A Phase 1b Study of PUR1800 in Patients With COPD

This is a randomised, placebo-controlled, double-blind 3-way crossover study in which PUR1800, or placebo is dosed daily for 14 consecutive days in adult subjects with stable COPD over three discrete TPs. Subjects will be randomised to one of the following 3 treatment sequences:

Sequence Period 1 Period 2 Period 3

1. Placebo PUR1800 250 μg PUR1800 500 μg
2. PUR1800 250 μg Placebo PUR1800 500 μg
3. PUR1800 250 μg PUR1800 500 μg Placebo

Since this is the first study in humans in which the iSPERSE formulation is being administered, the 3 treatment sequences are designed in order to ensure that the lower dose of PUR1800 (250 μg) is administered prior to the administration of the higher dose of PUR1800 (500 μg).

The study design is as follows

Informed Consent: Before any study specific procedures are conducted or study requirements are expected of a patient, the patient must review and sign an IEC-approved informed consent form.

Screening: Subjects will be screened for eligibility to participate in the study within 28 days before randomisation (i.e. TP1, Day 1).

Treatment Periods:

Period 1: On Day 1 all subjects who are eligible for entry into the study will be randomised to 1 of 3 treatment sequences and receive either placebo or the lowest nominal dose of PUR1800 (PUR1800 250 μg) for 14 consecutive days.

Period 2: Following a washout period of at least 28 days after the completion of Period 1 dosing, subjects will receive a treatment other than what the subject received during Period 1 for 14 consecutive days.

Period 3: Following a washout period of at least 28 days after the completion of Period 2 dosing, subjects will receive the treatment that the subject had not received during Periods 1 or 2 (either placebo or PUR1800, 500 μg) for 14 consecutive days.

End of Study (EOS): Subjects will return to the study site 28 days after the last dose of the last TP (or in the event of early withdrawal after the last dose received, if possible) for an EOS visit. Unscheduled visits are permitted at the discretion of the investigator.

Eligibility Criteria:
Inclusion Criteria:

Patients must meet all the following:

1. Male or female patients aged 40 to 75 years of age with a body mass index

   ≥ 17 and ≤ 35 kg/m2.
2. Female patients must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method (See Section 9.4.1).
3. Male patients with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s) (See Section 9.4.1).
4. Female patients must agree not to donate ova/oocytes during the study and for 30 days after the last dose of IMP.
5. Male patients must agree not to donate semen during the study and for 90 days after the last dose of IMP.
6. Confirmed diagnosis by a physician of COPD with symptoms compatible with COPD for at least 1 year prior to screening.
7. Severity of Disease: patients who conform to the current severity classification for GOLD Grade II/III disease in terms of post-bronchodilator spirometry at screening: Post-salbutamol FEV1/FVC ratio of \< 0.70. Post-salbutamol FEV1 ≥ 40 % and ≤ 80 % of predicted normal values (based on the Global Lung Function Initiative \[GLI-2012\]\[1\]).
8. Current or previous tobacco smoker with a smoking history of ≥ 10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent).
9. Vital signs recorded from automated blood pressure equipment within the following normal ranges: Blood pressure; systolic value of 90 mmHg to 160 mmHg, diastolic value of 60 mmHg to 90 mmHg and pulse rate ≥ 60 and

   ≤100 beats per minute at screening and prior to randomisation.
10. Able to provide written Informed Consent Form (ICF) prior to participation in any study-related activities, and to comply with the requirements of the study.
11. Able to perform technically acceptable spirometry at screening.
12. Able to produce a sputum sample of adequate quality at either the Screening or Baseline visit prior to randomisation.
13. Able to demonstrate the correct inhalation technique for use of the delivery device and to generate sufficient peak inspiratory flow (PIF) (at least 40 L/min) using the In-Check DIAL device at screening and prior to randomisation.

Exclusion Criteria:

Patients who meet any of the following are not eligible:

1. Upper or lower respiratory tract infection within 6 weeks prior to screening or prior to randomisation.
2. COPD exacerbation requiring oral steroids and/or antibiotics, within the 6 weeks prior to screening or prior to randomisation.
3. Clinically significant abnormal laboratory values at screening that, in the opinion of the investigator would make the patient inappropriate for the study or put the patient at undue risk, specifically liver function tests (LFTs: aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], gamma-glutamyl transferase \[GGT\], total bilirubin) \>3 x upper limit of normal (ULN); hemoglobin \<10 gm/dL; absolute neutrophil count (ANC) \<1000; white blood cells (WBC) \>20,000; Platelets \<100,000 and \>500,000; prothrombin time (PT) \>14 seconds.
4. QTcF of \>450 msec in males or \>470 msec in females on any of the three individual ECG measurements at screening or prior to randomisation.
5. History of drug or alcohol abuse within the past 2 years prior to screening or prior to randomisation.
6. History of regular alcohol consumption within 6 months prior to screening or prior to randomisation defined as an average weekly intake of \>21 units for males, or \>14 units for females, where one unit is equivalent to 8 g of alcohol: a half-pint (\~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
7. Positive alcohol breath test result at screening or prior to randomisation.
8. Positive urine drugs of abuse test result (unless in the opinion of the investigator this can be explained by the patient's current medications) at screening or prior to randomisation; unexpected or unexplained positive results may require discussion with Sponsor.
9. Current users of e-cigarettes and those who have used these products within one month prior to screening or between screening and randomisation.
10. Known sensitivity to the study drug or any of the excipients of the formulation, or history of clinically significant sensitivity to any agent that, in the opinion of the investigator, would make participation in the study inadvisable.
11. Donated blood or blood products or had substantial loss of blood (more than 500 mL) within 3 months before the first administration of study drug, or intention to donate blood or blood products during the study.
12. Participated in an interventional study involving an experimental therapeutic agent within 3 months of screening or prior to randomisation.
13. Women who have a positive serum β-human chorionic gonadotropin (hCG) pregnancy test at screening or a positive urinary hCG pregnancy test prior to randomisation, is pregnant, lactating, or planning to become pregnant during the study.
14. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or HIV results. Patients who are HBs antibody positive or HB core antibody positive are not excluded provided the HBsAg result is negative. Patients who are HCV Ab positive are not excluded if a subsequent HCV RNA test is negative.
15. Planned surgery or procedures during the participation of the study and for 28 days after the conclusion of study participation.
16. Employee of the investigator or study centre with direct involvement in the proposed study or other studies under the direction of that investigator or study centre, as well as family members of the employees or the investigator.
17. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
18. The patient is unable or unwilling to comply fully with the study protocol.
19. Patient is mentally or legally incapacitated.
20. Unable or unwilling to undergo multiple venepuncture procedures or the patient has poor access to veins suitable for cannulation.
21. Any other reason that, in the opinion of the investigator, would make participation in the study inadvisable.
22. A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation within the last 5 years.
23. A history of \> 1 hospitalisation for COPD in the previous 1 year prior to screening.
24. Evidence of cor pulmonale or clinically significant pulmonary hypertension.
25. Requires routine treatment for COPD using one (or more) of the following therapies within the 6 weeks before screening or prior to randomisation: Oral Beta-2 agonists Methyl xanthines Phosphodiesterase (PDE) inhibitors Oral leukotriene inhibitors Oral or parenteral glucocorticoids Antibiotic therapies for acute infections (Note: chronic antibiotic use for prophylaxis, e.g. macrolides, is acceptable).
26. Other respiratory disorders: Patients with a current diagnosis of asthma, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, known alpha-1 antitrypsin deficiency or other active pulmonary diseases other than COPD.
27. Patients with a history of chronic uncontrolled disease including, but not limited to, cardiovascular, endocrine, neurological, hepatic, gastrointestinal, renal, hematologic, urologic, immunologic, or ophthalmic diseases that, in the opinion of the investigator, would make participation in the study inadvisable.
28. Patients with a history of sleep apnoea requiring non-invasive ventilation or supplemental oxygen during sleep.
29. Previous lung resection or lung reduction surgery.
30. Active participation in a pulmonary rehabilitation program.
31. Has had major surgery within 6 weeks prior to screening or prior to randomisation.
32. A disclosed history, or one known to the Investigator, of significant noncompliance in previous investigational studies or with prescribed medications.
33. History of unstable or uncontrolled hypertension or has been diagnosed with hypertension in last 3 months prior to screening or prior to randomisation.
34. Requires supplemental oxygen, even on an occasional basis.
35. Received a live vaccine within 6 weeks prior to screening or prior to randomisation.