This study is an open labelled randomised controlled trial (RCT) conducted at National Cancer Institute, Putrajaya, Malaysia. Since this is an open labelled RCT study, blinding will not occur. Study is conducted in Surgical Gynaecologic Department which involved multidisciplinary clinic and female surgical ward. The RCT will conform to the Consolidated Standards of Reporting Trials (CONSORT) statement for reporting RCT with two arms comparing an intervention group to control group24. After consented to participate, subjects will be allocating into intervention and control group randomly. Randomisation will be done by computerised generated random number.
Subjects
One hundred and ten subjects fulfilling the eligibility criteria will be enrolled into study. Ambulated Malaysian aged over 18 years and scheduled for elective surgery for (suspected) GC, will be included in this study. Those who allergic to soy or whey protein, diagnosed with chronic renal disease, ischemic heart disease and diabetic mellitus or involved in other intervention study are excluded. Time of enrolment will be started from admission day until discharged day (throughout hospitalisation for elective surgery).
Recruitment procedure
Patients’ perioperative feeding will be managed according to FTR surgery program1. Candidates who been referred to surgical gynaecologic department and complying with the inclusion criteria will be approached to participate in the RCT study. Oral and written information about the study procedures will be provided by gynaecologic surgeon or dietitian in an undisturbed consultation room. Gynaecologic surgeon and dietitians involved in recruitment have been trained and instructed in the recruitment procedure in order to maximize the recruitment rate. Patients are provided with patient information sheet and study consent form and given sufficient time consider and discuss participation with family members before decision making. Dietitian will contact the patient to confirm the participation in the study. Written informed consent form will be collected on the admission day. Subjects will be required to attend dietitian clinic to have anthropometry and dietary assessment on the day of admission.
Randomisation
Consented subjects will be randomised into two groups: The intervention (CHO-P) group and control group (CO) before baseline assessment. Randomisation is done by a computer-generated randomisation number which is prepared by independent statistician. Allocation randomised numbers will be concealed in sealed envelopes by study coordinator. The envelop will only be opened after consented and before baseline assessment.
Intervention Group (CHO-P)
Intervention group will receive a specific drink of a lactose-free clear tea-colour fruit flavoured fluid contains 14% whey protein, 86% carbohydrates and 0% lipids. Subjects in CHO-P group will be given 474ml evening drink which provides 500 kcal and 18g whey protein on the evening of a day before operation. Three hours prior to operation, subjects will be provided with 237ml drink with 250 kcal and 9g whey protein. Before operation, subjects fast for solids for 6 hours from the operation. Staff nurse in-charged will monitor anaesthetic risk of drinking whey protein infused carbohydrate drinks and ensured subject to finish specific drinks prior to surgery. Subjects will be provided with same specific clear fluid (474ml which provide 500 kcal and 18g whey protein) after 4 hours’ post-operation (without present of bowel sound) and reviewed by dietitian. When they tolerated at least 500ml of specific clear fluids, they are given a regular solid diet.
Control Group
The subjects in control group fasting from 12 mid-nights on the day of operation with the last meal was minimal 12-hours before operation. On the day of post-operation day, subjects were reviewed by gynaecologist. They were allowed for clear fluid once there is bowel sound. After tolerated clear fluid, they proceed for nourishing fluid then soft diet and they will only receive a regular solid diet after tolerating soft diet.
Discharged Criteria
Gynaecologic surgeon will determine time to discharge of subjects according to discharged criteria. Discharge was allowed based on pre-established criteria (oral pain management, independent mobilisation, sufficient food intake, gastrointestinal function, and the absence of a suspicion of complications)13.
Criteria for withdrawal
The participation will be voluntary, and subject will be free to withdraw anytime from the study without giving any reason and this will in no way affect subject’s future treatment.
