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

NCT03893565 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: 204869
• Study Type: interventional
• Target: 104
• Locations: 15 countries
• Sites: 61

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.

Conditions

Colitis, Ulcerative

Keywords

GSK2831781; Ulcerative colitis; Anti-LAG3 cell Depleting monoclonal antibody; Dose-response

Outcome Measures

Primary Outcomes (8)

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Double-Blind Induction Phase

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect or other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. AEs and SAEs were collected up to Week 14 (for participants who later entered the Double Blind ETP) and Week 12 (for participants who later entered OL Induction Phase).

  Up to a maximum of Week 14

• Number of Participants With Worst-case Vital Signs Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase

  Vital signs were measured in a seated or semi-supine position after 5 minutes rest. The clinical concern range for vital signs were: systolic blood pressure (SBP) (lower: \<85 and upper: \> 160 millimeters of mercury \[mmHg\]); diastolic blood pressure (DBP) (lower: \<45 mmHg and upper: \>100 mmHg); pulse rate (PR) (lower: \<40 and upper: \>110 beats per minute \[bpm\]) and temperature (Temp) (lower: \<35 and upper: \>38 degree Celsius). Participants were counted in the worst-case category that their value changed to (low, within range or no change, or high), unless there was no change in their category. Participants whose value category was unchanged (e.g. High to High), or whose value became within range, were recorded in the "To within (w/in) Range or No Change category". Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100 percent (%).

  Up to Week 10

• Number of Participants With Worst-case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase

  Blood samples were collected for the assessment of hematology parameters. The clinical concern range for the parameters were: hematocrit (Hct) (low: 0.201 and high: \>0.599 proportion of red blood cells in blood); hemoglobin (Hgb) (low: \<80 and high: \>180 grams per liter \[g/L\]), lymphocytes (Lymph) (low: \<0.8x10\^9 cells/L); neutrophil (Neut) count (low: \<1.5x10\^9 cells/L); platelet (plat) count (low: \<100x10\^9 cells/L and high: \>550x10\^9 cells/L); leukocytes (leuko) (low: \<3x10\^9 cells/L and high: \>20x10\^9cells/L) and eosinophils (Eos) (high: \>=1x10\^9 cells/L). Participants were counted in the worst-case category that their value changed to (low, w/in range or no change, or high), unless there was no change in their category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%.

  Up to Week 10

• Number of Participants With Worst-case Clinical Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase

  Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: albumin (Alb) (low: \<30 and high: \>55 g/L), calcium (Ca) (low: 2 and high: 2.75 millimoles per liter \[mmol/L\]), urea (high: \>10.5 mmol/L); creatinine (Creat) (high: change from Baseline \>26 micromoles per liter \[µmol/L\]), glucose (Glu) (low: \<3.5 and high: \>7.9 mmol/L); estimated glomerular filtration rate (eGFR) (low: \<60 milliliters per minute per 1.73 square meter \[mL/min/1.73m\^2)\]; potassium (Pot) (low: \<3 and high: \>5.5 mmol/L); sodium (Sod) (low: \<130 and high: \>150 mmol/L); protein (Pro) (low: \<50 and high: \>85 g/L) and C-reactive protein (CRP) (high: \>30 milligrams/L). Participants were counted in the worst-case category that their value changed to (low, w/in range or no change, or high), unless there was no change in their category.

  Up to Week 10

• Number of Participants With Worst-case Liver Function Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase

  Blood samples were collected for the assessment of liver function parameters. The clinical concern range for liver function parameters were: alanine aminotransferase (ALT) (high: \>=2 times upper limit of normal \[ULN\]); aspartate aminotransferase (AST) (high: \>=2 times ULN); alkaline phosphatase (ALP) (high: \>=2 times ULN) and bilirubin (Bil) (high: \>=1.5 times ULN). Participants were counted in the worst-case category that their value changed to (within range or no change, or high), unless there was no change in their category. Participants whose value category was unchanged (e.g. High to High), or whose value became within range, were recorded in the "To within (w/in) Range or No Change category".

  Up to Week 10

• Number of Participants With Worst-case Urinalysis Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase

  Urine samples were collected for the assessment of urine parameters by dipstick and microscopy. The dipstick test gives results in a semi-quantitative manner, and results can be read as Trace, 1+, 2+ indicating proportional concentrations in the urine sample. The clinical concern range for urine parameters were: Bil (high: \>1+), glu (high: \>1+); ketone (ket) (high: \>2+); leuko (high: \>1+); leukocyte esterase (LE); nitrite (nit) (high: positive); occult blood (OB) (high: \>1+); potential of hydrogen (pH) (low: \<4.6 and high: \>8); prot (high:\>1+); erythrocytes (erythro) (high: \>3 cells per high power field \[hpf\]); specific gravity (sp gra) (low: \<1.001 and high: \>1.035) and urobilinogen (uro) (high: \>1 mg/deciliter).

