| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
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| 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 compare the effect of UMEC/VI 62.5/25 mcg with TIO/OLO 5/5mcg once daily on lung function in subjects with moderate COPD over 8 weeks of treatment. |
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| E.2.2 | Secondary objectives of the trial |
| To compare the effect of UMEC/VI 62.5/25 mcg with TIO/OLO 5 /5mcg on other measures of efficacy and measures of healthrelated quality of life |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
[1] Type of subject:
Outpatient.
[2] Informed Consent:
A signed and dated written informed consent prior to study participation
[3] AGE
Subjects 40 years of age or older at Visit 1
[4] Gender
Male and female subjects are eligible to participate in the study.
At the discretion of the study investigator and in alignment with local country acceptable criteria, a female is eligible to enter and participate in the study 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:
Non-reproductive potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile) defined as:
Pre-menopausal females with one of the following:
- Documented tubal ligation
- Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral or tubal occlusion
- Hysterectomy
- Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study.
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
OR
Reproductive potential, has a negative pregnancy test at screening, and agrees to one of the methods below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from methods used consistently and correctly (i.e., in accordance with the local approved product label and per study investigator discretion and the instructions of the physician from 30 days prior to the first dose of study medication and until to followup contact):
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.
- 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 [Hatcher, 2007a]
- Oral Contraceptive, either combined or progestogen alone
- Injectable progestogen
- Contraceptive vaginal ring
- Percutaneous contraceptive patches
- 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.
- 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] Diagnosis:
A diagnosis of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society [Celli, 2004].
[6] Smoking History:
Current or former cigarette smokers with a history of cigarette smoking of ≥ 10 packyears
[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g. 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack-years)]. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to calculate pack-year history.
[7] Severity of Disease:
A pre and post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and a postalbuterol/salbutamol FEV1 of <or=70% to ≥ 50 % of predicted normal values at Visit 1.
Predicted values will be based upon the ERS Global Lung Function Initiative [Quanjer,
2012].
[8] Dyspnea:
A score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1.
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
[1] Pregnancy:
Women who are pregnant or lactating or are planning on becoming pregnant during the study.
[2] Asthma:
A current diagnosis of asthma.
[3] Other Respiratory Disorders:
α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying cause of COPD
Other respiratory disorders: Subjects with active tuberculosis are excluded. Subjects with other respiratory disorders are excluded if these conditions are the primary cause of their respiratory symptoms.
[4] Other Diseases/Abnormalities:
Any subject who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness. In addition, any subject who has any other condition that is likely to affect respiratory function should not be included in the study.
[5] Severe Hepatic Impairment:
Unstable liver disease: Current active liver or biliary disease.
[6] Unstable or life threatening cardiac disease:
Investigational Product should be used with caution in subjects with severe cardiovascular disease. In the opinion of the investigator, use should only be considered if the benefit is likely to outweigh the risk in conditions such as:
- Myocardial infarction or unstable angina in the last 6 months
- Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months
- NYHA Class IV heart failure
[7] Contraindications:
Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.
[8] Antimuscarinic effects:
Subjects with medical conditions such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction should be excluded unless, in the opinion of the study physician, the benefit outweighs the risk.
[9] Hospitalization:
Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1. Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening (V1) and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable).
Other respiratory tract infections that have not resolved at least 7 days prior to Screening (V1).
[10] Lung Resection:
Subjects with lung volume reduction surgery (including procedures such as endobronchial valves) within the 12 months prior to Screening (V1).
[11] 12-Lead ECG:
The Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject’s medical history and exclude subjects who would be at undue risk by participating in the trial. Subjects with the following abnormalities are excluded from participation in the study:
- Atrial fibrillation with rapid ventricular rate >120 bpm
- Sustained or nonsustained ventricular tachycardia
- Second degree heart block Mobitz type II or third degree heart block (unless pacemaker or defibrillator had been inserted)
[12] Medication Prior to Spirometry:
Unable to withhold albuterol/salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
[13] Medications Prior to Screening:
Use of the following medications according to the following defined time intervals prior
to Screening (Visit 1): Refer to Table in Protocol page 23
[14] Oxygen:
Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3L/min at screening.
[15] Maintenance Use of Short-Acting Bronchodilators:
Regular use of short-acting bronchodilators
[16] Pulmonary Rehabilitation Program:
Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Screening (Visit 1). Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
[17] Drug or Alcohol Abuse:
A known or suspected history of alcohol or drug abuse within 2 years prior to Screening
(Visit 1) that in the opinion of the investigator would prevent the subject from completing the study procedures.
[18] Affiliation with Investigator Site:
Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
[19] Inability to Read:
In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete a questionnaire.
Subjects who fail to meet inclusion and exclusion criteria at the Screening Visit will be considered screen failures and cannot be re-screened.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
•Proportion of responders according to FEV1 (a responder is defined as a ≥100mL change in Trough FEV1 from baseline) at Week 8
• Rescue albuterol/salbutamol use (percentage of rescue-free days and mean number of Inhalations/day) captured in e diary
•Trough FEV1, at Week 4
•Trough FVC at Weeks 4 and 8
•Trough IC at Weeks 4 and 8
•COPD Assessment Test (CAT) score at Weeks 4 and 8
•Proportion of responders according to CAT (defined as a ≥1 unit improvement in score from baseline) at Weeks 4 and 8
•Time to clinically important deterioration composite endpoint
•Inhaler ease of use
•Inhaler errors
•Assessment of respiratory daily symptoms over Weeks 1-8 using Evaluating Respiratory Symptoms- COPD (E-RS) and its subscales (breathlessness, cough and sputum and chest symptoms)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Proportion of responders according to FEV1 (a responder is defined as a ≥100mL change in Trough FEV1 from baseline) at Week 8
• Rescue albuterol/salbutamol use (percentage of rescue-free days and mean number of Inhalations/day) captured in e diary
•Trough FEV1, at Week 4
•Trough FVC at Weeks 4 and 8
•Trough IC at Weeks 4 and 8
•COPD Assessment Test (CAT) score at Weeks 4 and 8
•Proportion of responders according to CAT (defined as a ≥1 unit improvement in score from baseline) at Weeks 4 and 8
•Time to clinically important deterioration composite endpoint
•Inhaler ease of use
•Inhaler errors
•Assessment of respiratory daily symptoms over Weeks 1-8 using Evaluating Respiratory Symptoms- COPD (E-RS) and its subscales (breathlessness, cough and sputum and chest symptoms)
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| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| Spain |
| United Kingdom |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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