E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Obstructive Pulmonary Disease (COPD) which may also be called emphysema or chronic bronchitis |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
The primary objective is to demonstrate a decrease in muscle sympathetic nerve activity (MSNA) evaluated by microneurography as bursts/100 heart beats after acute administration of salmeterol in COPD subjects. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To evaluate if changes in MSNA after acute administration of salmeterol in COPD subjects are correlated with changes in FEV1, heart rate variability (HRV) or baroreflexes.
• To evaluate changes in MSNA from Baseline after 4 weeks of salmeterol treatment in COPD subjects.
• To evaluate if changes in MSNA from Baseline after 4 weeks of salmeterol treatment in COPD subjects are correlated with changes in FEV1, HRV or baroreflexes.
• To assess safety and tolerability of treatment with salmeterol.
• To evaluate a reduction in arterial stiffness.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product that may impact subject eligibility is provided in the current Prescribing Information for Serevent® Diskus® (50 µg). Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Subjects with COPD of GOLD Class II or III with a post-bronchodilator spirometry
forced expiratory volume in one second (FEV1) <70% predicted and FEV1/vital capacity (VC) <70% in accordance with the GOLD executive summary [Rabe, 2007]. Post-bronchodilator spirometry will be performed approximately 10-15
minutes after the subject has self-administered a SABA (fenoterol or salbutamol per inhalation).
2. Male or female subjects, aged > 40 and < 80 years. Females of non child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile), and women of child bearing potential with a negative pregnancy test at Screening who agree to use consistently and correctly a highly effective contraceptive method may be included.
3. Subject is ambulatory (outpatient).
4. Subjects using inhaled therapy have to abstain from their medication prior to visit 1 (time interval per medication see table 1).
5. Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening Visit. Previous smokers are defined as those who have stopped smoking for at least 1 month prior to Visit 1.
6. Subjects willing and able to sign the informed consent before study start. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study (for detailed information on prohibited medications see also Protocol page 22, Table 1):
1. Women who are pregnant or lactating.
2. Subjects not willing or unable to sign the informed consent before study start.
3. Subjects with a current diagnosis of asthma.
4. Subjects with α-1 antitrypsin deficiency as the underlying cause of COPD.
5. Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases.
6. Subjects with lung volume reduction surgery within the 12 months prior to Screening.
7. Subjects who have been hospitalized due to poorly controlled COPD within 6 weeks prior to the Screening Visit.
8. Subjects with poorly controlled COPD, defined as the occurrence of an exacerbation managed with systemic corticosteroids or antibiotics prescribed by a physician 6 weeks prior to the Screening Visit.
9. Frequent exacerbations necessitating the therapy with inhaled glucocorticosteroids according to the GOLD guideline.
10. COPD with nasal intermittent positive pressure ventilation (NIPPV).
11. Treatment with drugs having direct sympathomimetic activity (e.g. theophylline, moxonidine, clonidine).
12. Oral medication with beta2-sympathomimetics.
13. Inhaled therapy with sodium cromoglycate or nedocromil sodium.
14. Treatment with systemic, oral or parenteral (intra-articular) corticosteroids.
15. Treatment with strong cytochrome P450 3A4 inhibitors.
16. Treatment with any other investigational drug.
17. Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen use ≤ 12 hours per day is not exclusionary.
18. Medication prior to spirometry: Subjects who are medically unable to withhold their SABA for the 6-hour period required prior to spirometry testing at each study visit.
19. Subjects with clinically significant sleep apnoea that is uncontrolled.
20. Unstable angina pectoris or signs and history of left heart failure with a left ventricular ejection fraction < 40%.
21. Arterial hypertension necessitating treatment with > 3 antihypertensive drugs.
22. Clinically evident polyneuropathy.
23. Diabetes mellitus necessitating any insulin therapy.
24. Severe concomitant disease (likely to reduce life expectancy to less than 3 years).
25. Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant neurological, psychiatric, renal, hepatic, immunological, endocrine or haematological abnormality that is uncontrolled. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Effect (i.e. the immediate change before versus after 1 inhalation at Visit 1) of inhaled salmeterol on MSNA evaluated as burst/100 heart beats relative to placebo.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Muscle sympathetic nerve activity (MSNA) will be measured at visit 1 (week 0) and visit 2 (week 4 +/- 4 days). |
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E.5.2 | Secondary end point(s) |
• Change in MSNA (evaluated by microneurography as bursts/100 heart beats) from Baseline after 4 weeks of salmeterol treatment (Visit 2)
• Changes in HRV (in the time and frequency domain) from Baseline after acute administration of salmeterol and after 4 weeks of salmeterol treatment (Visit 2)
• Changes in spontaneous baroreflex sensitivity from Baseline after acute administration of salmeterol and after 4 weeks of salmeterol treatment (Visit 2)
• Changes in FEV1 from Baseline after acute administration of salmeterol and after 4 weeks of salmeterol treatment (Visit 2)
• VC, FRC (helium and body), TLC and RV
• Resting ventilation (respiration rate and tidal volume)
• Plasma norepinephrine, epinephrine and Brain Natriuretic Peptide (BNP)
• Rate of subjects with diastolic dysfunction on echocardiography |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Visit 1 and Visit 2: all of the secondary endpoints will be measured; additionally, the subjects will be contacted by phone two weeks after visit 1 to document signs and symptoms of COPD, concomitant medication, (serious) adverse events, compliance check (study medication and rescue medication). |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
effect on muscle sympathetic nerve activity (MSNA) in the peroneal nerve |
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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 | No |
E.8.1.2 | Open | No |
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 | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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
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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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |