Trophic Enteral Feeding Combined With Supplemental Parenteral Nutrition Treatment in Patients With Severe Stroke (OPENS-2): a Multicentre, Prospective, Randomised, Open-label, Blinded-endpoint Trial
Phase: PHASE3
Conditions: Severe Stroke, Acute Stroke, Dysphagia
Sponsor: Wen Jiang-3

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Original protocol 
(Issue Date: 26th July 2022) 

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OPENS-2: A phase III, multicenter, investigator-initiated, open-label, 
randomized, parallel-group, superiority trial to assess the clinical 
effectiveness of trophic enteral nutrition with supplemental 
parenteral nutrition versus full enteral feeding in patients with acute 
severe stroke. 
 
Trial sponsor:           Xijing Hospital, The Fourth Military Medical University 
                      Changle West Road 127, Xincheng district, Xi’an City, China 
Trial Funder(s):         Shaanxi Special Support Program for Leading Talents (2020-44)  
Shaanxi Cerebrovascular Diseases Clinical Medical Research Center  
(2021LCZX-11) 
Trial Registry Number：  NCT05998902 
 
 
Protocol version:        Version 1.0 
Protocol Version date:    26/07/2022 
 
Name&Role:                     Signature:                   Date: 
Chief investigator:  
Professor Wen Jiang              
           26 July 2022              

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Table of Contents 
1. Study synopsis ............................................................................................................................. 6 
2. Flow chart and schedule of assessment ................................................................................... 10 
2.1 Flow Chart ....................................................................................................................... 10 
2.2 Schedule of Assessments ................................................................................................. 10 
3. List of Abbreviations ................................................................................................................. 12 
4. Background................................................................................................................................ 14 
5. Study objectives ......................................................................................................................... 17 
5.1 Primary Objectives ......................................................................................................... 17 
5.2 Secondary Objectives ...................................................................................................... 17 
6. Organizational Structure.......................................................................................................... 17 
6.1 Trial Steering Committee ............................................................................................... 18 
6.2 Data Safety and Monitoring Board ............................................................................... 18 
6.3 Ethics Advisory Board .................................................................................................... 18 
6.4 Trial Management Committee ....................................................................................... 19 
6.5 Data Management and Coordinating Center ............................................................... 19 
6.6 Imaging Core Laboratory .............................................................................................. 19 
6.7 Endpoint Adjudication Committee ................................................................................ 20 
6.8 Clinical Events Committee ............................................................................................. 20 
7. Trial Design ................................................................................................................................ 20 
8. Selection of participants ........................................................................................................... 21 
8.1 Inclusion Criteria ............................................................................................................ 21 
8.2 Exclusion Criteria ........................................................................................................... 22 
9. 
Informed Consent ................................................................................................................. 22 
9.1 Patients with Capacity to Consent ................................................................................. 22 
9.2 Patients Lacking Capacity to Consent .......................................................................... 23 
10. Imaging .................................................................................................................................... 24 
11. Randomization procedures ..................................................................................................... 24 
12. Blinding/Unblinding................................................................................................................ 25 
13. Trial interventions ................................................................................................................... 25 
13.1 Calculation of Caloric and Protein Requirements ..................................................... 25 
13.2 Full enteral feeding ....................................................................................................... 26 
13.3 Trophic EN combined with SPN .................................................................................. 26 
13.4 Delivery and Management of EN and PN ................................................................... 26 
13.5 Blood Glucose Management30, 31 .................................................................................. 28 
14. Study Schedule ........................................................................................................................ 28 
14.1 Enrollment period (Visit V0, Randomization) ............................................................ 28 

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14.1.1 Pre-enrollment (Visit V0) ................................................................................... 28 
14.1.2 Randomization (R) ............................................................................................. 29 
14.2 Treatment period .......................................................................................................... 29 
14.3 Critical Care Unit Discharge (Visit V1) ...................................................................... 30 
14.4 Follow Up period ........................................................................................................... 30 
14.4.1 At 28 days post-randomization (Visit V2) ........................................................ 30 
14.4.2 At 90 days post-randomization (Visit V3) ........................................................ 30 
15. Outcomes ................................................................................................................................. 31 
15.1 Primary efficacy outcomes ........................................................................................... 31 
15.2 Secondary efficacy outcomes ........................................................................................ 31 
15.3 Safety outcomes ............................................................................................................. 31 
16. Assessment ............................................................................................................................... 31 
16.1 Assessment of efficacy ................................................................................................... 31 
16.2 Assessment of safety ...................................................................................................... 36 
17. Data management guidelines ................................................................................................. 37 
17.1 Case Report Forms (CRFs) and data entry ................................................................ 37 
17.2 Data quality and control ............................................................................................... 38 
17.3 Data security and storage ............................................................................................. 38 
18. Safety ........................................................................................................................................ 39 
18.1 Adverse Events .............................................................................................................. 39 
18.2 Serious Adverse Events................................................................................................. 39 
18.3 Recording and reporting procedures .......................................................................... 40 
18.4 Follow up ........................................................................................................................ 41 
18.5 Central processing ......................................................................................................... 42 
19. Withdrawal .............................................................................................................................. 42 
19.1 Patient Withdrawal ....................................................................................................... 42 
19.2 Trial Treatment Withdrawal ....................................................................................... 42 
19.3 Withdrawal of Consent ................................................................................................. 43 
19.4 Study Site Withdrawal .................................................................................................. 43 
20. Trial Closure ............................................................................................................................ 43 
21. Statistics ................................................................................................................................... 44 
21.1 Sample size calculation ................................................................................................. 44 
21.2 Analysis population ....................................................................................................... 45 
21.3 Interim analysis ............................................................................................................. 46 
21.4 Analysis of results .......................................................................................................... 46 
22. Ethical and regulatory consideration .................................................................................... 48 
22.1 Ethical compliance ........................................................................................................ 48 
22.2 Monitoring and Quality Assurance ............................................................................. 48 
22.3 Liability and Insurance................................................................................................. 50 
23. Publication and dissemination policy .................................................................................... 50 

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23.1 Dissemination Plan ........................................................................................................ 50 
23.2 Reporting Obligations ................................................................................................... 51 
23.3 Publication Policy .......................................................................................................... 51 
24. References ................................................................................................................................ 51 
25. Appendixes ............................................................................................................................... 56 
25.1 Appendix 1 NIHSS ........................................................................................................ 56 
25.2 Appendix 2 GCS ............................................................................................................ 62 
25.4 Appendix 4 NRS-2002 ................................................................................................... 66 
25.5 Appendix 5 APACHE Ⅱ ............................................................................................... 69 
 

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1. Study synopsis 
Study Title 
A phase III, multicenter, investigator-initiated, open, randomized, 
parallel-group, superiority trial to assess the clinical effectiveness 
of trophic enteral nutrition with supplemental parenteral nutrition 
versus full enteral feeding in patients with acute severe stroke. 
Public title 
Optimizing Early Nutrition Support in Severe Stroke -2 
Contact for queries 
Public queries: 
Dr. Xuan Wang 
Phone: +86 18791988671 
E-mail: wangxuan@fmmu.edu.cn 
Scientific queries: 
 Pro. Wen Jiang 
Phone:  +86 13991905538 
E-mail: jiangwen@fmmu.edu.cn 
Countries of recruitment 
China 
Health condition 
Acute Stroke requiring intensive care 
Arms and Interventions 
Caloric requirements will be calculated based on body mass index 
(BMI). For patients with a BMI between 18 and 30 kg/m², the 
daily caloric target is actual body weight (in kilograms) multiplied 
by 25 kcal; for patients with a BMI below 18 or above 30 kg/m², 
the formula (height [cm] - 105) × 25 kcal will be applied15. 
Caloric delivery will follow a stepwise escalation: one-third of the 
target on intervention day 1, half on day 2, and the full target from 
day 3 to day 7. An acceptable delivery range is 70% to 100% of 
the target. The protein intake target for all participants is set at 1.2 
to 1.5 grams per kilogram of body weight per day.  
 
Experimental: Trophic enteral feeding combined with 
supplemental parenteral nutrition. Patients will receive the 
trophic enteral feeding with a caloric target of 500kcal/d (≤20 

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ml/h), and the remaining caloric-protein requirement are 
supplemented by parenteral nutrition. 
 
Active Comparator: Full enteral feeding. Patients will receive 
full enteral feeding through nasogastric tube or nasointestinal 
tube. 
Inclusion Criteria 
1. Age≥18 years; 
2. Definite diagnosis of acute stroke (GCS≤12 or NIHSS≥11); 
3. The randomized nutritional treatment could be initiated up to 
72 hours after symptom onset; 
4. Any cases of profiles #3 through 5 in Water Swallowing Test 
or with disorder of consciousness; 
5. Plan to receive enteral feeding for at least 7 days; 
6. Informed consent. 
Exclusion Criteria 
1. 
Receiving parenteral nutrition support 
2. 
Contraindications of enteral nutrition 
3. 
Complicated with the disease which only have life 
expectancy < 7 days 
4. 
Dementia or severe disability (mRS>4) before stroke 
5. 
Presence of coexisting medical conditions that could interfere 
with outcome assessment and/or follow-up (a. advanced 
cancer; b. severe pulmonary dysfunction [forced expiratory 
volume in 1 second < 50% or/and moderate to severe acute 
lung injury (PaO2/FiO2)<200mmHg]; c. cardiac insufficiency 
(NYHA class > I; cardiac structural and/or functional 
abnormalities such as EF< 50%, abnormal cardiac chamber 
enlargement, moderate/severe ventricular hypertrophy, or 
moderate/severe valvular stenosis); d. Severe liver failure 
[Child-Pugh score≥7]; e. Severe renal failure [glomerular 
filtration rate ≤30mL/min or serum creatinine ≥4mg/dL] 

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6. 
Currently participating in other clinical trial 
7. 
Pregnant woman 
8. 
Patient who is considered highly likely not to adhere to the 
study treatment or follow-up protocol. 
Study Design 
Phase 
III, 
investigator-initiated, 
randomized, 
open-label, 
blinded-endpoint multicenter trial 
Sample size 
546 
Primary Efficacy 
outcome 
Incidence of post stroke pneumonia from randomization to day 7.  
Secondary Efficacy 
outcomes 
• 
Time from randomization to onset of the post-stroke 
pneumonia within 7 days post-randomization 
• 
Daily calorie and protein delivery during the first 7 days 
post-randomization 
• 
Insulin dosage during the first 7 days post-randomization 
• 
The usage rate of prokinetic agents during the first 7 days 
post-randomization 
• 
Occurrence of nosocomial infections from randomization to 
ICU discharge  
• 
Length of ICU stay 
• 
Incidence of tracheotomy, mechanical ventilation, continuous 
renal replacement therapy, and venous thrombosis from 
randomization to ICU discharge 
• 
Usage rate of vasoactive agents from randomization to ICU 
discharge 
• 
The score of National Institute of Health stroke scale at ICU 
discharge 
• 
Glasgow Coma Scale at ICU discharge 
• 
Modified Rankin scale at ICU discharge 
• 
Modified Rankin scale at 90 days 

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Safety Endpoints 
• 
All-cause mortality during ICU stay  
• 
All-cause mortality at 28 days 
• 
Incidence of cardiac failure from randomization to ICU 
discharge 
• 
Incidence of gastrointestinal complications (Vomiting, 
diarrhea, gastric retention, gastrointestinal bleeding) during 
the first 7 days post-randomization 
 
   
 

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2. Flow chart and schedule of assessment  
2.1 Flow Chart 
 
 
2.2 Schedule of Assessments  
 
Trial period 
 
Enrolment 
Treatment 
Follow Up 
Timepoint 
V0 
R 
Intervention 
Period a 
V1 
ICU Discharge date 
V2 
(28±3d) 
V3 
(90±7d) 
Enrolment 
Eligibility screen 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Intervention or comparator 

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Nutritional support intervention 
 
 
X 
 
 
 
Assessments  
Demographic data 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
Pre-stroke mRS 
X 
 
 
 
 
 
NIHSS 
X 
 
 
X 
 
 
GCS  
X 
 
 
X 
 
 
NRS-2002 
X 
 
 
 
 
 
APACHE-II 
 
 
X 
 
 
 
BMI  
 
 
X 
 
 
 
mRS 
 
 
 
X 
 
X 
Vital signs 
X 
 
X 
X 
 
 
Brain CT/MRI 
X 
 
 
 
 
 
Chest CT or X-ray 
X 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
Echocardiography 
X 
 
 
 
 
 
White blood cell count 
X 
 
 
 
 
 
Local laboratory result 
X 
 
 
 
 
 
Blood glucose 
 
 
X 
 
 
 
Gastric residual volume 
 
 
X 
 
 
 
Pneumonia Monitoring b 
 
 
X 
X 
 
 
Complication monitoring 
 
 
X 
X 
 
 
Adverse events 
 
 
X 
X 
X 
X 
V = Visit; R = Randomization; d = day 
a or death, extubation, ICU discharge if＜7 days. 
b items including temperature, breathing, sputum, blood oxygen saturation. If necessary, check white blood cell 
count and perform chest CT or X-ray.  

