| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease |
|
| 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 | LLT |
| E.1.2 | Classification code | 10010953 |
| E.1.2 | Term | COPD exacerbation |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of once daily repeat inhaled doses of GSK2269557 on lung parameters derived from HRCT scans in subjects with acute exacerbation of COPD, compared to placebo |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the effect of once daily repeat inhaled doses of GSK2269557 on lung parameters derived from HRCT scans in subjects with acute exacerbation of COPD, compared to placebo
-To assess the safety and tolerability of once daily repeat inhaled doses of
GSK2269557 administered to subjects with acute exacerbation of COPD,
compared to placebo
-To evaluate the plasma PK of once daily repeat inhaled doses of GSK2269557 administered to subjects with acute exacerbation of COPD.
-To evaluate the effect of once daily repeat inhaled doses of GSK2269557 on lung function parameters in subjects with acute exacerbation of COPD, compared to placebo
-To evaluate the number of treatment failures of once daily repeat inhaled doses of GSK2269557 administered to subjects with acute exacerbation of COPD, compared to placebo
-To evaluate the time to next exacerbation after once daily repeat inhaled doses of GSK2269557 administered to subjects with acute exacerbation of COPD, compared to placebo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) AGE
-Between 40 and 80 years of age inclusive, at the time of signing the informed consent.
2) TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
-The subject has a confirmed and established diagnosis of COPD, as defined by the GOLD guidelines for at least 6 months prior to entry.
-The subject has a post-bronchodilator FEV1/FVC < 0.7 and FEV1 ≤ 80 % of predicted, documented in the last 5 years.
-Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to include corticosteroid and antibiotics. Acute exacerbation to be confirmed by an experienced physician and represent a recent change in at least two major and one minor symptoms, one major and two minor symptoms, or all 3 major symptoms.
Major symptoms:
- Subjective increase in dyspnea
- Increase in sputum volume
- Change in sputum colour
Minor symptoms:
- Cough
- Wheeze
- Sore throat
The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years.
3) WEIGHT
- Body weight >or= 45 kg and body mass index (BMI) within the range 18 – 32 kg/m2
4) SEX
-Male
-Female subject: is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:
1. Non-reproductive potential defined as:
-Pre-menopausal females with one of the following:
-Documented tubal ligation
-Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
-Hysterectomy
-Documented Bilateral Oophorectomy
-Postmenopausal defined as 12 months of spontaneous amenorrhea. Females whose menopausal status is in doubt will be required to use, or have been using, one of the highly effective contraception methods as specified below from 30 days prior to the first dose of study medication and until completion of the follow-up visit.
2. Reproductive potential and agrees to follow one of the options listed below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication and until completion of the follow-up visit.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penilevaginal intercourse on a long term and persistent basis.
1. Contraceptive subdermal implant that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label
2. Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label
3. Oral Contraceptive, either combined or progestogen alone
4. Injectable progestogen
5. Contraceptive vaginal ring
6. Percutaneous contraceptive patches
7. Male partner sterilization with documentation of azoospermia prior to the female subject’s entry into the study, and this male is the sole partner for that subject.
8. Male condom combined with a vaginal spermicide.
These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
Specific inclusion criteria for Male subjects with female partners of reproductive potential is outlined below:
Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until after the completion of the follow up visit.
1. Vasectomy with documentation of azoospermia.
2. Male condom plus partner use of one of the contraceptive options below:
-Contraceptive subdermal implant that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label
-Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a <1% rate of failure per year, as stated in the product label
-Oral Contraceptive, either combined or progestogen alone
Injectable progestogen
-Contraceptive vaginal ring
-Percutaneous contraceptive patches
These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
5)] INFORMED CONSENT
-Capable of giving signed informed consent as described in Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
|
|
| E.4 | Principal exclusion criteria |
1) CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER
FUNCTION AND QTC INTERVAL)
To avoid recruitment of subjects with a severe COPD exacerbation, the presence of any one of the following severity criteria will render the subject ineligible for inclusion in the study:
-Need for invasive mechanical ventilation (short term (< 48h) NIV or CPAP is acceptable)
-Haemodynamic instability or clinically significant heart failure
-Confusion
-Clinically significant pneumonia, identified by chest X-ray (if available) or on the CT scan performed during screening, as judged by the Investigator and in
consultation with the GSK Medical Monitor, if required. (NOTE: Since CT is more sensitive than X-ray for detecting pneumonia, minor patches of infection or bronchopneumonia seen on CT at screening are expected and therefore allowed.)
