Trial Title:
Effectiveness of Probiotics for the Prevention of Gastrointestinal Toxicity in Children With Leukemia
NCT ID:
NCT06560879
Condition:
Probiotics
Gastrointestinal Diseases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Conditions: Official terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Gastrointestinal Diseases
Digestive System Diseases
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
An experimental, longitudinal, prospective, prolective, analytical, concurrent,
randomized, triple-blind: randomized controlled clinical trial
Primary purpose:
Prevention
Masking:
Triple (Participant, Care Provider, Outcomes Assessor)
Masking description:
Interventions packaged in identical, odorless, tasteless, opaque capsules; stored in
identical white plastic bottles.
Intervention:
Intervention type:
Biological
Intervention name:
Lactobacillus casei
Description:
Lacticaseibacillus casei is a species of Gram-positive anaerobic bacteria found in the
intestine and mouth of humans. This lactic acid-producing bacterium is used in the dairy
industry in the production of probiotic foods.
Arm group label:
Lactobacillus casei
Intervention type:
Biological
Intervention name:
Lactobacillus rhamnosus
Description:
A live form of a bacterium that makes lactic acid (a substance derived from milk sugars
and also made by the body). Lactobacillus rhamnosus GG is given to help with digestion
and normal bowel function. In addition, it may help maintain a healthy gastrointestinal
tract. It is being studied for the prevention of infections in patients who received
donor stem cell transplants and for other conditions.
Arm group label:
Lactobacillus rhamnosus
Intervention type:
Biological
Intervention name:
Bifidobacterium bifidum
Description:
B. bifidum is an essential bacteria found in the human intestine. When it is low or
absent all together in the human intestine, it is an indication of being in an unhealthy
state. Intestinal flora can be improved if someone takes oral B. bifidum. Also, oral B.
bifidum is used for other things such as therapy for enteric and hepatic disorders, for
activating the immune response, and for preventing some cancers
Arm group label:
Bifidobacterium bifidum
Intervention type:
Dietary Supplement
Intervention name:
Placebo
Description:
Microcrystalline cellulose is a term for refined wood pulp and is used as a texturizer,
an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent
in food production.The most common form is used in vitamin supplements or tablets
Arm group label:
Placebo
Summary:
Background: Acute lymphoblastic leukemia (ALL) is a common malignant neoplasm in
children. Although chemotherapy achieves remission in over 70% of cases, it can cause
gastrointestinal toxicity in up to 32.5%. Some studies suggest that administering
probiotics reduces this risk, but the evidence remains inconsistent.
Objective: To evaluate the effectiveness and safety of administering L. casei, L.
rhamnosus or B. bifidum compared to a placebo for the prevention of gastrointestinal
toxicity, decreased intestinal permeability, and changes in intestinal microbiota in
pediatric patients diagnosed with acute lymphoblastic leukemia receiving chemotherapy.
Methods: A total of 120 participants aged 6 to 17 years, diagnosed with ALL and receiving
consolidation phase chemotherapy without gastrointestinal comorbidities, will be
included. Participants will be administered daily 2 capsules containing either 1) L.
casei, 2) L. rhamnosus, 3) B. bifidum or 4) placebo daily for 8 weeks. The clinical
status of the participants will be evaluated weekly by the oncology service to determine
the presence of gastrointestinal toxicity and adverse events. Changes in intestinal
permeability will be assessed by measuring beta-lactoglobulin in a blood sample using the
ELISA technique, while changes in the intestinal microbiota will be analyzed by genomic
sequencing at baseline and at the end of follow-up.
Statistical analysis: Descriptive analysis will use measures of central tendency and
dispersion. For quantitative variables, the mean and standard deviation or median with
minimum and maximum values will be calculated depending on the distribution type.
Frequencies and proportions will be calculated for qualitative variables, presented in
tabular and graphical form. To compare the quantitative variables between the four
interventions, a multi-way ANOVA test will be used.
The risk of gastrointestinal toxicity and adverse events will be analyzed by calculating
the relative risk and 95% confidence interval. Differences between the interventions will
be analyzed using survival analysis with the Kaplan-Meier and Log-Rank tests. Sequencing
data will be analyzed using the Qiime2 program, filtered to generate a phylogenetic tree
using the Silva database. Corresponding plots will be generated for each taxonomic level.
Alpha (intra-group) and Beta (inter-group) diversity will be presented by ordination
plots using principal component analysis with the ANCOM program
Detailed description:
Background Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by the
uncontrolled proliferation of immature lymphoid cells. It is the most common neoplasm in
children, representing up to 53.1% of all oncologic processes in Mexico [1-6].
Fortunately, with the current chemotherapeutic treatments, disease remission is achieved
in 98% of cases; however, the chemotherapeutic treatments have side effects that can lead
to gastrointestinal toxicity (7.7 to 32.5%), which is associated with up to 50%
mortality.
Among the most common gastrointestinal manifestations resulting from this toxicity are
mucositis, pancreatitis (2 to 8%), diarrhea (10 to 82%), and colitis associated with
decreased Bacillus spp and Bidifobacterium spp, increasing the risk of necrosis and
intestinal perforation of the terminal ileum and cecum. Hence, several studies have been
conducted to identify agents that can reduce the incidence of gastrointestinal toxicity
like as probiotics which are a group of saprophytic microorganisms (bacteria, viruses,
fungi and protozoa) that live in equilibrium on the skin and mucous membranes, mainly in
the intestine, have garnered attention.
Probiotics are known to have several beneficial functions such as promoting the
absorption of carbohydrates, short-chain fatty acids and calcium; facilitating the
synthesis of lipids and vitamins; modulate and reduce the concentration of inflammatory
mediators in the intestinal mucosa; improve mucosal blood flow, thus reducing the risk of
ischemic areas in the intestine; and strengthen the immune system.
Although research has been conducted on the use of probiotics to prevent or reduce the
toxic effects of chemotherapy, the results are still inconclusive because the effect of
probiotics has been analyzed in multiple combinations, which makes it difficult to
distinguish the specific effects per phylum. This complicates the generation of
standardized therapeutic schemes to improve the quality of care of these patients. If
this project successfully identifies the effectiveness and safety of these probiotics, it
will enable to development of new therapeutic strategies aimed at improving the quality
of healthcare for these patients, reducing the frequency and severity of gastrointestinal
complications secondary to the administration of chemotherapy.
Objective To evaluate the effectiveness and safety of the administration of Lactobacillus
casei, Lactobacillus rhamnosus and Bifidobacterium bifidum compared to placebo in
reducing the risk of gastrointestinal toxicity, decreasing intestinal permeability, and
changing intestinal microbiota without the development of adverse effects in pediatric
patients diagnosed with ALL receiving consolidation chemotherapy in the Oncology Service
of the Instituto Nacional de Pediatría.
General Description of the Study
1. Participant selection and consent:
- Participants meeting the study selection criteria will be selected.
- Informed consent will be obtained from the participant's parents or guardians
and, if appropriate, from the patient if older than 8 years of age. They will
be informed about the benefits, complications and adverse effects of the
interventions (Appendix 1-3).
- If the parents or guardians prefer treatment outside the research project, the
patient will be treated according to the established national protocols used in
the Oncology Service of the Instituto Nacional de Pediatría.
- Consent will also be obtained for the use of personal data as per Appendices 4
and 5. This data includes participant and parent names, birth date, sex, CURP,
address, contact number, medical history, general habits, pathological
conditions, social conditions, to be used exclusively for this research
project.
- Data will be handled with strict confidentiality, stored in an electronic
database for five years by project personnel.
2. Initial Assessments:
- A pediatric oncologist will perform a medical history, physical examination,
anthropometry, fecal and serum sampling.
- A nutritionist will evaluate the participant´s nutritional status and body
composition.
A) Physical examination:
- Participant will remove outer clothing and shoes and sit on the examination
table.
- The pediatric oncologist will visually inspect for skin lesions using a lamp
and tongue depressor if necessary.
- Body temperature will be measured with a digital thermometer.
- Participants will lie supine for palpation, percussion, and/or auscultation to
assess cardiac, and abdominal conditions.
B) Anthropometry
- Weight will be measured three times using a Seca scale.
- Height will be measured three times using a stadiometer.
- Waist circumference will be measured at the midpoint between the lower edge of
the last rib and the upper edge of the iliac crest.
- Hip circumference will be measured 15 cm below the waist.
- Arm circumference will be measured around the biceps muscle.
- Thigh circumference will be measured around the upper third of the thigh.
C) Nutritional Status
- Height-for-Age (H-A), Weight-for-Age (W-A), Weight-for-Height (W-H), and Body
Mass Index (BMI) indices will be classified according to NOM-008-SSA2-1993
standards.
D) Body composition
- Participants will remove metallic objects, empty their bladder, and lie supine
on a non-conductive bed.
- Electrode placement will be prepared with a cleansing towel and an electrically
conductive towel.
- Electrodes will be placed on hands and feet, and a multifrequency bioelectric
impedance device will measure body composition at six different frequencies.
- Data will be adjusted to WHO percentile curves.
E) Fecal samples
- Participants will collect stool samples at home using provided kits and
instructions.
- Samples will be transported in a cooler to the Instituto Nacional de Pediatría
on the same day for analysis and will be stored in the freezer at -70°C until
the end of the project.
F) Serum samples
- A 3 ml blood sample will be collected by peripheral venipuncture.
- Serum samples will be processed to determine antibodies against
beta-lactoglobulin using the sandwich enzyme immunoassay technique.
Assessments will be conducted weekly for clinical condition, anthropometry, and body
composition at weeks 1, 4, and 8, and fecal and serum samples at weeks 1 and 8.
3. Preparation of interventions:
- Interventions will be prepared in a Baker Company Class II Type A2 vertical
laminar flow hood.
- The required amounts of lyophilized probiotic powder and microcrystalline
cellulose will be mixed for 5 minutes (2:30 clockwise and 2:30
counterclockwise) at a speed of 25 rpm and encapsulated at a dose of: L. casei
and L. rhamnosus at 2.5 billion CFU per capsule, B. bifidum at 1 billion CFU
per capsule and placebo 300 mg of microcrystalline cellulose.
- Each intervention will be stored in labeled sterile bags and refrigerated at 2
to 8°C.
- Capsules will be quality checked for UFC content at Bacteriology Laboratory by
dilution and sequencing, and any deviations will result in process adjustments.
4. Participant Allocation:
- Participants will be randomly assigned to interventions using a
computer-generated sequence, adjust in balanced blocks of five. (Appendix 7).
- An external researcher will place intervention names in opaque envelopes,
labeled with random numbers of the sequence.
- Participants will draw a random number to be assigned to an intervention,
communicated to the principal investigator.
5. Intervention Administration:
- Participants will receive bottles with 14-16 capsules of the assigned
intervention, stored in a cooler with refrigerated gel packs.
- Participants will take one capsule before breakfast and one before lunch for
one week, recording adherence in a logbook and repeating this process for eight
weeks.
6. Clinical Evaluation:
- Weekly clinical evaluations will be conducted for mucositis, diarrhea, colitis,
flatulence, abdominal distention, and constipation, graded according to the
Common Terminology Criteria for Adverse Events (CTCAE) scale (V 4.02) [39]. If
necessary, the pediatric oncologist will initiate treatment according to the
Oncology service plan.
7. Data Collection:
- If antibiotics are required or the chemotherapy consolidation phase is
completed, participants will be eliminated from the study, and final
assessments will be conducted.
- Data from weekly clinical evaluations, nutritional assessments, and study
follow-ups will be recorded in a data collection form (Appendix 8) and entered
an electronic Excel database for statistical analysis using STATA 18 by a
blinded researcher.
The sample size was calculated based on data from the study by Reyna-Figueroa, which
reported a 0% incidence of diarrhea during the administration L. rhamnosus compared to
10% in participants who did not receive probiotics. Using the formula for proportions,
with an alpha error of 0.05, 80% power, and estimating a loss rate of 20%, a sample size
of 30 participants was determined for each of the four groups.
Statistical analysis A descriptive analysis will be performed using measures of central
tendency to understand the characteristics of the studied sample and to determine the
type of distribution of each variable using the Kolmogorov-Smirnoff normality test. For
quantitative variables, the mean and standard deviation or median with minimum and
maximum values will be calculated, depending on the type of distribution and summarized
in tabular form; and data graphically represented by boxplot or bars chats as
appropriate.
To compare the quantitative variables between the four interventions, a multi-way ANOVA
test will be used. For qualitative variables, the chi-squared test will be used to
compare the groups, adjusting for the nutritional status of the participants.
The risk of gastrointestinal toxicity and adverse events will be analyzed by the relative
risk or Peto's odds ratio and 95% confidence interval. Differences between the
interventions will be analyzed using survival analysis with the Kaplan-Meier and Log-Rank
tests. Sequencing data will be analyzed using the Qiime2 program, filtered to generate a
phylogenetic tree using the Silva database. Corresponding plots will be generated for
each taxonomic level. Alpha (intra-group) and Beta (inter-group) diversity will be
presented by ordination plots using principal component analysis with the ANCOM program.
Noted that patients who drop out of the study will have their results analyzed up to
their last record, and all analyses will be conducted on an intention-to-treat basis.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients older than 6 years and younger than 17 years with a recent diagnosis of
acute lymphoblastic leukemia, confirmed by bone marrow aspirate and interpreted by a
pediatric oncologist.
- Participants of both sexes
- Participants receiving treatment at the Oncology Service of the Instituto Nacional
de Pediatría.
- Receiving chemotherapy according to national health protocols in the consolidation
phase.
- Informed consent
- Informed assent for those older than 8 years.
Exclusion Criteria:
- Allergy to probiotics.
- Consumption of another probiotic
- Enteropathies affecting intestinal absorption (e.g., malabsorption syndrome, short
bowel syndrome, intestinal malrotation, chronic nonspecific ulcerative colitis,
Crohn's disease).
- Chronic diarrhea (>15 days of duration)
- Presence of mucosal lesions
- Impossibility of enteral feeding
- Renal insufficiency
- Peritoneal dialysis
- Water and electrolyte disorders
- Surgical intestinal bypass (e.g., colostomy, ileostomy)
- Congenital metabolic disorders
- Septicemia
- Body temperature > 38° C
- Received broad-spectrum antibiotics (piperacillin/tazobactam, fourth generation
cephalosporins, aminoglycosides, carbapenem and/or metronidazole) within the past 30
days.
Gender:
All
Minimum age:
6 Years
Maximum age:
17 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National Institute of Pediatrics
Address:
City:
Mexico City
Zip:
04530
Country:
Mexico
Start date:
September 1, 2024
Completion date:
August 31, 2026
Lead sponsor:
Agency:
National Institute of Pediatrics, Mexico
Agency class:
Other
Source:
National Institute of Pediatrics, Mexico
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06560879
https://seer.cancer.gov/statfacts/html/leuks.html
