IMD-1041 Chronic Obstructive Pulmonary Disease: Proof of Concept (POC) Study
IMD-1041 Chronic Obstructive Pulmonary Disease: Proof of Concept (POC) Study
COPD is a lung disease in which the lung is damaged, making it hard to breathe. In COPD, the
 airways/tubes that carry air in and out of the lungs are partly obstructed, making it
 difficult to get air in and out. COPD gets gradually worse over time. At the moment there is
 no cure for COPD. The best way to slow the disease is to stop smoking. Current medications
 are used to alleviate shortness of breath and cough, and to treat infections of the lungs
 that can worsen COPD.

 Institute of Medicinal Molecular Design, Inc. (IMMD), a Japanese Drug Discovery Company is
 developing a compound code named IMD-1041. IMD-1041 is an investigational drug, meaning it is
 not yet on the market. It is an IKKb inhibitor developed for the treatment of COPD. Unlike
 most other medications used for COPD currently, IMD-1041 is in capsule form and needs to be
 taken twice a day. It is also unlike all other drugs in use because it treats the underlying
 cause of the symptoms.

 The purpose of this study is to see if IMD-1041 has the ability to reduce inflammatory
 derived symptoms and airway remodelling (changes) by looking at certain changes in chemical
 levels in the blood and sputum (phlegm).
The dose level of IMD 1041 has been selected based on previous clinical trials. The dose to
 be studied, 400mg, is considered to be efficacious, and is supported by the clinical data in
 healthy subjects and type 2 diabetic patients.

 Single oral doses of 800 mg and multiple oral doses of 400 mg twice daily of IMD-1041 have
 been shown to be safe and well tolerated by healthy subjects.

 Twice daily doses of 200 mg of IMD-1041 have been shown to be safe and well tolerated when
 given to diabetic patients for 12 weeks.

 A placebo (dummy medication) arm has been selected as it is considered the most reliable
 method to minimise patient and investigator bias and current COPD guidelines suggest the most
 useful comparison would be with placebo. Exposure placebo will allow a reliable evaluation of
 IMD 1041, as well as the adverse events caused by the drug compared to those resulting from
 the COPD natural course.

 All patients will be able to remain on the current medications apart from theophylline which
 is expected to have effects on IKK beta.

 The current treatments for COPD do not include a medication of this mechanism of action,
 who's main aim is to reduce inflammatory and fibrotic changes which cause the symptoms which
 current standard COPD medications treat.

 The study will last for 12-14 weeks, including a 7 day screening period, visit 0
 baseline/randomisation visit, visit 1 and visit 3 for all study spec tests, visit 2 and
 4/follow up as either a site or telephone contact to check subject compliance and adverse
 events.

 Prior to selection the Investigator will evaluate the eligibility of patients for entry into
 the trial by reviewing the patients' medical records against the inclusion/exclusion criteria
 specified in the protocol.

 There will be a potential pre-screening visit up to 3 weeks prior to randomisation. This
 visit will only be applicable for patients who need to stop the medication theophylline which
 need to be stopped 2 weeks prior to screening. At this visit potential patients will be
 provided with the information about study activities and requirements. After signing the
 informed consent form the patient will be asked to stop the medication and return to the
 study site for screening at least 2 weeks after the visit.

 All patients will attend the clinical site for initial screening up to 7 days prior to
 randomisation. If the patient has not been 'pre-screened' as described above, they will be
 given information pertaining to study activities and requirements. After signing the informed
 consent form evaluations will be performed to confirm the patients' eligibility according to
 the study protocol. The patients' medical history, physical examination, clinical laboratory
 tests, electrocardiogram (ECG) tracing, blood pressure, pregnancy screening (women of child
 bearing potential only) will be performed. Blood will be taken for routine clinical
 laboratory testing.

 Following successful screening, patients will return to the site up to seven days (but at
 least 1 day) after the screening visit for randomisation. There will be a 50:50 chance of the
 patient being randomised to either IMD 1041 or placebo of whichever they will remain on for
 the duration of the study. The following will then happen prior to randomisation:

 -  Patient asked about current health problems, adverse events and any changes to
 concomitant medications since screening.

 -  Vitals signs

 -  Blood will be taken for clinical lab evaluations and biomarker sampling

 -  Lung functions

 -  Induced sputum for biomarker sampling

 -  2 questionnaires completed Following all of the above evaluations the patient will be
 randomised and medication dispensed. (A total of 280 tablets will be dispensed, which
 equates to 4 weeks supply, plus 56 tablets as spares in case of loss or delayed next
 visit.)

 Visit 1 will occur 4 weeks after visit 0 (+/- 2 days). At this visit the following will
 occur:

 -  Patient asked about current health problems, adverse events and any changes to
 concomitant medications since screening.

 -  vitals signs

 -  Blood will be taken for clinical lab evaluations, PK analysis and biomarker sampling

 -  Lung functions

 -  Induced sputum for biomarker sampling

 -  Medication will be dispensed. A total of either 4(224) or 8(448) weeks supply will be
 dispensed depending on whether or not you will attend the clinical site for visit 3.

