor will permit any and all academic publications arising from the trial data provided that 
no publication containing unblinded trial data precedes publication of the overall trial results in a 
peer-review journal, they are approved by the trial executive committee, and the publication 
authors notify the sponsor at least 30 days prior to submittal for publication with a copy of such 
proposed publication for the sponsor’s review and comment. Employees or consultants of the 
sponsor will only be named as authors in any such publication if the parties agree that it is 
appropriate under the usual conventions used by academic institutions for naming authors in 
scientific publications.  Upon request of the sponsor the publication or disclosure shall be delayed 
for up to 60 days in order to allow for the filing of a patent application. 
 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a coordinating 
investigator will be designated by mutual agreement. 
 
A trial executive committee shall be formed and include at least the trial principal investigator and 
co-principal investigator, the statistical consultant, and representatives of the sponsor.  The trial 
executive committee will be co-authors on all publications and presentations.  The primary author 
list for the primary publication will consist of the executive committee and the site principal / 
qualified investigator at each of the sites.  A formal publication policy will be presented and 
developed by the trial executive. 
 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
 
10.1.12  Audits and Inspections 
In accordance with the principles of ICH E6 Guideline for Good Clinical Practice, the study site 
may be inspected by regulatory authorities and/or audited by the sponsor or its designates. The 
investigator and relevant clinical support staff will be required to be actively involved in audits 
and inspections, including staff interviews, and to make all necessary documentation and data 
available upon request. 
 
During the course of the study and/or after it has been completed, one or more investigator site 
audits may be undertaken by auditors from the sponsor or its delegates. The purpose of these 
audits is to determine whether or not the study is being/has been conducted and monitored in 
compliance with recognized ICH E6 Guideline for Good Clinical Practice, protocol and approved 
amendment requirements, applicable local SOPs, and local laws and regulations. It is the 
responsibility of the investigator and site staff to promptly address, by coordinating with the 
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sponsor, any deficiencies stemming out of regulatory inspections and sponsor or delegate audits, 
and to ensure that agreed-upon corrective and preventive actions are implemented as soon as 
possible. 
 
An inspection by any regulatory authority may occur at any time during or after completion of the 
study. If an investigator is contacted by a regulatory authority for the purpose of conducting an 
inspection or to discuss any compliance issues, he/she is required to contact the sponsor 
immediately. 
 
 
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affected hemisphere will be compared between groups by comparing volume loss/gliosis between 
the 90-d and post-thrombectomy MRI.  
 
 
For all interval times assessed from imaging, the time zero will be the first slice of the NCCT scan.  
Imaging date and time will be collected in the CRF. 
 
Notes:  
The use of a dynamic CTA or multiphase CTA data acquisition protocol is preferred.  
Baseline NCCT and CTA may be completed at a hospital affiliated with the trial site. 
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10.4 Appendix 5: Collection of Pregnancy Information 
Male participants with partners who become pregnant: 
 
The investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive study drug. After obtaining the necessary signed informed consent 
from the pregnant female partner directly, the investigator will record pregnancy information on 
the Pregnancy Reporting Form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 4 weeks following the estimated delivery date. 
Any termination of the pregnancy will be reported regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure.  
 
Female Participants who become pregnant: 
 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study.  The initial information will be recorded on the 
Pregnancy Reporting Form and submitted to the sponsor within 24 hours of learning of a 
participant’s pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the participant and the neonate, 
and the information will be forwarded to the sponsor. Generally, follow-up will not be required 
for longer than 4 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at >22 
weeks gestational age) is always considered to be an SAE and will be reported as such. 
 
Any post-study pregnancy related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the sponsor as described in Section 8.2.4. While the 
investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention but will continue to be followed to the end of the trial. 
 
