Proforma for Approval of Research Project by Ierb

ST. JOHN’S MEDICALCOLLEGEHOSPITAL

PROFORMA FOR APPROVAL OF RESEARCH PROJECT BY IERB

IERB Study Ref. No.
1. / Title of the project / Effect of Probiotics on Feed Tolerance in Very Low Birth Weight Neonates- A Randomized Controlled Trial
2. / Names of the Principal Investigator & Co-investigators with Designation and qualifications

Please add extra box, if space is inadequate
CV to be provided for PI / CI, if not from SJNAHS

Particulars / Name, Designation & Qualification / Contact Address & Telephone No / Mobile No and e-mail ID / Signature
Principal Investigator / Dr. Shashidhar.A
Senior Resident
Dept.of Neonatology
St. John’s Medical College / Department of Neonatology
St. Johns Medical College
Contact: +91-9916069965

Co-PI / Co-investigator
(1) / Dr.Swarnarekha Bhat
Prof & Head
Dept. of Neonatology
St. John’s Medical College Hospital / Department of Neonatology
St Johns Medical College and Hospital
Contact: +91-9845036280

(2) / Dr.Suman Rao P.N.
Associate Prof
St Johns Medical College and Hospital / Department of Neonatology
St Johns Medical College and Hospital
Contact:+91-9019569652

(3) / Dr. Saudamini Nesargi
Assistant Professor Department of Neonatology
St. John’s Medical College and Hospital / Department of Neonatology
St Johns Medical College and Hospital
Contact: +91-9243472262

(4) / Dr.Chandrakala
Assistant Prof
Department of Neonatology
St. John’s Medical College and Hospital / Department of Neonatology
St Johns Medical College and Hospital
Contact:+91-9902001972

3. / Specify whether Basic Science / Behavioral / Clinical trial / Epidemiologic / others / Clinical Trial
4. / Name & Address of the Sponsor
(if applicable) / N/A

Outline of previous work in the field with relevant references: (Introduction, review of literature, justification for study, highlighting the need for the study, potential risks and benefits and outcome measures).

In clinical trials – drug detail in brief including information on the rationale for using the drug & safety profile.Information from earlier Phase 1-4 studies, if any. (Not more than 2-3 pages)

Introduction:

Optimal nutrition during the neonatal period is essential for growth and development throughout infancy and into childhood. A delay in reaching full enteral feedings is also associated with a poorer mental outcome in preterm neonates at 24 months corrected age1.

Optimization of enteral nutrition in preterm neonates has thus become a priority.

A number of feeding strategies have thus evolved reflecting the desperate attempts to prevent/minimize feed intolerance in preterm neonates in the absence of a clear understanding of the pathophysiology of feed intolerance and necrotizing enterocolitis (NEC) 2. Probiotics are one the most promising interventions to prevent NEC in neonates.However, not enough data on effect of probiotics on feed intolerance is available at present.

Review of literature and justification for study:

Enteral feeding intolerance is a major problem in premature infants, resulting in prolonged hospitalisation and a predisposition to serious complications due to prolonged use of parenteral nutrition3.Second to prematurity, feedings and feeding practices are frequently implicated in the development of necrotizing enterocolitis4.Enteral supplementation of probiotics prevents severe NEC and all-cause mortality in preterm infants. Review of available evidence supports a change in practice5 Following recent data, many centres are currently supplementing preterm infants routinely with probiotics.

Feeding intolerance has been considered as a precursor of NEC and many strategies have been tried in its prevention6.Probiotics by themselves, or stimulated by prebiotic fermentation, are important modulators of the intestinal immune system, helps to produce a balanced T-helper cell response and prevents an imbalance contributing in part to clinical disease. An adequate establishment of the intestinal flora after birth is strictly related to motility maturation and plays a crucial role in the development of gut barrier function and the innate and adaptative immune system7. In some RCTs done for prevention of NEC,probiotics have been shown to reduce time to full feeds, hospitalization days and days on total parenteral nutrition (TPN)5.

Need for the study:

The neonatal immune system is dependent on external stimuli to develop mature immune competence. Breast milk and the indigenous intestinal microbiota are considered the most important sources of maturational stimuli8. It is also well established that the composition of the intestinal microbiota is aberrant and its establishment delayed in neonates who require intensive care, which might increase the risk of developing NEC9.

