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Lactobacillus Plantarum in Preventing Acute Graft Versus Host Disease in Children Undergoing Donor Stem Cell Transplant

Sponsor
Children's Oncology Group (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03057054
Collaborator
National Cancer Institute (NCI) (NIH)
167
Enrollment
43
Locations
2
Arms
62
Anticipated Duration (Months)
3.9
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized phase III trial studies how well Lactobacillus plantarum works in preventing acute graft versus host disease in children undergoing donor stem cell transplant. Lactobacillus plantarum may help prevent the development of gastrointestinal graft versus host disease in children, adolescents, and young adults undergoing donor stem cell transplant.

Condition or Disease Intervention/Treatment Phase
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
  • Biological: Lactobacillus plantarum strain 299
  • Biological: Lactobacillus plantarum strain 299v
  • Other: Placebo Administration
 Phase 3

Detailed Description

PRIMARY OBJECTIVE:
  1. To determine efficacy of orally-administered Lactobacillus plantarum (LBP) in preventing the development of gastrointestinal (GI) acute graft versus host disease (aGvHD) in children and adolescents undergoing alternative donor allogeneic hematopoietic cell transplantation (alloHCT).
EXPLORATORY OBJECTIVES:

  1. To determine whether orally-administered LBP decreases the incidence of grade II-IV aGvHD following alternative donor alloHCT.

  2. To determine whether LBP administration maintains intestinal integrity as measured by mean serum citrulline levels and reduction in mucosal barrier injury (MBI) bacteremia.

  3. To measure the effects of LBP on the intestinal flora phylogenetic composition during and after alternative donor alloHCT using 16S ribosomal ribonucleic acid (rRNA) gene deep sequencing.

  4. To measure effects of LBP on intestinal flora function during and after alternative donor alloHCT using metagenomic and metabolite profiling.

  5. To measure proposed immunomodulatory effects of LBP in mean serum levels of alloreactive-induced inflammatory cytokines (IL-2, IL-6, IL-12p70, IFN gamma, TNF alpha, etc) in patients receiving LBP compared to placebo.

  6. To determine whether LBP administration reduces the incidence of Clostridium difficile-associated diarrhea in alternative donor HCT patients.

  7. To determine whether LBP administration reduces hospital days within the first 120 days post hematopoietic cell transplant (HCT).

  8. To define the safety of orally administered LBP strains 299 and 299v in alternative donor HCT patients as measured by incidence of Lactobacillus plantarum bacteremia.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive Lactobacillus plantarum strains 299 and 299v orally (PO) or through nasojejunal (NJ), nasogastric (NG) or gastronomy (G) tube once daily (QD) on day 1 of transplant conditioning regimen to 56 days post alloHCT. Patients undergo alloHCT at day 0.

ARM II: Patients receive placebo PO or through NJ, NG or G tube QD on day 1 of transplant conditioning regimen to 56 days post alloHCT. Patients undergo alloHCT at day 0.

After completion of study treatment, patients are followed up for 120 days from alloHCT.

Study Design

Study Type:
Interventional
Actual Enrollment :
167 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Prevention
Official Title:
The Effectiveness of Lactobacillus Plantarum (LBP, IND# 17339) in Preventing Acute Graft-Versus-Host Disease (GvHD) in Children Undergoing Alternative Hematopoietic Progenitor Cell Transplantation (HCT)
Actual Study Start Date :
Apr 30, 2018
Actual Primary Completion Date :
Jun 30, 2022
Anticipated Study Completion Date :
Jun 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm I (Lactobacillus plantarum, alloHCT)

Patients receive Lactobacillus plantarum strains 299 and 299v PO or through NJ, NG or G tube QD on day 1 of transplant conditioning regimen to 56 days post alloHCT. Patients undergo alloHCT at day 0.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Undergo alloHCT
Other Names:
  • Allogeneic
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT
  • Stem Cell Transplantation, Allogeneic

    • Biological: Lactobacillus plantarum strain 299
    Given PO or via NJ, NG or G tube
    Other Names:
  • DSM 6595

    • Biological: Lactobacillus plantarum strain 299v
    Given PO or via NJ, NG or G tube
    Other Names:
  • DSM 9843
  • Lp 299v

    		•
    Placebo Comparator: Arm II (placebo, alloHCT)

    Patients receive placebo PO or through NJ, NG or G tube QD on day 1 of transplant conditioning regimen to 56 days post alloHCT. Patients undergo alloHCT at day 0.

    Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    Undergo alloHCT
    Other Names:
  • Allogeneic
  • Allogeneic Hematopoietic Cell Transplantation
  • Allogeneic Stem Cell Transplantation
  • HSC
  • HSCT
  • Stem Cell Transplantation, Allogeneic

    • Other: Placebo Administration
    Given PO or via NJ, NG or G tube

    Outcome Measures

    Primary Outcome Measures

    1. Incidence of stage 1-4 gastrointestinal (GI) acute graft versus host disease (aGVHD) [Up to 120 days post stem cell infusion]

      The proportion of eligible patients having stage 1-4 GI aGvHD incidence from Day 0 through Day 120 will be compared between the two arms.

    Other Outcome Measures

    1. Incidence of grade II-IV overall graft versus host disease [Up to 120 days post stem cell infusion]

      Similar analysis approach will be used as described for the primary outcome measure but using the dichotomous cumulative incidence of grade II-IV acute graft versus host disease as the endpoint measure.

    2. Incidence of blood stream infection [Up to 120 days post stem cell infusion]

      The incidence of mucosal barrier blood stream infections will be compared between two groups.

    3. Incidence of Clostridium difficile-associated diarrhea [Up to 120 days post stem cell infusion]

      Proportion of C. diff during the study period will be compared between arms.

    4. Plasma levels of citrulline [Up to 120 days post stem cell infusion]

      The citrulline levels at each of the time points will be summarized and described by arm.

    5. Graft versus host disease biomarkers [Up to 120 days post stem cell infusion]

      Descriptive analysis will be used to examine the association between graft versus host disease outcomes and bacterial genes, pathways, and metabolites.

    6. Blood/stool measures of intestinal flora assessed using sequencing [Up to 120 days post stem cell infusion]

      The association between Lactobacillus plantarum administration and bacterial genes and pathways, and bacterial metabolites will be evaluated.

    7. Laboratory correlative measures for allogeneic-induced inflammation [Up to 120 days post stem cell infusion]

      The effects of Lactobacillus plantarum on pro-inflammatory (LBP) cytokines in allogeneic hematopoietic cell transplantation recipients will be examined.

    8. Hospital days [Up to 120 days post stem cell infusion]

      Total hospital days over the study period is calculated as the duration between the date of admission for conditional therapy and the date of discharge (or the study end date). Hospital days will be compared between arms.

    9. Incidence of Lactobacillus plantarum bacteremia [Up to 120 days post stem cell infusion]

      Patients who have at least one incidence (positive) of Lactobacillus plantarum during any reporting period is considered evaluable for this aim. The proportion of C. diff during the study period will be compared between arms.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    2 Years to 25 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • All clinical and laboratory studies, if applicable, must be obtained within 21 days prior to start of protocol therapy (repeat if necessary); protocol therapy must begin within 6 months of study enrollment

    • Patient must have a diagnosis that is managed with an alternative donor allogeneic hematopoietic cell transplant

    • Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of >= 70; patients who are unable to walk because of a chronic underlying condition (such as paralysis), but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing performance score

    • Hematopoietic cell transplant (HCT)

    • Patient must be receiving cells from alternative donor defined as one of the following:

    • Unrelated donor with a complete human leukocyte antigen (HLA) match or a 1 or 2 HLA mismatch, considering only HLA-A, HLA-B, HLA-C, and HLA-DRB1

    • Related donor with a 1 or more HLA mismatch (including haplo-identical)

    • Note: History of HCT or other cellular therapy (e.g. chimeric antigen receptor [CAR]-T cells, donor lymphocyte infusions) is permitted

    Exclusion Criteria:

    • Patient plans on receiving stem cells from a matched (8/8) related donor

    • Patient has used a probiotic dietary supplement within the previous 30 days of enrollment; (consumption of yogurt products is allowed)

    • Patient has a history of severe GI tract insult including but not limited to previous bowel perforation, grade 4 neutropenic colitis or typhlitis, inflammatory bowel syndrome, short small bowel syndrome (Crohn's disease, ulcerative colitis), history of gastrointestinal GVHD, or history of bowel resection

    • Patient has a medical, psychiatric or social issue that would compromise patient safety or compliance with protocol therapy, or interfere with consent, study participation, follow up, or interpretation of study results

    • Female patients who are pregnant are not eligible; women of childbearing potential require a negative pregnancy test prior to enrollment

    • Patient has diarrhea at the time of enrollment which is Clostridium difficile toxin positive

    • Patient is receiving antibiotic therapy for an active bacterial infection

    • Patient is allergic to all third or fourth generation cephalosporins, carbapenems, and all aminoglycosides, which are used to empirically treat LBP bacteremia

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States 35233
    2 City of Hope Comprehensive Cancer Center Duarte California United States 91010
    3 Children's Hospital Los Angeles Los Angeles California United States 90027
    4 UCSF Benioff Children's Hospital Oakland Oakland California United States 94609
    5 Rady Children's Hospital - San Diego San Diego California United States 92123
    6 UCSF Medical Center-Mission Bay San Francisco California United States 94158
    7 Children's Hospital Colorado Aurora Colorado United States 80045
    8 Yale University New Haven Connecticut United States 06520
    9 Alfred I duPont Hospital for Children Wilmington Delaware United States 19803
    10 Children's National Medical Center Washington District of Columbia United States 20010
    11 University of Florida Health Science Center - Gainesville Gainesville Florida United States 32610
    12 Nemours Children's Clinic-Jacksonville Jacksonville Florida United States 32207
    13 Nemours Children's Hospital Orlando Florida United States 32827
    14 Johns Hopkins All Children's Hospital Saint Petersburg Florida United States 33701
    15 Kapiolani Medical Center for Women and Children Honolulu Hawaii United States 96826
    16 Riley Hospital for Children Indianapolis Indiana United States 46202
    17 Children's Hospital New Orleans New Orleans Louisiana United States 70118
    18 Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland United States 21287
    19 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    20 C S Mott Children's Hospital Ann Arbor Michigan United States 48109
    21 Helen DeVos Children's Hospital at Spectrum Health Grand Rapids Michigan United States 49503
    22 University of Mississippi Medical Center Jackson Mississippi United States 39216
    23 Children's Mercy Hospitals and Clinics Kansas City Missouri United States 64108
    24 Hackensack University Medical Center Hackensack New Jersey United States 07601
    25 Roswell Park Cancer Institute Buffalo New York United States 14263
    26 NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center New York New York United States 10032
    27 University of Rochester Rochester New York United States 14642
    28 New York Medical College Valhalla New York United States 10595
    29 UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    30 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    31 Nationwide Children's Hospital Columbus Ohio United States 43205
    32 University of Oklahoma Health Sciences Center Oklahoma City Oklahoma United States 73104
    33 Oregon Health and Science University Portland Oregon United States 97239
    34 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    35 The Children's Hospital at TriStar Centennial Nashville Tennessee United States 37203
    36 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    37 Medical City Dallas Hospital Dallas Texas United States 75230
    38 Children's Hospital of San Antonio San Antonio Texas United States 78207
    39 Methodist Children's Hospital of South Texas San Antonio Texas United States 78229
    40 University of Wisconsin Carbone Cancer Center Madison Wisconsin United States 53792
    41 Alberta Children's Hospital Calgary Alberta Canada T3B 6A8
    42 Hospital for Sick Children Toronto Ontario Canada M5G 1X8
    43 Centre Hospitalier Universitaire Sainte-Justine Montreal Quebec Canada H3T 1C5

    Sponsors and Collaborators

    • Children's Oncology Group
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Michael L Nieder, Children's Oncology Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Children's Oncology Group
    ClinicalTrials.gov Identifier:
    NCT03057054
    Other Study ID Numbers:
    • ACCL1633
    • NCI-2017-00208
    • ACCL1633
    • COG-ACCL1633
    • ACCL1633
    • R01CA201788
    • UG1CA189955
    First Posted:
    Feb 17, 2017
    Last Update Posted:
    Jul 21, 2022
    Last Verified:
    Jul 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Multiple Myeloma
    Neoplasms, Plasma Cell
    Graft vs Host Disease

    Study Results

    No Results Posted as of Jul 21, 2022