 
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10.5 Appendix 6: Abbreviations 
AHA 
American Heart Association  
AIS 
Acute Ischemic Stroke 
AE 
Adverse Event 
ASPECTS 
Alberta Stroke Program Early Computerized Tomography Score 
β-hCG 
Beta-human Chorionic Gonadotropin 
BI 
Barthel Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CT 
Computed Tomography 
CTA 
Computed Tomographic Angiography 
CTP 
Computed Tomographic Perfusion 
CXR 
Chest X-ray 
DWI 
Diffusion Weighted Imaging 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
eCRF 
Electronic Case Report Form 
EQ-5D-5L 
EuroQol health-related quality of life 
EVT 
Endovascular Thrombectomy  
FDA 
Food and Drug Administration 
FLAIR 
Fluid Attenuated Inversion Recovery 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
ICA 
Internal Carotid Artery  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
LAR 
Legally Authorized Representative  
LFT 
Liver Function Tests 
LVO 
Large Vessel Occlusion 
MAP 
Mean Arterial Pressure 
MCA 
Middle Cerebral Artery  
mCTA 
Multiphase Computed Tomography Angiography  
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MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Magnetic Resonance 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
n 
Number of Observations 
NaCl 
Sodium Chloride 
NCCT 
Non-contrast Computed Tomography Scan 
NIHSS 
National Institutes of Health Stroke Scale 
pH 
Potential Hydrogen 
PI 
Principal Investigator 
PP 
Per Protocol 
QA 
Quality Assurance 
RR 
Risk Ratio 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TICI 
Thrombolysis in Cerebral Infarction Score 
USA/US 
United States of America 
VAS 
Visual Analogue Scale 
 
 
 
 
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10.6 Appendix 7: Adjusted QTcF Calculation 
 
QTcF Measurement Adjustment in Patients with a Widened QRS Complex > 110 ms 
 
The duration of the ECG QT interval reflects the combination of cardiac depolarization which is 
measured as duration of the QRS interval and cardiac repolarization, which is defined by the JT 
interval. 
 
 
Normal values for the rate-corrected QTc interval are defined largely from populations of subjects 
with normal QRS durations, without bundle branch blocks or intra-ventricular conduction delays. 
In the setting of a widened QRS complex (> 110 ms), however, using the QTcF interval 
measurement may lead to overestimating cardiac repolarization, since the QTcF would be 
prolonged due to the contribution from the widened QRS complex. In other words, the QTcF 
interval could be prolonged despite cardiac repolarization being normal (i.e., a normal JTc 
interval).  For example, if the QRS duration was 150 ms and the QTcF was 500 ms, cardiac 
repolarization is not meaningfully prolonged when it is considered that a normal QRS duration is 
conservatively 90 ms.  So, in this case 60 ms (150 ms – 90 ms) of the QTcF of 500 ms is due to 
excessive QRS prolongation and thus the QTcF “adjusted” for the QRS widening is 440 ms (500 
ms – [ 150 ms – 90 ms]).  
 
Thus, in subjects with a QRS duration > 110 ms, a QTcF adjusted for the widened QRS duration 
can be used to assess if a patient meets criteria for protocol exclusion, drug hold, or 
discontinuation using the below formula: 
 
Adjusted QTcF = measured QTcF – [measured QRS – 90 ms] 
 
Another example: 
 
 
 