Interpretation of the results from various studies is hindered by the fact that several different probiotic strains and dosages have been used. A number of issues need to be resolved before general guidelines regarding the use of probiotics in the neonatal period can be given10.

Outcome measures:

Primary outcome- time to reach full enteral feeds
Secondary outcomes –
incidence of feed intolerance
incidence of NEC stage 2 or more
duration of hospital stay
days on TPN
weight gain
mortality

Benefits:

Probiotic supplementation to VLBW neonates is likely to improve feed tolerance, reduce NEC and all-cause mortality and duration of hospital stay.

Potential risks:

ByFederal Drug Administration (FDA) regulations, they are‘generally recognized as safe (GRAS)’
Case reports of systemic infections caused by probiotic organismsare reported in biomedical literature11,12
However the meta-analysis shows that probiotics are safe and well tolerated and provide a more robust safety data of probiotics use5.

References:

Morris BH, Miller-Loncar CL, Landry SH, Smith KE, Swank PR, Denson SE. Feeding, medical factors, and developmental outcome in premature infants. Clin Pediatr 1999;38:451–457.
Patole S. Strategies for prevention of feed intolerance in preterm neonates: A systematic review. JMatern Fetal Neonat Med2005;18: 67–76
Mohammadizadeh M, Ghazinour M, Iranpour R: Efficacy of prophylactic oral erythromycin to improve enteral feeding tolerance in preterm infants: a randomised controlled study. Sing Med J 2010; 51: 952-956

SchurrP, PerkinsEM. The relationship between feeding and necrotizing enterocolitis in very low birth weight infants. Neonatal Network 2008; 27: 397-406.
AlFaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD005496. DOI: 10.1002/14651858.CD005496.pub3.
Cobb BA, Waldemar CA, Namasivayam A. Gastric residuals and their relationship to necrotizing enterocolitis in very low birth weight infants. Pediatr. 2004;113:50–53
Indrio F, Riezzo G, Cavallo L, Di Mauro A, Francavilla R. Physiological basis of food intolerance in VLBW. J MaternFetal Neonat Med 2011; 24: 64-66
Holt PG, Jones CA. The development of the immune system during pregnancy and early life. Allergy 2000;55:688-97.
Martin R, Langa S, Reviriego C, Jiminez E, Marin ML, Xaus J,et al. Human milk is a source of lactic acid bacteria for the infant. J Pediatr 2003;143:754-8
Rautava S. Potential uses of probiotics in the neonate. Semin Fetal Neonatal Med 2007;12: 45-53
De Groote MA, Frank DN, Dowell E, Glode MP, Pace NR. Lactobacillus rhamnosus

GG bacteremia associated with probiotic use in a child with short gut syndrome. Pediatr Infect Dis J 2005;24:278-80.

Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatr 2005;115:178-81.

7.Aims and Objective(s) of the Study:

Aim:To evaluate the effect of Probiotics on Feed Tolerance in Very Low Birth Weight Neonates.

Objectives:

Primary:

To compare feed tolerance of very low birth weight neonatesadministered probiotics versus no probiotics.

Secondary:

To compare the difference in the morbidity* and mortality rates in very low birth weight neonates in probiotic group and no probiotic group.

*morbidity defined by:

incidence of feed intolerance
incidence of NEC stage 2 or more
duration of hospital stay
days on TPN
weight gain
mortality

8.Proposed Methodology (Not more than 2-3 pages)

(i)Subjects

Inclusion Criteria

All neonates (infants in the first 28 days of life) with a birth weight between 750 g to 1499 g admitted to NICU SJMCH Bangalore and started enteral feeds.
Outborn babies admitted within 72 hrs of life

Exclusion Criteria
Neonates GI tract anomalies, severe congenital malformations.
Refusal of consent.
Not started enteral feeds by day 14 of life.
Outborn babies fed within 72 hrs.

Type of subjects:

Males and / or Females:Patients (male and female)
Volunteers : No
Patients:Yes
Vulnerable subjects:Yes

If yes, does it include Pregnant women / Children / elderly / Fetuses / Prisoners / destitute / Service providers / Terminally ill / Others (Specify)……………………

Neonates with a birth weight less than 1.5 kg.

(iii) Sample size and the basis for the same

The sample size was determined based on data from a previous study and was calculated using N-Master biostatistical software-

The sample size was calculated using hypothesis testing for a difference between two meansusing the following parameters:

Standard deviation group 1:1.4
Standard deviation group 2:2
Mean difference:1
Effect size:0.5
Type 1 error : 5%
Power : 90%
1 / 2 sided: 2 sided

Sample size:( in each group)63

(iv) Trial Subject’s age group: 0 – 28 days

(v)Following selection of subjects as listed above, describe the methodology to be followed in the proposed study in detail – please be SPECIFIC and BRIEF, describe preferably in steps.

All neonates with a birth weight less than 1.5 kg, admitted to the NICUfulfilling the inclusion criteria will be included in this study. Study is designed as a double blind randomized controlled trial.
After a writteninformed consent is taken from the guardian, the subjects will be randomly allocated into two groups using SPSS. Sequentially numbered opaque sealed envelopes will be used to randomize the infants into either of the two groups. Intervention: Probiotic group receives a combination of lactobacillus, bifidobacter sp. once a day at a dose of 109 CFU from the time of initiation of enteral feeds till discharge in powdered form dissolved in breast milk and the no probiotic group. The probiotic supplementation will be continued till discharge with feeds and interrupted when feeds are withheld.

Control group : The no probiotic group will receive only breast milk.

Feeding will be initiated, advanced, stopped and restarted as per unit protocol.

The infant will be clinically monitored daily for feed intolerance, sepsis. Parenteral nutrition will be continued till 100ml/kg/day of feeds are reached. Full feeds are defined as 150ml/kg/day. The weight will be checked daily on a calibrated digital weighing machine with a sensitivity of +10 g. NEC is defined and staged as per modified Bell’s staging. The infants will be discharged as per unit protocol

Definition of feed intolerance is presence of any one of the following:
Abdominal distension ≥2cm from the previous measurement
Vomiting ≥2 episodes in the past 6 hrs
Gastric aspirate blood stained or bilious
>2 episodes of voluminous gastric aspirates in a 6 hr period

The following parameters will be studied

Day of reaching full feeds.
Weight gain
Number of episodes of feed intolerance
Days on TPN
Duration of hospital stay
Incidence of NEC
Mortality till discharge

(vi)If the research subjects are to undergo any procedures during their participation in the study (like collection of blood/urine/feces, venepuncture, Xrays, intubation, special diet, drugs administered with dose, others) please specify the procedures.

Probiotic formulation is administered to the control group

(vii)State any potential or known hazards of the procedure listed in the above clause. How does the investigator intend to overcome this aspect?

More than 1370 infants have been enrolled in probiotic studies. Till date, twocasesof sepsis with lactobacillus used as oral formulation have been reported.

Babies enrolled will be clinically monitored for sepsis and septic screen followed by blood culture will be done on clinical suspicion.

(viii)Does the study include any procedure involving radioisotopes or irradiation? If so, give details.

(ix)If placebos are used, justify the use of the same. What precaution will be taken to ensure the safety of the patient given placebo? Is any standard treatment withheld?

(x)State the statistical analysis proposed to be used?

Objectives / Statistical Model / Inferential statistics

To estimate the difference in time to reach full feeds in probiotic and no probiotic group

Odds ratio
95% confidence interval of the odds ratio

/ Chi square test or Fischer’s exact test

To compare the morbidity and mortality rates in in probiotic and no probiotic group

Odds ratio
95% confidence interval of the odds ratio

/ Chi square test or Fischer’s exact test

(xi)Duration of the study:

The study will be based in the NICU at St. John’sMedical College Hospital. All the neonates whose birth weight is less than 1500gms who are admitted during the period of May 2012 to November 2013 will be eligible for the study.

(xii)Which consultant / investigator(s) are responsible for conducting the study?

Principal investigator/ co- investigators

Neonatologists working in the NICU will be responsible for monitoring the babies.

9.Study Design : (tick the single most appropriate one)

Case Control study
Community based trial / intervention
Secondary Data analysis
Clinical Trial (Hospital)-Yes
Family follow-up study
Descriptive study
Cross Sectional Study
Cohort Study
Record Review
Vaccine Trial
Surveillance / Monitoring
Validational Study(hospital)
Others (Specify)

10.Determination of Risk : (Tick all that applies):

Does the research involve:

Human exposure to radioactive agents? No
Human exposure to infectious agents? No
Investigational new drug? No
Investigational new device? No
New treatment regime? Yes
Use of new vaccines? No
Observation of public behavior? No
Fetal tissue or abortus? No
Pathological or diagnostic clinical specimen only? No
Existing data available via public archives source? No
Existing data available from co-investigator? No

11.What is the Investigator’s personal experience with the proposed study,patient management and the associated techniques involved? (Give details of the preliminary work by the investigator, wherever appropriate)

The Principal Investigator and Co-Investigators of the present study are full time physicians in the NICU. The investigators have vast experience in management of VLBW infants. The team has completed a study on effect of erythromycin in feed intolerance. In addition, a pilot study will be conducted by the same team using the above protocol.

12.Will any sample collected from the patients be sent :

To extramural institutions within IndiaNo
To any other place outside IndiaNo

(if so, please specify)

13. In case the samples are preserved for future tests, how long will they be preserved and how is the use of such samples controlled?

Not applicable

14. Informed Consent

How will the informed consent be obtained and by whom? (Please specify PI / Co-PI/ Nurse / Counselor / Research staff / Any other……………………………)

Consent will be taken by the Principal Investigator/ Co-investigator, via a written consent form.

Is the informed consent written / oral with a witness / audio-visual? Informed written consent will be taken.

Is the form of consent with the explanatory note (Patient Information Sheet – PIS) appended?

(The PIS should be in understandable, simple language and should include the research aspect of the study; Sponsor of study; Purpose and procedures; risks and discomforts; Benefits; Compensation for participation or for study related injury; Alternatives to participation and right to withdraw; Confidentiality of records; Contact information; Statement that consent is voluntary)

Yes

16.Please state whether subjects will have to bear expenses related to any of the following and state how the expenses would be met:

(i)Cost of Medicineyes

(ii)Cost of InvestigationsNo

(iii)Cost of travelNo

(iv)Any other costs (Specify) No

17.Will the subjects receive financial benefit / other material benefit as a result of participation in this study? Please specify.

18.Is there a compensation for injury (due to the study) given by Sponsor / Investigator / Insurance / any other means? If yes, please specify.

19.Conflict of interest:

Is there any conflict of interest involving the study team? (financial / non-financial)

Please mark as applicable and explain if the response if YES:

I or my immediate family members own or control

shares of the concerned company No

I or my immediate family members have a proprietary

Interest in the product that I have contracted to test

(Financial interest also includes interest in a company No

that would benefit from the approval of the test product)

I will notify the sponsor and the IERB if there are any

changes in the information disclosed herein that occur

during the clinical trial / study and for one year following Yes

completion of the trial / study

(iii) Is the Clinical Trial Agreement enclosed? No

20.a) How many ongoing trials are you currently involved in?

None

b) How much of time (on a daily / weekly basis) can you allot for the present study?

5 hours a week

21.In case of chart review / retrospective studies, please mention as to how the identify of the patient is delinked and how confidentiality is maintained?

Not applicable

22.Confidentiality: Please mark on (Yes / No)

a) Is the information recorded in such a manner that subjects can

be identified from the information provided directly or through

identifiers liked to the subject? No

b) Does the research deal with sensitive aspects of the subject’s

behavior such as sexual behavior, alcohol use or illegal conduct

such as drug use? No

c) Could the information recorded about the individual, if got

to be known outside the research:

(i) Place the subject at risk or criminal or civil liability? No

(ii) Damage the subject’s financial standing, reputation or

employability; social rejection, lead to stigma, divorce etc? No

d) Is confidentiality maintained in handling of data by staff? Yes

23.Risk assessment: do you consider this research (Check one)

Greater than minimal
Not more than minimal risk
No risk
Only part of the diagnostic test

(Minimal risk is a “a risk where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical, psychological examinations or test. For eg., the risk of drawing a small amount of blood from a healthy individual for research purposes is not greater than the risk of doing so as a part of routine physical examination”