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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

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.

Condition or disease Intervention/treatment Phase
Ulcerative Colitis Drug: Interleukin-2 (aldesleukin). Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Low Dose Subcutaneous Interleukin-2 (IL-2) For The Treatment of Ulcerative Colitis.
Study Start Date : February 2015
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Aldesleukin

Arm Intervention/treatment
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.

Drug: Interleukin-2 (aldesleukin).
Description of intervention is covered in "Arm", above.
Other Name: Proleukin.

Primary Outcome Measures :
  1. 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.

  2. Maximum tolerated dose. [ Time Frame: 8 weeks. ]
    Identification of the dose cohort at which the MTD occurs.

Secondary Outcome Measures :
  1. 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.

  2. 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02200445

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Contact: Maddie Carrellas 617-732-9173
Contact: Alexandra B Griffith 617-919-4592

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United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Anastasia Nelina    617-919-4592   
Contact: Alexandra Griffith    617-919-4592   
Principal Investigator: Athos Bousvaros, MD         
Brigham & Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Madeline Carrellas, BS    617-732-9223   
Contact: Ami Merker, BS   
Principal Investigator: Joshua Korzenik, MD         
Sub-Investigator: Jessica Allegretti, MD         
Sub-Investigator: Matt Hamilton, MD         
Sponsors and Collaborators
Scott Snapper
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Principal Investigator: Scott B Snapper, MD PhD Boston Children’s Hospital
Study Director: Jessica R Allegretti, MD, MPH Brigham and Women's Hospital

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Responsible Party: Scott Snapper, Associate Professor of Medicine, Boston Children’s Hospital Identifier: NCT02200445    
Other Study ID Numbers: IRB-P00009599
2015P000016 ( Other Identifier: Brigham & Women's Hospital, Boston MA )
First Posted: July 25, 2014    Key Record Dates
Last Update Posted: February 6, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Scott Snapper, Boston Children’s Hospital:
Ulcerative colitis
Inflammatory bowel disease
Interleukin 2
Regulatory T Cells
T-Lymphocytes, Regulatory
Additional relevant MeSH terms:
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Colitis, Ulcerative
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Pathologic Processes
Inflammatory Bowel Diseases
Antineoplastic Agents
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents