Study of Aztreonam for Inhalation in Children With Cystic Fibrosis and New Infection of the Airways by Pseudomonas Aeruginosa Bacteria (ALPINE 2)

Randomized, Double-Blind, Phase 3B Trial to Evaluate the Safety and Efficacy of 2 Treatment Regimens of Aztreonam 75 mg Powder and Solvent for Nebulizer Solution / Aztreonam for Inhalation Solution (AZLI) in Pediatric Subjects With Cystic Fibrosis (CF) and New Onset Respiratory Tract Pseudomonas Aeruginosa (PA) Infection/Colonization

The primary objective of this study is to evaluate the safety and efficacy of a 14-day course versus a 28-day course of aztreonam for inhalation solution (AZLI) in pediatric participants with new onset Pseudomonas aeruginosa respiratory tract infection or colonization.

Study Overview

• Status: Terminated
• Conditions: Cystic Fibrosis; Pseudomonas Aeruginosa Respiratory Tract Infection/Colonization
• Intervention / Treatment: Drug: AZLI; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 149
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Medizinische Universität Graz
  • Innsbruck, Austria, 06020
    • Medizinische Universitat Innsbruck
• Belgium
  • Brussels, Belgium, 1020
    • Hôpital Universitaire des Enfants Reine Fabiola
  • Edegem, Belgium, 2650
    • UZ Antwerpen
• Denmark
  • Aarhus N, Denmark, 8200
    • Aarhus University Hospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
• France
  • Bordeaux, France, 33076
    • Hopital des enfants - GH Pellegrin
  • Grenoble, France, 38043
    • CHU Grenoble Alpes
  • Paris, France, 75019
    • Hopital Robert Debre Aphp
• Germany
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Kiel, Germany, 24116
    • Städtisches Krankenhaus Kiel
• Greece
  • Thessaloniki, Greece, 54642
    • General Hospital of Thessaloniki,3rd Dept of Pediatrics
• Israel
  • Haifa, Israel, 3109601
    • Rambam Health Corporation
  • Haifa, Israel, 3436212
    • Lady Davis Carmel Medical Center
  • Jerusalem, Israel, 9765422
    • Hadassah University Hospital Mount Scopus
  • Petah Tikva, Israel, 4920230
    • Schneider Children's Medical Center of Israel
• Italy
  • Catania, Italy, 95123
    • Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca Granda
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria "Federico II"
  • Roma, Italy, 00165
    • Ospedale Pediatrico Bambino Gesù
  • Roma, Italy, 00161
    • Azienda Policlinico Umberto - Universita La Sapienza di Roma
  • Verona, Italy, 37126
    • Azienda Ospedaliera Universitaria integrata Verona
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU University Medical Center
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d Hebron
  • Esplugues de Llobregat, Spain, 08950
    • Hospital Sant Joan de Deu
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Malaga, Spain, 29011
    • Hospital Regional Universitario de Málaga
  • Sabadell, Spain, 08208
    • Corporació Sanitària Parc Taulí
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZG
    • NHS Grampian
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital NHS Foundation Trust
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon and Exeter Foundation NHS Trust
  • Leicester, United Kingdom, LE1 5WW
    • University Hospitals of Leicester NHS Trust
  • London, United Kingdom, SE5 9RS
    • Kings College Hospital NHS Foundation Trust
  • London, United Kingdom, E1 1BB
    • Barts and the London Children's Hospital
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital
  • Middlesbrough, United Kingdom, TS4 3BW
    • South Tees Hospitals NHS Foundation Trust
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Children's Hospital NHS Trust
  • Southampton, United Kingdom, SO16 6YD
    • Southampton University Hospitals NHS Trust, Southampton General Hospital
  • Stoke on Trent, United Kingdom, ST4 6QG
    • University Hospitals of North Midlands NHS trust Royal Stoke University Hospital
• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California San Francisco (UCSF) - Benioff Children's Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Health System
  • Florida
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital Outpatient Care Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H Lurie Childrens Hospital of Chicago
    • Chicago, Illinois, United States, 60637
      • Corner Children's Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • Clinical Research of Charlotte
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • USC Department of Pediatrics/Division of Pediatric Pulmonology
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Tyler, Texas, United States, 75708
      • The University of Texas Health Science Center at Tyler
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Diagnosis of cystic fibrosis (CF) as determined by the 2008 CF Consensus Conference criteria: Sweat chloride level ≥ 60 milliequivalents per liter (mEq/L) by quantitative pilocarpine iontophoresis; or a genotype with 2 identifiable mutations consistent with CF; or an abnormal nasal transepithelial potential difference (NPD), and 1 or more clinical features consistent with CF
• Documented new onset of positive respiratory tract culture for PA within 30 days of screening 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 one second (FEV1) ≥ 80% predicted (for subjects ≥ 6 years of age who can reliably perform spirometry assessments)
• Clinically stable with no evidence of acute significant respiratory symptoms that would require administration of intravenous (IV) antipseudomonal antibiotics, oxygen supplementation, or hospitalization

Key Exclusion Criteria:

• Use of IV or inhaled antipseudomonal antibiotics within 2 years of screening
• Use of oral antipseudomonal antibiotics for a respiratory event within 30 days of study entry (screening visit)
• History of intolerance to inhaled short acting β2 agonists
• History of lung transplantation
• Current requirement for daily continuous oxygen supplementation or requirement of more than 2 L/minute at night
• Hospitalization for a respiratory event within 30 days prior to screening
• Changes in bronchodilator, corticosteroid, dornase alfa, or hypertonic saline medications within 7 days prior to screening.
• Significant changes (per investigators discretion) in physiotherapy technique or schedule within 7 days prior to screening
• 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
• Presence of a condition or abnormality that would compromise the subject's safety or the quality of the study data, in the opinion of the Investigator
• Known hypersensitivity to aztreonam, its metabolites, or formulation excipients in AZLI
• Respiratory cultures performed within 24 months prior to screening that are positive for ANY Burkholderia spp. or Non-tuberculous mycobacteria (NTM)

Note: Other protocol defined Inclusion/Exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AZLI + Placebo; 75 mg/ml of aztreonam will be administered thrice daily (TID) for 14 days followed by placebo to match (PTM) aztreonam TID for 14 days.	Drug: AZLI; Administered via the PARI Altera® Nebulizer System. Participants < 2 years will receive via the SmartMask® Baby, 2 to < 6 years via the SmartMask Kids® and > 6 years via the nebulizer mouthpiece.; Other Names: Cayston®; Aztreonam; Drug: Placebo; Administered via the PARI Altera® Nebulizer System. Participants < 2 years will receive via the SmartMask® Baby, 2 to < 6 years via the SmartMask Kids® and > 6 years via the nebulizer mouthpiece.
EXPERIMENTAL: AZLI; 75 mg/ml of aztreonam will be administered TID for 28 days.	Drug: AZLI; Administered via the PARI Altera® Nebulizer System. Participants < 2 years will receive via the SmartMask® Baby, 2 to < 6 years via the SmartMask Kids® and > 6 years via the nebulizer mouthpiece.; Other Names: Cayston®; Aztreonam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants With Pseudomonas Aeruginosa (PA)-Negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs 28-Day Treatment Group	28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group and Weeks 4 to 8 for the 28 Day treatment group)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time From Primary Eradication to PA Recurrence Over a 108-Week Post-Treatment Follow-up Period	The primary eradication was achieved when all cultures through 28 days post AZLI treatment were PA negative. Recurrence after PA eradication was defined as first positive PA culture result in participant who successfully met primary endpoint and had no PA-positive culture from local lab at Week 4 through Week 6 for AZLI 14 Days group or through Week 8 for AZLI 28 Days group.	Last dose date of AZLI up to Week 112
Percentage of Participants With PA-negative Cultures Through 28 Days Post-Treatment in the 14-Day Treatment Group vs Historical Pooled Data for PA Eradication at 28 Days Post-Treatment in Participants Treated With Tobramycin Nebulizer Solution (TNS)		28 days post treatment (Weeks 4 to 6 for the 14 Day treatment group)
Time to PA Recurrence for a Sub-Group of Participants Matching the Population in the TNS ELITE Study Over a 108-Week Post-Treatment Follow-up Period	In ELITE study (NCT00391976), participants with cystic fibrosis who had early PA infection received TNS. Published criteria for efficacy analysis population in ELITE study included: Participants must be ≥ 6 months at randomization; No history of positive anti-PA antibody (no anti-PA immunoglobulin G [IgG] antibody interpretation at Screening/Baseline) on record; Did not use anti-pseudomonal antibiotics through 28 days after completion of active treatment and within 2 years of Screening; Non-missing PA culture result at 28 days after last dose of AZLI; PA negative through 28 days after completion of active treatment; No important protocol deviation related to compliance with study drug administration; Documented new onset of positive respiratory tract culture for PA within 30 days of Screening 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).	Last dose date of AZLI up to Week 112

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 28, 2017
• Primary Completion (ACTUAL): May 27, 2020
• Study Completion (ACTUAL): September 23, 2021

Study Registration Dates

• First Submitted: July 13, 2017
• First Submitted That Met QC Criteria: July 13, 2017
• First Posted (ACTUAL): July 17, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 14, 2022
• Last Update Submitted That Met QC Criteria: May 26, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Pancreatic Diseases; Fibrosis; Infections; Communicable Diseases; Cystic Fibrosis; Respiratory Tract Infections; Pseudomonas Infections; Anti-Infective Agents; Anti-Bacterial Agents; Aztreonam
• Other Study ID Numbers: GS-US-205-1850; 2016-002749-42 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at https://www.gileadclinicaltrials.com/transparency-policy/
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No