Effectiveness of Probiotics for the Prevention of Gastrointestinal Toxicity in Children With Leukemia
NCT Number: NCT06560879
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2
Conditions: Probiotics|Gastrointestinal Diseases|Precursor Cell Lymphoblastic Leukemia-Lymphoma
Interventions: BIOLOGICAL: Lactobacillus casei|BIOLOGICAL: Lactobacillus rhamnosus|BIOLOGICAL: Bifidobacterium bifidum|DIETARY_SUPPLEMENT: Placebo
Sponsor: National Institute of Pediatrics, Mexico
Sex: ALL
Age: CHILD
Enrollment: 120
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: TRIPLE (PARTICIPANT, CARE_PROVIDER, OUTCOMES_ASSESSOR)|Primary Purpose: PREVENTION
Start Date: 2024-09-01
Completion Date: 2026-08-31
Locations: National Institute of Pediatrics, Mexico City, Coyoacan, 04530, Mexico

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

Primary Outcome Measures: Prevention of Mucositis, Inflammation of the oral mucosa and gastrointestinal tract, triggered by the activation of inflammatory cytokines. For the evaluation, the pediatric oncologist will perform the physical examination of the oral cavity and report his findings as follows:

* Number of participants with mucositis
* Participants with mucositis will be evaluated with:

A) The number and location of lesion(s). B) The maximum diameter of the largest lesion in centimeters. C) The severity of lesions

Grade 1: Mucosal erythema, preserved feeding Grade 2: Focal pseudomembranous ulceration, modified food intake Grade 3: Confluent pseudomembranous ulcers, bleeding with minimal trauma, inability to feed or hydrate.

Grade 4: Tissue necrosis, significant spontaneous bleeding, 8 weeks|Prevention of Diarrhea, Increase in stool frequency or a decrease in stool consistency.

For the evaluation, the pediatric oncologist will question the participant about the characteristics of the bowel movements and perform a physical examination of the abdomen. His findings will be reported as follows: The findings will be recorded as follows:

* Number of participants with diarrhea
* Participants with diarrhea will be evaluated with:

A) Number of bowel movements per day B) Duration of diarrhea in days C) Stool content: None, blood, mocus, fat, food

D) Classification of the diarrhea episode:

Grade 1: Fewer than 4 stools per day. Grade 2: 4 to 6 stools per day, requiring intravenous hydration for less than 24 hours.

Grade 3: More than 7 stools per day, requiring IV hydration for more than 24 hours, and necessitating hospitalization.

Grade 4: Severe dehydration with hemodynamic consequences, requiring urgent IV hydration., 8 weeks|Prevention of Colitis, Inflammation and edema of the intestinal mucosa accompanied by abdominal pain, watery and bloody diarrhea. For the evaluation, the pediatric oncologist and pediatric surgeon, will perform a physical examination, laboratory and imaging studies. Findings will be recorded as follows:

* Number of participants with colitis
* Participants with colitis will be assessed with:

A) Pain intensity using a visual analog scale (0 = no pain to 10 = severe pain).

B) Location of pain (generalized or in one or more of the 9 abdominal regions) C) Duration of abdominal pain in days

D) Classification of colitis:

Grade 1 = asymptomatic Grade 2 = abdominal pain, presence of mucus or blood on evacuation Grade 3 = abdominal pain, fever, changes in evacuation rhythm with ileus or signs of peritoneal irritation.

Grade 4 = Intestinal perforation, ischemia, hemorrhage, toxic megacolon or intestinal necrosis., 8 weeks|Adverse events (flatulence), Production of intestinal gas mixture that is expelled through the rectum.

For evaluation, the pediatric oncologist will ask the participant if there has been an increase in the frequency and amount of intestinal gas production during the week, and depending on the characteristics of the abdomen, flatulence will be classified according to the number of gases expelled per day. The findings will be recorded as follows:

- Number of participants with gas. Absence \< 25 gases per day Presence \> 25 gases per day, 8 weeks|Adverse events (distention), Increased abdominal girth due to excessive gas in the bowel

For evaluation, the pediatric oncologist will ask the participant if he/she has had an increase in abdominal girth during the week and will measure the abdominal girth using a circumference tape placed around the midpoint between the lower edge of the last rib and the upper edge of the iliac crest without applying pressure and will ask the participant to take a deep breath and at the moment of exhalation the measurement will be taken in centimeters., 8 weeks|Adverse events (constipation), Infrequent bowel movements accompanied by scanty and hard stools. For evaluation, the pediatric oncologist and pediatric surgeon will ask the participant if has had difficulty passing stools during the week and will perform a physical examination. The findings will be recorded as follows:

* Number of participants with constipation absent = \> 1 defecation per day present \< 1 defecation per day
* Participants with constipation will be assessed with:

A) Frequency of defecation per week B) Length of constipation in days

C) Classification of constipation:

Grade 1 = occasional or intermittent symptoms, sporadic use of laxatives, dietary changes, or need for enemas.

Grade 2 = persistent symptoms with frequent use of laxatives or enemas Grade 3 = symptoms interfere with activities of daily living and require manual bowel movements Grade 4 = risk of death from bowel obstruction or toxic megacolon, 8 weeks|Adverse events (vomiting), Violent expulsion of gastric contents by mouth.

To assess this, the pediatric oncologist will ask the participant if he/she has experienced this during the week. The findings will be recorded as follows:

* Number of participants who vomited absent present \> 1 event per day
* Participants with vomiting will be assessed with:

A) Frequency of vomiting per day. B) Duration of vomiting C) Volume of vomiting

D) Content of vomiting:

* water
* blood
* mucus
* food, 8 weeks
Secondary Outcome Measures: Blood Beta-Lactoglobulin Concentration, To determine the functional status of the intestinal wall as a selective barrier to the passage of toxic substances and dietary proteins into the blood (intestinal permeability), the medical oncologist will take a peripheral blood sample by venipuncture and analyze it by sandwich enzyme immunoassay technique for the detection of antibodies against beta-lactoglobulin at the beginning and end of the participant's follow-up. The results will be reported in ng/mL., 8 weeks|Changes in alpha and beta diversity of the intestinal microbiota, Gut microbiota, gut microbiome, or gut flora are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals.The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota.The gut is the main location of the human microbiome.The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut-brain axis, 8 weeks|Adverse events (fever), Increase in body temperature \> 38° C in response to a medical condition.

For evaluation, the pediatric oncologist will ask about the presence of fever during the week and will take the body temperature with a digital thermometer. The findings will be recorded as follows

- Number of participants with fever absent \< 38 °C present \> 38 °C, 8 weeks|Adverse events (nausea), Feeling of unpleasantness or intense disgust with proximity to vomiting due to an triggering event.

To assess this, the pediatric oncologist will ask the participant if he/she is experiencing, or has experienced during the week, a feeling of intense disgust. The findings are recorded as follows

- Number of participants with nausea absent present, 8 weeks