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Study to Investigate Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of GSK2646264

Primary Purpose

Urticaria

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

GSK2646264 0.5% topical cream

GSK2646264 1% topical cream

Placebo

About this trial

This is an interventional treatment trial for Urticaria focused on measuring Urticaria, SYK Inhibitor

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria for all subjects in Parts A, B and C

Male or female subject aged at least 18 years (Yrs) at the time of signing the informed consent. The upper age limit of subjects is defined in the specific inclusion criteria for each cohort.
All subjects must be free from scarring or skin markings (e.g. tattoos or piercings) and open wounds (e.g. scarring or skin markings) on the defined areas of the body that cream will be applied onto, unless in the opinion of the investigator it will not compromise the subjects safety and quality of data.
Able to refrain from exposure to extended and direct sunlight during the study period, from screening (SCR) until follow up, especially the area that is under treatment during the study.
Able to refrain from shaving and waxing the areas on which the study cream will be applied during the duration of the study from SCR to follow up.
Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in protocol. This criterion must be followed from the time of the first dose of study medication until the follow up visit or a time period that is 5 terminal half-live post-last dose which will be determined following Part A of the study.
Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Willing, committed and able to return for all clinic visits and complete all study-related procedures. Able to read, understand and complete study- related questionnaires.

Inclusion criteria specific for healthy subjects (Part A)

The subject is aged between 18 and 55 yrs of age inclusive, at the time of signing the informed consent.
Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 19 to 30 kg per square meter (m^2 )(inclusive).
Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with the GSK Medical Monitor (MM) if required, agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
Demonstration of a positive weal and flare reaction (>=3 millimeter (mm) in diameter relative to negative control) to at least one allergen from a battery of allergens (mixed grass pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander) on skin prick testing at SCR.
Subjects must be free from any past or present benign or malignant skin conditions and disease, unless in the opinion of the investigator it will not compromise the subject's safety and quality of data.
Non-smokers or if the subject is a tobacco smoke: smokes less than 5 cigarettes per day and commits to not smoke tobacco for the duration of the in-house stay, and commits to stable and moderate use (as determined by the Investigator) of tobacco or nicotine-containing products, including nicotine patches/gum, during the course of the study, as long as the patches do not interfere with the study procedures.
A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records; or postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli international unit [MlU]/milliliter [mL] and estradiol <40 picogram (pg)/mL (<147 picomoles/litre) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods described 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. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

Additional Inclusion criteria specific for subjects with CU (Part B)

Diagnosed with CU for more than six weeks as confirmed by medical history and with a positive cold stimulation test assessed by TEMPTest 4.0 prior to first dose.
The subject is aged between 18 and 70 yrs of age inclusive, at the time of signing the informed consent.
Body weight >=50 kg and BMI within the range 19 to 35 kg/m^2 (inclusive).
Other than a diagnosis of CU, the subject should have no other co-morbidities which would introduce additional risk factors and will not interfere with the study procedures, as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with the GSK MM if required, agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedure.
In addition, the following criterion will apply to a minimum of 4 patients in Part B: Demonstration of a positive weal and flare reaction (>=3 mm relative to negative control) to at least one allergen from a battery of allergens (mixed grass pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander) on skin prick testing at SCR,
Subjects must be free from any past or present benign or malignant skin conditions and disease, other than the specified condition required for eligibility of subjects as defined in the specific inclusion criteria for CU cohort unless in the opinion of the investigator it will not compromise the subjects safety and quality of data.
Non-smokers or if the subject is a tobacco smoker: smokes less than 5 cigarettes per day and commits to not smoke tobacco for the duration of the in-house stay, and commits to stable and moderate use (as determined by the Investigator) of tobacco or nicotine-containing products, including nicotine patches/gum, during the course of the study, as long as the patches do not interfere with the study procedures.
Female subjects must agree to use one of the contraception methods listed in protocol, 28 days before their SCR visit and until the followup visit or a time period that is 5 terminal half-live post-last dose which will be determined following Part A of the study.

Additional Inclusion criteria specific for subjects with CsU (Part C)

The subject is aged between 18 and 70 yrs of age inclusive, at the time of signing the informed consent.
Body weight >=50 kg and BMI within the range 19 to 35 kg/m2 (inclusive)
Subjects who have a score of >14 on the UAS7 questionnaire with between 4-10 weals observed in a defined area of the body will be included in this study. This area must include either both arms, or both legs or both sides of their torso for 7 consecutive days during the SCR period, prior to the Day 1 visit. If a subject has not completed 7 consecutive days of UAS questionnaire prior to dosing on Day 1 due to exceptional circumstances, the SCR period may be extended until the subject has completed 7 consecutive days of UAS questionnaire. This will only be at the discretion of the Investigator.
No other aetiology identified for chronic urticaria such as drug-related or inducible urticaria as determined by history, physical examination and laboratory studies.
Subjects must be free from any past or present benign or malignant skin conditions and disease, other than the specified condition required for eligibility of subjects as defined in the specific inclusion criteria for CsU cohort unless in the opinion of the investigator it will not compromise the subjects safety and quality of data.
Other than a diagnosis of CsU the subject should have no other co-morbidities which would introduce additional risk factors and will not interfere with the study procedures, as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with the GSK MM if required, agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
Female subjects must agree to use one of the contraception methods 28 days before their SCR visit listed in protocol and until the follow-up visit or a time period that is 5 terminal half-live post-last dose which will be determined following Part A of the study.

