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Trial record 1 of 2 for:    204869
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Safety, Tolerability, Efficacy and Dose-response of GSK2831781 in Ulcerative Colitis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03893565
Recruitment Status : Terminated (The trial was stopped based on the assessment of clinical data.)
First Posted : March 28, 2019
Results First Posted : April 27, 2022
Last Update Posted : April 27, 2022
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Colitis, Ulcerative Drug: GSK2831781 - Double Blind Phase Drug: Placebo Drug: GSK2831781 - Open Label phase Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a parallel group, placebo controlled study where participants will be randomized to receive either GSK2831781 or placebo.
Masking: Double (Participant, Investigator)
Masking Description: 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.
Primary Purpose: Treatment
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
Actual Study Start Date : May 6, 2019
Actual Primary Completion Date : May 17, 2021
Actual Study Completion Date : May 17, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: GSK2831781-Double blind phase
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 will be administered intravenously in the double blind induction phase and subcutaneously in the double blind ETP (both according to randomization).

Experimental: GSK2831781- Open label phase
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
GSK2831781 will be administered intravenously in the open label induction phase and subcutaneously in the open label ETP.

Placebo Comparator: Placebo matching GSK2831781- Double blind phase
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
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).




Primary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Double-Blind Induction Phase [ Time Frame: Up to a maximum of Week 14 ]
    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).

  2. Number of Participants With Worst-case Vital Signs Results by Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase [ Time Frame: Up to Week 10 ]
    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 (%).

  3. Number of Participants With Worst-case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase [ Time Frame: Up to Week 10 ]
    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%.

  4. Number of Participants With Worst-case Clinical Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase [ Time Frame: Up to Week 10 ]
    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.

  5. Number of Participants With Worst-case Liver Function Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase [ Time Frame: Up to Week 10 ]
    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".

  6. Number of Participants With Worst-case Urinalysis Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Induction Phase [ Time Frame: Up to Week 10 ]
    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).

  7. Number of Participants With Maximum Corrected QT (QTc) Values Post-Baseline Relative to Baseline-Double-Blind Induction Phase [ Time Frame: Up to Week 10 ]
    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.

  8. Change From Baseline in Complete 4-domain Mayo Score at Week 10 [ Time Frame: Baseline and 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.


Secondary Outcome Measures :
  1. Number of Participants With AEs and SAEs-Double-Blind Extended Treatment Phase [ Time Frame: Week 14 to 30 ]
    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.

  2. Number of Participants With Worst-case Vital Signs Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase [ Time Frame: Week 14 to 30 ]
    Vital signs were measured in a seated or semi-supine position after 5 minutes rest. The clinical concern range for vital signs were: SBP (lower: <85 and upper: > 160 mmHg); DBP (lower: <45 mmHg and upper: >100 mmHg); PR (lower: <40 and upper: >110 bpm) and 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 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%.

  3. Number of Participants With Worst-case Hematology Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase [ Time Frame: Week 14 to 30 ]
    Blood samples were collected for the assessment of hematology parameters. The clinical concern range for the parameters were: Hct (low: 0.201 and high: >0.599 proportion of red blood cells in blood); Hgb (low: <80 and high: >180 g/L), Lymph (low: <0.8x10^9 cells/L); Neut count (low: <1.5x10^9 cells/L); plat count (low: <100x10^9 cells/L and high: >550x10^9 cells/L); leuko (low: <3x10^9 cells/L and high: >20x10^9cells/L) and Eos (high: >=1x10^9 cells/L). 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 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%.

  4. Number of Participants With Worst-case Clinical Chemistry Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase [ Time Frame: Week 14 to 30 ]
    Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: Alb (low: <30 and high: >55 g/L), C) (low: 2 and high: 2.75 mmol/L), urea (high: >10.5 mmol/L); Creat (high: change from Baseline >26 µmol/L), Glu (low: <3.5 and high: >7.9 mmol/L); eGFR (low: <60 mL/min/1.73m^2]; Pot low: <3 and high: >5.5 mmol/L); Sod (low: <130 and high: >150 mmol/L); Pro (low: <50 and high: >85 g/L) and CRP (high: >30 milligrams/L). 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 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%.

  5. Number of Participants With Worst-case Liver Function Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase [ Time Frame: Week 14 to 30 ]
    Blood samples were collected for the assessment of liver function parameters. The clinical concern range for liver function parameters were: ALT (high: >=2 times ULN); AST (high: >=2 times ULN); ALP (high: >=2 times ULN) and Bil (high: >=1.5 times ULN). 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 w/in Range or No Change category".

