Prospective Clinical Study on Vitamin D Replacement in Bronchiectasis - A Pilot Study
Phase: PHASE4
Conditions: Bronchiectasis
Sponsor: Queen Mary Hospital, Hong Kong

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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Application for Institutional Review Board Approval of Study Protocol  
 
1. Title 
Prospective clinical study on Vitamin D replacement in bronchiectasis – A pilot study 
2. Investigator 
Principal investigator:  
 
Dr. W.C. KWOK, Clinical Assistant Professor 1 
1: Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, 
Queen Mary Hospital, Hong Kong 
 
3. Background 
Bronchiectasis refers to a suppurative lung condition characterized by pathological dilatation 
of bronchi. It is one of the most common chronic airway diseases in Chinese populations (1). 
The prevalence increased by 2.31-fold between 2013 and 2017 among Chinese urban adults ≥ 
18 years (2) . Although there is no official epidemiological report on the prevalence of 
bronchiectasis in Hong Kong, a local study that validated the diagnostic coding for 
bronchiectasis in an electronic health record system in Hong Kong recorded 19617 patients 
with the diagnostic code of bronchiectasis among all public hospitals from 2011 to 2020 (3). 
 
The main pathogenesis of bronchiectasis involves airway inflammation, abnormal mucus 
clearance, and bacterial colonisation, resulting in progressive airway destruction and distortion. 
In recent years, evidence suggests a central role of airway inflammation and immune 
dysregulation in the evolution of bronchiectasis (4). The classic type of airway inflammation 
is neutrophilic, characterised by abundant neutrophils in sputum and bronchoalveolar lavage 
fluid, and detected in bronchial biopsy from patients with bronchiectasis, even in a clinically 
stable-state (5). 
Bronchiectasis is also characterized by having micro-organism (bacterial, especially 
Pseudomonas aeruginosa and non-tuberculous mycobacteria) colonization as well as 
exacerbation. The progressive destruction perpetuates in a vicious cycle, even when the initial 
insult has subsided. Patients with extensive bronchiectasis present with chronic cough, copious 
purulent sputum, haemoptysis, progressive loss of lung function, and episodes of infective 
exacerbations.  

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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Bronchiectasis exacerbation is associated with negative impact on morbidity, mortality, quality 
of life, and healthcare costs. (6-8) EMBARC Bronchiectasis Registry demonstrated that around 
50% of patients had two or more exacerbations annually and one in every three required 
hospitalizations (9). The prognosis, with respect to hospitalization, mortality and severity, can 
be predicted by using validated scoring system such as bronchiectasis severity index (BSI) and 
FACED score (using a combination of forced expiratory volume in the first second (FEV1), 
patient’s age, the presence of Pseudomonas aeruginosa colonization, disease extent and degree 
of dyspnea to predict five-year all-cause mortality) (10, 11). In addition, health-related quality 
of life (HRQOL) is severely impaired in bronchiectasis (12).  
Vitamin D is known to have immune and inflammatory-modulating effects (13, 14). Both 
25(OH)D: calcifediol and its active form, 1,25-dihydroxyvitamin D (1,25(OH)2D: calcitriol), 
play critical roles in protection against invasive pathogens and reducing risks of autoimmunity. 
Low 25(OH)D status was reported to increase the susceptibility to infections and developing 
autoimmunity. According to a systematic review, data strongly suggested that maintaining 
serum 25(OH)D concentrations of more than 125 nmol/L is associated with significant risk 
reduction from viral and bacterial infections, sepsis, and autoimmunity (15). Most adequately 
powered, well-designed, randomized controlled trials with sufficient duration supported 
substantial benefits of vitamin D. Data confirmed that keeping an individual's serum 25(OH)D 
concentrations above 125 nmol/L reduces risks from community outbreaks, sepsis, and 
autoimmune disorders.  
There is epidemiological finding of association between vitamin D deficiency and the risk 
of respiratory tract infections (16, 17). Seasonal vitamin D insufficiency due to reduced sun 
exposure was reported to be associated with increase in tuberculosis risk (18). Vitamin D 
deficiency has been associated with worse clinical outcomes in Coronavirus disease 2019 
(COVID-19) (19). Vitamin D supplementation was shown to have small effect on reducing the 
risk of acute respiratory infections compared with placebo (20).  
Vitamin D may also play a role in chronic respiratory diseases. High deficiency rate of 
25(OH)D was reported to be associated with severity of chronic obstructive pulmonary disease 
(COPD) (21). Serum vitamin D levels were also inversely associated with COPD risk, severity, 
and exacerbation (22). Vitamin D deficiency is associated with increased risk of COPD and 
severe COPD but not with COPD exacerbation. Vitamin D deficiency was associated with a 
significant decrease in lung function in asthmatic children (23). Supplementation of Vitamin D 
was reported to improve the indicators of asthma and COPD, especially in pulmonary function, 
(St. George's Respiratory Questionnaire (SGRQ) scores, interleukin-5 (IL-5), and IgE (24). 
Vitamin D supplementation can also reduce the rate of asthma exacerbations requiring 
treatment with systemic corticosteroids (25).  

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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Given the role of vitamin D in immune regulations and the reported infection risks among 
patients with vitamin D deficiency, it is not surprising that vitamin D deficiency may be linked 
to poor outcome in bronchiectasis, a disease characterized by chronic bacterial colonization 
and exacerbation which is mediated through infectious pathogens. 
Vitamin D level has been shown to be a good predictor of clinical and radiological severity of 
bronchiectasis (26, 27). Vitamin-D deficient patients had higher sputum levels of inflammatory 
markers and demonstrated a more rapid decline in lung function over 3 years follow-up. (28) 
Vitamin D deficiency is a non-trivial issue in this disease population since as many as 50% 
were found to be deficient. (28) Colonization rate of Pseudomonas aeruginosa were also found 
to correlate with vitamin D level (21.4% vs. 10.4% vs. 3.6%) in deficient, insufficient and 
sufficient patients respectively. (28) Vitamin-D deficient patients also had lower predicted 
FEV1 by percentage predicted and more frequent pulmonary exacerbations, demonstrating the 
correlation between exacerbation frequency and vitamin D status (29). Finally, a New Zealand 
study looked at how Vitamin D supplementation affect the frequency or severity of 
exacerbations though most patients were not Vitamin D-deficient as baseline. (30).  It is 
important to note that bronchiectasis exacerbation is not the primary outcome of any of the 
above studies and therefore important confounders such as the intrinsic disease severity or 
degree of Pseudomonas aeruginosa colonization were not properly adjusted in this study.  
Limitations do exist in these studies on Vitamin D level and bronchiectasis. Firstly, the studies 
aforehand mentioned were conducted among Caucasian and middle-east populations (26-29). 
It has been well reported that the aetiology of bronchiectasis varies greatly across ethnic groups 
(14). There is also geographical variation in epidemiology and microbiology of bronchiectasis. 
Secondly, relatively small sample sizes were used in these prior studies. 
Our group is also conducting a prospective clinical study on serum 25-hydroxyvitamin D (25-
OH D) level and risk of bronchiectasis exacerbation (UW 22-317) which started in January 
2023 and targeted for completion by end of 2024. There were 104 subjects recruited who will 
be followed up for 12 months. In this ongoing study, 42 (39.3%) of the patients had vitamin D 
deficiency with baseline vitamin D level below 50 nmol/L. There were 70 patients who 
completed the interim analysis at 6 months. Patients who are vitamin D deficient had increased 
risks of developing bronchiectasis exacerbation (10% in Vitamin D deficient group and 0% in 
vitamin D non-deficient group), p-value = 0.082. Patients who are vitamin D deficient had 
increased risks of developing hospitalized bronchiectasis exacerbation (13.3% in vitamin D 
deficient group and 2.5% in vitamin D non-deficient group), p-value = 0.041. Patients with 
vitamin D deficiency also had higher SGRQ score (symptom domain) [39.4 ± 22.5 vs 28.1 ± 
20.4, p = 0.011], SGRQ score (impact domain) [23.6 ± 19.3 vs 16.0 ± 14.9, p = 0.024] and total 
SGRQ score [29.3 ± 18.1 vs 22.9 ± 15.2, p = 0.063]. The data from this preliminary local pilot 
data suggested that vitamin D deficiency might have important role in bronchiectasis in terms 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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of symptom burden and exacerbation risks.  
There are several issues and limitations in the previous study on vitamin D supplementation in 
adults with bronchiectasis (31). Firstly, patients with co-existing respiratory diseases such as 
asthma in 7 (21%) of the patients were included. This might affect the validity of the results as 
the benefits of vitamin D supplementation has been shown in prior studies. Secondly, the mean 
serum 25(OH)D level at baseline before vitamin D supplementation was 70.5 ± 35.3 nmol/L, 
signifying that a substantial portion of the patients recruited are not vitamin D deficient 
(defined as serum 25(OH)D level < 50 nmol/L). Some of the outcomes measured are also not 
bronchiectasis specific. The primary outcome was serum 25(OH)D levels before and after 
vitamin D3 supplementation, which is indeed unrelated to bronchiectasis. The change in 
vitamin D level after replacement is rather expected and might not have clinical values in 
bronchiectasis management. For the secondary outcomes, Dartmouth COOP charts score, 
SNOT-20 score, Lund–Kennedy score and Leicester cough questionnaire (LCQ) score are all 
not specific to bronchiectasis. Measuring non-bronchiectasis specific outcomes undermines the 
ability of the study to assess for the benefits of vitamin D supplementation in bronchiectasis. 
As bronchiectasis has rather distinct clinical features which are not present in other chronic 
respiratory diseases (such as haemoptysis), measuring its specific outcomes is critical to assess 
treatment benefits.  
This study therefore seeks to address the limitations in previous related studies on vitamin D 
replacement and bronchiectasis exacerbation occurrence through a self-controlled pilot study. 
We aim to investigate whether vitamin D replacement in bronchiectasis patients with vitamin 
D deficiency can reduce hospitalized bronchiectasis exacerbation occurrence. Patients who 
participated in the prior study entitled “Prospective clinical study on serum 25-hydroxyvitamin 
D (25-OH D) level and risk of bronchiectasis exacerbation” (UW 22-317) will be invited for 
participation during regular clinic follow-up and management in Queen Mary Hospital. If they 
are willing to join the further research, they will be recruited in this self-controlled study. There 
are some differences from usual management to non-CF bronchiectasis subjects. The study 
subjects would be checked for their blood 25-hydroxyvitamin-D level during the study period. 
The non-CF bronchiectasis subjects with Vitamin D deficiency would be given 1000 IU and 
2000 IU (if needed). We aim to correct their Vitamin D deficiency completely, aiming at blood 
25-hydroxyvitamin-D level >=50, i.e. treat to target. The dose depends on the level of Vitamin 
D after replacement. If blood 25-hydroxyvitamin-D level is 50 or above, then 1000 IU is suffice. 
If blood 25-hydroxyvitamin-D level is still below 50, we will increase to 2000 IU. 
4. Hypothesis 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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We hypothesize that replacing vitamin D to raise the blood 25-hydroxyvitamin-D level 
above 50 nmol/L can reduce the occurrence of hospitalized bronchiectasis exacerbation 
among patients with bronchiectasis and baseline vitamin D deficiency. 
 
5. Objectives 
To investigate whether vitamin D replacement in bronchiectasis patients with vitamin D 
deficiency can reduce hospitalized bronchiectasis exacerbation occurrence.  
 
6. Subject recruitment 
A prospective self-controlled study will be conducted to assess the potential benefits of 
vitamin D supplementation, aiming at raising the blood 25-hydroxyvitamin-D level above 
50 nmol/L.  
This study will be conducted at the Department of Medicine, Queen Mary Hospital. The 
Division of Respiratory Medicine at Queen Mary Hospital is a tertiary referral centre 
serving the entire territory and is the major receiving unit for patients with various 
respiratory diseases (including bronchiectasis) in the Hong Kong West Cluster. 
Patients who participated in the prior study entitled “Prospective clinical study on serum 
25-hydroxyvitamin D (25-OH D) level and risk of bronchiectasis exacerbation” (UW 22-
317) will be invited for participation during regular clinic follow-up and management in 
Queen Mary Hospital. If they are willing to join the further research, they will be recruited 
in this self-controlled study. There were 104 subjects in the aforementioned study who will 
be separated into two groups according to their Baseline blood 25-hydroxyvitamin-D level: 
vitamin D deficient (below 50 nmol/L) and vitamin D non-deficient (at or above 50 nmol/L). 
There were initially 42 and 62 patients in the vitamin D deficient and vitamin D non-
deficient groups respectively. Patients would be rechecked for 25-hydroxyvitamin-D level 
to confirm the persistence of deficiency at the recruitment visit.  
The following eligibility criteria will apply. 
Inclusion criteria: Patients with 
1. ages 18 years or above, male or female. 
2. confirmed diagnosis of non-CF bronchiectasis based on high-resolution computed 
tomography (HRCT) scan. 
3. participation in the prior study entitled “Prospective clinical study on serum 25-
hydroxyvitamin D (25-OH D) level and risk of bronchiectasis exacerbation” (UW 22-
317) 
 
Exclusion criteria: Patients with 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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1. underlying asthma, COPD and other co-existing respiratory diseases 
2. underlying osteoporosis  
3. supplementary Vitamin D in their regimen 
4. advanced chronic kidney disease with estimated glomerular filtration rate (eGFR) < 
30mL/min  
 
7. Brief outline of methodology 
The following will be performed at the recruitment visit: Detailed medical history 
(Demographics, duration of bronchiectasis, co-morbidities, exacerbation history), 
questionnaires (SGRQ, Modified Medical Research Council (mMRC) dyspnoea scale, 
bronchiectasis impact measure (BIM), Bronchiectasis Health Questionnaire (BHQ)), 
physical examination, blood tests (Complete blood count, liver and renal function test, 
25-hydroxyvitamin-D level, calcium and phosphate level, erythrocyte sedimentation rate, 
C-reactive protein, high-sensitivity C-reactive protein), and sputum analysis (Bacterial 
smear and culture, acid fast bacilli smear and culture). The detailed study procedures are 
summarized in Table 1. The estimated duration for each visit would be 15 minutes. 
 
Outcome measurement 
The primary outcome measure is the proportion of patients who develop hospitalized 
bronchiectasis exacerbation during the follow-up period of 12 months, when compared 
with the 1-year period before. The Vitamin D deficient group will be compared with their 
historical data collected in the prior study entitled “Prospective clinical study on serum 
25-hydroxyvitamin D (25-OH D) level and risk of bronchiectasis exacerbation” (UW 22-
317) as self-control, as well as the vitamin D non-deficient group.  
The secondary outcomes include the change in SGRQ, BIM and BHQ score at 6 and 12 
months from baseline, as well as change in number of all/hospitalized bronchiectasis 
exacerbation in the follow up period of 12 months. 
Those with vitamin D deficiency will be replaced with vitamin D3 at 1000 IU at the first 
visit. Vitamin D3 1000 IU is expected to increase blood 25-hydroxyvitamin-D level by 
25 nmol/L.  Blood 25-hydroxyvitamin-D level will be rechecked 3 months after 
replacement. If the blood 25-hydroxyvitamin-D level is still below 50 nmol/L, the vitamin 
D3 replacement dosage will be increased to 2000 IU. Blood 25-hydroxyvitamin-D level 
will be checked again at 6 and 12 months. 
Patients will be followed up at 3, 6 and 12 months after recruitment.  Except for the 
sputum analysis and blood tests, the same measures in Table 1 will be performed at 6 and 
12 months.  In addition, patients will be assessed on their bronchiectasis exacerbation 
record (both bronchiectasis exacerbation managed in an out-patient setting and 
hospitalized bronchiectasis exacerbation). 
Methods 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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Blood 25-hydroxyvitamin-D level 
25-hydroxyvitamin-D will be measured in nmol/L, using in-house liquid chromatography 
with tandem mass spectrometry (LC/MS-MS) developed by the Department of Chemical 
Pathology of Queen Mary Hospital. Vitamin D deficiency is defined as 25-
hydroxyvitamin-D level below 50 nmol/L, while sufficient vitamin D level is defined as 
above 50 nmol/L, per the Endocrine Society guidelines (32, 33). 
Bronchiectasis exacerbation 
Bronchiectasis exacerbation was defined as [1] a deterioration in three or more of the 
following key symptoms for at least 48 hours, including cough, sputum volume and/or 
consistency, sputum purulence, dyspnea and/or exercise tolerance, fatigue and/or malaise, 
hemoptysis AND [2] clinician assessment that a change in bronchiectasis treatment was 
required usually with administration of antibiotics treatment. 
Hospitalized bronchiectasis exacerbations are those exacerbations that fulfil the criteria 
above and also need at least 24 hours in-patient stay for treatment.  
SGRQ 
SGRQ is a disease-specific instrument designed to measure impact on overall health, daily 
life, and perceived well-being in patients with obstructive airway disease. Consisting of 2 
parts with 50 items, it addresses frequency and severity of patients’ symptoms as well as 
activities that cause or are limited by breathlessness. Scores range from 0 to 100, with 
higher scores indicating more limitations.  The minimally important difference is a mean 
change of 4 units for slightly efficacious treatment, 8 units for moderately efficacious 
change and 12 units for very efficacious treatment (34, 35). SGRQ has been validated in 
patients with bronchiectasis and is considered a valid and sensitive instrument for 
determining quality of life in bronchiectasis patients (36). 
BIM 
Bronchiectasis Impact Measure (BIM) is another tool developed to assess patient-reported 
outcome in bronchiectasis. BIM is a self-administered outcome measure designed to 
collect patient-perceived health impact at baseline or after a follow-up period in an 
intervention. It was designed to address some of the perceived limitations of existing tools 
by being simple (eight items), giving greater scope for a range of responses (10-point 
visual analogue scale for each item) and by focusing on the impact of disease on quality 
of life rather than on  the frequency or severity of symptoms. BIM consists of eight 
domains, namely: cough, sputum, breathlessness, tiredness, activity, general health, 
control, and exacerbations. A score ranges from 0 to 10 for each domain, with 10 being 
most severe. The total score is 80. BIM has been validated and shown to have excellent 
internal consistency. The domains were also shown to strongly correlate with 
bronchiectasis severity and exacerbation history. Statistically significant changes in all 
BIM domains were observed during an acute exacerbation. PI of this study translated and 
validated the Traditional Chinese version of BIM in year 2024. 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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BHQ 
BHQ was developed by Spinou et al. (37). Despite the questionnaire’s simplicity, the 
authors concluded that the questionnaire works well in a different population from the 
development cohort. The instrument comprises 10 questions, each scored on a 7-point 
scale, to assess quality of life related to bronchiectasis on individuals for a recall period 
of 2 weeks. The total score ranges from 10 to 70, with a lower score indicating a more 
negative impact on HRQOL. PI of this study translated and validated the Traditional 
Chinese version of BIM in year 2024. 
Table 1: Study Procedures 
 
Study Visit 
Visit 
V1 
V2 
V3 
V4 
Months 
0 
3 
6 
12 
Written informed consent 
✓ 
 
 
 
Body height, body weight and body 
mass index 
✓ 
 
 
 
Medical history and previous 
medication 
✓ 
✓ 
✓ 
✓ 
Blood samples 
✓ 
✓ 
✓ 
✓ 
Sputum investigation 
✓ 
 
 
 
Lung function tests  
✓ 
 
 
 
Blood pressure and pulse 
measurement 
✓ 
✓ 
✓ 
✓ 
Physical examination 
✓ 
✓ 
✓ 
✓ 
mMRC score 
✓ 
 
✓ 
✓ 
SGRQ score 
✓ 
 
✓ 
✓ 
BIM questionnaire 
✓ 
 
✓ 
✓ 
BHQ questionnaire 
✓ 
 
✓ 
✓ 
Vitamin D replacement  
(Only for patients with Vitamin D 
deficiency) 
✓  
(Dosage: 1000 
IU) 
✓ 
(Dosage will be 
increased to 
2000 IU if 
blood vitamin D 
level is below 
50 nmol/L)  
✓ 
✓ 
 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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Those with vitamin D deficiency will be replaced with vitamin D3 at 1000 IU at the first 
visit. Vitamin D3 1000 IU is expected to increase blood 25-hydroxyvitamin-D level by 
25 nmol/L.  Blood 25-hydroxyvitamin-D level will be rechecked 3 months after 
replacement. If the blood 25-hydroxyvitamin-D level is still below 50 nmol/L, the vitamin 
D3 replacement dosage will be increased to 2000 IU. Blood 25-hydroxyvitamin-D level 
will be checked again at 6 and 12 months. There are some differences from usual 
management to non-CF bronchiectasis subjects. The study subjects would be checked for 
their blood 25-hydroxyvitamin-D level during the study period. The non-CF 
bronchiectasis subjects with Vitamin D deficiency would be given 1000 IU and 2000 IU 
(if needed). We aim to correct their Vitamin D deficiency completely, aiming at blood 25-
hydroxyvitamin-D level >=50, i.e. treat to target. The dose depends on the level of 
Vitamin D after replacement. If blood 25-hydroxyvitamin-D level is 50 or above, then 
1000 IU is suffice. If blood 25-hydroxyvitamin-D level is still below 50, we will increase 
to 2000 IU. 
Patients will be followed up at 3, 6 and 12 months after recruitment.  Except for the 
sputum analysis and blood tests, the same measures in Table 1 will be performed at 6 and 
12 months.  In addition, patients will be assessed on their bronchiectasis exacerbation 
record (both bronchiectasis exacerbation managed in an out-patient setting and 
hospitalized bronchiectasis exacerbation). 
 
Subjects (with justification on the sample size) 
Patients who participated in the prior study entitled “Prospective clinical study on serum 
25-hydroxyvitamin D (25-OH D) level and risk of bronchiectasis exacerbation” (UW 22-
317) will be recruited in this self-controlled study.  
There were 104 subjects in the aforementioned study who will be separated into two 
groups according to their Baseline blood 25-hydroxyvitamin-D level: vitamin D deficient 
(below 50 nmol/L) and vitamin D non-deficient (at or above 50 nmol/L). There were 
initially 42 and 62 patients in the vitamin D deficient and vitamin D non-deficient groups 
respectively. 
 
Data processing and analysis  
The demographic and clinical data will be described in actual frequency or mean ± SD, 
or median and interquartile range, where appropriate.  
Baseline demographic and clinical data will be tabulated, as well as compared between 
Vitamin D deficient and vitamin D non-deficient groups by independent t-test or non-
parametric tests where appropriate.  
In the Vitamin D deficient group, the proportion of patients with hospitalized 
bronchiectasis exacerbation before and after vitamin D replacement will be compared by 
binary logistic regression. The number of all/hospitalized bronchiectasis exacerbation 
before and after vitamin D replacement will be compared by will be compared with linear 
regression. 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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The proportion of patients with all/hospitalized bronchiectasis exacerbation and between 
vitamin D deficient and vitamin D non-deficient groups will be compared by binary 
logistic regression. The number of all/hospitalized bronchiectasis exacerbation b between 
vitamin D deficient and vitamin D non-deficient groups will be compared by will be 
compared with linear regression.  
Covariates including FACED score, age, gender and smoking status will be adjusted in 
multivariate analysis. For secondary outcome, the change in SGRQ, BIM and BHQ scores 
at the end of study will be compared between the two groups by linear regression and 
adjusted for confounders in multivariate analysis. A p-value of <0.05 will be considered 
statistically significant. All the statistical analyses will be performed using the latest 
version of Statistical Package for the Social Sciences (SPSS) software. 
8. Potential hazards to subjects in the study 
Patients will undergo blood tests and breathing (lung function) tests. The breathing tests 
may be associated with some discomfort, such as chest soreness, shortness of breath and 
lightheadedness. Pain, bruising or infection may occur from the needle puncture sites. 
Should patients’ non-CF bronchiectasis significantly worsen in the course of the study, 
study doctor will withdraw them from the study and provide appropriate medical 
treatment.  
Over-replacement of Vitamin D may lead to Vitamin D toxicity which can have the 
following symptoms: nausea, vomiting, loss of appetite, constipation, dehydration, 
fatigue, irritability, confusion, weakness and/or weight loss. In this study, the blood serum 
25(OH)D level will be checked before the start of Vitamin D replacement and at 3 months 
after replacement, to ensure the replacement is adequate but not excessive. 
 
9. Confidentiality and use of results 
The demographic and clinical data collected from study subjects will be stored securely 
at the study site for 5 years, with access by the principal investigator or his designated 
research staff. These data will only be used for the study as outlined in this protocol and 
individual patient’s identity will be removed after completion of statistical analyses.  
 
10. Personal experience of the investigators in the field 
The Division of Respiratory Medicine has a strong track record in conducting clinical 
research on bronchiectasis. Queen Mary Hospital is a well-recognised tertiary referral and 
research centre in the field of respiratory medicine, with numerous research on 
bronchiectasis and respiratory diseases conducted therein during the past years. All the 
investigators are experienced and accredited specialist. Within the last 3 years, the PI (Dr 
WC Kwok) has served as the first author of 9 out of 10 publications on bronchiectasis.  

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
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The current research team (clinical and basic research) under the supervision of the PI 
consists of 1 senior research assistant, 1 research assistant, 1 technician, and 2 
postgraduate students (MPhil). The current research team also has expertise in research 
related to bone and mineral metabolism. 
11. Funding and Conflict of interests 
There is no funding received for this study. There will be no conflict of interests from both 
the department and any of the investigators involved. 
12. Declaration 
The information supplied above is to the best of our knowledge and belief accurate. We 
shall comply with the principles enunciated in the present Declaration of Helsinki. 
 
References 
1. 
Gao YH, Lu HW, Mao B, Guan WJ, Song YL, Li YY, et al. The Establishment of China 
Bronchiectasis Registry and Research Collaboration (BE-China): Protocol of a prospective 
multicenter observational study. Respir Res. 2022;23(1):328. 
2. 
Feng J, Sun L, Sun X, Xu L, Liu L, Liu G, et al. Increasing prevalence and burden of 
bronchiectasis in urban Chinese adults, 2013-2017: a nationwide population-based cohort study. 
Respir Res. 2022;23(1):111. 
3. 
Kwok WC, Tam TCC, Sing CW, Chan EWY, Cheung CL. Validation of diagnostic coding for 
bronchiectasis in an electronic health record system in Hong Kong. Pharmacoepidemiol Drug Saf. 
2023;32(10):1077-82. 
4. 
Boyton RJ, Altmann DM. Bronchiectasis: Current Concepts in Pathogenesis, Immunology, 
and Microbiology. Annu Rev Pathol. 2016;11:523-54. 
5. 
Fuschillo S, De Felice A, Balzano G. Mucosal inflammation in idiopathic bronchiectasis: 
cellular and molecular mechanisms. Eur Respir J. 2008;31(2):396-406. 
6. 
Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, Loebinger MR, et al. 
European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J. 
2017;50(3). 
7. 
McDonnell MJ, Aliberti S, Goeminne PC, Restrepo MI, Finch S, Pesci A, et al. Comorbidities 
and the risk of mortality in patients with bronchiectasis: an international multicentre cohort study. 
Lancet Respir Med. 2016;4(12):969-79. 
8. 
Beijers RJ, van den Borst B, Newman AB, Yende S, Kritchevsky SB, Cassano PA, et al. A 
Multidimensional Risk Score to Predict All-Cause Hospitalization in Community-Dwelling Older 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
12 
Individuals With Obstructive Lung Disease. J Am Med Dir Assoc. 2016;17(6):508-13. 
9. 
Chalmers JD, Aliberti S, Polverino E, Vendrell M, Crichton M, Loebinger M, et al. The 
EMBARC European Bronchiectasis Registry: protocol for an international observational study. 
ERJ Open Res. 2016;2(1). 
10. Martinez-Garcia MA, de Gracia J, Vendrell Relat M, Giron RM, Maiz Carro L, de la Rosa 
Carrillo D, et al. Multidimensional approach to non-cystic fibrosis bronchiectasis: the FACED 
score. Eur Respir J. 2014;43(5):1357-67. 
11. Chalmers JD, Goeminne P, Aliberti S, McDonnell MJ, Lonni S, Davidson J, et al. The 
bronchiectasis severity index. An international derivation and validation study. Am J Respir Crit 
Care Med. 2014;189(5):576-85. 
12. Quittner AL, O'Donnell AE, Salathe MA, Lewis SA, Li X, Montgomery AB, et al. Quality of 
Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal 
important difference scores. Thorax. 2015;70(1):12-20. 
13. Brumpton BM, Langhammer A, Henriksen AH, Camargo CA, Jr., Chen Y, Romundstad PR, 
et al. Vitamin D and Lung Function Decline in Adults With Asthma: The HUNT Study. Am J 
Epidemiol. 2016;183(8):739-46. 
14. Chandrasekaran R, Mac Aogain M, Chalmers JD, Elborn SJ, Chotirmall SH. Geographic 
variation in the aetiology, epidemiology and microbiology of bronchiectasis. BMC Pulm Med. 
2018;18(1):83. 
15. Wimalawansa SJ. Infections and Autoimmunity-The Immune System and Vitamin D: A 
Systematic Review. Nutrients. 2023;15(17). 
16. Moustaki M, Loukou I, Priftis KN, Douros K. Role of vitamin D in cystic fibrosis and non-
cystic fibrosis bronchiectasis. World J Clin Pediatr. 2017;6(3):132-42. 
17. Roth DE, Abrams SA, Aloia J, Bergeron G, Bourassa MW, Brown KH, et al. Global 
prevalence and disease burden of vitamin D deficiency: a roadmap for action in low- and middle-
income countries. Ann N Y Acad Sci. 2018;1430(1):44-79. 
18. Wallis RS, Zumla A. Vitamin D as Adjunctive Host-Directed Therapy in Tuberculosis: A 
Systematic Review. Open Forum Infect Dis. 2016;3(3):ofw151. 
19. Feiner Solis A, Avedillo Salas A, Luesma Bartolome MJ, Santander Ballestin S. The Effects 
of Vitamin D Supplementation in COVID-19 Patients: A Systematic Review. Int J Mol Sci. 
2022;23(20). 
20. Jolliffe DA, Camargo CA, Jr., Sluyter JD, Aglipay M, Aloia JF, Ganmaa D, et al. Vitamin D 
supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of 
aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021;9(5):276-92. 
21. Zhu B, Zhu B, Xiao C, Zheng Z. Vitamin D deficiency is associated with the severity of 
COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:1907-
16. 
22. Zhu M, Wang T, Wang C, Ji Y. The association between vitamin D and COPD risk, severity, 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
13 
and exacerbation: an updated systematic review and meta-analysis. Int J Chron Obstruct Pulmon 
Dis. 2016;11:2597-607. 
23. Zhang LL, Gong J, Liu CT. Vitamin D with asthma and COPD: not a false hope? A 
systematic review and meta-analysis. Genet Mol Res. 2014;13(3):7607-16. 
24. Wang Y, Wang J, Chen L, Zhang H, Yu L, Chi Y, et al. Efficacy of vitamin D supplementation 
on COPD and asthma control: A systematic review and meta-analysis. J Glob Health. 
2022;12:04100. 
25. Jolliffe DA, Greenberg L, Hooper RL, Griffiths CJ, Camargo CA, Jr., Kerley CP, et al. 
Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-
analysis of individual participant data. Lancet Respir Med. 2017;5(11):881-90. 
26. Ferri S, Crimi C, Heffler E, Campisi R, Noto A, Crimi N. Vitamin D and disease severity in 
bronchiectasis. Respir Med. 2019;148:1-5. 
27. Niksarlioglu EY, Kilic L, Bilici D, Yigitbas B, Uysal MA, Camsari G. Vitamin D Deficiency 
and Radiological Findings in Adult Non-Cystic Fibrosis Bronchiectasis. Turk Thorac J. 
2020;21(2):87-92. 
28. Chalmers JD, McHugh BJ, Docherty C, Govan JR, Hill AT. Vitamin-D deficiency is 
associated with chronic bacterial colonisation and disease severity in bronchiectasis. Thorax. 
2013;68(1):39-47. 
29. Sami R, Zohal M, Marhamati KA, Rajabi S, Shokri-Mashhadi N. 25-Hydroxy vitamin D and 
body composition are associated with pulmonary function in non-cystic fibrosis bronchiectasis: A 
cross-sectional study. Clin Nutr ESPEN. 2021;46:527-31. 
30. Bartley J, Garrett J, Camargo CA, Jr., Scragg R, Vandal A, Sisk R, et al. Vitamin D3 
supplementation in adults with bronchiectasis: A pilot study. Chron Respir Dis. 2018;15(4):384-92. 
31. Bartley J, Garrett J, Camargo CA, Jr., Scragg R, Vandal A, Sisk R, et al. Vitamin D(3) 
supplementation in adults with bronchiectasis: A pilot study. Chron Respir Dis. 2018;15(4):384-92. 
32. Nowson CA, McGrath JJ, Ebeling PR, Haikerwal A, Daly RM, Sanders KM, et al. Vitamin D 
and health in adults in Australia and New Zealand: a position statement. Med J Aust. 
2012;196(11):686-7. 
33. Paxton GA, Teale GR, Nowson CA, Mason RS, McGrath JJ, Thompson MJ, et al. Vitamin D 
and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a 
position statement. Med J Aust. 2013;198(3):142-3. 
34. Jones PW. Quality of life, symptoms and pulmonary function in asthma: long-term treatment 
with nedocromil sodium examined in a controlled multicentre trial. Nedocromil Sodium Quality of 
Life Study Group. Eur Respir J. 1994;7(1):55-62. 
35. Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma 
and COPD. Eur Respir J. 2002;19(3):398-404. 
36. Chan SL, Chan-Yeung MM, Ooi GC, Lam CL, Cheung TF, Lam WK, et al. Validation of the 
Hong Kong Chinese version of the St. George Respiratory Questionnaire in patients with 

Study protocol_Vitamin D replacement in bronchiectasis V1 (dated 06032024) 
14 
bronchiectasis. Chest. 2002;122(6):2030-7. 
37. Spinou A, Siegert RJ, Guan WJ, Patel AS, Gosker HR, Lee KK, et al. The development and 
validation of the Bronchiectasis Health Questionnaire. Eur Respir J. 2017;49(5).