All Cohorts Exclusion Criteria

Thyroid stimulating hormone levels outside normal range.
Subjects with a history of Graves disease.
Subjects with a history of any thyroid cancer.
Unable or unwilling to avoid use of topical creams/lotions at sites where medication will be applied. Washing with soap and water will be permitted.
Based on averaged corrected QT interval for heart rate (Fridericia's) [QTcF] values of triplicate ECGs obtained over a brief recording period: QTcF > 450 msec; or QTcF >480 milliseconds (msec) in subjects with Bundle Branch Block.
Alanine aminotransferase, alkaline phosphatase and bilirubin ≥ 1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or previous history of uncomplicated cholecystectomy.
History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
History of sensitivity to any of the study medications, or components thereof, history of anaphylaxis or a history of drug or other allergy that, in the opinion of the investigator or GSK MM, contraindicates their participation.
Unable to refrain from vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half lives (whichever is longer) prior to the SCR visit until the completion of the follow-up assessments, unless in the opinion of the Investigator, in consultation with the GSK MM if required, the medication will not interfere with the study procedures or compromise subject safety.
A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of SCR.
A positive test for HIV antibody.
Lactating females.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Exposure to more than four new chemical entities within 12 months prior to the first dosing day
Use of topical steroids or calcinurin inhibitors are prohibited during the study from SCR to follow up.
Exclusion related to prior drug treatments: Intake of oral corticosteroids within 7 days >10 milligram (mg) per day prior to first SCR visit; Use of depot corticosteroids within 7 days prior to first SCR visit; Subjects who are taking anticoagulants (e.g. warfarin) must not be on warfarin within 21 days prior to SCR. Subjects who are having psoralen combined with ultraviolet A (PUVA) treatment must not be using PUVA treatment within 21 days prior to SCR.
Subjects who work for the Sponsor, CRO, or one of the study centres. Country Specific Exclusion criteria for Germany that applies to Part A, Part B and Part C.
Subjects who live in detention on court order or on regulatory action, see §40 subsection 1 sentence 3 no. 4 AMG. (Arzneimittelgesetz).

Additional Exclusion for Part A - Healthy Subjects

Use of H1 antihistamines within 3 days prior to first SCR visit Additional Exclusion for Part B - CU Subjects
Exclusion related to prior drug treatments: Use of Zaditen (Ketotifen) within 14 days prior to first SCR visit; Use of Doxepin AZU and other tricyclic antidepressants with antihistaminergic properties within 14 days prior to first SCR visit; Use of H2 antihistamines within 7 days prior to first SCR visit; Use of H1 antihistamines within 7 days prior to first SCR visit; Use of monteleukast or any other leukotriene antagonist within 7 days prior to first SCR visit; Use of biologicals including omalizumab within 5 months prior to first SCR visit.

Additional Exclusion for Part C- CsUpatients

Exclusion related to prior drug treatments: Intake of cyclosporin within 10 days prior to first SCR visit; Intake of other immunosuppressant drugs within 28 days of first SCR visit; Use of monteleukast or any other leukotriene antagonist within 7 days prior to first SCR visit; Use of Dapsone within 7 days prior to first SCR visit; Use of Zaditen (Ketotifen) within 14 days prior to first SCR visit; Use of Doxepin AZU and other tricyclic antidepressants with antihistaminergic properties within 14 days prior to first SCR visit; Use of H2 antihistamines within 7 days prior first SCR visit; Use of biologicals including omalizumab within 5 months prior to first SCR visit; Use of H1 antihistamines above the licensed dose within 3 days prior to first SCR visit.

Sites / Locations

GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Part A: Dose group 1

Part A: Dose group 2

Part B

Part C

Arm Description

Subjects will be treated topically with 0.5 % GSK2646264 cream and placebo cream on an area of approximately 12 x 3 centimetre (cm) on the volar aspect of the arm which approximates to 0.2% total body surface area (BSA), on each arm. On Day 2 and Day 3 subjects will receive active treatment and placebo on the same arms as on Day 1, with the percentage BSA being 1% on Day 2 and 5% on Day 3.

Subjects will be treated topically with 1 % GSK2646264 cream and placebo cream on the morning and evening of Day 1 starting at the final % BSA dosed at Day 3 in group 1 which is anticipated to be 5%. In dose group 2, the starting BSA will increase to 10% at Day 3 and then 20% by Day 5. Administration of the evening (PM) dose will be dependent on the data from Part A Dose group 1.

Cold urticaria subjects will receive treatment to 4 defined areas (right and left arms and legs). Subjects will be treated with maximum tolerated strength of GSK2646264 cream (0.5% or 1%) and placebo cream in morning or in morning and evening to 2 specified areas of ~5% BSA on the subject's legs for the CU assessment and to 2 specified areas of 0.2% BSA on the volar aspect of the arm. The maximum tolerated strength and evening dosing will be dependent on the data from the Part A

Chronic spontaneous urticaria subjects will be treated with the maximum tolerated strength of GSK2646264 cream from Part A (0.5% or 1%) and placebo cream onto defined areas (right and left arms and, legs and front torso) from Days 1 to 7. The total % BSA for an individual subject will be decided by the investigator prior to randomization. The maximum % BSA and the frequency of dosing will be decided after part A of the study.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Part A

Number of Participants With AEs and SAEs Part A

Number of Participants With AEs and SAEs Part B

Number of Participants With AEs and SAEs Part C

Number of Participants With AEs and SAEs Defined by Severity Part A

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. An SAE is 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, or is a congenital anomaly/birth defect or is medically significant. AE and SAE were categorized as mild=an event that was easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities, moderate=an event that was sufficiently discomforting to interfere with normal everyday activities and severe=an event that prevented normal everyday activities.

Number of Participants With AEs and SAEs Defined by Severity Part A

Number of Participants With AEs and SAEs Defined by Severity Part B

Number of Participants With AEs and SAEs Defined by Severity Part C

Change From Baseline in Vital Sign Parameter Heart Rate for Part A

Vital sign heart rate was measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2, Day 3, Day 4 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in Vital Sign Parameter Heart Rate for Part A

Vital sign heart rate was measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2 (pre-dose), Day 3 (pre-dose), Day 4 (pre-dose), Day 5, Day 6, Day 7, Day 8 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in Vital Sign Parameter Heart Rate for Part B

Vital sign heart rate was measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2 (pre-dose), Day 3 (pre-dose), Day 6, Day 9, Day 12, Day 15 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in Vital Sign Parameter Heart Rate for Part C

Vital sign heart rate was measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 4 (pre-dose), Day 7 (pre-dose), Day 10, Day 15 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed.

Change From Baseline in Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part A

Vital signs SBP and DBP were measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2, Day 3, Day 4 and follow-up. Baseline was defined as assessments performed at Day 1 (pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in Vital Sign Parameters SBP and DBP for Part A

Vital signs SBP and DBP were measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2 (pre-dose), Day 3 (pre-dose), Day 4 (pre-dose), Day 5, Day 6, Day 7, Day 8 and follow-up. Baseline was defined as assessments performed at Day 1 (pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in Vital Sign Parameters SBP and DBP for Part B

Vital signs SBP and DBP were measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 2 (pre-dose), Day 3 (pre-dose), Day 6, Day 9, Day 12, Day 15 and follow-up. Baseline was defined as assessments performed at Day 1(pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in Vital Sign SBP and DBP for Part C

Vital signs SBP and DBP were measured in the semi-supine position after 10 minutes of rest. Assessments were performed at Day 4 (pre-dose), Day 7 (pre-dose), Day 10, Day 15 and follow-up. Baseline was defined as assessments performed at Day 1 (pre-dose). Change from Baseline was calculated as the post-dose visit value minus the Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed.

Change From Baseline in Electrocardiogram (ECG) Parameters for Part A

Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, corrected QT (QTc-Bazett [QTcB], QTC interval-Fredericia [QTcF]) intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in Electrocardiogram (ECG) Parameters for Part A

Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, corrected QT (QTc-Bazett [QTcB], QTC interval-Fredericia[QTcF]) intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in ECG Parameters for Part B

Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, QTcB, QTcF intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Change From Baseline in ECG Parameters for Part C

Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, QTcB, QTcF intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed.

Number of Participants With Clinical Chemistry Data Outside the Range of Potential Clinical Importance (PCI) for Part A

Clinical chemistry parameters assessed were alanine amino transferase (ALT), albumin (low <30 grams/liter), alkaline phosphatase, aspartate aminotransferase (AST), calcium (low <2 millimoles/liter and high >2.75 millimoles/liter), chloride, creatinine (high >159 micromoles/liter), direct bilirubin, gamma glutamyl transferase (GGT low <8 units/liter and high >78 units/liter), glucose (low <3 millimoles/liter and high >11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low <3 millimoles/liter and high >5.5 millimoles/liter), sodium (low <130 millimoles/liter and high >150 millimoles/liter), total bilirubin, total protein and urea/blood urea nitrogen (BUN). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part A

Clinical chemistry parameters assessed were alanine amino transferase (ALT), albumin (low <30 grams/liter), alkaline phosphatase, AST, calcium (low <2 millimoles/liter and high >2.75 millimoles/liter), chloride, creatinine (high >159 micromoles/liter), direct bilirubin, GGT (low <8 units/liter and high >78 units/liter), glucose (low <3 millimoles/liter and high >11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low <3 millimoles/liter and high >5.5 millimoles/liter), sodium (low <130 millimoles/liter and high >150 millimoles/liter), total bilirubin, total protein and urea/BUN). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part B

Clinical chemistry parameters assessed were ALT, albumin (low <30 grams/liter), alkaline phosphatase, AST, calcium (low <2 millimoles/liter and high >2.75 millimoles/liter), chloride (low <98 millimoles/liter and high >106 millimoles/liter), creatinine (high >159 micromoles/liter), direct bilirubin, GGT (low <8 units/liter and high >78 units/liter), glucose (low <3 millimoles/liter and high >11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low <3 millimoles/liter and high >5.5 millimoles/liter), sodium (low <130 millimoles/liter and high >150 millimoles/liter), total bilirubin, total protein and urea/BUN (low <2.9 and high >7.1). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part C

Clinical chemistry parameters assessed were ALT, albumin (low <30 grams/liter), alkaline phosphatase, AST, calcium (low <2 millimoles/liter and high >2.75 millimoles/liter), chloride (low <98 millimoles/liter and high >106 millimoles/liter), creatinine (high >159 micromoles/liter), direct bilirubin, GGT (low <8 units/liter and high >78 units/liter), glucose (low <3 millimoles/liter and high >11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low <3 millimoles/liter and high >5.5 millimoles/liter), sodium (low <130 millimoles/liter and high >150 millimoles/liter), total bilirubin, total protein (low <60 grams/liter and high >78 grams/liter) and urea/BUN (low <2.9 millimoles/liter and high >7.1 millimoles/liter). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Number of Participants With Hematology Data Outside the Range of PCI for Part A

Hematology parameters assessed were basophils (high >0.1x10^9 cells/Liter), eosinophils (high >0.44x 10^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low <0.8x10^9 cells/Liter), mean corpuscle hemoglobin (MCH low <28 picograms and high >32 picograms), mean corpuscle hemoglobin concentration (MCHC low <32 grams/liter and high >36 grams/liter), mean corpuscle volume (MCV), monocytes (high >0.208x 10^9 cells/Liter), platelet count, red blood cell (RBC low <4.2x10^6 cells/microliter and high 5.9x10^6 cells/microliter) count, total neutrophils and white blood cell (WBC) count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Number of Participants With Hematology Data Outside the Range of PCI for Part A

Hematology parameters assessed were basophils (high >0.1x10^9 cells/Liter), eosinophils (high >0.44x 10^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low <0.8x10^9 cells/Liter), MCH (low <28 picograms and high >32 picograms), MCHC (low <32 grams/liter and high >36 grams/liter), MCV, monocytes (high >0.208x10^9 cells/Liter), platelet count, RBC count (low <4.2x10^6 cells/microliter and high 5.9x10^6 cells/microliter) count, total neutrophils, WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Number of Participants With Hematology Data Outside the Range of PCI for Part B

Hematology parameters assessed were basophils (high >0.1x10^9 cells/Liter), eosinophils (high >0.44x 10^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low <0.8x10^9 cells/Liter), MCH (low <28 picograms and high >32 picograms), MCHC (low <32 grams/liter and high >36 grams/liter), MCV, monocytes (high >0.208x10^9 cells/Liter), platelet count, RBC count (low <4.2x10^6 cells/microliter and high 5.9x10^6 cells/microliter) count, total neutrophils and WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Number of Participants With Hematology Data Outside the Range of PCI for Part C

Hematology parameters assessed were basophils (high >0.1x10^9 cells/Liter), eosinophils (high >0.44x 10^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low <0.8x10^9 cells/Liter), MCH (low <28 picograms and high >32 picograms), MCHC low <32 grams/liter and high >36 grams/liter), MCV, monocytes (high >0.208x10^9 cells/Liter), platelet count, RBC count (low <4.2x10^6 cells/microliter and high 5.9x10^6 cells/microliter) count, total neutrophils and WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Number of Participants With Tolerability Assessment for Part A

Tolerability was assessed with the skin irritation scoring system of study, where the score consists of a numeric score according to the dermal response scoring as follows 0=no evidence of irritation, 1=minimal erythema, barely perceptible (pink), 2=moderate erythema (definite redness), 3=strong erythema (intense redness), 4=definite edema, 5=erythema, edema, and papules, 6=vesicular eruption, 7=strong reaction spreading beyond test site, and a letter according to the other effects scoring, Z=no other effect, A=slight glazed appearance, B=marked glazing, C=glazing with peeling and cracking, F=glazing with fissures, G=film of dried serous exudate covering all or part of the patch site, H=small petechial erosions and/or scabs. For each skin assessment, letter grade will be converted to numeric values as below: A=0, Z=0, B=1, C=2, F=3, G=3, H=3. A combined score for each participant was calculated by adding all numeric and letter scores. A maximum score of 3 was allowed.

Number of Participants With Tolerability Assessment for Part B

Number of Participants With Tolerability Assessment for Part C

Secondary Outcome Measures

Plasma GSK2646264 Pharmacokinetic (PK) Concentrations for Part A

Blood samples were collected to assess the plasma concentration of GSK2646264 for Part A on Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (1,2,4,8,12,24 hours) and Day 3 (1,2,4,8,12,24 hours). The actual date and time of each blood sample collection was recorded. PK Population comprised of all randomized participants of the Safety Population for whom a pharmacokinetic sample was obtained and analyzed.

Plasma GSK2646264 Pharmacokinetic (PK) Concentrations for Part A

Blood samples were collected to assess the plasma concentration of GSK2646264 for Part A on Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (1,2,4,8,12,24 hours), Day 3 (1,2,4,8,12,24 hours) and Day 4 post-dose at Day 5 (30 and 36 hours), Day 6 (48,54 and 60 hours), Day 7 (72,78 and 84 hours) and Day 8 (96 hours). The actual date and time of each blood sample collection was recorded.

Plasma GSK2646264 PK Concentrations for Part B

Blood samples were collected to assess the plasma concentration of GSK2646264 for Part B on Day 1 (Pre-dose,1,4,8,12,24 hours), Day 2 (1,4,8,12,24 hours), Day 3 (1,4,8,12,24 hours), Day 6, Day 9, Day 12, Day 15 and follow-up (Day 17 to 19). The actual date and time of each blood sample collection was recorded.

Plasma GSK2646264 PK Concentrations for Part C

Blood samples were collected to assess the plasma concentration of GSK2646264 for Part C on Day 1 (Pre-dose,1 and 4 hours), Day 4 (Pre-dose and 4 hours), Day 7 (Pre-dose and 4 hours), Day 10, Day 15 and follow-up. The actual date and time of each blood sample collection was recorded.

Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of GSK2646264 for Part A

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the AUC (0-T) was determined using the currently approved and validated software.

AUC (0-t) of GSK2646264 for Part A

Maximum Plasma Concentration (Cmax) of GSK2646264 for Part A

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the Cmax was determined using the currently approved and validated software.

Cmax of GSK2646264 for Part A

Blood samples were collected at the indicated time points to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the Cmax was determined using the currently approved and validated software.

Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of GSK2646264 for Part A

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the AUC (0-24) was determined using the currently approved and validated software. NA indicated data was not collected due to insufficient participants with data.

Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of GSK2646264 for Part A

Time to Cmax (Tmax) of GSK2646264 for Part A

Blood samples were collected at the indicated time points to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the tmax was determined using the currently approved and validated software.

Tmax of GSK2646264 for Part A

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the tmax was determined using the currently approved and validated software.

Terminal Half-life (t1/2) of GSK2646264 for Part A

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the t1/2 was determined using the currently approved and validated software. NA indicated t1/2 could not be calculated as we need at least 3 time points after Cmax within the same participant and this criteria could not be fulfilled due to lack of available data.

t1/2 of GSK2646264 for Part A

AUC [0-t] of GSK2646264 for Part B

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the AUC (0-t) was determined using the currently approved and validated software.

Cmax of GSK2646264 for Part B

AUC (0-24) of GSK2646264 for Part B

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the AUC (0-24) was determined using the currently approved and validated software. NA indicates that geometric coefficient of variation could not be computed for Part B (3.5% BSA) GSK2646264 1% as a single participant was analyzed on Day 2.

Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of GSK2646264 for Part B

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the AUC (0-infinity) was determined using the currently approved and validated software.

Terminal Half-life (t1/2) of GSK2646264 for Part B

Tmax of GSK2646264 for Part B

Cmax of GSK2646264 for Part C

Tmax of GSK2646264 for Part C

t1/2 of GSK2646264 for Part C

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the t1/2 was determined using the currently approved and validated software. NA indicated data was not collected due to insufficient number of participants with data to calculate half life.

Full Information

NCT ID

NCT02424799

First Posted

November 13, 2014

Last Updated

March 27, 2019

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT02424799

Brief Title

Study to Investigate Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of GSK2646264

Official Title

A Randomised Double Blind (Sponsor Unblinded), Single and Repeat Ascending Dose First Time in Human Study in Healthy Subjects, Cold Urticaria and Chronic Spontaneous Urticaria Subjects to Investigate Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of GSK2646264

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Completed

Study Start Date

November 17, 2014 (Actual)

Primary Completion Date

November 10, 2017 (Actual)

Study Completion Date

November 10, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

5. Study Description

Brief Summary

This First Time in Human (FTIH) study, which will be performed in three parts, is designed to investigate the safety, local tolerability, pharmacokinetics and pharmacodynamics after single and repeat topical applications of up to 2 strengths of GSK2646264 and corresponding placebo within the same subject, in healthy adult subjects (Part A), subjects with cold urticaria (CU, Part B) and subjects with chronic spontaneous urticaria (CsU, Part C). The study will also measure short term effects of GSK2646264 on the number and size of weals in subjects with CsU, and in healthy subjects and subjects with CU following provocation tests.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Urticaria

Keywords

Urticaria, SYK Inhibitor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

34 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part A: Dose group 1

Arm Type

Experimental

Arm Description

Arm Title

Part A: Dose group 2

Arm Type

Experimental

Arm Description

Arm Title

Part B

Arm Type

Experimental

Arm Description

Arm Title

Part C

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

GSK2646264 0.5% topical cream

Intervention Description

GSK2646264 0.5% topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars

Intervention Type

Drug

Intervention Name(s)

GSK2646264 1% topical cream

Intervention Description

GSK2646264 1% topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) Part A

Description

Time Frame

Up to Day 7

Title

Number of Participants With AEs and SAEs Part A

Description

Time Frame

Up to Day 11

Title

Number of Participants With AEs and SAEs Part B

Description

Time Frame

Up to Day 19

Title

Number of Participants With AEs and SAEs Part C

Description

Time Frame

Up to Day 23

Title

Number of Participants With AEs and SAEs Defined by Severity Part A

Description

Time Frame

Up to Day 7

Title

Number of Participants With AEs and SAEs Defined by Severity Part A

Description

Time Frame

Up to Day 11

Title

Number of Participants With AEs and SAEs Defined by Severity Part B

Description

Time Frame

Up to 19 days

Title

Number of Participants With AEs and SAEs Defined by Severity Part C

Description

Time Frame

Up to 23 days

Title

Change From Baseline in Vital Sign Parameter Heart Rate for Part A

Description

Time Frame

Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 4 and follow-up (Day 5 to Day 7)

Title

Change From Baseline in Vital Sign Parameter Heart Rate for Part A

Description

Time Frame

Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 4 (pre-dose), Day 5, Day 6, Day 7, Day 8 and follow-up (Day 9 to Day 11)

Title

Change From Baseline in Vital Sign Parameter Heart Rate for Part B

Description

Time Frame

Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 6, Day 9, Day 12, Day 15 and follow-up (Day 17 to Day 19)

Title

Change From Baseline in Vital Sign Parameter Heart Rate for Part C

Description

Time Frame

Baseline and (Day 1 pre-dose), Day 4 (pre-dose), Day 7 (pre-dose), Day 10, Day 15, follow-up (Day 23)

Title

Change From Baseline in Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part A

Description

Time Frame

Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 4 and follow-up (Day 5 to Day 7)

Title

Change From Baseline in Vital Sign Parameters SBP and DBP for Part A

Description

Time Frame

Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 4 (pre-dose), Day 5, Day 6, Day 7, Day 8 and follow-up (Day 9 to Day 11)

Title

Change From Baseline in Vital Sign Parameters SBP and DBP for Part B

Description

Time Frame

Baseline (Day 1 pre-dose) and Day 2 (pre-dose), Day 3 (pre-dose), Day 6, Day 9, Day 12, Day 15 and follow-up (Day 17 to Day 19)

Title

Change From Baseline in Vital Sign SBP and DBP for Part C

Description

Time Frame

Baseline (Day 1 pre-dose) and Day 4 (pre-dose), Day 7 (pre-dose), Day 10, Day 15 and follow-up (Day 23)

Title

Change From Baseline in Electrocardiogram (ECG) Parameters for Part A

Description

Time Frame

Baseline (Day -1) and Day 4, and follow-up (Day 5 to Day 7)

Title

Change From Baseline in Electrocardiogram (ECG) Parameters for Part A

Description

Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, corrected QT (QTc-Bazett [QTcB], QTC interval-Fredericia[QTcF]) intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Time Frame

Baseline (Day -1) and Day 8 and follow-up (Day 9 to Day 11)

Title

Change From Baseline in ECG Parameters for Part B

Description

Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, QTcB, QTcF intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value.

Time Frame

Baseline (Day -1) and Day 3 (pre-dose) and follow-up (Day 17 to Day 19)

Title

Change From Baseline in ECG Parameters for Part C

Description

Triplicate 12-lead ECGs were obtained at screening and during the study single ECGs were taken. At each time point during the study ECG was taken using an ECG machine that automatically calculates the heart rate and measured the PR interval, QRS duration, QTcB, QTcF intervals, RR interval and uncorrected QT interval. Baseline was defined as assessment performed at Day -1. Change from Baseline was calculated as the post-dose visit value minus the Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed.

Time Frame

Baseline (Day -1) and Day 7 (pre-dose) and follow-up (Day 23)

Title

Number of Participants With Clinical Chemistry Data Outside the Range of Potential Clinical Importance (PCI) for Part A

Description

Time Frame

Day 4 and follow up (Day 5 to Day 7)

Title

Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part A

Description

Time Frame

Day 5, Day 7 and follow up (Day 9 to Day 11)

Title

Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part B

Description

Time Frame

Day 3 and follow up (Day 17 to Day 19)

Title

Number of Participants With Clinical Chemistry Data Outside the Range of PCI for Part C

Description

Clinical chemistry parameters assessed were ALT, albumin (low <30 grams/liter), alkaline phosphatase, AST, calcium (low <2 millimoles/liter and high >2.75 millimoles/liter), chloride (low <98 millimoles/liter and high >106 millimoles/liter), creatinine (high >159 micromoles/liter), direct bilirubin, GGT (low <8 units/liter and high >78 units/liter), glucose (low <3 millimoles/liter and high >11.1 millimoles/liter), phosphorus (low 0.97 millimoles/liter and high 1.45 millimoles/liter), potassium (low <3 millimoles/liter and high >5.5 millimoles/liter), sodium (low <130 millimoles/liter and high >150 millimoles/liter), total bilirubin, total protein (low <60 grams/liter and high >78 grams/liter) and urea/BUN (low <2.9 millimoles/liter and high >7.1 millimoles/liter). Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Time Frame

Day 1, Day 7 and follow up (Day 23)

Title

Number of Participants With Hematology Data Outside the Range of PCI for Part A

Description

Time Frame

Day 4 and follow up (Day 5 to Day 7)

Title

Number of Participants With Hematology Data Outside the Range of PCI for Part A

Description

Hematology parameters assessed were basophils (high >0.1x10^9 cells/Liter), eosinophils (high >0.44x 10^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low <0.8x10^9 cells/Liter), MCH (low <28 picograms and high >32 picograms), MCHC (low <32 grams/liter and high >36 grams/liter), MCV, monocytes (high >0.208x10^9 cells/Liter), platelet count, RBC count (low <4.2x10^6 cells/microliter and high 5.9x10^6 cells/microliter) count, total neutrophils, WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Time Frame

Day 5, Day 7 and follow up (Day 9 to Day 11)

Title

Number of Participants With Hematology Data Outside the Range of PCI for Part B

Description

Hematology parameters assessed were basophils (high >0.1x10^9 cells/Liter), eosinophils (high >0.44x 10^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low <0.8x10^9 cells/Liter), MCH (low <28 picograms and high >32 picograms), MCHC (low <32 grams/liter and high >36 grams/liter), MCV, monocytes (high >0.208x10^9 cells/Liter), platelet count, RBC count (low <4.2x10^6 cells/microliter and high 5.9x10^6 cells/microliter) count, total neutrophils and WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Time Frame

Day 3 and follow up (Day 17 to 19)

Title

Number of Participants With Hematology Data Outside the Range of PCI for Part C

Description

Hematology parameters assessed were basophils (high >0.1x10^9 cells/Liter), eosinophils (high >0.44x 10^9 cells/Liter), hematocrit, hemoglobin, lymphocytes (low <0.8x10^9 cells/Liter), MCH (low <28 picograms and high >32 picograms), MCHC low <32 grams/liter and high >36 grams/liter), MCV, monocytes (high >0.208x10^9 cells/Liter), platelet count, RBC count (low <4.2x10^6 cells/microliter and high 5.9x10^6 cells/microliter) count, total neutrophils and WBC count. Values flagged as high and low of PCI for participants have been presented. Only categories with non-zero values have been presented.

Time Frame

Day 1, Day 7 and follow up (Day 23)

Title

Number of Participants With Tolerability Assessment for Part A

Description

Time Frame

Up to Day 4

Title

Number of Participants With Tolerability Assessment for Part B

Description

Time Frame

Up to Day 3

Title

Number of Participants With Tolerability Assessment for Part C

Description

Time Frame

Up to Day 7

Secondary Outcome Measure Information:

Title

Plasma GSK2646264 Pharmacokinetic (PK) Concentrations for Part A

Description

Time Frame

Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (1,2,4,8,12,24 hours) and Day 3 (1,2,4,8,12,24 hours)

Title

Plasma GSK2646264 Pharmacokinetic (PK) Concentrations for Part A

Description

Time Frame

Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (1,2,4,8,12,24 hours), Day 3 (1,2,4,8,12,24 hours) and Day 4 post-dose at Day 5 (30 and 36 hours), Day 6 (48,54 and 60 hours), Day 7 (72,78 and 84 hours) and Day 8 (96 hours)

Title

Plasma GSK2646264 PK Concentrations for Part B

Description

Time Frame

Day 1 (Pre-dose,1,4,8,12,24 hours), Day 2 (1,4,8,12,24 hours), Day 3 (1,4,8,12,24 hours), Day 6, Day 9, Day 12, Day 15 and follow-up (Day 17 to 19)

Title

Plasma GSK2646264 PK Concentrations for Part C

Description

Time Frame

Day 1 (Pre-dose,1 and 4 hours), Day 4 (Pre-dose and 4 hours), Day 7 (Pre-dose and 4 hours), Day 10, Day 15 and follow-up (Day 23)

Title

Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of GSK2646264 for Part A

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2 and Day 3

Title

AUC (0-t) of GSK2646264 for Part A

Description

Time Frame

Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (Pre-dose,1,2,4,8,12,24 hours), Day 3 (Pre-dose,1,2,4,8,12,24 hours) and Day 4 post-dose

Title

Maximum Plasma Concentration (Cmax) of GSK2646264 for Part A

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2 and Day 3

Title

Cmax of GSK2646264 for Part A

Description

Time Frame

Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (Pre-dose,1,2,4,8,12,24 hours), Day 3 (Pre-dose,1,2,4,8,12,24 hours) and Day 4 post-dose

Title

Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of GSK2646264 for Part A

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2,3 and 4

Title

Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of GSK2646264 for Part A

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2,3 and 4

Title

Time to Cmax (Tmax) of GSK2646264 for Part A

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2 and Day 3

Title

Tmax of GSK2646264 for Part A

Description

Time Frame

Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (Pre-dose,1,2,4,8,12,24 hours), Day 3 (Pre-dose,1,2,4,8,12,24 hours) and Day 4 post-dose

Title

Terminal Half-life (t1/2) of GSK2646264 for Part A

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 and 24 hours post-dose on Days 1,2,3 and 4

