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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Final protocol 
(Issue Date: 22nd September 2023) 
 
 

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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 2.1 
Protocol Version date:    22/09/2023 
 
Name&Role:                     Signature:                   Date: 
Chief investigator:  
Professor Wen Jiang           
            22 Sep 2023              

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Protocol Version History 
Version Date 
Version 
Summary of main changes from previous version 
26/07/2022 
1.0 
NA 
20/07/2023 
2.0 
 
Intervention optimization (Section 13.3) 
 
Expanding exclusion criteria (Section 8.2) 
22/09/2023 
2.1 
 
Secondary outcome measure specification 
(Section 15.2&16.1) 
 
Adding pre-specified exploratory endpoints and 
corresponding analytical methods (Section 
15.4&21.4) 
 
Improving the reliability of the statistical 
analysis by expanding adjusted and subgroup 
analyses, and refining sensitivity analyses 
(Section 21.4) 
 
 
 
 

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Table of Contents 
1. Study synopsis ............................................................................................................................. 7 
2. Flow chart and schedule of assessment ................................................................................... 11 
2.1 Flow Chart ....................................................................................................................... 11 
2.2 Schedule of Assessments ................................................................................................. 11 
3. List of Abbreviations ................................................................................................................. 13 
4. Background................................................................................................................................ 15 
5. Study objectives ......................................................................................................................... 18 
5.1 Primary Objectives ......................................................................................................... 18 
5.2 Secondary Objectives ...................................................................................................... 18 
6. Organizational Structure.......................................................................................................... 19 
6.1 Trial Steering Committee ............................................................................................... 19 
6.2 Data Safety and Monitoring Board ............................................................................... 19 
6.3 Ethics Advisory Board .................................................................................................... 20 
6.4 Trial Management Committee ....................................................................................... 20 
6.5 Data Management and Coordinating Center ............................................................... 20 
6.6 Imaging Core Laboratory .............................................................................................. 21 
6.7 Endpoint Adjudication Committee ................................................................................ 21 
6.8 Clinical Events Committee ............................................................................................. 21 
7. Trial Design ................................................................................................................................ 22 
8. Selection of participants ........................................................................................................... 22 
8.1 Inclusion Criteria ............................................................................................................ 22 
8.2 Exclusion Criteria ........................................................................................................... 23 
9. Informed Consent ..................................................................................................................... 24 
9.1 Patients with Capacity to Consent ................................................................................. 24 
9.2 Patients Lacking Capacity to Consent .......................................................................... 24 
10. Imaging .................................................................................................................................... 25 
11. Randomization procedures ..................................................................................................... 25 
12. Blinding/Unblinding................................................................................................................ 26 
13. Trial interventions ................................................................................................................... 26 
13.1 Calculation of Caloric and Protein Requirements ..................................................... 26 
13.2 Full enteral feeding ....................................................................................................... 27 
13.3 Trophic EN combined with SPN .................................................................................. 27 
13.4 Delivery and Management of EN and PN ................................................................... 27 
13.5 Blood Glucose Management30, 31 .................................................................................. 29 
14. Study Schedule ........................................................................................................................ 29 

