Deposition of Inhaled Prolastin in Cystic Fibrosis Patients (CF2)

Multicenter, Randomized, Parallel Group Study to Investigate the Optimal Deposition Site for Inhaled Prolastin® in Patients With Cystic Fibrosis (CF)

The objective of this trial is to determine the optimal region of the lung for depositing Prolastin (alpha-1 antitrypsin; AAT) by inhalation in order to treat cystic fibrosis (CF). The AKITA® nebulizer has settings which can be varied to target the inhaled drug to either the deep lung or to the upper airways in a one to one randomization. The study will measure how much of the activity of the enzyme elastase is inhibited by AAT.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Alpha1-Proteinase Inhibitor (Human)

Detailed Description

The optimum deposition site (bronchial or peripheral) in CF patients for AAT will be investigated by measuring several parameters in induced sputum. The study will start with a 2 week run-in period in which the planned 60 patients inhale isotonic saline once daily. This period is followed by a 4 week treatment period where 30 patients inhale AAT for peripheral deposition and 30 patients inhale AAT for bronchial deposition. Six patients in each group will be asked to collect spontaneous sputum at home.

Twenty-five milligrams of AAT will be deposited at one of the two target sites using the AKITA® device. The inhalation should take place in the evening between 18.00 and 23.00 h.

Patients will inhale saline once daily for 2 weeks (run-in period) followed by 4 weeks of once daily inhalation of AAT. Induced sputum will be collected at visits to the clinic at the start of the run-in, at the start of AAT treatment, and at 2 and 4 weeks after the start of AAT treatment.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with diagnosis of CF
• Age >= 8 years
• Forced expiratory volume at one second (FEV1) > 25 % of predicted value
• Free elastase activity checked at visit 1 must be positive (free elastolytic activity in the sample, 2 standard deviations above of the negative blank samples in the assay.) .
• Patient must be positive at least 3 times for pseudomonas in the last 2 years
• Patient must be positive for pseudomonas at Visit 1
• Patient must be able to perform reliable spirometry
• Patient must be on stable concomitant therapy at least 2 weeks prior to visit 1 and during the study
• Written informed consent of the patient or legal representative(s)

Exclusion Criteria:

• FEV1 < 25% of predicted value post-bronchodilator
• History of lung transplant
• Any lung surgery within the past 2 years
• On any thoracic surgery waiting list
• Severe concomitant disease (serious malignant disease, congestive heart failure New York Heart Association (NYHA) III/IV, cor pulmonale with the need of oxygen therapy)
• Severe liver cirrhosis with ascites, hypersplenism or grade III/IV esophageal varices.
• Known selective immunoglobulin A (IgA) deficiency with known antibody against IgA (anti-IgA antibody)
• Active pulmonary exacerbation within the 4 weeks prior to screening
• Current Smoking
• Pregnancy or lactation
• Women of child-bearing age without adequate contraception
• Any medical condition which the investigator feels will prohibit the patient from completing the trial
• Participation in another clinical trial within 30 days prior to inclusion at visit 1

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group 1; Bronchial Deposition Intervention: Alpha1-Proteinase Inhibitor (Human) Dosage: 25 mg in lungs, one inhalation per day over 4 weeks	Drug: Alpha1-Proteinase Inhibitor (Human); 25 mg of Alpha1-Proteinase Inhibitor (Human) in the lungs, one inhalation per day over 4 weeks.; Other Names: TAL-05-00007; BAY x 5747; BAY 10-5233; NDC 13533-601-30; NDC 13533-601-35; Prolastin®; Alpha-1 antitrypsin (AAT); A1AT
EXPERIMENTAL: Group 2; Peripheral Deposition Intervention: Alpha1-Proteinase Inhibitor (Human) Dosage: 25 mg in lungs, one inhalation per day over 4 weeks	Drug: Alpha1-Proteinase Inhibitor (Human); 25 mg of Alpha1-Proteinase Inhibitor (Human) in the lungs, one inhalation per day over 4 weeks.; Other Names: TAL-05-00007; BAY x 5747; BAY 10-5233; NDC 13533-601-30; NDC 13533-601-35; Prolastin®; Alpha-1 antitrypsin (AAT); A1AT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Free Elastase in Induced Sputum From Baseline to Week 4	Baseline vs Week 4

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in Alpha-1-anti-trypsin (A1AT) Activity in Induced Sputum From Baseline at Week 4	Baseline vs Week 4
Change in Total Immunoglobulin G (IgG) Fragments in Induced Sputum From Baseline at Week 4	Baseline vs Week 4
Change in Total Bacterial Load in Induced Sputum From Baseline to Week 4	Week 4
Change in Pseudomonas Load in Induced Sputum From Baseline at Week 4	Baseline vs Week 4
Change in Neutrophil Number in Induced Sputum From Baseline at Week 4	Baseline vs Week 4

Collaborators and Investigators

• Sponsor: Grifols Therapeutics LLC
• Investigators: Principal Investigator: Matthias Griese, MD, Kinderklinik und Kinderpoliklinik im Haunerschen Kinderspital

Publications and helpful links

General Publications

• Griese M, Latzin P, Kappler M, Weckerle K, Heinzlmaier T, Bernhardt T, Hartl D. alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur Respir J. 2007 Feb;29(2):240-50. doi: 10.1183/09031936.00047306. Epub 2006 Oct 18.

Helpful Links

• FDA Approved Product Labeling Information

Study record dates

Study Major Dates

• Study Start: December 1, 2003
• Primary Completion (ACTUAL): June 1, 2004
• Study Completion (ACTUAL): June 1, 2004

Study Registration Dates

• First Submitted: June 13, 2007
• First Submitted That Met QC Criteria: June 13, 2007
• First Posted (ESTIMATE): June 15, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): August 21, 2014
• Last Update Submitted That Met QC Criteria: August 5, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Protease Inhibitors; Alpha 1-Antitrypsin
• Other Study ID Numbers: 100452