E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.1 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
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 |
- To evaluate the safety and tolerability of CTX-4430 administered orally once-daily to cystic fibrosis (CF) patients for 48 weeks
- To evaluate the efficacy of CTX-4430 administered orally once-daily to CF patients for 48 weeks as determined by the absolute change from Baseline in FEV1 (forced expiratory volume in 1 second) percent predicted
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E.2.2 | Secondary objectives of the trial |
1. Efficacy evaluation of CTX-4430 as determined by the relative change from Baseline in FEV1 percent predicted
2. Evaluation of the effect of orally administered CTX-4430 on FVC % predicted and FEF25-75% predicted
3. Evaluation of the effect of orally administered CTX-4430 on time to first pulmonary exacerbation while in the study
3.1 Evaluation of the effect of orally administered CTX-4430 on the number of pulmonary exacerbations
3.2 Evaluation of the effect of orally administered CTX-4430 on specified biomarkers (sputum DNA and elastase and serum hs-CRP)
Exploratory Objectives:
- Effect evaluation of orally administered CTX-4430 on sputum bacterial density
- Population PK of orally administered CTX-4430 after first dose and at steady state
- Change from Baseline evaluation in subject’s health-related QOL while on CTX-4430 administered orally 1x daily for 48 w |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients are eligible to participate in the study if they meet all of the following inclusion criteria:
1. 18 to 30 years of age inclusive at the time of Screening
2. Documented, confirmed diagnosis of pulmonary CF (defined as follows):
• CF signs and symptoms AND
• Either 2 CFTR mutations on genetic testing OR sweat chloride ≥60 mEq/L
3. Medically stable, in the Investigator’s opinion
4. At least 1 pulmonary exacerbation, based on the Investigator’s judgment, in the 12 months before Screening
5. Resolution of any pulmonary exacerbation of CF at least 14 days before Screening, in the Investigator’s opinion
6. On a stable regimen of CF treatments with no change for at least 14 days before Screening and between Screening and Baseline
7. If on ivacaftor or ivacaftor-lumacaftor combination, on a stable regimen for at least 8 weeks before Baseline
8. No clinical or radiological evidence, per the Investigator’s site procedures, of clinically significant lung abnormalities (e.g., major atelectasis, pneumothorax)
9. FEV1 ≥50 percent predicted at Screening
10. Resting oxygen saturation >92% on room air
11. Body mass index (BMI) ≥17.0 kg/m2
12. No use of tobacco or nicotine-containing products for at least 6 months before Screening and agreement not to use such products for the duration of the study
13. Females of childbearing potential must have a negative pregnancy test at Screening (unless surgically sterile) and must agree to use a highly effective contraception method from screening throughout the duration of the study
14. Able to perform reproducible spirometry according to European Respiratory Society/American Thoracic Society guidance
15. Able to swallow investigational product (IP) whole
16. Able to comply with the study procedures, in the opinion of the Investigator
17. Has provided informed consent to participate in the study. |
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E.4 | Principal exclusion criteria |
Patients are eligible to participate in this study if they meet none of the following exclusion criteria:
1. In the opinion of the Investigator, any significant clinical/laboratory/radiological/spirometric sign of unstable or unexpectedly deteriorating respiratory disease within 14 days before Screening or between Screening and Baseline (These clinical/laboratory/radiological/ spirometric signs include, but are not limited to, features suggestive of a pulmonary exacerbation as suggested by the modified Fuchs’ criteria.)
2. A medical condition that is unstable, could be adversely impacted by participation in the study, or could impact assessment of the study results, in the opinion of the Investigator
3. History of organ transplantation
4. History of either alcoholism or drug abuse within 2 years before Screening
5. Positive alcohol or drug test at Screening
6. Clinically significant hemoptysis (e.g., > approximately 30 cc per episode, or clinically significant in the Investigator’s opinion) within 180 days before Screening
7. Positive culture for Burkholderia cepacia complex or Mycobacterium species within 24 months before Screening or between Screening and Baseline
8. Active allergic bronchopulmonary aspergillosis at Screening or at Baseline
9. Any clinically significant ECG abnormality, in the Investigator’s opinion
10. Positive serology for HIV-1 or HIV-2 antibody, hepatitis C virus antibody, or hepatitis B surface antigen at Screening
11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 2x the upper limit of normal (ULN) at Screening
12. Bilirubin >1.25 x ULN at Screening
13. Neutrophil count <1.5 x 109/L at Screening
14. Clinically unstable pancreatic function, in the opinion of the Investigator. Evidence of unstable pancreatic function could include:
• Clinically significant weight loss (≥5% after a previously stable period)
• Evidence of uncontrolled hyperglycemia or recent hypoglycemia
• Change in pancreatic enzyme requirements in the 60 days before Screening
15. Use of a 5-lipoxygenase (5-LO) inhibitor (e.g., zileuton), leukotriene receptor antagonists (e.g. montelukast, zafirlukast), systemic corticosteroids, or systemic antibiotic therapy (other than chronic azithromycin use for CF) within 14 days before Screening or between Screening and Baseline
16. Regular use (>3 times per week) of a high-dose NSAID (e.g., >1.6 g ibuprofen/day) within 60 days before Screening or between Screening and Baseline
17. Participation in a clinical trial for any medical product within 60 days before Screening or between Screening and Baseline
18. Pregnant or nursing women |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: Analysis of change from Baseline to Week 48 in FEV1 percent predicted
Safety: AE recording |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety, AE recording: screening, baseline and at weeks 4 , 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52.
Efficacy, spirometry: screening, baseline and at weeks 4, 8, 12, 16, 24, 32, 40, 48, 52.
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E.5.2 | Secondary end point(s) |
CLINICAL ENDPOINTS
- spirometry-based secondary endpoints will be analyzed using the same methods as the primary endpoint. For time points prior to 48 weeks, only descriptive statistics will be presented.
- Pulmonary exacerbations: time to first pulmonary exacerbation and number of pulmonary exacerbations.
BIOMARKER ENDPOINTS
- sputum DNA and elastase, serum hs-CRP
EXPLORATORY ENDPOINTS
- pharmacokinetics
- sputum bacterial density (P aeruginosa, Burkholderia cepacia complex, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and Staphylococcus aureus (including methicillin–resistant S aureus and small colony variants of S aureus [CFUs])
- change from Baseline in subject’s health-related quality of life (HRQOL): Cystic Fibrosis Questionnaire |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
PHARMACOKINETICS
- PK sampling: predose and at 1, 2, 4, and 6 hours postdose, at baseline and steady state (week 4 and/or week 8)
CLINICAL ENDPOINTS
- spirometry-based secondary endpoints: screening, baseline and at weeks 4 , 8, 12, 16, 24, 32, 40, 48, 52.
- Pulmonary exacerbations checklist: baseline and at weeks 4 , 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52
BIOMARKER ENDPOINTS
- Sputum (DNA + elastase): baseline and at weeks 8, 24, 48
- serum hs-CRP: baseline and at weeks 4, 8, 12, 24, 32, 40, 48 and 52
EXPLORATORY ENDPOINTS
- sputum bacterial density: baseline and at weeks 8, 24, 48
- health-related quality of life, Cystic Fibrosis Questionnaire: baseline and at weeks 12, 24, 48 |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
France |
Germany |
Italy |
Netherlands |
United Kingdom |
United States |
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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.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 21 |