Adverse events and data safety monitoring
There are no serious side effects identified and low anaesthetic risk of drinking whey protein 3 hours before operation (vomiting/nausea) in this study. If there is any adverse event during the study in subjects, it will be recorded in the electronic medical record. In the adverse event directly resulting from the study product or a medical procedure required for this study, subject will be referred to a medical doctor as soon as possible and the expenses involve will be paid by the sponsor. There is no additional medication/treatment involved in study. Staff nurse in-charged will monitor subjects if there are any adverse events after consuming study product. If there is any adverse events/inter-current illness, staff nurse in-charged will report to medical officer in-charged (gynaecology) immediately. Medical officer will initiate appropriate treatment. Study findings shall potentially improve treatment outcomes. The expected benefit outweighs the minimal risk to subjects and thus this study should be supported. If any injuries do occur as a direct result of participating in the study, treatment for such injuries shall be provided by the sponsors. There is not prorated payment for participation in this study.
Protocol Amendment
Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol. Such amendment will be agreed upon by National Cancer Institute and Universiti Putra Malaysia and approved by the Medical Research and Ethics Committee (MREC) prior to implementation and notified to the health authorities in accordance with local regulations.
Data collection procedure
Data will be collected at baseline, during post-operative hospitalisation and upon discharged post-operation. Table 1 illustrates the framework for data collection procedures and the study outcomes.
Table 1 Data collection procedures and the study outcomes
Procedure/Parameters
|
Location
|
Baseline
|
Pre-Operation
|
Post-operation
|
Post-operative Hospitalization
|
Discharge
|
1-month post-discharged
|
Enrollment
|
Clinic
|
|
|
|
|
|
|
Allocation
|
Clinic
|
|
|
|
|
|
|
Data collection
|
Ward
|
|
|
|
|
|
|
Age
|
|
√
|
|
|
|
|
|
Ethnic
|
|
√
|
|
|
|
|
|
Education level
|
|
√
|
|
|
|
|
|
Employment status
|
|
√
|
|
|
|
|
|
Marital status
|
|
√
|
|
|
|
|
|
Diagnosis
|
|
√
|
|
|
|
|
|
Other comorbidity
|
|
√
|
|
|
|
|
|
Cancer stage
|
|
|
|
√
|
|
|
|
ASA score
|
|
√
|
|
|
|
|
|
Height
|
|
√
|
|
|
|
√
|
|
Weight changes past 1-month
|
|
√
|
|
|
|
|
|
Body composition (Weight, Muscle mass, FM, FFM and MUAC)
|
|
√
|
|
|
|
√
|
|
Handgrip strength
|
|
√
|
|
|
|
√
|
|
PG-SGA
|
|
√
|
|
|
|
|
|
Diet recall
|
|
√
|
|
|
√
|
√
|
|
Hemoglobin
|
|
|
√
|
√
|
|
|
|
Glucose level
|
|
|
√
|
√
|
|
|
|
C-reactive protein
|
|
|
√
|
√
|
|
|
|
Albumin
|
|
|
√
|
√
|
|
|
|
Length of post-operative stay
|
|
|
|
|
|
√
|
|
Length of bowel function
|
|
|
|
|
√
|
|
|
Length of solid food toleration
|
|
|
|
|
√
|
|
|
Length of clear fluid toleration
|
|
|
|
|
√
|
|
|
Post-operative complication (PONV, ileus & infection)
|
|
|
|
|
√
|
|
|
Readmission within 1 month post-discharged
|
|
|
|
|
|
|
√
|
Reason of readmission (infection & wound debridement)
|
|
|
|
|
|
|
√
|
ASA: American Society of Anaesthesiologists; FM: Fat Mass; FFM: Fat Free Mass; MUAC: Mid Upper arm circumference; PG-SGA: Patient Generated Subjective Global Assessment; PONV: Post-operative Nausea & Vomiting
Outcomes measurement
Baseline characteristics
Subject characteristics such as socio-demographic data (age, ethnic, education level and marital status), clinical characteristic (diagnosis, other comorbidity and American Society of Anaesthesiologists (ASA) score), nutritional status (PG-SGA score, weight changes past 1-month, height, body composition and dietary intake), functional status (handgrip strength) and biochemical profile (haemoglobin, C-reactive protein, albumin and glucose level) will be collected.