QTcF= 505 ms 
 
 
Adjusted QTcF = 505 ms – [157 ms – 90 ms] = 438 ms 
QRS= 157 ms 
 
**Note: Adjusted QTcF calculation should be done by someone qualified and experienced in making this calculation. 
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11 REFERENCES 
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DALYs GBD and Collaborators H. Global, regional, and national disability-adjusted life-
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Fisher M. The ischemic penumbra: identification, evolution and treatment concepts. 
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Tymianski M. Novel approaches to neuroprotection trials in acute ischemic stroke. Stroke. 
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McTaggart RA, Holodinsky JK, Ospel JM, Cheung AK, Manning NW, Wenderoth JD, Phan 
TG, Beare R, Lane K, Haas RA, Kamal N, Goyal M and Jayaraman MV. Leaving No Large 
Vessel Occlusion Stroke Behind: Reorganizing Stroke Systems of Care to Improve Timely 
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Saver JL. Time is brain--quantified. Stroke. 2006;37:263-6. 
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Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Davalos A, 
Majoie CB, van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe A, Jahan R, 
Diener HC, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millan M, 
Davis SM, Roy D, Thornton J, Roman LS, Ribo M, Beumer D, Stouch B, Brown S, 
Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG and collaborators H. 
Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of 
individual patient data from five randomised trials. Lancet. 2016;387:1723-31. 
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del Zoppo GJ. Lessons from stroke trials using anti-inflammatory approaches that have 
failed. ErnstScheringResFoundWorkshop. 2004:155-184. 
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Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, 
Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF, Kamal NR, Montanera WJ, Poppe AY, 
Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns 
PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, 
Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, 
Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD and 
Investigators ET. Randomized assessment of rapid endovascular treatment of ischemic 
stroke. N Engl J Med. 2015;372:1019-30. 
10. Hill MD, Goyal M, Menon BK, Nogueira RG, McTaggart RA, Demchuk AM, Poppe AY, 
Buck BH, Field TS, Dowlatshahi D, van Adel BA, Swartz RH, Shah RA, Sauvageau E, 
Zerna C, Ospel JM, Joshi M, Almekhlafi MA, Ryckborst KJ, Lowerison MW, Heard K, 
Garman D, Haussen D, Cutting SM, Coutts SB, Roy D, Rempel JL, Rohr AC, Iancu D, 
Sahlas DJ, Yu AYX, Devlin TG, Hanel RA, Puetz V, Silver FL, Campbell BCV, Chapot R, 
Teitelbaum J, Mandzia JL, Kleinig TJ, Turkel-Parrella D, Heck D, Kelly ME, Bharatha A, 
Bang OY, Jadhav A, Gupta R, Frei DF, Tarpley JW, McDougall CG, Holmin S, Rha JH, 
Puri AS, Camden MC, Thomalla G, Choe H, Phillips SJ, Schindler JL, Thornton J, Nagel S, 
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Heo JH, Sohn SI, Psychogios MN, Budzik RF, Starkman S, Martin CO, Burns PA, Murphy 
S, Lopez GA, English J, Tymianski M and Investigators E-N. Efficacy and safety of 
nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, 
double-blind, randomised controlled trial. Lancet. 2020. 
11. Laing KK, Simoes S, Baena-Caldas GP, Lao PJ, Kothiya M, Igwe KC, Chesebro AG, 
Houck AL, Pedraza L, Hernandez AI, Li J, Zimmerman ME, Luchsinger JA, Barone FC, 
Moreno H, Brickman AM and Alzheimer's Disease Neuroimaging I. Cerebrovascular 
disease promotes tau pathology in Alzheimer's disease. Brain Commun. 2020;2:fcaa132. 
12. Nair AB and Jacob S. A simple practice guide for dose conversion between animals and 
human. J Basic Clin Pharm. 2016;7:27-31. 
13. Cook DJ, Teves L and Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the 
gyrencephalic primate brain. Nature. 2012;483:213-7. 
14. Paganoni S, Alshikho MJ, Luppino S, Chan J, Pothier L, Schoenfeld D, Andres PL, Babu S, 
Zurcher NR, Loggia ML, Barry RL, Luotti S, Nardo G, Trolese MC, Pantalone S, Bendotti 
C, Bonetto V, De Marchi F, Rosen B, Hooker J, Cudkowicz M and Atassi N. A pilot trial of 
RNS60 in amyotrophic lateral sclerosis. Muscle Nerve. 2019;59:303-308. 
15. Zhao W and Weng Y. Block urn design - a new randomization algorithm for sequential trials 
with two or more treatments and balanced or unbalanced allocation. Contemp Clin Trials. 
2011;32:953-61. 
16. Johnston SC, Easton JD, Farrant M, Barsan W, Battenhouse H, Conwit R, Dillon C, Elm J, 
Lindblad A, Morgenstern L, Poisson SN and Palesch Y. Platelet-oriented inhibition in new 
TIA and minor ischemic stroke (POINT) trial: rationale and design. Int J Stroke. 
2013;8:479-83. 
17. Khatri P, Kleindorfer DO, Devlin T, Sawyer RN, Jr., Starr M, Mejilla J, Broderick J, 
Chatterjee A, Jauch EC, Levine SR, Romano JG, Saver JL, Vagal A, Purdon B, Devenport J, 
Pavlov A, Yeatts SD and Investigators P. Effect of Alteplase vs Aspirin on Functional 
Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic 
Deficits: The PRISMS Randomized Clinical Trial. JAMA. 2018;320:156-166. 
18. Zhao W and Durkalski V. Managing competing demands in the implementation of response-
adaptive randomization in a large multicenter phase III acute stroke trial. Stat Med. 
2014;33:4043-52. 
19. Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, Johnston KC, Johnston 
SC, Khalessi AA, Kidwell CS, Meschia JF, Ovbiagele B, Yavagal DR and American Heart 
Association Stroke C. 2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early 
Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A 
Guideline for Healthcare Professionals From the American Heart Association/American 
Stroke Association. Stroke; a journal of cerebral circulation. 2015. 
20. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, 
Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele 
B, Scott PA, Sheth KN, Southerland AM, Summers DV and Tirschwell DL. Guidelines for 
the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 
Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare 
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Professionals From the American Heart Association/American Stroke Association. Stroke. 
2019;50:e344-e418. 
21. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, 
Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele 
B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL and American Heart 
Association Stroke C. 2018 Guidelines for the Early Management of Patients With Acute 
Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart 
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22. Banks JL and Marotta CA. Outcomes validity and reliability of the modified Rankin scale: 
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23. Quinn TJ, Dawson J, Walters MR and Lees KR. Reliability of the modified Rankin Scale: a 
systematic review. Stroke. 2009;40:3393-5. 
24. Kasner SE. Clinical interpretation and use of stroke scales. Lancet Neurol. 2006;5:603-12. 
25. Mahoney FI and Barthel DW. Functional Evaluation: The Barthel Index. Md State Med J. 
1965;14:61-5. 
26. Quinn TJ, Langhorne P and Stott DJ. Barthel index for stroke trials: development, 
properties, and application. Stroke. 2011;42:1146-51. 
27. Brooks R. EuroQol: The current state of play. Health Policy. 1996;37:53-72. 
28. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G and Badia X. 
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). 
Qual Life Res. 2011;20:1727-36. 
 
 
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12 INVESTIGATOR’S AGREEMENT 
 
I have read the attached protocol: A Randomized, Blinded, Placebo-controlled, Parallel Group 
Design to Determine the Safety of RNS60 in Large Vessel Occlusion Stroke Patients Undergoing 
Endovascular Thrombectomy. (RNS60 Stroke Trial) and agree to abide by all provisions set forth 
therein. 
 
I agree to comply with the current International Conference on Harmonisation Guidelines for 
Good Clinical Practice and the laws, rules, regulations and guidelines of the community, state or 
locality relating to the conduct of the clinical study. 
 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor. 
 
 
 
 
Name of Site Principal Investigator 
 
Signature 
 
 
 
Name of Clinical Site 
 
Date 
 
 
 
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13 ADDENDUM 
13.1 COVID-19 Considerations 
Minimizing Risk to Participants and Staff  
The protocol includes the following adaptations to minimize risk while prioritizing the overall 
well-being and best interests of all involved in the trial.  This protocol was written considering the 
impact of COVID-19 on trial participants, site staff and sponsor staff. With these priorities in 
mind, the protocol design will still permit assessment of safety of RNS60. 
•
Minimize the number of study visits to align with the trial endpoints
•
Minimize the number of trial specific activities.  The trial was designed to align with
standard of care protocols for acute stroke.  For example, obtaining data from standard of
care assessments conducted during routine stroke care, for the collection and reporting of
some safety outcomes (vital signs, laboratory results) and imaging outcomes.
•
Conduct visits by telemedicine or by telephone at Day 30 and Day 90, where permitted,
when a participant is unable to attend the site physically.  This will permit the timely
collection of efficacy endpoints (mRS, NIHSS, BI and EQ-5D-5L) and safety data (AE
and SAE collection).  If the contact is made by phone, only the NIHSS assessment will not
be completed, all other assessments will be obtained.
•
Use of remote electronic consent, where permitted, to obtain initial consent from the
LAR, who may not be able to enter the hospital, and to obtain regained capacity consent
from participants who did not consent prior to their discharge from hospital.
•
Use of electronic Clinical Outcome Assessments (eCOA) for the conduct of the mRS,
NIHSS, BI and EQ-5D-5L assessments at Day 30, and Day 90 timepoints.  This will
permit site staff to collect trial endpoints even if they are not permitted into the hospital,
reduce data entry time and reduce the time on-site for CRAs in order to monitor the data.
In addition to the above items included in the protocol, ongoing risk assessments and monitoring 
of the COVID-19 situation will be conducted by the sponsor with input from the investigators. 
These ongoing assessments include changes to any of the following: 
•
Potential impact on trial participants
•
Potential impact on trial site staff, including local or central IRBs
•
Potential impact on sponsor/CRO staff conducting site monitoring and central review of
data.
The outcome of these ongoing assessments could result in site-specific mitigation plans, which 
could include: 
•
Suspension of enrollment at that site
•
Suspension of on-site visits by participants at that site, replacing the physical data capture
with some remote measures (telephone or telemedicine, where permitted)
•
Suspension of on-site visits being conducted by the CRA, replacing the monitoring with
remote review of data and telephone contacts with the site
•
Other mitigation plans, as appropriate.
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13.2 Assessment Questionnaires 
Below is a sample of the assessment questionnaires and instructions to be used in the trial. 
Modified Rankin Scale (mRS) 
Clinician Reported Outcome 
English example  
National Institute of Health Stroke Scale 
(NIHSS) 
Clinician Reported Outcome 
English example.   
Barthel Index 
Clinician Reported Outcome 
English example.   
EQ-5D-5L 
Patient Reported Outcome  
USA, English Interviewer Administered example  
See https://euroqol.org/ for device, country, and 
language specific versions 
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Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
Hospital ________________________(___ ___-___ ___) 
Date of Exam ___ ___/___ ___/___ ___ 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days 
[ ] 3 months [ ] Other ________________________________(___ ___) 
Time: ___ ___:___ ___   [ ]am [ ]pm
Person Administering Scale _____________________________________ 
Administer stroke scale items in the order listed.  Record performance in each category after each subscale exam.  Do not go 
back and change scores.  Follow directions provided for each exam technique.  Scores should reflect what the patient does, not 
what the clinician thinks the patient can do.  The clinician should record answers while administering the exam and work quickly. 
Except where indicated, the patient should not be coached (i.e., repeated requests to patient to make a special effort). 
Instructions 
  Scale Definition 
Score 
1a.  Level of Consciousness: The investigator must choose a 
response if a full evaluation is prevented by such obstacles as an 
endotracheal tube, language barrier, orotracheal trauma/bandages.  A 
3 is scored only if the patient makes no movement (other than reflexive 
posturing) in response to noxious stimulation. 
