E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cystic fibrosis and chronic infection of lower respiratory tract with Pseudomonas aeruginosa |
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E.1.1.1 | Medical condition in easily understood language |
Cystic fibrosis and chronic lung infection with a bacterium (germ) called Pseudomonas aeruginosa |
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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 | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011762 |
E.1.2 | Term | Cystic fibrosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 primary objective of this study is to evaluate the safety and efficacy of a CAT regimen with AZLI and TIS in adult and pediatric subjects with CF and pulmonary PA infection. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males or females ≥ 6 years of age
2. Diagnosis of CF as determined by the 1997 CF Consensus Conference criteria: At least 1 or more accompanying clinical features consistent with CF AND
— Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test
OR
— Abnormal nasal transepithelial potential difference (NPD) test
OR
— Two well-characterized, disease-causing genetic mutations in the CF transmembrane conductance regulator (CFTR) gene
3. Documented presence of PA in 2 lower respiratory tract cultures (eg, sputum, throat swab) within the 12 months prior to or at Screening (Visit 1). Cultures must be a minimum of 3 months apart, with the most recent PA-positive culture within 3 months prior to Screening Visit 1. A PA-positive sputum or throat swab culture at Screening (Visit 1) can qualify as the most recent PA-positive culture.
4. Subject must be able to perform reproducible pulmonary function tests (PFTs)
5. FEV1 ≥ 25% and ≤ 75% predicted at Screening (Visit 1)
6. History of at least 1 hospitalization or 1 course of IV antibiotics for an acute respiratory exacerbation within the previous 12 months from Screening
7. Clinically stable with no evidence of significant respiratory symptoms or, if obtained for clinical evaluation, no acute chest radiograph findings at Screening (Visit 1) or Enrollment (Visit 2) that would require administration of IV antibiotics, oxygen supplementation, or hospitalization
8. Chest radiograph without significant acute findings (eg, infiltrates [lobar or diffuse interstitial], pleural effusion, pneumothorax); or chest radiograph, CT, or MRI obtained and interpreted within the 90 days prior to enrollment, without acute findings and no significant intercurrent illness; chronic, stable findings (eg, chronic scarring or atelectasis) are allowed
9. Subjects must be able to provide written informed consent (or assent if applicable) prior to any study related procedures; parent/guardian must be able to give written informed consent prior to any study related procedure
10. A negative urine pregnancy test is required for female subjects of childbearing potential (see Section 1)
11. All sexually active female subjects who are not postmenopausal, or surgically sterile, or who do not have medically documented ovarian failure and are of childbearing potential must agree to use highly effective contraception (per Section 7.8.2) during heterosexual intercourse throughout the study and for 30 days after the last dose of TIS or study drug;
females utilizing hormonal contraceptives as a birth control method must have used the same method for at least 3 months prior to start of TIS treatment
12. Male subjects who are sexually active are required to use barrier contraception (condom with spermicide) during heterosexual intercourse and refrain from sperm donation from screening through to study completion and for 90 days from the last dose of TIS or study drug |
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E.4 | Principal exclusion criteria |
1. Concurrent use of oral, IV, or inhaled antibiotics at Enrollment (Visit 2)
2. Concurrent hospitalization at Enrollment (Visit 2)
3. History of sputum or throat swab culture yielding Burkholderia spp. or any rapid growing mycobacterial infection (eg, M. abscessus) within 2 years of Enrollment (Visit 2)
4. Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone per day or 20 mg prednisone every other day
5. Current requirement for daily continuous oxygen supplementation or requirement (medically necessary) of more than 2 L/minute at night (subject would not meet this exclusion criterion if supplemental oxygen is used for comfort only)
6. Administration of any investigational drug or device within 28 days of Enrollment (Visit 2) or within 6 half-lives of the investigational drug (whichever is longer)
7. History of local or systemic hypersensitivity to monobactam or aminoglycoside antibiotics (inhaled or systemically administered) or history of aminoglycoside antibiotic-associated toxicity (oto-, renal, or neuromuscular toxicity)
8. History of allergies/intolerance to inhaled short-acting β2 agonists
9. History of lung transplantation
10. Changes in chronic azithromycin use, bronchodilator (BD), dornase alfa, physiotherapy technique or regimen, hypertonic saline, or corticosteroid medications within 28 days prior to Enrollment (Visit 2)
11. Pregnant or lactating females; a negative serum or urine pregnancy test is required for female subjects of childbearing potential (see Section 7.8.2)
12. Abnormal renal or hepatic function results at most recent test within the previous 90 days, defined as
— AST, ALT > 3 times upper limit of normal range (ULN)
— Creatinine >1.5 time ULN
13. Presence of any condition or abnormality that would compromise subject safety or the quality of data, or any serious or active medical or psychiatric illness, which in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance with the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the rate of protocol-defined exacerbations from Day 1 through Week 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Study visits from from Day 1 through Week 24. |
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E.5.2 | Secondary end point(s) |
• Average actual change from baseline in FEV1 % predicted at the end of each course of study drug (Weeks 4, 12, and 20)
• Percent of subjects who use non-study IV or inhaled antibiotics for protocol-defined pulmonary exacerbations, Day 1 to Week 24
• Time to first protocol-defined pulmonary exacerbation
• Rate of hospitalizations for a respiratory event
• Average change from baseline in the CFQ-R Respiratory Symptom Scale (RSS) score at the end of each course of study drug (Weeks 4, 12, and 20) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
E.6.13 | Others | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |