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

• Register: ClinicalTrials.gov
• Last refreshed on: 5 July 2021
• Main ID: NCT03893565
• Date of registration: 26/03/2019
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: Safety, Tolerability, Efficacy and Dose-response of GSK2831781 in Ulcerative Colitis
• Scientific title: A Multicentre Randomized, Double-blind, Placebo-controlled Phase 2 Study to Evaluate the Safety, Tolerability, Efficacy, Dose-response, Pharmacokinetics and Pharmacodynamics of Repeat Dosing of an Anti-LAG3 Cell Depleting Monoclonal Antibody (GSK2831781) in Patients With Active Ulcerative Colitis
• Date of first enrolment: May 6, 2019
• Target sample size: 104
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT03893565
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 2

Countries of recruitment

Belgium, Bulgaria, Canada, Czechia, Estonia, France, Hungary, India, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Serbia, Slovakia, South Africa, Ukraine, United Kingdom, United States

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion criteria

Inclusion Criteria:

- Participants must be 18 years of age or older and > 40 kilograms (kg) at the time of
signing the informed consent.

- 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 4-domain 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.

- 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] and nudix hydrolase 15 [NUDT15] genetic mutations precluding
use), ciclosporin, tacrolimus or methotrexate; inadequate response to, loss of
response to, intolerance to, or demonstrated dependence on oral corticosteroids;
inadequate response to, loss of response to, or intolerance to at least one approved
advanced therapy for UC including anti- tumor necrosis factor (TNF) therapies (example
given [e.g.] infliximab, adalimumab, golimumab, or biosimilar), anti-integrin
therapies, anti-interleukin (IL)-12/23 monoclonal antibodies or Janus Kinase (JAK)
inhibitors.

- 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 participants with left-sided colitis of >12 years duration. For
participants for whom this criterion does not apply, colorectal cancer surveillance
should be undertaken according to local or national guidelines for participants with
age >=50, or with other known risk factors for colorectal cancer.

- Both male and female participants are eligible to participate.

- 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); A WOCBP who agrees 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:

- Participants with a current diagnosis of indeterminate colitis, inflammatory bowel
disease-unclassified, Crohn's disease, infectious colitis, or ischemic colitis.

- Participants 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.

- Participants with any uncontrolled medical conditions, other than active ulcerative
colitis, 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: 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 participant. 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
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 Purified Protein Derivative (PPD) testing. If the PPD
reaction is less than (<) 5 millimeter (mm), then the participant is eligible. If the
reaction is >= 5mm, or PPD testing is not undertaken, the participant 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 participant 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 anticipated inability 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


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Colitis, Ulcerative

Intervention(s)

Drug: GSK2831781 - Open Label phase

Drug: Placebo

Drug: GSK2831781 - Double Blind Phase

Primary Outcome(s)

Change from Baseline in Complete 4-domain Mayo Clinic Score at Week 10 [Time Frame: Baseline and at Week 10]

Number of participants with adverse events (AEs) and serious adverse events (SAEs) in the Double Blind Induction Phase [Time Frame: Up to Week 14]

Number of participants with findings of potential clinical importance for vital signs, clinical laboratory parameters and QT interval corrected (QTc) in the Double Blind Induction Phase. [Time Frame: Up to Week 14]

Secondary Outcome(s)

Number of participants with adapted Mayo Clinical Response at Week 10 [Time Frame: At Week 10]

Histological severity as determined by the Nancy Histological Index at Week 10 [Time Frame: At Week 10]

Number of participants with adapted Mayo clinical remission at Week 10 [Time Frame: At Week 10]

Number of participants with AEs and SAEs in the double blind ETP [Time Frame: Up to Week 42]

Time to reach Cmax (Tmax) of GSK2831781 [Time Frame: Up to Day 379]

Change from Baseline in adapted Mayo endoscopic score and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) at Week 10 [Time Frame: Baseline and up to Week 10]

Number of participants with adapted Mayo endoscopic score of 0 or 1 at Week 10 [Time Frame: At Week 10]

Number of participants with anti-drug antibodies at each visit [Time Frame: Up to Week 10]

Histological severity as determined by Robarts Histopathology Index at Week 10 [Time Frame: At Week 10]

Maximum observed plasma concentration (Cmax) of GSK2831781 [Time Frame: Up to Day 379]

Area under the concentration-time curve over the dosing interval (AUC [0-tau]) of GSK2831781 [Time Frame: Up to Day 379]

Number of participants with findings of potential clinical importance for vital signs, clinical laboratory parameters and QTc in the double blind ETP [Time Frame: Up to Week 42]

Change from Baseline in partial Mayo score over time [Time Frame: Baseline and up to Week 10]

Number of participants with symptomatic remission over time [Time Frame: Up to Week 10]

Change from Baseline in fecal calprotectin over time [Time Frame: Baseline and up to Week 10]

Change from Baseline in serum C reactive protein over time [Time Frame: Baseline and up to Week 10]

Histological severity as determined by Geboes Histological Index at Week 10 [Time Frame: At Week 10]

Secondary ID(s)

204869

Source(s) of Monetary Support

Please refer to primary and secondary sponsors