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Multidose Safety and Tolerability Study of Dose Escalation of Liposomal Amikacin for Inhalation (ARIKAYCE™)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Insmed Incorporated
ClinicalTrials.gov Identifier:
NCT00777296
First received: October 15, 2008
Last updated: November 17, 2016
Last verified: September 2015
  Purpose
A major factor in the respiratory health of CF subjects is acquisition of chronic Pseudomonas aeruginosa infections. The infection rate with P. aeruginosa increases with age and by age 18 years, 80% of CF subjects in the U.S. are infected. Liposomal Amikacin for Inhalation (Arikayce™) is a sterile aqueous liposomal suspension consisting of amikacin sulfate encapsulated in liposomes. This formulation of amikacin maximizes the achievable dose and delivery to the lungs of subjects infected via a nebulizer. Because liposome particles are small enough to penetrate and diffuse through sputum into the bacterial biofilm, they deposit drug in close proximity to the bacterial colonies (Meers, et al., 2008) (Clancy, et al., 2013), thus improving the bioavailability of amikacin at the infection site. The clinically achievable doses of amikacin in the LAI formulation can effectively increase the half-life of the drug in the lungs, and decrease the potential for systemic toxicity. LAI offers several advantages over current therapies in treating CF subjects with chronic infection caused by P. aeruginosa.

Condition Intervention Phase
Cystic Fibrosis
Drug: Arikayce™
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1b/2a Multidose Safety and Tolerability Study of Dose Escalation of Liposomal Amikacin for Inhalation (ARIKAYCE™) In Cystic Fibrosis Patients With Chronic Infections Due To Pseudomonas Aeruginosa.

Resource links provided by NLM:


Further study details as provided by Insmed Incorporated:

Primary Outcome Measures:
  • To evaluate the safety and tolerability of nebulized Arikace™. Safety will be evaluated by changes in FEV1, SaO2, chemistry and hematology lab tests, vital signs, and clinical exam, assess treatment-emergent AEs. [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To assess pharmacokinetics (PK) of Arikace™ in serum [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]
  • To assess pharmacokinetics (PK) of Arikace™ in urine [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]
  • To evaluate sputum amikacin levels [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]
  • To evaluate change in Pulmonary function [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]
  • To evaluate change in density of Pseudomonas aeruginosa in sputum [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]
  • To evaluate time to and duration of systemic antipseudomonal rescue therapy [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]
  • To evaluate change in CFQ-R measurements [ Time Frame: 28 Days ] [ Designated as safety issue: Yes ]

Study Start Date: February 2007
Study Completion Date: February 2010
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1 - 280 mg Arikayce
Subjects in this cohort will receive 280 mg of Arikayce
Drug: Arikayce™
Placebo Comparator: Cohort 1 - Placebo
Subjects in this arm of cohort 1 will receive matching placebo
Drug: Placebo
Experimental: Cohort 2 - 560 mg Arikayce
Subjects in this cohort will receive 560 mg of Arikayce
Drug: Arikayce™
Placebo Comparator: Cohort 2 - Placebo
Subjects in this arm of cohort 2 will receive matching placebo
Drug: Placebo

Detailed Description:

Cystic fibrosis (CF) is a genetic disease resulting from mutations in a 230 kb gene on chromosome 7 known as the cystic fibrosis transmembrane conductance regulator (CFTR). Study subjects with CF manifest pathological changes in a variety of organs that express CFTR. The lungs are frequently affected, the sequelae being chronic infections and airway inflammation. The principal goal of treatment of subjects with CF is to slow the chronic deterioration of lung function.

This is a Phase 2a study of safety, and tolerability of 28 days of daily dosing of two dose (280mg, and 560 mg) cohorts of Arikayce™ versus placebo. Study subjects will be randomized to receive either study drug or placebo (1.5% NaCl) by inhalation via a PARI eFlow nebulizer. Cohort 1 (280mg) will complete 28 days of daily dosing with Arikayce™ and 14 day post dosing safety evaluation by the Safety Committee (DSMB) before initiation of enrollment in Cohort 2 (560mg). Cohort 2 will complete 28 days of daily dosing, and a 14 day post dosing safety assessment by the DSMB to evaluate safety data. All study patients will be followed for safety, pharmacokinetics, clinical and microbiologic activity for 28 days post completion of study treatment.

The total study period will be up to 56 days, with screening visit occurring within the preceding 14 days prior to randomization. Patients will be clinically evaluated during the first 48 hours post-randomization, and weekly for the 28 days treatment period, and during the follow up visits at study days 35, 42, 49 and 56 days to determine safety, tolerability, pharmacokinetics (PK), and clinical, and microbiologic activity.

