| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| in subjects with chronic obstructive pulmonary disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Obstructive Pulmonary Disease (COPD) is a condition that affects the lungs in which people can: Feel as if they cannot breathe, feel their chest is tight, have coughing, have excess mucus. |
|
| 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 |
|
| 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 FF/UMEC/VI with FF/VI + UMEC
on lung function after 24 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the effects of FF/UMEC/VI with FF/VI + UMEC
on health related quality of life and dyspnoea after 24 weeks of treatment.
- To compare the effect of FF/UMEC/VI with FF/VI + UMEC
on time to first moderate or severe exacerbation during 24 weeks of treatment.
- To compare the PK of FF, UMEC and VI when given as FF/UMEC/VI or FF/VI+UMEC in a subset of subjects
- To compare the safety profile of FF/UMEC/VI with FF/VI + UMEC over 24 weeks of treatment
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Hair Sample, Scalp & Finger Secretion PK Sub-Study, Apendix 12.8. of Protocol of main study version 01, dated 25JAN2016. The objective is to To collect hair samples, and scalp and finger sweat, in a non-invasive way, for PK analysis among COPD subjects taking part in PK subset A, in Study 200812. |
|
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Informed Consent: A signed and dated written informed consent prior to study participation.
2. Type of subject: Outpatient.
3. Age: Subjects 40 years of age or older at Screening (V1).
4. Gender: Male or female subjects.
Females:
A 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:
a. 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 [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.
b. Reproductive potential and agrees to follow one of the options listed in the Modified
List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) (see Appendix 5) from 30 days prior to the first dose of study treatmentand until after the last dose of study treatmentand completion of
the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
5. COPD Diagnosis: An established clinical history 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 pack-years at Screening (V1) [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)]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Screening (V1).
NOTES:
Pipe and/or cigar use cannot be used to calculate pack-year history.
7. Severity of COPD symptoms: A score of ≥10 on the COPD Assessment Test (CAT) at Screening (V1).
8. Severity of COPD Disease: A post-albuterol/salbutamol FEV1/FVC ratio of <0.70
at Screening (V1).
9. Existing COPD maintenance treatment: Subject must be receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening (V1).
NOTES:
Subjects receiving only PRN COPD medications are not eligible.
10. History of Exacerbations: Subjects must demonstrate:
a post-bronchodilator FEV1 < 50% predicted normal at Screening (V1) and a documented history of ≥ 1 moderate or severe COPD exacerbation in the 12 months prior to Screening
OR
a post-bronchodilator 50% ≤FEV1 < 80% predicted normal at Screening (V1) and a documented history of ≥ 2 moderate exacerbations or a documented history of ≥1 severe COPD exacerbation (hospitalised) in the 12 months prior to
Screening (V1).
NOTES:
Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations [Quanjer, 2012].
A documented history of a COPD exacerbation (e.g., medical record verification) is a medical record of worsening COPD symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or
hospitalisation (for a severe exacerbation). Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment
of worsening symptoms of COPD, such as increased dyspnoea, sputum volume, or sputum purulence (colour). Subject verbal reports are not acceptable.
11. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
|
| 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: Subjects with a current diagnosis of asthma.
3. α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying cause of COPD.
4. 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.
5. Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (V1).
6. Risk Factors for Pneumonia: immune suppression or other risk factors for pneumonia .
7. 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.
8. Other Respiratory tract infections that have not resolved at least 7 days prior to Screening (V1)
9. Abnormal Chest x-ray: Chest x-ray reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD, or another condition that would hinder the ability to detect an infiltrate on chest x-ray. All subjects will have a chest x-ray at Screening (V1) [or historical radiograph or CT scan obtained within 3 months prior to Screening (V1).
10. Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine or haematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
11. Unstable liver disease: ALT >2xULN; and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment).
12. Unstable or life threatening cardiac disease: subjects with any of the following at Screening (V1) would be excluded:
-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
13. Abnormal and clinically significant 12-Lead ECG finding: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. 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.
An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following:
-AF with rapid ventricular rate >120 BPM;
-sustained or nonsustained VT;
-Second degree heart block Mobitz type II and third degree heart block.
14. Contraindications: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the investigator contraindicates study participation.
15. Cancer: Subjects with carcinoma that has not been in complete remission for at least 3 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 3 year waiting period if the subject has been considered cured by treatment.
16. Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3L/min.
17. Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit.
18. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years.
19. Non-compliance: Refer to Protocol (v01) page 33
20. Questionable validity of consent: Refer to Protocol (v01) page 33
21. Affiliation with investigator site: Refer to Protocol (v01) page 33
22. Inability to read: Refer to Protocol (v01) page 33
23. Medication prior to Screening: Refer to Protocol (v01) page 34
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in trough FEV1 at 24 weeks |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Spirometry will be done at visits 2,3,4 and 5. |
|
| E.5.2 | Secondary end point(s) |
• Proportion of Responders based on the St George Respiratory Questionnaire (SGRQ) Total Score at Week 24
• Change from baseline in SGRQ Total Score at Week 24
• Proportion of Responders based on Transitional Dyspnoea Index (TDI) focal score at Week 24
• TDI focal score at Week 24
• Time to first moderate or severe exacerbation
• Population PK (in a subset of approximately 180 subjects)
• Incidence of adverse events and adverse events of special interest,
• ECG measurements
• Vital signs
• Haematological and clinical chemistry parameters
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Over 24 weeks
For PK Subgroup A: At week 12 & Week 24
For PK Subgroup B: over 24 hrs starting at Week 12
For PK Sub-study: At Baseline, Week 12 and Week 24
|
|
| 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 | 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) | Yes |
| 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) | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Argentina |
| Australia |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| Spain |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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