Clinical Trial: Characterisation of T-cell Response to Keyhole Limpet Hemocyanin (KLH) and Tuberculin Purified Protein Derivative (PPD)

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Characterisation of the T-cell Response in Delayed Type Hypersensitivity Reactions to Keyhole Limpet Hemocyanin (KLH) and Tuberculin Purified Protein Derivative (PPD) in H

Brief Summary:

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 s

Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome:

  • Part A: Skin inflammatory response measurement as induration by the ball point pen technique [ Time Frame: Over a four day period after 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 millimetre (mm) outside the edge of the induration and toward the centre with just enough pressure to indent the skin slightly.
  • Part A: Skin inflammatory response measurement as erythema diameter by Laser Doppler Imaging (LDI) and ruler measurement [ Time Frame: Over a four day period after challenge ]
    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.
  • Part A: Skin inflammatory response measurement as induration by characterisation and measurement of the T-cells in skin biopsies [ Time Frame: Over a three day period after challenge ]
    T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells
  • Part B: Characterisation of T-ce

    Original Primary Outcome:

    • Part A: Skin inflammatory response measurement as induration by the ball point pen technique [ Time Frame: Over a three day period after 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 millimetre (mm) outside the edge of the induration and toward the centre with just enough pressure to indent the skin slightly.
    • Part A: Skin inflammatory response measurement as erythema diameter by Laser Doppler Imaging (LDI) and ruler measurement [ Time Frame: Over a three day period after challenge ]
      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.
    • Part A: Skin inflammatory response measurement as induration by characterisation and measurement of the T-cells in skin biopsies [ Time Frame: Over a three day period after challenge ]
      T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells
    • Part B: Characterisation of T-

      Current Secondary Outcome:

      • Part A: Characterisation and measurement of the T-cells in skin biopsies. [ Time Frame: At 48hrs (Day 3) after challenge ]
        T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells
      • Part B: Skin inflammatory response measurement in Cohort 1 by the ball point pen technique [ Time Frame: 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 ]
        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.
      • Part B: Skin inflammatory response measurement in Cohort 2 by the ball point pen technique [ Time Frame: Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second 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.
      • Part B: Erythema diameter measured in Cohort 1 by Laser Doppler Imaging (LDI) and ruler measurement. [ Time Frame: 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 ]
        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.
      • Part B: Erythema diameter measured in Cohort 2 by Laser Doppler Imaging (LDI) and ruler measurement. [ Time Frame: Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second challenge. ]
        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.
      • Part B: Characterisation and measurement of the T-cells in skin biopsies in Cohort 1. [ Time Frame: 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. ]
        T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells
      • Part B: Characterisation and measurement of the T-cells in skin biopsies in Cohort 2. [ Time Frame: Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second challenge. ]
        T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells
      • Part A and B: Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: 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. ]
        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 and B: changes in clinical laboratory measurements to access safety and tolerability [ Time Frame: Screening and up to 14 days post last visit ]
      • Part A and B: Trends in and change from baseline for blood pressure measurements [ Time Frame: 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 [ Time Frame: Screening and up to 14 days post last visit ]
        Electrocardiograph (ECG) is a machine that measures the electrical activity of the heart and records changes in the hearts' rhythm.
      • Immediate local hypersensitivity assessment [ Time Frame: 15-30 minutes after each SC and ID challenge immunization in each Study part/Cohort ]
        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 h

        Original Secondary Outcome:

        • Part A: Characterisation and measurement of the T-cells in skin biopsies. [ Time Frame: At 48hrs (Day 3) after challenge ]
          T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells
        • Part B: Skin inflammatory response measurement in Cohort 1 by the ball point pen technique [ Time Frame: 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 ]
          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.
        • Part B: Skin inflammatory response measurement in Cohort 2 by the ball point pen technique [ Time Frame: Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second 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.
        • Part B: Erythema diameter measured in Cohort 1 by Laser Doppler Imaging (LDI) and ruler measurement. [ Time Frame: 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 ]
          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.
        • Part B: Erythema diameter measured in Cohort 2 by Laser Doppler Imaging (LDI) and ruler measurement. [ Time Frame: Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second challenge. ]
          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.
        • Part B: Characterisation and measurement of the T-cells in skin biopsies in Cohort 1. [ Time Frame: 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. ]
          T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells
        • Part B: Characterisation and measurement of the T-cells in skin biopsies in Cohort 2. [ Time Frame: Cohort 2: At 48hrs (Day3) and 120hrs (Day 6) after first challenge. At 48hrs (Day 31) and 120hrs (Day 34) after second challenge. ]
          T-cells will be analysed by immunocytochemistry or other techniques to characterise the T-cells
        • Part A and B: Number of subjects with adverse events as a measure of safety and tolerability [ Time Frame: 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. ]
          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 and B: changes in clinical laboratory measurements to access safety and tolerability [ Time Frame: Screening and up to 14 days post last visit ]
        • Part A and B: Trends in and change from baseline for blood pressure measurements [ Time Frame: 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 [ Time Frame: Screening and up to 14 days post last visit ]
          Electrocardiograph (ECG) is a machine that measures the electrical activity of the heart and records changes in the hearts' rhythm.
        • Immediate local hypersensitivity assessment [ Time Frame: 15-30 minutes after each SC and ID challenge immunization in each Study part/Cohort ]
          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 h

          Information By: GlaxoSmithKline

          Dates:
          Date Received: February 14, 2013
          Date Started: February 22, 2013
          Date Completion:
          Last Updated: May 12, 2017
          Last Verified: May 2017