GSK2982772 Study in Subjects With Ulcerative Colitis

NCT02903966 | Completed Phase 2 Results

• 2 other identifiers: 2021522016-001833-29
• Study Type: interventional
• Target: 36
• Locations: 7 countries
• Sites: 23

Brief Summary

This study is the first experience with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with active ulcerative colitis (UC). The primary objective will be to investigate the safety and tolerability of repeat oral doses of GSK2982772 60 mg or placebo three times daily for 42 days (Part A) followed by open label with GSK298772 60 mg three times daily for 42 days (Part B). In addition to pharmacokinetics (PK), a number of experimental and clinical endpoints will be employed to obtain information on the pharmacodynamics (PD), and preliminary efficacy in subjects with active UC. Although no formal hypothesis will be tested, these endpoints will enable a broader understanding of the mechanism of action and potential for clinical efficacy of GSK2982772 in UC. Within 30 Days of screening visit, subjects will be randomized to receive either GSK2982772 60 mg or placebo orally three times daily for 42 Days (6 weeks) in a 2:1 ratio in Part A study. Subjects who complete the Part A study will move to open label Part B study to receive GSK2982772 60 mg three times daily for an additional 42 Days (6 weeks). After the open label (Part B) treatment period, subjects will enter the Follow-up period which lasts for 28 Days (+/- 3 Days) post the last administration of study medication. The total duration of participation in the study will be approximately 20 Weeks from screening to the last study visit.

Conditions

Colitis, Ulcerative

Keywords

Tolerability; GSK2982772; Safety; Pharmacokinetics; RIP1 kinase inhibitor; Ulcerative colitis; Pharmacodynamics

Outcome Measures

Primary Outcomes (14)

• Part A: Number of Participants With Common (>=5%) Non-serious Adverse Events (Non-SAEs) and Any Serious Adverse Events (SAEs)

  An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; other important medical events; is associated with liver injury and impaired liver function.

  Up to Day 43

• Part B: Number of Participants With Common (>=5%) Non Serious AEs and SAEs

  An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; other important medical events; is associated with liver injury and impaired liver function.

  From Day 44 to Day 112

• Part A: Number of Participants With Worst Case Abnormal Clinical Chemistry Parameters by Potential Clinical Importance (PCI) Criteria

  Clinical chemistry parameters with PCI ranges: aspartate amino transferase (AST), alanine amino transferase (ALT), and alkaline phosphatase (ALP) (high: \>=2 times upper limit of normal \[ULN\] units per liter \[U/L\]); calcium (low: \<2 millimoles per liter \[mmol/L\] and high: \>2.75 mmol/L); glucose (low: \<3 and high: \>9 mmol/L); potassium (low: \<3 and high: \>5.5 mmol/L); sodium (low: \<130 and high: \>150 mmol/L); total bilirubin (high: \>=1.5 times ULN micromoles per liter \[µmol/L\]); high density lipoproteins (HDL) 0.9 to 99.99 mmol/L; low density lipoprotein (LDL) 0 to 3.35 mmol/L; triglycerides 0 to 2.24 mmol/L, creatinine (high: change from Baseline \[BL\]\>44.2 µmol/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 within Range or No Change'

  Up to Day 43

• Part B: Number of Participants With Worst Case Abnormal Clinical Chemistry Parameters by Potential Clinical Importance (PCI) Criteria

  Clinical chemistry parameters with their PCI ranges were: AST, ALT, and ALP (high: \>=2 ULN \[U/L\]); calcium (low: \<2 mmol/L and high: \>2.75 mmol/L); glucose (low: \<3 and high: \>9 mmol/L); potassium (low: \<3 and high: \>5.5 mmol/L); sodium (low: \<130 and high: \>150 mmol/L); total bilirubin (high: \>=1.5 times ULN \[µmol/L\]); HDL 0.9 to 99.99 mmol/L; LDL 0.to 3.35 mmol/L; triglycerides 0 to 2.24 mmol/L, creatinine (high: change from BL \>44.2 µmol/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 within Range or No Change' category.

  From Day 44 to Day 112

• Part A: Number of Participants With Worst Case Abnormal Hematology Parameters by PCI Criteria

  Hematology parameters with their PCI ranges were: hematocrit (high: \>0.54 proportion of red blood cells in blood and low: change from BL\<0.075); hemoglobin (high: \>180 grams per liter \[g/L\] and low: change from BL\<25 g/L); lymphocytes (low: \<0.8 Giga cells/L); platelet count (low: \<100 Giga cells/L and high: \>550 Giga cells/L); neutrophil count (low: \<1.5 Giga cells/L); white blood cell (WBC) count (low: \<3 Giga cells/L and high: \>20 Giga 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 within Range or No Change' category. Participants were counted twice if the participant had both values that changed 'To Low' and 'To High'.

