Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.
Information source: University of Miami
ClinicalTrials.gov processed this data on December 21, 2014
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Alpha 1 Antitrypsin Deficiency
Intervention: Alpha-1 Antitrypsin (human) (Drug)
Phase: Phase 2
Sponsored by: Michael Campos, MD
Official(s) and/or principal investigator(s):
Michael A Campos, MD, Principal Investigator, Affiliation: University of Miami
Michael A Campos, MD, Phone: (305)243-6387, Email: firstname.lastname@example.org
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
Official title: Effect of a Higher Dose of Alpha-1 Antitrypsin Augmentation Therapy on Lung Inflammation in Subjects With Alpha-1 Antitrypsin Deficiency.
Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: CHANGES IN CYTOKINE PROFILE IN BRONCHOALVEOLAR LAVAGE
CHANGES IN SERUM INFLAMMATORY MARKERS
EFFECT OF DOUBLE DOSE ZEMAIRA ON ELASTIN DEGRADATION
EFFECT OF DOUBLE DOSE ZEMAIRA ON NEUTROPHIL APOPTOSIS AND MIGRATION
CHANGES IN NEUTROPHILIC LUNG INFILTRATION
NUMBER OF ADVERSE EVENTS REPORTED
CHANGES IN METABOLIC AND COAGULATION PROFILES
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
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.
Minimum age: 18 Years.
Maximum age: 75 Years.
- Males or Females aged between 18 and 75 years.
- Diagnosis of AATD with an "at-risk" genotype (i. e.Pi ZZ, SZ or Znull)
- Evidence of COPD (emphysema or airflow obstruction) with FEV1 < 80%
- Receiving standard dose of augmentation therapy for at least 1 month at the dose of
- At least ONE of the following criteria of disease severity:
- 1 or more acute exacerbations 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
- 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.
- Documented FEV1 decline of at least > 60 ml/year for 2 consecutive years while
receiving augmentation therapy
Exclusion Criteria at study entry:
- Patients participating in other clinical trials.
- Use of chronic antibiotics or oral steroids
- Continues to smoke
- Contraindications for bronchoscopy
- Inability to sign informed consent
- Pregnancy or willing to become pregnant
- Known IgA deficiency
Criteria to be met before first bronchoscopy:
- FEV1 > 40% predicted
- At least 4 weeks on Zemaira
- No Recent exacerbation (> 4 weeks)
- No recent use of systemic steroids or exacerbations (> 4 weeks)
- Should be on standard COPD treatment as specified below
Medications: Subjects will be receiving standard COPD medications during the trial. These
medications will include at least one long-acting bronchodilator and an inhaled steroid.
Subjects that are not using these medications will be started on them at least 1 month
before starting the study.
Subjects will be recruited from the investigator own pool of patients, and by invitation
through patient support groups and Alpha-1 Foundation's Research Registry. We anticipate
enrollment of 20 subjects.
Subjects not receiving Zemaira: Subjects with AATD and COPD receiving augmentation therapy
with a brand other than Zemaira® (Glassia®, Prolastin®, Aralast®) who are interested in
participating in this study, will have to be switched to Zemaira®.
Subjects of childbearing potential: Zemaira has no pregnancy safety recommendations. In
general It is unknown if Zemaira can cause harm to the fetus. Because this study uses an
IND label, we will not enroll pregnant women or women with childbearing potential not
using acceptable birth control methods. Acceptable methods of birth control include:
- birth control pills taken for at least one month before study enrolment.
- Implanted birth control devices such as Implanon®, if received at least one month
- Intra-uterine devices
- Hysterectomy or surgical sterilization
- Abstinence (no sexual intercourse)
- Double-barrier method including a diaphragm with spermicidal gel or a condom with
contraceptive foam We will monitor urine pregnancy tests, at study entry, before and
after receiving double dose of augmentation therapy and at the last study visit.
Locations and Contacts
Michael A Campos, MD, Phone: (305)243-6387, Email: email@example.com
Division of Pulmonary and Critical Care, Human Reseach, U of Miami, Miami, Florida 33136, United States; Recruiting
Michael A Campos, MD, Phone: 305-243-3045, Email: firstname.lastname@example.org
Patricia Rebolledo, MD, Phone: (305)243-5549, Email: email@example.com
Michael A Campos, MD, Principal Investigator
Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010 Oct;4(5):289-312. Epub 2010 Jul 22. Review.
Stockley RA, Bayley DL, Unsal I, Dowson LJ. The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2002 Jun 1;165(11):1494-8.
Petrache I, Hajjar J, Campos M. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biologics. 2009;3:193-204. Epub 2009 Jul 13.
Starting date: July 2012
Last updated: October 13, 2014