StemCell Therapy

Study design and period

The trial is a single center, two-armed phase III study. The trial has been registered at http://www.clinicaltrials.gov (NCT03201926). Patients will be recruited by the Pancreatobiliary Cancer Clinic, Gangnam Severance Hospital, Yonsei University College of Medicine. The expected total duration of patient accrual is 2years and 6months and the follow-up period is 6months.

The primary endpoint is to evaluate body cell mass index at 2months postoperatively. Secondary endpoints include other body composition changes as well as nutrition index and immune function.

Patients scheduled for surgery with pancreatobiliary disease and liver cancer (HCC, CCC, and metastatic liver cancer)

Karnofsky performance status 70

Patients who provide informed consent

Patients who underwent palliative surgery

Patients with uncontrolled preoperative conditions

Previous history of surgery affecting nutritional status (ex, gastrectomy, colectomy, etc)

Pregnant and lactating women

Patients with an allergy to mealworms

The output of the sample size will be based on an independent two-sample t test. It is expected that there will be a difference in body cell mass between the standard meal group (control) and the group ingesting the mealworms. Assuming an alpha value of 0.05 and 1- (power) of 0.8, 75 samples will need to be obtained for each group; considering the dropout rate of 10%, 84 samples will need to be obtained for each group. The total of the two groups is 168. The primary endpoint will be the number of subjects and body cell mass. A comparison will then be made between the two groups at 2months. A subgroup analysis of pancreatobiliary and liver disease will also be performed as a secondary endpoint. Patients with pancreatobiliary and liver disease in our clinic have a 2:1 ratio. Therefore, the 168 patients were divided into two groups: one with 112 patients and the other with 56 patients. Patients with pancreaticobiliary disease (Group A & B) and liver (Group C) disease were assigned through stratified randomization. Pancreatobiliary disease group is divided into enteral feeding group(Group A) and non enteral feeding group.(Group B).

All patients who are potential candidates for hepatopancreatobiliary surgery will undergo a standard evaluation that will include contrast-enhanced computed tomography (CT), endoluminal ultrasound (EUS), magnetic resonance imaging (MRI), and positron emission tomography (PET-CT), which will be discussed at the preoperative conference.

Patients recommended for major hepatopancreatobiliary surgery (such as a liver resection, pancreaticoduodenectomy, or total/distal pancreatectomy) will be contacted and provided with a participant information sheet. Patients will be divided into three groups according to the type of surgery.

Patients receiving dietary supplementation with mealworms after their pancreatectomy, bile duct resection and hepatectomy will be given the mealworms during their hospitalization period and for another 2months after discharge. The patients in group A will undergo enteral feeding after surgery (for those who undergo a pancreaticoduodenectomy, nutrients will be administered by an enteral feeding tube for early feeding while securing the pancreatojejunostomy). A feeding nasojejunal tube will be placed for patients in the enteral feeding group. Enteral feeding (Newcare 300 RTH, Daesang, Korea) will start within 24h postoperatively at a rate of 20mL/h. The velocity will be progressively increased by 20mL/d until reaching the full nutritional goal (25kcal/kg). Enteral feeding will be delivered by an infusion pump for 18h/day with 6h of rest.

On postoperative day 7, abdominal and pelvic CT scans will be obtained, and if there are no complications, we will then start patients on a clear liquid diet for 1day. In addition, the patients will be permitted to have a full liquid diet for 2days and then a soft diet for 3days following the liquid diet.

The patients of group B will undergo oral feeding 2days after the surgery. (distal pancreatectomy, total pancreatectomy and bile duct resection) We will start patients clear liquid diet for 1day. The patients will be permitted to have a full liquid diet for 2days and soft diet for 3days following the liquid diet.

