ST - Clinical Trials Registry

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ST. JOHN’S MEDICAL COLLEGE HOSPITAL
PROFORMA FOR APPROVAL OF RESEARCH PROJECT BY IERB
IERB Study Ref. No.
1.
2.
Title of the project
Effect of Probiotics on Feed Tolerance in Very Low Birth Weight NeonatesA Randomized Controlled Trial
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 &
Contact Address & Telephone
Signature
Qualification
No / Mobile No and e-mail ID
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
[email protected]
Co-PI / Co-investigator
(1)
(2)
(3)
(4)
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
[email protected]
Dr.Suman Rao P.N.
Associate Prof
St Johns Medical College
and Hospital
Dr. Saudamini Nesargi
Assistant Professor
Department of
Neonatology
St. John’s Medical
College and Hospital
Dr.Chandrakala
Assistant Prof
Department of
Neonatology
St. John’s Medical
College and Hospital
Department of Neonatology
St Johns Medical College and
Hospital
Contact:+91-9019569652
[email protected]
Department of Neonatology
St Johns Medical College and
Hospital
Contact: +91-9243472262
[email protected]
Department of Neonatology
St Johns Medical College and
Hospital
Contact:+91-9902001972
[email protected]
1
3.
Specify whether Basic Science / Behavioral /
Clinical trial / Epidemiologic / others
4.
Clinical Trial
N/A
Name & Address of the Sponsor
(if applicable)
6.
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.
2
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 –
o incidence of feed intolerance
o incidence of NEC stage 2 or more
o duration of hospital stay
o days on TPN
o weight gain
o 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:
 By Federal Drug Administration (FDA) regulations, they are ‘generally
recognized as safe (GRAS)’
 Case reports of systemic infections caused by probiotic organisms are 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:
1. 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.
2. Patole S. Strategies for prevention of feed intolerance in preterm neonates: A
systematic review. J Matern Fetal Neonat Med 2005;18: 67–76
3. 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
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4. Schurr P, Perkins EM. The relationship between feeding and necrotizing enterocolitis
in very low birth weight infants. Neonatal Network 2008; 27: 397-406.
5. 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.
6. 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
7. Indrio F, Riezzo G, Cavallo L, Di Mauro A, Francavilla R. Physiological basis of food
intolerance in VLBW. J Matern Fetal Neonat Med 2011; 24: 64-66
8. Holt PG, Jones CA. The development of the immune system during pregnancy and
early life. Allergy 2000;55:688-97.
9. 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
10. Rautava S. Potential uses of probiotics in the neonate. Semin Fetal Neonatal Med
2007;12: 45-53
11. 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.
12. 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:
1. To compare feed tolerance of very low birth weight neonates administered
probiotics versus no probiotics.
Secondary:
1. 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:
o incidence of feed intolerance
o incidence of NEC stage 2 or more
o duration of hospital stay
o days on TPN
o weight gain
o mortality
8.
Proposed Methodology (Not more than 2-3 pages)
(i) Subjects
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 Inclusion Criteria
o 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.
o 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
Volunteers
Patients
Vulnerable subjects
:
:
:
:
Patients (male and female)
No
Yes
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 softwareThe sample size was calculated using hypothesis testing for a difference between two
means using 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)
(v)
Trial Subject’s age group: 0 – 28 days
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.
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



All neonates with a birth weight less than 1.5 kg, admitted to the NICU fulfilling the
inclusion criteria will be included in this study. Study is designed as a double blind
randomized controlled trial.
After a written informed 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:
o Abdominal distension ≥2cm from the previous measurement
o Vomiting ≥2 episodes in the past 6 hrs
o Gastric aspirate blood stained or bilious
o >2 episodes of voluminous gastric aspirates in a 6 hr period
The following parameters will be studied
o Day of reaching full feeds.
o Weight gain
o Number of episodes of feed intolerance
o Days on TPN
o Duration of hospital stay
o Incidence of NEC
o 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, two cases of
sepsis with lactobacillus used as oral formulation have been reported.
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 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.
No
(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?
No
(x)
State the statistical analysis proposed to be used?
Objectives
Statistical Model
Inferential
statistics
Chi square test or
 To estimate the difference in time to  Odds ratio
reach full feeds in probiotic and no  95% confidence interval Fischer’s exact
test
probiotic group
of the odds ratio
Chi square test or
 To compare the morbidity and  Odds ratio
mortality rates in in probiotic and no  95% confidence interval Fischer’s exact
test
probiotic group
of the odds ratio
9.
(xi)
Duration of the study:
The study will be based in the NICU at St. John’s Medical 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.
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
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
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.
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12.
Will any sample collected from the patients be sent :
 To extramural institutions within India
No
 To any other place outside India
No
(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
a.
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.
b.
Is the informed consent written / oral with a witness / audio-visual?
Informed written consent will be taken.
15.
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:
17.
(i)
Cost of Medicine
yes
(ii)
Cost of Investigations No
(iii)
Cost of travel
(iv)
Any other costs (Specify) No
No
Will the subjects receive financial benefit / other material benefit as a result of
participation in this study? Please specify.
No
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18.
Is there a compensation for injury (due to the study) given by Sponsor /
Investigator / Insurance / any other means? If yes, please specify.
No
19.
Conflict of interest:
Is there any conflict of interest involving the study team? (financial / nonfinancial)
Please mark as applicable and explain if the response if YES:
I.


II.
I or my immediate family members own or control
shares of the concerned company
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
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
completion of the trial / study
(iii)
20.
Is the Clinical Trial Agreement enclosed?
No
No
Yes
No
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
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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?
d) Is confidentiality maintained in handling of data by staff?
23.
No
Yes
Risk assessment: do you consider this research (Check one)
I.
II.
III.
IV.
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”
24.
Is the proposal funded?
No
If yes, the sponsor’s name:
25.
Is the proposal being submitted for funding?
No
If yes, name of funding agency:……………………………………………………..
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Declaration by the Principal Investigator:
I certify that the statements herein are true, complete and accurate to the best of my
knowledge. I am aware that any false, fictitious of fraudulent statement or claims may subject
me to criminal, civil or administrative penalties. I agree to accept responsibility for the
scientific conduct of the project and to provide the required progress reports as and when
required.
Signature of PI:…………………
Date :
Checklist:
Sl.No.
Documents
Yes
No
1
Covering letter
yes
2
Project proposal
yes
3
Patient Information Sheet
yes
4
Informed Consent Form / Assent Form in English
yes
5
Informed Consent Form/ Assent Form in regional languages with
back translations *
6
Clinical Trial protocol *
7
Investigator’s brochure for recruiting subjects *
no
8
Copy of advertisements / Information brochures
no
9
Questionnaire (if any)
10
Clearance certificate from DCGI / DGFT *
no
yes
no
yes
12
no
11
Insurance Certificate *
no
12
Copy of the Clinical Trial Agreement *
no
13
CV’s of the PI / Co-PI / Co-investigators / Guide
no
(if they are from outside St. John’s)
14
Soft copies of the above documents
no
15
IERB processing Fees
no
* Documents for Clinical Trials only
INVESTIGATOR’S COPY
(Need not submit a print out of this page)
Please Note: (MUST for all applications)

All the questions need to be answered. If not applicable, enter “not applicable”. DON’T
delete any questions from the Proforma.

Should have the signatures of all the investigators.

The proposal should be routed through Head of Department

Two hard copies of the documents need to be submitted in Times New Roman font,
size 12, and printed on both sides.

Soft Copy in CD (should contain ALL THE DOCUMENTS - 1 No.)
OR send the soft copy to: [email protected]

One soft copy of the proforma, English version of Patient Information Sheet and
Informed Consent Form should be in Word Document and saved as a separate folder
marked as IERB PROFORMA

Processing Fees:
(i) A cheque / DD for Rs. 15,000/- (exclusive of TDS) in favour of “ST.JOHN’S
MEDICALCOLLEGE” (Fees only for sponsored trials which are submitted
through St. John’s faculty) w.e.f. 1st March 2010
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(ii) A cheque/DD for Rs. 20,000/- (exclusive of TDS) in favour of “ST.JOHN’S
MEDICALCOLLEGE” (Fee only for sponsored trials which are submitted
directly) w.e.f. 1st March 2010

Fees exemption for:
(i) Student studies, (both mural and extra-mural)
(ii) Projects sponsored by Research Organizations like ICMR, DBT, DST, (if fee
waiver is requested)
(iii)All departmental projects

The IERB Office timings are 9.00am to 1.00pm and 2.00pm to 4.30pm for all
correspondence and communications.The Documents should be submitted between
11.00am and 1.00pm only.

IERB format is available in the IERB Office, Ground Floor of the College Building
(Contact No : 25634123 / 22065780) or send your request to [email protected]
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