Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.
Condition: Alpha 1 Antitrypsin Deficiency
MeSH terms: Pneumonia; Alpha 1-Antitrypsin Deficiency; Inflammation
Intervention: Alpha-1 Antitrypsin (human)
Intervention description: Comparison of Zemaira (Alpha 1 Antitrypsin Human) 120 mg/kg/weekly for four weeks versus 2 phases with same drug administered at standard doses of 60 mg/kg/weekly for four weeks each
Intervention MeSH terms: Protease Inhibitors; Alpha 1-Antitrypsin; Protein C Inhibitor
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Alpha 1

Summary:

      The current treatment of individuals with alpha-1 antitrypsin deficiency (AATD) who develop
      lung disease (COPD) is the administration of intravenous purified alpha-1 antitrypsin
      (augmentation therapy) at a fixed dose of 60 mg/kg per week. This dose aims at increasing the
      deficient AAT serum levels just above a predetermined "safety threshold" of 11 uM. However,
      normal levels of AAT are between 25-50 uM.

      AAT has shown not only to inhibit lung proteases such as neutrophil elastase, but also to
      modulate inflammation. Given that many subjects with AATD who receive augmentation therapy
      still have significant lung disease and inflammation, this study will evaluate whether
      doubling the dose to 120 mg/kg/week has an effect in decreasing lung inflammation.

      Only the dosing of 60 mg/kg /week has received FDA approval. FDA has granted an IND number to
      this study to test the higher dose of 120 mg/kg/week.

      The study will evaluate systemic (serum) and pulmonary (bronchoscopy samples)markers of
      inflammation in 3 phases: standard dose (4 weeks), double dose (4 weeks) and standard dose (4
      weeks).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Males or Females aged between 18 and 75 years.

          -  Diagnosis of AATD, based on documentation of "at-risk" genotypes such as Pi ZZ, SZ or
             Znull OR documentation of a pre-therapy AAT level < 11 µM.

          -  Evidence of COPD (emphysema or airflow obstruction) with FEV1 < 80%

          -  Receiving standard dose of augmentation therapy (with any commercial formulation) for
             at least 1 month at the dose of 60 mg/kg/week.

          -  At least ONE of the following criteria of disease severity:

               -  2 or more acute exacerbations or 1 hospitalization due to respiratory symptoms in
                  the past 12 months. Definition of exacerbations: the use of antibiotics and a
                  course of steroids to treat a flare of pulmonary symptoms, regardless if the
                  subject required emergency room care or hospital admission. The diagnosis of the
                  acute exacerbation will be obtained by direct history obtained from the patient
                  and confirmed by the PI. Attempts should be made to have documentation from the
                  patient's treating physicians, although not required for study entry.

               -  St. George Respiratory Questionnaire (SGRQ) total score ≥ 60.

               -  Chronic bronchitis: daily or almost daily sputum expectoration at least 3 months
                  of the year for at least 2 consecutive years. The diagnosis of chronic bronchitis
                  will be obtained by direct history obtained from the patient and confirmed by the
                  PI. Attempts should be made to have documentation from the patient's treating
                  physicians, although not required for study entry.

               -  Documented FEV1 decline of at least ≥ 60 ml/year for 2 consecutive years while
                  receiving augmentation therapy

        Exclusion Criteria:

        - Patients unsuitable to have a bronchoscopy due to poor clinical condition as judged by
        the PI. In general we will exclude subjects with hypoxemia, coagulopathy or FEV1 below 40%
        predicted.

        Note: Subjects with FEV1 values below 40% predicted may be included and reassessed after
        optimization of therapy. Final determination to include the patient if deemed suitable for
        the procedure will be determined by the PI before first planned bronchoscopy (regardless of
        FEV1 value).

          -  Patients participating in other clinical trials.

          -  Use of chronic antibiotics or oral steroids

          -  Continues to smoke

          -  Inability to sign informed consent

          -  Pregnancy or willing to become pregnant

          -  Known IgA deficiency (we will include only patients already receiving augmentation
             therapy so it will be unlikely to encounter this exclusion criteria)