Long Term Safety and Tolerability Study of Open-Label Liposomal Amikacin for Inhalation (ARIKACE™) in Cystic Fibrosis Patients With Chronic Infection Due to Pseudomonas Aeruginosa
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 206
- 主要终点
- Treatment Emergent Adverse Events (TEAEs) up to Day 672
研究概览
简要总结
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.
详细描述
This was a long-term, open-label, multi-cycle extension study for patients in the Phase 3 study TR02-108 and TR02-109 who had successfully completed the 168-day study period and met study safety criteria. As this was a safety and tolerability long-term extension study, no sample size calculations were performed. All patients who completed TR02-108, were compliant with the study protocol, and did not meet any of the criteria listed for study discontinuation (safety reasons or non-compliance) were able to participate in this open-label study.
The end of study visit for TR02-108 was to serve as the baseline study visit (Day 1) for TR02-110 if the patient had signed the informed consent at least 4 days prior to the end of study visit and met all safety criteria for TR02-110. If the end of study visit was not used as the baseline visit, a separate baseline visit (Day 1) was to be performed within 14 days of completing TR02-108.
Patients were to receive a delivered dose of 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. The study was implemented as 2 consecutive extension periods, each consisting of 48 weeks (approximately 12 months). Patients were re-consented for the second extension period at the completion of the first extension period. The total study period was up to 96 weeks (approximately 2 years).
During the first 28 days of treatment, patients were evaluated at the study site bi-weekly for safety, tolerability and efficacy. Thereafter, for the duration of the study, patients were evaluated at the study site on the first and last days of dosing during the on-treatment periods. During the study, starting with the off-treatment period of Cycle 1, patients were contacted by telephone once during every 28-day period to assess safety. A final site visit occurred 28 days after last dose of LAI. Arikace™, Arikayce™,Liposomal Amikacin for Inhalation (LAI), and Amikacin Liposome Inhalation Suspension (ALIS) may be used interchangeably throughout this study and other studies evaluating amikacin liposome inhalation suspension.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •Subject met any of the listed criteria for study drug discontinuation in protocol TR02-
- •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
研究组 & 干预措施
LAI
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).
干预措施: Liposomal amikacin for inhalation (Drug)
结局指标
主要结局
Treatment Emergent Adverse Events (TEAEs) up to Day 672
时间窗: From Study Initiation up to Day 672
Treatment emergent adverse events including serious adverse events (SAE) and adverse events (AE) leading to permanent discontinuation of study drug
Laboratory Abnormalities up to Day 672
时间窗: Baseline, Day 377 and 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
Acute Tolerability as Measured by Pulmonary Function Test (PFT) Changes Pre to Post Dose
时间窗: Day 1, Day 84, Day 196, Day 281, Day 337, Day 449, Day 532 and Day 644
Number of Subjects with a \>15% in Decline in Forced Expiratory Volume in 1 Second (FEV1) From Predose to Postdose
Respiratory Rate: Change From Baseline to Day 672
时间窗: From Study Initiation up to Day 672
Respiratory rate was recorded at every visit as per standard practice at each investigational site.
Heart Rate: Change From Baseline From Day 672
时间窗: From Study Initiation up to Day 672
Pulse rate (after at least 5-minute rest) was recorded at every visit as per standard practice at each investigational site.
Systolic BP: Change From Baseline at Day 672
时间窗: From Study Initiation up to Day 672
Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.
Diastolic BP: Change From Baseline at Day 672
时间窗: From Study Initiation up to Day 672
Sitting blood pressure was recorded at every visit as per standard practice at each investigational site.
Body Temperature: Change From Baseline at Day 672
时间窗: From Study Initiation up to Day 672
Body temperature was recorded at every visit as per standard practice at each investigational site.
Oxygen Saturation: Change From Baseline at Day 672
时间窗: From Study Initiation up to 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.
Minimum Inhibitory Concentrations (MICs) for Pseudomonas Aeruginosa (Pa) and Burkholderia Species From Day 1 to Days 169, 337, 505 and 672
时间窗: Day 1, Day 169, Day 337, Day 505 and Day 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.
Evaluation of Audiology
时间窗: Day 337 and Day 672
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.
Change in Serum Creatinine Throughout the Study
时间窗: Baseline, Day 337 and Day 672
* Common Terminology Criteria for Adverse Events (CTCAE) Grade 1: \> ULN-1.5 × ULN * CTCAE Grade 2: \> 1.5 × ULN to 3.0 x ULN
次要结局
- 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)