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Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Repeat Doses of GSK2982772 in Subjects With Psoriasis

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ClinicalTrials.gov Identifier: NCT02776033
Recruitment Status : Completed
First Posted : May 18, 2016
Last Update Posted : June 25, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
This is the first study with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with active plaque-type psoriasis (PsO). The primary objective will be to investigate the safety and tolerability of repeat oral doses of GSK2982772 60 milligram (mg) twice daily (BID) for 84 days in Cohort 1 and 60 mg thrice daily (TID) for 84 days in Cohort 2. In addition, a number of experimental and clinical endpoints will be employed to obtain information on the pharmacokinetics, pharmacodynamics, and efficacy in subjects with active PsO. There will be two Cohorts of subjects. In Cohort 1 after a screening period of up to 30 days, approximately 30 subjects will be randomized to receive either GSK2982772 60 mg BID or placebo for 84 days (12 Weeks), followed by a follow-up period (28 days). In Cohort 2 after a screening period of up to 30 days, approximately 24 subjects will be randomized to receive either GSK2982772 60 mg TID or placebo for 84 days (12 Weeks), followed by a follow-up period (28 days). The total duration of participation is approximately 20 Weeks from screening to the last study visit.

Condition or disease Intervention/treatment Phase
Psoriasis Drug: GSK2982772 Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 47 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multicentre, Randomised, Double-blind (Sponsor-unblinded), Placebo-controlled, Repeat Dose Study to Investigate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2982772 in Subjects With Active Plaque-type Psoriasis
Actual Study Start Date : August 30, 2016
Actual Primary Completion Date : January 4, 2018
Actual Study Completion Date : January 4, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Psoriasis

Arm Intervention/treatment
Experimental: GSK2982772 receivers in Cohort 1
Randomized subjects will receive GSK2982772 BID (approximately 12 hours apart) via oral route for 84 days.
Drug: GSK2982772
GSK2982772 will be supplied as a white to almost white, round, film coated 30 mg oral tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.

Placebo Comparator: Placebo receivers in Cohort 1
Randomized subjects will receive placebo BID via oral route for 84 days.
Drug: Placebo
Matching placebo will be supplied as a white to almost white, round film coated tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.

Experimental: GSK2982772 receivers in Cohort 2
Randomized subjects will receive GSK2982772 TID (approximately 8 hours apart) via oral route for 84 days
Drug: GSK2982772
GSK2982772 will be supplied as a white to almost white, round, film coated 30 mg oral tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.

Placebo Comparator: Placebo receivers in Cohort 2
Randomized subjects will receive placebo TID via oral route for 84 days.
Drug: Placebo
Matching placebo will be supplied as a white to almost white, round film coated tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.




Primary Outcome Measures :
  1. Number of subjects with adverse events (AE) during Cohort 1 [ Time Frame: Up to Day 116 ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

  2. Number of subjects with AE during Cohort 2 [ Time Frame: Up to Day 116 ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

  3. Number of subjects with abnormal hematology parameters during Cohort 1 [ Time Frame: Up to Day 116 ]
    The hematology parameters will include: platelet count, red blood cell count, hemoglobin, hematocrit, white blood cells, mean corpuscular volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils, and basophils

  4. Number of subjects with abnormal hematology parameters during Cohort 2 [ Time Frame: Up to Day 116 ]
    The hematology parameters will include: platelet count, red blood cell count, hemoglobin, hematocrit, white blood cells, mean corpuscular volume, mean corpuscular hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils, and basophils

  5. Number of subjects with abnormal clinical chemistry parameters during Cohort 1 [ Time Frame: Up to Day 116 ]
    The clinical chemistry parameters will include: blood urea nitrogen, creatinine, glucose, triglycerides, potassium, sodium, calcium, total cholesterol, high-density lipoprotein cholesterol, aspartate aminotransferase , alanine aminotransferase, alkaline phosphatase, total and direct bilirubin, total protein, albumin, and low-density lipoprotein cholesterol

  6. Number of subjects with abnormal clinical chemistry parameters during Cohort 2 [ Time Frame: Up to Day 116 ]
    The clinical chemistry parameters will include: blood urea nitrogen, creatinine, glucose, triglycerides, potassium, sodium, calcium, total cholesterol, high-density lipoprotein cholesterol, aspartate aminotransferase , alanine aminotransferase, alkaline phosphatase, total and direct bilirubin, total protein, albumin, and low-density lipoprotein cholesterol

  7. Number of subjects with abnormal urinalysis parameters during Cohort 1 [ Time Frame: Up to Day 116 ]
    Urinalysis will include specific gravity; dipstick method will be used to measure pH, glucose, protein, blood and ketones. Microscopic examination will be done if blood or protein is abnormal

  8. Number of subjects with abnormal urinalysis parameters during Cohort 2 [ Time Frame: Up to Day 116 ]
    Urinalysis will include specific gravity; dipstick method will be used to measure pH, glucose, protein, blood and ketones. Microscopic examination will be done if blood or protein is abnormal

  9. Number of subjects with abnormal systolic blood pressure (SBP) and diastolic blood pressure (DBP) during Cohort 1 [ Time Frame: Up to Day 116 ]
    Blood pressure will be measured in supine or semi-supine position after 5 minutes rest

  10. Number of subjects with abnormal SBP and DBP during Cohort 2 [ Time Frame: Up to Day 116 ]
    Blood pressure will be measured in supine or semi-supine position after 5 minutes rest

  11. Number of subjects with abnormal heart rate during Cohort 1 [ Time Frame: Up to Day 116 ]
    Heart rate will be measured in supine or semi-supine position after 5 minutes rest

  12. Number of subjects with abnormal heart rate during Cohort 2 [ Time Frame: Up to Day 116 ]
    Heart rate will be measured in supine or semi-supine position after 5 minutes rest

  13. Number of subjects with abnormal respiratory rate during Cohort 1 [ Time Frame: Up to Day 116 ]
    Respiratory rate will be measured in supine or semi-supine position after 5 minutes rest

  14. Number of subjects with abnormal respiratory rate during Cohort 2 [ Time Frame: Up to Day 116 ]
    Respiratory rate will be measured in supine or semi-supine position after 5 minutes rest

  15. Number of subjects with abnormal body temperature during Cohort 1 [ Time Frame: Up to Day 116 ]
    Body temperature will be measured in supine or semi-supine position after 5 minutes rest

  16. Number of subjects with abnormal body temperature during Cohort 2 [ Time Frame: Up to Day 116 ]
    Body temperature will be measured in supine or semi-supine position after 5 minutes rest

  17. Number of subjects with electrocardiograms (ECGs) finding during Cohort 1 [ Time Frame: Up to Day 116 ]
    PR, QRS, QT, and QT interval corrected (QTc) for heart rate using Fridericia's (QTcF) or Bazzett's formula ( QTcB intervals) will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-supine or supine position after 5 minutes rest

  18. Number of subjects with ECGs finding during Cohort 2 [ Time Frame: Up to Day 116 ]
    PR, QRS, QT, and QTc for heart rate using QTcF or QTcB intervals will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-supine or supine position after 5 minutes rest


Secondary Outcome Measures :
  1. Pre-dose plasma concentrations of GSK2982772 60 mg BID: Cohort 1 [ Time Frame: Pre-dose on Day 43 (Week 6) and on Day 85 (Week 12) ]
    Change in pre-dose plasma concentrations following 60 mg BID doses of GSK2982772

  2. Pre-dose plasma concentrations of GSK2982772 60 mg TID: Cohort 2 [ Time Frame: Pre-dose on Day 43 (Week 6) and on Day 85 (Week 12) ]
    Change in pre-dose plasma concentrations following 60 mg TID doses of GSK2982772

  3. Post-dose plasma concentrations of GSK2982772 60 mg BID: Cohort 1 [ Time Frame: One, 2, 4 and 6 hours post dose on Day 1 and Day 43 ]
    Change in post-dose plasma concentrations following 60 mg BID doses of GSK2982772

  4. Post-dose plasma concentrations of GSK2982772 60 mg TID: Cohort 2 [ Time Frame: One, 2, 4 and 6 hours post dose on Day 1 and Day 43 ]
    Change in post-dose plasma concentrations following 60 mg TID doses of GSK2982772

  5. Change from Baseline in histopathological scoring of psoriatic lesional biopsies following GSK2982772 60 mg BID: Cohort 1 [ Time Frame: Baseline (pre-dose on Day 1) and Day 43 ]
    Change from Baseline in histopathological scoring of psoriatic lesional biopsies for the following: Keratin 16 (K16), Cluster of differentiation 3 (CD3)/CD11c, CD161, elastase positive dermal cells and epidermal thickness, after 60 mg BID doses of GSK2982772

  6. Change from Baseline in histopathological scoring of psoriatic lesional biopsies following GSK2982772 60 mg TID: Cohort 2 [ Time Frame: Baseline (pre-dose on Day 1) and Day 43 ]
    Change from Baseline in histopathological scoring of psoriatic lesional biopsies for the following: Keratin 16 (K16), Cluster of differentiation 3 (CD3)/CD11c, CD161, elastase positive dermal cells and epidermal thickness, after 60 mg TID doses of GSK2982772