 0 =    Alert; keenly responsive. 
 1 = Not alert; but arousable by minor stimulation to obey, 
answer, or respond. 
 2 = Not alert; requires repeated stimulation to attend, or is 
obtunded and requires strong or painful stimulation to 
make movements (not stereotyped). 
 3 = Responds only with reflex motor or autonomic effects or 
totally unresponsive, flaccid, and areflexic. 
______ 
1b.  LOC Questions:  The patient is asked the month and his/her age. 
The answer must be correct - there is no partial credit for being close.  
Aphasic and stuporous patients who do not comprehend the questions 
will score 2.  Patients unable to speak because of endotracheal 
intubation, orotracheal trauma, severe dysarthria from any cause, 
language barrier, or any other problem not secondary to aphasia are 
given a 1.  It is important that only the initial answer be graded and that 
the examiner not "help" the patient with verbal or non-verbal cues. 
 0 = 
Answers both questions correctly. 
 1 = 
Answers one question correctly. 
 2 = 
Answers neither question correctly.  
______ 
1c.  LOC Commands:  The patient is asked to open and close the 
eyes and then to grip and release the non-paretic hand.  Substitute 
another one step command if the hands cannot be used.  Credit is 
given if an unequivocal attempt is made but not completed due to 
weakness.  If the patient does not respond to command, the task 
should be demonstrated to him or her (pantomime), and the result 
scored (i.e., follows none, one or two commands).  Patients with 
trauma, amputation, or other physical impediments should be given 
suitable one-step commands.  Only the first attempt is scored. 
 0 = Performs both tasks correctly. 
 1 = Performs one task correctly. 
 2 = Performs neither task correctly. 
______ 
2.
Best Gaze:  Only horizontal eye movements will be tested.
Voluntary or reflexive (oculocephalic) eye movements will be scored,
but caloric testing is not done.  If the patient has a conjugate
deviation of the eyes that can be overcome by voluntary or reflexive
activity, the score will be 1.  If a patient has an isolated peripheral
nerve paresis (CN III, IV or VI), score a 1.  Gaze is testable in all
aphasic patients.  Patients with ocular trauma, bandages, pre-existing
blindness, or other disorder of visual acuity or fields should be tested
with reflexive movements, and a choice made by the investigator.
Establishing eye contact and then moving about the patient from side
to side will occasionally clarify the presence of a partial gaze palsy.
 0 = Normal. 
 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, 
but forced deviation or total gaze paresis is not present. 
 2 = Forced deviation, or total gaze paresis not overcome by the 
oculocephalic maneuver. 
______ 
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Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
Hospital ________________________(___ ___-___ ___) 
Date of Exam ___ ___/___ ___/___ ___ 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days 
[ ] 3 months [ ] Other ________________________________(___ ___) 
3. Visual:  Visual fields (upper and lower quadrants) are tested by
confrontation, using finger counting or visual threat, as appropriate.
Patients may be encouraged, but if they look at the side of the
moving fingers appropriately, this can be scored as normal.  If there is
unilateral blindness or enucleation, visual fields in the remaining eye
are scored.  Score 1 only if a clear-cut asymmetry, including
quadrantanopia, is found.  If patient is blind from any cause, score 3.
Double simultaneous stimulation is performed at this point.  If there is
extinction, patient receives a 1, and the results are used to respond to
item 11.
 0 = No visual loss. 
 1 = Partial hemianopia. 
 2 = Complete hemianopia. 
 3 = Bilateral hemianopia (blind including cortical blindness). 
______ 
4. Facial Palsy:  Ask – or use pantomime to encourage – the patient
to show teeth or raise eyebrows and close eyes.  Score symmetry of
grimace in response to noxious stimuli in the poorly responsive or
non-comprehending patient.  If facial trauma/bandages, orotracheal
tube, tape or other physical barriers obscure the face, these should
be removed to the extent possible.
 0 = Normal symmetrical movements. 
 1 = Minor paralysis (flattened nasolabial fold, asymmetry on 
smiling). 
 2 = Partial paralysis (total or near-total paralysis of lower 
face). 
 3 = Complete paralysis of one or both sides (absence of 
facial movement in the upper and lower face). 
______ 
5. Motor Arm:  The limb is placed in the appropriate position: extend
the arms (palms down) 90 degrees (if sitting) or 45 degrees (if
supine).  Drift is scored if the arm falls before 10 seconds.  The
aphasic patient is encouraged using urgency in the voice and
pantomime, but not noxious stimulation.  Each limb is tested in turn,
beginning with the non-paretic arm.  Only in the case of amputation or
joint fusion at the shoulder, the examiner should record the score as
untestable (UN), and clearly write the explanation for this choice.
 0 =  No drift; limb holds 90 (or 45) degrees for full 10 seconds. 
 1 =  Drift; limb holds 90 (or 45) degrees, but drifts down before 
full 10 seconds; does not hit bed or other support. 
 2 =  Some effort against gravity; limb cannot get to or 
maintain (if cued) 90 (or 45) degrees, drifts down to bed, 
but has some effort against gravity. 
 3 =  No effort against gravity; limb falls. 
 4 =  No movement. 
  UN = Amputation or joint fusion, explain:  _____________________ 
 5a.  Left Arm 
 
 5b.  Right Arm  
______ 
______ 
6. Motor Leg:  The limb is placed in the appropriate position:  hold
the leg at 30 degrees (always tested supine).  Drift is scored if the leg
falls before 5 seconds.  The aphasic patient is encouraged using
urgency in the voice and pantomime, but not noxious stimulation.
Each limb is tested in turn, beginning with the non-paretic leg.  Only
in the case of amputation or joint fusion at the hip, the examiner
should record the score as untestable (UN), and clearly write the
explanation for this choice.
 0 =  No drift; leg holds 30-degree position for full 5 seconds. 
 1 =  Drift; leg falls by the end of the 5-second period but does 
not hit bed.    
 2 =  Some effort against gravity; leg falls to bed by 5 
seconds, but has some effort against gravity. 
 3 =  No effort against gravity; leg falls to bed immediately. 
 4 =  No movement. 
  UN = Amputation or joint fusion, explain: ________________ 
6a.  Left Leg 
6b.  Right Leg 
______ 
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Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
Hospital ________________________(___ ___-___ ___) 
Date of Exam ___ ___/___ ___/___ ___ 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days 
[ ] 3 months [ ] Other ________________________________(___ ___) 
______ 
7. Limb Ataxia:  This item is aimed at finding evidence of a unilateral
cerebellar lesion.  Test with eyes open.  In case of visual defect,
ensure testing is done in intact visual field.  The finger-nose-finger
and heel-shin tests are performed on both sides, and ataxia is scored
only if present out of proportion to weakness.  Ataxia is absent in the
patient who cannot understand or is paralyzed.  Only in the case of
amputation or joint fusion, the examiner should record the score as
untestable (UN), and clearly write the explanation for this choice.  In
case of blindness, test by having the patient touch nose from
extended arm position.
 0 = Absent. 
 1 = Present in one limb. 
 2 = Present in two limbs. 
 UN = Amputation or joint fusion, explain:  ________________ 
______ 
8.
Sensory:  Sensation or grimace to pinprick when tested, or
withdrawal from noxious stimulus in the obtunded or aphasic patient.
Only sensory loss attributed to stroke is scored as abnormal and the
examiner should test as many body areas (arms [not hands], legs,
trunk, face) as needed to accurately check for hemisensory loss.  A
score of 2, “severe or total sensory loss,” should only be given when
a severe or total loss of sensation can be clearly demonstrated.
Stuporous and aphasic patients will, therefore, probably score 1 or 0.
The patient with brainstem stroke who has bilateral loss of sensation
is scored 2.  If the patient does not respond and is quadriplegic, score
2. Patients in a coma (item 1a=3) are automatically given a 2 on this
item.
 0 = Normal; no sensory loss. 
 1 = Mild-to-moderate sensory loss; patient feels pinprick is 
less sharp or is dull on the affected side; or there is a 
loss of superficial pain with pinprick, but patient is aware 
of being touched. 
 2 = Severe to total sensory loss; patient is not aware of 
being touched in the face, arm, and leg. 
______ 
9. Best Language:  A great deal of information about comprehension
will be obtained during the preceding sections of the examination.
For this scale item, the patient is asked to describe what is happening
in the attached picture, to name the items on the attached naming
sheet 
and 
to 
read 
from 
the 
attached 
list 
of 
sentences.
Comprehension is judged from responses here, as well as to all of
the commands in the preceding general neurological exam.  If visual
loss interferes with the tests, ask the patient to identify objects placed
in the hand, repeat, and produce speech.  The intubated patient
should be asked to write. The patient in a coma (item 1a=3) will
automatically score 3 on this item.  The examiner must choose a
score for the patient with stupor or limited cooperation, but a score of
3 should be used only if the patient is mute and follows no one-step
commands.
 0 = No aphasia; normal. 
 1 =  Mild-to-moderate aphasia; some obvious loss of fluency 
or facility of comprehension, without significant 
limitation on ideas expressed or form of expression.  
Reduction of speech and/or comprehension, however, 
makes conversation about provided materials difficult 
or impossible.  For example, in conversation about 
provided materials, examiner can identify picture or 
naming card content from patient’s response. 
 2 = Severe aphasia; all communication is through fragmentary 
expression; great need for inference, questioning, and guessing 
by the listener.  Range of information that can be exchanged is 
limited; listener carries burden of communication.  Examiner 
cannot identify materials provided from patient response. 
 3 = Mute, global aphasia; no usable speech or auditory 
comprehension. 
______ 
10.
Dysarthria: If patient is thought to be normal, an adequate
sample of speech must be obtained by asking patient to read or
repeat words from the attached list.  If the patient has severe
aphasia, the clarity of articulation of spontaneous speech can be
rated.  Only if the patient is intubated or has other physical barriers to
producing speech, the examiner should record the score as
untestable (UN), and clearly write an explanation for this choice.  Do
not tell the patient why he or she is being tested.
 0 = Normal. 
 1 = Mild-to-moderate dysarthria; patient slurs at least some 
words and, at worst, can be understood with some 
difficulty. 
 2 = Severe dysarthria; patient's speech is so slurred as to be 
unintelligible in the absence of or out of proportion to 
any dysphasia, or is mute/anarthric. 
UN = Intubated or other physical barrier, 
explain:_____________________________ 
______ 
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Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
Hospital ________________________(___ ___-___ ___) 
Date of Exam ___ ___/___ ___/___ ___ 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days 
