Aztreonam Lysine for Pseudomonas Infection Eradication Study (ALPINE)

Open-Label Phase 2 Trial to Evaluate the Safety and Efficacy of Aztreonam 75 mg Powder and Solvent for Nebuliser Solution/Aztreonam for Inhalation Solution (AZLI) in Pediatric Patients With Cystic Fibrosis (CF) and New Onset Lower Respiratory Tract Culture Positive for Pseudomonas Aeruginosa (PA)

This is an open-label, multi-center study in pediatric patients age 3 months to less than 18 years with cystic fibrosis (CF) and newly detected Pseudomonas aeruginosa (PA) pulmonary colonization/infection. All eligible participants will be treated with a 28-day course of Aztreonam for Inhalation Solution (AZLI) 75 mg 3 times daily. After completion of study drug, subjects will be followed up through Day 196 for safety and recurrence of PA.

The primary objective is to evaluate the proportion of participants with PA-negative cultures at all time points during a 6-month monitoring period (through Day 196) after cessation of AZLI treatment. Microbiological cultures will be obtained at Baseline, Day 28 (end of AZLI treatment), Day 56 (1 month after completing AZLI treatment), Day 112 (3 months after completing AZLI treatment), and Day 196 (6 months after completing AZLI treatment).

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Aztreonam for Inhalation Solution (AZLI)

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Medizinische Universität Innsbruck Abt. für Kinder- und Jugendheilkunde, Pädiatrie III (Zystische Fibrose)
• Belgium
  • Brussels, Belgium, 1020
    • Hôpital Universitaire des Enfants Reine Fabiola Brussels
  • Brussels, Belgium, 1090
    • Paediatrics, University Hospital Brussels (UZB)
  • Ghent, Belgium, 9000
    • Pediatric Respiratory Department, Ghent University Hospital
  • Leuven, Belgium, 3000
    • Pediatric Pulmonology, Dept Pediatrics University Hospital Gasthuisberg
• France
  • Bordeaux, France, 33076
    • CHU de Boredaux Hôpital des Enfants - Pellegrin CEDRE
  • Clermont Ferrand, France, 63003
    • CRCM mixte / CHU ESTAING
  • Creteil, France, 94000
    • CHI de Créteil Departement pediatrie
  • Lisieux, France, 14100
    • Centre hospitalier Robert Bissons CRCM - service pédiatrie
  • Paris, France
    • Hôpital Robert Debré
  • Paris, France, 75743
    • Service pédiatrie II Hôpital Necker Enfants Malades
  • Roscoff, France, 29684
    • Centre de Ressources et de Compétences sur la Mucoviscidose ( CRCM), Roscoff, France
• Germany
  • Berlin, Germany, 13353
    • Charité Campus Virchow Klinikum, Universitätsmedizin Berlin, Klinik für Pädiatrie mit Schwerpunkt Pneumologie/Immunolgie Prof. Wahn
  • Bochum, Germany
    • Klinik fur Kinder- und Jugendmedizinim St Josef-Hopsital
  • Erlangen, Germany, 91054
    • Universitätsklinikum Essen, Zentrum für Kinderheilkunde - Abteilung Allg. Kinderheilkunde/Neuropaediatrie
  • Essen, Germany
    • Universitaetsklinikum Bonn-Zentrum fuer Kinderheikunde
  • Frankfurt, Germany, 60590
    • Christiane Herzog CF-Center, Goethe University Hospital
  • Giessen, Germany, 35392
    • Universitätsklinikum Giessen und Marburg GmbH
  • Tubingen, Germany, 72076
    • University Children's Hospital
• Italy
  • Catania, Italy, 95123
    • Azienda Ospedaliero-Universitaria di Catania, Dipartimento di Pediatria, UO Broncopneumologia Pediatrica
  • Florence, Italy, 50139
    • Cystic Fibrosis Centre Paediatric Department, A. Meyer Children Hospital Florence
  • Napoli, Italy, 80131
    • Universita' Federico II di Napoli
  • Rome, Italy, 00165
    • Fondazione IRCCS, Ospedale Pediatrico, Bambino Gesu' di Roma
  • Verona, Italy, 37126
    • Centro Fibrosi Cistica di Verona, Azienda Ospedaliera Universitaria Integrata di Verona
• Netherlands
  • Rotterdam, Netherlands, 3015 GJ
    • Division of Respiratory Medicine and Allergology, Department of Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
  • Utrecht, Netherlands, 3584 EA
    • Longziekten Universitair Medisch (PEDIATRIC), Ultrecht
• Poland
  • Bialystok, Poland, 15-003
    • ISPL Centrum Medyczne
  • Gdansk, Poland, 80-308
    • Specjalistyczny Zespół Opieki Zdrowotnej nad Matką i Dzieckiem, Poradnia Leczenia Mukowiscydozy
  • Rabka Zdroj, Poland, 34-700
    • Instytut Gruźlicy i Chorób Płuc, Klinki Pneumologii i Mukowiscydozy
  • Warszawa, Poland, 01-211
    • Instytut Matki i Dziecka Klinika Pediatrii
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall D' Hebron Pediatric Pneunmonology and Cystic Fibrosis Clinic
  • Madrid, Spain, 28049
    • Hospital Ramón y Cajal
  • Madrid, Spain, 28009
    • Hospital infantil Universitario Niño Jesus, Servicio de Neumología Pediatrica
  • Madrid, Spain
    • Hospital Infantil La Paz
  • Malaga, Spain, 29011
    • Hospital Materno-Infantil Carlos Haya, Servicio de Neumología Pediatrica
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic- Jacksonville
    • Orlando, Florida, United States, 32801
      • Nemours Childrens Clinic Orlando
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital and Clinics
    • St. Louis, Missouri, United States, 63104
      • Saint Louis University
  • New York
    • Great Neck, New York, United States, 11021
      • Cohen Children's Medical Center of NY
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Chapel Hill
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Toledo, Ohio, United States, 43606
      • Toledo Children's Hospital CF Research Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • PennState Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53201
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females age 3 months to less than 18 years
• Diagnosis of CF as determined by the 1997 CF Consensus Conference criteria:
• Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test OR
• Abnormal nasal transepithelial potential difference test OR
• Two well-characterized, disease-causing genetic mutations in the CF transmembrane conductance regulator (CFTR) gene AND
• One or more clinical features consistent with CF
• Documented new onset of positive lower respiratory tract culture (e.g., throat swab, sputum, or BAL) for PA within 30 days of study entry (prior to screening visit) defined as either first lifetime documented PA-positive culture OR PA recovered after at least a 2 year history of PA-negative respiratory cultures (at least 2 cultures per year)
• Forced expiratory volume in 1 second (FEV1) ≥ 80% predicted at screening visit (subjects ≥ 6 years of age)
• Clinically stable with no evidence of significant respiratory symptoms or, if obtained for clinical evaluation, no chest radiograph findings at screening that would have required administration of IV antipseudomonal antibiotics, oxygen supplementation, or hospitalization.
• All sexually active females who were of childbearing potential must agree to use a highly effective method of contraception during heterosexual intercourse throughout the study. Females utilizing hormonal contraceptives as a birth control method must have used the same method for at least 3 months prior to study drug dosing.
• Males must agree to use barrier contraception (condom with spermicide) during heterosexual intercourse from screening through to study completion and for 90 days from the last dose of study investigational medicinal product
• Participants and/or parent/guardian must be able to give written informed consent prior to any study related procedure

Exclusion Criteria:

• Use of IV or inhaled antipseudomonal antibiotics within 2 years of study entry (screening visit)
• Use of oral antipseudomonal antibiotics within 30 days of study entry (screening visit)
• History of sputum or throat swab culture yielding Burkholderia spp. within 2 years prior to screening visit
• History of local or systemic hypersensitivity to monobactam antibiotics
• History of intolerance to inhaled short acting beta 2 agonists
• History of lung transplantation
• History of AZLI (or Cayston®) administration
• Administration of any investigational drug or device within 28 days prior to screening visit or within 6 half-lives of the investigational drug (whichever is longer)
• Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone per day or 20 mg prednisone every other day
• Current requirement for daily continuous oxygen supplementation or requirement of more than 2 L/minute at night
• Hospitalization for pulmonary-related illness within 28 days prior to screening visit
• Changes in or initiation of chronic azithromycin treatment within 28 days prior to screening visit
• Changes in antimicrobial, bronchodilator (BD), corticosteroid, dornase alfa, or hypertonic saline medications within 7 days prior to screening visit; for participants on a stable regimen of hypertonic saline (28 days on/28 days off), beginning or ending a cycle of hypertonic saline is allowed
• Changes in physiotherapy technique or schedule within 7 days prior to screening visit
• Abnormal renal or hepatic function results at most recent test within the previous 12 months, defined as:
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times upper limit of normal (ULN), or
• Serum creatinine > 2 times ULN for age
• Pregnant or lactating females; a negative urine pregnancy test is required for all females of childbearing potential (unless surgically sterile), and confirmatory serum pregnancy test in the event of an initial positive urine test result
• Any serious or active medical or psychiatric illness (including drug or alcohol abuse), which in the opinion of the investigator, would interfere with treatment, assessment, or compliance with the protocol
• Presence of a condition or abnormality that would compromise the patient's safety or the quality of study data, in the opinion of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aztreonam for Inhalation Solution (AZLI); Participants will receive one 28-day course of AZLI, then will be followed for a 24-week period (through Day 196).	Drug: Aztreonam for Inhalation Solution (AZLI); AZLI 75 mg administered 3 times daily via the investigational eFlow® nebulizer; Other Names: Cayston®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Evaluable Analysis Set)	The percentage of participants with PA-negative cultures at all time points after cessation of active treatment at Day 28 (assessed at Days 56, 112, and 196) was summarized for the Evaluable Analysis Set.	Day 28 to Day 196
Percentage of Participants With PA-negative Cultures at All Time Points After Cessation of Active Treatment (Sensitivity Analysis Set)	The percentage of participants with PA-negative cultures at all time points after cessation of active treatment at Day 28 (assessed at Days 56, 112, and 196) was summarized for the Sensitivity Analysis Set.	Day 28 to Day 196

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in FEV1% Predicted	Spirometry assessments were performed only in participants ≥ 6 years of age. Forced expiratory volume in 1 second (FEV1) % predicted was defined as FEV1 of the participant divided by the average FEV1 in the population for any person of similar age, sex and body composition.	Baseline to Days 28, 56, 112, and 196
Change From Baseline in CFQ-R RSS Score	Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) only in participants ≥ 6 years of age. The range of scores (units) is 0 to 100 with higher scores indicating fewer symptoms.	Baseline to Days 28, 56, 112, and 196
Percentage of Participants With PA-negative Cultures	The percentage of participants with a PA-negative culture was summarized at each visit.	Days 28, 56, 112, and 196
Use of Additional (Non-study) Antipseudomonal Antibiotics	The percentage of participants who used additional (non-study) antipseudomonal antibiotics (an indication of PA exacerbation) while on treatment and posttreatment was summarized.	Baseline to Day 196
Change From Baseline in Weight		Baseline to Days 28, 56, 112, and 196
Change From Baseline in Height		Baseline to Days 28, 56, 112, and 196
Change From Baseline in Body Mass Index (BMI)		Baseline to Days 28, 56, 112, and 196
Pharmacokinetics (PK) Peak and Trough Plasma Concentrations of Aztreonam	The plasma concentration of aztreonam for participants < 6 years of age was obtained 1 hour after the first dose of AZLI on Day 1 and immediately prior to the last dose of AZLI on Day 28.	Day 1 (1 hour postdose) and Day 28 (immediately prior to dosing)

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Mark Bresnik, MD, Gilead Sciences

Publications and helpful links

General Publications

• Tiddens HA, De Boeck K, Clancy JP, Fayon M, H G M A, Bresnik M, Derchak A, Lewis SA, Oermann CM; ALPINE study investigators. Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study. J Cyst Fibros. 2015 Jan;14(1):111-9. doi: 10.1016/j.jcf.2014.06.003. Epub 2014 Aug 1.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: June 15, 2011
• First Submitted That Met QC Criteria: June 16, 2011
• First Posted (Estimate): June 17, 2011

Study Record Updates

• Last Update Posted (Estimate): July 17, 2014
• Last Update Submitted That Met QC Criteria: July 7, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: Cystic fibrosis; Pseudomonas aeruginosa; CF; PA; AZLI; aztreonam
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Pseudomonas Infections; Anti-Infective Agents; Anti-Bacterial Agents; Aztreonam
• Other Study ID Numbers: GS-US-205-0162