Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.

NCT01669421 | Completed Phase 2 Results

• 1 other identifier: 20100844
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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).

Conditions

Alpha 1 Antitrypsin Deficiency

Keywords

Alpha 1

Outcome Measures

Primary Outcomes (1)

• Changes in Inflammatory Biomarkers in Bronchoalveolar Lavage Fluid

  Assess the variations in the levels of several cytokines and inflammatory biomarkers in BAL after changing A1PI dosing. Measures were done using the bead technology.

  Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)

Secondary Outcomes (2)

• Change in Inflammatory Biomarkers in Serum Samples

  Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)

• Number of Adverse Events Reported

  From Week 1 to week 12

Other Outcomes (1)

• Elastin Degradation in BAL

  Week 4 vs Week 8 vs Week 12

Study Arms (3)

Alpha-1 Antitrypsin (human) standard dose baseline

EXPERIMENTAL

Alpha-1 Antitrypsin (human) 60 mg per kg per week for 4 weeks. Study week 4

Drug: Alpha-1 Antitrypsin (human)

Alpha-1 Antitrypsin (human) Double dose

EXPERIMENTAL

Alpha-1 Antitrypsin (human) 120 mg/kg per week for 4 weeks. Study week 8

Drug: Alpha-1 Antitrypsin (human)

Alpha-1 Antitrypsin (human) standard dose

EXPERIMENTAL

4 weeks on A1PI at 60 mg/kg per week after the other 2 phases. Collected@ study week 12

Drug: Alpha-1 Antitrypsin (human)

Interventions

Alpha-1 Antitrypsin (human) DRUG

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

Also known as: Zemaira, Alpha-1 proteinase inhibitor (human)

Alpha-1 Antitrypsin (human) Double dose; Alpha-1 Antitrypsin (human) standard dose; Alpha-1 Antitrypsin (human) standard dose baseline

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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

You may not qualify if:

• \- 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

Sponsors & Collaborators

• Michael Campos, MD: lead
• CSL Behring: collaborator

Study Sites (1)

Division of Pulmonary and Critical Care, Human Reseach, U of Miami

Miami, Florida, 33136, United States

Location

Related Publications (4)

• 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.

  PMID: 20650978 BACKGROUND

• 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.

  PMID: 12045122 BACKGROUND

• 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.

  PMID: 19707408 BACKGROUND

• 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.

  PMID: 30965011 DERIVED

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Interventions

alpha 1-Antitrypsin

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Glycoproteins; Glycoconjugates; Carbohydrates; Serpins; Peptides; Amino Acids, Peptides, and Proteins; Acute-Phase Proteins; Blood Proteins; Proteins; Alpha-Globulins; Serum Globulins; Globulins

Results Point of Contact

• Title: Michael Campos
• Organization: University of Miami

mcampos1@med.miami.edu

305-243-3045

Study Officials

• Michael A Campos, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 14, 2012
• First Posted: August 21, 2012
• Study Start: July 1, 2012
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: May 8, 2019
• Results First Posted: May 8, 2019

Record last verified: 2019-04

Locations

US (1)