  Up to Week 10

• Number of Participants With Maximum Corrected QT (QTc) Values Post-Baseline Relative to Baseline-Double-Blind Induction Phase

  Twelve lead electrocardiograms (ECGs) were obtained using an ECG machine that automatically calculated the QT interval corrected for heart rate according to either Bazett's formula (QTcB) or Fridericia's formula (QTcF). The clinical concern range for the QTcB and QTcF intervals was upper: \>450 milliseconds.

  Up to Week 10

• Change From Baseline in Complete 4-domain Mayo Score at Week 10

  The Complete 4-domain Mayo Score is a 12-point scoring system where disease is evaluated based on the four components: stool frequency, rectal bleeding, physician global assessment (PGA) and endoscopic appearance (with mild friability associated with an endoscopic score of 1). The score for each component ranges from 0 (normal/none) to 3 (severe). The complete Mayo score is calculated as the sum of four components and ranges from 0 to 12. Higher scores indicate greater disease severity. Baseline value was the latest pre-dose assessment with a non-missing value from Double-Blind Induction study phase. Change from Baseline was calculated as value at specified time point minus Baseline value.

  Baseline and Week 10

Secondary Outcomes (23)

• Number of Participants With AEs and SAEs-Double-Blind Extended Treatment Phase

  Week 14 to 30

• Number of Participants With Worst-case Vital Signs Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase

  Week 14 to 30

• Number of Participants With Worst-case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase

  Week 14 to 30

• Number of Participants With Worst-case Clinical Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase

  Week 14 to 30

• Number of Participants With Worst-case Liver Function Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase

  Week 14 to 30

Study Arms (3)

GSK2831781-Double blind phase

EXPERIMENTAL

Eligible participants will receive GSK2831781 intravenously in the double blind induction phase at different dose levels. Participants identified as Responders at Week 10 will then receive GSK2831781 subcutaneously during the double-blind ETP from Week 14 until Week 26

Drug: GSK2831781 - Double Blind Phase

GSK2831781- Open label phase

EXPERIMENTAL

Eligible participants will receive GSK2831781 intravenously in the open label induction phase. Participants identified as Non-Responders at Week 10 will receive GSK2831781 from Week 12 until Week 22. Participants identified as Responders at Week 22 will enter open label ETP to receive GSK2831781 from Week 26 until Week 38. Participants identified as Non- Responders at Week 22 will discontinue treatment.

Drug: GSK2831781 - Open Label phase

Placebo matching GSK2831781- Double blind phase

PLACEBO COMPARATOR

Eligible participants will receive Placebo in the double blind induction phase Participants identified as Responders at Week 10 will continue to receive Placebo subcutaneously during the double-blind ETP from Week 14 until Week 26.

Drug: Placebo

Interventions

GSK2831781 - Double Blind Phase DRUG

GSK2831781 will be administered intravenously in the double blind induction phase and subcutaneously in the double blind ETP (both according to randomization).

GSK2831781-Double blind phase

Placebo DRUG

Placebo (commercial saline solution) will be administered intravenously in the double blind induction phase and subcutaneously in the double blind ETP (both according to randomization).

Placebo matching GSK2831781- Double blind phase

GSK2831781 - Open Label phase DRUG

GSK2831781 will be administered intravenously in the open label induction phase and subcutaneously in the open label ETP.

GSK2831781- Open label phase

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (61)

