A Phase III Study of Efficacy of Lactobacillus CD2 Lozenges in Preventing High-Dose Chemotherapy Induced Oral Mucositis in Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation

Study Overview
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Brief Summary
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The study will be conducted at departments of Medical Oncology and Hematology, All India Institute of Medical Sciences (AIIMS). Patients with various malignancies who are taken up for high dose chemotherapy followed by stem cells transplant (blood and marrow transplant) have very high chances of developing severe oral mucositis (generally 60-80% in different studies and our own previous experiences). This not only causes significant morbidity but also hampers quality of life needing use of parenteral nutrition, analgesics, and antibiotics. No definite treatment exists for prevention or treatment of oral mucositis in this group of patients. Though one study has suggested that use of IV palifermin (a keratinocyte growth factor) will reduce duration and severity. Palifermin is very expensive and not available in country. Recently investigators have shown effectiveness of a probiotic Lactobacillus CD 2 in reducing incidence and severity of chemo-radiotherapy induced mucositis in head and neck squamous cell cancer patients. (Published online in European Journal of Cancer: http://dx.doi.org/10.1016/j.ejca.2011.06.010)European Journal of Cancer 2012;4:875-881.No significant toxicity has been reported with its use. A pilot study on similar aspect was completed recently at our center(Clinical trial.gov identifier:NCT 01480011) and in 31 patients who received this only 6 (20%) developed grade III or IV Mucositis. Now, investigators want to study the efficacy of this drug to reduce severity of mucositis in patients undergoing myeloablative hematopoietic stem cell transplantation. The study drug and placebo will be supplied by CD Pharma India Private Limited. Investigators further give undertaking that study will be carried as per GCP and declaration of Helsinki.

Detailed Description
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Study Design Placebo controlled double blind randomized, multi center clinical trial. Study Population and Number of Subjects Total of 108 patients undergoing myeloablative allogeneic or autologous hematopoietic stem cell transplantation and receiving high-dose chemotherapy as conditioning regimen at AIIMS (departments of Medical Oncology and Hematology) will be enrolled for the study and will be equally divided in two groups (drug and placebo). Study Center The study will be carried at Departments of Medical Oncology and Hematology of All India Institute of Medical Sciences, New Delhi, India. More centers are likely to be added. Study Objectives To test whether the probiotic Lactobacillus CD2 (drug) lozenges can reduce the incidence and severity of conditioning therapy induced oral mucositis in patients undergoing haematopoietic stem cell transplantation. Investigational Product Drug: The trial medication is in the form of lozenge, which is supposed to be dissolved by itself in mouth. It contains not less than 2x109 (2 billion) viable cells of Lactobacillus CD2 as active ingredient. Placebo: The placebo is a mix of sugars and salts used as excipients in the active formulation. Note: Placebo and drug lozenges will be similar in physical appearance and color. Dose of Study drug The daily dose of trial medications will be 4-6 lozenges per day, one lozenge to be taken every 2-3 hours preferably not before the meal. The lozenge should be kept in mouth for it to dissolve by itself. A hot beverage (e.g. tea, coffee, milk etc.) should not be taken for at least half an hour before and after the medication since elevated temperature can inactivate the bacteria. Duration of treatment The treatment will start 4-7 days before starting chemotherapy for conditioning regime of HSCT and will continue till resolution of mucositis or Day+24 post stem cell infusion which-ever is earlier. Efficacy Assessments Clinical activity will be defined as reduction in the incidence and severity of chemotherapy induced mucositis in HSCT patients. Most recent version of CTCAE; clinical score of CTC V4.03 ( as also outlined in CTCAE version 3.0) will be used for mucositis assessment. Also,WHO and Oral Mucositis assessment score will be recorded. The study will have the following primary and secondary endpoints: Primary endpoint 1. Determine the incidence of grade III and IV mucositis in patients undergoing allogeneic or autologous haematopoietic stem cell transplantation in two groups. Secondary endpoint Determine the incidence of all Grade of mucositis in patients undergoing allogenic or autologous haematopoietic stem cell transplantation in two groups. Duration of and time period for healing of chemotherapy induced oral mucositis. Determine incidence and severity of dysphagia and requirement of IV antibiotics in two groups Safety Assessments Medical History Physical Examination Vital Signs (blood pressure, pulse rate and respiratory rate) Laboratory Examinations Adverse Events

Official Title
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A Randomized Double Blind Placebo Controlled Phase III Study of Efficacy of Lactobacillus CD2 Lozenges in Preventing High-Dose Chemotherapy Induced Oral Mucositis in Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation

Conditions
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Oral Mucositis in Patients Undergoing HSCT

Intervention / Treatment
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* Drug: Lactobacillus CD 2
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 10 and 70 years. Karnofsky Performance Score ≥ 70%. Confirmed histological diagnosis of cancer/leukaemia for which haematopoietic stem cell transplantation is as approved modality of therapy. Patients eligible to receive high-dose chemotherapy as part of conditioning regime. Concomitant co morbid condition if present, controlled by medicines. Serum creatinine upto 1.8mg/dl. Total bilirubin 2mg/dl. Liver enzymes within three times of normal limit. Expected survival > 6 months. Exclusion Criteria: Pregnant women and lactating mothers. Patients with history of AIDS Patients who have taken any other investigational product in last 4 weeks. Patients having untreated symptomatic dental infection. Patients with WHO Grade 3 or 4 oral Mucositis. Other serious concurrent illness. Inconclusive histological diagnosis. Patients on anticancer antibiotics. Patients with signs and symptoms of systemic infections. Patient's/guardian's refusal to sign informed consent.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lactobacillus CD 2 lozenges<br>2x109 (2 billion) viable cells of Lactobacillus CD2 as active ingredient | Drug: Lactobacillus CD 2<br>* 2x109 (2 billion) viable cells of Lactobacillus CD2 as active ingredient<br>Other: Placebo<br>* The placebo is a mix of sugars and salts used as excipients in the active formulation<br>|
| Placebo Comparator: Placebo lozenges<br>The placebo is a mix of sugars and salts used as excipients in the active formulation | Drug: Lactobacillus CD 2<br>* 2x109 (2 billion) viable cells of Lactobacillus CD2 as active ingredient<br>Other: Placebo<br>* The placebo is a mix of sugars and salts used as excipients in the active formulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of mucositis grade(Common Terminology Criteria of Adverse Events (CTCAE) and World health Organization (WHO) | 1. Determine the incidence of grade III and IV mucositis in patients undergoing allogeneic or autologous haematopoietic stem cell transplantation in two groups | Day 0-Days 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence,duration and time period of mucositis Common Terminology Criteria of Adverse Events (CTCAE) and World health Organization (WHO) | 1. Determine the incidence of all Grade of mucositis in patients undergoing allogenic or autologous haematopoietic stem cell transplantation in two groups (Criteria for assessment is given in Appendix 1). | Day 0-Days 24 | 
| Incidence,duration and time period of mucositis Common Terminology Criteria of Adverse Events (CTCAE) and World health Organization (WHO) | Duration of and time period for healing of chemotherapy induced oral mucositis. | Day0- days 24 | 
| Incidence,duration and time period of mucositis Common Terminology Criteria of Adverse Events (CTCAE) and World health Organization (WHO) | Determine incidence and severity of dysphagia and requirement of IV antibiotics in two groups | day 0- days 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lactobacillus CD 2, oral mucositis, hematopoietic stem cell transplantation