Beta Blocker Therapy in Moderate to Severe COPD
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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
    

Intervention name(s): Carvedilol; Bisoprolol; Beclometasone/formoterol; Tiotropium; Beclometasone
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Dose titration: 3.125mg bid for 1 week, 6.25mg bid for 1 week, 12.5mg bid for 4 weeks.; Dose titration: 1.25mg od for 1 week, 2.5mg od for 1 week, 5mg for 4 weeks.; 2 puffs bid for first 5 weeks in each treatment arm; 1 puff daily for first 4 weeks of each treatment arm; 2 puffs bid for final week (week 6) of each treatment arm
Other intervention name(s): Fostair 100/6; Spiriva 18mcg; Clenil 200
Intervention MeSH terms: Beclomethasone; Carvedilol; Bisoprolol; Formoterol Fumarate; Tiotropium Bromide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: COPD; Beta blockers; Cardioselective; Non-cardioselective; Impulse oscillometry