| Eligibility |
Inclusion Criteria
All subjects:
1. Subject's written informed consent obtained prior to any study-related procedure;
2. Male and female subjects aged 40 to 80 years inclusive at screening;
3. Ability to understand the study procedures and the risks involved, and ability to be
trained to use the inhalers correctly and to generate sufficient peak inspiratory flow
(PIF, at least 40 L/min) using the In-Check device set as per NEXThaler® inhaler
resistance;
4. Subjects must weigh at least 45kg for females and 50 kg for males to participate in
the study, and must have a body mass index (BMI) within the range of 18 to 35 kg/m2
inclusive;
5. Non- or ex-smokers who smoked < 5 pack years (pack years = the number of cigarette
packs per day times the number of years) and stopped smoking > 1 year prior to
screening;
6. Oral body temperature < 37.5°C;
7. Mean values of triplicate recording of 12-lead digitised electrocardiogram (ECG)
considered as normal (40 beats per min [bpm] = heart rate [HR] = 110 bpm, 120 ms = PR
interval [PR] = 210 ms, QRS interval [QRS] = 120 ms, QT interval corrected using
Fridericia's formula [QTcF] = 450 ms for males and QTcF = 470 ms for females);
8. Lung function measurements within normal limits at screening: forced expiratory volume
within the first second (FEV1) > 80% predicted and FEV1/Forced vital capacity (FVC)
ratio > 0.70;
9. For female subjects:
a. Women of child bearing potential (WOCBP) fulfilling one of the following criteria:
i. WOCBP with fertile male partners: they and/or their partner must be willing to use
at least an acceptable effective birth control method from the signature of the
informed consent and until follow up contact; or ii. WOCBP with non-fertile male
partners (contraception is not required in this case); b. Female subjects of
non-childbearing potential defined as physiologically incapable of becoming pregnant.
Tubal ligation or partial surgical interventions are not acceptable;
Healthy subjects only:
10. Good mental and physical status, determined on the basis of the medical history and a
general clinical examination;
11. Blood pressure within normal limits at screening and prior to study treatment
administration: diastolic blood pressure (DBP) 40-89 mmHg and systolic blood pressure
(SBP) 90-139 mmHg, extremes included;
12. Serum creatinine within the normal range and an eGFR = 90 mL/min/1.73 m2 as determined
by the MDRD equation;
13. Matched to at least one renal impaired subject enrolled in the study with respect to
age (±10 years), gender, race and body weight (±15%);
Renal impaired subjects only:
14. Good mental status, determined on the basis of the medical history and a general
clinical examination;
15. Blood pressure at screening and prior to study treatment administration: DBP 40 100
mmHg and SBP 90 170 mmHg, extremes included;
16. Subjects must have a chronic stable renal disease based on the medical history,
physical examination, and clinical laboratory results:
1. "Chronic" is defined as > 6 months;
2. "Stable" is defined as the absence of significant progression and/or
deterioration of the renal disease for the past 12 weeks (fluctuations in
creatinine levels within ±20% in the last 12 weeks are accepted); Subjects may
have concurrent stable medical conditions in addition to renal impairment, but
may be included only if the Investigator, in consultation with the Sponsor's
Clinical Research Physician, considers that the condition will not introduce an
additional risk factor, and will not interfere with the study objectives and
procedures (e.g. subjects with stable diabetes or essential hypertension may be
included);
17. Subjects with renal impairment must have the following absolute eGFR values as
determined by the MDRD equation: mild renal impairment must have an absolute eGFR of =
60 to < 90 mL/min/1.73 m2; moderate renal impairment must have an absolute eGFR of =
30 to < 60 mL/min/1.73 m2; severe renal impairment must have an absolute eGFR of < 30
mL/min/1.73 m2 not requiring dialysis.