  7. Change in messenger ribonucleic acid (mRNA) expression of inflammatory gene transcripts in psoriatic lesional biopsies following GSK2982772 60 mg BID: Cohort 1 [ Time Frame: Baseline (pre-dose on Day 1), and Day 43 ]
    Change in mRNA expression profile of inflammatory gene transcripts: interleukin-4 (IL-4), IL-10, IL-17, IL-21, IL-22, IL-23, tumor necrosis factor (TNF) and interferon (IFN-gamma) following 60 mg BID doses of GSK2982772

  8. Change in mRNA expression of inflammatory gene transcripts in psoriatic lesional biopsies following GSK2982772 60 mg TID: Cohort 2 [ Time Frame: Baseline (pre-dose on Day 1), and Day 43 ]
    Change in mRNA expression profile of inflammatory gene transcripts: interleukin-4 (IL-4), IL-10, IL-17, IL-21, IL-22, IL-23, tumor necrosis factor (TNF) and interferon (IFN-gamma) following 60 mg TID doses of GSK2982772

  9. Percentage change from Baseline in the index psoriatic lesion following GSK2982772 60 mg BID: Cohort 1 [ Time Frame: Day 1 (pre-dose), Day 15, Day 29, Day 43 (pre-dose), Day 57, Day 71 and Day 85 ]
    The Psoriatic Lesion Severity Sum (PLSS) is the sum of the erythema, scaling and plaque thickness scores; change from Baseline will be assessed following 60 mg BID doses of GSK2982772

  10. Percentage change from Baseline in the index psoriatic lesion following GSK2982772 60 mg TID: Cohort 2 [ Time Frame: Day 1 (pre-dose), Day 15, Day 29, Day 43 (pre-dose), Day 57, Day 71 and Day 85 ]
    The PLSS is the sum of the erythema, scaling and plaque thickness scores; change from Baseline will be assessed following 60 mg TID doses of GSK2982772

  11. Actual PLSS scores in the index psoriatic lesion following GSK2982772 60 mg BID: Cohort 1 [ Time Frame: Day 1 (pre-dose), Day 15, Day 29, Day 43 (pre-dose), Day 57, Day 71 and Day 85 ]
    The PLSS is the sum of the erythema, scaling and plaque thickness scores; Actual PLSS scores will be assessed following 60 mg BID doses of GSK2982772

  12. Actual PLSS scores in the index psoriatic lesion following GSK2982772 60 mg TID: Cohort 2 [ Time Frame: Day 1 (pre-dose), Day 15, Day 29, Day 43 (pre-dose), Day 57, Day 71 and Day 85 ]
    The PLSS is the sum of the erythema, scaling and plaque thickness scores; Change from Baseline will be assessed following 60 mg TID doses of GSK2982772



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Between 18 and 75 years of age inclusive, at the time of signing the informed consent.
  • Subjects who do not have any medical conditions, other than active plaque-type psoriasis, that in the opinion of the Investigator put the subject at unacceptable risk or interfere with study assessments or integrity of the data. All medical conditions must be stable for the duration of the study.
  • Presence of active chronic plaque-type psoriasis as determined by the Investigator for at least 6 months (confirmed by the subject or medical record) before first dose of study treatment (Day 1).
  • Subject has psoriasis plaques involving Body Surface Area >=3% assessed at screening and before dosing on Day 1.
  • Physician Global Assessment >=3.
  • Subject must agree to avoid prolonged exposure to natural sunlight, tanning beds or phototherapy devices for the duration of the study
  • Subject has at least two stable plaques assessed at screening and before dosing on Day 1:

Both must be of a suitable size (>=3 centimeter [cm] by 3 cm) and one in a site suitable for repeat biopsy, and one in a site suitable for index lesion PLSS scoring.

Both plaques must have a PLSS lesional score >=2 for the induration component (moderate or above), >=1 for erythema and scaling with a total score of >=5.

The biopsy lesion must not be on the face, groin, scalp, knees, elbows, or on the palmar/plantar surfaces of the hands/feet, and must be shielded from natural light with clothing.

  • Subject is naive to any biologic therapies for psoriasis, OR has had previous exposure to a single anti- TNF biologic agent in the context of a previous clinical trial. The anti-TNF biologic agent must have been discontinued more than 8 weeks prior to screening visit (12 Weeks or 5 half lives whichever is longer from first dose).
  • A body mass index within the range of 18.5-35 kilogram per meter square (kg)/m^2 (inclusive).
  • Male and Female subjects:

Males: Male subjects with female partners of child bearing potential must comply with the pre specified contraception requirements.

Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotropin test), not lactating, and is either of non-reproductive potential or reproductive potential. If of reproductive potential, then the subject should agree to follow one of the options listed per GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential from 30 days prior to the first dose and until 30 days after the last dose of study medication The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

  • Capable of giving signed informed consent

Exclusion Criteria:

  • Subjects with clinically overt concurrent psoriatic arthritis who are receiving chronic disease-modifying anti-rheumatic medications therapy (other than non-steroidal anti-inflammatory drug), as judged by the Investigator.
  • Has nonplaque forms of psoriasis (e.g. erythrodermic, guttate, or pustular), as judged by the Investigator.
  • Has current drug-induced psoriasis (e.g., a new onset of psoriasis or an exacerbation from beta blockers, calcium channel blockers, or lithium).
  • Subject with current history of Suicidal Ideation Behaviour as measured using the Columbia Suicide Severity Rating Scale or a 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 or intramuscular) antibiotics (antibacterials, antivirals, antifungals, or antiparasitic agents) within 60 days before first dose.

A history of opportunistic infections within 1 year of screening (e.g. pneumocystis jirovecii, cytomegalovirus, pneumonitis, 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 subject.

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 locally-read follow up chest X-ray, shows no evidence of current or previous pulmonary tuberculosis, the subject may be eligible for the study at the discretion of the Investigator and medical monitor.

  • ECG for heart rate QTc >450 milliseconds (msec) or QTc >480 msec in subjects with bundle branch block.
  • Alanine aminotransferase >2×upper limit of normal (ULN) and bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) at screening.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Current or history of renal disease or estimated glomerular filtrate rate by Chronic Kidney Disease Epidemiology Collaboration equation <60 mL/min/1.73 m^2.
  • Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.
  • A major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
  • A planned surgical procedure that, in the opinion of the Investigator, makes the subject unsuitable for the study.
  • A history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell carcinoma) or carcinoma in situ of the uterine cervix that has been fully treated and shows no evidence of recurrence.
  • A history of hypertrophic scarring or keloid formation, or known allergy to lidocaine or other local anaesthetics.
  • The subject has received treatment with the specified therapies listed in the protocol, or changes to those treatments, within the specified timeframe.

Other medications (including vitamins, herbal and dietary supplements) will be considered on a case-by-case basis, and will be allowed if in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject safety.

  • History of alcohol or drug abuse that would interfere with the ability to comply with the study.
  • Subject intends to sunbathe or use a tanning device (sun bed or solarium) within 14 days prior to Day 1 and until completion of the follow up visit (Day 112).
  • History of sensitivity to any of the study treatments, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
  • Received a live or attenuated vaccine within 30 days of randomization OR plan to receive a vaccination during the study until completion of the follow-up visit.
  • The subject has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives, whichever is longer before the first dose of study medication, or plans to take part in another clinical trial at the same time as participating in this clinical trial. Subjects who were randomized into Cohort 1 are not eligible to be re-randomized into Cohort 2.
  • Hemoglobin <11 g/deciliter (dL); hematocrit <30%, white blood cell count =<3,000/millimeter (mm)^3 (<=3.0×10^9/L) ; platelet count <=100,000/microliter (µL) (<=100 × 10^9/L); absolute neutrophil count <=1.5×10^9/L at the screening visit.
  • Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. As potential for and magnitude of immunosuppression with this compound is unknown, subjects with presence of hepatitis B core antibody (HBcAb) should be excluded. Subjects positive for HBsAg and/or positive for anti-HBcAb (regardless of anti-HBs antibody status) are excluded.
  • A positive serology for human immunodeficiency virus 1 or 2 at screening.
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 3 months.
  • Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day

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): NCT02776033


Locations
Canada, Ontario
GSK Investigational Site
Markham, Ontario, Canada, L3P1X2
GSK Investigational Site
Peterborough, Ontario, Canada, K9J 5K2
GSK Investigational Site
Waterloo, Ontario, Canada, N2J 1C4
Canada, Quebec
GSK Investigational Site
Montreal, Quebec, Canada, H2K 4L5
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02776033     History of Changes
Other Study ID Numbers: 203167
First Posted: May 18, 2016    Key Record Dates
Last Update Posted: June 25, 2018
Last Verified: June 2018

Keywords provided by GlaxoSmithKline:
tolerability
safety
GSK2982772
RIP1 kinase inhibitor
psoriasis

Additional relevant MeSH terms:
Psoriasis
Skin Diseases, Papulosquamous
Skin Diseases