This randomized study of rapid EN versus conventional administration in acute stroke patients (Rapid EN Trial) is an investigator-initiated, multicenter, prospective, randomized, open-treatment clinical trial conducted between October 2020 and March 2024. The Institutional Review Board of each hospital approved this trial. All the enrolled patients and their relatives provided written informed consent. This trial was registered as a UMIN Clinical Trial (ID: 000046610). Figure 1 shows a flowchart of the trial design.

Patients aged ≥20 years who developed stroke within 7 days from onset, had difficulty with oral intake and could raise their head more than 30 degrees represented the target population in the Rapid EN trial. Patients who had difficulty with oral intake were defined as having severely altered consciousness (JCS 10–300), or modified water swallowing test (MWST) (10) <4. Patients with obstructive gastrointestinal tract disease unfit for enteral feeding were excluded. Table 1 shows the inclusion and exclusion criteria.

Eligible patients are randomized into a 1:1 ratio using a web-based data management system to undergo either rapid administration (rapid EN group) or conventional administration (conventional EN group) of EN within 72 h of admission. Using a minimization algorithm, we balanced the number of patients in the two treatment groups at each hospital.

All the patients received EN using dobhoff tube, NG tube or PEG tube. The enteral feeding dose was 100 mL for the first 3 days and was determined by each institution for each patient for 4–7 days. EN was administered at a rate of 100 mL in 5 min for 7 days in patients randomized to the Rapid EN group and 100 mL in more than 30 min in patients randomized to the Conventional EN group. The type of enteral nutritional supplement is unspecified and freely chosen by each patient.

Performances at baseline, three complications of enteral nutrition, including vomiting, diarrhea, and pneumonia, for 3–7 days from the start of EN, location of stroke, the length of hospital stay and clinical outcomes will be assessed by a third independent observer blinded to the group assignment. Vomiting was defined as one or more episodes associated with EN initiation. Diarrhea was defined as a score of 6 or 7 on the Bristol Stool Scale (11), persisting for more than 2 days. Pneumonia was defined as physician-observed pneumonia based on imaging and clinical status. Clinical outcomes were assessed using the modified Rankin scale (mRS) score (range, 0 [no symptoms] to 6 [death]) (12); favorable clinical outcomes were defined as an mRS score of 0–2 at 90 days after stroke onset.

The primary outcome is the incidence of one or more complications (vomiting, diarrhea, or pneumonia) within 7 days of EN initiation for comparing non-inferiority in the rapid EN and conventional EN groups.

Secondary outcomes were total time spent on EN, incidence of vomiting, diarrhea, and pneumonia within 3 and 7 days of EN, incidence of one or more of the three complications in patients with ischemic or hemorrhagic stroke, and rate of favorable clinical outcome. The efficacy and safety endpoints are presented in Table 2.

A previous observational study (9) showed that the proportion of patients with one or more complications, defined as vomiting, diarrhea, or pneumonia, was 22/45 (48.9%) in the rapid EN group and 14/26 (53.8%) in the conventional EN group. Based on previous reports, the non-inferiority margin was defined as a minimum clinically important difference (MCID) of 5% in the outcome (13). According to those results, we estimated that 622 patients would need to be enrolled to detect non-inferiority of the rapid EN group compared with the conventional EN group, based on a 1-sided α level of 0.025 and a power of 0.80. In total, 700 patients (350 per intervention and control group) were recruited, accounting for possible treatment failures, protocol violations, and dropouts.

Data is monitored centrally by members of the central coordinating center. Members occasionally visit collaborating hospitals to review source materials according to an order from the steering committee. Responsible authorities, related ethics committees, and directors of collaborating hospitals have the right to review the source material if necessary.

An independent data and safety monitoring board (DSMB) oversees the conduct of the trial. Any unexpected event is immediately reported to the DSMB. All safety endpoints are analyzed after the inclusion of 100 and 400 patients. In any case of concern regarding the safety of the participants, the steering committee recommend continuing, stopping, or modifying the trial.

An intention-to-treat (ITT) analysis will be applied according to the consolidated standards of Reporting Trials (14). As needed, an analysis will be performed on the per-protocol set as a sensitivity analysis of the ITT results. Patient demographic data will be analyzed descriptively. Categorical variables will be assessed using the chi-square test or Fisher’s exact test. In contrast, continuous variables will be assessed using Student’s t-test or Wilcoxon rank-sum test, as appropriate. The primary outcome is the proportion of patients with one or more complications at 7 days between the rapid EN and conventional EN groups, as analyzed using univariate logistic regression analysis. Multivariate logistic regression analysis adjusted for potential confounders was performed as a sensitivity analysis. The primary outcome’s odds ratio (OR) will be calculated with the corresponding 95% confidence interval (CI). This clinical trial aimed to demonstrate the non-inferiority of Rapid EN over Conventional EN. If noninferiority is statistically demonstrated for the primary endpoint and the incidence in the rapid EN group is lower than that in the conventional EN group, superiority tests will be implemented. All statistical tests are one-sided, and p < 0.025 are considered statistically significant.

The Rapid EN trial is organized by a central coordinating center located at the Nippon Medical School and is conducted in approximately 16 centers in Japan. The Rapid EN trial was funded by JSPS Kakenhi Grants (Number 20K19651 to Kentaro Suzuki).