Exclusion Criteria
All subjects:
1. Participation to another clinical study where an investigational treatment was
received, and last investigations were performed less than 8 weeks prior to screening;
2. Subjects with history of breathing problems (i.e. history of asthma including
childhood asthma);
3. Positive human immunodeficiency virus (HIV) 1 or HIV2 serology;
4. Positive results from the Hepatitis serology which indicates acute or chronic
hepatitis B or hepatitis C at screening (i.e. positive hepatitis B surface antigen
[HBsAg], hepatitis B core antibody [immunoglobulin M antibody to hepatitis B core
antigen, IgM anti-HBc], hepatitis C virus [HCV] antibody);
5. Documented coronavirus disease 2019 (COVID-19) diagnosis within the last 8 weeks, or
complications from this disease, which have not resolved within 14 days prior to
screening or to study treatment administration;
6. Blood donation or blood loss (= 450 mL) less than 2 months prior to screening or prior
to study treatment administration;
7. Abnormal liver enzymes at screening (alanine aminotransferase [ALT] or Aspartate
aminotransferase [AST] > 1.5 times the upper limit of normal [ULN], total bilirubin >
1.5 times the ULN);
8. Current haemodialysis or peritoneal dialysis or indications for these procedures;
9. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism or excretion of orally administered drugs (e.g. history of
bariatric surgery, stomach/intestinal significant resection, portacaval shunting);
10. Subject with severe heart failure as defined by the New York Heart Association
functional classification III and IV;
11. Positive urine test for cotinine;
12. Documented history of alcohol abuse within 12 months prior to screening or a positive
alcohol breath test;
13. Documented history of drug abuse within 12 months prior to screening or a positive
urine drug screen evaluated at screening or prior to study drug administration;
14. Intake of non-permitted concomitant medications;
15. Presence of any current infection, or previous infection that resolved less than 7
days;
16. Known intolerance and/or hypersensitivity to any of the excipients contained in the
formulation used in the study;
17. Unsuitable veins for repeated venepuncture;
18. Heavy caffeine drinker (average of > 5 cups or glasses per day of caffeinated
beverages e.g. coffee, tea, cola, calculated by number of standard espresso portions);
19. For females only: pregnant or lactating women, where pregnancy is defined as the state
of a female after conception and until termination of the gestation, confirmed by a
positive serum human chorionic gonadotropin laboratory test;
20. Contra-indications/warnings/precaution for use: contra indications to the
investigational medicinal product (IMP) constitute an exclusion criterion;
21. The use of any kind of smoking electronic devices within 6 months before screening;
Healthy subjects only:
22. Abnormal haemoglobin [Hb] level defined as < 130 g/L for males and < 110 g/L for
females at screening;
23. Current diagnosis or history of nephrolithiasis (kidney stone);
24. Clinically relevant and uncontrolled respiratory, cardiovascular, hepatic,
gastrointestinal, renal, endocrine, metabolic (especially subjects with deficiency in
glucuronidation), neurologic, haematologic, neoplastic or psychiatric disorders that
may interfere with successful completion of this study according to the Investigator's
judgment;
25. Clinically relevant abnormal laboratory values at screening suggesting an unknown
disease and requiring further clinical investigation or which may impact the safety of
the subject or the evaluation of the result of the study according to the
Investigator's judgment;
Renal impaired subjects only:
26. Abnormal Hb level defined as = 80 g/L at screening;
27. Clinically relevant and/or uncontrolled respiratory, cardiovascular, hepatic,
gastrointestinal, endocrine, metabolic (especially subjects with deficiency in
glucuronidation), neurologic, haematologic, neoplastic or psychiatric disorders that
may interfere with successful completion of this study;
28. Acute renal disease caused by drug toxicity;
29. History of clinically significant (CS) chronic or recurrent urinary tract infection,
active and requiring antibiotic treatment within the past 30 days;
30. Secondary renal disease associated with impaired liver metabolism (hepatorenal
syndrome) or due to malignancy;
31. Significant risk factors for progression of the renal disease within 3 months prior to
screening (e.g. uremic pericarditis, pleuritis, bleeding disorders, eGFR < 15
mL/min/m2);
32. Subjects who underwent a nephrectomy;
33. Subjects with a functioning organ transplant or who are registered on a transplant
list.
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