Title

t1/2 of GSK2646264 for Part A

Description

Time Frame

Day 1 (Pre-dose,1,2,4,8,12,24 hours), Day 2 (Pre-dose,1,2,4,8,12,24 hours), Day 3 (Pre-dose,1,2,4,8,12,24 hours) and Day 4 post-dose at Day 5 (30 and 36 hours), Day 6 (48,54 and 60 hours), Day 7 (72,78 and 84 hours) and Day 8 (96 hours)

Title

AUC [0-t] of GSK2646264 for Part B

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3

Title

Cmax of GSK2646264 for Part B

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3 (Day 4)

Title

AUC (0-24) of GSK2646264 for Part B

Description

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the AUC (0-24) was determined using the currently approved and validated software. NA indicates that geometric coefficient of variation could not be computed for Part B (3.5% BSA) GSK2646264 1% as a single participant was analyzed on Day 2.

Time Frame

Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3 (Day 4)

Title

Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of GSK2646264 for Part B

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3

Title

Terminal Half-life (t1/2) of GSK2646264 for Part B

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3

Title

Tmax of GSK2646264 for Part B

Description

Time Frame

Pre dose, 1 ,2, 4, 8, 12 hours post-dose on Days 1,2,3 and 24 hours post last dose on Day 3

Title

Cmax of GSK2646264 for Part C

Description

Time Frame

Pre dose and 4 hours post-dose on Days 1, 4 and 7

Title

Tmax of GSK2646264 for Part C

Description

Time Frame

Pre dose and 4 hours post-dose on Days 1, 4 and 7

Title

t1/2 of GSK2646264 for Part C

Description

Blood samples were collected at the indicated time point to investigate the PK profile of GSK264624. From the GSK2646264 concentration-time data, the t1/2 was determined using the currently approved and validated software. NA indicated data was not collected due to insufficient number of participants with data to calculate half life.