 Visit 2 will occur 4 weeks after visit 1 (+/- 3 days). This visit will be either on site or
 over the telephone and will be decided by the Principal Investigator on a case-by-case basis.
 At this visit the following will occur:

 -  Patient asked about current health problems, adverse events and any changes to
 concomitant medications since screening.

 -  Medication dispensed. A total of 4 weeks supply (224 tablets) will be dispensed for
 patients who attend the site for this visit.

 Visit 3 will occur up to 4 weeks after visit 2 (+/- 3 days). At this visit the following will
 occur:

 -  Patient asked about current health problems, adverse events and any changes to
 concomitant medications since screening.

 -  vitals signs

 -  Blood will be taken for clinical lab evaluations, PK analysis and biomarker sampling

 -  Lung functions

 -  Induced sputum for biomarker sampling

 -  2 questionnaires completed

 -  All medication return and final accountability documented

 Visit 4, the follow up visit will be via telephone and will occur 2 weeks after visit 3 (+/-
 3 days). The following will occur:

 -  Patient asked about current health problems, adverse events and any changes to
 concomitant medications since screening.
Inclusion Criteria:

 -  Males and non-pregnant, non-lactating females aged 40 to 80 years of age at the time
 of the screening visit. (Women of childbearing potential will be allowed to enter the
 trial only if they are using one medically approved (i.e., mechanical or
 pharmacological) contraceptive measure. A female is considered to be of childbearing
 potential unless she has had an hysterectomy, is at least one year post-menopausal, or
 has undergone tubal ligation. All women of childbearing potential must have a negative
 pregnancy test at screening visit and week 12 (Visit 3)

 -  Patients with a clinical diagnosis of COPD, grade 2 or 3 according to the GOLD
 guidelines 2007 and stable airway obstruction

 -  Patients with a post salbutamol FEV1 ≥ 30% of the predicted value, < 80% of the
 predicted value (i.e., 30% ≤ 100 x observed post-salbutamol FEV1/predicted FEV1 <80%)
 or who is deemed suitable by the Investigator (at either screening or baseline)

 -  Post-salbutamol FEV1/forced vital capacity (FVC) <70% (i.e,. 100 x post-salbutamol
 FEV1/FVC <70%)

 -  Current, or ex-cigarette smokers with a smoking history of at least 10 pack-years

 -  Patients who have the ability to produce a viable sputum sample (≤ 50% squamous cells)

 -  Predominant current diagnosis of smoking related COPD

 -  Patients who were eligible and able to participate in the trial and who consented to
 do so in writing after the purpose and nature of the investigation had been explained
 to them

 Exclusion Criteria:

 -  History or current diagnosis of asthma, allergic rhinitis or atopy. N.B. Misdiagnosed
 asthma or childhood asthma is acceptable, however must be confirmed by the
 Investigator

 -  Eosinophil count >600 cells/mm3

 -  A respiratory tract infection (including the upper respiratory tract) or COPD
 exacerbation in the 6 weeks prior to the screening visit

 -  Patients who have been hospitalised for an acute COPD exacerbation in the 12 months or
 an exacerbation in the last 3 months which was treated with oral steroids prior to the
 screening visit

 -  Use of long-term oxygen therapy (≥15 hours/day)

 -  Clinically significant respiratory conditions defined as: Known active tuberculosis,
 History of interstitial lung or pulmonary thromboembolic disease, Pulmonary resection
 during the past 12 months, History of life-threatening COPD, History of bronchiectasis
 secondary to respiratory diseases other than COPD (e.g., cystic fibrosis, Kartagener's
 syndrome, etc), Patients who in the Investigator's opinion may need pulmonary
 rehabilitation or a thoracotomy during the trial

 -  Clinically significant cardiovascular conditions defined as: Myocardial infarction
 during the last 6 months, Unstable arrhythmia which required changes in the
 pharmacological therapy or other intervention during the last 12 months, or newly
 diagnosed arrhythmia within the previous 3 months, Hospitalisation within the previous
 12 months for heart failure functional classes III (marked limitation of activity and
 only comfortable at rest) and IV (need of complete rest, confinement to bed or chair,
 discomfort at any physical activity and presence of symptoms at rest) as per the New
 York Heart Association

 -  Patients with any other serious or uncontrolled physical or mental dysfunction at the
 discretion of the Investigator, which could place the patient at higher risk derived
 from his/her participation in the study, could confound the results of the trial, or
 is likely to prevent the patient from complying with the requirements of the trial or
 completing the trial period

 -  Patients who are not able to perform reproducible spirometry attempts at the screening
 visit or during the repeat at baseline

 -  Clinically relevant abnormalities in the results of laboratory, ECG parameters (QTc >
 470 milliseconds), or physical examination at the screening evaluation if the
 abnormality defines a disease state listed as an exclusion criterion, except for those
 related to COPD

 -  Patients with a history of drug and/or alcohol abuse that may prevent compliance with
 trial activities

 -  Treatment with any IMP within 3 month prior to screening visit

 -  Changes to any concomitant therapy either for COPD or any other well-controlled
 illness within 1 month prior to screening visit

 -  Treatment with a prohibited medication as detailed in Section 5.8