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Trial registered on ANZCTR


Registration number
ACTRN12615000052538
Ethics application status
Approved
Date submitted
18/12/2014
Date registered
22/01/2015
Date last updated
14/10/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
A double-blind, randomised, placebo-controlled study of roxithromycin and doxycycline combination, roxithromycin alone, or matching placebo for 12 weeks in adults with frequent exacerbations of chronic obstructive pulmonary disease
Scientific title
In adults with frequent exacerbations of chronic obstructive pulmonary disease, does roxithromycin alone or in combination with doxycycline for 12 weeks, compared with matching placebo, reduce rate of exacerbations?
Secondary ID [1] 285873 0
nil
Universal Trial Number (UTN)
U1111-1165-3296
Trial acronym
INSPIRE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic obstructive pulmonary disease 293790 0
Exacerbations of chronic obstructive pulmonary disease 293791 0
Condition category
Condition code
Respiratory 294093 294093 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: oral tablet roxithromycin 300mg once daily and oral tablet doxycycline 100mg placebo once daily for 12 weeks.
Arm 2: oral tablet roxithromycin 300mg once daily and oral tablet doxycycline 100mg once daily for 12 weeks.
Arm 3: oral tablet roxithromycin 300mg placebo once daily and oral tablet doxycycline 100mg placebo once daily for 12 weeks.

Mode and type of administration = oral tablets.

Compliance was assessed by tablet counts. Subjects were instructed to bring their study medication bottles to visits 3 (2 weeks), 4 (6 weeks) and 5 (12 weeks).
Intervention code [1] 290854 0
Treatment: Drugs
Comparator / control treatment
matching placebos i.e. microcellulose tablets of identical appearance as the active drugs (roxithromycin and doxycycline)
Control group
Placebo

Outcomes
Primary outcome [1] 293879 0
Frequency of moderate and severe exacerbations of COPD. This is a composite primary outcome of the number of moderate and severe exacerbations of COPD. An acute exacerbation was defined by either at least 2 out of 3 of the following, on 3 consecutive days or more, change in sputum production; change in sputum purulence; and change in breathlessness; or diagnosed and treated by the investigator based on clinical symptoms. Exacerbation severity was defined as ‘mild’ if it was self-managed by the patient at home (e.g. increase in bronchodilator and/or non-prescription medication use); ‘moderate’ if it required treatment with antibiotic and/or an increase in dose of, or initiation of corticosteroids by a medical practitioner; or ‘severe’ if it resulted in hospitalisation or death due to an exacerbation of COPD. The number of exacerbations will be determined from the daily diary card provided to the subjects and from the investigator assessment during any study visits.
Timepoint [1] 293879 0
48-week post treatment period
Secondary outcome [1] 312072 0
Frequency of exacerbations of COPD. This is a composite secondary outcome of the number of mild, moderate and severe exacerbations of COPD. An acute exacerbation was defined by either at least 2 out of 3 of the following, on 3 consecutive days or more, change in sputum production; change in sputum purulence; and change in breathlessness; or diagnosed and treated by the investigator based on clinical symptoms. Exacerbation severity was defined as ‘mild’ if it was self-managed by the patient at home (e.g. increase in bronchodilator and/or non-prescription medication use); ‘moderate’ if it required treatment with antibiotic and/or an increase in dose of, or initiation of corticosteroids by a medical practitioner; or ‘severe’ if it resulted in hospitalisation or death due to an exacerbation of COPD. The number of exacerbations will be determined from the daily diary card provided to the subjects and from the investigator assessment during any study visits.
Timepoint [1] 312072 0
12 week active treatment period
Secondary outcome [2] 312073 0
Frequency of exacerbations of COPD. This is a composite secondary outcome of the number of mild, moderate and severe exacerbations of COPD. An acute exacerbation was defined by either at least 2 out of 3 of the following, on 3 consecutive days or more, change in sputum production; change in sputum purulence; and change in breathlessness; or diagnosed and treated by the investigator based on clinical symptoms. Exacerbation severity was defined as ‘mild’ if it was self-managed by the patient at home (e.g. increase in bronchodilator and/or non-prescription medication use); ‘moderate’ if it required treatment with antibiotic and/or an increase in dose of, or initiation of corticosteroids by a medical practitioner; or ‘severe’ if it resulted in hospitalisation or death due to an exacerbation of COPD. The number of exacerbations will be determined from the daily diary card provided to the subjects and from the investigator assessment during any study visits.
Timepoint [2] 312073 0
First 24-week post-treatment period
Secondary outcome [3] 312074 0
Frequency of exacerbations of COPD. This is a composite secondary outcome of the number of mild, moderate and severe exacerbations of COPD. An acute exacerbation was defined by either at least 2 out of 3 of the following, on 3 consecutive days or more, change in sputum production; change in sputum purulence; and change in breathlessness; or diagnosed and treated by the investigator based on clinical symptoms. Exacerbation severity was defined as ‘mild’ if it was self-managed by the patient at home (e.g. increase in bronchodilator and/or non-prescription medication use); ‘moderate’ if it required treatment with antibiotic and/or an increase in dose of, or initiation of corticosteroids by a medical practitioner; or ‘severe’ if it resulted in hospitalisation or death due to an exacerbation of COPD. The number of exacerbations will be determined from the daily diary card provided to the subjects and from the investigator assessment during any study visits.
Timepoint [3] 312074 0
Last 24-week post-treatment period
Secondary outcome [4] 312075 0
Spirometric volume changes (FEV1 and FVC)
Timepoint [4] 312075 0
Baseline, 12 weeks, 36 weeks and 60 weeks
Secondary outcome [5] 312076 0
Chronic Respiratory Disease Questionnaire (CRQ) scores
Timepoint [5] 312076 0
Baseline, 12 weeks, 36 weeks and 60 weeks
Secondary outcome [6] 312077 0
Adverse events covers any sign, symptom, syndrome or illness that appears or worsens in a subject during the period of observation in the clinical study and that may impair the well being of the subject. The term also covers laboratory findings or results of other diagnostic procedures that are considered to be clinically relevant (e.g. that require unscheduled diagnostic procedures or treatment measures, or result in withdrawal from the study). The adverse event may be: a new illness, worsening of a sign or symptom of the condition under treatment or of a concomitant illness, an effect of the study medication, an effect of a comparator drug, unrelated to participation in the clinical study, a combination of one or more of these factors. Thus no causal relationship with the study medication is implied by the use of the term "adverse event". Adverse events observed by the investigator or reported by the subject will be documented (these include from medical history, physical examination, 12 lead electrocardiogram during visit studies, laboratory data).
Timepoint [6] 312077 0
60 week period (visit 1 (week -4 to -2), visit 2 (week 0), visit 3 (week 2), telephone call (week 4), visit 4 (week 6), telephone call (week 9), visit 5 (week 12), telephone call (week 16), telephone call (week 20), visit 6 (week 24), telephone call (week 28), telephone call (week 32), visit 7 (week 36), telephone call (week 40), telephone call (week 44), visit 8 (week 48), telephone call (week 52), telephone call (week 56) and visit 9 (week 60)).

Eligibility
Key inclusion criteria
Subjects aged 45 years or older;
Meeting spirometric criteria for COPD (FEV1 less than or equal to 70% of predicted, ratio of FEV1 over FVC (FEV1/FVC) greater than or equal to 60%, reversibility of less than or equal to10% of predicted FEV1 or less than or equal to 200ml if predicted FEV1 less than or equal to 2L);
Smoking history greater than or equal to 20 pack years;
At least three confirmed moderate or severe COPD exacerbations in the past two years (i.e. requiring treatment with antibiotics and/or oral corticosteroids and/or hospitalisation);
Positive serology for C. pneumoniae (IgG antibody titre greater than or equal to 1:64).
Minimum age
45 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Pulmonary disease other than COPD;
Treatment with antibiotics, exacerbation or an investigational drug in the four weeks before randomisation;
Pregnancy (serum pregnancy test) or breast feeding;
History of hypersensitivity to macrolides, tetracyclines, beta-lactams or sulfamethoxazole:trimethoprim;
Serious cardiovascular, hepatic, renal or other systemic diseases;
Known long QT syndrome or corrected QT interval (QTc) greater than 450ms, sick sinus syndrome, bradycardia (less than 50 beats per minute) or severe hypokalaemia;
Epilepsy;
Treatment with medicine known to have important interaction with macrolides or tetracyclines;
Impaired hepatic function (aspartate aminotransferase or alanine aminotransferase greater than or equal to 2 times of the upper limit of normal (ULN), alkaline phosphatase greater than or equal to 1.25 times the ULN, bilirubin greater than 2 times the ULN and albumin less than 30g/L);
Or unlikely to comply.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Visit 1 (Week -(2-4)): Screening visit - subject was asked to withhold inhaled beta-agonists (4 hours short-acting, 12 hours for long acting and 24 hours for salmeterol), and inhaled ipratropium bromide for 6 hours prior to the study visit (and subsequent visits when spirometry is to be conducted). Signed informed consent. Reviewed eligibility criteria. Demographics. Medical history. Spirometry. Pregnancy test. Screening blood tests. Collection of sputum. Provide daily diary card.
Visit 2 (Week 0): Randomisation - recheck eligibility criteria. CRQ. Physical examination. 12-lead ECG. Chest x-ray. Spirometry if not done at visit 1. Adverse events and concomitant medication. Diary card. Patient ID card. Allocation of randomisation number, in sequence, with corresponding medication labelled box (Bottle 1, A+B). The subject were issued with 2 week supply of study medicine.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Hoechst Marion Roussel in Australia provided subject sequential numbers by computerised sequence generation (simple randomisation using a randomisation table created by computer software) for randomisation of subjects into one of the three arms with 1:1:1 ratio.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Comparison of baseline characteristics was done using the chi-squared test, student’s t-test or Wilcoxon rank-sum test. Comparison of event rates (number of events/exposure patient days) among the three treatment arms was done using a Poisson model. Analysis of variance models were used to test for differences in numbers of exacerbations among the three treatment groups. Statistical analyses for all secondary outcome variables were performed at the end of the 60-week study period in comparison with baseline values. Analysis of time to first moderate or severe exacerbations was performed using log-logistic distribution model. CRQ scores were analysed using autoregressive models and likelihood-ratio tests. All randomised patients were included in the intention-to-treat analyses. Data were entered and managed in a Clintrial database. The SAS statistical package was used for all analyses.
The mean number of moderate and severe exacerbations per year was estimated to be 2.5 (SD 1) in each group. An analysis of variance-based F-test would require 83 subjects in each treatment group to have 90% power to detect a difference in the exacerbation rate of 0.5 per year at the 5% significance level. Thus a total of 249 subjects would be required. If dropout rate was approximately 20%, 312 subjects would be required.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 3276 0
Western Hospital - Footscray
Recruitment hospital [2] 3277 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 3278 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [4] 3279 0
The Prince Charles Hospital - Chermside
Recruitment hospital [5] 3280 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 3281 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [7] 3282 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [8] 3283 0
Fremantle Hospital and Health Service - Fremantle
Recruitment hospital [9] 3284 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [10] 3285 0
Concord Repatriation Hospital - Concord
Recruitment hospital [11] 3286 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [12] 3287 0
Liverpool Hospital - Liverpool
Recruitment hospital [13] 3288 0
Royal Hobart Hospital - Hobart
Recruitment outside Australia
Country [1] 6556 0
New Zealand
State/province [1] 6556 0
Waikato
Country [2] 6557 0
New Zealand
State/province [2] 6557 0
Auckland

Funding & Sponsors
Funding source category [1] 290455 0
Commercial sector/Industry
Name [1] 290455 0
Hoechst Marion Roussel Pty Ltd
Address [1] 290455 0
27 Sirius Road
Lane Cove NSW 2066
Country [1] 290455 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Hoechst Marion Roussel Pty Ltd (Sanofi-Aventis Australia Pty Ltd)
Address
27 Sirius Road
Lane Cove NSW 2066
Country
Australia
Secondary sponsor category [1] 289157 0
None
Name [1] 289157 0
nil
Address [1] 289157 0
nil
Country [1] 289157 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292126 0
Auckland Ethics Committee
Ethics committee address [1] 292126 0
Ethics committee country [1] 292126 0
New Zealand
Date submitted for ethics approval [1] 292126 0
Approval date [1] 292126 0
17/11/1999
Ethics approval number [1] 292126 0
98/11/212
Ethics committee name [2] 292127 0
Waikato Ethics Committee
Ethics committee address [2] 292127 0
Ethics committee country [2] 292127 0
New Zealand
Date submitted for ethics approval [2] 292127 0
Approval date [2] 292127 0
19/11/1999
Ethics approval number [2] 292127 0
63/98/563

Summary
Brief summary
The aim of this study was to determine whether prophylactic antibiotic therapy reduced the number and seriousness of respiratory illnesses of these patients suffer due to their chronic obstructive pulmonary disease.
Trial website
Trial related presentations / publications
Shafuddin, E., Mills, G., Holmes, M., Poole, P., Mullins, P. and Black, P. (2015). A double-blind, randomised, placebo-controlled study of roxithromycin and doxycycline combination, roxithromycin alone, or matching placebo for 12 weeks in adults with frequent exacerbations of chronic obstructive pulmonary disease. Journal of Negative Results in BioMedicine, 14(1).
Public notes

Contacts
Principal investigator
Name 53110 0
Dr Peter Black
Address 53110 0
Department of Medicine
Auckland Hospital
2 Park Road
Grafton, Auckland 1142
Country 53110 0
New Zealand
Phone 53110 0
+64 09 3797440
Fax 53110 0
Email 53110 0
pn.black@auckland.ac.nz
Contact person for public queries
Name 53111 0
Dr Graham Mills
Address 53111 0
Waikato District Health Board
Pembroke Street
Private Bag 3200
Hamilton 3240
NEW ZEALAND

Country 53111 0
New Zealand
Phone 53111 0
+6478398899
Fax 53111 0
Email 53111 0
graham.mills@waikatodhb.health.nz
Contact person for scientific queries
Name 53112 0
Dr Graham Mills
Address 53112 0
Waikato District Health Board
Pembroke Street
Private Bag 3200
Hamilton 3240
NEW ZEALAND

Country 53112 0
New Zealand
Phone 53112 0
+6478398899
Fax 53112 0
Email 53112 0
graham.mills@waikatodhb.health.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary