Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis

• Sponsor: Pharmaxis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00669331
• Collaborator: (none)
• Enrollment: 485
• Locations: 83
• Arms: 2
• Duration (Months): 50
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

No gold standard therapy exists for clearing mucus from the airways of patients with bronchiectasis. While rhDNase has a proven place in the treatment of cystic fibrosis (CF), it failed to improve Forced expiratory volume in one second (FEV1) in a short-term non-CF bronchiectasis study and has been shown to be detrimental after 6 months therapy in non CF bronchiectasis, moreover it has no proven effect on mucociliary clearance. Hypertonic saline has been shown to have a comparable mode of action to inhaled mannitol, but has yet to be examined as a long term treatment option in bronchiectasis.

The purpose of this study is to examine the efficacy and safety of 52 weeks treatment with inhaled mannitol in subjects with non-cystic fibrosis bronchiectasis. Previous studies with inhaled mannitol have demonstrated improvement in mucociliary clearance; mucus rehydration; improvement in quality of life and respiratory symptoms in patients with bronchiectasis and pulmonary function in cystic fibrosis. The results of this current study in combination with a recently completed 3 month study seek to confirm these early findings and to extend the evidence to support its use as a mucoactive therapy in subjects with bronchiectasis.

We hypothesize that mannitol will improve the overall health and hygiene of the lung through regular and effective clearing of the mucus load. As a consequence of the reduction in mucus load and inflammatory process, the frequency of bronchiectasis related pulmonary exacerbations and the need for exacerbation related antibiotic treatment should fall. Days in hospital and community health care costs are expected to change in line with improvements in respiratory health.

Finally, we plan to demonstrate that inhaled mannitol is safe and well tolerated over a 52 week period. We will test these hypotheses using 400 mg mannitol twice daily (BD) against control.

Condition or Disease	Intervention/Treatment	Phase
Bronchiectasis	Drug: Inhaled mannitol; Drug: Matched control	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 485 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: : A Phase III Multicenter, Randomized, Parallel Group, Controlled, Double Blind Study to Investigate the Safety and Efficacy of Inhaled Mannitol Over 12 Months in the Treatment of Bronchiectasis.
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mannitol Inhaled mannitol 400mg	Drug: Inhaled mannitol; 400mg dose of Mannitol BD (twice a day) for 52 weeks
Placebo Comparator: Control Matched control - inhaled mannitol 50mg	Drug: Matched control; 50mg dose of Mannitol BD (twice a day) for 52 weeks

Outcome Measures

Primary Outcome Measures

1. Rate of Graded Pulmonary Exacerbations [52 weeks]

   A graded pulmonary exacerbation was defined as a worsening in signs and symptoms requiring a change in treatment (Center for Drug Evaluation and Research (CDER), 2007). Grade I was required 3 main signs and symptoms, Grade II 2 main signs and symptoms and Grade III 1 main and one or more minor signs and symptoms. Main signs and symptoms were increased cough, sputum volume or sputum purulence. Minor were upper respiratory tract infection, fever, increased wheezing, increased dyspnea, increase in respiratory rate, increase in cardiac frequency of >20%, and increased malaise, fatigue or lethargy. Rate is defined as the number of all GPE events observed in one treatment year

Secondary Outcome Measures

1. Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score [52 weeks]

   The SGRQ was collected at baseline, week 6, week 16, week 28, week 40 and week 52. Change in total score was calculated from baseline. Total scores are a weighted sum across all questions. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. Higher scores indicate lower quality of life. Outcome data table gives the raw mean total score at each visit.

2. Antibiotic Use Prescribed for Treated Pulmonary Exacerbations [52 weeks]

   Rate of antibiotic treated graded pulmonary exacerbations, using the same definition of a graded pulmonary exacerbation as the primary endpoint. A graded pulmonary exacerbation was considered to be anti-biotic treated if use of oral, IV or inhaled antibiotic use was recorded related to the GPE event.

3. Time to First Graded Exacerbation [52 weeks]

   Time to first graded exacerbation is defined as the duration (in months) from the randomisation date to the start of the first reported graded PE during the on-treatment period. Patients without reported graded PE event will be censored at the last participation.

4. Duration of Graded Exacerbations [52 weeks]

   Duration of graded exacerbations is defined as the number of days with graded PE within one treatment year. Mean days estimated via negative binomial model with treatment, region and baseline pulmonary exacerbation rate as predictors, with log of follow-up time as the offset variable

5. Sputum Volume [52 weeks]

   24 hour sputum weight, measured at baseline, week 6, week 16, week 28, week 40, week 52

6. Daytime Sleepiness Scores [52 weeks]

   Epworth Sleepiness Scale (ESS) score was calculated as the sum of scores for each of eight individual questions, such that a total score of zero represents no daytime sleepiness, and a total score of 24 represents the maximum degree of daytime sleepiness. Measured at baseline, 6 weeks, 16 weeks, 28 weeks, 40 weeks, 52 weeks

7. Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second) [52 weeks]

8. Lung Function - Change in FVC (Forced Vital Capacity) [52 weeks]

9. Lung Function - Change in FEV1/FVC [52 weeks]

   FEV1 expressed as a ratio of FVC. Endpoint is expressed as a percentage ie FEV1/FVC*100

10. Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC) [52 weeks]

11. Safety Profile - Sputum Microbiology [52 weeks]

    sputum microbiology assessed as the presence of abnormal flora in sputum sample taken at any post baseline visit

12. Safety Profile - Clinical Chemistry [52 weeks]

    Clinical chemistry was assessed as clinically significant abnormal liver function test and clinically significant abnormal urea/electrolyte test at any point post baseline.

13. Safety Profile - Hematology [52 weeks]

    hematology assessed as clinically significant abnormal FBC (Full Blood count) at any point post baseline.

14. • (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations [52 weeks]

    Mean rate of hospitalisations (number/year) summarised and analysed to take account of differing follow-up times.

Other Outcome Measures

1. Health Related Costs of Treating Patients With Bronchiectasis [52 weeks]

   In the presence of a significant primary endpoint, these data were intended to be derived using the trial data together with external information (Note as the primary objective of this study did not reach statistical significance, health related costs were not assessed)

2. Health Status and Utility Scores [52 weeks]

   In the presence of a significant primary endpoint, these data were intended to be derived from the trial data and external information (Note as the primary objective of this study did not reach statistical significance, differences in health status and utility scores were not assessed)

3. Health Related Quality of Life (HRQL) and Quality Adjusted Life Years (QALYs) by Treatment Group Using Utility Scores From the Health Utilities Index Questionnaire [52 weeks]

   In the presence of a significant primary endpoint, these data were intended to be derived using the trial data and external information (Note as the primary objective of this study did not reach statistical significance, HRQL and QALYs were not collected).

4. Cost Effectiveness of Treating Patients With Bronchiectasis With Inhaled Mannitol [52 weeks]

   In the presence of a significant primary endpoint, these data were intended to be derived using the trial data and external information (Note as the primary objective of this study did not reach statistical significance, cost effectiveness was not collected).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Have given written informed consent to participate in this study in accordance with local regulations

2. Have documented evidence of confirmed diagnosis of (non-cystic fibrosis) bronchiectasis by computed tomography (CT), High resolution computed tomography (HRCT) or bronchogram

3. Be aged 18 - 85 years inclusive, male and female

4. Have FEV1 (Forced expiratory volume in one second) ≥ 40% and ≤85% predicted* and ≥1.0L (*according to NHANES III predicted tables) measured at Visit 0A (V0A)

5. Clinician documented history of at least 2 pulmonary exacerbations, each requiring antibiotic therapy, in the last 12 months prior to Visit 0A (V0A) and a total of at least 4 in the last 2 years prior to Visit 0A

6. Have a total SGRQ (St George's respiratory questionnaire) score of ≥30 at Visit 0B (V0B)

7. Have a production of ≥10g of sputum at Visit 0B Have reported chronic sputum production of ≥1 tablespoon (15mL) per day on the majority of days in the 3 months prior to Visit 0A

8. Be able to perform all the techniques necessary to measure lung function

9. Have FEV1 ≥40% predicted* and ≥1.0L (*according to NHANES III 1999 predicted tables) measured at V0B (Baseline result prior to MTT (Mannitol Tolerance Test) administration)

Exclusion Criteria

1. Be investigators, site personnel directly affiliated with this study, or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biologically or legally adopted.

2. Have bronchiectasis as a consequence of cystic fibrosis or focal endobronchial lesion or otherwise curable causes (e.g. foreign body aspiration)

3. Be considered "terminally ill" or listed for transplantation

4. Be using hypertonic saline in the 14 days prior to commencing Visit 0B or thereafter at any time during the study

5. Have previously used inhaled mannitol (Bronchitol) for more than a day

6. Have had a significant episode of hemoptysis (>60 mL) in the previous 6 months

7. Have had rescue antibiotics in the 4 weeks prior to V0B (chronic background antibiotic therapy accepted)

8. Have smoked within the last 3 months and must not smoke during their participation in the study

9. Have had a myocardial infarction in the three months prior to Visit 0A

10. Have had a cerebral vascular accident in the three months prior to Visit 0A

11. Have had major ocular surgery in the three months prior to Visit 0A

12. Have had major abdominal, chest or brain surgery in the three months prior to Visit 0A

13. Have a known cerebral, aortic or abdominal aneurysm

14. Have actively treated Mycobacterium tuberculosis

15. Have actively treated or unstable nontuberculous mycobacterial (NTM)infection or be under consideration for NTM treatment in the next 12 months

16. Have unstable Allergic bronchopulmonary aspergillosis (ABPA) requiring steroid therapy (≤5mg dose oral steroids in stable ABPA accepted)

17. Have end stage interstitial lung disease

18. Have active malignancy including melanoma (other skin carcinomas exempted). Remissions from any malignancy ≥2 years also exempted

19. Be breast feeding or pregnant, or plan to become pregnant while in the study

20. Be using an unreliable form of contraception (female subjects at risk of pregnancy only)

21. Be participating in another investigational drug study, parallel to, or within 4 weeks of Visit 0A

22. Have a known intolerance to mannitol or β2-agonists

23. Have uncontrolled hypertension - e.g. for adults: systolic blood pressure (BP) > 190 and or diastolic BP > 100

24. Subject has a condition or is in a situation which in the Investigator's opinion may put the subject at significant risk, may confound results or may interfere significantly with the patient's participation in the study

25. Have previously been screen failed for the study (exceptions - see section 3.3.2 Eligibility Criteria - Rescreening)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Jewish Medical and Research Center	Denver	Colorado	United States	80206
2	University of Connecticut Health Center, Pulmonary Division	Farmington	Connecticut	United States	06030-1321
3	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
4	University of Miami	Miami	Florida	United States	33136
5	Florida Pulmonary Research	Winter Park	Florida	United States	32789
6	The University of Chicago Hospitals	Chicago	Illinois	United States	60637
7	Chest Medicine Clinical Services, LLC	Skokie	Illinois	United States	60076
8	Allergy and Critical Care Medicine Pulmonary Clinical Research Unit	Rochester	Minnesota	United States	55905
9	Saint Luke's Hospital	Chesterfield	Missouri	United States	63017
10	Pulmonary and Allergy Associates	Summit	New Jersey	United States	07901
11	Winthrop University Hospital	Mineola	New York	United States	11501
12	Research Associates of New York	New York	New York	United States	10028
13	University of North Carolina	Chapel Hill	North Carolina	United States	27514
14	The Oregon Clinic, PC/Pulmonary Division	Portland	Oregon	United States	97220
15	University of Pennsylvania Medical Center	Philadelphia	Pennsylvania	United States	19104
16	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
17	South Carolina Pharmaceutical Research	Spartanburg	South Carolina	United States	29303
18	Alamo Clinical Research Associates	San Antonio	Texas	United States	78212
19	Pulmonary Associates of Richmond, Inc	Richmond	Virginia	United States	23225
20	Instituto Argentino de Investigación Neurológica	Ciudad Autónoma de Buenos Aires	Ciudad Autónoma de Buenos Aires,	Argentina	C1015ABR
21	Centro Privado de Medicina Respiratoria	Entre Rios	Paraná Entre Ríos	Argentina	E3100BHK
22	Hospital Zonal Especializado en Agudos y Cronicos "Dr Antonio A. Cetrangolo	Florida Partido de Vicente López	Provincia de Buenos Aires	Argentina	B1602DOH
23	Centro Respiratorio Quilmes	Quilmes	Provincia de Buenos Aires	Argentina	B1878FNR
24	Hospital Privado - Centro Medico de Cordoba	Cordoba	Provincia de Cordoba	Argentina	X5016KEH
25	Insares	Mendoza	Provincia de Mendoza	Argentina	M5500CCG
26	Clinica del Torax	Rosario	Provincia de Santa Fe	Argentina	S2000DBS
27	Instituto Cardiovascular de Rosario	Rosario	Provincia de Santa Fe	Argentina	S2000DSR
28	Sanatorio Parque	Rosario	Provincia de Santa Fe	Argentina	S2000KZD
29	Investigaciones en Patologias Respiratorias	San Miguel de Tucumán	Provincia de Tucumán	Argentina	T4000IAR
30	Hospital Interzonal General de Agudos "Dr Jose Penna"	Bahia Bianca	Provinica de Buenos Aires	Argentina	B8001DDU
31	Corporacion medica de General San Martin	Mathew 4071	San Martin Provincia de Buenos Aires	Argentina	B1650CSQ
32	Atención Integral en Reumatología (AIR)	Buenos Aires		Argentina	CP1426
33	Centro Médico Dra. De Salvo	Ciudad Autonoma de Buenos Aires		Argentina	CP1426ABO
34	Woolcock Institute of Medical Research	Glebe	New South Wales	Australia	2037
35	St George Hospital	Kogarah	New South Wales	Australia	2217
36	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
37	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
38	Repatriation General Hospital	Daws Park	South Australia	Australia	5041
39	The Queen Elizabeth Hospital	Woodville	South Australia	Australia	5011
40	St Vincent's Hospital	Fitzroy	Victoria	Australia	3065
41	Western Hospital	Footscray	Victoria	Australia	3011
42	The Rooms of Dr C Steinfort	Geelong	Victoria	Australia	3220
43	Royal Melbourne Hospital	Melbourne	Victoria	Australia	3050
44	ULB Hopital Erasme - Department of Pneumology	Brussels		Belgium	B-1070
45	Cliniques Universitaires St. Luc (UCL) - Department of Pulmonology	Brussels		Belgium	B-1200
46	UZ Leuven (University Hospital Leuven) - Depatment of Pulmonary Medicine	Leuven		Belgium	B-3000
47	Pontificia Universidad Catolica de Chile	Santiago de Chile	Santiago	Chile
48	Universidad de Chile	Santiago de Chile	Santiago	Chile
49	Hospital Regional de Talca	Talca		Chile	1990
50	IKF Pneumologie GmbH and Co KG	Frankfurt	Hessen	Germany	60596
51	Medizinische Hochschule Hannover Klinik für Pneumologie	Hannover	Niedersachsen	Germany	30625
52	Lungen und Bronchialheikunde	Bonn	Nordrhein-Westfalen	Germany	53123
53	Pneumologisch Studienzentrum	Leipzig	Sachsen	Germany	4357
54	Medisch Centrum Alkmaar - Department of Pulmonary Medicine	Alkmaar	Alkmaar AM	Netherlands	1800
55	Medisch Centrum Leeuwarden (MCL) - Department of Pulmonology	Leeuwarden	Leeuwarden AD	Netherlands	8934
56	Atrium MC -Department of Pulmonary Diseases	Heerlen		Netherlands	6419
57	Green Lane Clinical Centre	Greenlane	Auckland	New Zealand	1051
58	Middlemore Hospital	Auckland		New Zealand	1640
59	Waikato Hospital	Hamilton		New Zealand	3240
60	West Wales General Hospital	Carmarthen	Carmarthenshire	United Kingdom	SA31 2AF
61	Royal Derby Hospital	Derby	Derbyshire	United Kingdom	DE22 3NE
62	Royal Devon and Exeter Hospital	Exeter	Devon	United Kingdom	EX2 5DW
63	Torbay Hospital	Torquay	Devon	United Kingdom	TQ2 7AA
64	Castle Hill Hospital	Cottingham	East Yorkshire	United Kingdom	HU16 5JQ
65	Glenfield Hospital	Leicester	Leicestershire	United Kingdom	LE3 9QP
66	Nottingham City Hospital	Nottingham	Nottinghamshire	United Kingdom	NG5 1PB
67	Churchill Hospital	Headington	Oxfordshire	United Kingdom	OX3 7LJ
68	Royal Shrewsbury Hospital	Shrewsbury	Shropshire	United Kingdom	SY3 8XQ
69	Sheffield Northern General Hospital	Sheffield	South Yorkshire	United Kingdom	S5 7AU
70	Stafford Hospital	Stafford	Staffordshire	United Kingdom	ST16 3SA
71	Ashford & St Peters Hospital	Chertsey	Surrey	United Kingdom	KT16 0PZ
72	University Hospital of North Tees	Stockton	Teeside	United Kingdom	TS19 8PE
73	Llandough Hospital	Cardiff	Vale of Glamorgan	United Kingdom	CF64 2XX
74	Birmingam Queen Elizabeth Hospital	Birmingham	West Midlands	United Kingdom	B15 2TH
75	Wolverhampton New Cross Hospital	Wolverhampton	West Midlands	United Kingdom	WV10 0QP
76	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 22N
77	Belfast City Hospital	Belfast		United Kingdom	BT9 7AB
78	University Hospital Aintree	Liverpool		United Kingdom	L9 7AL
79	Royal Brompton Hospital	London		United Kingdom	SW3 6NP
80	Freeman Hospital	Newcastle-upon-Tyne		United Kingdom	NE7 7DN
81	North Tyneside General Hospital	North Shields		United Kingdom	NE29 8NH
82	Southampton General Hospital	Southampton		United Kingdom	SO16 6YD
83	Wrexham Maelor Hospital	Wrexham		United Kingdom	LL13 7TD

Sponsors and Collaborators

• Pharmaxis

Investigators

• Principal Investigator: Diana Bilton, MD, Brompton Hospital London UK
• Principal Investigator: Greg Tino, MD, University of Pennsylvania Medical Centre, Philadelphia
• Principal Investigator: Alan Barker, MD, Oregon Health Sciences University, Portland Oregon

Study Documents (Full-Text)

None provided.

More Information

Publications

• Daviskas E, Anderson SD, Eberl S, Chan HK, Bautovich G. Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis. Am J Respir Crit Care Med. 1999 Jun;159(6):1843-8.
• Daviskas E, Anderson SD, Eberl S, Chan HK, Young IH. The 24-h effect of mannitol on the clearance of mucus in patients with bronchiectasis. Chest. 2001 Feb;119(2):414-21.
• Daviskas E, Anderson SD, Eberl S, Young IH. Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis. Eur Respir J. 2008 Apr;31(4):765-72. Epub 2007 Dec 5.
• Daviskas E, Anderson SD, Gomes K, Briffa P, Cochrane B, Chan HK, Young IH, Rubin BK. Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum. Respirology. 2005 Jan;10(1):46-56.
• Daviskas E, Anderson SD, Young IH. Inhaled mannitol changes the sputum properties in asthmatics with mucus hypersecretion. Respirology. 2007 Sep;12(5):683-91.
• Daviskas E, Anderson SD. Hyperosmolar agents and clearance of mucus in the diseased airway. J Aerosol Med. 2006 Spring;19(1):100-9. Review.
• Daviskas E, Robinson M, Anderson SD, Bye PT. Osmotic stimuli increase clearance of mucus in patients with mucociliary dysfunction. J Aerosol Med. 2002 Fall;15(3):331-41. Review.

• Responsible Party: Pharmaxis
• ClinicalTrials.gov Identifier: NCT00669331
• Other Study ID Numbers: DPM-B-305
• First Posted: Apr 30, 2008
• Last Update Posted: Apr 29, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Pharmaxis: randomized clinical trial; mannitol; mucoactive
• Additional relevant MeSH terms: Bronchiectasis; Mannitol

Study Results

Participant Flow

Pre-assignment Detail	Prior to randomisation, subjects underwent a Mannitol Tolerance Test (MTT) - only those who passed the MTT were eligible to be randomised. 581 patients in total underwent the MTT

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Period Title: Randomisation to First Dose
STARTED	244	241
COMPLETED	233	228
NOT COMPLETED	11	13
Period Title: Randomisation to First Dose
STARTED	233	228
COMPLETED	191	189
NOT COMPLETED	42	39

Baseline Characteristics

Arm/Group Title	Mannitol	Control	Total
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks	Total of all reporting groups
Overall Participants	233	228	461
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.30 (14.06)	60.26 (13.02)	59.77 (13.55)
Sex: Female, Male (Count of Participants)
Female	147 63.1%	142 62.3%	289 62.7%
Male	86 36.9%	86 37.7%	172 37.3%
Baseline Pulmonary Exacerbation rate (events/year) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [events/year]	3.20 (1.38)	3.25 (1.40)	3.22 (1.39)
Baseline % of Predicted FEV1 (participants) [Number]
<60%	101 43.3%	107 46.9%	208 45.1%
>=60%	132 56.7%	121 53.1%	253 54.9%
Extent of Bronchiectasis (participants) [Number]
Diffuse	133 57.1%	118 51.8%	251 54.4%
Focal	77 33%	73 32%	150 32.5%
Both (Diffuse and Focal)	23 9.9%	37 16.2%	60 13%

Outcome Measures

1. Primary Outcome

Title	Rate of Graded Pulmonary Exacerbations
Description	A graded pulmonary exacerbation was defined as a worsening in signs and symptoms requiring a change in treatment (Center for Drug Evaluation and Research (CDER), 2007). Grade I was required 3 main signs and symptoms, Grade II 2 main signs and symptoms and Grade III 1 main and one or more minor signs and symptoms. Main signs and symptoms were increased cough, sputum volume or sputum purulence. Minor were upper respiratory tract infection, fever, increased wheezing, increased dyspnea, increase in respiratory rate, increase in cardiac frequency of >20%, and increased malaise, fatigue or lethargy. Rate is defined as the number of all GPE events observed in one treatment year
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and Treated (referred to as the ITT population in this trial)

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Raw rate	1.95	2.10
Rate from negative binomial model	1.69	1.84

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3115
	Comments
	Method	Negative binomial regression model
	Comments	Negative binomial regression model with treatment, region and baseline PE rate as predictors and log of follow-up time as an offset variable
Method of Estimation	Estimation Parameter	Rate Ratio Mannitol:Control
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	For rate ratio, Mannitol rate is the numerator, Control rate is the denominator

2. Secondary Outcome

Title	Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score
Description	The SGRQ was collected at baseline, week 6, week 16, week 28, week 40 and week 52. Change in total score was calculated from baseline. Total scores are a weighted sum across all questions. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. Higher scores indicate lower quality of life. Outcome data table gives the raw mean total score at each visit.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and treated with one or more post-baseline SGRQ data available

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	228	219
Baseline	52.98 (14.64)	52.22 (14.71)
Week 6	44.09 (17.49)	44.55 (18.49)
Week 16	40.67 (19.07)	44.23 (19.89)
Week 28	41.45 (18.58)	43.46 (19.05)
Week 40	40.39 (18.86)	43.51 (19.96)
Week 52	41.43 (19.60)	42.25 (19.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0457
	Comments
	Method	Mixed model repeated measures analysis
	Comments	Model included treatment, visit, treatment*visit, region and baseline SGRQ Total score.
Method of Estimation	Estimation Parameter	LS mean difference across the 52 weeks
	Estimated Value	-2.40
	Confidence Interval	(2-Sided) 95%; -4.76 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	difference calculated Mannitol-control. Negative difference is in favour of mannitol since lower scores indicate improved quality of life.

3. Secondary Outcome

Title	Antibiotic Use Prescribed for Treated Pulmonary Exacerbations
Description	Rate of antibiotic treated graded pulmonary exacerbations, using the same definition of a graded pulmonary exacerbation as the primary endpoint. A graded pulmonary exacerbation was considered to be anti-biotic treated if use of oral, IV or inhaled antibiotic use was recorded related to the GPE event.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and treated (referred to as ITT)

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Number [events/year]	1.9	2.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2754
	Comments
	Method	Negative binomial regression model
	Comments	Negative binomial regression model with treatment, region and baseline pulmonary exacerbation rate as predictors, log follow-up as offset
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Rate ratio is for mannitol vs control.

4. Secondary Outcome

Title	Time to First Graded Exacerbation
Description	Time to first graded exacerbation is defined as the duration (in months) from the randomisation date to the start of the first reported graded PE during the on-treatment period. Patients without reported graded PE event will be censored at the last participation.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and treated

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Median (95% Confidence Interval) [months]	5.4	4.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0218
	Comments
	Method	Regression, Cox
	Comments	Cox regression model was stratified by region and baseline PE rate
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.63 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Duration of Graded Exacerbations
Description	Duration of graded exacerbations is defined as the number of days with graded PE within one treatment year. Mean days estimated via negative binomial model with treatment, region and baseline pulmonary exacerbation rate as predictors, with log of follow-up time as the offset variable
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and treated

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Mean (95% Confidence Interval) [Days with GPE]	31.49	35.74

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments	Analysed using a negative binomial model with treatment, region and baseline pulmonary exacerbation rate as predictors, and with log of follow-up time as the offset variable
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3602
	Comments
	Method	Negative binomial model
	Comments	treatment, region and baseline pulmonary exacerbation rate as predictors, and with log of follow-up time as the offset variable
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Sputum Volume
Description	24 hour sputum weight, measured at baseline, week 6, week 16, week 28, week 40, week 52
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Baseline	28.88 (18.71)	28.96 (19.92)
Week 6	24.97 (23.17)	22.82 (20.06)
Week 16	23.69 (22.09)	20.25 (16.99)
Week 28	22.92 (25.66)	18.88 (17.83)
Week 40	21.56 (21.58)	18.17 (16.67)
Week 52	20.54 (24.07)	18.33 (16.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0355
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes treatment, visit, treatment*visit, region and baseline sputum weight (g).
Method of Estimation	Estimation Parameter	ls mean difference across 52 weeks
	Estimated Value	2.76
	Confidence Interval	(2-Sided) 95%; 0.19 to 5.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference mannitol-control

7. Secondary Outcome

Title	Daytime Sleepiness Scores
Description	Epworth Sleepiness Scale (ESS) score was calculated as the sum of scores for each of eight individual questions, such that a total score of zero represents no daytime sleepiness, and a total score of 24 represents the maximum degree of daytime sleepiness. Measured at baseline, 6 weeks, 16 weeks, 28 weeks, 40 weeks, 52 weeks
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Baseline	7.23 (4.85)	6.89 (4.89)
Week 6	6.07 (4.78)	6.87 (4.74)
Week 16	6.21 (5.10)	6.50 (4.86)
Week 28	6.05 (4.73)	6.57 (4.82)
Week 40	6.32 (5.10)	6.33 (4.83)
Week 52	6.09 (4.98)	6.34 (5.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1159
	Comments
	Method	Mixed Models Analysis
	Comments	Model includes treatment, visit, treatment*visit, region and baseline ESS score
Method of Estimation	Estimation Parameter	LS mean diff across post-baseline visits
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.99 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Negative change indicates an improvement in ESS score. Difference calculated Mannitol - Control.

8. Secondary Outcome

Title	Lung Function - Change in FEV1 (Forced Expiratory Volume in One Second)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and treated with at least one post-baseline spirometry assessment

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	229	219
Least Squares Mean (95% Confidence Interval) [mL]	2.36	-5.20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6677
	Comments
	Method	Mixed Models Analysis
	Comments	Model of absolute change from baseline in FEV1. Model includes terms for treatment, visit, trt*visit, region and baseline value
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	7.56
	Confidence Interval	(2-Sided) 95%; -27.01 to 42.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	ls mean difference Mannitol-Control

9. Secondary Outcome

Title	Lung Function - Change in FVC (Forced Vital Capacity)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and treated with at least one post-baseline spirometry assessment

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	229	219
Least Squares Mean (95% Confidence Interval) [mL]	0.15	-15.70

10. Secondary Outcome

Title	Lung Function - Change in FEV1/FVC
Description	FEV1 expressed as a ratio of FVC. Endpoint is expressed as a percentage ie FEV1/FVC*100
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and treated with at least one post-baseline spirometry assessment

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	229	219
Least Squares Mean (95% Confidence Interval) [ratio (expressed as a %)]	-0.08	0.09

11. Secondary Outcome

Title	Lung Function - Change in FEF25-75 (Forced Expiratory Flow Rate Averaged Over 25th -75th Percentile of FVC)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Randomised and treated with at least one post-baseline spirometry assessment

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	229	219
Least Squares Mean (95% Confidence Interval) [mL/s]	-18.21	-3.40

12. Secondary Outcome

Title	Safety Profile - Sputum Microbiology
Description	sputum microbiology assessed as the presence of abnormal flora in sputum sample taken at any post baseline visit
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Number [participants]	81 34.8%	81 35.5%

13. Secondary Outcome

Title	Safety Profile - Clinical Chemistry
Description	Clinical chemistry was assessed as clinically significant abnormal liver function test and clinically significant abnormal urea/electrolyte test at any point post baseline.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	288
Subjects with Clin sig liver funtion tests at wk52	2 0.9%	0 0%
Subjects with clin sig urea/electrolyte test wk52	3 1.3%	0 0%

14. Secondary Outcome

Title	Safety Profile - Hematology
Description	hematology assessed as clinically significant abnormal FBC (Full Blood count) at any point post baseline.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Number [participants]	13 5.6%	5 2.2%

15. Secondary Outcome

Title	• (Exploratory) Number of Hospitalizations Due to Pulmonary Exacerbations
Description	Mean rate of hospitalisations (number/year) summarised and analysed to take account of differing follow-up times.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	233	228
Mean (95% Confidence Interval) [hospitalisations/year]	0.12	0.20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mannitol, Control
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0928
	Comments
	Method	Negative binomial regression
	Comments
Method of Estimation	Estimation Parameter	Rate ratio
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Other Pre-specified Outcome

Title	Health Related Costs of Treating Patients With Bronchiectasis
Description	In the presence of a significant primary endpoint, these data were intended to be derived using the trial data together with external information (Note as the primary objective of this study did not reach statistical significance, health related costs were not assessed)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

No data were collected. Since the primary objective was not significant in this study, further exploration of health economic endpoints was not done.

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol 400mg Inhaled mannitol: 400mg dose of Mannitol BD for 52 weeks	Matched control - inhaled mannitol 50mg Matched control: 50mg dose of Mannitol BD for 52 weeks
Measure Participants	0	0

17. Other Pre-specified Outcome

Title	Health Status and Utility Scores
Description	In the presence of a significant primary endpoint, these data were intended to be derived from the trial data and external information (Note as the primary objective of this study did not reach statistical significance, differences in health status and utility scores were not assessed)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

No data were collected. As the primary objective of this study did not reach statistical significance, health status and utility scores were not derived.

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	0	0

18. Other Pre-specified Outcome

Title	Health Related Quality of Life (HRQL) and Quality Adjusted Life Years (QALYs) by Treatment Group Using Utility Scores From the Health Utilities Index Questionnaire
Description	In the presence of a significant primary endpoint, these data were intended to be derived using the trial data and external information (Note as the primary objective of this study did not reach statistical significance, HRQL and QALYs were not collected).
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

No data were collected for this assessment. As the primary objective of this study did not reach statistical significance, HRQL and QALYs were not derived.

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	0	0

19. Other Pre-specified Outcome

Title	Cost Effectiveness of Treating Patients With Bronchiectasis With Inhaled Mannitol
Description	In the presence of a significant primary endpoint, these data were intended to be derived using the trial data and external information (Note as the primary objective of this study did not reach statistical significance, cost effectiveness was not collected).
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Not collected. As the primary objective of this study did not reach statistical significance, cost effectiveness data were not collected.

Arm/Group Title	Mannitol	Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks	Matched control: Inhaled mannitol 50mg BD for 52 weeks
Measure Participants	0	0

Adverse Events

Time Frame	52 weeks
Arm/Group Title	Mannitol		Control
Arm/Group Description	Inhaled mannitol Inhaled mannitol: 400mg BD for 52 weeks		Matched control: Inhaled mannitol 50mg BD for 52 weeks
All Cause Mortality
	Mannitol		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Mannitol		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/233 (18.5%)		51/228 (22.4%)
Blood and lymphatic system disorders
Anaemia	0/233 (0%)		1/228 (0.4%)
Cardiac disorders
Angina Pectoris	1/233 (0.4%)		0/228 (0%)
Cardiac Failure Congestive	1/233 (0.4%)		0/228 (0%)
Myocardial Infarction	0/233 (0%)		1/228 (0.4%)
Pericarditis	0/233 (0%)		1/228 (0.4%)
Gastrointestinal disorders
Abdominal Pain	0/233 (0%)		2/228 (0.9%)
Abdominal Pain Upper	1/233 (0.4%)		0/228 (0%)
Diverticulum	0/233 (0%)		1/228 (0.4%)
Inguinal hernia	1/233 (0.4%)		1/228 (0.4%)
General disorders
Catheter related complication	1/233 (0.4%)		0/228 (0%)
Chest pain	2/233 (0.9%)		0/228 (0%)
Condition Aggravated	21/233 (9%)		26/228 (11.4%)
Disease prodomal stage	1/233 (0.4%)		0/228 (0%)
Multi-organ failure	0/233 (0%)		1/228 (0.4%)
Hepatobiliary disorders
Cholecystisis	1/233 (0.4%)		0/228 (0%)
Infections and infestations
Appendicitis	0/233 (0%)		1/228 (0.4%)
Dacryocystisis	0/233 (0%)		1/228 (0.4%)
Diverticulitis	0/233 (0%)		1/228 (0.4%)
Gastroenteritis	0/233 (0%)		1/228 (0.4%)
Lobar pneumonia	1/233 (0.4%)		2/228 (0.9%)
Lower respiratory tract infection	0/233 (0%)		1/228 (0.4%)
Lung abscess	1/233 (0.4%)		0/228 (0%)
Lung infection pseudomonal	0/233 (0%)		1/228 (0.4%)
Pneumonia	7/233 (3%)		7/228 (3.1%)
Swine Influenza	1/233 (0.4%)		0/228 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/233 (0%)		1/228 (0.4%)
Fibula Fracture	1/233 (0.4%)		0/228 (0%)
Seroma	0/233 (0%)		1/228 (0.4%)
Skin lacreation	2/233 (0.9%)		0/228 (0%)
Tibia fracture	1/233 (0.4%)		0/228 (0%)
Metabolism and nutrition disorders
Gout	0/233 (0%)		1/228 (0.4%)
Hyponatraemia	1/233 (0.4%)		0/228 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/233 (0.4%)		0/228 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma	1/233 (0.4%)		0/228 (0%)
Non-small cell lung cancer metastatic	0/233 (0%)		1/228 (0.4%)
Oesophageal adenocarcinoma	1/233 (0.4%)		0/228 (0%)
Thyroid cancer	0/233 (0%)		1/228 (0.4%)
Nervous system disorders
Loss of consciousness	0/233 (0%)		1/228 (0.4%)
Syncope	1/233 (0.4%)		0/228 (0%)
Transient global amnesia	0/233 (0%)		1/228 (0.4%)
Reproductive system and breast disorders
Ovarian cyst ruptured	1/233 (0.4%)		0/228 (0%)
Varicocele	0/233 (0%)		1/228 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/233 (0.4%)		0/228 (0%)
Epistaxis	1/233 (0.4%)		0/228 (0%)
Haemoptysis	1/233 (0.4%)		1/228 (0.4%)
Pharyngeal pouch	0/233 (0%)		1/228 (0.4%)
Pneumothorax	0/233 (0%)		1/228 (0.4%)
Surgical and medical procedures
Bladder repair	0/233 (0%)		1/228 (0.4%)
Vascular disorders
Deep vein thrombosis	0/233 (0%)		1/228 (0.4%)
Other (Not Including Serious) Adverse Events
	Mannitol		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	215/233 (92.3%)		214/228 (93.9%)
Gastrointestinal disorders
Diarrhoea	15/233 (6.4%)		21/228 (9.2%)
Nausea	14/233 (6%)		18/228 (7.9%)
General disorders
Condition aggravated	149/233 (63.9%)		159/228 (69.7%)
Infections and infestations
Lower respiratory tract infection	16/233 (6.9%)		21/228 (9.2%)
Lower respiratory tract infection bacterial	12/233 (5.2%)		9/228 (3.9%)
Nasopharyngitis	36/233 (15.5%)		30/228 (13.2%)
Sinusitis	17/233 (7.3%)		14/228 (6.1%)
Investigations
Bacteia sputum identified	30/233 (12.9%)		30/228 (13.2%)
Musculoskeletal and connective tissue disorders
Back pain	19/233 (8.2%)		13/228 (5.7%)
Nervous system disorders
Headache	27/233 (11.6%)		32/228 (14%)
Respiratory, thoracic and mediastinal disorders
Cough	30/233 (12.9%)		22/228 (9.6%)
Dsypnoea	20/233 (8.6%)		16/228 (7%)
Haemoptysis	24/233 (10.3%)		23/228 (10.1%)
Oropharyngeal pain	10/233 (4.3%)		18/228 (7.9%)

Limitations/Caveats

Relatively few studies in this area -ideal choice of endpoints not well-defined. No widely accepted exacerbation definition. Relies on patients' accurate & timely symptom reporting.Unclear event end-dates may impact on counting of subsequent events.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.