|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|Diseases [C] - Respiratory Tract Diseases [C08]
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|-To assess the safety and tolerability of up to three multiple ascending dose levels of inhaled POL6014 after 15 days q.d. or b.i.d.
-To identify the highest tolerated dose level and associated dose regimen of inhaled POL6014 after 15 days q.d. or b.i.d. treatment.
Cohort C only:
-To assess the safety and tolerability of one lower dose level of inhaled POL6014 over 28 days q.d.
|Secondary objectives of the trial
|-To assess the pharmacokinetics (PK) in plasma, sputum and urine of up to 3 multiple ascending dose levels of inhaled POL6014 after 15 days q.d or b.i.d.; determine when steady state is reached during 15 days q.d. or b.i.d. treatment
Cohort C only:
-To assess the pharmacokinetics (PK) in plasma, sputum and urine of one lower dose level of inhaled POL6014 over 28 days q.d.; determine when steady state is reached during 28 days q.d. at one lower dose level
|Trial contains a sub-study
|Principal inclusion criteria
|1.Patient has given written informed consent to participation in the trial prior to their enrolment and any trial-related procedure.
2.Male patients or female patients of non-childbearing potential, aged 18 to 55 years, inclusive. Women of non-childbearing potential are defined as those who have no uterus, or ligation of the fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries. Documentation of surgical procedure is required for patients who have had a hysterectomy or tubal ligation.
3.Men must agree to practice contraception from start of study medication up to 90 days after the last dose of the study medication.
4.Patient with a diagnosis of CF documented by a compatible clinical or radiographic presentation and laboratory criteria, more specifically, sweat or genetic testing (i.e., presence of the most common genetic defect ΔF 508 or any other mutation that can produce CF).
5.Patient should confirm to produce frequently spontaneous sputum with a frequency of over 3 expectorates per day. Patient should be capable of producing a spontaneous sputum sample at screening (within a time range of approx. 3h during the screening visit).
6.Except for CF and CF-related diseases, no other significant disease as assessed by a screening examination including medical history, physical examination, vital signs, ECG assessment, pulmonary function testing (PFT), and clinical laboratory results. Deviations of clinical laboratory results can be accepted if they are in accordance with the diagnosis of CF and CF-related diseases, supposed they do not indicate a clinical state that is expected to constitute a significant additional risk.
7.Patient must have an FEV1 ≥ 40% of predicted value at screening.
8.Body mass index (BMI) between 16.5 and 30 (both inclusive).
9.Non-smoker or ex-smoker who has stopped smoking for at least one (1) year prior to the Screening Visit.
10.Patient should be willing to refrain from caffeine- or theophylline-containing products within 24 h prior to a clinic visit for a full PK profile.
11.Ability to inhale in an appropriate manner (Patients will be trained to inhale from the eFlow® nebuliser device with a commercially available saline solution at the Screening Visit once informed consent has been obtained).
12.For patients with routine courses of inhaled antibiotics, patients should agree to start routine course of inhaled antibiotic cycle on the same day or not earlier than 3 days before IMP administration.
13. Applicable ONLY for Cohort C: Patient must have an FEV1 ≥ 50% of predicted value at screening
|Principal exclusion criteria
|1.Patient with unstable lung disease, as defined by a change in treatment regimen during the preceding two (2) weeks, or a significant new finding on chest radiography (such as, but not limited to, pneumothorax, lobar/segmental collapse or consolidation), or in the opinion of the investigator, patient with a decline in pulmonary status within the last 12 months not considered a part of the usual, chronic progression of CF lung disease. Routine cyclic antibiotic treatment regimens including ”off/on” cycles are not considered to be changes to treatment regimens.
2.Patient has had an exacerbation of respiratory symptoms within the past four (4) weeks before screening/randomization that required initiation of a new or altered respiratory therapy, and, in the opinion of the investigator, the patient has not returned to a stable level of health
3.Patient with a history of lung transplantation.
4.Patient with a history of clinically significant renal, hepatic, gastrointestinal, cardiovascular and particularly respiratory disease (excluding CF and CF-related disease).
5.Patient with active gastrointestinal ulcer, history of intracranial bleedings, injuries and other bleedings.
6.Patient, as per assessment of the investigator, with severe hepatic impairment (e.g. laboratory values (ALT, AST > 3 x ULN and total bilirubin > 1.5 x ULN) or Child-Pugh-Class C could be indicative of such condition).
7.ECG abnormalities of clinical relevance (e.g., QTc according to Bazett’s formula ≥440 ms, PR >200 ms, or QRS ≥120 ms).
8.Patient with a resting heart rate in supine position <50 bpm, systolic blood pressure <100 mmHg or >140 mmHg, diastolic blood pressure <60 mmHg or >90 mmHg.
9.Proneness to orthostatic dysregulation, fainting, or blackouts.
10.Diagnosis of a tricuspid insufficiency in combination with a mean pulmonary arterial pressure (mPAP) > 25 mmHg, measured by Doppler echography, or, if no tricuspid insufficiency is detectable, any echocardiographic or clinical signs of severe pulmonary heart disease (cor pulmonale) or depending congestive heart failure.
11.History or presence of any malignancy.
12.Positive results in any of the following virology tests: human immunodeficiency virus (HIV) antibodies and antigen, Anti-hepatitis B-core antibody, hepatitis B surface antigen (HbsAg) and anti-hepatitis C virus antibody.
13.Known local or systemic hypersensitivity to any aerosol, medication or food that led to admission to an emergency room.
14.Participation in another clinical study with any investigational medicinal product (IMP) or device, before randomisation, within an interval of 5 half-lives (minimum 4 weeks) from the last use of that investigational drug.
15.Blood or plasma donation of more than 500 mL during the previous month before randomisation, as declared by the patient.
16.Mental condition rendering the patient incapable to understand the nature, scope, and possible consequences of the study.
17.Not willing to comply with all clinical study procedures.
|E.5 End points
|Primary end point(s)
|-Proportion of patients with changes from baseline in physical examination findings
-Changes from baseline in laboratory safety assessments (clinical chemistry, haematology, urinalysis)
-Changes from baseline and pre-dose in vital signs (blood pressure, pulse, respiratory rate body temperature)
-Changes from baseline and pre-dose in ECG parameters
-Occurrence and severity of AEs
-Proportion of patients with local irritation of the nose or pharynx by visual inspection
-Proportion of patients with bronchospasm by symptoms such as dyspnoea, wheezing, chest tightness, cough
-Changes from baseline and pre-dose in lung function parameters (FEV1, FVC) by spirometry
-Changes from baseline in oxygen saturation in peripheral blood as measured by pulse oximetry.
|Timepoint(s) of evaluation of this end point
|In-house stay (D1-D2), Clinical Visit D8, In-house stay (D14-D16), Follow-up (D21-D24)
|Secondary end point(s)
|PK parameters derived from plasma, urine and sputum concentrations of POL6014 and metabolites
|Timepoint(s) of evaluation of this end point
|Sputum and plasma PK samples: V2, 3, 4
Urine sample: V2 and 4
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
|Other trial design description
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|Trial has a data monitoring committee
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
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial months