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1 Clinical Trial Details (PDF Generation Date :- Sat, 16 Dec :41:27 GMT) CTRI Number Last Modified On 16/04/2015 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2015/04/ [Registered on: 21/04/2015] - Trial Registered Retrospectively Yes Interventional Probiotic Randomized, Parallel Group, Placebo Controlled Trial A RANDOMIZED CONTROLLED TRIAL TO STUDY THE EFFECT OF PROBIOTICS ON CHANGE IN LEVELS OF INFLAMMATORY MEDIATORS IN CRITICALLY ILL CHILDREN WITH SEVERE SEPSIS. EVALUATION OF EFFECT OF PROBIOTICS ON CHANGE IN CYTOKINE LEVELS IN CRITICALLY ILL CHILDREN WITH SEVERE SEPSIS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (PILOT STUDY) Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) Details Contact Person (Public Query) Designation Affiliation Details of Principal Investigator ARUN BANSAL Phone Fax Designation Affiliation ADDITIONAL PROFESSOR POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION & RESEARCH DIVISION OF PEDIATRIC CRITICAL CARE DEPARTMENT OF PEDIATRICS, ADVANCED PEDIATRICS CENTRE, PGIMER,, INDIA drarunbansal@gmail.com Details Contact Person (Scientific Query) SURESH KUMAR SENIOR RESIDENT Phone Fax Designation POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION & RESEARCH DIVISION OF PEDIATRIC CRITICAL CARE DEPARTMENT OF PEDIATRICS, ADVANCED PEDIATRICS CENTRE, PGIMER,, INDIA DIVISION OF PEDIATRIC CRITICAL CARE DEPARTMENT OF PEDIATRICS, ADVANCED PEDIATRICS CENTRE, PGIMER,, INDIA sureshangurana@gmail.com Details Contact Person (Public Query) ARUN BANSAL ADDITIONAL PROFESSOR page 1 / 6

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study Details of Ethics Committee Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Affiliation Phone Fax POSTGRADUATE INSTITUTE OF MEDICAL EDUCATION & RESEARCH DIVISION OF PEDIATRIC CRITICAL CARE DEPARTMENT OF PEDIATRICS, ADVANCED PEDIATRICS CENTRE, PGIMER,, INDIA drarunbansal@gmail.com Source of Monetary or Material Support > POST GRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH (PGIMER),, INDIA Type of Sponsor List of Countries of Principal Investigator Dr Arun Bansal Primary Sponsor Details POST GRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH POST GRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH (PGIMER),, INDIA Research institution and hospital of Site Site Phone/Fax/ POST GRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH, PEDIATRIC INTENSIVE CARE UNIT, DEPARTMENT OF PEDIATRICS, ADVANCED PEDIATRIC CENTRE, POST GRADUATE INSTITUTE OF MEDICAL EDUCATION AND RESEARCH, INDIA drarunbansal@gmail.co m of Committee Approval Status Date of Approval Is Independent Ethics Committee? Institute ethics committee (intramural), PGIMER, Status Approved 24/09/2014 No Date Approved/Obtained 30/01/2015 Health Type Patients Condition CRITICALLY ILL CHILDREN WITH SEVERE SEPSIS Type Details Intervention PROBIOTICS Probiotic group will receive page 2 / 6

3 Inclusion Criteria VSL#3 (VSL Pharmaceuticals, Inc. Tawson, MD USA) which is a high-dose, multi-strain probiotic product. Each sachet of VSL#3 contains 450 billion viable lyophilized bacteria consisting of 4 strains of Lactobacillus ( L. paracasei, L. plantarum, L. acidophilus, and L. delbrueckii subsp. bulgaricus); 3 strains of Bifidobacterium (B. longum, B. breve, and B. infantis); 1 strain of Streptococcus (Streptococcus salivarius subsp. thermophilus); and maltose and silicon dioxide as base. The dose will be one sachet twice a day (900 billion CFU/day) orally or through feeding tube (whichever is possible) for 7 days. Comparator Agent PLACEBO Placebo group will receive only maltose and silicon dioxide. Age From Age To Gender Details 3.00 Month(s) Year(s) Both Inclusion Criteria 1. Any patient admitted to PICU with diagnosis of severe sepsis. 2. Age group: 3 months-12 years. Exclusion Criteria Details Exclusion Criteria 1. Hospital stay of >72 hours prior to PICU admission. 2. Children who cannot tolerate enteral nutrition. 3. Known chronic illness. 4. Suspected or proven viral infection. 5. Known immunodeficiency states or malignancy. 6. Children on prior steroids/immunotherapy. 7. Children with severe acute malnutrition (as per WHO). 8. Children who received probiotic therapy in last 1 month. Method of Generating Random Sequence Method of Concealment Blinding/Masking Computer generated randomization Sequentially numbered, sealed, opaque envelopes Participant, Investigator and Outcome Assessor Blinded Primary Outcome Outcome Timepoints Change in levels of cytokines (IL-6, IL-12, IL-17, Day 1 and day 7 TNF-?, IL-10, and TGF-?) in critically ill children with severe sepsis receiving probiotics and those receiving placebo Secondary Outcome Outcome Timepoints To compare the two groups for: SOFA score on day 1 and 7 Incidence of health care associated infection (HCAI) Patients will be followed up till the discharge from PICU or death. page 3 / 6

4 Length of PICU stay Survival or death Target Sample Size Phase of Trial Date of First Enrollment () Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial () Publication Details Brief Summary Total Sample Size=40 Sample Size from =40 N/A 01/11/2014 No Date Specified Years=1 Months=0 Days=0 Not Applicable Open to Recruitment The hypothesis of this study is to determine whether administration of probiotic (VSL#3 ) will have immuno-modulatory effects on critically ill children with severe sepsis in form of decrease in pro-inflammatory cytokines (IL-6, IL-12, IL-17, and TNF-?) and increase in anti-inflammatory cytokines (IL-10 and TGF-?). Aim: To compare the change in levels of cytokines in critically ill children with severe sepsis receiving probiotics and those receiving placebo. Primary Objectives: Change in levels of cytokines in critically ill children with severe sepsis receiving probiotics and those receiving placebo. Secondary Objectives: To compare the two groups for: SOFA score on day 1 and 7 Incidence of health care associated infections (HCAI) Length of PICU stay Survival or death. Study design: Randomized, double-blind, placebo-controlled trial (Pilot study). Study setting: 15-bedded PICU of a tertiary care and teaching hospital, the Advanced Pediatrics Centre (APC) in Post-Graduate Institute of Medical Education and Research (PGIMER),,. Study period: Recruitment: December 2014 to November 2015 Inclusion criteria: Any patient admitted to PICU with diagnosis of severe sepsis Age group: 3 months-12 years. Exclusion criteria: Hospital stay of >72 hours prior to PICU admission Children who cannot tolerate enteral nutrition page 4 / 6

5 Known chronic illness Suspected or proven viral infection Known immunodeficiency states or malignancy Children on prior steroids/immunotherapy Children with severe acute malnutrition (as per WHO) Children who received probiotic therapy in last 1 month. Sample size estimation: This being a pilot trial, calculation of sample size has not been done and a convenient sample size would be chosen. A minimum of 20 children would be enrolled in each group. Enrolment: Parents or legal guardians of children who satisfy the above eligibility criteria will be invited by the investigator to participate in the study and written informed consent will be obtained from them. Parents are free not to participate, or to withdraw from the study at any point of time. All children, irrespective of their enrollment in the study, will receive standard PICU care as per the unit s existing protocol. A patient information sheet furnishing details of the study will be provided to the parents. Patients will be enrolled on day of admission to PICU. Samples for cytokine levels will be taken on next morning and after that probiotics or placebo will be started. Detailed methodology: Randomization: All patients satisfying inclusion criteria will be divided into 2 groups by using computer generated randomization table. Block randomization will be used to divide patients into two groups and we will assume that all confounding variables are equally distributed among two groups. Any unmatched confounding factor will be taken care during analysis by multiple logistic regressions. A person not involved in the study will perform the random number allocation and prepare opaque, sealed envelopes containing the allocation number. As with the progress of disease (sepsis) there may be change in the level of cytokines (pro-inflammatory and anti-inflammatory) over the course of time, we planned randomized control trial to study the effect of probiotics on change in level of cytokines in children with severe sepsis and compare the change with that in placebo group. Group A will receive VSL#3 (VSL Pharmaceuticals, Inc. Tawson, MD USA) which is a high-dose, multi-strain probiotic product. Each sachet of VSL#3 contains 450 billion viable lyophilized bacteria consisting of 4 strains of Lactobacillus, 3 strains of Bifidobacterium, 1 strain of Streptococcus; and maltose and silicon dioxide as base. Group B will receive only maltose and silicon dioxide as placebo. The VSL#3 contains individual strains as follows: L. paracasei 1.2% weight by weight (w/w) L. plantarum 12% w/w L. acidophilus 6.7% w/w L. delbrueckii subsp. bulgaricus 7.1% w/w B. longum, B. breve, and B. infantis 13.7% w/w in ratio of 1:1:1 Streptococcus salivarius subsp. thermophilus 59.3% w/w. Probiotics or placebo in powdered form with similar appearance, smell and taste will be packed in similar looking sachet. Fourteen sachet of either probiotics or placebo will be packed in opaque packet with random allocation number on it. Probiotics or placebo will be administered to enrolled patients in dose of one sachet twice a day orally or through nasogastric/orogastric tube depending on clinical status of patients for duration of 7 days. All PICU staff, investigators, study patients/guardians, and person doing data entry and analysis will not be aware of group allocation. The codes will be broken only after completion of study and analysis. Clinical monitoring protocol: All children would be managed and monitored as per the existing unit s protocols for children with sepsis. All data would be prospectively recorded on a pre-designed performa. At the time of enrollment, baseline data regarding age, sex, weight, height, history of presenting illness, examination findings, admission diagnosis, time from admission in PICU transfer and to randomization, pediatric risk of mortality III (PRISM III) scores, need of ventilation, presence and severity of hemodynamic instability (requirement for fluid boluses, dose of vasoactive agents, if any), SOFA score on day 1 and 7, HCAI, length of PICU stay, final outcome (survival/death), and adverse events related to probiotics would be recorded. Sample collection, transport, and processing: Peripheral blood sample (3 ml) will be obtained in plain vial from each patient by venipuncture using aseptic precautions on day 1 and day 7 of enrollment for estimation of cytokine levels. The blood sample will be immediately transported to laboratory on ice where it will be transferred to a serum separating tube and centrifuged at 2500 rpm for 20 minutes after clotting. The sera will be carefully harvested and will be stored at -80 C until analysis. Detection of IL-6, IL-12, IL-17, TNF-?, IL-10, and TGF-?: Concentration of IL-6, IL-12, IL-17, TNF-?, IL-10, and TGF-? will be quantitatively determined by enzyme-linked immunosorbent assay (ELISA) according to the procedure and standards described by the manufacturer of the kits used. Outcomes: Primary: Change in levels of cytokines (IL-6, IL-12, IL-17, TNF-?, IL-10, and TGF-?) in critically ill children with severe sepsis receiving probiotics and those receiving placebo. Secondary: To compare the two groups for: SOFA score on day 1 and 7 Incidence of health care associated infection (HCAI) Length of PICU stay page 5 / 6

