Patient selection
Inclusion criteria
All TBI patients admitted directly or transferred to the intensive care units of participating hospital are evaluated for eligibility for entry into the randomized clinical trial. Preliminary eligibility criteria are summarized in Table 1.
Exclusion criteria
Patients meeting all preliminary eligibility criteria are considered potentially eligible for study. Patients are next screened for the presence of any specific exclusion which would preclude study entry. These exclusions are designed to eliminate patients for whom participation may be dangerous or patients with serious medical disorders whose impact on operative outcome may obscure the importance of nutritional, clinical and inflammatory factors. These are summarized in Table 2.
Default criteria
Once randomization has taken place, patients are removed from the study only for the following reasons: 1) patient’s or physician’s request, 2) Significant change in patient's treatment process, 3) create any exclusion criteria, 4) Sensitivity to pycnogenol supplementation.
Sample size
Sample size calculations were based upon Luzzi et alʼ s study (33) witch showed the mean CRP change in the treatment group was 60% and in the control was unchanged or Up to a maximum of 15%.
Based on The formula for comparing two proportions of a qualitative attribute from two independent statistical societies, sample size was determined 25 individuals in each group, (α= 0.05, β=0.1, the power of study is 90%).Assuming a probable drop in the sample, 30 patients in each group are considered.
Study procedures
The university's executive committee will oversee the project's implementation and progress, information security, safety of trial participants, and scientific impact assessment. Also this committee will review data from the trial. The trial sponsor will undertake auditing of the trial procedure.
Randomization and masking
We will randomly allocate eligible patients on enrolment (1:1) to either the control group or the intervention group. The randomization list of unique patient identifiers, is generated by the computer-generated random block size site. The classification is based on age (18 to 40 and 40 to 65 years old), gender (male / female) and APACHEII score (0 to 35 and 35 to 71) using quadruple blocks.
Nutritionist or clinicians will keep the sealed opaque envelope containing the unique patient identifier and the study group allocation in a locked cabinet in the study laboratory. They are opened by the second nutritionist. Investigators, all study staff hospital attending clinical teams, and patients were masked to the study group allocation.
Intervention
We do a pragmatic, parallel-group, double-blind, randomized controlled trial. We enroll 60 patients who are admitted to ICU at hospital of university in Tehran, Iran. All participants or their first degree relatives give informed consent to the clinician before participating.
Participants are randomly divided in two groups. The method of randomization and masking are explained above. At the first visit, baseline data are gathered and intervention group will receive pycnogenol supplement (OLIGOPIN) in the form oral capsules containing 50 mg pycnogenol plus 130 mg Microcrystalline Cellulose. OLIGOPIN powder of each capsule are dissolved in 10 ml deionized water and given to patients via gavage (3 capsule per day) for 10 days.
Control group will receive oral capsules containing 130 mg Microcrystalline Cellulose with 10 ml of deionized water via gavage (3 capsule per day) for 10 days.
The capsules are given by the investigator to the patients by gavage, so fidelity to the intervention will be strong, However for more certainty, at the end of each day, the number of capsules remaining for each patient will be checked.
In order to control the confounding effect of food intake, both the control group and the intervention group receive the standard formulas based on their daily required energy via enteral root feeding.
Possible risk assessment of intervention
Initially, an intervention with a dose of 150 mg of pycnogenol is started for 10 patients, and in the absence of clinical complications and observing the expected effect on the reduction of inflammatory markers, the same dose continues. Otherwise, it is reduced to 100 mg, if there is any adverse effect.
There have been no reports of serious adverse event in any clinical trials or commercial use of OLIGOPIN. However, these patients are regularly evaluated biochemically and clinically each day, and liver function test including serum levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase) checked. If there are any potential complications from intervention or, if the physician determines that the intervention should be discontinued, the supplements will be immediately removed from the patient's enteral nutrition.
Data collection
Data will be collected at four main times: at the base line, at 5th day of intervention, at 10th day of intervention and at the 28-day follow-up visit. At the base line demographic characteristics are gathered via a questionnaire. Anthropometric assessment including height (via ulna length), weight ( by using portable scale “Balas”), body mass index and body composition ( by using bio impedance device “Inbody”), are done at the base line, 5th day of intervention and at the end of intervention.
In order to evaluate inflammatory and oxidative stress markers, 10 cc of venous blood is taken from each patient at the base line, at the 5th day and at the end of the study. Then, the serum sample is isolated and used to measure the markers via ELISA kits. APACHE ІІ (for assessment of clinical status of patients) and Nutric questionnaires (for assessment of nutritional status) filled out at the base line, 5th day and the end of study. SOFA questionnaire (for assessment of organ failure) filled out every other day. The mortality rate will be asked by phone within 28 days of the start of the intervention.
SPIRIT diagram of recommended content for the schedule of enrolment, interventions, and assessments shown in figure 1.
Data management
Specially designed forms are completed by study staff at each time point, and scanned, verified and committed to a local site database within 48 h of completion. Completed forms are stored as the source documentation in a locked cabinet, with access restricted to specified study team members. The forms are identified by unique participant ID number and do not contain any patient identifiable information. Queries based on data in the database are generated daily, including date, range and logic checks.
Outcomes
The measurable outcomes summarized in table 3.
Statistical methods
The trial profile will be summarized using a CONSORT flow chart, including reasons for non-eligibility and non-enrolment (34).
The objective of this clinical trial is to determine if pycnogenol supplementation improves clinical and nutritional outcome in TBI patients admitted in ICU or not. To answer this question, the outcome of patients receiving PYC supplement will be compared with the outcome of patients receiving placebo.
All analyses will be conducted by initially assigned study arm in an intention-to-treat analysis, and adjusted for randomization site. Thus, all randomized patients who will receive at least one dose of study treatment and who will have both a baseline and at least one post baseline measurement will be analyzed. The data will be expressed as mean ± SD. Statistical analyses will be conducted with SPSS version 11.5 (SPSS Institute, Chicago, Ill). Chi-square test with Yates correction will be done for non-continuous variables for the prevalence study. Student t test will be done to assess the statistical significance of the continuous variables. Comparable nonparametric test (Mann-Whitney U test) will be substituted when tests for normality and equal variance failed. A value of P b .05 will be used as a criterion for statistical significance. Survival analysis will be performed with Kaplan-Meier test. The study design flow diagram summarized in figure 2.