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3. List of Abbreviations 
AE 
Adverse Event 
AIS 
Acute Ischemia Stroke 
APACHE 
Acute Physiology and Chronic Health Evaluation 
BMI  
Body Mass Index 
CEC 
Clinical Events Committee 
CT 
Computed Tomography 
CRF 
Case Report Form 
CRRT 
Continuous Renal Replacement Therapy  
DSMB 
Data and Safety Monitoring Board 
EAB 
Ethics Advisory Board 
EAC 
Endpoint Adjudication Committee 
ECG  
Electrocardiogram 
EN 
Enteral Nutrition 
GCP 
Good Clinical Practice 
GCS 
Glasgow coma scale 
GRV 
Gastric residual volume 
ITT 
Intention To Treat 
LAR 
Legally Authorized Representative 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institute of Health stroke scale 
NRS 
Nutritional Risk Screening 
PI 
Principal Investigator 

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PN 
Parenteral nutrition 
PP  
Per-Protocol 
QC 
Quality Control  
RCT 
Randomized controlled trial 
RR 
Relative Risk 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SPN 
Supplemental Parenteral nutrition 
TEN 
Trophic Enteral Nutrition 
TMC 
Trial Management Committee 
TSC 
Trial Steering Committee 
PSP 
Post stroke pneumonia 
 

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4. Background 
Stroke has become the leading cause of death and disability among adults in China, 
imposing a heavy medical and economic burden on society and families1. Actively 
optimizing comprehensive management measures for the acute phase of stroke is of 
great significance for improving disease prognosis. Stroke-associated pneumonia 
(SAP) is the most common complication of stroke, with an incidence rate as high as 
40% in patients with severe stroke during the acute phase2. SAP is an independent risk 
factor for death and poor prognosis in stroke patients potentially increasing 30-day 
mortality by threefold3,4,5,6. Therefore, reducing the incidence of SAP will help lower 
stroke mortality.  
 
Due to impaired consciousness and swallowing dysfunction, patients with severe 
stroke often require nutritional support, thus establishing it as a critical component of 
comprehensive management. Currently, nutritional support for critically ill patients 
primarily involves enteral nutrition (EN) and parenteral nutrition (PN). EN helps 
protect gastrointestinal function7,8, but carries a significant risk of aspiration during 
implementation, which can lead to aspiration pneumonia9,10,11. Trophic feeding, an EN 
strategy that provides minimal nutrients, may reduce the incidence of reflux in 
critically ill patients12. However, relying solely on trophic feeding for patients with 
severe stroke often fails to meet their caloric demands. Our previous multi-center 
RCT, published in Lancet Neurology, demonstrated that low-calorie feeding during 
the first week after severe stroke was associated with increased mortality13. 
Conversely, while PN can ensure adequate energy delivery, it is associated with 
complications such as intestinal mucosal atrophy, gut microbiota disruption, and deep 
vein infections, which may consequently increase mortality risk14. Thus, the 
identification of an optimal nutritional support regimen for patients with severe stroke, 
which effectively balances gastrointestinal protection, adequate nutrient delivery, and 
SAP risk reduction, is of paramount importance to improving prognosis. 
 

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4.1 Lack of effective clinical measures to prevent SAP 
SAP is the most common complication of stroke and a significant risk factor for 
stroke-related mortality3,4,5. International epidemiological data indicate a SAP 
incidence ranging from 7% to 38% 15,16,17. Data from China's National Stroke Registry 
shows SAP incidences of 11.4% for ischemic stroke and 16.9% for hemorrhagic 
stroke18,19. The incidence rises significantly in severe stroke cases, reaching up to 40% 
within the first week2. SAP is an independent risk factor for death and poor prognosis 
in stroke patients, potentially tripling 30-day mortality and being associated with 
increased one-year mortality6. Aspiration resulting from impaired consciousness and 
swallowing dysfunction post-stroke is a key pathogenic mechanism20. This condition, 
common in severe stroke, involves weakened protective reflexes and poor 
respiration-swallowing coordination, which allow secretions or gastric contents to 
enter the lungs.  
 
Given the significant burden of SAP, international researchers have explored 
preventive strategies, among which prophylactic antibiotic use has been a focus. 
However, two major randomized controlled trials, the STROKE-INF study and the 
PASS study, did not yield positive results. The STROKE-INF study found that 
prophylactic use of ceftriaxone for 7 days in stroke patients with swallowing 
dysfunction did not reduce the incidence of SAP within 14 days post-stroke21. The 
PASS study found that prophylactic use of ceftriaxone for 4 days after stroke onset 
also did not improve functional outcomes at 90 days22. Currently, there is a lack of 
effective clinical measures for preventing SAP, highlighting a critical gap in stroke 
care that awaits innovative solutions. 
 
4.2 Clinical dilemma of EN vs. PN in severe stroke 
While EN is endorsed as the first-line therapy by guidelines from ESPEN and China23, 
with recommendations for initiation within 24-48 hours, its application is frequently 
complicated by aspiration risk and gastrointestinal intolerance, which can interrupt 
feeding and prevent the achievement of nutritional goals9,10,11. In recent years, owing 

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to its improved safety profile and demonstrably superior nutritional target attainment 
rates, early PN has gained considerable endorsement in critical care settings24,25. Thus, 
a core clinical dilemma in nutritional support for critically ill patients is the trade-off 
between EN, which preserves gut integrity but often faces poor tolerance, and PN, 
which ensures nutrient delivery but carries its own distinct risks. The latest ASPEN 
consensus states that no significant difference in clinical outcomes between EN and 
PN during the first week of critical illness, affirming both as acceptable options26. 
Developing tailored nutritional approaches for specific subpopulations, such as 
patients with severe stroke, represents an important area for further research. 
 
4.3 Potential Benefits of Combined Trophic Enteral Nutrition and Supplemental 
Parenteral Nutrition 
Trophic feeding is defined as a nutritional strategy that involves the provision of 
minimal amounts of nutrients. As a form of EN trophic feeding offers distinct 
advantages over PN, including preservation of intestinal epithelial integrity, 
stimulation of brush border enzyme secretion, maintenance of tight junctions between 
epithelial cells, and prevention of bacterial translocation12. Compared to full-dose EN, 
trophic feeding has been demonstrated to reduce the incidence of gastrointestinal 
intolerance and decrease reflux episodes in patients with severe acute lung injury12. 
However, in cases of severe stroke, the administration of low-calorie trophic feeding 
may be associated with increased mortality15, highlighting the potential risks of 
relying solely on this approach. While PN ensures reliable nutrient delivery, concerns 
persist regarding its adverse effects, such as intestinal mucosal atrophy, disruption of 
gut microbiota, hyperglycemia, and catheter-related bloodstream infections14. The 
combination of EN and PN in critically ill patients represents a strategic approach that 
integrates the benefits of both modalities while mitigating their individual limitations. 
A European multi-center RCT demonstrated that supplemental PN added to early EN 
to achieve full nutritional targets significantly reduced the incidence of nosocomial 
infections within 28 days among critically ill patients27. In addition, our retrospective 
data suggest that early supplemental PN (SPN) in combination with EN significantly 

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delays the onset of new-onset pneumonia and nosocomial infections in patients with 
severe stroke. A meta-analysis comparing combined PN and EN versus EN alone in 
critically ill patient indicated that the combined regimen did not increase risks such as 
in-hospital mortality, ICU length of stay, or duration of mechanical ventilation28. 
Although SPN in addition to EN represents an effective nutritional strategy for 
critically ill patients, its efficacy has yet to be confirmed specifically in those with 
severe cerebrovascular disease. 
 
5. Study objectives 
The OPENS-2 study aims to assess, in a multicenter, randomized, open-label, 
blinded-endpoint setting, the efficacy and safety of combining trophic EN with SPN 
for nutritional support in patients with acute severe stroke. The findings of OPENS-2 
are likely to have a direct impact on clinical practice, particularly in the domain of 
nutritional therapy. 
5.1 Primary Objectives 
To determine whether the combination of trophic EN and SPN reduces the incidence 
of pneumonia within the first 7 days after enrollment in patients with severe stroke 
requiring nutritional support. 
5.2 Secondary Objectives  
• 
To compare nutritional delivery (caloric/protein intake) and insulin requirements 
during the first 7 days. 
• 
To assess gastrointestinal tolerance (complications, prokinetic agent use) during 
the first 7 days. 
• 
To evaluate clinical outcomes, including other infections, ICU length of stay, 
mortality (ICU & 28-day), and specific complications/interventions. 
• 
To measure neurological function (NIHSS, GCS) and functional status (mRS) at 
ICU discharge and 90 days. 
 
6. Organizational Structure 

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OPENS-2 trial is an investigator-initiated study which is organized by the Xijing 
Hospital, Fourth Military Medical University. The following boards and institutions 
will assure the success of the clinical trial: 
 
6.1 Trial Steering Committee 
The TSC provides strategic oversight and ensures the operational integrity of the 
study. Its core duties include approving the trial protocol, monitoring overall progress, 
allocating resources, and addressing critical issues. The TSC will make impartial 
decisions on trial modifications, early termination, or continuation based on interim 
data or external evidence. It also oversees the dissemination of trial results to ensure 
transparency and ethical compliance. By balancing scientific rigor, operational 
efficiency, and stakeholder accountability, the TSC safeguards the trial’s validity and 
alignment with its original objectives.  
 
6.2 Data Safety and Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) is charged with the 
ongoing safety review and ethical oversight of the OPENS-2 trial. The DSMB's 
mandate includes monitoring unblinded safety data (including adverse events and 
deaths), conducting rigorous risk-benefit evaluations, and recommending actions 
regarding trial modification or termination. Additionally, it ensures adherence to 
ethical and regulatory standards and maintains strict independence from investigators 
to avoid bias. The board is composed of an experienced neurologist, an intensive care 
physician, and a biostatistician, who are not participants of the OPENS-2 consortium 
and not involved in the clinical trial in any other way. The DSMB conducts regularly 
scheduled or ad hoc meetings to review critical safety and efficacy data, providing 
impartial guidance to ensure participant protection and uphold the trial’s scientific 
integrity. 
 
