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

July 20, 2020 updated by: Insmed Incorporated

Phase 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.

A major factor in the respiratory health of cystic fibrosis (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 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, 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Cystic fibrosis 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 (280 mg, 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. Arikace™, Arikayce™, Liposomal Amikacin for Inhalation (LAI) and Amikacin Liposome Inhalation Suspension (ALIS) are all the same may be used interchangeably throughout the study and other studies evaluating amikacin liposome inhalation suspension.

Study Type

Interventional

Enrollment (Actual)

66

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Key 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
  • Requiring treatment within 2 years prior to screening, and/or history of allergic bronchopulmonary aspergillosis.
  • 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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Cohort 1 - 280 mg ARIKACE™
Subjects in this cohort will receive 280 mg of ARIKACE™
Drug: ARIKACE™
Study start date is before Jan 18, 2017.
Other Names:
  • Arikayce
  • liposomal amikacin for inhalation
Placebo Comparator: Cohort 1 - Placebo
Subjects in this arm of cohort 1 will receive matching placebo
Drug: Placebo
Study start date is before Jan 18, 2017.
Experimental: Cohort 2 - 560 mg ARIKACE™
Subjects in this cohort will receive 560 mg of ARIKACE™
Drug: ARIKACE™
Study start date is before Jan 18, 2017.
Other Names:
  • Arikayce
  • liposomal amikacin for inhalation
Placebo Comparator: Cohort 2 - Placebo
Subjects in this arm of cohort 2 will receive matching placebo
Drug: Placebo
Study start date is before Jan 18, 2017.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinically Significant Laboratory Abnormalities.
Time Frame: 28 Days
Changes in chemistry and hematology lab tests (clinically significant value of CTCAE grade ≥ 3).
28 Days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetics (PK) of Arikace™ in Serum.
Time Frame: Day 1, Day 14 and Day 28
Measure PK parameters (AUC0-infinity) of Arikace™ in serum.
Day 1, Day 14 and Day 28
Pharmacokinetic (PK) of Arikace in Serum (Cmax).
Time Frame: Day 1, Day 14 and Day 28
Measure PK parameter (Cmax) of Arikace™ in serum.
Day 1, Day 14 and Day 28
Pharmacokinetics (PK) of Arikace™ in Sputum (AUC).
Time Frame: 28 days
Measure PK parameter (AUC0-24) of Arikace™ in sputum.
28 days
Pharmacokinetics (PK) of Arikace™ in Urine.
Time Frame: Day 1, Day 14 and Day 28
Measure PK parameter (Ae0-24 (mg) of Arikace™.
Day 1, Day 14 and Day 28
Sputum Amikacin Levels of Arikace™.
Time Frame: Day 1, Day 14 and Day 28
Measure PK parameter (sputum amicakin concentration) of Arikace™ in sputum.
Day 1, Day 14 and Day 28
Pulmonary Function: FEV1 %-Predicted.
Time Frame: Baseline, Day 28, and Day 56
Relative Change (%) from Baseline to End of treatment (Day 28) and Day 56 in Pulmonary Function.
Baseline, Day 28, and Day 56
Pulmonary Function: FEV1.
Time Frame: Baseline, Day 28, and Day 56
Mean Percent Change (%) from Baseline to End of treatment (Day 28) and Day 56 in Pulmonary Function.
Baseline, Day 28, and Day 56
Change From Baseline in Log10CFU Per Gram (Density) of Pseudomonas Aeruginosa in Sputum.
Time Frame: Day 7, Day 14, Day 21, Day 28 and Day 35
End-of-treatment (Day 28) from baseline in density of P. aeruginosa (log10 CFU/g) in sputum.
Day 7, Day 14, Day 21, Day 28 and Day 35
Duration of Systemic Antipseudomonal Rescue Therapy.
Time Frame: Through study duration, approximately 56 days
Duration of systemic antipseudomonal rescue therapy during the study in both the ARIKACE™ and placebo groups.
Through study duration, approximately 56 days
Number of Subjects Requiring Antipseudomonal Rescue Therapy.
Time Frame: Through study duration, approximately 56 days
Number of Subjects requiring systemic antipseudomonal rescue therapy during the study in both the ARIKACE™ and placebo groups.
Through study duration, approximately 56 days
CFQ-R Respiratory Scale (Absolute Change From Baseline).
Time Frame: Baseline/Day 1, Day 15, Day 28 and Day 42
Quality of Life was measured by the absolute change from baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory scale. Disease specific instrument designed to measure impact on overall health, daily life, perceived well-being and symptoms in patients with a diagnosis of cystic fibrosis. Scores range from 0 to 100, with higher scores indicating better health. Scores for each Health Related Quality of Life (HRQoL) domain; after recoding, each item is summed to generate a domain score and standardized.
Baseline/Day 1, Day 15, Day 28 and Day 42

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Insmed Incorporated

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 22, 2007

Primary Completion (Actual)

February 27, 2008

Study Completion (Actual)

February 27, 2008

Study Registration Dates

First Submitted

October 15, 2008

First Submitted That Met QC Criteria

October 21, 2008

First Posted (Estimate)

October 22, 2008

Study Record Updates

Last Update Posted (Actual)

July 30, 2020

Last Update Submitted That Met QC Criteria

July 20, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TR02-105

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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