• The CTP was harmonised globally following further comments received from the FDA after the opening of the IND. The treatment phase was extended to a 24- month, placebo-controlled period, and the co-primary endpoints were amended from time to first exacerbation to FOE and exacerbation-free days. • The sample size was recalculated based on the revised primary endpoint and study duration (previously 330, now 374 subjects). • Extensive revisions were made to the inclusion and exclusion criteria to clarify the subject selection criteria and avoid cases of duplication and/or ambiguities in the previous protocol version. The changes did not materially alter the population being studied. • Screen failure criteria previously referred to as “Withdrawal Criteria” were deleted. • Safety variables were amended to include additional information regarding anti-microbial resistance (additional sputum sample analyses) and renal function tests. • Secondary study objectives were included (previously not explicitly stated). • Details regarding the optional open-label extension period (previously introduced for US sites only) were removed.

• The CTP was modified following agreement with the FDA during a type C meeting held on 31 October 2018 to revert to a single primary endpoint of FOE, with exacerbation-free days being included as a secondary endpoint and reducing the duration of the treatment period to 12 months. The study objective was amended accordingly to have 1 single primary objective of frequency of exacerbations in the 12-month treatment period. The number of patients to be randomised was amended in light of the revised study duration and single primary efficacy endpoint and resulting sample size re-calculation. • Inclusion criterion #5 was amended from “had 1 positive sputum culture for P. aeruginosa in the 12 months preceding the Screening Visit (but performed at least 30 days before the Screening Visit)” to “have a documented history of P. aeruginosa infection”. • Exclusion criterion #2 was expanded to specify “known history of hypogammaglobulinaemia requiring treatment with immunoglobulin, unless fully replaced and considered immuno-competent by the Investigator”. • Exclusion criterion #9 was amended from “receiving long-term domiciliary oxygen therapy or non-invasive ventilation for the management of respiratory failure” to “respiratory failure requiring long-term domiciliary oxygen therapy or non-invasive ventilation”. • Exclusion criterion #17 was amended to include examples of chronic macrolides. • The duration for excluding pregnancy or breast-feeding in exclusion criterion #19 was amended to 1 year.

•The CTP was amended to reflect the transition in contract research organisation from Chiltern International Ltd. (a Covance Company) to Syneos Health. • Inclusion criterion #3 was amended from “diagnosed with NCFB by computerised tomography (CT) or high resolution CT (HRCT) as recorded in the subject’s notes” to “are diagnosed with NCFB by computerised tomography (CT) or high resolution CT (HRCT) as recorded in the subject’s notes and this was their predominant condition being treated”. • Inclusion criterion #4 was amended to allow patients experiencing 2 NCFB pulmonary exacerbations requiring inhaled antibiotics to be enrolled. • Inclusion criterion #7 was amended to allow patients with a pre-bronchodilator FEV1 ≥25% (as opposed to ≥30%). • Inclusion criterion #8 was amended to reflect the fact that any positive result for 1 of the 3 potential sputum samples collected during the periods between Visit 1 and Visit 2 allowed for patient inclusion. • Exclusion criterion #14 (“known to be intolerant to inhaled beta-2 agonists (bronchodilators”) was deleted. Zambon removed this requirement due to feedback that, as many patients could tolerate the IMP without it, the mandated use was an unnecessary burden on patients who would prefer not to use it. The use of the bronchodilator was to aid tolerability, not to improve efficacy. In addition, a statement was added to allow subject to continue in the study without pre-bronchodilator use prior to IMP administration. • Exclusion criterion #13 (as re-numbered) was amended from “known or suspected to be allergic or unable to tolerate colistimethate sodium or other polymixins (IV or inhaled) including evidence of bronchial hyperreactivity” to “known or suspected to be allergic or unable to tolerate colistimethate sodium (IV or inhaled) or other polymixins, including evidence of bronchial hyper-reactivity following inhaled colistimethate sodium”.

•The wording regarding the definition of the resolution of pulmonary exacerbations was re-phrased, and the following statement was added: “The occurrence of a pulmonary exacerbation does not mandate the discontinuation of the subject from the study, unless it occurs between Visit 1 and Visit 2 and/or the Investigator believes discontinuation is in the subject’s best interest.” • Acute and/or short-term administration of oxygen therapy/ventilator assistance was included as an acceptable rescue medication.

• Country-specific amendments of CTP version 4.0 were incorporated. • Changes to the conduct and duration of the study required due to the COVID-19 pandemic were made including inclusion of a contingency plans for remote visits during the COVID-19 pandemic. • Provisions were included for the original sample size to be recalculated at a later date to take into consideration: a) treatment exposure for withdrawn subjects and b) a planned blinded review of the exacerbation rate. • Clarification was added to specify that subjects not using the recommended bronchodilator prior to IMP administration needed to be clinically assessed to determine whether this was appropriate. • The Screening period (between Visits 1 and 2) was extended from 30 days to 45 days to allow for sufficient time for the processing of sputum samples for the analysis of P. aeruginosa. A clarification was added that re-screening for subjects who screen failed for reasons other than a negative result for P. aeruginosa was permitted at any time. For subjects with a negative result for P. aeruginosa, re-screening was also permitted after approximately 3 months from the last Screening test. • The units for P. aeruginosa were corrected to CFU/mL. • Provisions were included for the use of paper quality of life questionnaires when the electronic tablet supplied to sites malfunctioned or there were other technical issues. • The reporting of episodes of pneumonia as pulmonary exacerbations was clarified. • A Data Assessment Committee was established for the assessment of the impact of COVID-19 on the study, and blinded review of pulmonary exacerbation data, and details were included.