Chronic Obstructive Pulmonary Disease Clinical Trial
Official title:
Evaluation of Effects of Chronic Dose Exposure to Cardioselective and Non-cardioselective Beta Blockers on Measures of Cardiopulmonary Function in Moderate to Severe COPD.
Beta blockers are a type of medication mainly used for heart disease. They are commonly used
to treat 'angina' and to prevent heart attacks. Patients with COPD are more likely to suffer
from heart disease and so already benefit from this treatment for this reason. In addition to
this, new research suggests that there may be further benefit of using beta blockers for
COPD, even without also having heart disease.
The reason why beta blockers are not widely used in COPD at present is because of their
potential to make symptoms of COPD worse by causing the airways to narrow. Beta blockers are
the opposite type of medication to 'beta-agonists' such as salbutamol which you may be taking
for symptoms of breathlessness or wheezing. Nevertheless beta blockers are still used in COPD
where the benefits (for example heart disease) outweigh any risks.
Current COPD treatment includes inhaled steroids and long acting beta agonists, often given
in a combination inhaler (e.g. Seretide or Symbicort) to treat both airway inflammation and
airway narrowing, leading to improvement in symptoms. Another drug commonly used is
Tiotropium (Spiriva) which is another type of long acting inhaler medication to help with
widening the airways.
In this study, we wish to find out if two different types of beta blocker cause different
effects on the airways in COPD patients. One type of beta blocker is more 'selective' in
acting mainly on the heart, with the other type having more general or 'non-selective'
effects on both the heart and lungs. By doing this we will also be able to look at how the
beta blockers work alongside the 'usual' inhaler treatment described above.
Screening Visit A member of the research team will discuss the Patient Information Sheet with
the participant, answer any questions posed and written informed consent will be obtained.
Prior to screen participants will be asked to withhold tiotropium for 48 hours ipratropium
bromide for 12 hours and salbutamol for 6 hours.
A general physical examination will be carried out by a qualified medical practitioner.
A pregnancy test from a urine sample will be performed for all female participants with
advice issued to both male and female participants to use contraception throughout the
duration of the study.
The following will be measured:
Spirometry with sequential reversibility to 400μg salbutamol then 80 μg ipratropium bromide
according to American Thoracic Society guidelines Resting Electrocardiogram Whole body
plethysmography (where possible) Impulse Oscillometry
Oxygen saturations breathing room air after 5 mins rest Heart rate and blood pressure. 6
Minute Walk Test (if physically able)
Inhaler technique will be assessed and confirmed adequate.
Full blood count, renal function, electrolytes, liver enzymes and random blood glucose will
be measured.
Participants will be checked against all inclusion and exclusion criteria. Those found to be
eligible will proceed to the run-in period.
Run-in period Participants who are taking inhaled corticosteroids, combination inhalers, Long
acting bata agonists or long-acting anti-muscarinics will have these discontinued.
All participants entering the run-in period will be commenced on Fostair
(Beclometasone/Formoterol) 100/6, 2 puffs twice daily via spacer device for approximately 2
weeks.
Participants will be given a PiKO monitor to record domiciliary Forced expiratory volume1 and
Forced expiratory Volume6 twice daily (approximately 12 hours apart) in a diary supplied by
the department as well as domiciliary oxygen saturation and Heart Rate monitor to be recorded
twice daily. They will also complete a daily diary of reliever use and symptoms. These will
all be performed from the beginning of the run-in period to the end of the study.
At the end of run-in, participants will be again checked against all inclusion and exclusion
criteria and the hief Investigator or medical investigator for the study will sign the
declaration on the Case Report Form, to confirm the subject's suitability to receive the
study drug according to study protocol. Those eligible will proceed to study visit 1. Those
who do not fulfil the study criteria will be returned to their pre-study medication and their
GP informed of any medically relevant data.
Study Visit 1 (Baseline 1) Participants will attend the department on the morning of their
study visit.
Participants will be asked to withhold their ipratropium for 12 hours and salbutamol for 6
hours prior to visit.
Diaries of symptoms, reliever use and domiciliary FEV1 will be reviewed.
Baseline measurements to be recorded are:
IOS Slow Vital Capacity Spirometry Resting ECG Resting O2 sats HR and BP St George's
Respiratory Questionnaire 6MWT (where physically possible and only if performed at screen)
Echocardiogram (where technically possible) Serum (after at least 30mins supine posture):
Aldosterone, Angiotensin II, BDNF, BNP, Potassium
Provided average HR>60bpm and average systolic BP>110mmHg the participant will be randomised
to 1 of 2 beta-blocker treatments comprising:
1. Carvedilol: 1 week of 3.125mg bid, 1 week of 6.25mg bid, 4 weeks of 12.5mg bid or
2. Bisoprolol: 1 week of 1.25mg od, 1 week of 2.5mg od, 4 weeks of 5mg od
Participants will be given their first 4 weeks of randomised IMP for the treatment period at
this study visit.
When titrating their beta-blocker at home, should the participant start to experience
side-effects related to beta-blocker therapy or they find that their HR is dropping below
55bpm they will be informed to phone the department working hours) or the emergency mobile
number (out of hours).
Participants will be allowed to complete each treatment arm on their maximum tolerated dose
of beta-blocker, should this be less than the maximum prescribed dose.
Participants in both treatment arms will continue taking Fostair 100/6, 2 puffs bid via
spacer device for the first 5 weeks of each treatment period. For the final (6th) week of
each treatment period they will receive inhaled beclometasone dipropionate (as Clenil) 200μg,
2 puffs bid via spacer device, instead of Fostair.
Participants in both treatment arms will be given Tiotropium 18μg (via handihaler) od for the
first 4 weeks of each treatment period. Tiotropium will then be discontinued for the final 2
weeks of each treatment period.
Participants will be given a salbutamol inhaler to use as initial reliever therapy along with
an ipratropium inhaler second line on a PRN basis.
The IMPs will be issued to the participant by a member of the research team delegated the
task. The allocation will be checked and countersigned by a second delegated member of staff.
Inhaler technique for the different devices will be checked.
A participant instruction and appointment leaflet will be issued and discussed fully with the
participant and any questions answered. It will detail:
Emergency contact numbers Instructions on how to take heart rate and O2 sats measurements How
to perform domiciliary FEV1 and FEV6 How to write in the diary Potential side effects of
study drugs Recording of AEs and concomitant medication use Withholding times for relievers
Titration/Discontinuation times for IMPs
Reminders to return medication and bottles at each visit
Study visit 2
Measurements to be recorded at this visit are:
IOS Slow VC Spirometry Resting O2 sats HR and BP (as previously described in 3.5.5) Resting
ECG 6MWT (where physically possible and only if performed previously in study) SGRQ
Participants will be given their final 2 weeks of randomised IMP (at their maximum tolerated
dose) for that treatment period.
Participants will discontinue their tiotropium for the remaining 2 weeks of the treatment
period at this study visit.
Study visit 3
. As for study visit 2 with the addition of Serum BDNF, Potassium
Participants will discontinue their Fostair inhaler at this study visit and be given Clenil
(beclometasone) 200ug, 2 puffs bid to take instead for the final week of the treatment
period.
Study visit 4 As before plus, Echocardiogram (where technically possible) Serum (after at
least 30mins supine posture): Aldosterone, Angiotensin II, BDNF, BNP, Potassium
Participants will finish treatment period 1 at this point and enter a 2 week period of
washout (of beta-blocker) prior to crossing over to the other treatment arm.
Participants will discontinue their Clenil and beta-blocker and return to taking Fostair
100/6, 2 puffs bid for the 2 week washout period.
Study Visit 5 (Baseline 2)
Measurements to be recorded are:
IOS Slow VC Spirometry Resting ECG Resting O2 sats HR and BP (as previously described in
3.5.5) SGRQ 6MWT (where physically possible and only if performed at screen) Serum (after at
least 30mins supine posture): Aldosterone, Angiotensin II, BDNF, BNP, Potassium
Provided average HR>60bpm and average systolic BP>110mmHg the participant will be crossed
over to the beta-blocker treatment that they have not yet received (based on original
randomisation) comprising:
1. Carvedilol: 1 week of 3.125mg bid, 1 week of 6.25mg bid, 4 weeks of 12.5mg bid
2. Bisoprolol: 1 week of 1.25mg od, 1 week of 2.5mg od, 4 weeks of 5mg od Measurements will
be repeated as per Study Visit 1.
Study Visits 6 & 7 Visit 6 will be the same as visit 2 Visit 7 will be the same as visit 3
Study Visit 8
Measurements to be recorded are:
IOS Slow VC Spirometry Resting ECG Resting O2 sats HR and BP (as previously described in
3.5.5) SGRQ 6MWT (where physically possible and only if performed at screen) Echocardiogram
(where technically possible) Serum (after at least 30mins supine posture): Aldosterone,
Angiotensin II, BDNF, BNP, Potassium
Participants will finish treatment period 2, and, therefore, the study at this point. They
will be returned to their usual prescribed medication.
End of Study Period. The study will be complete when the last enrolled participant completes
the last visit
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