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Study of ExoFlo for the Treatment of Medically Refractory Ulcerative Colitis

Primary Purpose

Ulcerative Colitis, Inflammatory Bowel Diseases

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ExoFlo
Sponsored by
Direct Biologics, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ulcerative Colitis focused on measuring ExoFlo, Ulcerative Colitis, Extracellular Vesicle, Inflammatory Bowel Diseases

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Males and Females 18-75 years of age
  • Ulcerative colitis of at least 6 months duration with medically refractory symptoms
  • Failed to have improvement of disease while receiving at least one monoclonal antibody (infliximab, adalimumab, certolizumab, golimumab, vedolizumab, ustekinumab) or tofacitinib for 8 weeks duration prior to enrollment.
  • Or has a contra-indication to monoclonal antibodies
  • Exposure to corticosteroids, 5-ASA drugs, thiopurines, methotrexate, anti-TNF therapy, anti-integrin and anti-interleukin in the past are permitted but a washout period of 8 weeks for any monoclonal antibody is necessary.
  • If receiving conventional immunomodulators (ie, AZA, 6-MP, or MTX), must have been taking them for ≥12 weeks, and on a stable dose for at least 4 weeks.
  • If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for atleast 4 weeks.
  • If receiving oral 5-ASA compounds, the dose must have been stable for at least 4 weeks.
  • If receiving oral corticosteroids, the dose must be ≤20 mg/day prednisone or its equivalentand must have been stable for at least 4 weeks.
  • If receiving budesonide, the dose must have been stable for at least 2 weeks.
  • If oral 5-ASA compounds or oral corticosteroids (including budesonide) have been recently discontinued, they must have been stopped for at least 2 weeks.
  • The following medications/therapies must have been discontinued before first administration of study agent:
  • TNF-antagonist therapy (e.g. infliximab, etanercept, certolizumab, adalimumab, golimumab, vedolizumab, ustekinumab) for at least 8 weeks.
  • Cyclosporine, tacrolimus, or sirolimus, for at least 4 weeks.
  • 6-thioguanine (6-TG) must have been discontinued for at least 4 weeks.
  • Rectal corticosteroids (ie, corticosteroids [including budesonide] administered to the rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks.
  • Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid colon viafoam or enema or suppository) for at least 2 weeks.
  • Parenteral corticosteroids for at least 2 weeks.
  • Total parenteral nutrition (TPN) for at least 2 weeks.
  • Antibiotics for the treatment of UC (eg, ciprofloxacin, metronidazole, or rifaximin) for atleast 2 weeks.
  • No colonic dysplasia and malignancy as ruled out by colonoscopy within 30 days of MSC delivery
  • Ability to comply with protocol
  • Competent and able to provide written informed consent
  • Stated willingness to comply with all study procedures and availability for the duration of the study
  • If patient is of reproductive capacity, willing to use adequate birth control measures while they are in the study

Exclusion Criteria:

  • Inability to give informed consent.
  • Clinically significant medical conditions within the six months before administration of ExoFlo: e.g. myocardial infarction, active angina, congestive heart failure or other conditions that would, in the opinion of the investigators, compromise the safety of the patient.
  • Patients with confirmed HIV, Hepatitis B, or Hepatitis C infections
  • Abnormal AST or ALT at screening defined as AST >100 or ALT > 100
  • Abnormal basic laboratory values with the following cut-offs:
  • Alkaline phosphate >200
  • WBC >13
  • Hemoglobin <7
  • Platelets <50 or > 1 million
  • eGRF < 60
  • HbA1C > 8%
  • Subjects with abnormal coagulation studies:
  • Prothrombin time (PT) > 1.5 times the upper limits of normal
  • Partial thromboplastin time (PTT) > 1.5 times the upper limits of normal
  • International normalized ratio (INR) > 1.5 times the upper limits of normal
  • Subjects with hyperbilirubinemia and evidence of liver disease as defined by AST > 100 or ALT > 100 or PT > 1.5 times the upper limits or normal or PT/INR > 1.5 time the upper limits of normal.
  • Subjects with abnormal vital signs as defined by any of the following:
  • Systolic blood pressure >160 or <90 mmHg
  • Diastolic blood pressure >90 or <60 mmHg
  • Pulse <60 or >105 bpm
  • Respiratory Rate <9 and >25 breaths per minute
  • Temperature: >100.4 degrees Fahrenheit
  • SpO2 : <92%
  • History of cancer including melanoma (with the exception of localized skin cancers) within 5 years of study enrollment
  • Investigational drug within one year of study enrollment
  • Pregnant or breast feeding.
  • If patient is of reproductive capacity, unwilling to use adequate birth control measures while they are in the study
  • Fulminant colitis requiring emergency surgery
  • Concurrent active clostridium difficile infection of the colon
  • Concurrent CMV infection of the colon
  • Evidence of colonic perforation
  • Massive hemorrhage from the colon requiring emergent surgery
  • Crohn's colitis or indeterminate colitis
  • Microscopic, ischemic or infectious colitis
  • Neoplasia of the colon and preoperative biopsy
  • Presence of an ostomy
  • Prior small bowel resection
  • Previous colonic resection
  • Colonic stricture that unable to pass an adult colonoscope
  • Active or latent tuberculosis
  • Unable to wean off corticosteroids
  • Patients with extra colonic ulcerative colitis including primary sclerosing cholangitis
  • Patients with history of or current evidence of alcohol or drug abuse or dependence, recreational use of illicit drug or prescription medications, or have use of medical marijuana within 90 days of study entry
  • Patients with known allergy to local anesthetics
  • Patients taking anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix) to reduce the risk of bleeding/ hemarthrosis
  • Individuals with inherited or acquired hypercoagulable states, history of thromboembolic events or bleeding disorders
  • Electrocardiogram demonstrating cardiac arrhythmia, except for sinus tachycardia within the predefined limit of no greater than 105 bpm.

Sites / Locations

  • Phillip Fleshner, MDRecruiting
  • NYU Langone Inflammatory Bowel Disease CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

15ml at Day 0, 2, 4, 30 ml at Week 2, Week 6, and every 4 weeks after to week 46

Arm Description

IV administration of 15 mL study agent at Day 0, Day 2, Day 4 and 30 mL at Week 2, Week 6 and every 4 weeks thereafter to week 46 (total # doses = 15).

Outcomes

Primary Outcome Measures

Safety of intravenous ExoFlo in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies.
Safety will be defined as lack of serious adverse events or adverse advents related to treatment with the study therapeutic.
Feasibility of intravenous ExoFlo in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies.
The study will not be considered feasible if more than three subjects are not capable of receiving the ExoFlo based on ability to release or deliver the cells. If a subject misses any single dose of ExoFlo, they will be withdrawn and not replaced.

Secondary Outcome Measures

To evaluate the efficacy of intravenous ExoFlo in inducing clinical remission or response at week 6 and week 46.
Efficacy will be evaluated as: Clinical remission: Mayo Score of less than or equal to 2 with no individual sub score greater than 1. Clinical response: Reduction in Mayo Score of greater than or equal to 3 points and greater than or equal to 30 percent from baseline with an accompanying decrease in rectal bleeding sub score of greater than or equal to 1 point or absolute rectal bleeding sub score of less than or equal to 1 point.
To evaluate the efficacy of intravenous ExoFlo in improving disease-specific health related quality of life.
Efficacy will be evaluated as: Improvement on the 36 Item Short Form Health Survey (SF-36) Improvement on the EuroQol 5 Dimensions Survey (EQ-5D)
To evaluate the pharmacokinetics and pharmacodynamics of ExoFlo therapy, including changes in C-reactive protein (CRP) and fecal calprotectin.
Evaluated as: Measuring changes in C-reactive protein (CRP) and fecal calprotectin.
To evaluate treatment failure as defined by disease worsening, need for rescue medications or surgical intervention for treatment of UC, or study drug-related adverse event leading to discontinuation from the study.
Evaluated as: Number of subjects with disease worsening, needing rescue medications or surgical intervention for treatment of UC, or study drug-related adverse events leading to discontinuation of study.

