Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.
| Status: | Completed |
|---|---|
| Conditions: | Pneumonia |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 10/14/2017 |
| Start Date: | July 2012 |
| End Date: | May 2016 |
Effect of a Higher Dose of Alpha-1 Antitrypsin Augmentation Therapy on Lung Inflammation in Subjects With Alpha-1 Antitrypsin Deficiency.
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).
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).
This is a pilot study to test the effect of double dose augmentation therapy with Zemaira
(CSL Behring) on lung inflammation, compared with standard doses of 60 mg/kg/week.
Our hypothesis is that some patients with AATD receiving augmentation therapy at the standard
dose of 60 mg/kg/week continue to have a significant lung inflammation that may lead to
detrimental clinical consequences. This inflammation can be further reduced with higher AAT
dosing.
The study will enroll 20 subjects with AATD and COPD already receiving augmentation therapy
with any brand at standard doses for at least a month. For inclusion and exclusion criteria
see below.
Protocol:
The study will take place over approximately 12 weeks: a month receiving Zemaira at standard
dose (60 mg/kg/week), a month at double dose (120 mg/kg/week) and a month at standard dose
(60 mg/kg/week). The infusions at standard doses will be done at home and infusions with
higher doses will be provided at the study site.
the study involves scheduled blood draws for clinical labs and serum for research samples. At
the end of each phase a bronchoscopy will be performed (3 in total) to obtain research
samples (lung lavage, brushings and endobronchial biopsies).
The first bronchoscopy after receiving 4 weeks of standard augmentation therapy will assess
the "residual" inflammation that may be present despite augmentation therapy. The second
bronchoscopy after double dose augmentation therapy phase will be to assess changes
(decreases) in inflammatory markers. The third bronchoscopy after resuming standard dosing is
to assess if inflammation returned to baseline levels (required for proof of concept).
There will be approximately 9 visits to the study clinic. This study does not include placebo
(no active drug) treatment. Besides blood draws and bronchoscopy, the study will include
questionnaires, lung function testing and urine sample testings.
(CSL Behring) on lung inflammation, compared with standard doses of 60 mg/kg/week.
Our hypothesis is that some patients with AATD receiving augmentation therapy at the standard
dose of 60 mg/kg/week continue to have a significant lung inflammation that may lead to
detrimental clinical consequences. This inflammation can be further reduced with higher AAT
dosing.
The study will enroll 20 subjects with AATD and COPD already receiving augmentation therapy
with any brand at standard doses for at least a month. For inclusion and exclusion criteria
see below.
Protocol:
The study will take place over approximately 12 weeks: a month receiving Zemaira at standard
dose (60 mg/kg/week), a month at double dose (120 mg/kg/week) and a month at standard dose
(60 mg/kg/week). The infusions at standard doses will be done at home and infusions with
higher doses will be provided at the study site.
the study involves scheduled blood draws for clinical labs and serum for research samples. At
the end of each phase a bronchoscopy will be performed (3 in total) to obtain research
samples (lung lavage, brushings and endobronchial biopsies).
The first bronchoscopy after receiving 4 weeks of standard augmentation therapy will assess
the "residual" inflammation that may be present despite augmentation therapy. The second
bronchoscopy after double dose augmentation therapy phase will be to assess changes
(decreases) in inflammatory markers. The third bronchoscopy after resuming standard dosing is
to assess if inflammation returned to baseline levels (required for proof of concept).
There will be approximately 9 visits to the study clinic. This study does not include placebo
(no active drug) treatment. Besides blood draws and bronchoscopy, the study will include
questionnaires, lung function testing and urine sample testings.
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)
We found this trial at
1
site
Miami, Florida 33136
Principal Investigator: Michael A Campos, MD
Phone: 305-243-3045
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