The patients of group C will undergo oral feeding 2days after surgery (which includes liver resections). We will then start the patients on a clear liquid diet for 1day. In addition, the patients will be permitted to have a full liquid diet for 2days and soft diet for 3days following the liquid diet. The mealworm powder include 3g of carbohydrate, 14.4g of protein and 11g of fat, 163kcal per 30g. (Table 1) As a result of a nutritional analysis of mealworm powder, 10.28g of carbohydrate, 48.26g of protein and 35.81g of fat were found per 100g. In particular, the protein includes essential amino acids as well as many unsaturated fatty acids ranging from 76 to 80% of the total fatty acids. In addition, iron and calcium and other minerals were found (Table 2).

Patients receiving dietary supplementation with grainpowder after pancreatectomy and hepatectomy will be given grainpowder for their hospitalization period and 2months after discharge. The grainpowder include 23g of carbohydrate, 2.9g of protein and 0.5g of fat, 106kcal per 30g. Group A will receive the grainpowder on postoperative day 7. And group B and C will receive grainpowder in the same dose as trial groups mealworms at the start of diet at postoperative 2days (Table 3).

The primary outcome is the body cell mass index as measured by body composition (Inbody S-10 (Biospace, Seoul, Korea)). The secondary outcome measures are as follows: nutritional index (weight, soft lean mass, fat free mass, fat mass, PG-SGA [Scored Patient-Generated Subjective Global Assessment]) and immune function test (that assesses T cells, B cells, cytokines). We will confirm changes in immune cells through FACS (fluorescence-activated cell sorting). Based on the immune assay using blood samples from patients, we will identify changes in several cytokines.

Once the patients surgery is confirmed, the research staff will give the study staff a list of the patients. After determining the suitability of the patient, the study staff will assign the patient to the test or control group in a randomized sequence in the order in which they are enrolled. In addition, they will be assigned in a double-blinded manner.

The researchers will select patients after obtaining consent. Randomization will take place via an allocation randomization system 2days before the surgery, which will be directed by our department. Patients will be randomized to one of the treatment groups in a 1:1 ratio. After consent for study enrollment is obtained, the randomization process will be applied to identify the next allotment. The surgeons will be blind to the allotment throughout the enrollment process.

Patients and all team members will be blinded to the intervention. Adverse event (AE) and serious adverse event (SAE) need to be reported as soon as they are noted. This will not have any impact on the endpoint assessment of the patient.

The amount of food consumed by the patient daily will be assessed as a diary entry. The researcher collects the bags left over from the patients at the outpatient clinic. Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. Blood samples transferred to the laboratory of Gangnam Severance Hospital will be identifiable by unique trial numbers only. Results related to nutrient indicators (Inbody, PG-SGA) will be managed by a Gangnam Severance Nutrition Team. The blood sample associated with the immune function test will be transferred to the lab of the study staff in Gangnam Severance Hospital, which will then undergo FACS (Fluorescence-activated cell sorting).

If patients wish to voluntarily withdraw from the study, the patient will be asked if they would be given medical care until any AE symptoms resolve or the patients condition becomes stable.

Patients can quit the trial at any point without the need to give reasons for their decisions. If voluntary withdrawal occurs prior to diet intervention, the patient will not be randomized, and no more trial data will be collected for that patient. Patients can also withdraw from the trial following diet intervention.

All data will be entered into a single Microsoft Excel spreadsheet with participants identified only by their unique subject number. All entries will be double-checked by another member of the research team. Statistical analysis will be performed using IBM SPSS version 21.0 (IBM Corp; released 2012. IBM SPSS Statistics for Windows Version 21.0. Armonk, NY, USA). The mean difference in nutrient intakes, changes in body measurements, changes in body composition, and PG-SGA scores will be calculated using the Wilcoxon signed rank test and the Mann Whitney test.

The research team is responsible for monitoring the study. At 1week after discharge, the participants are asked whether they are willing to continue ingesting the mealworm. Every 2weeks after the patients visit their outpatient clinic, the monitoring researcher will check whether they are taking the mealworm regularly. The research team is also responsible for systematically reviewing the causes of withdrawal from the study. Assessment of these changes will be determined 2months after surgery (Table 4).

The study protocol was approved by the institutional review board at Gangnam Severance Hospital, Yonsei University of Korea (32017-0077). The study complies with the Declaration of Helsinki and the principles of Good Clinical Practice.

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