6 Powered by TCPDF ( REF/2014/10/ Survival or death. Follow up: Patients will be followed up till the discharge from PICU or death, whichever is earlier. Patients who will not be able to complete 7 days of study period (due to inability to receive study drug or death) will be excluded retrospectively. Implementation of study protocol: The study protocol will be discussed in multiple sessions with the treating physicians (junior and senior residents posted in PICU) by principal investigator on the first day of every month throughout the duration of the study. The principal investigator will enroll the patients and visit PICU at least twice a day and at times of requirement to ensure strict implementation of protocol i.e. to check the proper administration of probiotics or placebo and timely collection, storage, and transport of blood sample to the laboratory. The protocol will be displayed as a poster in PICU notice board. Weekly checks on protocol adherence would be carried out by the co-investigators/guides. Data entry and statistical Analysis: Appropriate data entry and statistical analysis will be performed on Microsoft Excel 2010 (Microsoft, Redmond, WA) and SPSS software version 20 (SPSS, Inc, Chicago, IL). Descriptive statistics (mean, SD, median, range, and percentages) will be used for baseline variables. Dichotomous outcomes will be compared by chi-square test or Fisher s exact test as applicable. Continuous variables will be compared by Student t test. Absolute risk, relative risks and 95% confidence intervals will be calculated. Paired t test will be used to compare the level of cytokines on day 1 and 7 in two groups. All tests will be two-tailed and p value <0.05 will be taken as significant. Ethical justification: Literature regarding the beneficial effects of probiotics in critically ill children is scarce. The present study entails assessment of level of cytokines in critically ill children with severe sepsis and to see the effect of probiotics on change in level of cytokines. This study would provide an insight into the role and mechanism of action of probiotics in critically ill children with severe sepsis. The study subjects stand to benefit as this vital information has prognostic and pathogenetic implications. Only 3 ml of peripheral venous blood would be collected by venipuncture on day 1 and 7 of enrollment from the participants observing aseptic precautions. The researchers would not require any extra-sampling or invasive procedure as part of the study apart from what the child requires depending on his/her clinical condition. Probiotics has been shown to be safe in critically ill children and in fact these children may derive the benefits as reported in literature. The possibility of side effects will be remote and if occur child can be withdrawn from study. There won t be any financial gain from pharmaceutical product used. Parents/Guardians would be informed about the potential benefits and risks of the study. Children would be enrolled only after obtaining written, informed consent from the parents or legal guardians. Assent would be taken from older children wherever feasible. There won t be any increase in duration of PICU stay and increase in cost of treatment as study drugs are being provided by the investigator. The parents of the child would be provided with the telephone number of the primary investigator and they would be free to contact him for any query regarding the study protocol. Confidentiality of the data will be maintained. The data that will be generated from the study, at no additional risk to the patient will help in understanding the benefits of probiotics in modification of immune status of critically ill children which could have indirect benefits on the outcome of these children. This study is an effort to find out effect of probiotics on various cytokines in critically ill children with severe sepsis. page 6 / 6