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This is an exploratory study to develop methodologies for the assessment of T-cell mediated therapies via skin immune challenges studies in healthy volunteers. The study will investigate what is the most appropriate; skin challenge agent, time and methodology to sample and characterise T-cells in the delayed type hypersensitivity (DTH) skin reaction. The skin challenge agents to be used in this study will be the neoantigen Keyhole Limpet Hemocyanin (KLH) and recall antigen Tuberculin Purified Protein Derivative (PPD). Part A of the study will assess an intradermal (ID) KLH challenge in three subjects to assess if the immune response to KLH is initiated by the innate or adaptive immune system. Each subject will receive one ID dose of 0.1 milligram (mg) KLH and will be assessed for a skin inflammatory response. Part B of the study will assess repeat ID challenges 28 days apart; the objective will be to characterise the T-cell response to each challenge and the kinetics of that response.
For Cohorts 1A and 1B, 16 subjects will receive an initial subcutaneous (SC) 5 mg dose of KLH. Fifteen days later the subjects will receive 0.1 mg ID KLH dose and the response will then be assessed 48 and 120 hours after the initial challenge. The ID KLH challenge will then be repeated 28 days later and the response will be assessed at 48 hours (Cohort 1A, 8 subjects) and at 120 hours (Cohort 1B, 8 subjects) post challenge. For Cohort 2, a repeat challenge of either 2 tuberculin Unit (TU) or 10 TU ID PPD will be administered 28 days apart, to 8 subjects. The first challenge response will be assessed 48 and 120 hours post challenge. The second challenge will be administered 28 days after the first and will be assessed at the same timepoints. The repeat challenge 28 days later will allow an intra-subject analysis and will determine if a subject can be used as their own control. Part C of the study will assess repeat ID challenges of PPD and PBS; the objective will be to characterise the T-cell response to each challenge and the kinetics of that response. For Cohort 1, 6 subjects will receive a 0.1ml ID dose of PBS and another dose 24 hours later. Each challenge will be assessed 48 hours post challenge. Approximately 2 subjects will have an assessment of their normal skin as a control. For Cohort 2, a repeat challenge of either 2TU or 10TU ID PPD will be administered 28 days apart, to 6 subjects. The first challenge response will be assessed 48 post challenge. The second challenge will be administered 28 days after the 1st and will be assessed at the same timepoint. The repeat challenge 28 days later will allow an intra-subject analysis and will determine if a subject can be used as their own control.
The total duration of this study for Part A is 14-18 days plus up to 30 days screening. The total duration of this study for Cohort 1A is 56-60 days plus up to 30 days screening. The total duration of this study for Cohort 1B is 59-63 days plus up to 30 days screening. The total duration of this study for Cohort 2 if 2TU is used is 45-49 days plus up to 30 day screening. The total duration of this study for Cohort 2 if 10TU is used is 48-51 days plus up to 30 days screening. The total duration of this study for Part C Cohort 1 is 15-19 days plus up to 30 day screening. The total duration of this study for Cohort 2 if 2TU is used is 42-46 days plus up to 30 day screening. The total duration of this study for Cohort 2 if 10TU is used is 45-49 days plus up to 30 days screening.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A: | Experimental | Subjects in the Part A will receive an ID injection of 0.1 mg KLH as 0.1 mL of KLH (1 mg/mL) in the upper right forearm and an ID injection of 0.1 mL of buffer in the lower right forearm and lower and upper left forearm on Day 1. |
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| Part B:Cohort 1A | Experimental | Subjects in the Part B Cohort 1A arm will receive a SC immunisation of 5 mg KLH in the right deltoid. On Day 15 subjects will return to the unit for an ID injection of 0.1 mg KLH as 0.1 mL of KLH (1 mg/mL) in the lower right and lower left forearm. On Day 43, 0.1mL of KLH (1 mg/mL) will be injected ID into the upper left forearm and the upper right forearm (The dose can be changed to either 5mg/1mg or 1mg/0.1mg depending on the results from the first 3 subjects in Cohort 1). |
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| Part B:Cohort 1B | Experimental | Subjects in the Part B Cohort 1B arm will receive a SC immunisation of 5 mg KLH in the right deltoid on Day 1. On Day 15 subjects will return to the unit for an ID injection of 0.1 mg KLH in the lower right and lower left forearm. On Day 43 subjects will then receive an ID injection of 0.1 mg KLH in the upper right and upper left forearms (The dose can be changed to either 5mg/1mg or 1mg/0.1mg depending on the results from the first 3 subjects in Cohort 1). |
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| Part B:Cohort 2 | Experimental | Subjects in the Part B Cohort 2 will receive an ID injection of 2TU (0.04 microg/mL) PPD in the upper right and upper left forearms on Day 1. On Day 3 (48 hours post challenge) If the induration is less than 6 mm, the subject will be re-challenged with 10 TU (0.04 microg/mL) PPD at a site at least 4 cm away from another challenge site. On Day 29 the subjects will have 2 ID injections of 2 TU or 10 TU (the same dose that produced an induration of 6 mm or more). |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| KLH 0.1 mg | Other | KLH will be administered as single ID injection of 0.1 mg as 0.1mL of KLH (1 mg/mL) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Part A: Skin inflammatory response measurement as induration by the ball point pen technique | The induration of wheals (defined as elevation and induration that are palpable in the skin) that develop as a result of intradermal immunisation with KLH or PPD will be measured in the vertical and horizontal plane using the ball point pen technique. The diameter of the induration will be measured by rolling a medium ball point pen from 10 to 20 millimetre (mm) outside the edge of the induration and toward the centre with just enough pressure to indent the skin slightly. | Over a four day period after challenge |
| Part A: Skin inflammatory response measurement as erythema diameter by Laser Doppler Imaging (LDI) and ruler measurement | A Laser Doppler Imager will measure the area occupied by a given wheal and associated erythema, which reflects superficial blood flow of a subject's arm. Erythema at the immunisation site will be measured in the vertical and horizontal plane using a plastic flexible mm ruler. Measurements will be taken for both challenge agent and buffer control injections. Place the zero line of the ruler just inside the left edge of the area of erythema and read the ruler line just inside the right edge. | Over a four day period after challenge |
| Part A: Skin inflammatory response measurement as induration by characterisation and measurement of the T-cells in skin biopsies | T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells | Over a three day period after challenge |
| Part B: Characterisation of T-cells in a skin DTH response | Lymphocyte Activation Gene 3 (LAG 3+) T-cells collected by Punch Biopsy or skin blister will be characterised and measured by Fluorescence activated cell sorter (FACS) analysis or other immunologic techniques | Cohort 1: Over a five day period after first challenge. Cohort 2: Over a five day period after first challenge |
| Measure | Description | Time Frame |
|---|---|---|
| Part A: Characterisation and measurement of the T-cells in skin biopsies. | T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells | At 48hrs (Day 3) after challenge |
| Part B: Skin inflammatory response measurement in Cohort 1 by the ball point pen technique |
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Inclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Cambridge | CB2 2GG | United Kingdom |
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| Label | URL |
|---|---|
| Results for study 117249 can be found on the GSK Clinical Study Register. | View source |
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| ID | Term |
|---|---|
| D003872 | Dermatitis |
| D004890 | Erythema |
| D006968 | Hypersensitivity, Delayed |
| ID | Term |
|---|---|
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012877 | Skin Manifestations |
| D012816 | Signs and Symptoms |
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| ID | Term |
|---|---|
| C032808 | keyhole-limpet hemocyanin |
| D014373 | Tuberculin |
| ID | Term |
|---|---|
| D000942 | Antigens, Bacterial |
| D001426 | Bacterial Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
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| Part C: Cohort 1 | Experimental | Subjects in the Part C Cohort 1 will receive an ID injection of 0.1 mL PBS in the upper right forearm on Day 1. On Day 2 subjects will receive an ID injection of 0.1 ml PBS in the upper left forearm. |
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| Part C: Cohort 2 | Experimental | Subjects in the Part C Cohort 2 will receive an ID injection of 2TU (0.04 microg/mL) PPD in the upper left forearms on Day 1. On Day 3 (48 hours post challenge) If the induration is less than 6 mm, the subject will be re-challenged with 10 TU (0.04 microg/mL) PPD at a site at least 4 cm away from another challenge site. On Day 29 the subjects will have 1 ID injections of 2 TU or 10 TU (the same dose that produced an induration of 6 mm or more). |
|
| KLH 5 mg | Other | KLH will be administered as single SC injection of 5 mg |
|
| PBS (0.1 mL) | Other | PBS will be administered in Part A on Day 1 as 3 ID injections and in Part C: Cohort 1 on Day 1 and Day 2 as a single ID injection |
|
| Tuberculin PPD | Other | Tuberculin PPD will be administered in Part B Cohort 2 on Day 1 as single ID injection of 2TU (0.04 microg/mL) in each forearm. In Part C Cohort 2 PPD will be administered on Day 1 as a single ID injection of 2TU. On day 3, if the induration is 6 mm or more; 2 ID injections of 2 TU will be administered on Day 29 in Part B Cohort 2 and 1injection of 2TU on Day 29 in Part C Cohort 2. On day 3, if the induration is less than 6 mm, subject will be re-challenged with 10 TU (0.04 microg/mL) PPD followed by 2 ID injections of 10 TU on Day 29 in Part B Cohort 2 or 1 ID injection of 10TU on Day 29 in Part C Cohort 2. |
|
| Part C: Characterisation of T-cells in a skin DTH response | Lymphocyte Activation Gene 3 (LAG 3+) T-cells collected by skin blister will be characterised and measured by Fluorescence activated cell sorter (FACS) analysis or other immunologic techniques | Cohort 1: Over a five day period after first challenge. Cohort 2: Over a three day period after first challenge |
The induration of wheals (defined as elevation and induration that are palpable in the skin) that develop as a result of intradermal immunisation with KLH or PPD will be measured in the vertical and horizontal plane using the ball point pen technique. The diameter of the induration will be measured by rolling a medium ball point pen from 10 to 20 mm outside the edge of the induration and toward the centre with just enough pressure to indent the skin slightly. |
| Cohort 1A: At 48hrs (Day 17) and 120hrs (Day 20) after first challenge. At Day 44 and 48hrs (Day 45) after second challenge. Cohort 1B: At 48hrs (Day 17) and 120hrs (Day 20) after first challenge. At Day 44, 45 and 120hrs (Day 48) after second challenge |
| Part B: Skin inflammatory response measurement in Cohort 2 by the ball point pen technique | The induration of wheals (defined as elevation and induration that are palpable in the skin) that develop as a result of intradermal immunisation with KLH or PPD will be measured in the vertical and horizontal plane using the ball point pen technique. The diameter of the induration will be measured by rolling a medium ball point pen from 10 to 20 mm outside the edge of the induration and toward the centre with just enough pressure to indent the skin slightly. | Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second challenge. |
| Part B: Erythema diameter measured in Cohort 1 by Laser Doppler Imaging (LDI) and ruler measurement. | A Laser Doppler Imager will measure the area occupied by a given wheal and associated erythema, which reflects superficial blood flow of a subject's arm. | Cohort 1A: At 48hrs (Day 17) and 120hrs (Day 20) after first challenge. At Day 44 and 48hrs (Day 45) after second challenge. Cohort 1B: At 48hrs (Day 17) and 120hrs (Day 20) after first challenge. At Day 44, 45 and 120hrs (Day 48) after second challenge |
| Part B: Erythema diameter measured in Cohort 2 by Laser Doppler Imaging (LDI) and ruler measurement. | A Laser Doppler Imager will measure the area occupied by a given wheal and associated erythema, which reflects superficial blood flow of a subject's arm. | Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second challenge. |
| Part B: Characterisation and measurement of the T-cells in skin biopsies in Cohort 1. | T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells | Cohort 1A: At 48hrs (Day 17) and 120hrs (Day 20) after first challenge. At 48hrs (Day 45) after second challenge. Cohort 1B: At 48hrs (Day 17) and 120hrs (Day 20) after first challenge. At 120hrs (Day 48) after second challenge. |
| Part B: Characterisation and measurement of the T-cells in skin biopsies in Cohort 2. | T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells | Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second challenge. |
| Part A and B: Number of subjects with adverse events as a measure of safety and tolerability | The safety and tolerability of skin challenges with KLH and PPD.administration will be assessed by adverse events (AEs), serious AE (SAE) or withdrawals due to toxicities | Part A: Day 1 to Day 4, Part B: Cohort 1A: Day 1 to Day 46.Part B: Cohort 1B:Day 1 to Day 49.Part B Cohort 2: Day 1 to 35. |
| Part A and B: changes in clinical laboratory measurements to access safety and tolerability | Screening and up to 14 days post last visit |
| Part A and B: Trends in and change from baseline for blood pressure measurements | Screening and up to 14 days post last visit |
| Trends in and change from baseline in measure of 12-lead ECG to access safety and tolerability | Electrocardiograph (ECG) is a machine that measures the electrical activity of the heart and records changes in the hearts' rhythm. | Screening and up to 14 days post last visit |
| Immediate local hypersensitivity assessment | Examination of injection site for evidence of immediate local hypersensitivity/wheal (erythema or induration will not be taken into consideration). The diameter of the wheal (central swelling/raised skin) at immunisation site, if present at time of hypersensitivity assessment, will be measured in vertical and horizontal plane using a millimetre (mm) ruler. The average will be the diameter value. If wheal is more than 5 mm in diameter than original bleb, then subject will be labelled as having immediate local hypersensitivity (ILH) and will undergo both serum total IgE and KLH or PPD prick tes | 15-30 minutes after each SC and ID challenge immunization in each Study part/Cohort |
| Part A and B: Trends in and change from baseline for heart rate measurements | Screening and up to 14 days post last visit |
| Part C: Skin inflammatory response measurement in Cohort 2 by the ball point pen technique. | The induration of wheals (defined as elevation and induration that are palpable in the skin) that develop as a result of intradermal immunisation with PPD will be measured in the vertical and horizontal plane using the ball point pen technique. The diameter of the induration will be measured by rolling a medium ball point pen from 10 to 20 mm outside the edge of the induration and toward the centre with just enough pressure to indent the skin slightly. | Cohort 2: At 48hrs (Day3) and 744hrs (Day 31). |
| Part C: Erythema diameter measured in Cohort 2 by Laser Doppler Imaging (LDI) and ruler measurement. | A Laser Doppler Imager will measure the area occupied by a given wheal and associated erythema, which reflects superficial blood flow of a subject's arm. | Cohort 2: At pre-challenge (Day1) and 48hrs (Day 3) after first challenge. At pre-challenge (Day 29) and 48hrs (Day 31) after second challenge. |
| Part C: Characterisation and measurement of the T-cells in skin blisters in Cohort 2. | T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells | Cohort 2: At 48hrs (Day3) and 72hrs (Day 4) after first challenge. At 48hrs (Day 31) and 69hrs (Day 32) after second challenge. |
| Part A , B and C: Number of subjects with adverse events as a measure of safety and tolerability | The safety and tolerability of skin challenges with KLH and PPD .administration will be assessed by adverse events (AEs), serious AE (SAE) or withdrawals due to toxicities | Part A: Day 1 to Day 4, Part B: Cohort 1A: Day 1 to Day 46.Part B: Cohort 1B:Day 1 to Day 49.Part B Cohort 2: Day 1 to 35. Part C: Cohort 1:Day 1 to Day 19. Part C Cohort 2: Day 1 to 46. |
| Part A, B and C: changes in clinical laboratory measurements to access safety and tolerability | Part A and B: Screening and up to 14 days post last visit. Part C: Screening and up to 14 days post last blister draw. |
| Part A and B: Screening and up to 14 days post last visit. Part C: Screening and up to 14 days post last blister draw. | Part A and B: Screening and up to 14 days post last visit. Part C: Screening and up to 14 days post last blister draw. |
| Trends in and change from baseline in measure of 12-lead ECG to access safety and tolerability | Electrocardiograph (ECG) is a machine that measures the electrical activity of the heart and records changes in the hearts' rhythm. | Part A and B: Screening and up to 14 days post last visit. Part C: Screening and up to 14 days post last blister draw. |
| Immediate local hypersensitivity assessments | Examination of injection site for evidence of immediate local hypersensitivity/wheal (erythema or induration will not be taken into consideration). The diameter of the wheal (central swelling/raised skin) at immunisation site, if present at time of hypersensitivity assessment, will be measured in vertical and horizontal plane using a millimetre (mm) ruler. The average will be the diameter value. If wheal is more than 5 mm in diameter than original bleb, then subject will be labelled as having immediate local hypersensitivity (ILH) and will undergo both serum total IgE and KLH or PPD prick tes | Part A and B: 15-30 minutes after each SC and ID challenge immunization in each Study part/Cohort. Part C: Screening and up to 14 days post last blister draw. |
| Part A and B: Trends in and change from baseline for heart rate measurement | Part A and B: Screening and up to 14 days post last visit. Part C: Screening and up to 14 days post last blister draw. |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D000941 |
| Antigens |
| D001685 | Biological Factors |