RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
1 Name of the candidate & address Dr. BHARATH KUMAR V D
#7-118 SREE CHAMUNDESHWARI KRUPA, BEHIND
VENKATESHWARA SAW MILL, BASTIPURA ROAD,
KOLLEGAL, CHAMRAJ NAGAR DIST 571440
2 Name of the institution BANGALORE MEDICAL COLLEGE & RESEARCH
3 Course of study and subject M.D in PHARMACOLOGY
4 Date of admission to the course 18th JUNE 2010
5 Title of topic “A COMPARATIVE STUDY OF PROBIOTIC,
PROKINETIC BASED TRIPLE THERAPY WITH
USFDA APPROVED REGIMEN IN THE
ERADICATION OF H.PYLORI IN A TERTIARY CARE
6 Brief resume of intended work:
6.1 Need for study:
Helicobacter pylori infection is a widespread disease leading to significant morbidity and
mortality, requiring an appropriate therapeutic approach1.
Effective treatment for H. pylori should achieve an eradication rate of over 90%2, 3. Its eradication
markedly reduces rate of ulcer relapse. Local prevalence of anti-microbial resistance should be
known, so that the appropriate antibiotics can be combined. The other factors like cost, simplicity
and tolerability should also be taken into account3.
Many meta-analysis studies have shown that 2 week regimens achieve better eradication rate than
one week regimens. Triple therapy regimens with proton pump inhibitors, clarithromycin and
amoxicillin or metronidazole are considered to be the most effective combinations for the treatment
of H. pylori infections worldwide because of their safety, cost effectiveness and simplicity4,5.
The increasing resistance to nitroimidazoles, poor tolerability due to side effects like diarrhea,
taste disturbances and bloating may result in non-compliance to currently used regimens, which
contributes to eradication failure6, 7.
Addition of Probiotics improves the antibiotic tolerability by reducing side effects like diarrhea,
and efficacy by reducing H.pylori density in gastric mucosa8, 9. Prokinetics improves dyspeptic
symptoms and increases patient compliance and quality of life10. There is lack of data in Indian
population regarding combination of probiotic and prokinetic based triple regimens.
Therefore, the present study is designed to compare the safety and eradication rate of USFDA
approved regimen [lansoprazole, amoxicillin and clarithromycin] with a new combination regimen
comprising of a probiotic, prokinetic (itopride) based triple therapy (pantoprazole, amoxicillin and
clarithromycin) practiced at Department of Surgical Gastroenterology, Victoria Hospital, Bangalore
Medical College and Research Institute.
6.2 Review of Literature:
Helicobacter pylori, which persistently colonize the stomach of ~50% of the world’s human
population, is the main risk factor for peptic ulceration as well as for gastric adenocarcinoma and
gastric MALT lymphoma. Treatment of H.pylori has revolutionized the management of peptic ulcer
disease, providing a permanent cure in many cases. The prevention of H. pylori colonization could
potentially represent primary prevention of gastric malignancy and peptic ulceration1.
When the treatment is indicated as per Indian consensus statements, the regimen selected should
have a known eradication rate of over 90% 2,3. Local prevalence of anti-microbial resistance should
be known, as well as additional factors like cost, simplicity and side effects should also be noted3.
Various H. pylori eradication regimens came into practice consisting of a proton pump inhibitor
(PPI) with antibiotics. Single drug regimens are not advocated due to the development of antibiotic
resistance. Dual treatments combining a proton pump inhibitor with clarithromycin or amoxicillin
showed unacceptably low eradication rates.
Later triple therapies consisting of colloid bismuth sub citrate, tetracycline and metronidazole for
two weeks was shown to produce high cure rates. Triple therapies with a combination of PPI and
two antibiotics have largely replaced the use of classical bismuth triple therapy in almost all
countries due to better tolerability and higher efficacy. These therapies of PPI with two antibiotics
are advocated as 7-14 day regimens with omeprazole, pantoprazole or lansoprazole in combination
with two antibiotics viz. clarithromycin, amoxicillin and metronidazole. PPI based triple therapy are
usually considered first line of treatment, when resistance to nitromidazole is high, then a
combination of PPI with amoxicillin and clarithromycin is used 4,5, 6,7.
US-FDA has recommended a regimen consisting of lansoprazole, amoxicillin and clarithromycin
for 14 days. The same regimen used in south east Asian patients showed 87% eradication rate5.
Meta-analyses have shown that probiotics administration improves antibiotic tolerability by
reducing side effects like diarrhea, bloating and taste disturbances. Probiotics also improves H.
pylori gastritis and decrease H. pylori density. Long term intake of probiotics reduces the risk of
development of disorders associated with high degrees of gastric inflammation8. Few studies have
also failed to demonstrate a significant role of probiotics in improving H.pylori therapy success9.
Addition of prokinetic to H. pylori eradication regimen results in symptom improvement in two
third of dyspeptic patients leading to improvement in quality of life10. There is lack of data in Indian
population combining probiotic and prokinetic in triple regimens.
6.3 Aims and Objectives:
1. To compare eradication rates of USFDA approved regimen with probiotic, prokinetic based
2. To assess the patient compliance and tolerability.
7 MATERIALS AND METHODS:
7.1 Source of data:
Outpatients and inpatients in the Department of Surgical Gastroenterology, Victoria hospital,
7.2 Methods of collection of data:
A. Study design: Comparative, prospective study.
B. Study period: Oct 2010- Sep 2012.
C. Sample design: Random sampling.
D. Sample size: 100patients with acid peptic disease
After obtaining approval and clearance from the institution ethical committee, patients will
be included for the study.
The study subjects fulfilling the inclusion/exclusion criteria will be randomly assigned into 2
groups of 50 patients in each group.
Group A: Patients treated with USFDA approved regimen.
Group B: Patients treated with prokinetic, probiotic based regimen.
E. Inclusion Criteria :
1. Patients of either sex aged between 18-60years
2. Patients with acid peptic disease (non-ulcer dyspepsia, gastro-duodenal ulcers and erosions,
GERD) with endoscopically proven H. pylori infection by both rapid urease test and
3. Patient who gives written informed consent.
F. Exclusion Criteria:
1. Patients on NSAIDS, anticoagulants, antibiotics or corticosteroids in the past 30 days.
2. Patients with co-morbid conditions – Ischemic heart disease, congestive cardiac failure, liver
disease and renal failure.
3. Pregnant and lactating women.
4. Patients with features of portal hypertension, gastric or any other malignancy or evidence of
significant gastrointestinal bleed.
5. Patients with known allergy to medications used.
6. Patients with previous gastric or esophageal surgery.
7. Non complying patients who are unable to give consent for the study.
100 patients diagnosed with H. pylori infection by upper Gastrointestinal endoscopy,
histopathological examination and rapid urease test( RUT) will be enrolled in the study after
obtaining informed consent and they will be randomly assigned into two different eradication
treatment groups. Demographic data, history, clinical examination and details of drug prescription
by the treating gastroenterologist will be recorded in the study proforma.
Group A will receive USFDA(United States Food and Drug Administration) approved regimen
with amoxicillin 1 gm, lansoprazole 30 mg and clarithromycin 500mg twice a day for 2 weeks
Group B will receive new regimen consisting of a probiotic and a prokinetic itopride 50mg, both
thrice daily, pantoprazole 40 mg, amoxicillin1 gm and clarithromycin 500mg twice daily for 2
Pantoprazole, lansoprazole and itopride to be taken half an hour before food
Combination of Pantoprazole and itopride will be given to group B and lansoprazole to group A
once daily for next 4 weeks.
The patients will be followed up at the end of 2nd and 6th week. At 6th week, rapid urease test and
endoscopy will be repeated, those patients with RUT and histopathology negative are considered
responders and then the percentage of responders in both groups will be compared.
H. Assessment tools:
Proforma to elicit sociodemographic data.
H. pylori infection will be diagnosed by endoscopic biopsies obtained, one from the antrum
and one from gastric body and the identification of the organism on histology by Giemsa
technique and by positivity of Rapid urease test.
A thorough physical/ gastro enterological evaluation will be carried out and recorded in the
Efficacy will be assessed by:
- H. pylori eradication will be considered to have been achieved when both histological
detection and RUT, are negative in all gastric sites tested.
- Ulcer healing defined as complete re-epithelisation of ulcerative lesion at endoscopy
- A comparative evaluation dyspepsia symptom score, dyspepsia questionnaire and gastritis
score will be done at baseline, 2nd and 6th week (annexure-4).
Safety will be evaluated by:
- Recording clinical adverse events
- Further adverse events will be classified according to their type, severity, and possible
relationship to treatment.
- Incidence of side effects will be assessed using a standardized questionnaire given to the
patient at the time of enrollment and to be filled in during treatment period, indicating the
type and degree of interference with daily activity of the patient (annexure-5) and also by
clinically significant abnormal laboratory investigations.
Tolerability will be analyzed in all compliant patients based on the side effects grading
At the end of two weeks when patient comes for 2nd visit treatment compliance will be
estimated by using a scale (annexure-9).
Relevant laboratory investigations :
- Random blood sugar, blood urea, serum creatinine, SGOT, SGPT.(Annexure-6)
I. The detailed schedule of patient visit is as follows :
Visit 1/ day1 / initial or baseline assessment-
Patients will be informed fully about the purpose and requirements of the study and written
informed consent will be obtained (Annexure-1).
Patient will be enrolled as per protocol criteria.
Each patient, who satisfies all the inclusion/exclusion criteria including routine laboratory
investigations, will qualify for inclusion in the study (Annexure-2A).
Details of patient’s demographic characteristics, medical history, and concomitant
medication history of habits, detailed physical examination and clinical findings will be
Blood sample for relevant laboratory investigations will be collected.
Patients will be issued two week medication and advised to take medication as prescribed.
The patient will be instructed to return for clinical assessment after two week and to bring
the medication kit with any tablets remaining unutilized.
Visit 2/ Day 14 -15 ( week 2)
Medication compliance, any intercurrent illness or change in concomitant medication will be
All observed or spontaneously volunteered adverse events will be recorded.
Clinical examination will be repeated.
Dyspepsia questionnaire will be recorded.
The patient will be issued a four week supply of active medication and reminded to take
medicine in the prescribed manner.
The patient will be instructed to return after four week and to bring the medication kit with
any tablets remaining unutilized.
Visit 3/ Day 42 -44 (6th week)
The number of tablets remaining unconsumed will be counted and compliance recorded.
Any intercurrent illness or change in concomitant medication will be noted.
Dyspepsia questionnaire will be recorded.
Clinical examination will be repeated.
Blood sample will be collected for assessment of routine laboratory investigations.
Global Evaluation of overall tolerability will be recorded (Annexure-8).
The study termination will be completed.
If any adverse event is persistent or there is any abnormal laboratory value of clinical
significance, appropriate follow up will be made. Patients will be advised about further
J. Statistical analysis:
Parametric variables will be analyzed using student t test and z test.
Non parametric variables will be analyzed using Fischer exact test and Chi- square test.
Any other suitable statistical method will be used at the time of data analysis after consulting
7.3 Does the study require any investigation to be conducted on patients or animals specify?
It does not require any animal studies.
These are the following investigations done for patients-
o Random blood glucose
o Serum creatinine
o Blood urea
o SGOT, SGPT
7.3 Has the ethical clearance been obtained from ethics committee of your Institution in case
Yes, ethical clearance has been obtained from the ethics committee of Bangalore medical
college and research institute.
8 LIST OF REFERENCES :
1. Atherton JC, Blaser MJ. Helicobacter pylori infections. In: Fauci AS, Braunwald E, Kasper
DL, Hauser SL, Longo DL, Jameson JL et al.Editors, Harrison’s Principles of Internal
Medicine. Vol. 1, 17th edition, McGraw hill, New York: 2009: 946-949.
2. Hoogerwerf WA, Pasricha PJ. In: Pharmacotherapy of gastric acidity, peptic ulcers and
gastroesophageal reflux disease. Bruton LL, Lazo JS, Parker KL. Editors. Goodman and
Gillman’s The Pharmacological Basis of Therapeutics. 11th ed., McGraw hill, New York:
3. Kate V, Ananthakrishnan N. Treatment of Helicobacter pylori infection- a review. Indian J
pharmacol 2001; 33: 410-416.
4. Zagari RM, Bianchi-Porro G, Fiocca R, Gasbarrini G, Rodo E, Bazzoli F. Comparison of 1
and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for helicobacter
pylori eradication: the HYPER study. Gut 2007; 56 : 475-479
5. Kausik SP, Vu C. Helicobacter pylori eradication with lansoprazole, amoxicillin and
clarithromycin: testing an ideal regimen in a multicultural south East Asian population and
examining factors potentially influencing eradication. Aust N Z J Med 2000 Apr;30(2):231-
6. Agah S, Shazad B, Abbaszaadeh B. Comparison of azithromycin and Metronidazole in a
quadruple therapy regimen for H.pylori eradication in dyspepsia. The Saudi journal of
gastroenterology 2009 15(4): 225-8
7. Talaie R, Zojaji H, Mirsattari D, Kaboli A, Alizadeh AHM, Zali MR. Comparison of two
different eardication regimens for H. Pylori: amoxicillin, metronidazole, bismuth and
omeprazole versus new regimen of penbactam, clarithromycin and omeprazole; a
randomized clinical trail. Gastroenterology and hepatology from bed to bench
8. Tong JL, Ran ZH, Shen J, Zhang CX, Xiao SD. Meta-analysis: the effect of
supplementation with probiotics on eradication rates and adverse events during Helicobacter
pylori eradication therapy. Aliment Pharmacol Ther 2007; 25, 155-168.
9. Scaccianoce G, Zullo A, Hassan C, Gentili F, Cristofari F, Cardinale V et al. Triple
therapies plus different probiotics for helicobacter pylori eradication. Eur Rev Med
Pharmacol Sci 2008; 12: 251-256.
10. Ang TL, Fock KM, Teo EK, Chan YH, Ng TM, Chua TS et al. Helicobacter pylori
eradication versus prokinetics in the treatment of functional dyspepsia: a randomized,
double blind study. J Gastroenterol 2006 jul; 41(7): 647-53.
9 SIGNATURE OF
10 REMARKS OF THE H. pylori is the commonest cause for ulcer relapse. Hence, the H. pylori
GUIDE eradication rate of a probiotic and prokinetic based novel regimen will
be evaluated in the present study.
11 NAME AND Dr. C.R. JAYANTHI MD.
DESIGNATION OF Professor & Head, Department of Pharmacology, Bangalore Medical
College & Research Institute, Bangalore.
11.3 CO-GUIDE Dr. K.V. ASHOK KUMAR MS, FICS, FSGE.
Professor and Head, Department of Surgical Gastroenterology,
Bangalore Medical College & Research Institute, Bangalore.
11.5 HEAD OF THE Dr. C.R. JAYANTHI MD.
DEPARTMENT Professor & Head, Department of Pharmacology, Bangalore Medical
College & Research Institute, Bangalore.
12 12.1 REMARKS OF