6.3 Ethics Advisory Board 

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Given the vulnerable nature of the severe stroke population and the complex 
risk-benefit considerations in the OPENS-2 trial, an independent EAB will be 
established to provide specialized guidance on emergent ethical issues. The EAB will 
work in conjunction with, and does not replace, the officially constituted Ethics 
Committee that provided initial approval for the trial. The EAB may be convened to 
advise on critical matters such as protocol revisions or trial termination from a 
specialized ethics perspective. 
 
6.4 Trial Management Committee 
The TMC holds primary responsibility for the comprehensive executive management 
and operational execution of the OPENS-2 trial. Its key functions encompass 
maintaining critical liaison with the Coordinating Centre as well as all financial 
stewardship, including overseeing funding applications and the disbursement of funds. 
The TMC also holds ultimate authority over the development and final approval of 
the study protocol, all trial-related materials, and data collection tools. Additionally, it 
addresses general trial management issues to ensure the study progresses efficiently. 
 
6.5 Data Management and Coordinating Center 
The Data Management and Coordinating Center is responsible for the day-to-day 
execution and coordination of the trial, providing comprehensive support across all 
study phases. Its responsibilities encompass trial management and coordination, data 
operations, and administrative and safety oversight, including assistance with ethics 
applications, budget management, CRF design, protocol training of investigators, 
management of investigator payments, monitoring and close-out site visits, 
organization of investigator meetings, handling of serious adverse event reporting and 
data analysis and collaboration on publications. 
 
6.6 Imaging Core Laboratory 
The Core Imaging Laboratory serves as the central blinded facility for all imaging 
assessments in the trial. During patient enrollment, the laboratory reviews baseline 

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chest images to identify and exclude subjects with pre-existing pulmonary infections. 
For all suspected pneumonia cases during the trial, the laboratory conducts 
standardized assessments through dual-reader review with adjudication when required. 
The laboratory team consists of a senior imaging director who provides final 
arbitration, 2 staff radiologists who perform primary image interpretation, and a data 
manager who handles image processing and quality control. All personnel remain 
blinded to clinical data and treatment allocation throughout the trial. 
 
6.7 Endpoint Adjudication Committee 
The independent EAC is composed of experts in intensive care medicine, 
neurocritical care medicine, and respiratory and critical care medicine. The committee 
is selected for their independence from trial implementation and sponsorship to 
prevent any potential conflicts of interest. All members undergo comprehensive 
training on standardized criteria for diagnosing pneumonia, ensuring consistency in 
their evaluations. The committee systematically adjudicates cases using predefined 
criteria and remains strictly blinded to treatment assignments throughout the process.  
 
6.8 Clinical Events Committee 
The CEC consists of three independent physician experts not involved in the trial 
conduct at any investigational sites. The committee will perform all assessments while 
blinded to treatment group assignment. Its responsibilities include validating all 
complications occurring during the study and categorizing each for severity and 
relatedness to the study intervention according to predefined criteria in the protocol. 
The CEC may request any additional source information and images to assist with the 
adjudication process. 
 
7. Trial Design 
OPENS-2 is a Phase III, multicenter, investigator-initiated, randomized, open-label, 
blinded-endpoint (PROBE) trial designed to assess the superiority of combined 

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trophic EN with SPN versus full EN in critically ill patients with AIS. Eligible 
participants will be randomly assigned (1:1) to one of the two nutritional strategies. 
The intervention will be administered for 7 days, unless interrupted by the initiation of 
exclusive oral feeding, discharge from the ICU, or death. All other aspects of clinical 
management will follow standard care at the discretion of the treating physician. 
 
The primary study center will be the Neuro-intensive care Unit at Xijing Hospital, 
Xi’an City, China. Upon approval, other selected centers will be approached for 
participation. Each site must demonstrate expertise in neurocritical care and severe 
stroke management, supported by a dedicated stroke team. Prior to patient enrollment, 
all sites will undergo mandatory training, covering study protocol adherence, 
nutritional risk screening, water drinking test administration and standardized 
assessments (GCS, NIHSS, mRS). 
 
8. Selection of participants  
Patients will be recruited from university and non-university, adult, neuro-intensive 
critical care units in China. Enrollment must be completed within 24 hours of their 
initial ICU admission. A local PI, who will be responsible for all trial-related activities, 
will be identified at each participating unit.  
 
8.1 Inclusion Criteria 
• 
Age≥18 years; 
• 
Definite diagnosis of acute stroke (GCS ≤12 or NIHSS≥11); 
• 
The randomized nutritional treatment could be initiated up to 72 hours after 
symptom onset; 
• 
Any cases of profiles #3 through 5 in Wate r Swallowing Test or with disorder of 
consciousness; 
• 
Plan to receive enteral feeding for at least 7 days; 
• 
Informed consent. 

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8.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from study enrolment. 
• 
Receiving parenteral nutrition support 
• 
Contraindications of enteral nutrition 
• 
Complicated with the disease which only have life expectancy < 7 days 
• 
Dementia or severe disability (mRS>4) before stroke 
• 
Presence of coexisting medical conditions that could interfere with outcome 
assessment and/or follow-up (a. advanced cancer; b. severe pulmonary 
dysfunction [forced expiratory volume in 1 second < 50% or/and moderate to 
severe acute lung injury (PaO2/FiO2)<200mmHg]; c. cardiac insufficiency 
(NYHA class > I; cardiac structural and/or functional abnormalities such as EF< 
50%, abnormal cardiac chamber enlargement, moderate/severe ventricular 
hypertrophy, or moderate/severe valvular stenosis); d. Severe liver failure 
[Child-Pugh score≥7]; e. Severe renal failure [glomerular filtration rate ≤
30mL/min or serum creatinine ≥4mg/dL] 
• 
Currently participating in other clinical trial 
• 
Pregnant woman 
• 
Patient who is considered highly likely not to adhere to the study treatment or 
follow-up protocol. 
 
9. Informed Consent 
9.1 Patients with Capacity to Consent 
Once eligibility has been confirmed, and if the patient is competent to give informed 
consent, an authorized unit doctor will describe the OPENS-2 trial to the patient. A 
standard Patient Information Sheet will be provided which will identify the title of the 
trial and include information about: the purpose of the trial, funding, the consequences 
of participating or not, use of personal data, patient confidentiality, data security and 
the future availability of the results of the trial. Patients will be encouraged to review 

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the information, ask questions, and discuss any concerns. A Consent Form will be 
provided indicating that: the information given, orally and in writing, has been read 
and understood; participation is voluntary and can be withdrawn at any time without 
consequence; and that consent is given for accessing records, collection and storage of 
personal information, information to be gathered from the medical record system, to 
be contacted and for follow-up. After ensuring full comprehension, the clinician will 
invite the patient to sign the consent form and provide a reliable means of contact 
within the research team for further communication. 
 
9.2 Patients Lacking Capacity to Consent 
Based on prior experience from the OPENS trial in severe stroke, only a minority of 
patients are expected to retain the capacity to provide informed consent. If, as is most 
likely, the patient will not be competent to give informed consent, his/her legally 
authorized representative (LAR) will be regarded as the legitimate representatives 
capable of providing informed consent. Authorized unit doctors will provide the LAR 
with the same informed consent process as that for the competent patients. The 
standard Patient Information Sheet will be given to the LAR, which will include 
details about the title of the trial, its purpose, funding sources, the consequences of 
participation or non-participation, the use of personal data, patient confidentiality, 
data security, and the future availability of the trial results. Potential risks and benefits 
of the OPENS-2 trial will be clearly communicated. The clinician will ensure the 
LAR fully understands the information, allow sufficient time for review and questions, 
and explicitly clarify that participation is voluntary and may be withdrawn at any time 
without detriment to clinical care. Following this discussion, written consent will be 
obtained. The LAR will also be provided with contact details of the research team for 
further inquiries. If and when the patient regains decision-making capacity, their 
direct consent for continued participation in the trial will be sought without delay. 
This procedure ensures that the rights, safety, and well-being of patients without 
decision-making capacity are rigorously protected. 
 

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10. Imaging 
Chest imaging is essential for determining patient eligibility in the OPENS-2 trial. All 
patients undergo chest CT scans unless exceptional circumstances preclude it, in 
which case bedside chest X-rays are performed to assess for infection. Imaging must 
be performed within 24 hours prior to randomization to exclude patients with active 
pulmonary infection. The chest imaging results of patients intended to be enrolled 
must undergo review and confirmation by the Core Imaging Laboratory. During the 
7-day intervention period, when clinical symptoms suggest respiratory infection 
requiring antibiotic therapy, attending physicians should promptly order chest imaging 
(CT preferred or X-ray) to guide clinical management. These images are used for 
real-time clinical decision-making by trained site staff and are separate from the 
endpoint adjudication process. For endpoint determination, all chest images from 
suspected pneumonia cases undergo centralized, blinded review by the Core Imaging 
Laboratory using predefined diagnostic criteria, providing the primary imaging 
evidence for the Endpoint Adjudication Committee's final pneumonia adjudication. 
Prior to study initiation, all site investigators complete standardized training in chest 
imaging evaluation, focusing on the recognition of radiological signs of pneumonia. 
 
11. Randomization procedures 
Randomization will be performed using a web-based system accessible through 
mobile devices or computers (http://www.epiedc.com/kf.php). The system will assign 
participants in a 1:1 ratio to either trophic EN with SPN group or full EN group with 
stratification by study site. The block size will not be disclosed, to ensure 
concealment. Once eligibility is confirmed and informed consent procedures are 
completed, randomization will occur immediately, with the aim of initiating 
nutritional support within 24 hours after the patient’s admission to the intensive care 
unit. Each randomized patient will receive a unique trial identification number. The 
randomization list will be generated by the independent statistical center using SAS 
9.4 software. 

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12. Blinding/Unblinding 
Given the practical nature of the nutritional interventions, this trial adopts an 
open-label design.  The treating clinical team is aware of treatment assignments to 
ensure proper protocol implementation, while most severe stroke patients are 
expected to experience impaired consciousness during the intervention period. To 
ensure objective endpoint assessment and data integrity, blinding is strictly 
maintained for the Endpoint Adjudication Committee, Core Imaging Laboratory 
personnel, and study statisticians throughout the trial period. These parties remain 
completely unaware of treatment group allocations until database lock and completion 
of the final analysis. 
 
13. Trial interventions 
Nutritional support will be initiated as soon as possible after randomization, with a 
maximum allowed window of 24 hours. The actual start time must be documented. 
 
13.1 Calculation of Caloric and Protein Requirements 
Caloric requirements will be estimated using predictive equations based on BMI. For 
patients with a BMI between 18 and 30 kg/m², the daily caloric target is actual body 
weight (in kilograms) multiplied by 25 kcal; for patients with a BMI below 18 or 
above 30 kg/m², the formula (height [cm] - 105) × 25 kcal will be applied13. Caloric 
delivery will follow a stepwise escalation: one-third of the target on intervention day 
1, half on day 2, and the full target from day 3 to day 7. An acceptable delivery range 
is 70% to 100% of the target. When calculating total caloric intake, calories derived 
from intravenous dextrose and propofol will be included. The protein intake target for 
all participants is set at 1.2 to 1.5 grams per kilogram of body weight per day. The 
specific dose will be determined by the attending physician based on clinical factors 
such as renal function and metabolic stress. 

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13.2 Full enteral feeding  
In the full-feeding group, EN will be initiated at 20 mL/h and advanced to goal rates 
as rapidly as tolerated, following a standardized protocol. EN was sourced from the 
unit’s standard suppliers in accordance with local hospital policies and procedures. 
The pharmacy or dietetic department (where applicable), along with all research staff, 
ensured the use of this product followed the manufacturer’s guidelines.  
 
