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Oncology

ONC: Probiotics (2006)

Citation:

Urbancsek H, Kazar T, Mezes I, Neumann K. Results of a double-blind, randomized study to evaluate the efficacy and safety of Antibiophilus in patients with radiation-induced diarrhoea.Eur J Gastroenterol Hepatol. 2001 Apr;13(4):391-6.

Study Design:

Randomized Controlled Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

To evaluate if the probiotic Lactobacillus rhamnosus (Antibiophilus) is tolerated and effective in treating mild to moderate radiation-induced diarrhea.

Inclusion Criteria:

Age 19-75 years (no one under age 20 participated meeting the ADA inclusion criteria)and,
Developed diarrhea within 4 weeks after receiving radiation (XRT) and,
XRT to abdominal region and,
Written informed consent

Exclusion Criteria:

Severe diarrhea-induced dehydration or
Bloody diarrhea

Description of Study Protocol:

Recruitment: 206 patients from 8/1996 to 6/1998 in two XRT clinics in Hungary

Design: Randomized, double-blind, placebo-controlled trial of Antibiophilus in patients experiencing XRT-induced diarrhea. Duration was up to one week until they felt improvement or cessation of diarrhea.

Blinding used: Both participants and researchers were blinded. The probiotic and placebo were prepackaged by the sponsor and only labeled with the patient number.

Intervention:

Treatment group (n=102): Consume 1.5 g of Lactobacillus rhamnosus (provided in a sachet) three times a day (distributed by Germania Pharmazeutika GmbH in Austria). Total probiotic consumption = 4.5 g/day.

Control group (n=103): Consume placebo (sachet contained: 700 mg corn starch, 797 mg microcrystalline cellulose, 1.37 mg iron oxide, 1.13 mg orange coloring agent, and 1 mg caramel aroma) three times a day

All were instructed to:

Suspend study medication in water and take 1 hour after meals
Take the study medication until improvement or cessation of their diarrhea for a maximum time period of up to one week
Permitted to take loperamide as the rescue medication if diarrhea was not improving (Opiod treatment had to be recorded as rescue medication as well).
Keep a diary of the date and time of rescue medication
Avoid any other anti-diarrheal medication

Statistical Analysis

Intent to treat analysis used.

Primary endpoint (hours to use of rescue medication) was analyzed using Kaplan-Meier curves for descriptive purposes and log-rank test for conclusions.

Secondary endpoints (number of bowel movements, severity of diarrhea, and consistency rating of bowel movements by investigator) were analyzed by:

chi-squared test for percentages
t test for between-group comparisons of averages and the repeated measures of start-versus-end comparisons
Mantel-Haenszel test for averages from patient diaries for treatment-by-time interactions

Percentages for categorical data; means and medians for quantitative data; statistical significance at p<0.05.

Data Collection Summary:

Timing of Measurements

At the initial visit, investigators recorded:

Prescribed concomitant medication, self-prescribed medication, and other medication prescribed
The number and consistency of bowel movements, and the severity of diarrhea

Patients self-reported in a diary for up to one week their bowel habits and date/time of rescue medication

At the follow-up visit (Day 7), investigators recorded:

The number and consistency of bowel movements, and severity of diarrhea
Sachet count for adherence to protocol

Dependent Variables

Time to and quantity of rescue medication usage in hours
Change in the average number of bowel movements
Grading of the severity of diarrhea
Consistency of bowel movements

Independent Variable:

Consumption of Antibiophilus three times a day

Control Variable:

Consumption of placebo three times a day

Description of Actual Data Sample:

Initial N: 206

Final N: 205 (one patient was a violation of age protocol and all data was excluded from analysis)

Intervention group - 102 patients (25% male/75% female)
Control group - 103 patients (26% male/74% female)

Age: Not significantly different between groups.

Intervention group - mean 59 years (28-81 range)
Control group - mean 60 years (33-86 range)

Ethnicity: no data provided

Other relevant demographics:

No statistically significant differences between two groups in terms of cancer diagnosis and stage, but exact data not recorded. Diagnosis included uterine, ovarian, prostate, rectum and other miscellaneous malignancies of the abdomen.

XRT:

typical daily dose of 2 Gy
median number of sessions was 25 prior to study
median dosage prior to study was 50 Gy

Other disease and medications: highly comparable and no reason for alternate source of diarrhea, but again data not recorded.

Body Weight: significant difference in weight at initial visit (p<0.10)

Intervention group - Mean 68 kg (44-108 kg range)
Control group - Mean 65 kg (38-103 kg range)

Location: Two XRT clinics in Hungary

Summary of Results:

Comparison between treatment and control groups

Variables	Probiotic Group	Control group	Statistical Significance of Group Difference
Time to usage of rescue medication	138 hrs +/- 5 hrs SE	125 hrs +/- 5 hrs SE	p=0.064
Percentage need for rescue medication	35%	48%	p= 0.057
Avg. # of daily bowel movements at study beginning	6.4	6.6	NS
Avg. # of daily bowel movements at study end	2.4	3.2	p<0.10
Rating of Diarrhea by investigators at study beginning	2.0 *	2.2*	NS
Rating of Diarrhea by investigators at study end	0.7*	1.0*	NS
Consistency of bowel movements at study beginning	1.9^	2.1^	NS
Consistency of bowel movements at study end	0.7^	1.0^	p<0.05

NS- non-significant

*- 0 for none, 1 for mild, 2 for moderate, 3 for severe

^- 0 for normal, 1 for soft, 2 for pasty, 3 for liquid

Comparison between two time points

Group/test Start End p-value

Intervention/number of bowel mvmts 6.4 2.4 P<0.001

Placebo/number of bowel mvmts 6.6 3.2 P<0.001

Intervention/diarrhea rating (2-moderate, 1-mild) 2.0 0.7 P<0.001

Placebo/diarrhea rating 2.2 1.0 P<0.001

Intervention/consistency rating (see above for scale) 1.9 0.7 P<0.001

Placebo/consistency rating 2.1 1.0 P<0.001

Patient diarrhea rating and consistency rating over time for both groups showed a P value of 0.001

No adverse events were noted.

Compliance with the study protocol was completed by a sachet count with no problems recorded.

Author Conclusion:

Although narrowly missing statistical significance, in patients experiencing radiation-induced diarrhea for two weeks, the intervention group received less and later anti-diarrheal medication than the control group.

Between the intervention and control group, the intervention group had a statistically significant improvement in the number and consistency of bowel movements.

Both group showed statistically significant improvements in number and consistency of bowel movements and diarrhea rating from the start to the end of the study.

Overall, Antibiophilus product produced greater benefits that outweigh the risks of using this product in treating radiation-induced diarrhea.

Funding Source:

Industry:

Germania Pharmazeutika GmbH (Austria).

Pharmaceutical/Dietary Supplement Company:

Reviewer Comments:

Overall this is study has strong design and adequate accrual numbers to show statistical and clinical significance. Authors addressed and monitored medications that could affect bowel habits (opioids) that could confound results.

Limitations:

The reason why the placebo group also had statistical ratings over time was not discussed.
Concerns that the data on cancer diagnosis is not detailed enough (primary or secondary diagnosis, actual numbers or percentages in each group, stage of disease that may impact extent of disease and amount and size of radiation field).
Did not exclude prior radiation therapy, other disease of GI tract, anyone undergoing chemotherapy.
No information on type of diet patients were to consume (including fluids) and if certain timing between doses (for example, at least 5 hours between meals).
Funding source was the same company who distributed the brand of probiotic.
Did not use the WHO grading for diarrhea.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	???
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	???
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	???
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		No
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	No

Group/test	Start	End	p-value
Intervention/number of bowel mvmts	6.4	2.4	P<0.001
Placebo/number of bowel mvmts	6.6	3.2	P<0.001
Intervention/diarrhea rating (2-moderate, 1-mild)	2.0	0.7	P<0.001
Placebo/diarrhea rating	2.2	1.0	P<0.001
Intervention/consistency rating (see above for scale)	1.9	0.7	P<0.001
Placebo/consistency rating	2.1	1.0	P<0.001