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Safety, Tolerability, Efficacy and Dose-response of GSK2831781 in Ulcerative Colitis

September 9, 2019

Overview

T cells are integral to the production and development of ulcerative colitis. GSK2831781 targets these specific T cells, and preliminary evidence towards this being a new effective treatment for ulcerative colitis looks promising. It is hypothesized that GSK2831781 will selectively deplete the activated T cells that are developing the disease, whilst largely sparing the other resting T cells. This study will investigate the safety, tolerability, effectiveness and dose-response of GSK2831781 in participants with moderate to severe active ulcerative colitis. 

 

The study consists of a 5-week screening window, 10-week Induction Phase, 20-week Extended Treatment Phase, and a 12-week Follow-Up Phase. Subjects may spend up to 54 weeks in total on study. Approximately 280 subjects will be included in the study.

 

Study Information

This is a double-blind study, with participants either receiving GSK2831781 or a placebo.

 

After week 10, the non-responders will be switched from double-blind to open-label treatment where they will receive GSK2831781. After this phase, those who respond will receive GSK2831781 maintenance dosing, and the non-responders will discontinue treatment.

The study began on May 6th 2019 and is estimated to be completed on April 11th 2022.

 

Inclusion Criteria

  • Subjects must be 18 years of age or older and weigh over 40 kilograms at the time of signing the informed consent.
  • Subjects must have a diagnosis of ulcerative colitis, established at least 3 months prior to screening, as documented by diagnostic sigmoidoscopy or colonoscopy, and biopsy.
  • Complete Mayo Score of 6 to 12, with disease extending >= 15 centimeters (cm) from the anal verge, with a centrally read endoscopic sub score of >=2 at screening endoscopy, and a rectal bleeding sub score >=1.
  • Subjects must have a history of at least one of the following: inadequate response to, loss of response to, or intolerance to: azathioprine or mercaptopurine (including thiopurine methyltransferase [TPMT] genetic mutation precluding use), ciclosporin, tacrolimus or methotrexate; inadequate response to, intolerance to, or demonstrated dependence on oral corticosteroids; inadequate response to, loss of response to, or intolerance to one biologic class only for the treatment of ulcerative colitis: either one or more anti- tumor necrosis factor (TNF) therapies (example given [e.g.] infliximab, adalimumab, golimumab, or biosimilar) or vedolizumab.
  • For subjects who have had Pancolitis for more than 8 years, left-sided colitis for more than 12 years; or subjects with primary sclerosing cholangitis, surveillance colonoscopy (performed according to local standards) within 12 months of screening (or during screening) is required. For participants age 50+, or with other known risk factors for colorectal cancer, but for whom the above does not apply, colorectal cancer surveillance should be undertaken according to local or national guidelines.
  • Female participants must not be pregnant, breastfeeding, and must either not be of childbearing potential or must agree to use a highly effective contraceptive method for at least 4 weeks prior to dosing, until the Follow-Up visit.
  • Capable of giving signed informed consent.

 

