Multidose Safety and Tolerability Study of Dose Escalation of Liposomal Amikacin for Inhalation (ARIKACE™)
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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. |
- 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 ]
- 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 |
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:
- Written informed consent obtained from the patient or designated legal guardian prior to the performance of any study related procedures in the extension period
- 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:
- Patient meets any of the criteria for exclusion as listed above in the main protocol
- Patient meets any criteria for study drug discontinuation in the main protocol
Contacts and Locations More Information
No publications provided
| 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 Pancreatic Diseases Digestive System Diseases Lung Diseases Respiratory Tract Diseases Genetic Diseases, Inborn |
Infant, Newborn, Diseases Pathologic Processes Amikacin Anti-Bacterial Agents Anti-Infective Agents Therapeutic Uses Pharmacologic Actions |
ClinicalTrials.gov processed this record on May 19, 2013