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

NCT02424799 | Completed Phase 1 Results

• 2 other identifiers: 2001962014-001015-39
• Study Type: interventional
• Target: 34
• Locations: 2 countries
• Sites: 6

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.

Conditions

Urticaria

Keywords

Urticaria; SYK Inhibitor

Outcome Measures

Primary Outcomes (31)

• Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) 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. Safety population comprised of all participants who took at least one dose of study treatment.

  Up to Day 7

• Number of Participants With AEs and SAEs 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.

  Up to Day 11

• Number of Participants With AEs and SAEs Part B

  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. Data is presented according to the percentage BSA as it impacted safety

  Up to Day 19

• Number of Participants With AEs and SAEs Part C

  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.

  Up to Day 23

• 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.

  Up to Day 7

• 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.

  Up to Day 11

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

  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. Data is presented according to the percentage BSA as it impacted safety

  Up to 19 days

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

  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.

  Up to 23 days

• 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.

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

• 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.

  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)

• 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.

  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)

• 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.

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

• 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.

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

• 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.

  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)

• 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.

  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)

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

  Day 3 and follow up (Day 17 to 19)

• 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.

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

• 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.

  Up to Day 4

• Number of Participants With Tolerability Assessment for Part B

  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.

  Up to Day 3

• Number of Participants With Tolerability Assessment for Part C

  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.

  Up to Day 7

Secondary Outcomes (23)

• Plasma GSK2646264 Pharmacokinetic (PK) Concentrations for Part A

  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)

• Plasma GSK2646264 Pharmacokinetic (PK) Concentrations for Part A

  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)

• Plasma GSK2646264 PK Concentrations for Part B

  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)

• Plasma GSK2646264 PK Concentrations for Part C

  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)

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

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

Study Arms (4)

Part A: Dose group 1

EXPERIMENTAL

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.

Drug: GSK2646264 0.5% topical cream; Drug: Placebo

Part A: Dose group 2

EXPERIMENTAL

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.

Drug: GSK2646264 0.5% topical cream; Drug: GSK2646264 1% topical cream; Drug: Placebo

Part B

EXPERIMENTAL

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

Drug: GSK2646264 0.5% topical cream; Drug: GSK2646264 1% topical cream; Drug: Placebo

Part C

EXPERIMENTAL

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.

Drug: GSK2646264 0.5% topical cream; Drug: GSK2646264 1% topical cream; Drug: Placebo

Interventions

GSK2646264 0.5% topical cream DRUG

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

Part A: Dose group 1; Part A: Dose group 2; Part B; Part C

GSK2646264 1% topical cream DRUG

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

Part A: Dose group 2; Part B; Part C

Placebo DRUG

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

Part A: Dose group 1; Part A: Dose group 2; Part B; Part C

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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).

You may not qualify if:

• 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.
• 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.
• 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,
• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (6)

GSK Investigational Site

Berlin, 10117, Germany

Location

GSK Investigational Site

Berlin, 14050, Germany

Location

GSK Investigational Site

Norwich, Norfolk, NR4 7UY, United Kingdom

Location

GSK Investigational Site

Norwich, Norfolk, NR4 7U, United Kingdom

Location

GSK Investigational Site

London, SE1 9RT, United Kingdom

Location

GSK Investigational Site

London, SE1 9R, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 34020509 DERIVED

MeSH Terms

Conditions

Urticaria

Interventions

GSK2646264

Condition Hierarchy (Ancestors)

Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

• GSK Clinical Trials

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

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2014
• First Posted: April 23, 2015
• Study Start: November 17, 2014
• Primary Completion: November 10, 2017
• Study Completion: November 10, 2017
• Last Updated: June 21, 2019
• Results First Posted: June 21, 2019

Record last verified: 2019-03

Locations

DE (2); GB (4)