Full Information

First Posted
November 17, 2021
Last Updated
August 31, 2023
Sponsor
Direct Biologics, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT05176366
Brief Title
Study of ExoFlo for the Treatment of Medically Refractory Ulcerative Colitis
Official Title
A Phase I Study of ExoFlo, an ex Vivo Culture-expanded Adult Allogeneic Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicle Isolate Product, for the Treatment of Medically Refractory Ulcerative Colitis
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 19, 2022 (Actual)
Primary Completion Date
July 1, 2024 (Anticipated)
Study Completion Date
September 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Direct Biologics, LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Protocol Summary Title: A Phase I study of ExoFlo, an ex vivo culture-expanded adult allogeneic bone marrow mesenchymal stem cell derived extracellular vesicle isolate product, for the treatment of medically refractory ulcerative colitis. Short Title: ExoFlo for ulcerative colitis Phase: 1 Methodology: Open label Study Duration: 24 months Subject Participation: 58 weeks Single or Multi-Site: Multi-Site
Detailed Description
Primary Objectives: To evaluate the feasibility of intravenous ExoFlo in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies. To evaluate the safety of intravenous ExoFlo in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies. Secondary Objectives: To evaluate the efficacy of intravenous ExoFlo in inducing clinical remission in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies. To evaluate the efficacy of intravenous ExoFlo in inducing clinical response in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies. To evaluate the efficacy of intravenous ExoFlo in improving disease-specific health-related quality of life. To evaluate the pharmacokinetics and pharmacodynamics of ExoFlo therapy, including changes in C-reactive protein (CRP) and fecal calprotectin. Number of Subjects: 10 Diagnosis and Main Inclusion Criteria: Subjects must have medically refractory ulcerative colitis and have no prior intestinal surgery for ulcerative colitis. Study Product, Dose, Route, Regimen: IV administration of 15 mL of study agent at Day 0, Day 2, Day 4, and 30 mL at Week 2, Week 6 and every 4 weeks thereafter to week 46 (n=10), (total # doses = 15). Statistical Methodology: This is a safety study with exploratory assessment of efficacy. The study has insufficient power to confirm efficacy. All assessments of efficacy will be exploratory for the purpose of hypothesis generation in larger sample sizes.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ulcerative Colitis, Inflammatory Bowel Diseases
Keywords
ExoFlo, Ulcerative Colitis, Extracellular Vesicle, Inflammatory Bowel Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
15ml at Day 0, 2, 4, 30 ml at Week 2, Week 6, and every 4 weeks after to week 46
Arm Type
Experimental
Arm Description
IV administration of 15 mL study agent at Day 0, Day 2, Day 4 and 30 mL at Week 2, Week 6 and every 4 weeks thereafter to week 46 (total # doses = 15).
Intervention Type
Biological
Intervention Name(s)
ExoFlo
Intervention Description
Intravenous administration of bone marrow mesenchymal stem cell derived extracellular vesicles
Primary Outcome Measure Information:
Title
Safety of intravenous ExoFlo in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies.
Description
Safety will be defined as lack of serious adverse events or adverse advents related to treatment with the study therapeutic.
Time Frame
58 Weeks
Title
Feasibility of intravenous ExoFlo in subjects with medically refractory ulcerative colitis who have failed, or are intolerant, or have a contraindication to one or more monoclonal antibodies.
Description
The study will not be considered feasible if more than three subjects are not capable of receiving the ExoFlo based on ability to release or deliver the cells. If a subject misses any single dose of ExoFlo, they will be withdrawn and not replaced.
Time Frame
58 Weeks
Secondary Outcome Measure Information:
Title
To evaluate the efficacy of intravenous ExoFlo in inducing clinical remission or response at week 6 and week 46.
Description
Efficacy will be evaluated as: Clinical remission: Mayo Score of less than or equal to 2 with no individual sub score greater than 1. Clinical response: Reduction in Mayo Score of greater than or equal to 3 points and greater than or equal to 30 percent from baseline with an accompanying decrease in rectal bleeding sub score of greater than or equal to 1 point or absolute rectal bleeding sub score of less than or equal to 1 point.
Time Frame
Week 6 and Week 46
Title
To evaluate the efficacy of intravenous ExoFlo in improving disease-specific health related quality of life.
Description
Efficacy will be evaluated as: Improvement on the 36 Item Short Form Health Survey (SF-36) Improvement on the EuroQol 5 Dimensions Survey (EQ-5D)
Time Frame
58 Weeks
Title
To evaluate the pharmacokinetics and pharmacodynamics of ExoFlo therapy, including changes in C-reactive protein (CRP) and fecal calprotectin.
Description
Evaluated as: Measuring changes in C-reactive protein (CRP) and fecal calprotectin.
Time Frame
58 Weeks
Title
To evaluate treatment failure as defined by disease worsening, need for rescue medications or surgical intervention for treatment of UC, or study drug-related adverse event leading to discontinuation from the study.
Description
Evaluated as: Number of subjects with disease worsening, needing rescue medications or surgical intervention for treatment of UC, or study drug-related adverse events leading to discontinuation of study.
Time Frame
58 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and Females 18-75 years of age Ulcerative colitis of at least 6 months duration with medically refractory symptoms Failed to have improvement of disease while receiving at least one monoclonal antibody (infliximab, adalimumab, certolizumab, golimumab, vedolizumab, ustekinumab) or tofacitinib for 8 weeks duration prior to enrollment. Or is intolerant or has a contra-indication to monoclonal antibodies Exposure to corticosteroids, 5-ASA drugs, thiopurines, methotrexate, anti-TNF therapy, anti-integrin and anti-interleukin in the past are permitted but a washout period of 8 weeks for any monoclonal antibody is necessary. If receiving conventional immunomodulators (ie, AZA, 6-MP, or MTX), must have been taking them for ≥12 weeks, and be on a stable dose for at least 4 weeks prior to receiving the first dose of the study drug. If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for at least 4 weeks prior to receiving the first dose of the study drug. If receiving oral 5-ASA compounds, the dose must have been stable for at least 4 weeks prior to receiving the first dose of the study drug. If receiving oral corticosteroids, the dose must be ≤20 mg/day prednisone or its equivalent and must have been stable for at least 4 weeks prior to receiving the first dose of the study drug. If receiving budesonide, the dose must have been stable for at least 2 weeks prior to receiving the first dose of the study drug. If oral 5-ASA compounds or oral corticosteroids (including budesonide) have been recently discontinued, they must have been stopped for at least 2 weeks prior to receiving the first dose of the study drug. The following medications/therapies must have been discontinued before first administration of study agent: TNF-antagonist therapy (e.g. infliximab, etanercept, certolizumab, adalimumab, golimumab, vedolizumab, ustekinumab) for at least 8 weeks. Cyclosporine, tacrolimus, or sirolimus, for at least 4 weeks. 6-thioguanine (6-TG) must have been discontinued for at least 4 weeks. Rectal corticosteroids (ie, corticosteroids [including budesonide] administered to the rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks. Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid colon viafoam or enema or suppository) for at least 2 weeks. Parenteral corticosteroids for at least 2 weeks. Total parenteral nutrition (TPN) for at least 2 weeks. Antibiotics for the treatment of UC (eg, ciprofloxacin, metronidazole, or rifaximin) for at least 2 weeks. No colonic dysplasia and malignancy as ruled out by colonoscopy within 30 days of MSC delivery Ability to comply with protocol Competent and able to provide written informed consent Stated willingness to comply with all study procedures and availability for the duration of the study If patient is of reproductive capacity, willing to use adequate birth control measures while they are in the study Exclusion Criteria: Inability to give informed consent. Clinically significant medical conditions within the six months before administration of ExoFlo: e.g. myocardial infarction, active angina, congestive heart failure or other conditions that would, in the opinion of the investigators, compromise the safety of the patient. Patients with confirmed HIV, Hepatitis B, or Hepatitis C infections Abnormal AST or ALT at screening defined as AST >100 or ALT > 100 Abnormal basic laboratory values with the following cut-offs: Alkaline phosphate >200 WBC >13 Hemoglobin <7 Platelets <50 or > 1 million eGFR < 60 HbA1C > 8% Subjects with abnormal coagulation studies: Prothrombin time (PT) > 1.5 times the upper limits of normal Partial thromboplastin time (aPTT) > 1.5 times the upper limits of normal International normalized ratio (INR) > 1.5 times the upper limits of normal Subjects with hyperbilirubinemia and evidence of liver disease as defined by AST > 100 or ALT > 100 or PT > 1.5 times the upper limits or normal or PT/INR > 1.5 time the upper limits of normal. Subjects with abnormal vital signs prior to first ExoFlo delivery as defined by any of the following: Systolic blood pressure >160 or <90 mmHg Diastolic blood pressure >90 or <60 mmHg Pulse <60 or >105 bpm Respiratory Rate <9 and >25 breaths per minute Temperature: >100.4 degrees Fahrenheit SpO2: <92% History of cancer including melanoma (with the exception of localized skin cancers) within 5 years of study enrollment Investigational drug within one year of study enrollment Pregnant or breast feeding. If patient is of reproductive capacity, unwilling to use adequate birth control measures while they are in the study Fulminant colitis requiring emergency surgery Concurrent active clostridium difficile infection of the colon Concurrent CMV infection of the colon via colonic biopsy with CMV stain taken within 90 days Evidence of colonic perforation Massive hemorrhage from the colon requiring emergent surgery in the 6 months prior to screening. Crohn's colitis or indeterminate colitis Microscopic, ischemic or infectious colitis Neoplasia of the colon and preoperative biopsy Presence of an ostomy Prior small bowel resection Previous colonic resection Colonic stricture that unable to pass an adult colonoscope Active or latent tuberculosis Unable to wean off corticosteroids Patients with extra colonic ulcerative colitis including primary sclerosing cholangitis Patients with history of or current evidence of alcohol or drug abuse or dependence, recreational use of illicit drug or prescription medications, or have use of medical marijuana within 90 days of study entry Patients with known allergy to local anesthetics Patients taking anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix) to reduce the risk of bleeding/ hemarthrosis Individuals with previously diagnosed, known inherited or acquired hypercoagulable states Electrocardiogram demonstrating cardiac arrhythmia, except for sinus tachycardia within the predefined limit of no greater than 105 bpm.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Amy Lightner, MD
Phone
512-354-7124
Email
alightner@directbiologics.com
First Name & Middle Initial & Last Name or Official Title & Degree
Stephanie Cahill
Email
scahill@directbiologics.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amy Lightner, MD
Organizational Affiliation
Direct Biologics, LLC
Official's Role
Study Director
Facility Information:
Facility Name
Phillip Fleshner, MD
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gayane Ovsepyan, MPH
Email
Gayane.Ovsepyan@cshs.org
First Name & Middle Initial & Last Name & Degree
Phillip Fleshner, MD
Facility Name
NYU Langone Inflammatory Bowel Disease Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emily Holmes
Email
Emily.Holmes@nyulangone.org
First Name & Middle Initial & Last Name & Degree
David Hudesman, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://directbiologics.com/
Description
Direct Biologics, LLC

Learn more about this trial

Study of ExoFlo for the Treatment of Medically Refractory Ulcerative Colitis

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