  Up to Day 43

• Part B: Number of Participants With Worst Case Abnormal Hematology Parameters by PCI Criteria

  Hematology parameters with their PCI ranges were: hematocrit (high: \>0.54 proportion of red blood cells in blood and low: change from BL\<0.075); hemoglobin (high: \>180 g/L and low: change from BL\<25 g/L); lymphocytes (low: \<0.8 Giga cells/L); platelet count (low: \<100 Giga cells/L and high: \>550 Giga cells/L); neutrophil count (low: \<1.5 Giga cells/L); WBC count (low: \<3 Giga cells/L and high: \>20 Giga 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 within Range or No Change' category. Participants were counted twice if the participant had both values that changed 'To Low' and 'To High'.

  From Day 44 to Day 112

• Part A: Number of Participants With Worst Case Abnormal Urinalysis Results by Dipstick Method

  Urine samples were collected for the assessment of following urine parameters by dipstick method: glucose, protein, blood and ketones. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine glucose, protein, blood and ketones can be read as negative (-), trace, 1+, 2+, 3+, 4+, 5+ indicating proportional concentrations in the urine sample. Number of participants with abnormal results were reported as 'increase to trace' or 'increase to 1+, 2+, 3+, 4+, 5+' relative to BL (Day 1) value. Participants whose value was unchanged (e.g., Trace to Trace), or whose value was decreased, were recorded in the 'No change or Decreased' category.

  Up to Day 43

• Part B: Number of Participants With Worst Case Abnormal Urinalysis Results by Dipstick Method

  Urine samples were collected for the assessment of following urine parameters by dipstick method: glucose, protein, blood and ketones. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters of urine glucose, protein, blood and ketones can be read as negative (-), trace, 1+, 2+, 3+, 4+, 5+ indicating proportional concentrations in the urine sample. Number of participants with abnormal results were reported as 'increase to trace' or 'increase to 1+, 2+, 3+, 4+, 5+' relative to BL (Day 1) value. Participants whose value was unchanged (e.g., Trace to Trace), or whose value was decreased, were recorded in the 'No change or Decreased' category.

  From Day 44 to Day 112

• Part A: Number of Participants With Worst Case Abnormal Blood Pressure Results by PCI Criteria

  Vital signs were measured in a semi-supine position after 5 minutes rest and included body temperature, systolic and diastolic blood pressure. The clinical concern range for vital signs were: systolic blood pressure (SBP) (low: \<85 and high: \>160 millimeters of mercury \[mmHg\]); diastolic blood pressure (DBP) (low: \<45 and high: \>100 mmHg). 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 Range or No Change' category.

  Up to Day 43

• Part B: Number of Participants With Worst Case Abnormal Blood Pressure Results by PCI Criteria

  Vital signs were measured in a semi-supine position after 5 minutes rest and included body temperature, systolic and diastolic blood pressure. The clinical concern range for vital signs were: SBP (low: \<85 and high: \>160 mmHg); DBP (low: \<45 and high: \>100 mmHg). 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 Range or No Change' category.

  From Day 44 to Day 112

• Part A: Number of Participants With Worst Case Abnormal Heart Rate (HR) Results by PCI Criteria

  Vital signs were measured in a semi-supine position after 5 minutes rest which included HR. The clinical concern range for HR (low \<40 beats per min \[bpm\] and high \>100 bpm). 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 Range or No Change' category.

  Up to Day 43

• Part B: Number of Participants With Worst Case Abnormal HR Results by PCI Criteria

  Vital signs were measured in a semi-supine position after 5 minutes rest which included HR. The clinical concern range for HR (low \<40 bpm and high \>100 bpm). 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 Range or No Change' category.

  From Day 44 to Day 112

• Part A: Number of Participants With Worst-case Abnormal Electrocardiogram (ECG) Findings

  12-lead ECGs were recorded with the participants in a supine position using an ECG machine. Number of participants with worst-case clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  Up to Day 43

• Part B: Number of Participants With Worst-case Abnormal ECG Findings

  12-lead ECGs were recorded with the participants in a supine position using an ECG machine. Number of participants with worst-case clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.

