Study to Investigate Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of GSK2646264
Condition: Urticaria
MeSH terms: Urticaria
Intervention: GSK2646264 0.5% topical cream; GSK2646264 1% topical cream; Placebo
Intervention description: GSK2646264 0.5% topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars; GSK2646264 1% topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars; Placebo topical cream is supplied as white-to-off-white aqueous cream stored in amber glass jars
Intervention MeSH terms: GSK2646264
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Urticaria; SYK Inhibitor

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.
    

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.