| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pseudomonas aeruginosa pulmonary infection/colonisation in patients with cystic fibrosis |
| Infezione/colonizzazione polmonare da Pseudomonas aeruginosa in pazienti con fibrosi cistica |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cystic Fibrosis |
| Fibrosi cistica |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011763 |
| E.1.2 | Term | Cystic fibrosis lung |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objectives of the study are to evaluate the efficacy, safety and tolerability of 3 cycles (28 days on-treatment and 28 days off treatment) of Arikace™ therapy. Change in pulmonary function, time to first pulmonary exacerbation, need for antipseudomonal antibiotics, change in sputum quantitative microbiology, hospitalization, patient reported symptoms/outcomes, and time off work/school will be assessed. Safety and tolerability will be evaluated throughout the study. |
| Gli obiettivi dello studio sono: valutare l’efficacia, la sicurezza e la tollerabilita' di 3 cicli (28 giorni di trattamento intervallati da 28 senza farmaco) della terapia con Arikace™. Saranno valutati: cambiamento nella funzionalita' polmonare, tempo alla prima esacerbazione polmonare, bisogno di antibiotici anti Pseudomonas, cambiamento nella microbiologia quantitativa dell’esecrato, ricovero, sintomi/esiti segnalati dal paziente e giorni lavorativi/di scuola persi. La sicurezza e la tollerabilita' saranno valutate per l’intera durata dello studio |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOKINETIC/PHARMACODYNAMIC:
Vers:2
Date:2011/02/23
Title:Randomized, open-label, active-controlled, multicenter study to assess
the efficacy, safety and tolerability of Arikace™ in Cystic Fibrosis
patients with chronic infection due to Pseudomonas aeruginosa
Objectives:Pharmacokinetic assessments will be conducted in a subgroup of study
subjects who consent to PK evaluation.
The objective will be to characterize the pharmacokinetics, including
bioavailability, and systemic exposure of amikacin for inhalation
(ArikaceTM) in CF subjects.
|
FARMACOCINETICA/FARMACODINAMICA:
Vers:2
Data:2011/02/23
Titolo:Studio multicentrico, randomizzato, in aperto, con controllo attivo, per valutare l’efficacia, la sicurezza e la tollerabilità di Arikace™ in pazienti con fibrosi cistica associata ad infezione cronica da Pseudomonas aeruginosa
Obiettivi:Pharmacokinetic assessments will be conducted in a subgroup of study
subjects who consent to PK evaluation.
The objective will be to characterize the pharmacokinetics, including
bioavailability, and systemic exposure of amikacin for inhalation
(ArikaceTM) in CF subjects.
|
|
| E.3 | Principal inclusion criteria |
| ) Written informed consent or assent obtained from the patient, parent or legal guardian prior to the performance of any study related procedures 2) Male or female study subjects ≥ 6 years of age (or older, if restricted by the local IRB/EC) at Screening 3) Diagnosis of CF confirmed by a positive sweat test > 60 mEq/liter or > 60 mmol/L or by DNA analysis revealing both mutated alleles consistent with CF disease 4) History of chronic infection with Pa confirmed by three documented positive cultures for Pa within the 2 years prior to Screening with at least one obtained within 6 months prior to Screening. The cultures could be obtained from the following respiratory secretions: sputum, deep throat swabs, or broncho-alveolar lavage fluid specimens 5) Sputum culture positive for Pa at Screening 6) Forced expiratory volume in 1 second (FEV1) ≥ 25% of predicted value at Screening using spirometer provided by sponsor 7) Oxygen saturation (SaO2) ≥ 90% while breathing room air at Screening 8) Ability to comply with study drug use, study visits, and study procedures as judged by the Investigator 9) Ability to expectorate ≥ 0.4 mL of sputum 10) Willingness to have specimens stored(no genetic testing) 11) Women of childbearing potential must have a negative result on their serum pregnancy test at Screening and use reliable methods of contraception (e.g., abstinence, hormonal or barrier methods, partner sterilization, or IUD) throughout the study duration. Women not of childbearing potential are defined as prepubescent, postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile |
| 1) Consenso informato scritto o assenso acquisito dal paziente, dal genitore o dal tutore legale prima di eseguire qualsiasi procedura connessa allo studio. 2) Soggetti di entrambi i sessi, di eta' ≥6 anni (o di eta' superiore, in base ai limiti imposti dall’IRB/CE locale) al momento dello screening. 3) Diagnosi di FC, confermata da un test del sudore positivo >60 mEq/litro o >60 mmol/l o dall’analisi del DNA che rileva la mutazione di entrambi gli alleli, compatibile con la fibrosi cistica. 4) Anamnesi di infezione cronica da Pa, confermata da tre colture positive documentate per Pa nei 2 anni precedenti lo screening, con almeno una coltura acquisita nei 6 mesi precedenti lo screening. Le colture devono essere acquisite dalle seguenti secrezioni respiratorie: esecrato, tampone faringeo profondo, o campioni del liquido di lavaggio broncoalveolare. 5) Coltura positiva dell’esecrato per Pa allo screening. 6) Volume espiratorio forzato in 1 secondo (FEV1) ≥25% rispetto al predetto allo screening, utilizzando lo spirometro fornito dal promotore. 7) Saturazione di ossigeno (SaO2) ≥90% respirando aria ambiente allo screening 8) Capacita' di aderire all’uso del farmaco in studio, alle visite e alle procedure, secondo l’opinione dello sperimentatore. 9) Capacita' di espettorare ≥0,4 ml di esecrato. 10) Disponibilita' ad acconsentire alla conservazione dei campioni (nessun test genetico) 11) Le donne potenzialmente fertili devono essere negative al test di gravidanza sierico allo screening; inoltre devono far uso di metodi contraccettivi affidabili (ad es., astinenza, metodi ormonali o di barriera, sterilizzazione del partner o IUD) per l’intera durata dello studio. Per donne non potenzialmente fertili si intendono ragazze prepubescenti, donne postmenopausali (ossia amenorreiche da almeno 1 anno), oppure sterili (sia di origine organica che chirurgica). |
|
| E.4 | Principal exclusion criteria |
| 1) Forced Expiratory Volume in 1 second (FEV1) <25% of predicted at Screening using spirometer provided by Insmed 2) History of hypersensitivity to aminoglycosides including tobramycin solution for inhalation 3) Prior exposure to Arikace™ (including clinical study) 4) History of major complications of lung disease (including atelectasis, pneumothorax, major pleural effusion), within 8 weeks prior to Screening 5) Hemoptysis of ≥60 mL in a 24-hour period within 4 weeks prior to Screening 6) History of acute pulmonary exacerbation requiring antibiotic treatment within 4 weeks prior to Screening 7) History of upper respiratory tract infection within 2 weeks prior to Screening 8) Use of antipseudomonal antibiotics (IV antibiotics, inhalation antibiotics, or oral) within 4 weeks prior to Day 1 9) Radiologic finding of new pulmonary infiltrate(s) within 3 months prior to Screening, or presence of other abnormalities suggesting clinically significant active pulmonary disease other than CF 10) Initiation of chronic therapy (e.g., TOBI, Colomycin, other inhaled antibiotics, high-dose ibuprofen, bronchodilators, inhaled antiinflammatory agents including steroids, low dose maintenance steroids, rhDNase, hypertonic saline, macrolides) within 4 weeks prior to study Day 1 11) History of positive culture for Burkholderia cepacia within 2 years prior to Screening 12) History of pulmonary tuberculosis or non-tuberculous mycobacterial lung disease treated within 2 years prior to Screening or requiring treatment at the time of screening 13) History of Allergic Broncho-Pulmonary Aspergillosis requiring systemic steroid treatment or any other condition requiring systemic steroids at a dose ≥ equivalent of 10 mg/day of prednisone within 3 months prior to Screening 14) Presence of any clinically significant cardiac disease as determined by investigator and/or, if QTc data are available, QTc prolongation > 450 msec (0.450 seconds) for males or QTc > 470 msec (0.470 seconds) for females or QTc prolongation > 440 msec (0.440 seconds) for all subjects 6 to 12 years of age 15) Acquired and primary immunodeficiency syndromes 16) History of hepatitis C or chronic active hepatitis B infection 17) Active pulmonary malignancy (primary or metastatic) or any malignancy requiring chemotherapy or radiation therapy within one year prior to Screening or anticipated during the study period 18) History of biliary cirrhosis with portal hypertension 19) History of lung transplantation 20) Elevated AST, ALT or GGT ≥ 3× the upper limit of normal (ULN) at Screening 21) Absolute neutrophils count ≤ 1000 at Screening 22) Serum creatinine > 2× ULN at Screening 23) Daily, continuous oxygen supplementation 24) Supplemental oxygen requirement of greater than 2 L/min at night 25) Administration of any investigational products within 8 weeks prior to study Day 1 26) Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements. 27) History of alcohol, medication, or illicit drug abuse within the 1 year prior to Screening 28) Smoking tobacco or any substance within 6 months prior to screening or anticipated inability to refrain from smoking throughout the study |
| 1) Volume espiratorio forzato in 1 secondo (FEV1) <25% rispetto al predetto allo screening, utilizzando lo spirometro fornito dal promotore. 2) Anamnesi di ipersensibilita' agli amminoglicosidi, compresa la soluzione di tobramicina per inalazione. 3) Precedente esposizione ad Arikace™ (compreso studio clinico). 4) Anamnesi di importanti complicanze di pneumopatia (compresi atelettasia, pneumotorace, importante effusione pleurica) nelle 8 settimane precedenti lo screening. 5) Emottisi di ≥60 ml nell’arco di 24 ore nelle 4 settimane precedenti lo screening. 6) Anamnesi di esacerbazione polmonare acuta, necessitante di trattamento antibiotico nelle 4 settimane precedenti lo screening. 7) Anamnesi di infezione delle alte vie respiratorie nelle 2 settimane precedenti lo screening. 8) Uso di antibiotici anti Pseudomonas (antibiotici e.v., inalatori od orali) nelle 4 settimane precedenti il Giorno 1. 9) Referti radiologici di nuove infiltrazioni polmonari nei 3 mesi precedenti lo screening, oppure presenza di altre anomalie suggestive di pneumopatia in atto clinicamente significativa, diversa dalla FC. 10) Avvio di terapia cronica (ad es., TOBI, Colomycin, altri antibiotici inalatori, alte dosi di ibuprofene, broncodilatatori, agenti antinfiammatori inalatori, compresi steroidi, basse dosi di mantenimento degli steroidi, rhDNasi, soluzioni saline ipertoniche, macrolidi) nelle 4 settimane precedenti il Giorno 1. 11) Anamnesi di coltura positiva per Burkholderia cepacia nei 2 anni precedenti lo screening. 12) Anamnesi di tubercolosi polmonare o pneumopatia da micobatteri non tubercolari, trattata nei 2 anni precedenti lo screening o necessitante di trattamento al momento dello screening. 13) Anamnesi di aspergillosi broncopolmonare necessitante di trattamento con steroidi sistemici, o qualsiasi altra condizione che richiede l’uso di steroidi sistemici ad una dose equivalente a ≥10 mg/die di prednisone nei 3 mesi precedenti lo screening. 14) Presenza di qualsiasi cardiopatia clinicamente significativa, come determinato dallo sperimentatore e/o, in caso di disponibilita' dei dati del QTc, prolungamento del QTc >450 msec (0,450 secondi) negli uomini, o QTc >470 msec (0,470 secondi) nelle donne, o prolungamento del QTc >440 msec (0,440 secondi) in tutti i soggetti di eta' compresa tra 6 e 12 anni. 15) Sindromi da immunodeficienza acquisita e primitiva. 16) Anamnesi di epatite C o infezione cronica in atto da epatite B. 17) Neoplasia polmonare maligna in atto (primitiva o metastatica), oppure qualsiasi neoplasia necessitante di chemioterapia o radioterapia nell’anno precedente lo screening, oppure prevista durante il periodo dello studio. 18) Anamnesi di cirrosi biliare associata a ipertensione portale. 19) Anamnesi di trapianto del polmone. 20) Elevati valori di AST, ALT o GGT ≥3 volte il limite superiore della norma (LSN) al momento dello screening. 21) Conta assoluta dei neutrofili ≤1000 allo screening. 22) Creatinina sierica >2 volte il LSN allo screening. 23) Supplemento d’ossigeno continuo, giornaliero. 24) Supplemento d’ossigeno superiore a 2 l/min alla notte. 25) Somministrazione di qualsiasi prodotto sperimentale nelle 8 settimane precedenti il Giorno 1. 26) Disturbi psicotici, da dipendenza o altro disturbo che limita la capacita' di accordare il consenso informato o di aderire ai requisiti dello studio. 27) Anamnesi di etilismo, farmacodipendenza o tossicodipendenza nell’anno precedente lo screening. 28) Tabagismo o consumo di altre sostanze nei 6 mesi precedenti lo screening, oppure la prevista incapacita' di astenersi dal fumo per l’intera durata dello studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The relative change in Forced Expiratory Volume in 1 second (FEV1 (liters)) from baseline (Day 1) to the end of the study (Day 168) |
| Variazione relativa nel volume espiratorio forzato in 1 secondo (FEV1 (litri)) dal basale (Giorno 1) fino alla conclusione dello studio (Giorno 168) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| 1) Relative change in FEV1 (liters) from Day 1 to the end of study 2) Relative change in FEV1 (% predicted) from Day 1 to the end of study 3) Time to first protocol defined pulmonary exacerbation and proportion of subjects experiencing a protocol defined pulmonary exacerbation 4) Time to first antipseudomonal antibiotic treatment for protocol defined pulmonary exacerbation 5) Change in log CFU Pa from baseline throughout study 6) Time to and number of hospitalizations for any cause 7) Change in respiratory symptoms from baseline throughout study as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R) |
| 1) Variazione relativa nel FEV1 (litri) dal Giorno 1 alla fine dello studio 2) Variazione relativa nel FEV1 (% rispetto al predetto) dal Giorno 1 alla fine dello studio 3) Tempo alla prima esacerbazione polmonare definita dal protocollo, e proporzione di soggetti colpiti da un’esacerbazione polmonare definita dal protocollo. 4) Tempo alla prima terapia antibiotica anti-Pseudomonas per esacerbazione polmonare definita dal protocollo. 5) Variazione del log UFC di Pa dal basale per l’intera durata dello studio. 6) Tempo al ricovero e numero di ricoveri per ogni causa. 7) Variazione dei sintomi respiratori dal basale durante l’intero studio, come determinato dal questionario specifico per la fibrosi cistica (CFQ-R, Cystic Fibrosis Questionnaire-Revised). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1) Day 1, 14, 28, 57, 84, 113 and 140 2) Day 1, 14, 28, 57, 84, 113, 140 and 168 5) Day 1, 14, 28, 57, 84, 113, 140, 168 7) Day 1, 14, 28, 57, 84, 113, 140 and 168 |
| 1) Giorno 1, 14, 28, 57, 84, 113 e 140 2) Giorno 1, 14, 28, 57, 84, 113, 140 e 168 5) Giorno 1, 14, 28, 57, 84, 113, 140, 168 7) Giorno 1, 14, 28, 57, 84, 113, 140 e 168 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability |
| Tollerabilita' |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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