Effectiveness of Probiotics for the Prevention of Gastrointestinal Toxicity and Changes in Gut Microbiota in Children with Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 2 期
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Prevention of Colitis
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
盲法说明
Interventions packaged in identical, odorless, tasteless, opaque capsules; stored in identical white plastic bottles.
入排标准
- 年龄范围
- 6 Years 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Lactobacillus casei
Oral administration of 1 capsule with Lactobacillus casei (2.5 billion CFU + microcrystalline cellulose) before breakfast and another capsule before lunch, for a total dose of 5 billion CFU/day.
干预措施: Lactobacillus casei (Biological)
Lactobacillus rhamnosus
Oral administration of 1 capsule with Lactobacillus rhamnosus (2.5 billion CFU + microcrystalline cellulose) before breakfast and another capsule before lunch, for a total dose of 5 billion CFU/day.
干预措施: Lactobacillus rhamnosus (Biological)
Bifidobacterium bifidum
Oral administration of 1 capsule with Bifidobacterium bifidum (1 billion CFU + microcrystalline cellulose) before breakfast and another capsule before lunch, for a total dose of 2 billion CFU/day.
干预措施: Bifidobacterium bifidum (Biological)
Placebo
Oral administration of 1 capsule of 300 mg of microcrystalline cellulose before breakfast and another before lunch (600 mg/day).
干预措施: Placebo (Dietary Supplement)
结局指标
主要结局
Prevention of Colitis
时间窗: 8 weeks
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.
Prevention of Mucositis
时间窗: 8 weeks
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
Prevention of Diarrhea
时间窗: 8 weeks
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.
Adverse events (flatulence)
时间窗: 8 weeks
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
Adverse events (distention)
时间窗: 8 weeks
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.
Adverse events (constipation)
时间窗: 8 weeks
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
Adverse events (vomiting)
时间窗: 8 weeks
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
次要结局
- Blood Beta-Lactoglobulin Concentration(8 weeks)
- Changes in alpha and beta diversity of the intestinal microbiota(8 weeks)
- Adverse events (fever)(8 weeks)
- Adverse events (nausea)(8 weeks)