Time Frame

Pre dose and 4 hours post-dose on Days 1, 4 and 7

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria for all subjects in Parts A, B and C Male or female subject aged at least 18 years (Yrs) at the time of signing the informed consent. The upper age limit of subjects is defined in the specific inclusion criteria for each cohort. All subjects must be free from scarring or skin markings (e.g. tattoos or piercings) and open wounds (e.g. scarring or skin markings) on the defined areas of the body that cream will be applied onto, unless in the opinion of the investigator it will not compromise the subjects safety and quality of data. Able to refrain from exposure to extended and direct sunlight during the study period, from screening (SCR) until follow up, especially the area that is under treatment during the study. Able to refrain from shaving and waxing the areas on which the study cream will be applied during the duration of the study from SCR to follow up. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in protocol. This criterion must be followed from the time of the first dose of study medication until the follow up visit or a time period that is 5 terminal half-live post-last dose which will be determined following Part A of the study. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Willing, committed and able to return for all clinic visits and complete all study-related procedures. Able to read, understand and complete study- related questionnaires. Inclusion criteria specific for healthy subjects (Part A) The subject is aged between 18 and 55 yrs of age inclusive, at the time of signing the informed consent. Body weight >=50 kilogram (kg) and body mass index (BMI) within the range 19 to 30 kg per square meter (m^2 )(inclusive). Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with the GSK Medical Monitor (MM) if required, agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Demonstration of a positive weal and flare reaction (>=3 millimeter (mm) in diameter relative to negative control) to at least one allergen from a battery of allergens (mixed grass pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander) on skin prick testing at SCR. Subjects must be free from any past or present benign or malignant skin conditions and disease, unless in the opinion of the investigator it will not compromise the subject's safety and quality of data. Non-smokers or if the subject is a tobacco smoke: smokes less than 5 cigarettes per day and commits to not smoke tobacco for the duration of the in-house stay, and commits to stable and moderate use (as determined by the Investigator) of tobacco or nicotine-containing products, including nicotine patches/gum, during the course of the study, as long as the patches do not interfere with the study procedures. A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records; or postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli international unit [MlU]/milliliter [mL] and estradiol <40 picogram (pg)/mL (<147 picomoles/litre) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods described 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. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. Additional Inclusion criteria specific for subjects with CU (Part B) Diagnosed with CU for more than six weeks as confirmed by medical history and with a positive cold stimulation test assessed by TEMPTest 4.0 prior to first dose. The subject is aged between 18 and 70 yrs of age inclusive, at the time of signing the informed consent. Body weight >=50 kg and BMI within the range 19 to 35 kg/m^2 (inclusive). Other than a diagnosis of CU, the subject should have no other co-morbidities which would introduce additional risk factors and will not interfere with the study procedures, as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with the GSK MM if required, agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedure. In addition, the following criterion will apply to a minimum of 4 patients in Part B: Demonstration of a positive weal and flare reaction (>=3 mm relative to negative control) to at least one allergen from a battery of allergens (mixed grass pollen, Dermatophagoides pteronyssinus, birch pollen and cat dander) on skin prick testing at SCR, Subjects must be free from any past or present benign or malignant skin conditions and disease, other than the specified condition required for eligibility of subjects as defined in the specific inclusion criteria for CU cohort unless in the opinion of the investigator it will not compromise the subjects safety and quality of data. Non-smokers or if the subject is a tobacco smoker: smokes less than 5 cigarettes per day and commits to not smoke tobacco for the duration of the in-house stay, and commits to stable and moderate use (as determined by the Investigator) of tobacco or nicotine-containing products, including nicotine patches/gum, during the course of the study, as long as the patches do not interfere with the study procedures. Female subjects must agree to use one of the contraception methods listed in protocol, 28 days before their SCR visit and until the followup visit or a time period that is 5 terminal half-live post-last dose which will be determined following Part A of the study. Additional Inclusion criteria specific for subjects with CsU (Part C) The subject is aged between 18 and 70 yrs of age inclusive, at the time of signing the informed consent. Body weight >=50 kg and BMI within the range 19 to 35 kg/m2 (inclusive) Subjects who have a score of >14 on the UAS7 questionnaire with between 4-10 weals observed in a defined area of the body will be included in this study. This area must include either both arms, or both legs or both sides of their torso for 7 consecutive days during the SCR period, prior to the Day 1 visit. If a subject has not completed 7 consecutive days of UAS questionnaire prior to dosing on Day 1 due to exceptional circumstances, the SCR period may be extended until the subject has completed 7 consecutive days of UAS questionnaire. This will only be at the discretion of the Investigator. No other aetiology identified for chronic urticaria such as drug-related or inducible urticaria as determined by history, physical examination and laboratory studies. Subjects must be free from any past or present benign or malignant skin conditions and disease, other than the specified condition required for eligibility of subjects as defined in the specific inclusion criteria for CsU cohort unless in the opinion of the investigator it will not compromise the subjects safety and quality of data. Other than a diagnosis of CsU the subject should have no other co-morbidities which would introduce additional risk factors and will not interfere with the study procedures, as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with the GSK MM if required, agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Female subjects must agree to use one of the contraception methods 28 days before their SCR visit listed in protocol and until the follow-up visit or a time period that is 5 terminal half-live post-last dose which will be determined following Part A of the study. All Cohorts Exclusion Criteria Thyroid stimulating hormone levels outside normal range. Subjects with a history of Graves disease. Subjects with a history of any thyroid cancer. Unable or unwilling to avoid use of topical creams/lotions at sites where medication will be applied. Washing with soap and water will be permitted. Based on averaged corrected QT interval for heart rate (Fridericia's) [QTcF] values of triplicate ECGs obtained over a brief recording period: QTcF > 450 msec; or QTcF >480 milliseconds (msec) in subjects with Bundle Branch Block. Alanine aminotransferase, alkaline phosphatase and bilirubin ≥ 1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or previous history of uncomplicated cholecystectomy. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. History of sensitivity to any of the study medications, or components thereof, history of anaphylaxis or a history of drug or other allergy that, in the opinion of the investigator or GSK MM, contraindicates their participation. Unable to refrain from vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half lives (whichever is longer) prior to the SCR visit until the completion of the follow-up assessments, unless in the opinion of the Investigator, in consultation with the GSK MM if required, the medication will not interfere with the study procedures or compromise subject safety. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of SCR. A positive test for HIV antibody. Lactating females. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than four new chemical entities within 12 months prior to the first dosing day Use of topical steroids or calcinurin inhibitors are prohibited during the study from SCR to follow up. Exclusion related to prior drug treatments: Intake of oral corticosteroids within 7 days >10 milligram (mg) per day prior to first SCR visit; Use of depot corticosteroids within 7 days prior to first SCR visit; Subjects who are taking anticoagulants (e.g. warfarin) must not be on warfarin within 21 days prior to SCR. Subjects who are having psoralen combined with ultraviolet A (PUVA) treatment must not be using PUVA treatment within 21 days prior to SCR. Subjects who work for the Sponsor, CRO, or one of the study centres. Country Specific Exclusion criteria for Germany that applies to Part A, Part B and Part C. Subjects who live in detention on court order or on regulatory action, see §40 subsection 1 sentence 3 no. 4 AMG. (Arzneimittelgesetz). Additional Exclusion for Part A - Healthy Subjects Use of H1 antihistamines within 3 days prior to first SCR visit Additional Exclusion for Part B - CU Subjects Exclusion related to prior drug treatments: Use of Zaditen (Ketotifen) within 14 days prior to first SCR visit; Use of Doxepin AZU and other tricyclic antidepressants with antihistaminergic properties within 14 days prior to first SCR visit; Use of H2 antihistamines within 7 days prior to first SCR visit; Use of H1 antihistamines within 7 days prior to first SCR visit; Use of monteleukast or any other leukotriene antagonist within 7 days prior to first SCR visit; Use of biologicals including omalizumab within 5 months prior to first SCR visit. Additional Exclusion for Part C- CsUpatients Exclusion related to prior drug treatments: Intake of cyclosporin within 10 days prior to first SCR visit; Intake of other immunosuppressant drugs within 28 days of first SCR visit; Use of monteleukast or any other leukotriene antagonist within 7 days prior to first SCR visit; Use of Dapsone within 7 days prior to first SCR visit; Use of Zaditen (Ketotifen) within 14 days prior to first SCR visit; Use of Doxepin AZU and other tricyclic antidepressants with antihistaminergic properties within 14 days prior to first SCR visit; Use of H2 antihistamines within 7 days prior first SCR visit; Use of biologicals including omalizumab within 5 months prior to first SCR visit; Use of H1 antihistamines above the licensed dose within 3 days prior to first SCR visit.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Berlin

ZIP/Postal Code

10117

Country

Germany

Facility Name

GSK Investigational Site

City

Berlin

ZIP/Postal Code

14050

Country

Germany

Facility Name

GSK Investigational Site

City

Norwich

State/Province

Norfolk

ZIP/Postal Code

NR4 7UY

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Norwich

State/Province

Norfolk

ZIP/Postal Code

NR4 7U

Country

United Kingdom

Facility Name

GSK Investigational Site

City

London

ZIP/Postal Code

SE1 9RT

Country

United Kingdom

Facility Name

GSK Investigational Site

City

London

ZIP/Postal Code

SE1 9R

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

34020509

Citation

Dickson MC, Walker A, Grattan C, Perry H, Williams N, Ratia N, Dewit O, Gisbert S, Metz M, Maurer M. Effects of a topical treatment with spleen tyrosine kinase inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: Results of a phase 1a/b randomised double-blind placebo-controlled study. Br J Clin Pharmacol. 2021 Dec;87(12):4797-4808. doi: 10.1111/bcp.14923. Epub 2021 Jun 18.

Results Reference

derived

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Study to Investigate Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of GSK2646264

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