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14.1 Enrollment period (Visit V0, Randomization) ............................................................ 30 
14.1.1 Pre-enrollment (Visit V0) ................................................................................... 30 
14.1.2 Randomization (R) ............................................................................................. 30 
14.2 Treatment period .......................................................................................................... 31 
14.3 Critical Care Unit Discharge (Visit V1) ...................................................................... 31 
14.4 Follow Up period ........................................................................................................... 32 
14.4.1 At 28 days post-randomization (Visit V2) ........................................................ 32 
14.4.2 At 90 days post-randomization (Visit V3) ........................................................ 32 
15. Outcomes ................................................................................................................................. 32 
15.1 Primary outcomes ......................................................................................................... 32 
15.2 Secondary efficacy outcomes ........................................................................................ 32 
15.3 Safety outcomes ............................................................................................................. 33 
15.4 Exploratory endpoints .................................................................................................. 33 
16. Assessment ............................................................................................................................... 33 
16.1 Assessment of efficacy ................................................................................................... 33 
16.2 Assessment of safety ...................................................................................................... 37 
17. Data management guidelines ................................................................................................. 39 
17.1 Case Report Forms (CRFs) and data entry ................................................................ 39 
17.2 Data quality and control ............................................................................................... 39 
17.3 Data security and storage ............................................................................................. 40 
18. Safety ........................................................................................................................................ 40 
18.1 Adverse Events .............................................................................................................. 40 
18.2 Serious Adverse Events................................................................................................. 41 
18.3 Recording and reporting procedures .......................................................................... 42 
18.4 Follow up ........................................................................................................................ 43 
18.5 Central processing ......................................................................................................... 44 
19. Withdrawal .............................................................................................................................. 44 
19.1 Patient Withdrawal ....................................................................................................... 44 
19.2 Trial Treatment Withdrawal ....................................................................................... 44 
19.3 Withdrawal of Consent ................................................................................................. 44 
19.4 Study Site Withdrawal .................................................................................................. 45 
20. Trial Closure ............................................................................................................................ 45 
21. Statistics ................................................................................................................................... 46 
21.1 Sample size calculation ................................................................................................. 46 
21.2 Analysis population ....................................................................................................... 47 
21.3 Interim analysis ............................................................................................................. 48 
21.4 Analysis of results .......................................................................................................... 48 
22. Ethical and regulatory consideration .................................................................................... 50 
22.1 Ethical compliance ........................................................................................................ 50 
22.2 Monitoring and Quality Assurance ............................................................................. 50 

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22.3 Liability and Insurance................................................................................................. 52 
23. Publication and dissemination policy .................................................................................... 52 
23.1 Dissemination Plan ........................................................................................................ 52 
23.2 Reporting Obligations ................................................................................................... 53 
23.3 Publication Policy .......................................................................................................... 53 
24. References ................................................................................................................................ 53 
25. Appendixes ............................................................................................................................... 58 
25.1 Appendix 1 NIHSS ........................................................................................................ 58 
25.2 Appendix 2 GCS ............................................................................................................ 64 
25.4 Appendix 4 NRS-2002 ................................................................................................... 68 
25.5 Appendix 5 APACHE Ⅱ ............................................................................................... 71 
 

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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 
Study Registry Number 
NCT05998902 
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.  

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 
Experimental: Trophic enteral feeding combined with 
supplemental parenteral nutrition. Patients will receive the 
trophic enteral feeding with a caloric target of 500kcal/d (20-
35 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. 
Admission with infection signs 
5. 
Dementia or severe disability (mRS>4) before stroke 
6. 
Antibiotics were used within the previous 7 days 
7. 
Subarachnoid 
hemorrhage, 
cerebral 
arteriovenous 
malformation 
8. 
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 

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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] 
9. 
Currently participating in other clinical trial 
10. Pregnant woman 
11. 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 utilization 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 

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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 [ordinal mRS, excellent 
outcome (mRS 0–1), and functional independence 
(mRS 0–2)] 
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 
 
 
 
 

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Intervention or comparator 
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 

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count and perform chest CT or X-ray.  
 
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 

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NRS 
Nutritional Risk Screening 
PI 
Principal Investigator 
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 

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data suggest that early supplemental PN (SPN) in combination with EN significantly 
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. 

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6. Organizational Structure 
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. 

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6.3 Ethics Advisory Board 
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. 
 

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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 
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. 
 

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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 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; 

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• 
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. 
 
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 
• 
Admission with infection signs 
• 
Dementia or severe disability (mRS>4) before stroke 
• 
Antibiotics were used within the previous 7 days 
• 
Subarachnoid hemorrhage, cerebral arteriovenous malformation 
• 
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. 
 

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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 
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 

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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. 
 
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 

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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. 
 
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 

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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. 
 
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 20–35 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: 
 

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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 
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. 