  6. Number of Participants With Worst-case Urinalysis Results by PCI Criteria Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase [ Time Frame: Week 14 to 30 ]
    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+); ket (high: >2+); leuko (high: >1+); LE; nit (high: positive); OB (high: >1+); pH (low: <4.6 and high: >8); prot (high:>1+); erythro (high: >3 cells per hpf); sp gra (low: <1.001 and high: >1.035) and uro (high: >1 mg/deciliter).

  7. Number of Participants With Maximum QTc Values Post-Baseline Relative to Baseline-Double-Blind Extended Treatment Phase [ Time Frame: Week 14 to 30 ]
    Twelve lead ECGs were obtained using an ECG machine that automatically calculated the QTcB and QTcF intervals. The clinical concern range for the QTcB and QTcF intervals was upper: >450 milliseconds.

  8. Number of Participants With Adapted Mayo Endoscopic Score of 0 or 1 at Week 10-Double-Blind Induction Phase [ Time Frame: Week 10 ]
    The adapted Mayo clinical score consists of three components: stool frequency, rectal bleeding, and endoscopic appearance. The score for each component ranges from 0 (normal/none) to 3 (severe). The adapted Mayo endoscopic score of 0 indicates normal or inactive disease and 1 indicates mild disease (erythema, decreased vascular pattern).

  9. Number of Participants With Adapted Mayo Clinical Remission at Week 10-Double-Blind Induction Phase [ Time Frame: Week 10 ]
    The adapted Mayo clinical score is based on the complete 4-domain Mayo clinical score, but without the PGA. It consists of three components: stool frequency, rectal bleeding, and mucosal endoscopic appearance. The score for each component ranges from 0 (normal/none) to 3 (severe). The total adapted Mayo score is calculated as the sum of all three components and ranges from 0 to 9. Higher scores indicate greater disease severity. Clinical remission is defined as adapted Mayo Clinical Score of <=2 with no individual sub-score >1 and a rectal bleeding sub score of 0 with stool frequency sub score not greater than Baseline.

  10. Number of Participants With Adapted Mayo Clinical Response at Week 10-Double-Blind Induction Phase [ Time Frame: Week 10 ]
    The adapted Mayo clinical score is based on the complete 4-domain Mayo clinical score, but without the PGA. It consists of three components: stool frequency, rectal bleeding, and mucosal endoscopic appearance. The score for each component ranges from 0 (normal/none) to 3 (severe). The total adapted Mayo score is calculated as the sum of all three components and ranges from 0 to 9. Higher scores indicate greater disease severity. Clinical response is defined as reduction in adapted Mayo clinical score >=3 points from Baseline and >=30% from Baseline and decrease in the rectal bleeding sub-score of >=1 point from Baseline (or a score of 0 or 1).

  11. Number of Participants With Symptomatic Remission at Week 10-Double-Blind Induction Phase [ Time Frame: 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, PGA and endoscopic appearance (with mild friability associated with an endoscopic score of 1). Symptomatic remission is defined as a rectal bleeding subscore of 0, and a stool frequency subscore of <=1, with no worsening from Baseline.

  12. Change From Baseline in Partial Mayo Score Over Time-Double-Blind Induction Phase [ Time Frame: Baseline and Weeks 2, 4, 6, and 10 ]
    The partial Mayo clinical score is based on the complete 4-domain Mayo clinical score but without the endoscopy sub-score. It consists of three components: stool frequency, rectal bleeding, and PGA. The score for each component ranges from 0 (normal/none) to 3 (severe). The total partial Mayo score is calculated as the sum of all three components and ranges from 0 to 9. 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.

  13. Change From Baseline in Adapted Mayo Endoscopy Score at Week 10-Double-Blind Induction Phase [ Time Frame: Baseline and Week 10 ]
    The adapted Mayo clinical score is based on the complete 4-domain Mayo clinical score, but without the PGA. It consists of three components: stool frequency, rectal bleeding, and mucosal endoscopic appearance. The total adapted Mayo endoscopy score ranges from 0 (normal or inactive disease) to 3 (severe disease [spontaneous bleeding, ulceration]). 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.

  14. Change From Baseline in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) at Week 10-Double-Blind Induction Phase [ Time Frame: Baseline and Week 10 ]
    UCEIS was used as an additional tool to assess disease activity based on 3 sub-scales: endoscopic vascular pattern, bleeding, erosions and ulcerations. Individual sub-scale scores were vascular pattern (0=Normal, 1=Patchy loss, 2=Obliterated); bleeding (0=None, 1=Mucosal, 2=Luminal mild, 3=Luminal severe); erosions and ulcerations (0=None, 1=Erosions, 2=Superficial ulcer, 3=Deep ulcer). UCEIS total score was calculated as the sum of all 3 sub-scale scores and ranges from 0 to 8, with higher scores indicating more severe disease. 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.

  15. Number of Responders for Robarts Histopathology Index (RHI) Remission at Week 10-Double-Blind Induction Phase [ Time Frame: Week 10 ]
    RHI was assessed by central reading of gut pinch biopsies. The RHI Score is a continuous score, ranging from 0-33 with higher scores indicating more severe disease. RHI Remission is defined as an RHI score <=6. Responders were defined as number of participants with RHI score <=6.

  16. Number of Responders for Nancy Histological Index Remission at Week 10-Double-Blind Induction Phase [ Time Frame: Week 10 ]
    Nancy Histological Index was assessed by central reading of gut pinch biopsies. Key domains for scoring of the indices include chronic inflammatory infiltrate, neutrophils in the epithelium, lamina propria neutrophils, erosion and ulceration scored from 0 to 3 and multiplied by a weighting factor. The total Nancy Histological Index score is calculated by summing the weighted scores of the histological items, with total scores ranging from 0 (no disease activity) to 33 (severe disease activity). Nancy Index Remission was defined as a grade of 0 or 1. Responders were defined as number of participants with Nancy Index score of 0 or 1.

  17. Number of Responders for Geboes Histological Index Remission at Week 10-Double-Blind Induction Phase [ Time Frame: Week 10 ]
    The Geboes Index is divided in 6 grades: architectural changes [grade 0], chronic inflammatory infiltrate [grade 1], lamina propria neutrophils and eosinophils [grade 2], neutrophils in epithelium [grade 3], crypt destruction [grade 4] and erosions or ulcerations [grade 5]. The subscores for grade 0 to 4 ranges from 0 (none/no abnormality) to 3 (marked increase/severe abnormality) and for grade 5 ranges from 0 (No erosion, ulceration, or granulation tissue) to 4 (Ulcer or granulation tissue). The overall Geboes score is derived by summing the subscores of the grades and ranges from 0 to 22, with higher scores indicating greater disease severity. Geboes Histological Remission was defined as a Geboes score <2. Responders were defined as number of participants with Geboes score <2.

  18. Change From Baseline in Serum CRP Level Over Time-Double-Blind Induction Phase [ Time Frame: Baseline and Weeks 2, 4, 6, and 10 ]
    Serum samples were collected at indicated time points to measure CRP levels. 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.

  19. Ratio to Baseline in Fecal Calprotectin Over Time-Double-Blind Induction Phase [ Time Frame: Baseline and Weeks 2, 4, 6, and 10 ]
    Fecal samples were collected at indicated time points to measure fecal calprotectin. Baseline value was the latest pre-dose assessment with a non-missing value from Double-Blind Induction study phase. Ratio to Baseline is the value at specified time point divided by Baseline value

  20. 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 [ Time Frame: Week 14 (pre-dose, 24, 72 and 168 hours post-dose); Week 18 (pre-dose and early withdrawal post-dose) ]
    Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of GSK2831781. PK parameters were calculated using standard non-compartmental analysis.

  21. Maximum Concentration (Cmax) of GSK2831781 Observed Following 1st SC Dosing in Double-Blind Extended Treatment Phase [ Time Frame: Week 14 (pre-dose, 24, 72 and 168 hours post-dose); Week 18 (pre-dose and early withdrawal post-dose) ]
    Blood samples were collected at indicated time points for PK analysis of GSK2831781. PK parameters were calculated using standard non-compartmental analysis.

  22. Time at Which the Maximum Concentration is Observed (Tmax) for GSK2831781 Following 1st SC Dosing in Double-Blind Extended Treatment Phase [ Time Frame: Week 14 (pre-dose, 24, 72 and 168 hours post-dose); Week 18 (pre-dose and early withdrawal post-dose) ]
    Blood samples were collected at indicated time points for PK analysis of GSK2831781. PK parameters were calculated using standard non-compartmental analysis.

  23. Number of Participants With Positive Anti-drug Antibodies at Each Visit-Double-Blind Induction Phase [ Time Frame: Baseline, Weeks 2, 4, 6, and 10 ]
    Serum samples were assessed for the presence of anti-drug antibodies using a tiered approach. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for the specificity using the confirmation assay. Samples that confirmed positive in the confirmation assay were reported as 'confirmed positive'.



Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03893565


Locations
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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] November 12, 2020
Statistical Analysis Plan  [PDF] June 2, 2021

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03893565    
Other Study ID Numbers: 204869
First Posted: March 28, 2019    Key Record Dates
Results First Posted: April 27, 2022
Last Update Posted: April 27, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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.
URL: http://clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
GSK2831781
Ulcerative colitis
Anti-LAG3 cell Depleting monoclonal antibody
Dose-response
Additional relevant MeSH terms:
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Colitis
Colitis, Ulcerative
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Pathologic Processes
Inflammatory Bowel Diseases