DB-3Q for the Treatment of Medically Refractory Crohn's Disease

A Phase 2a Study of DB-3Q for the Treatment of Medically Refractory Crohn's Disease

This research study is studying DB-3Q as a possible treatment for medically refractory Crohn's disease. The purpose of this study is to research and evaluate safety and effectiveness of the administration of bone marrow mesenchymal stem cell (bmMSC) derived extracellular vesicles product, DB-3Q, the study drug for Crohn's disease.

Inclusion Criteria:

1. Written informed consent from participant

2. Males and females 18-75 years of age

3. Diagnosed with Crohn's disease of at least 6 months duration with medically refractory symptoms that failed to respond or responded but recurred after one advanced immunologic therapy (must have been receiving at least one advanced immunological therapy for 14 weeks duration prior to screening, including, but not limited to, adalimumab, certolizumab, , infliximab, risankizumab, upadacitinib, ustekinumab and vedolizumab), or is intolerant, or has a contraindication to advanced immunological therapy with a next step of subtotal colectomy or escalation in medical management

4. Active CD as defined by a CDAI score ≥ 220 and/or SES-CD score ≥ 4

5. Exposure to corticosteroids, 5-aminosalicylic acid (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

6. If receiving conventional immunomodulators (i.e., azathioprine [AZA], mercaptopurine [6-MP], or methotrexate [MTX]), must have been taking them for ≥12 weeks, and on a stable dose for at least 4 weeks prior to initial administration of IMP

7. If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for at least 4 weeks prior to initial administration of IMP

8. 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 equivalent and must have been stable for at least 4 weeks prior to initial administration of IMP

9. If receiving budesonide, the dose must have been stable for at least 2 weeks prior to initial administration of IMP

10. 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 initial administration of IMP

11. The following medications/therapies must have been discontinued before initial administration of IMP:

    1. Monoclonal therapy (e.g., adalimumab, certolizumab, infliximab, risankizumab, ustenkinumab, and vedolizumab) for at least 8 weeks
    2. Cyclosporine, tacrolimus, or sirolimus, for at least 4 weeks
    3. 6-thioguanine (6-TG) must have been discontinued for at least 4 weeks
    4. JAK inhibitors (e.g., upadacitinib) must have been discontinued for at least 4 weeks
    5. Rectal corticosteroids (i.e., corticosteroids [including budesonide] administered to the rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks
    6. Rectal 5-ASA compounds (i.e., 5-ASAs administered to the rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks
    7. Parenteral corticosteroids for at least 2 weeks
    8. Total parenteral nutrition for at least 2 weeks
    9. Antibiotics for the treatment of CD (e.g., ciprofloxacin, metronidazole, or rifaximin) for at least 2 weeks

12. No colonic dysplasia and malignancy as ruled out by colonoscopy within 90 days prior to initial administration of IMP

13. If participant is of reproductive capacity, willing to use adequate birth control measures while in the study

Exclusion Criteria:

1. Lack of informed consent

2. Pregnant woman, woman of childbearing potential without a documented negative urine or serum pregnancy test, or woman who is breast feeding

3. Clinically significant medical conditions within the six months before initial administration of IMP: 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 participant

4. Confirmed Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infections

5. Aspartate aminotransferase (AST) or Alanine transaminase (ALT) greater than 3 times the upper limit of normal at screening

6. Abnormal basic laboratory values with the following cut-offs:

   1. Alkaline phosphate > 200 U/L
   2. WBC >13 109/L
   3. Hemoglobin < 7 g/dL
   4. Platelets < 50 or > 109/L
   5. eGFR < 60 mL/min/1.73m2
   6. HbA1C > 8%

7. Prothrombin time (PT), partial thromboplastin time (aPTT) or international normalized ratio (INR) greater than 1.5 times the upper limits of normal at screening

8. Clinically significant abnormal vital signs prior to initial administration of IMP as defined by:

   1. Systolic blood pressure >160 or <90 mmHg
   2. Diastolic blood pressure >90 or <60 mmHg
   3. Pulse <55 or >105 bpm
   4. Respiratory Rate (RR) <9 and >25 breaths per minute
   5. Temperature >100.4 degrees Fahrenheit
   6. SpO2 <92%

9. History of cancer including melanoma (with the exception of localized skin cancers) within 5 years of study enrollment

10. Ulcerative colitis or indeterminate colitis

11. Suspicion or presence of an intraabdominal or perianal abscess

12. Microscopic, ischemic or infectious colitis

13. Neoplasia of the colon on preoperative biopsy

14. Evidence of colonic perforation

15. Colonic stricture that unable to pass an adult colonoscope

16. Three or more prior small bowel resections

17. Presence of an ostomy

18. Massive hemorrhage from the colon requiring emergent surgery in the 6 months prior to screening

19. Fulminant colitis requiring emergency surgery

20. Concurrent active clostridium difficile infection of the colon

21. Concurrent Cytomegalovirus infection of the colon via colonic biopsy with CMV stain taken within 90 days prior to screening

22. Active or latent tuberculosis

23. Unable to wean off corticosteroids

24. Primary sclerosing cholangitis

25. History of or current alcohol or drug abuse or dependence, recreational use of illicit drugs or prescription medications, or use of medical marijuana within 90 days prior to screening

26. Known allergy to local anesthetics

27. Concurrent use of anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix)

28. History of known inherited or acquired hypercoagulable states.

29. Electrocardiogram demonstrating cardiac arrhythmia, except for sinus tachycardia within the predefined limit of no greater than 105 bpm.

30. Use of investigational therapy or treatment within 6 months prior to initial IMP administration