[ ] 3 months [ ] Other ________________________________(___ ___) 
11.
Extinction and Inattention (formerly Neglect):  Sufficient
information to identify neglect may be obtained during the prior
testing.  If the patient has a severe visual loss preventing visual
double simultaneous stimulation, and the cutaneous stimuli are
normal, the score is normal.  If the patient has aphasia but does
appear to attend to both sides, the score is normal.  The presence of
visual spatial neglect or anosagnosia may also be taken as evidence
of abnormality.  Since the abnormality is scored only if present, the
item is never untestable.
 0 = No abnormality. 
 1 = Visual, tactile, auditory, spatial, or personal inattention 
or extinction to bilateral simultaneous stimulation in one 
of the sensory modalities. 
 2 = Profound hemi-inattention or extinction to more than 
one modality; does not recognize own hand or orients 
to only one side of space. 
______ 
______ 
______ 
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You know how. 
Down to earth. 
I got home from work. 
Near the table in the dining 
room. 
They heard him speak on the 
radio last night. 
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MAMA 
TIP – TOP 
FIFTY – FIFTY 
THANKS 
HUCKLEBERRY 
BASEBALL PLAYER 
Date: May 9, 2022
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Provided by the Internet Stroke Center — www.strokecenter.org 
THE
Patient Name: 
___________________________
BARTHEL
Rater Name: 
___________________________
INDEX
Date: 
___________________________
Activity 
Score 
FEEDING 
0 = unable 
5 = needs help cutting, spreading butter, etc., or requires modified diet 
10 = independent 
______
BATHING 
0 = dependent 
5 = independent (or in shower) 
______
GROOMING 
0 = needs to help with personal care 
5 = independent face/hair/teeth/shaving (implements provided)  
______
DRESSING 
0 = dependent 
5 = needs help but can do about half unaided 
10 = independent (including buttons, zips, laces, etc.)  
______
BOWELS 
0 = incontinent (or needs to be given enemas) 
5 = occasional accident 
10 = continent 
______
BLADDER 
0 = incontinent, or catheterized and unable to manage alone 
5 = occasional accident 
10 = continent 
______
TOILET USE 
0 = dependent 
5 = needs some help, but can do something alone 
10 = independent (on and off, dressing, wiping)  
______
TRANSFERS (BED TO CHAIR AND BACK) 
0 = unable, no sitting balance 
5 = major help (one or two people, physical), can sit 
10 = minor help (verbal or physical) 
15 = independent 
______
MOBILITY (ON LEVEL SURFACES) 
0 = immobile or < 50 yards 
5 = wheelchair independent, including corners, > 50 yards 
10 = walks with help of one person (verbal or physical) > 50 yards 
15 = independent (but may use any aid; for example, stick) > 50 yards 
______
STAIRS 
0 = unable 
5 = needs help (verbal, physical, carrying aid) 
10 = independent 
______
TOTAL (0–100): ______
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Provided by the Internet Stroke Center — www.strokecenter.org 
The Barthel ADL Index: Guidelines 
1.
The index should be used as a record of what a patient does, not as a record of what a patient could do.
2.
The main aim is to establish degree of independence from any help, physical or verbal, however minor
and for whatever reason.
3.
The need for supervision renders the patient not independent.
4.
A patient's performance should be established using the best available evidence. Asking the patient,
friends/relatives and nurses are the usual sources, but direct observation and common sense are also
important. However direct testing is not needed.
5.
Usually the patient's performance over the preceding 24-48 hours is important, but occasionally longer
periods will be relevant.
6.
Middle categories imply that the patient supplies over 50 per cent of the effort.
7.
Use of aids to be independent is allowed.
References 
Mahoney FI, Barthel D.  “Functional evaluation: the Barthel Index.” 
Maryland State Medical Journal 1965;14:56-61.  Used with permission. 
Loewen SC, Anderson BA.  “Predictors of stroke outcome using objective measurement scales.” 
Stroke. 1990;21:78-81. 
Gresham GE, Phillips TF, Labi ML.  “ADL status in stroke: relative merits of three standard indexes.” 
Arch Phys Med Rehabil. 1980;61:355-358. 
Collin C, Wade DT, Davies S, Horne V.  “The Barthel ADL Index: a reliability study.” 
Int Disability Study.1988;10:61-63. 
Copyright Information 
The Maryland State Medical Society holds the copyright for the Barthel Index.  It may be used freely for non-
commercial purposes with the following citation: 
Mahoney FI, Barthel D.  “Functional evaluation: the Barthel Index.” 
Maryland State Med Journal 1965;14:56-61.  Used with permission. 
Permission is required to modify the Barthel Index or to use it for commercial purposes. 
Date: May 9, 2022
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Sample
© 2009 EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation. UK (English) v1.2
Health Questionnaire
English version for the UK
Date: May 9, 2022
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Sample
2
© 2009 EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation. UK (English) v1.2
Under each heading, please tick the ONE box that best describes your health TODAY.
MOBILITY
I have no problems in walking about

I have slight problems in walking about

I have moderate problems in walking about

I have severe problems in walking about

I am unable to walk about

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed

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Sample
3
© 2009 EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation. UK (English) v1.2
The worst health 
you can imagine

We would like to know how good or bad your health is TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Please mark an X on the scale to indicate how your health is TODAY.

Now, write the number you marked on the scale in the box below.
The best health 
you can imagine
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
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