Clinical trial NCT01669421: Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.
Official title: Effect of a Higher Dose of Alpha-1 Antitrypsin Augmentation Therapy on Lung Inflammation in Subjects With Alpha-1 Antitrypsin Deficiency.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alpha 1 Antitrypsin Deficiency
Keywords: Alpha 1
Lead sponsor: University of Miami
Sponsor class: OTHER
Collaborators: name: CSL Behring
First posted: 2012-08-21
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).

Detailed description: 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 and lung function testing.

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)

Primary outcomes:
measure: Changes in Inflammatory Biomarkers in Bronchoalveolar Lavage Fluid
timeFrame: Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)
Secondary outcomes:
measure: Change in Inflammatory Biomarkers in Serum Samples
timeFrame: Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)
measure: Number of Adverse Events Reported
timeFrame: From Week 1 to week 12
Other outcomes:
measure: Elastin Degradation in BAL
timeFrame: Week 4 vs Week 8 vs Week 12
Locations:
city: Miami
country: United States
facility: Division of Pulmonary and Critical Care, Human Reseach, U of Miami
state: Florida
Study officials:
affiliation: University of Miami
name: Michael A Campos, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010 Oct;4(5):289-312. doi: 10.1177/1753465810373911. Epub 2010 Jul 22.
citation: 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. doi: 10.1164/rccm.2109013.
citation: 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. doi: 10.2147/btt.2009.3088. Epub 2009 Jul 13.
citation: Campos MA, Geraghty P, Holt G, Mendes E, Newby PR, Ma S, Luna-Diaz LV, Turino GM, Stockley RA. The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial. Am J Respir Crit Care Med. 2019 Aug 1;200(3):318-326. doi: 10.1164/rccm.201901-0010OC.