Low Dose IL-2 for Ulcerative Colitis
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|ClinicalTrials.gov Identifier: NCT02200445|
Recruitment Status : Recruiting
First Posted : July 25, 2014
Last Update Posted : February 6, 2020
|Condition or disease||Intervention/treatment||Phase|
|Ulcerative Colitis||Drug: Interleukin-2 (aldesleukin).||Phase 1|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||28 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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:
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.
- 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.
- 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:
- 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.
- Clinical Remission: Subjects with a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point.
- 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:
- Mucosal Healing Present: An absolute Mayo endoscopy subscore of 0 or 1.
- 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.
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 ClinicalTrials.gov identifier (NCT number): NCT02200445
|Contact: Maddie Carrellasfirstname.lastname@example.org|
|Contact: Alexandra B Griffithemail@example.com|
|United States, Massachusetts|
|Boston Children's Hospital||Recruiting|
|Boston, Massachusetts, United States, 02115|
|Contact: Anastasia Nelina 617-919-4592 firstname.lastname@example.org|
|Contact: Alexandra Griffith 617-919-4592 email@example.com|
|Principal Investigator: Athos Bousvaros, MD|
|Brigham & Women's Hospital||Recruiting|
|Boston, Massachusetts, United States, 02115|
|Contact: Madeline Carrellas, BS 617-732-9223 firstname.lastname@example.org|
|Contact: Ami Merker, BS email@example.com|
|Principal Investigator: Joshua Korzenik, MD|
|Sub-Investigator: Jessica Allegretti, MD|
|Sub-Investigator: Matt Hamilton, MD|
|Principal Investigator:||Scott B Snapper, MD PhD||Boston Children’s Hospital|
|Study Director:||Jessica R Allegretti, MD, MPH||Brigham and Women's Hospital|