Amendment 1.1.; Protocol v2.0 & 2.1 Patients with a known hypersensitivity to albumin should not undergo perfusion scanning: this exclusion criterion for perfusion scanning has been added to section 5.2. These volunteers may still undergo other components of the study. The duration of the observation period post scan should be indicated. Patients are observed for one hour following hyperpolarised xenon lung MRI. This observation period has now been highlighted in section 4.3. The duration of the study should be limited to two years: this has been highlighted in section 4.4. In section 8.6 the time frame in which SAEs are reported to ORTU should be consistent. Version 2.0 was submitted to the MHRA to state that the ORTU will assess SAEs that are reported to it within seven days (previously one day). This was approved by the MHRA. However on further review by Sponsor andthe Respiratory Trials Unit, this was actually incorrect. Version 2.1 was then submitted, in which the time frame was reverted back to the original of one day. The information that should have been changed, is to state that ‘SAES occurring to a research participant during or within 24 hours (previously one hour) following Xe-129 lung MRI will be reported…’.

Amendment 2.0; Protocol 3.2 Addition of salbutamol element. Study visits and target number of participants: With the addition of the salbutamol component of the study patients make at least two and up to nine visits over the course of two years. All patients undertake the first two visits (enrolment visit and baseline visit; target recruitment number is 30, which is slightly smaller than the previous target number of 40). The total number of visits has not been increased compared to the first submission, as we no longer plan to do three monthly imaging during the first year. Dyspnoea or 'breathlessness' is assessed at each visit using a visual analogue score (repeated after the salbutamol intervention) and Dyspnoea 12 questionnaire. Technical issues pertaining to Xe-129 lung MRI: Technological development suggests that it may be possible for a patient to breathe one litre of a lower concentration of xenon than 100% and still acquire good quality images. Wording in the protocol has therefore been changed from ‘the patient breathes in from a bag containing 1L of xenon’ to ‘the patient breathes in from a 1L bag containing xenon’. The balance volume of gas in the 1L bag is nitrogen. Other amendments: In section 4.3 – correction to the radiation dose of a low dose CT as 1.7 mSv. The previous protocol had accidentally stated this was 0.3 to 0.5 mSv in error. The total number of low dose CT scans that a patient may have over two years is eight, which is in addition to the conventional CT chest at baseline (1.7 mSv). This scan thickness slice is actually 0.625 mm with t

Protocol V4.0_24Jul2013, Amendment SA03 Clarification of precise name of nuclear medicine scan. The correct name of the scan to be performed is a ventilation/perfusion nuclear medicine scan. The salbutamol & placebo will now be delivered as a multidose inhaler (MDI) via a volumatic spacer rather than via a nebuliser. Each lung imaging visit will take longer than initially anticipated to allow for periods of rest between the different scans. Changes to the timing of patient monitoring following Xenon MRI from 1 hour to 30min. and the use of iodinated contrast for the baseline CT chest Longitudinal visit: lung function must be carried out if more than 6 weeks after Cohort visit. Clarification of timings for visit 3/reproducibility visit. Clarification to the total number of hyperpolarised xenon gas inhalations each participant will undertake during the two year study period. The process for screening participants for hypersensitivity/allergy to iodinated contrast added to the protocol. New wording added to the protocol to allow for completion of calibration prior to actual Xe129 lung MRI scanning. New wording has been added to allow for completion of Xe129 MR sequences in the case of technical failure or nonsynchronisation of patient breathing and scanning. The use of an MDI to deliver the salbutamol/placebo will ensure that the patient remains blinded to the treatment. Description of updated blinding procedure with use of MDI device. This wording was added to clarify the total number of hyperpolarised xenon gas inhalations each participant will undertake during a two year study period. Explanation of the quantity of salbutamol being delivered via a multidose inhaler. The original end of study referred to the COPD cohorts study; 2 years refers to this study. Clarification to AE, SAE and pregnancy reporting.

SA04, Protocol V5.0_16May2014 Respiratory assessments (quality of life, exercise testing, lung function and daily diary cards) will now take place as part of this lung imaging protocol rather than the COPD Cohort from which these patients are recruited. The target sample size for this study of hyperpolarised xenon MRI lung imaging has also been increased from 30 to 100, to enable sub-group analysis, for example comparing imaging across different disease severities. A subgroup of patients undergoing lung imaging will be proceeding with endoscopic valve lung volume reduction surgery as part of their clinical care. These patients will undergo a different exercise test (six-minute walk test rather than an incremental shuttle walk test), and their follow-up will be at six months post procedure so that data collected will be comparable with other published series. These patients will not take part in follow-up studies and 1 and 2 years, salbutamol or exacerbation components of the follow-up. A recommendation for patients not to eat for 2 hours before CT scanning when contrast is used has been added to the patient information sheet. Dr Najib Rahman will temporarily take over as Chief Investigator and Principal Investigator for this trial from 23rd July 2014 to February 2015.

SA06, Protocol 08May2015 Simplification of study objectives: Reduction in the number of study visits from 11 to 3. Patients will now undertake the following visits: enrolment, baseline imaging with optional salbutamol element and the longitudinal visit at 1 year or at 6 months (if valve placement patient). Chief Investigator: Dr Najib Rahman will now be the permanent Chief Investigator. Stand-alone study: the Xenon in COPD imaging study will become a stand-alone study and will cease to be a sub-study of the COPD Cohort. Recruitment: this will cease from the COPD Cohort and instead, COPD patients will be recruited from a range of settings including Respiratory out-patient clinics, in-patient wards and pulmonary rehabilitation. The study team have made a video aimed at patients. In the video, a patient is interviewed about their experience of taking part in the trial. Patients will be shown this video if they express an interest in seeing it. The web link to the video has also been put in both patient information sheets. Addition of recruitment posters up in the hospital aimed at patients. Exacerbation-free period: the requirement for patients to be exacerbation free for 4 weeks prior to imaging has been reduced to 2 weeks. Study end date: we would like to extend the end date of the study from 2 years to 3 years after study initiation in order to achieve the primary aims of the amended study. Patient confidentiality: we have updated section 18, “Will my taking part in this study be kept confidential?”, in the patient information sheet to ensure it is consistent with the Patient Consent form. Valve placement/surgery patients: a separate Patient Information Sheet and GP letter have been produced which are more relevant to this group of patients. Patient Information Sheet (non-surgery patients) and Patient Consent Form (all patients): amended to reflect the above changes.

SA07, Protocol 7.0 - Flexibility of visits - Sample size reduced from 100 to 50 - Nuclear medicine scan removed at 1 year - PIS updated accordingly