Nutritional Intervention for Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

This is a multi-center, open-label, parallel-group randomized controlled study to investigate the effects of peri-transplant oral nutritional supplement (ONS) intervention on clinical disease outcomes among adult patients undergoing myeloablative allogeneic hematopoietic stem-cell transplantation (allo-HSCT).

Malnutrition occurs frequently in allo-HSCT recipients and is associated with higher risks of graft-versus-host disease (GVHD), transplant-related mortality, infection, and poor survival. Malnutrition, intestinal barrier injury and gut microbiota dysbiosis form a vicious cycle that worsens post-transplant complications. In addition, sleep disturbance and obstructive sleep apnea (OSA) are highly prevalent during transplantation and may mediate the relationship between nutritional status and transplant prognosis, which has rarely been objectively evaluated in existing nutrition-related transplant studies. Non-contact millimeter-wave radar-based sleep-breathing monitoring will be applied in this trial to objectively capture sleep-respiratory parameters without wearable devices.

A total of 160 eligible participants will be enrolled in this three-center multicenter study across three Chinese clinical sites (100 participants at the lead center, 30 participants at each of the two collaborative sites), and randomized at a 1:1 ratio within each center into either the intervention group or the control group (80 participants per arm). Randomization will be performed independently within each participating center. All participants will receive routine dietary and physical-activity guidance according to study manuals.

Participants assigned to the intervention group will receive daily 500 mL Kangquan-Gan enteral nutrition suspension (1 kcal/mL, polymeric whole-protein formula, 500 kcal per bottle, oral nutritional supplement). The initial administration starts at 20-50 mL with 2-3 h during the study observation; if gastrointestinal tolerance is acceptable, the dose will be gradually titrated up to the target 500 mL per day in divided doses (50-100 mL, 4-6 times daily). If gastrointestinal adverse reactions occur, ONS will be paused for 1-3 days and re-challenged. Persistent intolerance will lead to study withdrawal. Remaining energy requirements will be covered by regular oral diet. Parenteral nutrition (PN) will be supplemented when total energy intake continuously falls below 60 % of target energy for 3-5 consecutive days.

Participants in the control group will receive standard nutritional support with identical dietary guidance, without study-provided ONS. Daily dietary intake will be recorded. Parenteral nutrition will be used to compensate energy shortfalls to meet individual energy and protein targets. To reduce performance bias caused by heightened awareness of nutritional intake among control participants, participants from two study arms will be housed on separate wards whenever feasible.

Target energy is calculated as the sum of ONS, parenteral nutrition and ordinary dietary intake. Nutritional support teams (physicians, nurses, dietitians, pharmacists) will monitor daily energy intake and adjust nutritional strategies dynamically according to subject tolerance and clinical conditions. During the intervention period, participants are required to avoid other enteral nutritional products, probiotics and prebiotics that may interfere with study outcomes. Unintended consumption will be documented in case report forms.

Study assessments, physical measurements and biological sample collection will be performed at seven scheduled time-points: baseline (approximately 7 days before conditioning initiation), day 1 of conditioning, stem-cell infusion day, neutrophil engraftment (day +14 post-infusion), post-transplant day 30, day 60 and day 90. Collected biospecimens include stool samples (40 g of the first voided stool of the day at each time-point) for gut microbiota analysis. Fresh stool specimens will be transported to the key laboratory within 2 hours under 4 °C cold-chain conditions, processed and stored long-term at -80 °C for laboratory analyses. Evaluations cover anthropometrics, body-composition analysis, handgrip strength, nutritional assessment (NRS-2002, PG-SGA), laboratory biochemistry, hematology, inflammatory cytokines, immune-cell subsets, bone-marrow examinations, non-contact sleep-apnea monitoring, EORTC-QLQ-C30 quality-of-life questionnaire, 24-hour dietary recall and gastrointestinal symptom rating scale (GSRS).

Primary outcome measures include overall survival, transplant-related mortality, and cumulative incidence of acute graft-versus-host disease (aGVHD). Secondary outcomes cover incidence of conditioning-related toxicity, adverse-event rates, changes in BMI Z-score, body-fat percentage, skeletal-muscle mass, handgrip strength, and incidence of obstructive sleep apnea. Exploratory endpoints contain neutrophil and platelet engraftment time, albumin transfusion volume, antimicrobial-agent consumption, length of hospital stay and total hospitalization costs. Safety outcomes focus on the incidence of acute pancreatitis, hypersensitivity, grade-4 oral mucositis, refractory vomiting, and moderate-to-severe diarrhea; secondary safety variables include general adverse-event rates and abnormalities of liver- and renal-function laboratory parameters. Adverse events will be graded using CTCAE Version 5.0.

After completion of the 90-day intensive observation phase, all participants will undergo long-term follow-up via outpatient visits, telephone and WeChat contact up to 3 years post-transplant at scheduled time-points (6-month, 9-month, 1-year, 1.5-year, 2-year, 2.5-year, 3-year).

Primary analysis will be performed on the Full-Analysis Set (FAS); safety analysis will be based on the Safety-Set (SS); Per-Protocol-Set (PPS) will be used for sensitivity analysis. Statistical analyses will be performed using SAS 9.4. Cox proportional-hazards regression, logistic regression, repeated-measures analysis of variance, chi-square test, Fisher's exact test, t-test and Wilcoxon rank-sum test will be applied as appropriate. All statistical tests will be two-sided with α = 0.05.

Written informed consent must be obtained before any study-specific procedures. This trial complies with the Declaration of Helsinki. The study protocol, informed-consent documents and amendments are reviewed and approved by the institutional review board of the lead study site as well as ethics committees of each participating center.