Extension Study of Liposomal Amikacin for Inhalation in Cystic Fibrosis (CF) Patients With Chronic Pseudomonas Aeruginosa (Pa) Infection

NCT01316276 | Completed Phase 3 Results DMC

• 1 other identifier: TR02-110
• Study Type: interventional
• Target: 206
• Locations: 17 countries
• Sites: 50

Brief Summary

The purpose of this study is to evaluate the long term safety and tolerability of Liposomal Amikacin for Inhalation (LAI) 590 mg once daily (QD) in Cystic Fibrosis patients with chronic infection due to pseudomonas aeruginosa. This long-term, open-label, multi-cycle extension study enrolled subjects who had successfully completed study TR02-108, were compliant with the study protocol, and did not meet any of the listed study discontinuation criteria. The safety and tolerability of LAI were evaluated for up to approximately 2 years.

Conditions

Cystic Fibrosis

Keywords

Cystic Fibrosis; Respiratory Infections; Pulmonary Cystic Fibrosis; cystic fibrosis transmembrane conductance regulator (CFTR); Anti-bacterial Agent; Arikayce; ALIS; LAI

Outcome Measures

Primary Outcomes (12)

• Treatment Emergent Adverse Events (TEAEs) up to Day 672

  Treatment emergent adverse events including serious adverse events (SAE) and adverse events (AE) leading to permanent discontinuation of study drug

  From Study Initiation up to Day 672

• Laboratory Abnormalities up to Day 672

  * Number of Subjects with Grade 3 or Higher Abnormalities in Clinical Laboratory Values * Number of Subjects with Grade 3 or Higher Hematology Laboratory Value Abnormalities * Number of Subjects with Grade 3 or Higher Chemistry Laboratory Value Abnormalities

  Baseline, Day 377 and Day 672

• Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose

  Number of Subjects with a \>15% in Decline in Forced Expiratory Volume in 1 Second (FEV1) From Predose to Postdose

  Day 1, Day 84, Day 196, Day 281, Day 337, Day 449, Day 532 and Day 644

• Respiratory Rate: Change From Baseline to Day 672

  Respiratory rate was recorded at every visit as per standard practice at each investigational site.

  From Study Initiation up to Day 672

• Heart Rate: Change From Baseline From Day 672

  Pulse rate (after at least 5-minute rest) was recorded at every visit as per standard practice at each investigational site.

  From Study Initiation up to Day 672

• Systolic BP: Change From Baseline at Day 672

  Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.

  From Study Initiation up to Day 672

• Diastolic BP: Change From Baseline at Day 672

  Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.

  From Study Initiation up to Day 672

• Body Temperature: Change From Baseline at Day 672

  Body temperature was recorded at every visit as per standard practice at each investigational site.

  From Study Initiation up to Day 672

• Oxygen Saturation: Change From Baseline at Day 672

  Change in oxygen saturation as measured with pulse oximetry was performed via finger probes placed on the extremity opposite arterial lines and noninvasive blood pressure monitoring devices so that pulsatile flow was not interrupted.

  From Study Initiation up to Day 672

• Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672

  Sputum was cultured for quantitative microbiological evaluation of Pa and Burkholderia species in designated regional central microbiology laboratories. A standard microbiology protocol was used for Pa culture and identification for each morphologically distinct Pa phenotype. Although planned in the Statistical Analysis Plan (SAP), MICs of amikacin Burkholderia species were not determined due to the small number of isolates with Burkholderia. In addition, susceptibility testing of isolates of Pa and Burkholderia species against a panel of commonly used antipseudomonal antibiotics was planned but was not performed. The results of the following analyses for Pa isolates are presented. * Frequency of MIC of Amikacin * Frequency of MIC of Tobramycin MIC50: lowest concentration of the antibiotic at which 50 % of the isolates were inhibited.

  Day 1, Day 169, Day 337, Day 505 and Day 672

• Evaluation of Audiology

  Hearing was evaluated using air conduction \[AC\]. Bone conduction was required if the AC testing demonstrated a decrease of \>20 decibels \[dB\]. Hearing loss was categorized using Common Terminology Criteria for Adverse Events as follows: GRADE 1 (best): Adults \[A\] on a Monitoring Program \[MP\]: Threshold shift of 15-25 dB; Pediatric \[P\]: Threshold shift \>20 dB at 8 kilohertz (kHz). GRADE 2: \[A\] on a MP: Threshold shift of \>25 dB; \[A\] not enrolled in MP: hearing loss; hearing aid/intervention not indicated; \[P\]: Threshold shift \>20 dB at 4 kHz and above. GRADE 3: \[A\] enrolled in MP: Threshold shift of \>25 dB; therapeutic intervention indicated; \[A\]: Not enrolled in MP: hearing aid/intervention; \[P\]: therapeutic intervention, including hearing aids: Threshold shift \>20 dB at 3 kHz and above; additional speech-language related services. GRADE 4 (worst): \[A\]: Profound bilateral hearing loss; non-serviceable hearing; \[P\]: cochlear implant \& additional speech-language related services.

  Day 337 and Day 672

• Change in Serum Creatinine Throughout the Study

  * Common Terminology Criteria for Adverse Events (CTCAE) Grade 1: \> ULN-1.5 × ULN * CTCAE Grade 2: \> 1.5 × ULN to 3.0 x ULN

  Baseline, Day 337 and Day 672

Secondary Outcomes (4)

• Percent Change in FEV1 Throughout the Study

  Baseline, Day 337 and Day 672

• Number of Subjects Experiencing a Protocol Defined Pulmonary Exacerbation

  From Study Initiation up to Day 700

• Number of Subjects Initiating Treatment.

  From Study Initiation up to Day 672

• Number of Participants Who Received Antipseudomonal Antibiotic Treatment for Protocol Defined Pulmonary Exacerbation

  From Study Initiation up to Day 700

Study Arms (1)

LAI

EXPERIMENTAL

590 mg LAI QD via a PARI Investigational eFlow® Nebulizer System (eFlow®) for 28 days followed by a 28-day off-treatment period. This cycle (28 days on treatment, 28 days off treatment) was to be repeated for up to 12 cycles, divided into 2 periods of 6 cycles each (approximately 12 months each).

Drug: Liposomal amikacin for inhalation

Interventions

Liposomal amikacin for inhalation DRUG

* Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. * 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. * Administration time is approximately 13 minutes. * Liposomal amikacin for inhalation will be administered in two consecutive extension periods, each consisting of 6 cycles for a total of 12 cycles. Each cycle consists of 28 days on-treatment followed by 28 days off-treatment.

LAI

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent or assent
• Subject has completed study TR02-108, and has been compliant with the study protocol
• Women of childbearing potential must agree to use reliable methods of contraception for the duration of the study

You may not qualify if:

• Subject met any of the listed criteria for study drug discontinuation in protocol TR02-108.
• Abnormal laboratory assessments including LFT (≥ 3× upper limit of normal \[ULN\]), serum creatinine (\> 2× ULN) and absolute neutrophil count \[ANC\] (\< 1000).
• Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
• History of alcohol, medication or illicit drug abuse within the 6 months prior to consent.
• Smoking tobacco or any substance within 6 months prior to consent or anticipated inability to refrain from smoking throughout the study

Sponsors & Collaborators

• Insmed Incorporated: lead

Study Sites (50)

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Vienna, Austria

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Antwerp, Belgium

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Brussels, Belgium

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Ghent, Belgium

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Leuven, Belgium

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Pleven, Bulgaria

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Plovdiv, Bulgaria

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Sofia, Bulgaria

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Varna, Bulgaria

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Halifax, Canada

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Hamilton, Canada

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Vancouver, Canada

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Copenhagen, Denmark

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Lille, France

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Paris, France

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Berlin, Germany

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Essen, Germany

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Hamburg, Germany

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Hanover, Germany

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München, Germany

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Athens, Greece

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Marousi, Greece

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Budapest, Hungary

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Debrecen, Hungary

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Szeged, Hungary

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Dublin, Ireland

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Brescia, Italy

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Catania, Italy

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Parma, Italy

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Roma, Italy

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Verona, Italy

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Utrecht, Netherlands

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Gdansk, Poland

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Lodz, Poland

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Lublin, Poland

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Poznan, Poland

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Rabka-Zdrój, Poland

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Rzeszów, Poland

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Warsaw, Poland

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Belgrade, Serbia

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Banská Bystrica, Slovakia

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Bratislava, Slovakia

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Košice, Slovakia

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Barcelona, Spain

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Madrid, Spain

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Valencia, Spain

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Leeds, United Kingdom

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London, United Kingdom

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Nottingham, United Kingdom

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Penarth, United Kingdom

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Related Publications (1)

• Bilton D, Fajac I, Pressler T, Clancy JP, Sands D, Minic P, Cipolli M, Galeva I, Sole A, Quittner AL, Jumadilova Z, Ciesielska M, Konstan MW; CLEAR-110 Study Group. Long-term amikacin liposome inhalation suspension in cystic fibrosis patients with chronic P. aeruginosa infection. J Cyst Fibros. 2021 Nov;20(6):1010-1017. doi: 10.1016/j.jcf.2021.05.013. Epub 2021 Jun 16.

  PMID: 34144923 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis; Respiratory Tract Infections

Interventions

Inhalation

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Infections

Intervention Hierarchy (Ancestors)

Respiratory Mechanics; Respiration; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena

Results Point of Contact

• Title: Kevin Mange (Senior VP, Clinical Development)
• Organization: Insmed Incorporated

kevin.mange@insmed.com

908-947-2651

Study Officials

• Gina Eagle, MD

  Insmed Incorporated

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2011
• First Posted: March 16, 2011
• Study Start: October 5, 2012
• Primary Completion: July 16, 2015
• Study Completion: July 16, 2015
• Last Updated: June 17, 2020
• Results First Posted: July 26, 2019

Record last verified: 2020-06

Locations

FR (2); DE (5); BE (4); DK (1); GB (4); SE (1); GR (2); ES (3); IE (1); BU (4); SL (3); AU (1); PL (7); HU (3); NL (1); CA (3); IT (5)