Therapeutic Effect of Tacrosolv in Patients With Allergic Rhinoconjunctivitis
Condition: Allergic Conjunctivitis; Allergic Rhinitis
MeSH terms: Rhinitis; Rhinitis, Allergic; Conjunctivitis; Conjunctivitis, Allergic
Study type: Interventional
Phase: Phase 2

Summary: 
      Allergic conjunctivitis is one of the most common comorbidities of allergic diseases,
      especially of allergic rhinitis.

      Rhinoconjunctivitis is an allergic condition of the nasal mucosa and the eyes. Conjunctivitis
      is triggered by hypersensitivity to certain pollens and other airborne allergens and causes
      several symptoms such as reddened eyes, itchy eyes and can cause watery eyes and a scratchy
      feeling in the eye. Tacrolimus is a well-known immunosuppressiv active substance which is
      hardly soluble in water. Within Tacrosolv, Tacrolimus is completely dissolves in aqueous
      solution. The effectiveness of Tacrosolv will be tested for treatment of allergic
      conjunctivitis. Allergic subjects will be treated with aqueous formulation of tacrolimus
      'Tacrosolv 50 micrograms per milliliter, eye drops' for 8 days. On day 1 and day 8 allergic
      patients will be challenged with grass pollen for a period of 4 hours and subjective allergic
      symptoms will be assessed.
    

Detailed description: 
      This is a randomized, placebo controlled, crossover, double-blind, single site trial in adult
      subjects (18-65 years of age) who have demonstrated grass specific Immunglobulin E (IgE)
      reactivity and have a history of grass pollen induced rhinoconjunctivitis with or without
      controlled asthma. The crossover design will ensure that individual subjects will receive
      either one drop Tacrosolv compared to two drops placebo or 2 drops Tacrosolv compared to 1
      drop placebo.

      The primary objective of the trial is to demonstrate the safety and efficacy of two doses of
      Tacrosolv on day 8 of treatment. To assure full blinding, two study populations are treated
      in a crossover design against placebo.

      The evaluation will be based on the assessment of ocular symptoms during grass pollen
      challenge performed in the Vienna Challenge Chamber (environmental exposure chamber).

      Secondary objective of the trial is to evaluate the onset of action of either dose of
      Tacrosolv on day one of treatment as well as efficacy differences between low dose and high
      dose treatment on day eight.

      Visit 1 - Screening:

      At least one week prior to first treatment block, subjects will be screened for appropriate
      allergic response during a grass pollen challenge chamber session. A total ocular symptom
      score (TOSS) of at least 4 points out of 12 within the first two hours in the grass pollen
      challenge chamber is required to be included into the study.

      Visit 2 - Inclusion:

      In addition to the screening provocation the medical and allergic history, safety lab as well
      as retrieving inclusion and exclusion criteria will be assessed via anamnesis. Furthermore,
      all safety assessments will be conducted.

      Note: Visit 1 and visit 2 could be done on the same day!

      Visit 3 & 5: Day1 of the respective treatment period

      Eligible subjects will be randomly assigned to one of the four treatment arms (fully blinded)
      in the order of their screening numbers assigned at visit 1.

      Subjects will attend the study site about two hours ahead of the start of allergen
      provocation. After positive completion of all study relevant assessments, baseline values for
      symptom scores will be assessed approximately 45 minutes before entering the grass pollen
      challenge chamber. Subjects will receive their first treatment 30 minutes before entering the
      challenge chamber. During the 4 hours grass pollen challenge subjective and objective
      assessments will be recorded.

      The subjective ocular symptom score, as well as the other symptom scores, will be recorded
      every fifteen minutes during a 4-hour allergen exposure challenge. Before and after
      provocation session several ocular assessments will be performed.

      After the allergen challenge, subjects will receive study medication for the home treatment
      phase (days 2 to 7) and continue treatment into each conjunctival sac once a day (in the
      morning) until day 7.

      Visit 4 & 6: Day8 of respective treatment period

      On day 8 of their respective treatment block, subjects will attend the study site about two
      hours before provocation starts. Before receiving their last treatment dose, baseline symptom
      scores will be assessed. Subjects will take their last treatment dosage approximately half an
      hour before entering the challenge chamber for a 4-hour allergen exposure challenge.
      Subjective symptom scores will be recorded every fifteen minutes. Slit lamp biomicroscopy
      including all other ocular assessments as mentioned above will be performed before and after
      the provocation session.

      Between the respective study treatments, a wash-out period of at least 13 days must be
      adhered to allowing complete dissipation of the previous treatment.

      After the wash-out period, subjects change to their respective next treatment block.

      During the entire trial, subjects will be asked to monitor for adverse events (AEs), and they
      will record the use of concomitant medications on the provided form. Female subjects of
      child-bearing potential will complete a urine pregnancy test during screening and on D1 of
      each treatment period.

      Following parameters will be assessed:

        -  Subjective symptom score (nasal, ocular, respiratory) during the grass pollen challenge
           lasting for 4 hours - every 15 minutes

        -  Active anterior rhinomanometry (AAR) - every 60 minutes

        -  Lung function tests using regular spirometry for FEV1 and FVC - every 60 minutes

        -  Vital signs - every visit, pre- and post-challenge

        -  Physical examination - at Screening and Follow up

        -  Objective ocular measurements performed in the following order so that one does not
           affect the other:

             -  Break up time (BUT): Tear break up time will be measured following the guidelines
                published in the Report of the International Dry Eye Work Shop (DEWS) 2007.13

             -  Staining of the conjunctiva with lissamine green: it stains epithelial cells only
                if the cell membrane is damaged.

             -  Staining of the cornea with fluorescein: Principally for assessing corneal damage,
                fluorescein should be instilled in a similar way, but with the excess saline on the
                strip shaken off to instill a minimal volume.

             -  Conjunctival chemosis: Lid-parallel conjunctival folds (LIPCOF) will be evaluated
                with a slit-lamp microscope.

             -  Conjunctival redness: The most common clinical sign that is suggestive of ocular
                surface inflammation is conjunctival redness. Ocular redness can be easily detected
                with a pen torch or standard slit lamp biomicroscopic examination.

             -  Slit lamp microscopy: Assessment of eyelid edema and conjunctival papillae.

             -  Assessment of intraocular pressure (IOP) measured with tonometer.

             -  Assessment of further ocular symptoms including itching, blurred vision,
                grittiness.

        -  Safety laboratory assessments: Complete blood count with differential, blood chemistry,
           liver function, urine dipstick test - at screening visit, serology at screening and drug
           of abuse test on investigator's decision

        -  Skin Prick Test with skin prick test solution (Manufacturer Allergopharma) - at
           Screening or within the previous 12 months

        -  Specific CAP analysis (g6) - at Screening or within the previous 12 months

        -  Vital signs, physical examination and ECG - at screening and follow-up visit

        -  Adverse events - throughout the study

        -  Concomitant medication - throughout the study

      One to two weeks after the final provocation session, subjects will complete the trial after
      their follow up visit.

      The trial design is appropriate for the indication studied. Validated methods of data
      collection, analysis, and evaluation will be used for the trial.

      The trial endpoints are listed below:

      Primary efficacy endpoint:

      The primary efficacy endpoint will be the mean 'Total Ocular Symptom Score' (TOSS),
      calculated as the baseline adjusted mean of TOSS measured every 15 minutes during the grass
      pollen allergen exposure challenge from time-point 0 to 4 hours on day 8.

      TOSS is defined as the sum of the four individual ocular symptoms:

        -  ocular redness

        -  ocular itching

        -  watery eye

        -  gritty feeling

      each scored on a 4-point categorical scale from 0-3 with

      "0"= none "1"=mild "2"=moderate "3"=severe

      Secondary efficacy endpoints:

        -  Change in ocular redness image score

        -  Total nasal symptom score (TNSS) is the sum of the symptoms "nasal congestion",
           "rhinorrhea"", "itchy nose" and "sneezing".

        -  Total respiratory symptom score (TRSS) is the sum of the symptoms "cough", "wheeze",
           "dyspnea".

        -  Nasal airflow (AAR) will be assessed every 60 minutes during the four hours grass pollen
           allergen exposure challenge

      Each individual symptom of TNSS and TRSS will be scored on a 4-point categorical scale from
      0-3 (where "0"= none, "1"=mild, "2"=moderate, "3"=severe). TNSS and TRSS will be assessed
      every 15 minutes during the four hours grass pollen allergen exposure challenge.

      Safety endpoints:

        -  Adverse events (AEs)

        -  Safety laboratory

        -  ECG

        -  Spirometry (FeV1, FVC)

        -  Ocular assessments
    

Intervention name(s): Eye Drops, Solution in Single-Dose Container
Intervention type(s): Drug
Intervention description(s): Application of eye drops
Intervention MeSH terms: Ophthalmic Solutions
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized, placebo controlled, double-blind, single site trial in a validated allergen exposure chamber setting using grass pollen induced rhinoconjunctivitis.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Conjunctivitis; Allergic rhinoconjunctivitis; Tacrolimus; Allergen exposure chamber; Total Ocular Symptom Score; Onset of action; Tacrosolv; Ocular redness; Vienna Challenge Chamber