Clinical laboratory parameters, audiology testing, clinical adverse events and pulmonary function will be evaluated for all study subjects in order to determine the qualitative and quantitative safety and tolerability of Arikayce™ compared to Placebo. Serum, urine, and sputum specimens will be collected at periodic intervals to assess PK. Additionally; sputum samples will be collected to determine changes in bacterial density. Pulmonary function testing and CFQ-R measurements will be assessed at selected time points throughout the study.

DSMB has recommended the amendment of the main study to evaluate safety and efficacy of additional cycles of treatment with Arikayce™. All patients who were randomized in the main study, were compliant with the study protocol, and continue meeting study eligibility criteria can be consented to participate in the open-label extension to evaluate the safety, tolerability and efficacy of 560 mg once daily dose of Arikayce™ administered for six cycles over eighteen months. Each cycle will comprise of 28 days of treatment followed by 56 days off treatment. The total extension period will be up to 518 days (74 weeks, about 18 months).

Clinical laboratory parameters, audiology testing, clinical adverse events and pulmonary function will be evaluated for all study subjects in order to determine the longer term safety, tolerability, and efficacy of Arikayce™. Serum specimens will be collected at periodic intervals to assess PK for safety. Additionally, sputum samples will be collected to determine changes in bacterial density. Pulmonary function testing and CFQ-R measurements will be assessed at selected time points throughout the study.

  Eligibility

Ages Eligible for Study:   6 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent obtained from patient or designated legal guardian prior to the performance of any study related procedures.
  • Male or female study subjects ≥6 years of age or older
  • Confirmed diagnosis of CF
  • History of chronic infection with P. aeruginosa
  • Study subjects must produce a screening specimen that is positive for growth of P. aeruginosa
  • FEV1 ≥ 40% predicted at Screening
  • SaO2 ≥ 90% at Screening while breathing room air
  • Ability to comply with study medication use, study visits and study procedures as judged by the investigator
  • Ability to produce sputum or be willing to undergo an induction to produce sputum for clinical evaluation
  • Clinically stable with no evidence of acute upper or lower respiratory tract infection of history of pulmonary exacerbation within 4 weeks prior to screening

Exclusion Criteria:

  • Administration of any investigational drug within 8 weeks prior to Screening
  • Emergency room visit or hospitalization for CF or respiratory-related illness within 4 weeks prior to screening
  • History of alcohol, medication or illicit drug abuse within the 1 year prior to screening
  • History of lung transplant
  • Female of childbearing potential who is lactating or is not practicing an acceptable method of birth control (e.g., abstinence, hormonal or barrier methods, partner sterilization, or IUD)
  • Positive pregnancy test
  • Use of any anti-pseudomonal anitbiotics (IV antibiotics, all inhalation antibiotics, oral fluoroquinolones)within the 28 days prior to screening
  • Initiation of chronic therapy (i.e. TOBI®, high-dose ibuprofen, rhDNase, macrolide antibiotics) within 28 days prior to screening
  • History of sputum or throat swab culture yielding Burkholderia cepacia within 2 years of Screening
  • History of mycobacterial or Aspergillus infection
  • History of biliary cirrhosis with portal hypertension, or splenomegaly
  • History of daily, continuous oxygen supplementation or requirement for more than 2 L/min at night Change in chest x-ray at screening (or within the 3 months prior to screening)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00777296

Locations
Belgium
Leuven, Belgium
Hungary
Budapest, Hungary
Kaposvar, Hungary
Macedonia, The Former Yugoslav Republic of
Skopje, Macedonia, The Former Yugoslav Republic of
Poland
Rabka, Poland
Warsaw, Poland
Serbia
Belgrade, Serbia
Slovakia
Bratislava, Slovakia
Kosice, Slovakia
Ukraine
Keiv, Ukraine
Kharkiv, Ukraine
Sponsors and Collaborators
Insmed Incorporated
Investigators
Study Director: Gina Eagle, MD Insmed Incorporated
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Insmed Incorporated
ClinicalTrials.gov Identifier: NCT00777296     History of Changes
Other Study ID Numbers: TR02-105 
Study First Received: October 15, 2008
Last Updated: November 17, 2016
Health Authority: United States: Institutional Review Board
European Union: European Medicines Agency

Keywords provided by Insmed Incorporated:
Cystic Fibrosis
Respiratory Infections
Pulmonary Cystic Fibrosis
CFTR

Additional relevant MeSH terms:
Fibrosis
Cystic Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Amikacin
Anti-Bacterial Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on December 02, 2016