GSK Investigational Site

Northridge, California, 91324, United States

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GSK Investigational Site

Rialto, California, 92337, United States

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GSK Investigational Site

New York, New York, 10065, United States

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GSK Investigational Site

San Antonio, Texas, 78229, United States

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GSK Investigational Site

Sofia, 1612, Bulgaria

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GSK Investigational Site

Brno, 63600, Czechia

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GSK Investigational Site

Olomouc, 77900, Czechia

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GSK Investigational Site

Slaný, 274 01, Czechia

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GSK Investigational Site

Tallinn, 10117, Estonia

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GSK Investigational Site

Tallinn, 10617, Estonia

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GSK Investigational Site

Grenoble, 38043, France

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GSK Investigational Site

Nice, 06202, France

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GSK Investigational Site

Saint-Priest-en-Jarez, 42270, France

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GSK Investigational Site

Toulouse, 31059, France

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GSK Investigational Site

Vandœuvre-lès-Nancy, 54511, France

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GSK Investigational Site

Jaipur, 302001, India

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GSK Investigational Site

Ludhiana, 141001, India

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GSK Investigational Site

Nagpur, 440010, India

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GSK Investigational Site

Rajkot, 360005, India

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GSK Investigational Site

Varanasi, 221005, India

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GSK Investigational Site

Osaka, 530-0011, Japan

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GSK Investigational Site

Amsterdam, 1105 AZ, Netherlands

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GSK Investigational Site

Bydgoszcz, 85-168, Poland

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GSK Investigational Site

Elblag, 82-300, Poland

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GSK Investigational Site

Kamieniec Ząbkowicki, 57-230, Poland

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GSK Investigational Site

Katowice, 40-659, Poland

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GSK Investigational Site

Knurów, 44-190, Poland

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GSK Investigational Site

Krakow, 31-009, Poland

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GSK Investigational Site

Krakow, 31-501, Poland

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GSK Investigational Site

Lodz, 90-302, Poland

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GSK Investigational Site

Rzeszów, 35-326, Poland

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GSK Investigational Site

Sopot, 81-756, Poland

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GSK Investigational Site

Staszów, 28-200, Poland

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GSK Investigational Site

Torun, 87-100, Poland

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GSK Investigational Site

Warsaw, 03-340, Poland

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GSK Investigational Site

Wroclaw, 50-449, Poland

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GSK Investigational Site

Zamość, 22-400, Poland

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GSK Investigational Site

Krasnoyarsk, 660022, Russia

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GSK Investigational Site

Nizhny Novgorod, 603126, Russia

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GSK Investigational Site

Novosibirsk, 630005, Russia

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GSK Investigational Site

Saint Petersburg, 195257, Russia

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GSK Investigational Site

Saint Petersburg, 197022, Russia

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GSK Investigational Site

Samara, 443011, Russia

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GSK Investigational Site

Saratov, 410053, Russia

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GSK Investigational Site

Zrenjanin, 23000, Serbia

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GSK Investigational Site

Prešov, 080 01, Slovakia

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GSK Investigational Site

Port Elizabeth, Eastern Cape, 6001, South Africa

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GSK Investigational Site

Bloemfontein, 9301, South Africa

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GSK Investigational Site

Gauteng, 1619, South Africa

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GSK Investigational Site

Pretoria, 0002, South Africa

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GSK Investigational Site

Kharkiv, 61037, Ukraine

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GSK Investigational Site

Kiev, 02000, Ukraine

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GSK Investigational Site

Lviv, 79059, Ukraine

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GSK Investigational Site

Odesa, 65025, Ukraine

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GSK Investigational Site

Vinnytsia, 21009, Ukraine

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GSK Investigational Site

Vinnytsia, 21018, Ukraine

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GSK Investigational Site

Zaporizhzhia, 69050, Ukraine

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GSK Investigational Site

Zaporizhzhya, 69065, Ukraine

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GSK Investigational Site

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

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GSK Investigational Site

Headington, Oxfordshire, OX3 9DU, United Kingdom

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GSK Investigational Site

London, E11 1NR, United Kingdom

Location

Related Publications (1)

• D'Haens G, Peyrin-Biroulet L, Marks DJB, Lisi E, Liefaard L, Beaton A, Srinivasan N, Bouma G, Prasad N, Cameron R, Kayali Z, Tarzi R, Hanauer S, Sandborn WJ. A randomised, double-blind, placebo-controlled study of the LAG-3-depleting monoclonal antibody GSK2831781 in patients with active ulcerative colitis. Aliment Pharmacol Ther. 2023 Aug;58(3):283-296. doi: 10.1111/apt.17557. Epub 2023 Jun 16.

  PMID: 37323059 DERIVED

MeSH Terms

Conditions

Colitis, Ulcerative

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This will be a double-blind study. Induction doses will be matched with placebo. For Maintenance dosing, participant and investigator will be masked. Participants will be allocated to the next treatment phase according to their Responder status. Non-responders to the double-blind Induction Phase will receive treatment in Open-Label Induction phase where there will be no masking.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a parallel group, placebo controlled study where participants will be randomized to receive either GSK2831781 or placebo.

Study Record Dates

• First Submitted: March 26, 2019
• First Posted: March 28, 2019
• Study Start: May 6, 2019
• Primary Completion: May 17, 2021
• Study Completion: May 17, 2021
• Last Updated: April 27, 2022
• Results First Posted: April 27, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

SE (1); GB (3); PL (15); US (4); ES (2); CZ (3); FR (5); ZA (4); UA (8); SL (1); NL (1); RU (7); IN (5); BU (1); JP (1)