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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Insmed
ClinicalTrials.gov Identifier:
NCT00777296
First received: October 15, 2008
Last updated: May 3, 2012
Last verified: May 2012
  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 (Arikace™) is a sustained-release formulation of amikacin encapsulated inside nanoscale liposomal carriers designed for administration via inhalation. It is hypothesized that the sustained-release pulmonary targeting and biofilm penetration properties of this formulation will have several advantages over current therapies in treating CF subjects with chronic infection caused by P. aeruginosa.


Condition Intervention Phase
Cystic Fibrosis
Drug: Arikace™
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group 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 (ARIKACE™) In Cystic Fibrosis Patients With Chronic Infections Due To Pseudomonas Aeruginosa.

Resource links provided by NLM:


Further study details as provided by Insmed:

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 and urine, and 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 ]
  • To evaluate the longer term safety, tolerability and efficacy of 560 mg once daily dose of Arikace™ administered for six cycles over eighteen months. Each cycle comprising of 28 days of treatment followed by 56 days off treatment [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Exploratory evaluation of durability of clinical benefit [ Time Frame: 28 days ] [ Designated as safety issue: No ]

Enrollment: 66
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: A
Arikace at 560 mg
Drug: Arikace™
All patients participating in the extension period of the study will receive 560 mg once daily dose of Arikace™ administered for six cycles over eighteen months. Each cycle comprising of 28 days of treatment followed by 56 days off treatment. Safety, tolerability, serum PK, quantitative microbiology, spirometry and clinical data will be obtained during this period.

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 Arikace™ 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 Arikace™ 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 Arikace™ 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 Arikace™. 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 Arikace™ 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 Arikace™. 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
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

Main criteria for inclusion of patients participating in the 6 months extension period:

  1. Written informed consent obtained from the patient or designated legal guardian prior to the performance of any study related procedures in the extension period
  2. Patient meets all of the above listed inclusion criteria of the main protocol

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)

Main criteria for exclusion of patients participating in the 6 months extension period:

  1. Patient meets any of the criteria for exclusion as listed above in the main protocol
  2. Patient meets any criteria for study drug discontinuation in the main protocol
  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
Bulgaria
Accelsiors CRO and Consultancy Services
Sofia, Bulgaria, 1111
Sponsors and Collaborators
Insmed
Investigators
Study Director: Renu Gupta, MD Transave Inc.
  More Information

No publications provided by Insmed

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Insmed
ClinicalTrials.gov Identifier: NCT00777296     History of Changes
Other Study ID Numbers: TR02-105
Study First Received: October 15, 2008
Last Updated: May 3, 2012
Health Authority: United States: Institutional Review Board
European Union: European Medicines Agency

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

Additional relevant MeSH terms:
Cystic Fibrosis
Fibrosis
Digestive System Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Lung Diseases
Pancreatic Diseases
Pathologic Processes
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on November 24, 2014