Primary outcomes
The primary outcome will be the between-group difference in length of post-operative outcomes (length of post-operative hospital stays, clear fluid toleration, food toleration and bowel function return) between the intervention and control group. Length of post-operative hospital stay is defined as the time from operation end to discharge from the hospital. Length of clear fluid toleration is defined as the time from operation end to tolerate clear fluid. Length of food toleration is defined as the time from operation end to tolerate regular food. Length of bowel function return is defined as the time from operation end to flatus or bowel open. Primary outcomes will be assessed by gynaecologic surgeon and recorded on data collection form (progress in ward form) by nurse in-charged.
Secondary outcomes
Post-operative complications
Post-operative complications including post-operative nausea and vomiting (PONV), ileus and infection, will be monitored and recorded by surgical gynaecologic team. Overall complications were assessed during hospital stay; complication rates were defined per patient; a patient could have suffered from one or several complications14.
Readmission within 1-month post-discharged
Readmissions of study subjects will be documented from the day of discharge until 1-month (30 days) postoperatively. Readmission complications will be described separately from complications during hospital stay.
Other outcomes measures
Nutritional status
The changes within group (pre- and post-operation) and between groups (intervention and control group) for body composition [weight and muscle mass] and mid upper arm circumference (MUAC) will be assessed. Calibrated TANITA body composition analyser will be used to assess body composition while calibrated SECA measuring tape for MUAC.
Biochemical profile
The changes within group (pre- and post-operation) and between groups (intervention and control group) for biochemical profile (haemoglobin, C-reactive protein, albumin and glucose level) will be measured. Result of biochemical profile of study subjects will be accessed from medical record system.
Functional status
The changes within group (pre- and post-operation) and between groups (intervention and control group) for functional status (handgrip strength) will be measured by using calibrated JAMAR® Hand Dynamometer. Record the scores of three successive trials for non-dominant hand tested. The average score of the three trials was used to interpret a grip strength performance.
Confidentiality, Handling and storage of data documents
Subject’s names will be kept anonymous and will be linked only with a study identification number for this research for confidentially purposes. The identification number instead of patient identifiers will be used on subject data sheets. Digital documents and data will be kept in a password protected applications and folders. The hardcopy documents will be stored in a locked office of the investigators and maintained for a minimum of five years after the completion of the study. Subjects will not be allowed to view their personal study data, as the data will be consolidated into a database.
Sample size calculation
The study will be powered to detect difference between intervention and control group in the primary outcomes (post-operative outcomes). Sample size of study is calculated by using formula which was proposed by Woodword25. According to result of previous study by Balayla et al.20, study needs about 33 subjects per group. After adjustment with 80% respond rate and 90% expected eligible rate (power = 80%, alpha level = 0.05), study plans to recruit a total of 110 subjects (55 subjects each group) to account for 20% dropped-out rate.
Statistical analysis
All randomized RCT subjects will be included in analysis as an intention-to-treat (ITT) basis. ITT analysis includes every subject who is randomised according to randomised treatment assignment. According to Gupta26, ITT analysis reflects the practical clinical scenario because it admits noncompliance and protocol deviations, maintains prognostic balance generated from the original random treatment allocation as well as gives an unbiased estimate of treatment effect.
The analyses will be performed using IBM SPSS (version 23.0). Descriptive statistics will be utilised for described subjects’ characteristics. Data normality will be checked by using Shapira-Wilk test and reconfirmed by visual inspection of histogram and stem-leaf plots. Categorical data will be presented in mean ± standard deviation or median (interquartile range) as appropriate while categorical data in frequency and percentage.
Comparison of numerical data, which is normally distributed between two groups, will be analysed using the Independent t-test while Mann-Whitney test will be used if not normally distributed. Pearson's Chi-square test to study association between Categorical Data and Categorical Data while Fisher's exact test will be used if assumptions of Pearson's Chi-square test for Independence are not met. Multi-linear regression test will be used to determine factors related to POHS among surgical gynaecologic cancer patients. All probability values will be used two-sided and a level of significance of less than 0.05 (p-value < 0.05) was considered as statistically significant27.
Dissemination
This study will be conducted according to the principles of the latest Declaration of Helsinki, the Medical Research Involving Human Subjects Act (WMO) and the Good Clinical Practice standard (GCP). The study is investigator-initiated. We used the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist when writing this report28.