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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, 
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 

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• 
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. 
• 
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 

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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. 
• 
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 

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• 
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 
 
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 utilization 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 

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• 
Modified Rankin scale at ICU discharge 
• 
Modified Rankin scale at 90 days [ordinal mRS, excellent outcome (mRS 0–1), 
and functional independence (mRS 0–2)] 
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 
15.4 Exploratory endpoints 
• 
Hierarchical composite endpoint of all-cause mortality and post-stroke pneumonia 
within 90 days; 
• 
Hierarchical composite endpoint of all-cause mortality and post-stroke pneumonia 
within 7 days; 
• 
Time from randomization to the first occurrence of either all-cause death or post-
stroke pneumonia within 90 days. 
 
16. Assessment 
16.1 Assessment of efficacy 
• 
Pneumonia 
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 

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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. 
 
• 
Insulin Utilization  
This endpoint was defined as the proportion of patients requiring any insulin therapy 
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.  
 

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• 
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 
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, 

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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 
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 

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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), with this approach 
supplemented by key secondary analyses of the proportions of patients achieving 
functional independence (mRS 0-2) and an excellent outcome (mRS 0-1). 
 
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 

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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 
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. 
 

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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 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 

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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 
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 

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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 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. 

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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. 
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 

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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 
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-

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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 
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 

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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 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, 

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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), 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 

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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 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 

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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% 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, 
history of diabetes, history of chronic respiratory disease, and smoking.). Subgroup 

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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, 
history of chronic respiratory disease, smoking status, 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, specific clinical scenarios (including 
pneumonia occurring before nutritional support or after ICU discharge/transition to oral 
feeding), 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. The composite exploratory endpoints will be 
analyzed using win-ratio and Fine Gray competing-risk methods, respectively. 
 

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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 intensity 
dynamically adjusted based on continuous performance evaluation. 

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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. 
 
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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 
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  

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3. Stimulus Protocol: Prioritize non-destructive pain stimuli (supraorbital pressure > nail bed 
compression) to avoid skin breakdown. 
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 
□ 

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2 (Moderate) 
Weight loss > 5% in 2 months; OR BMI 
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 

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Score: ______ 
3. Interpretation: 
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 
≤1.4 
1.5-1.9 
2.0-3.4 
≥3.5 
- 

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acute renal failure) 
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 
2 
5 
□ 

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hypertension, 
etc.) 
or 
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. 
 
 

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Summary of Changes OPENS-2 PROTOCOL Version 1.0- Version 2.1 
Below is the table of changes. Deleted items are identified with Strikethrough font. Additional wording is in bold font. Revised text is formatted as bold and underlined. 
 
Protocol Version 1.0 Change From: 
Protocol Version 2.1  
Change To: 
Rationale 
Section 
1 
Study 
synopsis—Arms and 
Interventions 
Experimental: Trophic enteral feeding 
combined with supplemental parenteral 
nutrition. Patients will receive the trophic 
enteral feeding with a caloric target of 
500kcal/d (≤20 ml/h), and the remaining 
caloric-protein 
requirement 
are 
supplemented by parenteral nutrition. 
 
Experimental: 
Trophic 
enteral 
feeding 
combined with supplemental parenteral 
nutrition. Patients will receive the trophic 
enteral feeding with a caloric target of 
500kcal/d (20-35 ml/h), and the remaining 
caloric-protein 
requirement 
are 
supplemented by parenteral nutrition. 
To adjust the rate to a range that better 
supports the trophic calorie goal. 
Section 
1 
Study 
synopsis— 
Exclusion Criteria 
 
Add: 
 
Admission with infection signs 
 
Antibiotics were used within the previous 
7 days 
 
Subarachnoid 
hemorrhage, 
cerebral 
arteriovenous malformation 
To ensure that the primary endpoint of 
post-stroke pneumonia is assessed in a 
population without pre-existing or recent 
infections 

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Section 
1 
Study 
synopsis—
secondary 
efficacy 
outcomes 
 
Insulin dose during the first 7 days post-
randomization 
Modified Rankin scale at 90 days 
 
Insulin utilization during the first 7 days 
post-randomization  
 
Modified Rankin scale at 90 days [ordinal 
mRS, excellent outcome (mRS 0–1), and 
functional independence (mRS 0–2)] 
To enhance clinical interpretability and 
reduce variability from dose titration 
Section 8.2  
Exclusion Criteria 
 
Add: 
 
Admission with infection signs 
 
Antibiotics were used within the previous 
7 days 
 
Subarachnoid 
hemorrhage, 
cerebral 
arteriovenous malformation 
To ensure that the primary endpoint of 
post-stroke pneumonia is assessed in a 
population without pre-existing or recent 
infections 
Section 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. 
Patients randomized to the trophic EN with SPN 
group will receive enteral nutrition at a fixed rate 
of 20–35 mL/h, providing approximately 500 kcal 
per day. 
To adjust the rate to a range that better 
supports the trophic calorie goal. 
Section 
15.2 
Secondary efficacy 
Insulin dose during the first 7 days post-
randomization 
 
Insulin utilization during the first 7 days 
post-randomization  
To enhance clinical interpretability and 
reduce variability from dose titration 

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outcomes 
Modified Rankin scale at 90 days 
 
Modified Rankin scale at 90 days [ordinal 
mRS, excellent outcome (mRS 0–1), and 
functional independence (mRS 0–2)] 
Section 15.4 
Exploratory 
endpoints  
 
Add: Exploratory endpoints 
 
Hierarchical composite endpoint of all-
cause 
mortality 
and 
post-stroke 
pneumonia within 90 days (win ratio).  
 
Hierarchical composite endpoint of all-
cause 
mortality 
and 
post-stroke 
pneumonia within 7 days (win ratio). 
 
Time from randomization to the first 
occurrence of either all-cause death or 
post-stroke pneumonia within 90 days 
(time to event). 
To provide a holistic assessment of the 
intervention's clinical benefit 
Section 
16.1 
Assessment 
of 
efficacy  
Insulin Dose 
This endpoint was defined as mean daily 
insulin dose during the 7-day intervention 
Insulin Utilization  
This endpoint was defined as the proportion of 
patients requiring any insulin therapy during 
To reduce variability from dose titration 

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period. 
the 7-day intervention period. 
Section 
16.1 
Assessment 
of 
efficacy  
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). 
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), with this approach 
supplemented by key secondary analyses of the 
proportions of patients achieving functional 
independence (mRS 0-2) and an excellent 
outcome (mRS 0-1). 
To enhance clinical interpretability 
Section 21.4 
Analysis of results 
 
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). 
An adjusted analysis will also be performed, 
adjusting for pre-specified baseline covariates 
(e.g., age, NIHSS at ICU admission, stroke type, 
history 
of 
diabetes, 
history 
of 
chronic 
respiratory disease, and smoking).  
To strengthen the statistical model by 
more comprehensively adjusting for 
known prognostic factors and potential 
confounders, leading to a more reliable 
and unbiased estimate of the treatment 
effect. 
Section 21.4 
Analysis of results 
Subgroup analyses will be conducted to 
explore treatment effect consistency across 
Subgroup analyses will be conducted to explore 
treatment effect consistency across the following 
To allow for a more comprehensive 
exploration 
of 
treatment 
effect 

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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). 
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, 
history 
of 
chronic 
respiratory 
disease, 
smoking 
status, 
consciousness level (GCS 9–12 vs. ≤8), and time 
from stroke onset to nutrition initiation ( ≤24 
vs. >24 hours). 
heterogeneity. 
Section 21.4 
Analysis of results 
 
Sensitivity analyses will assess the impact 
of missing data, competing risks such as 
death, and potential center effects. 
Sensitivity analyses will assess the impact of 
missing 
data, 
specific 
clinical 
scenarios 
(including 
pneumonia 
occurring 
before 
nutritional 
support 
or 
after 
ICU 
discharge/transition to oral feeding), competing 
risks such as death, and potential center effects. 
To provide a more accurate estimate of 
the pneumonia risk. 
Section 21.4 
Analysis of results 
 
 
Add: 
The composite exploratory endpoints will be 
analyzed using win-ratio and Fine Gray 
To facilitate a robust analysis of the 
newly added composite endpoints. 

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competing-risk methods, respectively.