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

Phase 2

Not yet recruiting

• Conditions: Other ulcerative colitis,

• Registration Number: CTRI/2020/03/023899
• Lead Sponsor: GlaxoSmithKline Research Development Limited

Brief Summary

Ulcerative colitis is a form of inflammatory bowel disease characterized by chronic relapsing and remitting inflammation of the colon and rectum. There remains a high unmet need for novel treatments that achieve a higher rate of efficacy in resolving disease symptoms, and inducing and maintaining mucosal healing to achieve long-term corticosteroid-free remission. T cells are integral to the pathogenesis of ulcerative colitis, and clinical experience with anti-integrin monoclonal antibodies has established the principle of T cell-targeted therapies in the disease. GSK2831781 causes targeted depletion of Lymphocyte activation gene-3 (LAG3+) T cells, and has shown preliminary evidence of clinical efficacy in plaque psoriasis. It is therefore hypothesized that GSK2831781 will selectively deplete activated mucosal T cells in ulcerative colitis, but with relative sparing of resting T cells. This study will investigate the safety, tolerability, efficacy and dose-response of GSK2831781 in subjects 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. Non-Responders allocated to open label treatment who subsequently respond to treatment may spend up to 54 weeks in total on study. Approximately 280 subjects will be included in the study.

Detailed Description

Not available

Study Timeline

• Last Update Posted: 2020-02-25
• Study Start: 2020-03-20

Recruitment & Eligibility

• Status: Not Yet Recruiting
• Sex: All
• Target Recruitment: 320

Inclusion Criteria

• Participants are eligible to be included in the study only if all the following criteria apply AGE and WEIGHT Participant must be 18 years of age or older and >40kg at the time of signing the informed consent.
• TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS Participants who 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 ≥15cm from the anal verge, with a centrally read endoscopic subscore of ≥2 at screening endoscopy, and a rectal bleeding subscore ≥1.
• 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 UC: either one or more anti-TNF therapies (e.g. infliximab, adalimumab, golimumab, or biosimilar) OR vedolizumab.
• Surveillance colonoscopy (performed according to local standards) within 12 months of screening (or during screening, if required) for participants with: Pancolitis of >8 years duration; or Patients with left-sided colitis of >12 years duration; or Patients with primary sclerosing cholangitis.
• For patients for whom this criterion does not apply, colorectal cancer surveillance should be undertaken according to local or national guidelines for patients with age ≥50, or with other known risk factors for colorectal cancer.
• SEX Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP), see Section 10.4.1, WOCBP definitions.
• OR A WOCBP who agrees to use a highly effective contraceptive method for at least 4 weeks prior to dosing, until the Follow-Up visit.
• See Section 10.4.2, Contraceptive Guidance.
• INFORMED CONSENT Capable of giving signed informed consent as described in Section 10.1.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria

• Participants with a current diagnosis of indeterminate colitis, inflammatory bowel disease-unclassified, Crohn’s disease, infectious colitis, or ischaemic colitis. Participants with fulminant ulcerative colitis (as defined by 6 bloody stools daily AND 1 or more of: i) body temperature ≥100.4°F (or 38°C) or ii) heart rate >90 beats per minute), or toxic megacolon. Prior extensive colonic resection, subtotal or total colectomy, or proctocolectomy, or planned surgery for UC. Participants with any uncontrolled medical conditions, other than active UC, that in the opinion of the investigator put the participant 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 participant to complete the study. An active infection or a history of serious infections as follows:.
• 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).
• A history of opportunistic infections within 1 year of screening (e.g. Pneumocystis jirovecii, aspergillosis or CMV 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.
• Recurrent or chronic infection or other active infection that, in the opinion of the Investigator, might cause this study to be detrimental to the patient.
• Symptomatic herpes zoster within 3 months prior to screening.
• History of tuberculosis (active or latent), irrespective of treatment status.
• A positive diagnostic TB test at screening (defined as a positive QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the participant 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 PPD testing. If the PPD reaction is <5 mm, then the participant is eligible. If the reaction is ≥5 mm, or PPD testing is not undertaken, the participant is not eligible.
• 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 participant has a documented history of selective IgA deficiency). A major organ transplant (e.g. heart, lung, kidney, liver, pancreas) or haematopoietic 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.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective - To evaluate the safety and tolerability of repeat doses of GSK2831781	Week 10
- To characterise the efficacy dose response of GSK2831781 during the Induction Phase.	Week 10

Secondary Outcome Measures

Name	Time	Method
To investigate the	- Effect of repeat doses of GSK2831781 on clinical efficacy including endoscopic mucosal healing during the Induction Phase
Proportion of participants who achieve	-Mayo endo score of 0 or 1 at Wk 10

Trial Locations

Locations (8)

Dayanand Medical College and Hospital; 🇮🇳 Ludhiana, PUNJAB, India

Fortis Hospital Noida; 🇮🇳 East, DELHI, India

Midas institute of Gastroenterology; 🇮🇳 Nagpur, MAHARASHTRA, India

S. R. Kalla Memorial Gastro & General Hospital; 🇮🇳 Jaipur, RAJASTHAN, India

Sahyadri Specialty Hospital; 🇮🇳 Pune, MAHARASHTRA, India

Samvedana Hospital - Varanasi; 🇮🇳 Varanasi, UTTAR PRADESH, India

Shree Giriraj Multispeciality Hospital; 🇮🇳 Rajkot, GUJARAT, India

Sir Ganga Ram Hospital; 🇮🇳 Delhi, DELHI, India

Dayanand Medical College and Hospital

🇮🇳Ludhiana, PUNJAB, India

Dr Ajit Sood

Principal investigator

911612300791

ajitsood10@gmail.com