Exclusion Criteria

  • Subjects with a current diagnosis of indeterminate colitis, inflammatory bowel disease-unclassified, Crohn’s disease, infectious colitis, or ischemic colitis.
  • Subjects with fulminant ulcerative colitis (as defined by 6 bloody stools daily and 1 or more of body temperature >=100.4 degrees Fahrenheit (or 38 degree Celsius) or heart rate >90 beats per minute), or toxic megacolon.
  • Prior extensive colonic resection, subtotal or total colectomy, or proctocolectomy, or planned surgery for ulcerative colitis.
  • Subjects with any uncontrolled medical conditions, other than active ulcerative colitis, that in the opinion of the investigator put the subject at unacceptable risk or interfere with study assessments or integrity of the data. Other medical conditions should be stable at the time of screening and be expected to remain stable for the duration of the study.
  • Unstable lifestyle factors, such as alcohol use to excess or recreational drug use, to the extent that in the opinion of the investigator they would interfere with the ability of a subject to complete the study.
  • An active infection or a history of serious infections as follows: a) Use of antimicrobials (antibacterials, antivirals, antifungals or antiparasitic agents) for an infection within 30 days before first dose (topical treatments may be allowed at the Medical Monitor’s discretion). b) A history of opportunistic infections within 1 year of screening (e.g. Pneumocystis jirovecii, aspergillosis or Cytomegalovirus colitis). This does not include infections that may occur in immunocompetent individuals, such as fungal nail infections or vaginal candidiasis, unless it is of an unusual severity or recurrent nature. c) Recurrent or chronic infection or other active infection that, in the opinion of the Investigator, might cause this study to be detrimental to the subject. d) Symptomatic herpes zoster within 3 months prior to screening. e) History of tuberculosis (active or latent), irrespective of treatment status. f) A positive diagnostic tuberculosis test at screening (defined as a positive QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the subject may have the test repeated once and if their second test is negative they will be eligible. In the event a second test is also indeterminate, the investigator has the option to undertake Purified Protein Derivative (PPD) testing. If the PPD reaction is < 5 millimeter (mm), then the subject is eligible. If the reaction is >= 5mm, or PPD testing is not undertaken, the subject is not eligible. g) Positive Clostridium difficile toxin test during screening. However, rescreening can be undertaken following successful treatment.
  • Current or history of chronic liver or biliary disease (with the exception of Gilbert’s syndrome, asymptomatic gallstones or uncomplicated fatty liver disease).
  • Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency (unless the subject has a documented history of selective immunoglobulin A deficiency).
  • A major organ transplant (e.g. heart, lung, kidney, liver, pancreas) or hematopoietic stem cell/marrow transplant.
  • Any planned major surgical procedure during the study.
  • A history of malignant neoplasm within the last 5 years, except for adequately treated non-metastatic basal or squamous cell cancers of the skin (within 1 year) or carcinoma in situ of the uterine cervix (within 3 years) that has been fully treated and shows no evidence of recurrence.
  • A change in dose of oral sulfasalazine or aminosalicylate within 2 weeks prior to Baseline endoscopy.
  • Greater than 20 mg per day oral prednisolone (or equivalent), or a change in dose of corticosteroid within 2 weeks prior to baseline endoscopy, or be unable to maintain a stable dose of corticosteroids (<=20 mg oral prednisolone or equivalent) until Week 12.
  • Topical (rectal) corticosteroids or topical (rectal) aminosalicylate within 2 weeks prior to Baseline endoscopy.
  • Initiation or a change in dose of mercaptopurine or azathioprine (including initiation or discontinuation of allopurinol) or methotrexate within 8 weeks prior to Baseline endoscopy.
  • Treatment with ciclosporin, tacrolimus or thalidomide within 4 weeks prior to Baseline endoscopy.
  • Treatment with an anti-TNF biologic within 8 weeks prior to Baseline endoscopy, or vedolizumab within 12 weeks prior to Baseline endoscopy.
  • A history of treatment with vedolizumab and an anti-TNF biologic, regardless of treatment response (unless exposure to one or both drugs was only within a clinical trial setting).
  • A history of treatment with a monoclonal antibody therapy or targeted small molecule therapy for the treatment of ulcerative colitis not listed above.
  • Received live vaccination within 4 weeks of Day 1 or plan to receive during the study until Follow-Up.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives, or twice the duration of the biological effect of the investigation product (whichever is longer).
  • Absolute neutrophil count <1.5 times 10^9 cells per liter (L) or a hemoglobin <80 grams per liter (g/L) or lymphocyte count <0.8 times 10^9 cells /L.
  • Estimated glomerular filtration rate (GFR) by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) calculation <60 milliliter (mL) per minute per 1.73 m^2 at screening.
  • ALT >2 times upper limit of normal (ULN) and bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent) at screening.
  • Other clinically significant abnormalities of laboratory assessments, as judged by the investigator and/or GlaxoSmithKline Medical Monitor that could affect the safety of the subject, or the interpretation of the data from the study.
  • Presence of hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb), or positive hepatitis C antibody result at screening (NB. subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C ribonucleic acid [RNA] test is obtained).
  • Positive serology for human immunodeficiency virus (HIV) at screening.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 3 months.
  • QT interval corrected for heart rate (QTc) >450 milliseconds (msec) or QTc >480 msec for subjects with bundle branch block at screening and Day 1. The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or over read.

 

Location

You may participate in this trial in Rialto, California. For more information, you can contact GSK Clinical Trials at GSKClinicalSupportHD@gsk.com or on 877-379-3718.

 

Sponsors / Collaborators

This study is sponsored by GlaxoSmithKline, with Zeid Kayali as the Principal Investigator.

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