13.3 Trophic EN combined with SPN 
Patients randomized to the trophic EN with SPN group will receive enteral nutrition at 
a fixed rate of ≤20 mL/h, providing approximately 500 kcal per day. To meet the full 
calculated caloric and protein targets, the deficit not covered by EN will be 
supplemented with PN, administered via central or peripheral venous access.  
 
13.4 Delivery and Management of EN and PN  
The assigned nutritional strategy will be maintained for 7 days, until death, discharge 
from the ICU, or removal of the feeding tube (if clinically indicated). OPENS-2 will 
not mandate a single brand of EN or PN but will require that all products and 
protocols used by participating sites fall within the following common boundaries: 
 
The protocol for delivery of EN will cover: 
• 
Initial nasogastric/nasojejunal tube insertion/positioning in accordance with 
relevant clinical guidelines29. 
• 
Use of standard formula within the specified caloric and nitrogen ranges; 
• 
Adjustment of total volume according to fluid balance requirements; 
• 
Monitoring for nutritional-related complications (e.g. diarrhoea, gastrointestinal 
intolerance) 
• 
Gastric residual volume (GRV) will be monitored every 4 hours in patients 
receiving gastric feeding. If the gastric residual volume is below 200 mL, the 

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aspirate may be returned and feeding continued as planned; a volume exceeding 
100 mL warrants consideration of a prokinetic agent like metoclopramide, though 
it does not necessitate interruption of feeding13, and the use of erythromycin for 
this purpose should be avoided. If GRV exceeds 200 mL and is accompanied by 
other signs of intolerance, such as vomiting, distension, ileus, feeding should be 
held. For a single, resolved episode where symptoms abate completely within 2 
hours, feeding may resume at the previous rate. If the initial episode is severe, 
characterized by large-volume or recurrent vomiting, or if the problem recurs, 
feeding should be restarted at half of the previous rate and gradually increased 
back to the target after 6 hours of tolerance. If intolerance persists after restarting 
at half of the rate, an intensified management phase will be initiated: the EN rate 
will be further reduced to a minimal maintenance level (e.g., 20–25 mL/hour), an 
abdominal imaging study may be performed to assess gastrointestinal motility, 
and conversion to post-pyloric feeding should be actively considered. EN will 
only be completely stopped if recurrent aspiration occurs despite the minimal rate, 
with attempts to restart after the underlying cause is addressed. Every effort 
should be made to maintain feeding continuity; interruptions should only occur 
for procedures that pose a direct risk of aspiration or that require strict fasting. 
• 
Minimize periprocedual feeding interruptions. 
 
The protocol for delivery of PN will cover: 
• 
Central venous catheter insertion and care with a dedicated lumen for PN; 
• 
Use of standardized commercial PN solutions or individualized formulations 
prepared by the hospital pharmacy, adhering to protocol-specified macronutrient, 
electrolyte and micronutrient requirements tailored to the participant’s metabolic 
needs. All PN solutions (commercial or compounded) must meet pharmacopeial 
standards and undergo sterility and stability verification prior to administration. 
• 
Total volume adjusted according to fluid balance requirements; 
• 
Regular monitoring for PN-related complications (e.g., electrolyte imbalances, 

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hyperglycemia, catheter-related infections). 
 
13.5 Blood Glucose Management30, 31 
Glycaemic control should be implemented per international guidelines. The target 
blood glucose range for this trial is to be maintained between 7.8-10 mmol/L. 
Monitoring and control procedures should follow local institutional policies and 
guidelines. Blood glucose will be monitored at least every 4–6 hours, with 
intravenous insulin protocols used as needed to maintain targets, following local 
institutional guidelines. 
 
14. Study Schedule 
The schedule of assessments conducted during the study is shown in Part 2 (Flow 
Chart and Schedule of Assessments). The study includes three periods: Enrollment 
(Visit V0, Randomization), treatment and follow up (V1, V2, V3). 
Time points for data collection 
• 
Pre-enrollment (Screening) 
• 
Randomization (Baseline) 
• 
Daily during the 7-day intervention period 
• 
At discharge from the critical care unit (or on Day 7 if still in ICU) 
• 
At 28 days post-randomization (±3 days) 
• 
At 90 days post-randomization (±7 days) 
 
14.1 Enrollment period (Visit V0, Randomization)  
14.1.1 Pre-enrollment (Visit V0) 
After written informed consent is obtained from the patient or their legally authorized 
representative, data from standard-of-care assessments will be collected for screening 
and baseline characterization. The investigator shall document detailed information of 
all consented subjects to confirm final eligibility and record reasons for screening 
failures. 

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• 
Age 
• 
Diagnostic information and medical history 
• 
Physical examination 
• 
Determination of the pre-stroke mRS via interview of the patient or the patient’s 
legal representative 
• 
NIHSS and GCS scores 
• 
NRS-2002 score 
• 
Measurement of vital signs including blood pressure, heart rate, and respiratory 
rate 
• 
Laboratory tests 
• 
Arterial blood gas analysis 
• 
12-lead ECG 
• 
Echocardiography 
• 
Non-contrast CT scan or MRI scan  
• 
Checking of inclusion and exclusion criteria  
14.1.2 Randomization (R)  
Eligible patients will be randomized following confirmation that all inclusion criteria 
are met and no exclusion criteria apply. 
Data collected at randomization: 
• 
Patient identification code 
• 
Sex 
• 
Height, weight and BMI 
• 
APACHE-II score 
 
14.2 Treatment period 
The following data will be collected daily for the duration of the 7-day intervention 
period. 

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• 
Nutritional support access: for PN (central venous catheter site); for EN (feeding 
tube type and placement) 
• 
Nutritional delivery (formula type, volume, total calories and protein delivered); 
• 
Insulin administration (total daily dose) 
• 
Lowest and highest blood glucose 
• 
Use of prokinetic drugs 
• 
Signs, diagnostic tests, and results for new-onset pneumonia 
• 
Other infectious and non-infectious complications 
• 
Use of antibiotics  
• 
Vital signs 
• 
Survival status 
• 
Adverse events and serious adverse events 
 
14.3 Critical Care Unit Discharge (Visit V1) 
• 
Date of discharge 
• 
Routes of Nutritional Administration during the ICU Stay 
• 
Infectious and non-infectious complications during the ICU Stay 
• 
Acute stroke treatments administered 
• 
Survival status 
• 
Hospitalization expenses 
• 
Adverse events 
 
14.4 Follow Up period 
14.4.1 At 28 days post-randomization (Visit V2) 
• 
Survival status 
• 
Adverse events 
 
14.4.2 At 90 days post-randomization (Visit V3) 
• 
Survival status 
• 
Functional outcome: mRS 

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15. Outcomes 
15.1 Primary efficacy outcomes 
• 
Incidence of post-stroke pneumonia from randomization to day 7.  
15.2 Secondary efficacy outcomes 
• 
Time from randomization to onset of the post-stroke pneumonia within 7 days 
post-randomization 
• 
Daily calorie and protein delivery during the first 7 days post-randomization 
• 
Insulin dosage during the first 7 days post-randomization 
• 
The usage rate of prokinetic agents during the first 7 days post-randomization 
• 
Occurrence of nosocomial infections from randomization to ICU discharge  
• 
Length of ICU stay 
• 
Incidence of tracheotomy, mechanical ventilation, continuous renal replacement 
therapy, and venous thrombosis from randomization to ICU discharge 
• 
Usage rate of vasoactive agents from randomization to ICU discharge 
• 
The score of National Institute of Health stroke scale at ICU discharge 
• 
Glasgow Coma Scale at ICU discharge 
• 
Modified Rankin scale at ICU discharge 
• 
Modified Rankin scale at 90 days 
15.3 Safety outcomes 
• 
All-cause mortality during ICU stay  
• 
All-cause mortality at 28 days 
• 
Incidence of cardiac failure from randomization to ICU discharge 
• 
Incidence of gastrointestinal complications (Vomiting, diarrhea, gastric retention, 
gastrointestinal bleeding) during the first 7 days post-randomization 
 
16. Assessment 
16.1 Assessment of efficacy 
• 
Pneumonia 

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The primary outcome is the incidence of post stroke pneumonia, occurring from 
randomization until the end of the 7-day intervention period. Pneumonia will be 
defined and adjudicated using predefined criteria established by the Centers for 
Disease Control and Prevention (CDC), encompassing ventilator-associated 
pneumonia (VAP), non-ventilator-associated pneumonia, and other lower respiratory 
tract infections32. If a patient dies within 7 days, pneumonia is counted only if it 
occurred before death. If a patient is discharged from the ICU or transitions to oral 
feeding within 7 days, pneumonia occurring after that point but still within the 7-day 
window is included. The time from randomization to the onset of post-stroke 
pneumonia within the first 7 days was prespecified as a secondary endpoint. All 
investigators at participating sites will be trained to identify and report all potential 
pneumonia events throughout the study period. The EAC will adjudicate all reported 
potential pneumonia events while blinded to treatment assignment. The Committee 
will review all supporting documentation, including the blinded imaging assessment 
from the Core Imaging Laboratory, to determine the final diagnosis based on 
predefined criteria.  
 
• 
Nosocomial infections 
The analysis for this objective will utilize a binary endpoint of all new-onset, 
infections (including sepsis, urinary tract infections, bacteremia, etc.) from 
randomization to ICU discharge, defined by CDC/NHSN criteria32. This composite 
endpoint, as a key secondary outcome, will be tested for statistical significance under 
a pre-specified multiple testing strategy.  
 
• 
Daily calorie and protein delivery 
This endpoint assesses the adequacy of nutritional support by measuring daily caloric 
(kcal/day) and protein (g/day) delivery from all nutritional sources (EN and PN) 
during the 7-day intervention period. Total caloric intake will specifically include 
contributions from both nutritional formulations and non-nutritional intravenous 
sources, such as dextrose and propofol. 

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• 
Insulin Dose 
This endpoint was defined as mean daily insulin dose during the 7-day intervention 
period. 
 
• 
The usage rate of prokinetic agents 
The overall proportion of patients receiving at least one dose of a prokinetic agent 
(e.g., erythromycin, metoclopramide, mosapride) throughout the 7-day intervention.  
 
• 
Length of ICU stay 
This endpoint measures the duration from randomization to final discharge from the 
intensive care unit (ICU), calculated in whole days with any partial day rounded up 
(e.g., 6.3 days recorded as 7 days). Discharge is defined as transfer to a non-ICU 
setting (e.g., general ward), or death during the ICU stay. However, the actual timing 
of ICU discharge may be influenced by the availability of beds on regular wards, 
which could introduce bias. To more objectively reflect the patient's clinical recovery, 
this study will primarily evaluate the time to readiness for ICU discharge. This metric 
is defined as the duration from randomization to the time when the patient first meets 
all predefined clinical criteria for ICU discharge. A patient is considered ready for 
discharge upon meeting all the following conditions: a. No longer in need of, or at 
risk for needing, invasive mechanical ventilation; b. No longer in need of, or at risk 
for needing, vasoactive support; c. No agitation or altered consciousness requiring 
close monitoring and management; d. No severe acute metabolic or haematological 
disorder requiring close monitoring and management. All patients weaned from 
invasive mechanical ventilation and vasoactive drugs will be assessed daily against 
these readiness criteria. This strategy to mitigate bias from bed availability has been 
employed previously in ICU nutrition studies33. 
 
• 
The incidence of non-infection complications 
The cumulative incidence of the following clinically significant events occurring from 

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randomization until ICU discharge: tracheotomy, mechanical ventilation, continuous 
renal replacement therapy (CRRT), and venous thrombosis. Each complication will be 
analyzed and reported separately. 
-Tracheotomy: Surgical airway creation performed after randomization. 
-Mechanical ventilation: Invasive ventilation via endotracheal intubation or 
tracheostomy, initiated post-randomization and sustained for ≥24 consecutive hours.. 
Non-invasive ventilation is excluded. 
-CRRT: Any continuous extracorporeal renal support therapy (e.g., CVVH, CVVHD, 
CVVHDF) initiated post-randomization and lasting ≥24 hours. 
-Venous thrombosis: Radiologically confirmed deep vein thrombosis or pulmonary 
embolism, occurring de novo after randomization. 
 
• 
The usage rate of vasoactive agents 
The overall proportion of patients receiving at least one dose of vasoactive agents 
from randomization until ICU discharge. Vasoactive agents include norepinephrine, 
epinephrine, vasopressin, dopamine, dobutamine, and other catecholamine or 
non-catecholamine vasoactive drugs administered intravenously. Only intravenous 
administrations lasting ≥1 hour will be included. 
 
• 
The National Institutes of Health Stroke Scale 
The NIHSS is a standardized assessment tool for evaluating neurological deficits, 
which serves as a valid and reliable measure of disability and recovery after acute 
stroke. Scores range from 0 to 42, with higher scores indicating more severe 
neurological impairment. The scale encompasses multiple dimensions including level 
of consciousness, extraocular movements, motor and sensory functions, coordination, 
as well as language and speech capabilities. In this study, NIHSS assessments will be 
performed at baseline, daily during the intervention period, and on the day of 
discharge from the ICU. All assessors must undergo standardized training in NIHSS 
administration and pass a certification examination before participating in the rating 

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process. At each study site, NIHSS evaluations will be conducted by investigators 
who are blinded to treatment group assignments (See appendix 1). 
 
• 
The Glasgow Coma Scale (GCS) 
The GCS is a standardized neurological assessment tool used to objectively evaluate a 
patient’s level of consciousness based on three behavioral responses: eye opening, 
verbal performance, and motor responsiveness. Scores range from 3 to 15, with lower 
scores indicating a deeper level of impairment. In this study, assessments are 
scheduled at baseline, daily during the intervention period, and at ICU discharge, 
performed by blinded and trained assessors (See appendix 2). 
 
• 
The modified Rankin Scale (mRS) 
The mRS score is a validated and reliable clinician-reported measure of global 
disability, widely used to evaluate functional recovery after stroke. It assesses the 
degree of disability or dependence in daily activities, with scores ranging from 0 (no 
symptoms) to 6 (death). In this trial, the mRS will be assessed at two time points: on 
the day of discharge from the ICU and at 90 days (±7 days) after randomization. 
Premorbid mRS status will be retrospectively obtained and documented on the CRF. 
All follow-up assessors at each study site must undergo standardized training and 
certification in mRS administration, including the use of the Modified Rankin Scale–9 
Questions (mRS-9Q) questionnaire, prior to participating in the trial. Only those who 
successfully pass the certification process will be permitted to perform mRS 
evaluations. All assessors will remain blinded to treatment group assignments 
throughout the study. The mRS-9Q questionnaire will be employed as a structured 
interview tool to enhance the consistency and objectivity of the ratings. A written 
record of each assessment will be maintained (See appendix 3). The primary analysis 
for functional outcome will be the distribution of mRS scores at 90 days, analyzed 
using an ordinal logistic regression model (ordinal shift analysis). 
 

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16.2 Assessment of safety 
• 
All-cause mortality  
Mortality serves as a key safety endpoint in this trial, with assessment spanning two 
timeframes: all-cause mortality during the entire ICU stay (from randomization until 
ICU discharge) and all-cause mortality at 28 days (within 28±3 days after 
randomization). Mortality rates will be calculated as the number of deaths during each 
period divided by the total number of randomized subjects in each treatment group. 
 
• 
Cardiac failure  
Cardiac failure is defined as the onset or worsening of clinically significant cardiac 
dysfunction occurring between randomization and ICU discharge, diagnosed 
according to adapted AHA/ACC/HFSA criteria34. Diagnosis requires compatible 
clinical features (e.g., dyspnea, elevated jugular venous pressure, pulmonary crackles, 
or peripheral edema) supported by at least one objective criterion: elevated cardiac 
biomarkers (BNP ≥400 pg/mL or NT-proBNP ≥2000 pg/mL), echocardiographic 
evidence of structural or functional abnormality (e.g., new LVEF <40%, severe 
valvular dysfunction), or initiation of specific intravenous therapy (diuretics, 
vasodilators, or inotropes) for ≥24 hours for acute heart failure management. All 
events will be adjudicated by Clinical Events Committee blinded to treatment 
allocation. 
 
• 
Gastrointestinal complications  
The incidence of gastrointestinal complications will be assessed for events newly 
occurring from day 1 to day 7 post-randomization. These complications are defined as: 
vomiting, defined as the visible passage of enteral formula into the mouth, outside the 
mouth, or into the airway without nursing care or patient mobilization33; diarrhea, 
defined as ≥3 loose or liquid stools or more than 300 mL of liquid stool per day)35; 
gastric retention, defined as GRV >200 mL on two consecutive measurements despite 
prokinetic therapy), or the occurrence of overt vomiting or regurgitation; and 

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gastrointestinal bleeding, evidenced by haematemesis, coffee ground emesis, melaena, 
haematochezia, or bloody nasogastric aspirate36. All events require clinical 
documentation and adjudication by Clinical Events Committee, with pre-existing 
complications at baseline excluded. 
 
17. Data management guidelines 
17.1 Case Report Forms (CRFs) and data entry 
All study data for the OPENS-2 trial will be primarily captured on paper CRFs at the 
participating sites. The completed paper CRFs, along with any required supplemental 
forms (e.g., Withdrawal of Consent, Serious Adverse Event reports), will be 
submitted to the central Data Management and Coordinating Center. The hospital 
medical records and the original paper CRFs will serve as the source documents for 
the trial. The Chief Investigator is responsible for the data overall. Each participating 
center retains ownership of their local site data. Principal Investigator at each research 
site is accountable for the accuracy, completeness, and timeliness of data entry onto 
the CRFs. This responsibility may be delegated to authorized and trained site 
personnel, with oversight remaining with the PI.  
 
Following trial completion, a complete, cleaned, and de-identified final dataset will be 
created under the supervision of the Chief Investigator. This dataset will be stored 
securely with access controls. Investigators will have direct access to their own site's 
data; access to the full dataset or data from other sites will require a formal request 
and approval from the OPENS-2 Steering Committee. 
 
The investigators propose to use the following statement in the final manuscript. 
Non-identifiable individual participant data generated in this trial will be made 
available for sharing from 3 years from 9 months to 36 months after publication. The 
data will be accessible only to researchers who submit a written proposal for data use, 
which must be approved by the OPENS-2 Investigator Committee as 

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methodologically sound. Proposals should be directed to jiangwen@fmmu.edu.cn. 
 
17.2 Data quality and control 
To ensure the accuracy, completeness, and reliability of data in the OPENS-2 trial, 
standard operating procedures for data collection will be developed. Prior to study 
initiation, all site investigators will receive standardized training in CRF completion 
and must pass a certification assessment. During the study implementation phase, a 
three-tier quality control system will be enforced: investigators will perform 
immediate self-check upon CRF completion to verify data completeness and logical 
consistency; study coordinators will conduct secondary review, focusing on internal 
data consistency; and project monitors will perform periodic source data verification 
and process compliance audits. All issues identified through the quality control (QC) 
process will be formally communicated to the respective sites, requiring investigators 
to provide a formal response with supporting evidence. Prior to database locking, a 
final data cleaning process will be implemented to resolve all data discrepancies, 
followed by a review before final database lock. QC activities will be thoroughly 
documented and archived, establishing a traceable, closed-loop quality management 
system. 
 
17.3 Data security and storage 
The processing of personal data will be conducted in compliance with Chinese data 
protection laws and regulations, as well as relevant international legislation and 
established good practice. Robust measures will be implemented to ensure 
comprehensive data security, with special emphasis on protecting sensitive participant 
information. The study database will contain only de-identified data, with no 
personally identifiable information stored at any stage. All paper materials, including 
CRFs are stored in specially designed cabinets that are waterproof and fireproof, and 
only authorized staff have access to them. Discarded paper materials are shredded 
using specialized equipment, and the shredding process is supervised by two people. 
All paper source records will be retained for a minimum of 10 years from the point of 

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publication of data on the primary outcome. 
 
18. Safety 
18.1 Adverse Events 
Usually, AEs are defined in accordance with ICH E2A guidelines as any untoward 
medical occurrence in a patient receiving an investigational intervention, regardless of 
causal relationship. In the ICU setting, it is recognized that patients frequently exhibit 
abnormalities in laboratory values, signs, and symptoms as a consequence of their 
underlying critical illness or routine medical care. Such manifestations will not 
automatically be classified as AEs. An event will be considered an AE only if it meets 
either of the following criteria: (1) it is assessed as having a possible, probable, or 
definite relationship to the study treatment, or (2) it is judged to be inconsistent with 
the patient’s expected clinical course in the context of their underlying condition. All 
such cases will be referred to the Clinical Events Committee for final adjudication.  
 
When reporting, the underlying condition (e.g., "renal failure") should be documented 
rather than its manifestations (e.g., "hyperkalemia"). AE collection is limited to the 
period from initiation of study nutrition support until 48 hours after its discontinuation. 
All AEs must be followed until resolution or until a clinically adequate explanation is 
obtained, with follow-up frequency determined by the investigator. 
 
18.2 Serious Adverse Events 
The OPENS-2 trial enrolls critically ill stroke patients characterized by substantial 
baseline mortality, attributable to the seriousness of the stroke that required ICU 
management. This risk of death remains present despite the application of standard 
best-practice care. In accordance with international standards for ICU research, deaths 
considered part of the natural disease progression or expected complications of 
critical illness will not be reported as SAEs. Only those deaths deemed causally 
related to the study intervention or judged by the investigator to represent a potential 

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safety concern shall be reported as SAEs. All deaths, regardless of cause, will be 
thoroughly documented, including the cause of death, timing, and relationship to 
underlying conditions and undergo formal causality assessment by the investigators. 
All mortality data will be incorporated into the final analysis dataset for unified 
statistical analysis and reporting. 
 
The protocol mandates expedited reporting for specifically defined SAEs, with new or 
worsening heart failure events designated as the primary reportable SAE. Regardless 
of expectedness, any occurrence must be reported within 24 hours following the 
predefined SAE reporting procedure. Investigators are required to conduct a 
comprehensive assessment of the event, including determination of causality to the 
study intervention (categorized as definitely, probably, possibly, unlikely, or 
unrelated), and submit complete documentation to the Clinical Events Committee for 
final adjudication. 
 
18.3 Recording and reporting procedures 
All AEs that occur between randomization and 30 days post-randomization must be 
recorded on the CRFs. The onset date, severity, and assessed causality of any event 
must be documented using the definitions below. Within 24 hours of the investigator 
becoming aware of the SAE, all events must be reported to the trial coordinator who 
is available 24/7, using the trial specific OPENS-2 SAE Reporting Form. All sections 
of the OPENS-2 SAE Reporting Form must be completed.  
OPENS2 security desk Fax: +86 029-84775368. 
 
Table 1. Severity categorization of Adverse Event 
Grade 
Term 
Description 
Grade 1 
Mild 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 

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Grade 2 
Moderate 
Minimal, 
local, 
or 
noninvasive 
intervention 
indicated; limiting instrumental Activities of Daily 
Living (ADL). 
Grade 3 
Severe 
Medically 
significant 
but 
not 
immediately 
life-threatening; hospitalization or prolongation of 
hospitalization 
indicated; 
disabling; 
limiting 
self-care ADL. 
Grade 4 
Life-threatening 
Life-threatening consequences; urgent intervention 
indicated. 
Grade 5 
Fatal 
Death related to the AE. 
 
Table 2. Relationship definitions of Adverse Event 
Term 
Description 
None 
The adverse event is clearly and unequivocally due to a 
cause other than the trial treatment. 
Unlikely 
The available evidence does not support a causal 
relationship, as the event onset lacked a plausible temporal 
association with the trial treatment and is more clearly 
attributable to alternative factors (such as the patient's 
underlying medical condition or concomitant therapies). 
Possible 
The adverse event could be associated with the trial 
treatment, but the connection is uncertain. 
Probable 
The adverse event is likely due to the trial treatment. 
Definitely 
The adverse event is clearly and unequivocally linked to 
trial treatment and other possible contributing 
factors can be ruled out 
 
18.4 Follow up 
All AEs that lead to study withdrawal or persist at the study conclusion must be 

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followed up. Any SAE unresolved at the end of the study or at the time of a subject's 
discontinuation requires ongoing follow-up until one of the following criteria is met: 
resolution of the event, stabilization of the event, return to baseline status (if 
applicable), attribution to causes other than the study procedures, or determination 
that no additional information can be obtained. The delegated local investigator(s) 
must provide follow-up SAE Report(s) if the SAE had not resolved at the time the 
initial report was submitted. 
 
18.5 Central processing 
Upon receipt of a SAE report, clinical members of the OPENS-2 Clinical Events 
Committee, on behalf of the PI, will assess the event's severity, relationship to the 
study intervention, and expectedness to determine whether expedited reporting to the 
Ethics Committee is required. Concurrently, the Data Management and Coordinating 
Center will regularly submit safety information reports to the PI, TMG, TSC, and 
DSMB for review. 
 
19. Withdrawal 
19.1 Patient Withdrawal 
By consenting to participate in the OPENS-2 trial, the patient or their legally 
authorized representative agrees to undergo trial treatment, assessments, follow-up, 
and data collection. However, they retain the right to withdraw from the trial at any 
time without providing a reason and without any penalty or loss of benefits to which 
they are otherwise entitled. 
 
19.2 Trial Treatment Withdrawal 
The attending clinician may discontinue the trial intervention for an individual 
participant if it is deemed to be in the participant's best medical interest. The reasons 
for withdrawal must be documented in detail in the CRF. Unless consent is formally 
withdrawn, data collection and follow-up should continue in accordance with the trial 

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protocol. In cases where a patient expresses intent to discontinue trial treatment, the 
study site should explain the importance of remaining in the trial for data collection 
and follow-up. 
 
19.3 Withdrawal of Consent 
Upon withdrawal of consent for further trial participation, all intervention and data 
collection must cease immediately. A Withdrawal of Consent Form must be 
completed and submitted to the TMC. All data collected prior to the withdrawal will 
be retained for analysis. However, if the patient requests the destruction of all their 
data, the relevant data shall be securely destroyed. Patients withdrawn from the 
OPENS-2 trial will not be replaced, and this scenario has been accounted for in the 
sample size calculation. 
 
19.4 Study Site Withdrawal 
If a study site decides to cease patient recruitment before the end of the trial, the local 
PI must provide written notification to the TSC. All patients already recruited at that 
site must continue to be followed up in accordance with the OPENS-2 Trial Protocol. 
The TSC, upon recommendation from the TMC, may suspend or terminate a site's 
participation for significant or persistent protocol non-compliance. Such a decision 
will be communicated in writing. 
 
20. Trial Closure 
20.1 Timing of Trial Closure 
This trial will formally conclude once the last enrolled subject has completed the 
90-day follow-up. At this point, the Chief Investigator will submit a Trial Closure 
Declaration Form to the Ethics Committee. 
 
20.2 Archiving of Trial Documents 
Upon trial conclusion, the trial Data Management and Coordinating Center will 

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archive all central-level trial documents in accordance with ICH GCP guidelines. 
These documents, which include CRFs and other essential documents, will be 
securely stored for a minimum of 10 years before confidential destruction. 
Concurrently, the local PI is responsible for retaining locally held trial documents for 
the same 10-year duration, or longer if required by applicable regulations. Essential 
documents are defined as those that enable the evaluation of both trial conduct and 
data quality, while also serving as evidence of the site's adherence to ICH GCP and 
other regulatory requirements. All archived documents, whether stored centrally or 
locally, must be made available for regulatory inspection upon request. 
 
20.3 Early Termination of the Trial 
The Trial Steering Committee may recommend early termination of the trial based on 
recommendations from the DSMB or the TMC. The study may be terminated based 
on several considerations, including but not limited to:  
• 
Safety findings from this or other studies that indicate an unacceptable risk 
profile. 
• 
Insufficient enrollment rate or accrual that compromises the trial's feasibility or 
scientific validity.  
In such a case, the TMC will formally notify all study sites and Ethics Committees in 
writing, stating the reasons for termination and any necessary measures regarding 
participant treatment. All subjects who have been randomized will continue to 
complete follow-up as specified in the OPENS-2 trial protocol. 
 
21 Statistics 
21.1 Sample size calculation 
The sample size is based on the primary efficacy endpoint. We expect an 12.0% 
absolute difference between patients receiving trophic EN combined with SPN and 
patients receiving full EN (expected rates of post stroke pneumonia: 28% in patients 
receiving trophic EN combined with SPN and 40% in patients receiving full EN), 

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which corresponds to a risk ratio (RR) of 0.7037,38. In order to demonstrate the 
expected treatment effect with a type-1 error alpha of 0.05 (two tailed) and a power of 
80%, a sample size of n= 490 patients (n=245 per treatment group) is required. To 
safeguard against dilution of the treatment effect associated with an approximate 10% 
attrition rate (due to loss to follow-up, consent withdrawal and other reasons), we plan 
to enroll n=546 patients (n=273 per treatment group) for this study. 
 
21.2 Analysis population 
• 
Intention-to-Treat Population 
The ITT population includes all patients randomized into the trial, even if the subject 
does not receive the correct nutritional support, or does not follow the protocol until 
completion. This population will serve as the primary analysis set for efficacy 
endpoints, with all subjects analyzed according to the treatment group assigned during 
randomization.  
 
• 
Per-Protocol Population 
The PP population consists of patients from the ITT population who received the 
assigned nutritional support as randomized and complied with key trial procedures 
without major protocol violations that could impact efficacy outcomes. As this is an 
open-label trial, major protocol deviations will be identified through unblinded review 
prior to database lock. Patients will be excluded from the PP population based on the 
following criteria at a minimum: 
- 
Deviations in Nutrition Support Administration. 
Failure to achieve 7 days of nutrition support duration, unless the discontinuation 
is due to patient death, discharge from the ICU, the achievement of adequate oral 
intake, or is supported by a valid clinical justification; 
- 
Deviations in Nutrition Route.  
a) Failure to implement the assigned nutritional strategy according to 
randomization; 
b) (Trophic EN with SPN group) Exceeding the enteral nutrition rate limit (as 

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defined per protocol) for more than 24 consecutive hours;  
c) (Full EN group) Initiation of parenteral nutrition without appropriate clinical 
justification; 
d) Cessation of all nutritional support for more than 48 consecutive hours without 
valid medical reasons; 
- 
Other Major Deviations.  
a) Violation of inclusion/exclusion criteria with subsequent randomization 
b) Failure to perform protocol-required nutrition monitoring and data collection 
c) Serious violations of enteral/parenteral nutrition preparation and administration 
protocols. 
All protocol deviations must be thoroughly documented in the CRF(s) with 
explanations. The Steering Committee will provide final confirmation of all 
deviations prior to database lock and any analysis by treatment group.  
 
• 
Safety Population 
The Safety Population comprises all randomized patients who initiated nutritional 
support regimen. Patients who violated the randomization protocol will be 
additionally analyzed according to the actual nutritional strategy they received in a 
supplementary analysis. The classification of patients for the 'as-treated' analysis must 
be completed prior to database unblinding. Patients who immediately withdrew 
consent after randomization without receiving any nutritional support will be 
excluded from the Safety Population. 
 
21.3 Interim analysis 
No interim analysis is planned for this study. 
 
21.4 Analysis of results 
The efficacy analyses will be performed on the intention-to-treat (ITT) population. 
For the primary outcome, a modified Poisson regression model will be used to 
compare the proportions between treatment groups. The risk ratio (RR) with its 95% 

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confidence interval (CI) will be reported. An adjusted analysis will also be performed, 
adjusting for pre-specified baseline covariates (e.g., age, NIHSS at ICU admission, 
stroke type, and history of diabetes). Subgroup analyses will be conducted to explore 
treatment effect consistency across the following pre-specified subgroups: age (≤70 
vs. >70 years), Stroke severity (NIHSS at ICU admission 11-19 vs. ≥20),stroke type 
(ischemic vs. hemorrhagic), history of diabetes , consciousness level (GCS 9–12 vs. 
≤8), and time from stroke onset to nutrition initiation (≤24 vs. >24 hours), Missing 
primary outcome data will be handled using multiple imputation. Sensitivity analyses 
will assess the impact of missing data, competing risks such as death, and potential 
center effects. 
 
For binary secondary endpoints (e.g., tracheotomy, mechanical ventilation), a 
modified Poisson regression model will be used to estimate the RR and 95% CI as did 
for the primary endpoint analysis. For continuous secondary endpoints (e.g., 
calorie/protein delivery, NIHSS score at ICU discharge), linear regression models 
with treatment group as the study variable and baseline measurement as covariate if 
available will be applied to estimate mean differences and 95% CI; if normality 
assumptions are violated, the win ratio method will be employed. For ordinal 
secondary outcomes (e.g., 90-day mRS), an ordinal logistic regression model will be 
fitted to estimate the common odds ratio (cOR) and 95% CI; if the proportional odds 
assumption is violated, the generalized odds ratio (GenOR) with 95% CI will be 
reported. Time-to-event secondary outcomes (e.g., time to pneumonia) will be 
analyzed using survival methods, specifically the Fine-Gray subdistribution hazards 
model, accounting for competing risks where appropriate. Safety analyses will be 
performed on the safety population, grouped according to the actual nutritional 
support received. Safety endpoints (e.g., all-cause mortality, cardiac failure, 
gastrointestinal complications) will be compared using modified Poisson regression 
models. 

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22 Ethical and regulatory consideration 
22.1 Ethical compliance 
The OPENS-2 trial will be conducted in accordance with the ethical principles of the 
Helsinki Declaration. Prior to the initiation of the trial, the protocol, informed consent 
form(s), and all other study materials must receive written approval and authorization 
from the Ethics Committee of Xijing Hospital, Fourth Military Medical University. 
Each participating hospital’s Research Ethics Board (REB) has also approved the trial 
protocol and informed consent form(s). No trial procedures may commence at a 
center before these approvals are in place. All substantial amendments to the protocol 
will be submitted promptly to the REBs for their review and approval before 
implementation. The continued oversight of the trial will be ensured through the 
submission of annual progress reports to the REBs. 
 
The two nutritional strategies under investigation (trophic EN with SPN vs. full EN) 
are both utilized in clinical practice for the management of acute severe stroke. 
However, their comparative effects on the incidence of pneumonia and other clinical 
outcomes remain uncertain, which is the primary scientific question this trial aims to 
address. Therefore, patient participation is associated with the potential for direct 
benefit, and investigators are committed to ensuring that all enrolled subjects receive 
protocol-defined care under close monitoring. The OPENS-2 trial employs an 
independent DSMB to periodically review accumulating safety and efficacy data. The 
involvement of this independent body ensures that the safety and well-being of the 
subjects remain the highest priority at all times. 
 