-Subjects who have a history or current medical conditions or diseases that are not well controlled and, which as judged by the Investigator, may affect subject safety or influence the outcome of the study. (Note: Patients with adequately treated and well controlled concurrent medical conditions (e.g. hypertension or NIDDM) are permitted to be entered into the study).
-Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt
bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that might, in the opinion of the investigator, compromise the safety of the subject or affect the interpretation of the results.
-ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if
bilirubin is fractionated and direct bilirubin <35%).
-A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the exclusion criteria, outside of the reference range for the population being studied may be included if the Investigator [in consultation with the
GSK Medical Monitor if required] documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
-Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones)
- ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or demonstrating a clinically significant arrhythmia requiring treatment.
-QTcF > 450 msec or QTcF > 480 msec in subjects with Bundle Branch Block, based on single QTcF value.
-Subjects who have undergone lung volume reduction surgery.
20 CONCOMITANT MEDICATIONS
-Subject is currently on chronic treatment with macrolides; long term oxygen therapy (> 15 hours/day).
-The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-
TNF), anti-Interleukin-1 (anti-IL1), or any other immunosuppressive therapy within
60 days prior to dosing.
3) RELEVANT HABITS
-History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >28 units for males or >21 units for females. 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.
4) CONTRAINDICATIONS
-History of sensitivity to any of the study medications, or components thereof (such as lactose) or a history of drug or other allergy that, in the opinion of the investigator or
Medical Monitor, contraindicates their participation.
5) DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
-A known (historical) positive test for HIV antibody.
-Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
NOTE: Because of the short window for screening, treatment with GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal Investigator in consultation with the Medical Monitor.
-Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
-The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
-Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in specific imaging Airways Volume: siVaw at FRC and TLC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening, Day 12 and Day 28 |
|
| E.5.2 | Secondary end point(s) |
•Change from baseline in imaging Airways Volume: iVaw at FRC and TLC
•Change from baseline in imaging Airways resistance and specific airways resistance: iRaw, siRaw at FRC and TLC
•Change from baseline in imaging Total lung capacity and Lung lobar volumes at FRC and TLC after
•Change from baseline in imaging trachea length/diameter
•Adverse events (AEs)
•Hematology, clinical chemistry
•Vital signs
•12-lead ECG
•Day 1 plasma exposure up to 24 hours post dose for inpatients
•PK Trough concentration after 12 days, 28 days, 56 days and 84 days of treatment.
•Changes from baseline in FEV1 measured daily
•Changes from baseline in PEF measured daily
•Changes from baseline in Diffusion capacity (DLco, Kco) after 28 days and after 84 days of treatment
•Changes from baseline in Whole body plethysmography after 28 days and after 84 days of treatment, to include:
•Reliever use post-discharge (beta2-agonist and / or anticholinergic) in addition to regular therapy.
•Questionnaires CAT and MMRC scale at baseline, 28 days and 84 days
•Number of treatment failures as defined by at least one of:
1.Recurrent exacerbations
2.Prolonged treatment of current exacerbation (beyond 14 days)
3.Requirement for invasive mechanical ventilation
•Time to next exacerbation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Change from baseline in imaging
Screening, Day 12 and Day 28
•Adverse events (AEs)
•Number of treatment failures
•Time to next exacerbation
From start of study treatment until follow-up contact
•Hematology, clinical chemistry, Vital signs, 12-lead ECG
Screening, Day 1, Day 12, Day 28, Day 56, Day 84
•Day 1 plasma exposure up to 24 hours post dose
predose, 5 min, 3 and 24h postdose
•PK Trough concentration
Day 12, Day 28, Day 56 and Day 84
•Changes from baseline in FEV1 and PEF measured daily
•Reliever use post-discharge in addition to regular therapy.
From Day 1 to Day 84
•Changes from baseline in Diffusion capacity and Whole body plethysmography
Visit 2, Day 28, Day 84
•Questionnaires CAT and MMRC scale
Day 1, Day 28, Day 84
|
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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