Phase 1
N=16
A Study to Investigate the Pharmacokinetics (PK) of Modified Release (MR) Prototype Coated Tablet Formulations of GSK2982772
Autoimmune Diseases
Bottom Line
View on ClinicalTrials.gov: NCT03649412 ↗Enrolled (actual)
16
Serious AEs
0.0%
Results posted
May 2020
Primary outcome: Primary: Part A: Area Under the Curve From Time Zero to Infinity (AUC[0-inf]) of GSK2982772 240 mg in IR Formulation — 14.355 Hours*microgram per milliliter
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- GSK2982772 Modified Release (Drug); GSK2982772 Immediate Release (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- GlaxoSmithKline
- Primary completion
- May 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part A: Area Under the Curve From Time Zero to Infinity (AUC[0-inf]) of GSK2982772 240 mg in IR Formulation |
14.355 | — |
| PRIMARY Part A: AUC(0-inf) of GSK2982772 240 mg in MR Coated Tablet Formulation |
7.757; 8.346; 7.080 | — |
| PRIMARY Part A: AUC(0-inf) of GSK2982772 240 mg in MR Coated Tablet Formulation After High-fat Breakfast |
9.372; 8.220 | — |
| PRIMARY Part A: Area Under the Curve From Time Zero to the Last Measurable Concentration (AUC[0-t]) of GSK2982772 240 mg for IR Formulation |
14.269 | — |
| PRIMARY Part A: AUC(0-t) of GSK2982772 240 mg for MR Coated Tablet Formulation |
8.175; 7.828; 7.365 | — |
| PRIMARY Part A: AUC(0-t) of GSK2982772 240 mg for MR Coated Tablet Formulation After High-fat Breakfast |
9.359; 8.384 | — |
| PRIMARY Part A: Area Under the Curve From Time Zero to 24 Hours (AUC[0-24]) of GSK2982772 240 mg for IR Formulation |
14.268 | — |
| PRIMARY Part A: AUC(0-24) of GSK2982772 240 mg for MR Coated Tablet Formulation |
6.670; 5.784; 5.466 | — |
| PRIMARY Part A: AUC(0-24) of GSK2982772 240 mg for MR Coated Tablet Formulation After High-fat Breakfast |
7.136; 5.821 | — |
| PRIMARY Part A: Maximum Observed Concentration (Cmax) of GSK2982772 240 mg for IR Formulation |
3.177 | — |
| PRIMARY Part A: Cmax of GSK2982772 240 mg for MR Coated Tablet Formulation |
0.682; 0.527; 0.466 | — |
| PRIMARY Part A: Cmax of GSK2982772 240 mg for MR Coated Tablet Formulation After High-fat Breakfast |
0.824; 0.678 | — |
| PRIMARY Part A: Concentration at 24 Hours Post-dose (C24h) of GSK2982772 240 mg for IR Formulation |
0.015 | — |
| PRIMARY Part A: C24h of GSK2982772 240 mg for MR Coated Tablet Formulation |
0.196; 0.211; 0.165 | — |
| PRIMARY Part A: C24h of GSK2982772 240 mg for MR Coated Tablet Formulation After High-fat Breakfast |
0.213; 0.265 | — |
| PRIMARY Part A: Time to Cmax (Tmax) of GSK2982772 240 mg for IR Formulation |
2.000 | — |
| PRIMARY Part A: Tmax of GSK2982772 240 mg for MR Coated Tablet Formulation |
5.000; 10.000; 6.000 | — |
| PRIMARY Part A: Tmax of GSK2982772 240 mg for MR Coated Tablet Formulation After High-fat Breakfast |
8.000; 11.000 | — |
| PRIMARY Part A: Terminal Half-life (t1/2) of GSK2982772 240 mg for IR Formulation |
3.288 | — |
| PRIMARY Part A: t1/2 of GSK2982772 240 mg for MR Coated Tablet Formulation |
6.329; 6.953; 7.532 | — |
| PRIMARY Part A: t1/2 of GSK2982772 240 mg for MR Coated Tablet Formulation After High-fat Breakfast |
7.763; 6.589 | — |
| PRIMARY Part B: AUC(0-inf) of GSK2982772 for MR Coated Tablet Formulation After a High Fat Breakfast |
20.121; 20.178 | — |
| PRIMARY Part B: AUC(0-t) of GSK2982772 for MR Coated Tablet Formulation After a High Fat Breakfast |
19.865; 17.861 | — |
| PRIMARY Part B: Cmax of GSK2982772 for MR Coated Tablet Formulation After a High Fat Breakfast |
1.896; 1.791 | — |
| PRIMARY Part B: C24h of GSK2982772 for MR Coated Tablet Formulation After a High Fat Breakfast |
0.622; 1.176 | — |
| PRIMARY Part B: Tmax of GSK2982772 for MR Coated Tablet Formulation After a High Fat Breakfast |
12.000; 22.008 | — |
| PRIMARY Part B: t1/2 of GSK2982772 for MR Coated Tablet Formulation After a High Fat Breakfast |
4.961; 4.873 | — |
| PRIMARY Part A: Relative Bioavailability in Fed Versus Fasted Conditions (FrelFE) Based on AUC(0-inf) of GSK2982772 for MR Coated Tablet Formulation |
102.66; 113.66 | — |
| PRIMARY Part A: FrelFE Based on AUC(0-t) of GSK2982772 for MR Coated Tablet Formulation |
107.11; 107.81 | — |
| PRIMARY Part A: FrelFE Based on Cmax of GSK2982772 for MR Coated Tablet Formulation |
128.79; 112.15 | — |
| PRIMARY Part B: FrelFE of GSK2982772 Based on AUC(0-inf) for MR Coated Tablet Formulation in Fed vs Fasted State |
141.75; 97.13 | — |
| PRIMARY Part B: FrelFE of GSK2982772 Based on AUC (0-t) for MR Coated Tablet Formulation in Fed vs Fasted State |
129.63; 89.77 | — |
| PRIMARY Part B: FrelFE of GSK2982772 Based on Cmax for MR Coated Tablet Formulation in Fed vs Fasted State |
173.19; 102.39 | — |
| PRIMARY Part B: Frel of GSK2982772 Based on AUC (0-inf) for MR Coated Tablet Formulation in Fasted State |
214.21; 530.86; 247.82 | — |
| PRIMARY Part B: Frel of GSK2982772 Based on AUC (0-t) for MR Coated Tablet Formulation in Fasted State |
192.81; 539.66; 279.90 | — |
| PRIMARY Part B: Frel of GSK2982772 Based on AUC (0-24) for MR Coated Tablet Formulation in Fasted State |
175.58; 392.65; 223.63 | — |
| PRIMARY Part B: Frel of GSK2982772 Based on Cmax for MR Coated Tablet Formulation in Fasted State |
160.00; 338.70; 211.68 | — |
| PRIMARY Part A: Relative Bioavailability (Frelformulation) Based on AUC (0-inf) of GSK2982772 240 mg |
54.68; 48.32; 57.69 | — |
| PRIMARY Part A: Frelformulation Based on AUC (0-t) of GSK2982772 for MR Coated Tablet Formulation (240 mg) |
57.72; 49.61; 54.86 | — |
| PRIMARY Part A: Frelformulation Based on AUC(0-24) of GSK2982772 for MR Coated Tablet Formulation (240 mg) |
47.77; 36.85; 40.54 | — |
| PRIMARY Part A: Frelformulation Based on Cmax of GSK2982772 for MR Coated Tablet Formulation (240 mg) |
22.29; 14.16; 16.58 | — |
| SECONDARY Part A: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) |
2; 5; 3; 3; 3; 4 | — |
| SECONDARY Part A: Number of Participants With Emergent Clinical Chemistry Results by Potential Clinical Importance (PCI) Criteria |
16; 16; 16; 12; 16; 12 | — |
| SECONDARY Part A: Number of Participants With Emergent Hematology Results by Potential Clinical Importance Criteria |
16; 16; 16; 12; 16; 12 | — |
| SECONDARY Part A: Number of Participants With Abnormal Urinalysis Dipstick Results |
0; 2; 0; 1; 0; 0 | — |
| SECONDARY Part A: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) in IR Formulation |
-3.9; -3.3; -6.6; -1.1; -5.1; -1.4 | — |
| SECONDARY Part A: Change From Baseline in SBP and DBP in MR Formulation |
-2.7; -7.9; -7.3; -4.6; -3.4; -3.0 | — |
| SECONDARY Part A: Change From Baseline in Heart Rate in IR Formulation |
-2.6; 6.3; -2.1 | — |
| SECONDARY Part A: Change From Baseline in Heart Rate in MR Formulation |
-1.3; -6.1; 5.8; 3.1; -1.3; 5.4 | — |
| SECONDARY Part A: Change From Baseline in Respiration Rate in IR Formulation |
-0.4; -0.2; -0.8 | — |
| SECONDARY Part A: Change From Baseline in Respiration Rate in MR Formulation |
0.9; 2.5; 2.8; 2.0; 0.0; 1.1 | — |
| SECONDARY Part A: Change From Baseline in Body Temperature in IR Formulation |
0.04; 0.13; 0.10 | — |
| SECONDARY Part A: Change From Baseline in Body Temperature in MR Formulation |
-0.04; 0.14; -0.03; -0.06; -0.04; 0.12 | — |
| SECONDARY Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings in IR Formulation |
8; 0 | — |
| SECONDARY Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings in MR Formulation |
8; 10; 5; 9; 7; 0 | — |
Summary
Previous clinical studies of immediate release (IR) formulations of GSK2982772 resulted in a high peak to trough ratio of GSK2982772. Additionally, the short half-life for GSK2982772 (approximately 2 to 3 hours) necessitates twice a daily (BID) or thrice daily (TID) dosing of an IR formulation. As a result, MR formulations using a polymer matrix approach with minitablets in capsule and MR tablet formulations were investigated. The emerging PK data of the MR formulations investigated to date have demonstrated that a once daily (QD) PK profile can be achieved in the fasted state but the polymer matrix formulation is susceptible to food effects when administered with a high fat breakfast. The purpose of this study is to evaluate MR prototype coated tablet formulations. This study will evaluate the PK of MR prototype coated tablet formulations of GSK2982772. The study is divided into two parts; Part A and Part B. The MR tablet coating used in Part A and the initial periods of Part B will have an aperture drilled into the enteric coating of either side of the tablet. This allows