A Study to Compare the Pharmacokinetics (PK) of GSK2982772 Following Administration of Different Modified Release (MR) Formulations in Capsule and MR Tablet Formulations Relative to an Immediate Release (IR) Tablet Formulation and to Check the PK of MR Formulation in Capsule Following Repeat Doses

NCT03266172 | Completed Phase 1 Results

• 1 other identifier: 205017
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

GSK2982772 is a first-in-class, highly selective, receptor-interacting protein-1 (RIP1) kinase inhibitor being developed for the treatment of inflammatory bowel disease, plaque psoriasis (PsO), rheumatoid arthritis (RA) and other disease conditions. PK data from the first time in human (FTIH) study for GSK2982772 showed that the half life of GSK2982772 was short (approximately 2 to 3 hours). A once daily (QD) formulation would be more convenient from a subject perspective and could offer the advantage of providing a flatter GSK2982772 concentration time profile. Following completion of Parts A and B, it was determined that the slowest minitab formulation provided a PK profile suitable for QD dosing but this formulation was susceptible to a food effect. This study will evaluate the pharmacokinetics of GSK2982772 following administration of different minitab MR formulations in a capsule relative to an IR reference tablet formulation, the pharmacokinetics of selected MR formulation in capsule following repeat doses for 3 days and to compare the pharmacokinetics of GSK2982772 following administration of MR tablet formulations in the fed and fasted state relative to an IR tablet formulation. The study is divided into three parts: Part A will be a non-randomized 6 periods, sequential, 6-way fixed sequence design in which up to 4 MR minitab formulations in a capsule will be evaluated. Periods 1, 2, and 3 will evaluate a slow MR release duration (nominally 24 hours), a fast MR release duration (nominally 10 hours), and IR tablet respectively. Periods 4, 5 and 6 will have flexible dose regimen and it will depend on the outcomes of Period 1 to 3. Subjects will be admitted to the clinic the previous day before dosing. Each in-patient period will consist of 3 days and 2 nights followed by a minimum washout period of 7 days between doses, for both Part A and C. In Part A and C, 16 healthy subjects will be enrolled such that at least 12 evaluable subjects complete the study. Part B will be an open-label, repeat dose study in which the selected MR minitab formulation in capsule will be evaluated. Each in-patient period will consist of 5 days and 4 nights. There will be a minimum of 7 days washout period between the last morning dose of one period and the first dose of the next period. In Part B, 10 healthy subjects will be enrolled such that at least 6 evaluable subjects complete the study. Part C of the study will be a non-randomised 6 period, sequential, fixed sequence crossover design in which MR tablet formulations will be evaluated. Periods 1 and 2 will evaluate single dose administration of a 240 milligram (mg) MR tablet and the 240 mg IR tablet (reference), respectively. Periods 3, 4, 5 and 6 will be flexible and the dosing regimen will be dependent on the outcome of Periods 1 and 2.

Conditions

Autoimmune Diseases

Keywords

immediate release tablet; GSK2982772; Modified release; minitablet

Outcome Measures

Primary Outcomes (39)

• Area Under the Curve From Time Zero to Infinity (AUC[0-inf]) of GSK2982772 in IR Formulation: Part A

  Blood samples were collected from participants at indicated time points and analyzed for AUC (0-inf). Participants in the 'Safety Population' for whom a Pharmacokinetic (PK) sample was obtained and analyzed were part of PK Population.

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose

• AUC(0-inf) of GSK2982772 in MT Formulation :Part A

  Blood samples were collected from participants at indicated time points and analyzed for AUC (0-inf).

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC[0-t]) of GSK2982772 in IR Formulation : Part A

  Blood samples were collected from participants at indicated time points and analyzed for AUC (0-t)

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose

• AUC(0-t) of GSK2982772 in MT Formulation: Part A

  Blood samples were collected from participants at indicated time points and analyzed for AUC (0-t)

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• Area Under the Curve From Time Zero to 24 Hours (AUC[0-24]) of GSK2982772 in IR Formulation: Part A

  Blood samples were collected from participants at indicated time points and analyzed for AUC (0-24)

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose

• AUC(0-24) of GSK2982772 in MT Formulation: Part A

  Blood samples were collected from participants at indicated time points and analyzed for AUC (0-24)

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• Area Under the Curve From Time Zero to 12 Hours (AUC[0-12]) of GSK2982772 in IR Formulation: Part A

  Blood samples were collected from participants at indicated time points and analyzed for AUC (0-12)

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours post-dose

• AUC(0-12) of GSK2982772 in MT Formulation: Part A

  Blood samples were collected from participants at indicated time points and analyzed for AUC (0-12)

  Pre-dose, 2, 4, 6, 8, 10, and 12 hours post-dose

• Maximum Observed Concentration (Cmax) of GSK2982772 in IR Formulation: Part A

  Blood samples were collected from participants at indicated time points and analyzed for Cmax

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose

• Cmax of GSK2982772 in MT Formulation: Part A

  Blood samples were collected from participants at indicated time points and analyzed for Cmax

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• Concentration at 12 Hours Post-dose (C12hour) of GSK2982772 in Part A

  Blood samples were collected from participants at indicated time points and analyzed for C12hour.

  12 hours post-dose

• Concentration at 24 Hours Post-dose (C24hour) of GSK2982772 in Part A

  Blood samples were collected from participants at indicated time points and analyzed for C24hour.

  24 hours post-dose

• Relative Bioavailability (Frelformulation) Based on AUC (0-inf) of GSK2982772 in Part A

  Blood samples were collected at indicated time points for analysis of Frelformulation. Frelformulation for AUC (0-inf) was calculated as Geometric mean of AUC (0-inf) of MT (test) / Geometric mean of AUC (0-inf) of IR Formulation (reference) multiplied by 100.

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose (reference); Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose (test)

• Frelformulation Based on AUC (0-24) of GSK2982772 in Part A

  Blood samples were collected at indicated time points for analysis of Frelformulation. Frelformulation for AUC (0-24) was calculated as Geometric mean of AUC (0-24) of MT (test) / Geometric mean of AUC (0-24) of IR Formulation (reference) multiplied by 100.

  Pre-dose 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose (reference); Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose (test)

• Frelformulation Based on Cmax of GSK2982772 in Part A

  Blood samples were collected at indicated time points for analysis of Frelformulation. Frel was calculated as Geometric mean of Cmax of MT Formulation (test)/ Geometric mean of Cmax of IR Formulation (reference) multiplied by 100.

  Pre-dose,0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose(reference); Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose(test)

• Ratio of Cmax to C12hour of GSK2982772 in IR Formulation: Part A

  Blood samples were collected at indicated time points for analysis of ratio of Cmax to C12hour. Mean and standard deviation of ratio of Cmax to C12 hour has been presented.

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 26, 28, 30 and 32 hours post-dose

• Ratio of Cmax to C12hour of GSK2982772 in MT Formulation: Part A

  Blood samples were collected at indicated time points for analysis of ratio of Cmax to C12hour. Mean and standard deviation of ratio of Cmax to C12 hour has been presented.

  Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• Ratio of Cmax to C24hour of GSK2982772 in IR Formulation: Part A

  Blood samples were collected at indicated time points for analysis of ratio of Cmax to C24hour. Mean and standard deviation of ratio of Cmax to C24 hour has been presented.

  Pre-dose 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose

• Ratio of Cmax to C24hour of GSK2982772 in MT Formulation: Part A

  Blood samples were collected at indicated time points for analysis of ratio of Cmax to C24hour. Mean and standard deviation of ratio of Cmax to C24 hour has been presented.

  Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• Time to Cmax (Tmax) of GSK2982772 in IR Formulation: Part A

  Blood samples were collected at indicated time points for analysis of Tmax.

  Pre-dose 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours post-dose

• Tmax of GSK2982772 in MT Formulation: Part A

  Blood samples were collected at indicated time points for analysis of Tmax.

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• AUC(0-inf) of GSK2982772 for IR Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of AUC (0-inf)

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

• AUC(0-inf) of GSK2982772 for MM Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of AUC (0-inf).

  Pre-dose, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose

• AUC(0-t) of GSK2982772 for IR Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of AUC (0-t).

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

• AUC(0-t) of GSK2982772 for MM Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of AUC (0-t).

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose

• AUC(0-24) of GSK2982772 for IR Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of AUC (0-24)

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

• AUC(0-24) of GSK2982772 for MM Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of AUC (0-24)

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours post-dose

• AUC (0-12) of GSK2982772 for IR Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of AUC (0-12)

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours post-dose

• AUC (0-12) of GSK2982772 for MM Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of AUC (0-12)

  Pre-dose, 2, 4, 6, 8, 10, and 12 hours post-dose

• Cmax of GSK2982772 for IR Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of Cmax

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

• Cmax of GSK2982772 for MM Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of Cmax

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose

• C12 of GSK2982772 in Part C: Fasted State

  Blood samples was collected at indicated time point for analysis of C12

  12 hours post-dose

• C24 of GSK2982772 in Part C: Fasted State

  Blood samples was collected at indicated time point for analysis of C24

  24 hours post-dose

• Ratio of Cmax to C12hour of GSK2982772 for IR Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of ratio of Cmax to C12hour. Mean and standard deviation of ratio of Cmax to C12 hours has been presented.

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

• Ratio of Cmax to C12hour of GSK2982772 for MM Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of ratio of Cmax to C12hour. Mean and standard deviation of ratio of Cmax to C12 hours has been presented.

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose

• Ratio of Cmax to C24hour of GSK2982772 for IR Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of ratio of Cmax to C24hour. Mean and standard deviation of ratio of Cmax to C24 hours has been presented.

  Pre-dose,0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

• Ratio of Cmax to C24hour of GSK2982772 for MM Formulation in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of ratio of Cmax to C24hour. Mean and standard deviation of ratio of Cmax to C24 hours has been presented.

  Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose

• Frelformulation Based on AUC (0-t) of GSK2982772 in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of Frelformulation. Frel for AUC (0-t) was calculated as Geometric mean of AUC (0-t) of MM formulation (test) / Geometric mean of AUC (0-t) of IR Formulation (reference) multiplied by 100.

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose(reference); Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 and 32 hours post-dose(test)

• Frelformulation Based on AUC (0-24) of GSK2982772 in Part C: Fasted State

  Blood samples were collected at indicated time points for analysis of Frelformulation. Frel for AUC (0-24) was calculated as Geometric mean of AUC (0-24) of MM Fasted formulation (test) / Geometric mean of AUC (0-24) of IR Formulation (reference) multiplied by 100.

  Pre-dose, 0.33, 0.66, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose(reference); Pre-dose, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours post-dose(test)

Secondary Outcomes (41)

• Frelformulation Based on AUC (0-inf) of GSK2982772 After a High Fat Meal in Part A

  Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• Frelformulation Based on Cmax of GSK2982772 After a High Fat Meal in Part A

  Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30 and 32 hours post-dose

• AUC(0-24) of GSK2982772 in Part B

  Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 1 and Day 3

• Cmax of GSK2982772 in Part B

  Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 1 and Day 3

• Tmax of GSK2982772 in Part B

  Pre-dose 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 hours on Day 1 and Day 3

Study Arms (3)

Subjects in Part A

EXPERIMENTAL

Subjects in Part A will receive GSK2982772 MR (Period 1, 2, 4, 5 and 6) and GSK2982772 IR (Period 3)

Drug: GSK2982772 Modified Release; Drug: GSK2982772 Immediate Release

Subjects in Part B

EXPERIMENTAL

Subjects in Part B will receive GSK2982772 MR

Drug: GSK2982772 Modified Release

Subjects in Part C

EXPERIMENTAL

Subjects in Part C will receive GSK2982772 MR (Period 1, 3, 4, 5 and 6) and GSK2982772 IR (Period 2)

Drug: GSK2982772 Modified Release; Drug: GSK2982772 Immediate Release

Interventions

GSK2982772 Modified Release DRUG

GSK2982772 MR will be available as prototype MR minitablet in capsules with unit dose strength of 60 mg in Part A. In Part B, GSK2982772 MR minitablet in capsules with unit dose strength of 15, 30 or 60 mg will be administered by subjects for Days 1 to 3. In Part C, GSK2982772 MR tablet with unit dose strength of 240, 360 or 480 mg will be administered by subjects. GSK2982772 MR will be administered orally with 240 mL of water.

Subjects in Part A; Subjects in Part B; Subjects in Part C

GSK2982772 Immediate Release DRUG

In part A, GSK2982772 IR tablet will be available with unit dose strength of 30 mg and the total dose administered by subjects will be 120 mg (4 tablets of dose strength 30 mg) orally with 240 mL of water. In part C, GSK2982772 IR tablet will be available with unit dose strength of 30 mg and the total dose administered by subjects will be 240 mg (8 tablets of dose strength 30 mg) orally with 240 mL of water.

Subjects in Part A; Subjects in Part C

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
• Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
• Body weight greater than and equal to 50 kilogram (kg) and body mass index within the range 19.0 to 32.0 kilogram per meter square (kg/m\^2) (inclusive).
• A male subject must agree to use a highly effective contraception during the treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period.
• A female subject is eligible to participate if she is not pregnant, not breastfeeding, not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive during the treatment period and for at least 30 days before and 30 days after the last dose of study treatment.
• Capable of giving signed informed consent.

You may not qualify if:

• History of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal (GI), endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
• Parts A and C only: Any history of suicidal behavior within the past 6 months or any history of attempted suicide in a subject's lifetime.
• Part B only: Subjects with current history of suicidal ideation behavior as measured using the columbia-suicide severity rating scale (C-SSRS) or a history of attempted suicide.
• History of clinically significant psychiatric disorders as judged by the investigator. Depression requiring treatment in the last 2 years.
• History of herpes zoster (shingles) reactivation.
• History or diagnosis of obstructive sleep apnea.
• History of a significant respiratory disorder. Childhood asthma that has fully resolved is permitted.
• History or current evidence of febrile seizures, epilepsy, convulsions, significant head injury, or other significant neurologic conditions.
• A positive diagnostic tuberculosis (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.
• History of GI surgery (with exception of appendectomy).
• History of cholecystectomy or gall stones.
• Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active.
• ALT greater than 1.5 times upper limit of normal (ULN).
• Bilirubin greater than 1.5 times ULN (isolated bilirubin greater than 1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35 percentage of total).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Quotient Clinical: collaborator

Study Sites (1)

GSK Investigational Site

Nottingham, NG11 6JS, United Kingdom

Location

Related Publications (1)

• Tompson DJ, Whitaker M, Pan R, Johnson G, Fuller T, McKenzie L, Zann V, Powell M, Abbott-Banner K, Hawkins S. Development of a Prototype, Once-Daily, Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772. Pharm Res. 2021 Jul;38(7):1235-1245. doi: 10.1007/s11095-021-03059-z. Epub 2021 Jun 16.

  PMID: 34136987 BACKGROUND

MeSH Terms

Conditions

Autoimmune Diseases

Interventions

GSK2982772

Condition Hierarchy (Ancestors)

Immune System Diseases

Results Point of Contact

• Title: GSK Reponse 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 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part A of the study will be a non-randomized 6 period, sequential, 6-way fixed sequence design. Part B of the study will be a repeat dose study. Part C of the study will be a non-randomized 6 period, sequential, fixed sequence crossover design.

Study Record Dates

• First Submitted: August 25, 2017
• First Posted: August 30, 2017
• Study Start: September 27, 2017
• Primary Completion: November 21, 2018
• Study Completion: November 21, 2018
• Last Updated: August 13, 2021
• Results First Posted: January 9, 2020

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
• 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

GB (1)