22.2 Monitoring and Quality Assurance 
The OPENS-2 trial will implement a comprehensive, risk-based monitoring strategy. 
This approach combines ongoing remote oversight with targeted on-site visits to 
ensure participant safety, protocol compliance, and data integrity, with monitoring 

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intensity dynamically adjusted based on continuous performance evaluation. 
 
Initial On-Site Assessment 
All participating centers will undergo an initial monitoring visit (conducted on-site or 
remotely) after the enrolment of their first 10-15 patients. The primary objectives of 
this visit are: 
• 
To verify that data recorded in the paper CRFs are accurate and complete. Key 
data for 100% of the initial patients will undergo this verification. 
• 
To assess the overall conduct of the trial at the site, including the informed 
consent process, study nutritional preparation management, and adherence to 
Good Clinical Practice (GCP). 
 
Continuous Oversight and Performance Evaluation 
The monitoring team will regularly contact the centers through field visits, emails or 
phone calls, and send inspectors to assess the progress of the trial, the compliance of 
investigators and patients with the trial protocol, and to resolve urgent issues. 
• 
CRF Review: As completed CRF pages are submitted, the data management team 
will perform checks for completeness, legibility, and consistency. Queries will be 
generated and sent to the site for resolution. 
• 
Performance Metrics Tracking: Key indicators such as recruitment rates, 
screening failure reasons, and the timeliness of CRF submission will be monitored 
to identify centers performing outside of expected parameters. 
The findings from the initial monitoring visit, combined with the insights from this 
continuous centralized oversight, will be used to assign a risk status to each center. 
 
Dynamic, Risk-Based Follow-up Monitoring 
The frequency and intensity of subsequent on-site monitoring will be directly 
determined by the assigned risk status: 
• 
Centers with No Noticeable Findings: Sites demonstrating consistent protocol 
compliance, high-quality CRF completion, and timely query resolution will be 

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classified as low risk. These centers will not undergo further routine scheduled 
on-site monitoring but will remain under continuous centralized oversight. 
• 
Centers with Noticeable Findings: Sites with identified issues in data quality, 
protocol compliance, or GCP will be classified as elevated risk. These centers will 
receive a follow-up on-site visit within 4 months to address the specific findings. 
• 
Centers with persistent problems: If significant issues continue, monitoring will be 
intensified, including on-site visits at least three times per year. During these visits, 
source data verification (SDV) will be performed on a minimum of 50% of CRFs 
and associated source data. 
• 
Resolution and De-escalation: Once consecutive monitoring activities confirm that 
all significant findings have been resolved and site performance has stabilized, the 
intensified monitoring schedule will be discontinued, and the center's risk status 
will be downgraded accordingly. 
 
Throughout the trial, the monitor will work closely with site personnel to review 
CRFs, resolve data queries, and ensure the accurate and complete documentation of 
all trial data. 
 
22.3 Liability and Insurance 
The study sponsor shall maintain an appropriate insurance policy to cover claims 
arising from trial-related injury in accordance with applicable national laws. A 
certificate of this insurance will be provided to the investigator of the coordinating 
center where required. 
 
23. Publication and dissemination policy 
23.1 Dissemination Plan 
Ongoing trial progress will be communicated to local PIs via regular newsletters, 
emails, and offline conferences. Final results will be presented at relevant national and 
international scientific conferences and meetings. The findings will also be submitted 

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for publication in peer-reviewed scientific journals. A summary of the findings will be 
made available to patients and the public through patient support groups and the 
official trial website. 
 
23.2 Reporting Obligations 
The Data Management and Coordinating Center is responsible for submitting the trial 
results to the relevant Regulatory Authorities and Ethics Committees. This includes 
the provision of an annual safety report and a final study report upon trial completion, 
in accordance with applicable regulations. 
 
23.3 Publication Policy 
The primary manuscript for publication will be based on the pre-defined statistical 
analysis plan outlined in this clinical trial protocol. All publications and presentations 
will undergo review by the Trial Steering Committee prior to submission to ensure 
accuracy and consistency. All patient data will be anonymized prior to any 
publication or public dissemination. The authorship of the primary manuscript and 
any major secondary publications will be determined by the Trial Steering Committee 
based on the ICMJE criteria, with the intention of including key contributors from the 
participating sites. Investigators are not permitted to publish trial-related data that 
pertains to the overall trial results independently of the central publication committee 
to prevent fragmentation of findings. However, investigators retain the right to access 
and analyze data from their own site for local quality improvement or methodological 
studies, provided that any such publication is coordinated with the central committee 
to ensure consistency and avoid overlap with the primary trial outputs. 
 
24. References 
1. Wang W, Jiang B, Sun H, et al. Prevalence, incidence, and mortality of stroke in China: Results 
from 
a 
nationwide 
population-based 
survey 
of 
480 
687 
adults. 
Circulation. 
2017;135(8):759-771. doi:10.1161/CIRCULATIONAHA.116.025250 
2. Cohen DL, Roffe C, Beavan J, et al. Post-stroke dysphagia: A review and design considerations 

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for future trials. Int J Stroke. 2016;11(4):399-411. doi:10.1177/1747493016639057 
3. Suda S, Aoki J, Shimoyama T, et al. Stroke-associated infection independently predicts 
3-month poor functional outcome and mortality. J Neurol. 2018;265(2):370-375. 
doi:10.1007/s00415-017-8714-6 
4. Westendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, De Beek DV. Post-stroke 
infection: A systematic review and meta-analysis. BMC Neurol. 2011;11(1):110. 
doi:10.1186/1471-2377-11-110 
5. Finlayson O, Kapral M, Hall R, Asllani E, Selchen D, Saposnik G. Risk factors, inpatient care, 
and outcomes of pneumonia after ischemic stroke. Neurology. 2011;77(14):1338-1345. 
doi:10.1212/WNL.0b013e31823152b1 
6. De Montmollin E, Ruckly S, Schwebel C, et al. Pneumonia in acute ischemic stroke patients 
requiring invasive ventilation: Impact on short and long-term outcomes. J Infect. 
2019;79(3):220-227. doi:10.1016/j.jinf.2019.06.012 
7. Kudsk KA. Current aspects of mucosal immunology and its inﬂuence by nutrition. 
8. Jabbar A, Chang W, Dryden GW, McClave SA. Gut immunology and the differential response 
to 
feeding 
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starvation. 
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Clin 
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2003;18(6):461-482. 
doi:10.1177/0115426503018006461 
9. McClave SA, DeMeo MT, DeLegge MH, et al. North American summit on aspiration in the 
critically ill patient: Consensus statement. J Parenter Enter Nutr. 2002;26(6S). 
doi:10.1177/014860710202600613 
10.Uozumi M, Sanui M, Komuro T, et al. Interruption of enteral nutrition in the intensive care unit: 
A single-center survey. J Intensive Care. 2017;5(1):52. doi:10.1186/s40560-017-0245-9 
11. Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in 
critically ill adults. N Engl J Med. 2014;371(18):1673-1684. doi:10.1056/NEJMoa1409860 
12. The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) 
Clinical Trials Network, Rice TW, Wheeler AP, et al. Initial trophic vs full enteral feeding in 
patients with acute lung injury: The EDEN randomized trial. JAMA J Am Med Assoc. 
2012;307(8):795-803. doi:10.1001/jama.2012.137 
13. Zhao J, Yuan F, Song C, et al. Safety and efficacy of three enteral feeding strategies in patients 
with severe stroke in China (OPENS): A multicentre, prospective, randomised, open-label, 
blinded-endpoint 
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doi:10.1016/S1474-4422(22)00010-2 
14. Gramlich L, Kichian K, Pinilla J, Rodych NJ, Dhaliwal R, Heyland DK. Does enteral nutrition 
compared to parenteral nutrition result in better outcomes in critically ill adult patients? A 
systematic 
review 
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literature. 
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doi:10.1016/j.nut.2004.06.003 
15. Ji R, Wang D, Shen H, et al. Interrelationship among common medical complications after 
acute stroke: Pneumonia plays an important role. Stroke. 2013;44(12):3436-3444. 
doi:10.1161/STROKEAHA.113.001931 
16. Smith CJ, Bray BD, Hoffman A, et al. Can a novel clinical risk score improve pneumonia 
prediction in acute stroke care? A UK multicenter cohort study. J Am Heart Assoc. 
2015;4(1):e001307. doi:10.1161/JAHA.114.001307 
17. Teh WH, Smith CJ, Barlas RS, et al. Impact of stroke-associated pneumonia on mortality, 
length of hospitalization, and functional outcome. Acta Neurol Scand. 2018;138(4):293-300. 
doi:10.1111/ane.12956 
18. Ji R, Shen H, Pan Y, et al. Novel risk score to predict pneumonia after acute ischemic stroke. 
Stroke. 2013;44(5):1303-1309. doi:10.1161/STROKEAHA.111.000598 
19. Ji R, Shen H, Pan Y, et al. Risk score to predict hospital-acquired pneumonia after spontaneous 
intracerebral 
hemorrhage. 
Stroke. 
2014;45(9):2620-2628. 
doi:10.1161/STROKEAHA.114.005023 
20. De Jonge JC, Van De Beek D, Lyden P, et al. Temporal profile of pneumonia after stroke. 
Stroke. 2022;53(1):53-60. doi:10.1161/STROKEAHA.120.032787 
21. Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing 
pneumonia in patients with dysphagia (STROKE-INF): A prospective, cluster-randomised, 
open-label, masked endpoint, controlled clinical trial. The Lancet. 2015;386(10006):1835-1844. 
doi:10.1016/S0140-6736(15)00126-9 
22. Westendorp WF, Vermeij JD, Zock E, et al. The preventive antibiotics in stroke study (PASS): 
A pragmatic randomised open-label masked endpoint clinical trial. The Lancet. 
2015;385(9977):1519-1526. doi:10.1016/S0140-6736(14)62456-9 
23. Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive 
care unit. Clin Nutr. 2019;38(1):48-79. doi:10.1016/j.clnu.2018.08.037 
24. Altintas ND, Aydin K, Türkoğlu MA, Abbasoğlu O, Topeli A. Effect of enteral versus 
parenteral nutrition on outcome of medical patients requiring mechanical ventilation. Nutr Clin 
Pract. 2011;26(3):322-329. doi:10.1177/0884533611405790 
25. Reignier J, Boisramé-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in 
ventilated adults with shock: A randomised, controlled, multicentre, open-label, parallel-group 
study 
(NUTRIREA-2). 
The 
Lancet. 
2018;391(10116):133-143. 
doi:10.1016/S0140-6736(17)32146-3 
26. Compher C, Bingham AL, McCall M, et al. Guidelines for the provision of nutrition support 
therapy in the adult critically ill patient: The American society for parenteral and enteral 

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nutrition. J Parenter Enter Nutr. 2022;46(1):12-41. doi:10.1002/jpen.2267 
27. Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with supplemental 
parenteral nutrition in critically ill patients: A randomised controlled clinical trial. The Lancet. 
2013;381(9864):385-393. doi:10.1016/S0140-6736(12)61351-8 
28. Shi J, Wei L, Huang R, Liao L. Effect of combined parenteral and enteral nutrition versus 
enteral nutrition alone for critically ill patients: A systematic review and meta-analysis. 
Medicine (Baltimore). 2018;97(41):e11874. doi:10.1097/MD.0000000000011874 
29. Taylor BE, McClave SA, Martindale RG, et al. Guidelines for the provision and assessment of 
nutrition support therapy in the adult critically ill patient: Society of critical care medicine 
(SCCM) and American society for parenteral and enteral nutrition (a.S.P.E.N.). Crit Care Med. 
2016;44(2):390-438. doi:10.1097/CCM.0000000000001525 
30. Fuentes B, Ntaios G, Putaala J, et al. European stroke organisation (ESO) guidelines on 
glycaemia 
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doi:10.1177/2396987317742065 
31. Powers WJ, Rabinstein AA, Ackerson T, et al. 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 professionals from the American heart 
association/american 
stroke 
association. 
Stroke. 
2019;50(12). 
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32. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health 
care–associated infection and criteria for specific types of infections in the acute care setting. 
Am J Infect Control. 2008;36(5):309-332. doi:10.1016/j.ajic.2008.03.002 
33. Reignier J, Le Gouge A, Lascarrou JB, et al. Impact of early low-calorie low-protein versus 
standard-calorie standard-protein feeding on outcomes of ventilated adults with shock: Design 
and conduct of a randomised, controlled, multicentre, open-label, parallel-group trial 
(NUTRIREA-3). BMJ Open. 2021;11(5):e045041. doi:10.1136/bmjopen-2020-045041 
34. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the 
management of heart failure: A report of the American college of cardiology/american heart 
association joint committee on clinical practice guidelines. Circulation. 2022;145(18). 
doi:10.1161/CIR.0000000000001063 
35. Riddle MS, DuPont HL, Connor BA. ACG clinical guideline: Diagnosis, treatment, and 
prevention of acute diarrheal infections in adults. Am J Gastroenterol. 2016;111(5):602-622. 
doi:10.1038/ajg.2016.126 
36. the SUP-ICU co-authors, Krag M, Perner A, et al. Prevalence and outcome of gastrointestinal 
bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care 
Med. 2015;41(5):833-845. doi:10.1007/s00134-015-3725-1 

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37. De Jonge JC, Van De Beek D, Lyden P, et al. Temporal profile of pneumonia after stroke. 
Stroke. 2022;53(1):53-60. doi:10.1161/STROKEAHA.120.032787 
38. Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with supplemental 
parenteral nutrition in critically ill patients: A randomised controlled clinical trial. The Lancet. 
2013;381(9864):385-393. doi:10.1016/s0140-6736(12)61351-8 
 

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25. Appendixes 
25.1 Appendix 1 NIHSS  
 
NIHSS page 1 
 
 
 

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NIHSS page 2 
 
 
 
 
 
 
 
 
NIHSS page 3 

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NIHSS page 4 
 

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NIHSS page 5 
 
 
 
 

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NIHSS page 6 
 
 
 

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25.2 Appendix 2 GCS  
 
1. Sedated Patients: Assess GCS during daily sedation interruption (DSI) when clinically safe; if 
DSI is contraindicated, mark “NT (Not Testable – Sedated)”. 
2. Intubated Patients: Label verbal subscore as “T” (Intubated); calculate total score as E+M  
3. Stimulus Protocol: Prioritize non-destructive pain stimuli (supraorbital pressure > nail bed 
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4. Neuromuscular Blockade: Document use of NM blockers; GCS motor subscore is “NT” until 
blockade is reversed. 
Teasdale, G., & Jennett, B. (1974). Assessment of coma and impaired consciousness: A practical scale. The Lancet, *304*(7872), 81-84. 
https://www.glasgowcomascale.org/download-aid/ 

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25.3 Appendix 3 mRS  
 
 
 
 
 
Level of Function Survey – mRS-9Q  

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Q 1: Do you have any symptoms that are bothering you? 
□Yes □No 
Q 2: Are you able to do the same work as before? 
□Yes □No 
Q 3: Are you able to keep up with your hobbies? 
□Yes □No 
Q 4: Have you maintained your ties to friends and family? 
□Yes □No 
Q 5: Do you need help making a simple meal, doing household chores, or balancing a 
checkbook? 
□Yes □No 
Q 6: Do you need help with shopping or traveling close to home? 
□Yes □No 
Q 7: Do you need another person to help you walk? 
□Yes □No 
Q 8: Do you need help with eating, going to the toilet, or bathing? 
□Yes □No 
Q 9: Do you stay in bed most of the day and need constant nursing care? 
□Yes □No 
mRS-9Q: the mRS calculator (http://www.modifiedrankin.com/) 
 

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25.4 Appendix 4 NRS-2002 
Nutritional Risk Screening (NRS) 2002 
Patient Information 
Name: 
Gender: 
Age (y): 
Admission No.: 
Height (m): 
Weight (kg): 
BMI (kg/m²): 
Assessment Date: 
Clinical Diagnosis: 
Albumin (g/L): 
Assessor: 
Signature: 
1.Initial screening 
Answer the following questions. If any answer is "Yes", proceed to the final 
screening. If all answers are "No", the patient is re-screened at weekly intervals. If the 
patient e.g. is scheduled for a major operation, a preventive nutritional care plan is 
considered to avoid the associated risk status. 
 
Is the Body Mass Index (BMI) < 20.5 kg/m²? □ Yes □ No 
• 
Has the patient lost weight in the previous 3 months? □ Yes □ No 
• 
Was nutritional intake reduced in the previous week? □ Yes □ No 
• 
Is the patient severely ill? (e.g., in intensive care) □ Yes □ No 
2. Final Screening 
Score separately for impaired nutritional status and severity of disease (stress 
metabolism), then calculate the total score. 
A. Impaired Nutritional Status Score (0-3 points) 
Score 
Criteria 
□ Check 
0 
No impairment of nutritional status 
□ 
1 (Mild) 
Weight loss > 5% in 3 months; OR 
nutritional intake 50-75% of normal 
requirement in the previous week 
□ 
2 (Moderate) 
Weight loss > 5% in 2 months; OR BMI □ 

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18.5-20.5 kg/m² + impaired general 
condition; OR nutritional intake 25-50% 
of normal requirement in the previous 
week 
3 (Severe) 
Weight loss > 5% in 1 month (or > 15% 
in 3 months); OR BMI < 18.5 kg/m² + 
impaired 
general 
condition; 
OR 
nutritional intake 0-25% of normal 
requirement in the previous week 
□ 
Subtotal (Nutritional Status): ______ 
B. Severity of Disease Score (0-3 points) 
Score 
Criteria 
□ Check 
0 
Normal nutritional requirements (no stress 
metabolism) 
□ 
1 (Mild) 
Hip fracture; chronic diseases with acute 
complications (e.g., cirrhosis, COPD, 
chronic hemodialysis, diabetes, oncology) 
□ 
2 (Moderate) 
Major abdominal surgery, stroke, severe 
pneumonia, hematologic malignancy 
□ 
3 (Severe) 
Head injury, bone marrow transplantation, 
intensive care patients (APACHE II > 10) 
□ 
Subtotal (Disease Severity): ______ 
3. Total Score Calculation & Interpretation 
1. Age adjustment: Add 1 point if the patient is > 70 years old (to account for 
frailty). □ ≥70 y (1 point) □ <70 y (0 point) 
2. Total Score = Nutritional Status Score + Disease Severity Score + Age 
Adjustment Score: ______ 
3. Interpretation: 

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Total score ≥ 3: Nutritional risk present; initiate nutritional support planning. 
Total score < 3: No obvious nutritional risk; repeat screening weekly. 
Reference: Kondrup, J., Allison, S. P., Elia, M., Vellas, B., Plauth, M., & ESPEN. (2003). ESPEN guidelines for 
nutrition screening 2002. Clinical Nutrition, 22(4), 415-421. 

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25.5 Appendix 5 APACHE Ⅱ 
Acute Physiology and Chronic Health Evaluation Ⅱ 
Patient Information 
Name: 
Gender: 
Age (y): 
Admission No.: 
ICU Admission Time: 
Assessment Time (within 
24h of ICU admission): 
Assessor: 
Signature: 
1. Acute Physiology Score (APS) (0-60 points) 
Record the worst value of each parameter within 24 hours after ICU admission. Score 0-4 points 
for each item; total APS = sum of individual scores. 
Parameter 
0 Points 
1 Point 
2 Points 
3 Points 
4 Points 
Temperature (℃) 
36-38.4 
38.5-38.9 
39.0-40.9 
≥41.0 
≤35.9 
Mean 
Arterial 
Pressure (mmHg) 
70-109 
110-139 
140-179 
≥180 
≤69 
Heart Rate (bpm) 
70-109 
110-139 
140-179 
≥180 
≤69 
Respiratory 
Rate 
(breaths/min) 
12-24 
25-34 
35-49 
≥50 
≤11 
PaO₂/FiO₂ (mmHg) 
≥300 
- 
200-299 
<200 
(with 
mechanical 
ventilation) 
- 
Arterial pH 
7.33-7.49 
7.50-7.59 
7.60-7.69 
≥7.70 
≤7.32 
Serum 
Sodium 
(mmol/L) 
130-149 
150-154 
155-159 
≥160 
≤129 
Serum 
Potassium 
(mmol/L) 
3.5-5.4 
5.5-5.9 
6.0-6.9 
≥7.0 
≤3.4 
Serum 
Creatinine 
(mg/dL) (×2 for 
acute renal failure) 
≤1.4 
1.5-1.9 
2.0-3.4 
≥3.5 
- 

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Hematocrit (%) 
30-45.9 
46.0-49.9 
≥50.0 
- 
≤29.9 
White Blood Cell 
Count (10³/mm³) 
3.0-14.9 
15.0-19.9 
≥20.0 
- 
≤2.9 
Glasgow 
Coma 
Scale (GCS) 
15 
13-14 
10-12 
7-9 
≤6 
Acute Physiology Score (APS) Subtotal: ______ 
2. Age Score (0-6 points) 
Age 
Score 
□ Check 
≤44 years 
0 
□ 
45-54 years 
2 
□ 
55-64 years 
3 
□ 
65-74 years 
5 
□ 
≥75 years 
6 
□ 
Age Score Subtotal: ______ 
3. Chronic Health Score (0/2/5 points) 
Score only if the patient had severe organ dysfunction or immunocompromise before ICU 
admission. 
Condition 
Score  
(Elective Surgery) 
Score 
 (Non-Surgery/ 
Emergency Surgery) 
□ Check 
No severe chronic organ dysfunction 
or immunocompromise 
0 
0 
□ 
Severe organ dysfunction (NYHA 
Class Ⅳ heart failure, chronic 
hypoxia/obstructive lung disease, 
chronic dialysis, cirrhosis with portal 
hypertension, 
etc.) 
or 
2 
5 
□ 

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immunocompromise (chemotherapy, 
radiotherapy, AIDS, leukemia, etc.) 
Chronic Health Score Subtotal: ______ 
4. Total Score Calculation & Interpretation 
4.1 Total APACHE-II Score = APS Subtotal + Age Score Subtotal + Chronic Health Score 
Subtotal. Total score range: 0-71 points. 
4.2 Interpretation: The higher the total score, the more severe the patient's condition and the worse 
the prognosis.  
Score 0-4: Low severity, low mortality risk. 
Score 5-9: Mild severity, mild mortality risk. 
Score 10-14: Moderate severity, moderate mortality risk. 
Score 15-19: Severe severity, high mortality risk. 
Score ≥20: Critical severity, very high mortality risk. 
Reference: Knaus, W. A., Draper, E. A., Williams, R. G., & Zimmerman, J. E. (1985). APACHE Ⅱ: a severity of 
disease classification system. Critical Care Medicine, 13(10), 818-829.