some drug release to commence in the stomach whilst providing controlled release throughout the gastrointestinal (GI) tract. In Part B only, a new investigational medicinal product (IMP) will be manufactured to allow comparison of the tablet coating either with apertures (i.e., drilled) or without apertures (i.e., full coat/non drilled). Part A will be a 6-period, 6-way fixed sequence design, up to 4 MR tablet prototype coated formulations will be evaluated in fasted state at 240 milligrams (mg). Periods 1, 2 and 3 will evaluate MR1, IR tablet and MR2 respectively. Periods 4, 5 and 6 will be flexible and the dosing regimen will be dependent on the outcome of Periods 1 to 3. In addition, the impact of food (high fat meal, standard breakfast or administration 30 or 60 minutes before a standard breakfast) on selected MR prototype coated tablet formulations may also be evaluated in Period 4, 5 or 6 of Part A. Each inpatient period for MR regimens (Periods 1, 3, 4 to 6) will consist of 4 days and 3 nights, and the inpatient period for the IR tablet (Period 2) will consist of 3 days and 2 nights. There will be a minimum washout of 7 days between doses, and a follow-up visit will occur at 7 to 9 days after the last study treatment. The Part B of the study will be a 7-period fixed sequence which will evaluate the selected MR prototype coated tablet formulation(s) at different tablet strengths or as multiple unit doses and with or without apertures in the tablet coatings. There will be an interim review after each period 1 to 5 of Part B to select the dose level, formulation and prandial status for each subsequent period. An interim data review after Part B Period 6 will determine if optional Period 7 is required and the dose level, dosing time (morning or evening), formulation and prandial status for that period. Each inpatient period will consist of a 4-day and 3-night with a minimum of 7 days washout between doses. A follow-up visit will occur at 7 to 9 days after the last study treatment. Approximately 33 subjects will be enrolled in the study. The total duration for Part A will be approximately 10-12 weeks and 10-14 weeks for Part B (including screening period of approximately 4 weeks).
Eligibility Criteria
Inclusion Criteria
- Subject at the time of participation must be 18 to 65 years of age.
- Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
- Body weight greater than or equal to 50 kilogram (kg) and body mass index within the range 19.0 to 32.0 kg per squared meter (kg/m^2) (inclusive).
- Male or female subjects where male subjects are eligible to participate if they agree to the following during the intervention period until completion of the final follow up visit after the last dose of study treatment; refrain from sperm donation; plus either be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception/barrier like use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant; agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person.
- The eligible female subjects can participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of childbearing potential (WOCBP); is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of less than 1 percentage per year), preferably with low user dependency, for at least 30 days before first dose until completion of the final follow up visit after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction from Day 1 until 3 months after the last dose. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention; a WOCBP must have a negative highly sensitive serum pregnancy test within 24 hours before the first dose of study intervention; additional requirements for pregnancy testing during and after study intervention must be followed; the investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- Capable of giving an Informed Consent.
Exclusion Criteria
- 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.
- Any history of suicidal behavior within the past 6 months or any history of attempted suicide in subject's lifetime.
- 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. Hayfever is allowed unless it is active.
- Alanine t
Data sourced from ClinicalTrials.gov (NCT03649412). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.