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Low Dose IL-2 for Ulcerative Colitis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02200445
Recruitment Status : Recruiting
First Posted : July 25, 2014
Last Update Posted : February 6, 2020
Information provided by (Responsible Party):
Scott Snapper, Boston Children’s Hospital

Tracking Information
First Submitted Date  ICMJE July 22, 2014
First Posted Date  ICMJE July 25, 2014
Last Update Posted Date February 6, 2020
Study Start Date  ICMJE February 2015
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 23, 2014)
  • Number of subjects with serious and non-serious adverse events. [ Time Frame: 8 weeks ]
    Enumeration of the serious and non-serious adverse events seen in the study. Enumeration of any dose limiting toxicity seen in the study.
  • Maximum tolerated dose. [ Time Frame: 8 weeks. ]
    Identification of the dose cohort at which the MTD occurs.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 23, 2014)
  • Clinical efficacy. [ Time Frame: 8 weeks. ]
    This is a composite endpoint. The Mayo score, a validated disease activity score, will be used to categorize subjects into three groups, based on their response to treatment. Category definitions are as follows:
    1. Clinical Response: Subjects with a decrease from baseline in the total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the rectal bleeding sub-score of at least 1 point or an absolute rectal bleeding sub-score of 0 or 1.
    2. Clinical Remission: Subjects with a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point.
    3. No Response: Subjects who do not meet the criteria described above.
    The number of subjects who achieve endoscopic healing of their colonic mucosa will also be enumerated. Category definitions are as follows:
    1. Mucosal Healing Present: An absolute Mayo endoscopy subscore of 0 or 1.
    2. Mucosal Healing Absent: Subjects who do not meet the definition of mucosal healing described above.
  • Immunological response. [ Time Frame: 12 weeks. ]
    Enumeration of the number of subjects with a change in the absolute number of immune cells in the peripheral blood and lamina propria of subjects during the 8 weeks of treatment, and during the 4 weeks following cessation of treatment.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Low Dose IL-2 for Ulcerative Colitis
Official Title  ICMJE A Phase I Study of Low Dose Subcutaneous Interleukin-2 (IL-2) For The Treatment of Ulcerative Colitis.
Brief Summary The purpose of this study is to determine the safety and maximum tolerated dose (MTD) of Interleukin-2 in subjects with moderate-to-severe ulcerative colitis.
Detailed Description

Interleukin-2 (IL-2) is a T cell growth factor. IL-2 is currently licensed for the treatment of metastatic renal cell carcinoma and metastatic melanoma, where it promotes the expansion of anti-cancer cytotoxic T cells and natural killer (NK) cells. However at low doses (100-times lower than those used in cancer therapy), IL-2 promotes the selective expansion of regulatory T cells (Tregs): an immune modulating subset of CD4+ lymphocytes.

A recent phase 1 clinical trial from our collaborators at the Dana Farber Cancer Institute showed that low-dose IL-2 selectively expands Tregs in patients with treatment-resistant Graft vs. Host Disease (GvHD), and that low-dose IL-2 is safe in this condition. A detailed immunological analysis of samples from this study showed that low-dose IL-2 treatment was associated with increased Treg proliferation, increased de novo thymic generation of Tregs, and a resolution of defects in intracellular signalling and apoptosis seen in Tregs in chronic GvHD. A recent phase 1 study from another group showed that low-dose IL-2 is safe in the treatment of HCV-associated vasculitis. Low-dose IL-2 has also been shown to be well-tolerated in subjects with HIV.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Evidence from pre-clinical models of intestinal inflammation, and also from patients with monogenetic defects in Treg function, suggests that Tregs play a role in the prevention of inflammation in the intestine.

The treatment (or intervention) in this study is a once-daily, subcutaneous injection of IL-2, for a total of 8 weeks. The first 2 doses of the study drug will be administered by research nurses at Boston Children's Hospital. Further doses will be self-administered, at home. Training will be provided for correct self-administration.

This is a 3+3 dose escalation study of IL-2 in moderate-to-severe UC. This study design is powered to identify the MTD of low-dose IL-2 in UC. Once the MTD is identified, a further 10 subjects will receive IL-2 at that dose. Recruitment of between 2 and 28 patients is planned.

Dose levels are based on the experience of our collaborators in GvHD. In addition to determining the MTD, this study will determine if low-dose IL-2 is safe and well-tolerated in patients with moderate-to-severe ulcerative colitis. A detailed immunological analysis of samples obtained from this study will determine if low-dose IL-2 expands Tregs in vivo, in patients with moderate-to-severe UC. Immunological changes will then be correlated with clinical response.

The study will take place at Boston Children's Hospital. The study will involve 10 study visits. Most of the study visits involve blood tests. A flexible sigmoidoscopy or colonoscopy will be performed as part of the screening process. A flexible sigmoidoscopy will also be performed on completion of therapy, to determine clinical response.

The first two subjects to receive the study drug will be admitted overnight following the first dose. Subsequent doses will be administered on an out-patient basis. All other subjects will receive IL-2 on an out-patient basis.

Responders (with an acceptable side-effect profile) will be allowed to continue the study drug for at least 1 year. Compensation will be provided for participants.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Ulcerative Colitis
Intervention  ICMJE Drug: Interleukin-2 (aldesleukin).
Description of intervention is covered in "Arm", above.
Other Name: Proleukin.
Study Arms  ICMJE Experimental: Interleukin-2

Study drug: Interleukin-2 (aldesleukin, Proleukin, IL-2).

Each subject will receive an 8-week course of once-daily, subcutaneously administered IL-2. There will be three dose cohorts. Each subject will be recruited into a single dose cohort and receive a single dose level of IL-2 throughout the study.

The dose levels will be as follows:

  • Cohort 1: 0.3x10^6 IU/m^2/day.
  • Cohort 2: 1.0x10^6 IU/m^2/day.
  • Cohort 3: 1.5x10^6 IU/m^2/day.

Up to 6 subjects will be recruited to each dose cohort.

Once the maximum tolerated dose has been identified, a further 10 subjects will receive IL-2 at the maximum tolerated dose.

Intervention: Drug: Interleukin-2 (aldesleukin).
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 23, 2014)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 18-70 years.
  • A diagnosis of UC made by standard clinical, radiological, endoscopic and histological criteria.
  • Moderate to severe UC with a Mayo score of 6-12.
  • Failure to tolerate or failure to respond to at least one conventional therapy with the intention of inducing or maintaining remission (examples include oral corticosteroids, oral 5-aminosalicylates, azathioprine and/or 6-mercaptopurine, or a tumor necrosis factor (TNF) antagonist). Corticosteroid dependency (inability to taper oral corticosteroids without a recurrence of disease activity) is also included in this category.
  • Stable doses of concomitant medications.
  • A negative pregnancy test in the 2 weeks prior to anticipated commencement of the study drug, in female subjects of child-bearing age. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment.
  • Ability to provide informed consent.

Exclusion Criteria:

  • A diagnosis of Crohn's disease or Inflammatory Bowel Disease - Unspecified (IBD-U, a diagnostic classification formerly termed "indeterminate colitis").
  • Requirement for immediate surgical, endoscopic or radiological intervention for toxic megacolon, massive hemorrhage, perforation, sepsis, or intra-abdominal or perianal abscess.
  • Ileostomy, proctocolectomy or subtotal colectomy with ileorectal anastomosis.
  • History of colorectal cancer or dysplasia.
  • Positive stool test for Clostridium difficile.
  • Current medically significant infection.
  • Significant laboratory abnormalities, including;

    1. Hb < 8.0 g/dL, WBC < 2.5 x 103/mm3, Plt < 100 x 103/mm3.
    2. Creatinine ≥ 1.5x institutional upper limit of normal (ULN).
    3. Total bilirubin > 2.0 mg/dL, ALT > 2x institutional ULN, GGT > 2x institutional ULN. Elevated unconjugated bilirubin related to Gilbert's syndrome is allowed.
    4. Abnormal thyroid function tests.
  • Positive serology for HIV, hepatitis B virus (HBV) or HCV.
  • Positive screening test for tuberculosis (TB).
  • First dose of an anti-TNF medication within 4 weeks of anticipated study commencement, or a subsequent dose within 2 weeks of commencement; or ciclosporin or tacrolimus within 2 weeks of anticipated study commencement.
  • Received another investigational new drug (IND) within 5 half-lives of that agent before the planned commencement of SC IL-2.
  • Malignancy within the last 5 years.
  • Allergy to any component of the study drug.
  • Pregnant or lactating women.
  • Inability to comply with the study protocol or inability to give informed consent.
  • Prior exposure to IL-2.
  • Uncontrolled cardiac angina or symptomatic congestive cardiac failure (NYHA Class III or IV).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Maddie Carrellas 617-732-9173
Contact: Alexandra B Griffith 617-919-4592
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02200445
Other Study ID Numbers  ICMJE IRB-P00009599
2015P000016 ( Other Identifier: Brigham & Women's Hospital, Boston MA )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Scott Snapper, Boston Children’s Hospital
Study Sponsor  ICMJE Scott Snapper
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Scott B Snapper, MD PhD Boston Children’s Hospital
Study Director: Jessica R Allegretti, MD, MPH Brigham and Women's Hospital
PRS Account Boston Children’s Hospital
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP