Clinical trial NCT03893565: Safety, Tolerability, Efficacy and Dose-response of GSK2831781 in Ulcerative Colitis
Official 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Colitis, Ulcerative
Keywords: GSK2831781
Ulcerative colitis
Anti-LAG3 cell Depleting monoclonal antibody
Dose-response
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2019-03-28
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a parallel group, placebo controlled study where participants will be randomized to receive either GSK2831781 or placebo.
Primary purpose: TREATMENT

Brief summary: This is a Phase 2, multicenter, randomized, double-blind, parallel group, placebo-controlled study to investigate the safety, tolerability, efficacy 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, 30-week double-blind Extended Treatment Phase (ETP) with 42-week Follow-Up Phase. Non-Responders identified following the Week 10 assessment will be allocated to open label treatment, consisting of Induction (Weeks 12 to 22), an Open label ETP (Weeks 22 to 42) and a follow-Up to Week 54.


Eligibility 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 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, anti-integrin or anti-IL-12/23 biologics within 12 weeks prior to Baseline endoscopy, or a JAK inhibitor within 4 weeks prior to Baseline endoscopy.
* A history of inadequate response, loss of response, or intolerance to more than three classes of approved advanced therapies for UC (including anti-TNF therapies, anti-integrin therapies, anti-IL-12/23 monoclonal antibodies, or JAK inhibitors; but excluding exposure within a clinical trial setting), of which participants must not have had inadequate response (primary non-response) to more than two classes.
* Received fecal microbiota transplantation within 4 weeks prior to Baseline endoscopy.
* Received live vaccination within 4 weeks of Day 1 or plan to receive during the study until Follow-Up.
* The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the screening endoscopy day in the current study:

  1. Biologics: 3 months, 5 half-lives, or twice the duration of the biological effect of the investigational product (whichever is longer);
  2. New Chemical Entities (NCEs): 30 days, 5 half-lives, or twice the duration of the biological effect (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 participant, 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 (Nota bene \[NB\]-Participants with 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.
* QTc \>450 milliseconds (msec) or QTc \>480 msec for participants 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.
* Participants with hypersensitivity to GSK2831781 or any excipients in the clinical formulation of GSK2831781.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Double-Blind Induction Phase
timeFrame: Up to a maximum of Week 14
measure: Number of Participants With Worst-case Vital Signs Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase
timeFrame: Up to Week 10
measure: Number of Participants With Worst-case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase
timeFrame: Up to Week 10
measure: Number of Participants With Worst-case Clinical Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase
timeFrame: Up to Week 10
measure: Number of Participants With Worst-case Liver Function Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase
timeFrame: Up to Week 10
measure: Number of Participants With Worst-case Urinalysis Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase
timeFrame: Up to Week 10
measure: Number of Participants With Maximum Corrected QT (QTc) Values Post-Baseline Relative to Baseline-Double-Blind Induction Phase
timeFrame: Up to Week 10
measure: Change From Baseline in Complete 4-domain Mayo Score at Week 10
timeFrame: Baseline and Week 10
Secondary outcomes:
measure: Number of Participants With AEs and SAEs-Double-Blind Extended Treatment Phase
timeFrame: Week 14 to 30
measure: Number of Participants With Worst-case Vital Signs Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase
timeFrame: Week 14 to 30
measure: Number of Participants With Worst-case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase
timeFrame: Week 14 to 30
measure: Number of Participants With Worst-case Clinical Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase
timeFrame: Week 14 to 30
measure: Number of Participants With Worst-case Liver Function Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase
timeFrame: Week 14 to 30
measure: Number of Participants With Worst-case Urinalysis Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase
timeFrame: Week 14 to 30
measure: Number of Participants With Maximum QTc Values Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase
timeFrame: Week 14 to 30
measure: Number of Participants With Adapted Mayo Endoscopic Score of 0 or 1 at Week 10-Double-Blind Induction Phase
timeFrame: Week 10
measure: Number of Participants With Adapted Mayo Clinical Remission at Week 10-Double-Blind Induction Phase
timeFrame: Week 10
measure: Number of Participants With Adapted Mayo Clinical Response at Week 10-Double-Blind Induction Phase
timeFrame: Week 10
measure: Number of Participants With Symptomatic Remission at Week 10-Double-Blind Induction Phase
timeFrame: Week 10
measure: Change From Baseline in Partial Mayo Score Over Time-Double-Blind Induction Phase
timeFrame: Baseline and Weeks 2, 4, 6, and 10
measure: Change From Baseline in Adapted Mayo Endoscopy Score at Week 10-Double-Blind Induction Phase
timeFrame: Baseline and Week 10
measure: Change From Baseline in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) at Week 10-Double-Blind Induction Phase
timeFrame: Baseline and Week 10
measure: Number of Responders for Robarts Histopathology Index (RHI) Remission at Week 10-Double-Blind Induction Phase
timeFrame: Week 10
measure: Number of Responders for Nancy Histological Index Remission at Week 10-Double-Blind Induction Phase
timeFrame: Week 10
measure: Number of Responders for Geboes Histological Index Remission at Week 10-Double-Blind Induction Phase
timeFrame: Week 10
measure: Change From Baseline in Serum CRP Level Over Time-Double-Blind Induction Phase
timeFrame: Baseline and Weeks 2, 4, 6, and 10
measure: Ratio to Baseline in Fecal Calprotectin Over Time-Double-Blind Induction Phase
timeFrame: Baseline and Weeks 2, 4, 6, and 10
measure: Area Under the Concentration-time Curve Over the 1st Dosing Interval (AUC[0-tau]) for GSK2831781 Following SC Dosing in Double-Blind Extended Treatment Phase
timeFrame: Week 14 (pre-dose, 24, 72 and 168 hours post-dose); Week 18 (pre-dose and early withdrawal post-dose)
measure: Maximum Concentration (Cmax) of GSK2831781 Observed Following 1st SC Dosing in Double-Blind Extended Treatment Phase
timeFrame: Week 14 (pre-dose, 24, 72 and 168 hours post-dose); Week 18 (pre-dose and early withdrawal post-dose)
measure: Time at Which the Maximum Concentration is Observed (Tmax) for GSK2831781 Following 1st SC Dosing in Double-Blind Extended Treatment Phase
timeFrame: Week 14 (pre-dose, 24, 72 and 168 hours post-dose); Week 18 (pre-dose and early withdrawal post-dose)
measure: Number of Participants With Positive Anti-drug Antibodies at Each Visit-Double-Blind Induction Phase
timeFrame: Baseline, Weeks 2, 4, 6, and 10
Other outcomes:
Locations:
city: Northridge
country: United States
facility: GSK Investigational Site
state: California
city: Rialto
country: United States
facility: GSK Investigational Site
state: California
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Olomouc
country: Czechia
facility: GSK Investigational Site
city: Slany
country: Czechia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Grenoble Cedex 9
country: France
facility: GSK Investigational Site
city: Nice Cedex 3
country: France
facility: GSK Investigational Site
city: Saint-Priest en Jarez
country: France
facility: GSK Investigational Site
city: Toulouse
country: France
facility: GSK Investigational Site
city: Vandoeuvre les Nancy
country: France
facility: GSK Investigational Site
city: Jaipur
country: India
facility: GSK Investigational Site
city: Ludhiana
country: India
facility: GSK Investigational Site
city: Nagpur
country: India
facility: GSK Investigational Site
city: Rajkot
country: India
facility: GSK Investigational Site
city: Varanasi
country: India
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Bydgoszcz
country: Poland
facility: GSK Investigational Site
city: Elblag
country: Poland
facility: GSK Investigational Site
city: Kamieniec Zabkowicki
country: Poland
facility: GSK Investigational Site
city: Katowice
country: Poland
facility: GSK Investigational Site
city: Knurow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Lodz
country: Poland
facility: GSK Investigational Site
city: Rzeszow
country: Poland
facility: GSK Investigational Site
city: Sopot
country: Poland
facility: GSK Investigational Site
city: Staszow
country: Poland
facility: GSK Investigational Site
city: Torun
country: Poland
facility: GSK Investigational Site
city: Warsaw
country: Poland
facility: GSK Investigational Site
city: Wroclaw
country: Poland
facility: GSK Investigational Site
city: Zamosc
country: Poland
facility: GSK Investigational Site
city: Krasnoyarsk
country: Russian Federation
facility: GSK Investigational Site
city: Nizhniy Novgorod
country: Russian Federation
facility: GSK Investigational Site
city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Saint Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Samara
country: Russian Federation
facility: GSK Investigational Site
city: Saratov
country: Russian Federation
facility: GSK Investigational Site
city: St.Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Zrenjanin
country: Serbia
facility: GSK Investigational Site
city: Presov
country: Slovakia
facility: GSK Investigational Site
city: Port Elizabeth
country: South Africa
facility: GSK Investigational Site
state: Eastern Cape
city: Bloemfontein
country: South Africa
facility: GSK Investigational Site
city: Gauteng
country: South Africa
facility: GSK Investigational Site
city: Pretoria
country: South Africa
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kiev
country: Ukraine
facility: GSK Investigational Site
city: Lviv
country: Ukraine
facility: GSK Investigational Site
city: Odessa
country: Ukraine
facility: GSK Investigational Site
city: Vinnytsia
country: Ukraine
facility: GSK Investigational Site
city: Vinnytsia
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhzhia
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhzhya
country: Ukraine
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
state: Cambridgeshire
city: Headington
country: United Kingdom
facility: GSK Investigational Site
state: Oxfordshire
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: