Lactobacillus Rhamnosus in Prevention of Chemotherapy-related Diarrhoea

Randomized, Double Blind, Placebo Controlled, Cross-over Phase II Study on the Effects of Lactobacillus Rhamnosus GG Supplementation in Patients on 1st Line XELOXA Treatment for Metastatic Colorectal Cancer

Chemotherapy may cause diarrhoea, which may be associated with treatment delay and infections. The purpose of the study is to investigate whether oral supplementation with lactobacilli will alleviate chemotherapy related diarrhoea. Patients diagnosed with advanced colorectal cancer and who will receive chemotherapy will be randomly assigned to receive either lactobacilli or placebo during chemotherapy. The study is a prospective, multicenter, randomized, double-blind, placebo-controlled study. The primary outcome measure is frequency of moderate/severe diarrhoea. The study will also address safety and tolerability of chemotherapy, response to chemotherapy, and serum growth factor levels.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Dietary supplement: Lactobacillus Rhamnosus supplementation; Other: Placebo administration.

Detailed Description

This is a prospective, multicenter, randomized, cross-over, double-blind, placebo-controlled study. Patients diagnosed with advanced colorectal cancer with overt distant metastases and who will receive chemotherapy consisting of capecitabine, oxaliplatin and bevacizumab, given as 3-weekly cycles, will be randomly assigned to receive either lactobacilli (GefilusR) or placebo during the first 3 cycles of chemotherapy (for 9 weeks). Following this, the groups will be crossed over and those study participants who were allocated to lactobacilli will receive placebo for 9 weeks, and vice versa. Lactobacilli and placebo are administered twice daily. The total daily dose of lactobacilli is 20 billion CFU. The primary outcome measure is frequency of moderate/severe diarrhoea (grade 2-4). Adverse effects (including the frequency of diarrhoea, flatulence, bloating, constipation, and nausea) will be longitudinally monitored based on a patient diary and study visits. The study will also address safety and tolerability of chemotherapy, response to chemotherapy, progression-free survival, resectability of liver metastases, and serum growth factor levels. A total of 84 patients are planned to be entered.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, FIN-00029
    • Department of Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with histologically confirmed diagnosis of CRC, chemotherapy naïve for metastatic disease (prior adjuvant chemotherapy for CRC allowed), who are scheduled to start capecitabine treatment as first line chemotherapy for metastatic disease
• Age 18 or older
• Measurable or non-measurable metastatic disease
• Performance status ECOG performance status 0-2
• Life expectancy greater than 3 months
• Thrombocytes 100,000/µL or greater, neutrophils 1.500/µl or greater, Aspartate amino transferase/Alanine amino transferase <= 2.5 x Upper limit of normal (ULN) (< 5 x ULN if liver metastases present), Alkaline phosphatase <=2.5 x ULN (< 5 x ULN if liver metastases present), Serum bilirubin <= 1.5 x ULN, Serum Creatinine <= 1.5 x ULN, Urine dipstick of proteinuria <2+ (or U-Prot <100mg/dl). Patients discovered to have 2+ or greater proteinuria on dipstick urinalysis at baseline, must undergo a 24-hour urine collection and must have <= 1 g of protein/24 hr
• Women of childbearing potential must have a negative serum pregnancy test done prior to the administration of bevacizumab. Patient and their partner should prevent pregnancy (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) up to at least 6 months after last treatment completion or the last drug dose, whatever happens first
• Signed written informed consent according to ICH/GCP and the local regulations (approved by the Independent Ethics Committee [IEC]) will be obtained prior to any study specific screening procedures
• Patient must be able to comply with the protocol

Exclusion Criteria:

• Prior treatment with first-line chemotherapy for metastatic CRC
• Adjuvant treatment with bevacizumab within 12 months
• Acute or chronic diarrhea or colostomy
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 0 (Patients must have recovered from any major surgery)
• Near future planned radiotherapy for underlying disease (prior completed radiotherapy treatment allowed)
• Clinical or radiological evidence of CNS metastases
• Past or current history within the last 5 years of malignancies except for the indication under this study and curatively treated Basal and squamous cell carcinoma of the skin or In-situ carcinoma of the cervix
• Serious non-healing wound or ulcer
• Evidence of bleeding diathesis or coagulopathy
• Uncontrolled hypertension
• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤ 6 months), myocardial infarction (≤ 6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication
• Treatment with any investigational drug (including IMMP, EGFR inhibitors) or participation in another investigational study within 30 days prior to enrolment
• Evidence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the treatment or patient at high risk from treatment complications
• Ongoing treatment with aspirin (> 325 mg/day), continuous high dose NSAIDS or other medications known to predispose to gastrointestinal ulceration
• Pregnancy (positive serum pregnancy test) and lactation
• Any other serious or uncontrolled illness which, in the opinion of the investigator, makes it undesirable for the patient to enter the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lactophilus; Lactophilus supplementation	Dietary supplement: Lactobacillus Rhamnosus supplementation; Lactophilus supplementation is administered during chemotherapy.; Other Names: Probiotics
Placebo Comparator: Placebo; Placebo is administered during chemotherapy.	Dietary supplement: Lactobacillus Rhamnosus supplementation; Lactophilus supplementation is administered during chemotherapy.; Other Names: Probiotics; Other: Placebo administration.; Placebo is administered during chemotherapy.; Other Names: Placebo.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on the treatment-related grade 2 to 4 diarrhoea	Numbers of bowel movements per day.	18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on treatment related toxicity other than diarrhea	Adverse effects detected in the study groups.	18 weeks
Association between supplementation and response	Response rate assessed with imaging.	18 weeks
Effect on resectability of liver metastases	Numbers of liver resections carried out.	1 year

Collaborators and Investigators

• Sponsor: University of Helsinki
• Collaborators: Helsinki University Central Hospital
• Investigators: Study Director: Heikki Joensuu, M.D., Department of Oncology, Helsinki University Central Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 20, 2005

Study Record Updates

• Last Update Posted (Actual): November 24, 2021
• Last Update Submitted That Met QC Criteria: November 22, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: colorectal cancer; chemotherapy; probiotics; prevention; diarrhoea; adverse effects
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: ML18581