  From Day 44 to Day 112

Secondary Outcomes (21)

• Part A: Percentage of Participants Who Achieved an Absolute Mayo Endoscopy Subscore of 0 or 1 at Day 43

  Day 43

• Part B: Percentage of Participants Who Achieved an Absolute Mayo Endoscopy Subscore of 0 or 1 at Day 85

  Day 85

• Part A: Change From Baseline in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Total Score

  Baseline (screening - within 30 days prior to Day 1) and Day 43

• Part B: Change From Baseline in Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Total Score

  Baseline (screening - within 30 days prior to Day 1) and Day 85

• Part A: Change From Baseline in Mean C Reactive Protein (CRP)

  Baseline (Day 1, pre-dose) and Days 15, 29, 43

Study Arms (3)

GSK2982772 in Part A double-blind phase

EXPERIMENTAL

Subjects will receive GSK2982772 60 mg orally three times daily (approximately 8 hours apart) for 42 days (6 weeks).

Drug: GSK2982772

Placebo in Part A double-blind phase

PLACEBO COMPARATOR

Subjects will receive placebo orally three times daily (approximately 8 hours apart) for 42 days (6 weeks).

Drug: Placebo

GSK2982772 in Part B open label extension phase

EXPERIMENTAL

Subjects from GSK2982772 and placebo arm who complete Part A study will move to Part B open-label extension phase. All subjects will receive GSK2982772 60 mg three times daily (approximately 8 hours apart) for 42 days (6 weeks).

Drug: GSK2982772

Interventions

GSK2982772 DRUG

GSK2982772 is available as a 30 mg white to almost white, round film coated tablet which will be administered as two tablets three times a day as directed.

GSK2982772 in Part A double-blind phase; GSK2982772 in Part B open label extension phase

Placebo DRUG

Placebo is available as a white to almost white, round film coated tablet which will be administered as two tablets three times a day as directed.

Placebo in Part A double-blind phase

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Between 18 and 75 years of age inclusive, at the time of signing the informed consent.
• Subjects that do not have any medical conditions, other than active UC, that in the opinion of the Investigator put the subject at unacceptable risk or interfere with study assessments or integrity of the data. These medical conditions should be stable at the time of screening and are expected to remain stable for the duration of the study.
• Subject has had a confirmed diagnosis of active UC, as documented by complete diagnostic colonoscopy to the terminal ileum (TI) with biopsy performed \>=3 months prior to screening. If diagnostic colonoscopy was not performed to the TI, it must be documented by the principal investigator that the subject has diffuse inflammation from the rectum extending proximally to the colon in a continuous and uniform way.
• A Complete Mayo Score of \>=3 points and endoscopy sub score of 2 to 3 at screening, despite concurrent treatment with at least 1 of the following (oral corticosteroids or any oral 5-aminosalicylates (5-ASA) or purine analogues or all as defined): Oral 5-ASA at a stable dose (equivalent to \>=2.4 grams per day (g/day) of Asacol) for at least 4 weeks prior to first dose. Must remain on a stable dose until end of treatment; Purine analogues (azathioprine, mercaptopurine, thiopurines) or methotrexate for at least 12 weeks prior to first dose. Must remain on a stable dose until end of treatment; Stable low dose oral corticosteroid (up to 20 mg prednisolone or equivalent) for 2 weeks prior to sigmoidoscopy. Must remain on a stable dose until end of treatment.
• If on rectal 5-ASA or corticosteroids, must remain on a stable dose for at least 4 weeks prior to first dose. Must remain on stable dose until the end of treatment.
• A body mass index (BMI) within range of 18.5 to 35 kilogram per meter square (kg/m\^2) (inclusive) at screening.
• Male and Female subjects:
• Males: Male subjects with female partners of child bearing potential must comply with the contraception requirements.
• Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:
• Non-reproductive potential defined as 1) Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. 2) Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
• Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until at least 2 days after the last dose of study medication and completion of the follow-up visit. The Investigator is responsible for ensuring that subjects understand how to properly use methods of contraception.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and protocol.

You may not qualify if:

• Subject with diagnosis of indeterminate colitis, Crohn's Disease, infectious colitis, or ischemic colitis.
• Subject with fulminant UC, or UC limited to the rectum (disease extent \<15 centimeters (cm) from the anal verge).
• Subject with previous small bowel or colonic surgery(with exception of appendectomy), histological evidence of colonic dysplasia or bowel stricture.
• Subject with colostomy, fistulae or known symptomatic stenosis of the intestine.
• Subject with toxic megacolon.
• Subject with positive Clostridium difficile toxin test or active/previous colonic cytomegalo virus (CMV) infection.
• Subject with current history of suicidal ideation behavior (SIB) as measures using the Columbia Suicide Severity Rating Scale (C-SSRS) or history of attempted suicide.
• An active infection, or a history of infections as follows:
• Hospitalization for treatment of infection within 60 days before first dose (Day 1).
• Currently on any suppressive therapy for a chronic infection (such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).
• Use of parenteral (intravenous (IV) or intramuscular) antibiotics (antibacterials, antivirals, antifungals, or antiparasitic agents) for an infection within 60 days before first dose.
• A history of opportunistic infections within 1 year of screening (example: pneumocystis jirovecii, CMV pnemonitis, aspergillosis). This does not include infections that may occur in immunocompetent individuals, such as fungal nail infections or vaginal candidiasis, unless it is of an unusual severity or recurrent nature.
• Recurrent or chronic infection or other active infection that, in the opinion of the Investigator might cause this study to be detrimental to the patient.
• History of tuberculosis (TB), irrespective of treatment status. A positive diagnostic TB test at screening defined as a positive QuantiFERON-TB Gold test or T-spot test. In cases where the QuantiFERON or T-spot test is indeterminate, the subject may have the test repeated once, but they will not be eligible for the study unless the second test is negative. In cases where the QuantiFERON or T-spot test is positive, but a follow-up chest x-ray, locally read by a radiologist, shows no evidence of current or previous pulmonary tuberculosis, the subject may be eligible for the study at the discretion of the Investigator and GlaxoSmithKline (GSK) Medical Monitor.
• QTc \>450 millisecond (msec) or QTc \>480 msec for subjects with bundle branch block at screening.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (23)

GSK Investigational Site

Moreno Valley, California, 92555, United States

Location

GSK Investigational Site

San Diego, California, 92115, United States

Location

GSK Investigational Site

Marrero, Louisiana, 70072, United States

Location

GSK Investigational Site

Chesterfield, Michigan, 48047, United States

Location

GSK Investigational Site

Great Neck, New York, 11021, United States

Location

GSK Investigational Site

Cedar Park, Texas, 78613, United States

Location

GSK Investigational Site

Ulm, Baden-Wurttemberg, 89081, Germany

Location

GSK Investigational Site

Amsterdam, 1105 AZ, Netherlands

Location

GSK Investigational Site

Katowice, 40-660, Poland

Location

GSK Investigational Site

Ksawerów, 95-054, Poland

Location

GSK Investigational Site

Wroclaw, Poland

Location

GSK Investigational Site

Kaliningrad, 236022, Russia

Location

GSK Investigational Site

Moscow, 123098, Russia

Location

GSK Investigational Site

Rostov-on-Don, 344091, Russia

Location

GSK Investigational Site

Saint Pertersburg, 196247, Russia

Location

GSK Investigational Site

Stavropol, 355018, Russia

Location

GSK Investigational Site

Ufa, 450071, Russia

Location

GSK Investigational Site

Stockholm, SE-171 76, Sweden

Location

GSK Investigational Site

Stockholm, SE-182 88, Sweden

Location

GSK Investigational Site

Uppsala, SE-752 37, Sweden

Location

GSK Investigational Site

Stockport, Cheshire, SK2 7JE, United Kingdom

Location

GSK Investigational Site

Belfast, BT16 1RH, United Kingdom

Location

GSK Investigational Site

Dudley, DY1 2HQ, United Kingdom

Location

Related Publications (1)

• Weisel K, Scott N, Berger S, Wang S, Brown K, Powell M, Broer M, Watts C, Tompson DJ, Burriss SW, Hawkins S, Abbott-Banner K, Tak PP. A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis. BMJ Open Gastroenterol. 2021 Aug;8(1):e000680. doi: 10.1136/bmjgast-2021-000680.

  PMID: 34389633 DERIVED

MeSH Terms

Conditions

Colitis, Ulcerative

Interventions

GSK2982772

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
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2016
• First Posted: September 16, 2016
• Study Start: November 15, 2016
• Primary Completion: June 17, 2019
• Study Completion: June 17, 2019
• Last Updated: June 11, 2020
• Results First Posted: June 11, 2020

Record last verified: 2020-04

Locations

SE (3); GB (3); PL (3); RU (6); DE (1); NL (1); US (6)