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Trial registered on ANZCTR


Registration number
ACTRN12613001251718
Ethics application status
Approved
Date submitted
28/10/2013
Date registered
14/11/2013
Date last updated
14/11/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
The Indacaterol in Lymphangioleiomymotosis (LAM) Trial
Scientific title
A double blind, randomised placebo controlled within patient cross-over study to assess the efficacy and safety of indacaterol (150 micrograms once daily) in the symptomatic treatment of pulmonary lymphangioleiomyomatosis (LAM)
Secondary ID [1] 283470 0
Nil
Universal Trial Number (UTN)
Trial acronym
TILT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lymphangioleiomyomatosis 290384 0
Condition category
Condition code
Respiratory 290776 290776 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Double blind placebo controlled cross-over trial, studying efficacy and safety of inhaled indacaterol 150 micrograms daily in women with lymphangioleiomyomatosis. Treatment duration 2 weeks for active drug and placebo; washout period 2-6 weeks according to patient convenience. Inhaled medication will be returned at end of treatment periods to monitor adherence.
Intervention code [1] 288179 0
Treatment: Drugs
Comparator / control treatment
Identical placebo (glucose)
Control group
Placebo

Outcomes
Primary outcome [1] 290774 0
1. To evaluate the efficacy of indacaterol in terms of change in trough forced expiratory volume in 1 second (FEV1) versus baseline in women with lymphangioleiomyomatosis (LAM).
Timepoint [1] 290774 0
2 week treatment period for both active drug and placebo; assessments at baseline and end of treatment periods in each case. Symptom score monitoring during treatment periods.
Secondary outcome [1] 305261 0
Secondary
1. To examine the effect of indacaterol on quality of life measurements (QoL as measured by SF-36 and other measures) in women with LAM.
Timepoint [1] 305261 0
2 week treatment with drug and placebo; QoL and lung function measured at baseline and after treatment periods.
Secondary outcome [2] 305472 0
2. To examine the effect of indacaterol on airway inflammation in LAM using non-invasive exhaled breath monitoring (fractional exhaled nitric oxide assessment, electronic nose analysis (ENA)) and some blood based biomarkers including VEGF-D, HGF, ACE, MMP 2 and 9.
Timepoint [2] 305472 0
Measurements: FeNO, ENA, blood based biomarkers at baseline and after treatment periods.

Eligibility
Key inclusion criteria
Women:

1. Age: 18-80 inclusive.
1.2. Diagnosed with LAM and classified into possible, probable and definite according to ERS criteria (1).
1.3. Willingness and ability to participate in the study after fully informed consent.
1.4. Both sporadic LAM (sLAM) and TSC-LAM (tuberous sclerosis-related LAM) to be included.
1.5. Women with all severity categories of LAM are eligible to participate in the study but those on continuous home oxygen will be excluded, as well as those not sufficiently well to participate in the requisite tests.
Minimum age
18 Years
Maximum age
80 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1. Known sensitivity to indacaterol or the class of long acting beta agonists
2. Patients with severe medical condition(s) which in the view of the investigator prohibit participation in the study (e.g. uncontrolled diabetes, uncontrolled heart failure, severe renal or liver disease, high blood pressure, coronary artery disease, cardiac arrhythmias, thyroid disorders, or lactose intolerance).
3. Use of any other investigational agent within the last 30 days
4. Current smoking or smoking within 6 months of study start.
5. Concurrent respiratory disease including a diagnosis of asthma (provided LAM has not been misdiagnosed as asthma prior to the diagnosis of LAM). Pleural pathology from previous pleurodeses and disease related to LAM are not included in this category.
6. Respiratory tract infection of exacerbation within the previous 4 weeks. Patients can be re-entered into the trial after a 4 week recovery period, provided baseline FEV1 is within 10% of first study period.
7. Treatment with oral glucocorticosteroids within the previous 4 weeks.
8. Women of childbearing potential not using adequate contraceptive method(s) including the oral contraceptive pill, barrier contraception, IUD, as well as women who are breastfeeding.
9. Patients on continuous oxygen therapy.

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)
Randomization will be performed by the investigator according to a randomization study code. An unblinded pharmacist will dispense the study drug to ensure double blinding. The randomization code may be broken by the investigator only in a medical emergency. The reasons for this must be documented carefully.”
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Random computerised sequence generation - small number of subjects only
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Crossover
Other design features
Washout period of 2-6 weeks according to patient convenience.

Pre-study power calculation yields a sample size of 13 patients, to have 90% power (at alpha equals 0.05, two sided test) to detect a 10% difference, assuming a minimum difference of 100 mls between treatment groups. To be conservative, 15 patients will be included. FEV1 and FVC are highly reproducible in most patients, with differences between highest and lowest values of less than 6%, and these data are applicable to LAM patients. The advantage of a double blind crossover design is that variation is minimized. When considering the degree of change in FEV1 that is considered clinically meaningful by the regulators, a change of 5–10% from baseline values is usually considered to be clinically important, or an increase of FEV1 of greater than 12% or 200 mls. However, in this trial we are selecting for subjects who do not have bronchodilator reversibility so only a small lung function change is anticipated. In LAM, both FEV1 and DLCO have been reported as predictors of progression but a change in DLCO is not expected to change in this short-term trial, so this measurement is a secondary rather than a primary outcome variable).
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analyses will be performed according to the intention-to-treat principle. The primary outcome, the FEV1 response measured in milliliters per week over the course of 2 weeks (the FEV1 change), will be analyzed as the difference in the FEV1 slope between the placebo group and the indacterol group. Differences in FEV1 will be analysed by a student’s matched pair t-test.
For categorical outcomes, the data will be compared using Fisher's exact test or the chi-square test, as appropriate. For continuous variables, the medians will be compared with the use of the Wilcoxon rank-sum test. p values of less than 0.05 will be considered to indicate statistical significance. All reported p values will be two-sided, and unadjusted for multiple testing. All analyses will be performed with the use of SPSS software, version 4.0. .Data will be presented for the complete intent-to-treat population (all patients having taken at least one dose of study medication) as well as the per-protocol population (all patients who completed the study without major protocol deviations).

FeNO values will be log transformed and analysed using paired t-tests. ENA analysis will take place using appropriate statistics. Smellprints using the Cyranose 320 will be analysed using on-board learning software. Savitzky–Golay filtering (which performs a local polynomial regression (of degree k) on a series of values) will be utilised to process the sensor response data and baseline corrections will be applied to improve signal-to-noise ratio. To reduce the data from 32 individual sensors to a set of principal components, principal component analysis (PCA) will be used. This determines factors that capture the largest variance in the data. PCA factors will be then used to perform a linear canonical discrimination analysis for the construction of a pattern recognition algorithm. This will be achieved by enhancing the ratio of pooled within-class scatter to between-group distance. A cross validation value (CVV%) will be calculated, to give an estimate of error, or in other words, the accuracy in distinction between the smellprints from different subject groups. The Mahalanobis distance (M-distance) between group means, in units of standard deviation, will be calculated. This will be used to quantify the discrimination between sample groups, providing a measure of dissimilarity between two samples. Thus, M-distance and the ability to discriminate are directly related, so that values greater than 3 will be indicative of a high probability of discrimination (p less than 0.01).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
20/11/2013
Actual
Date of last participant enrolment
Anticipated
14/12/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 1620 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 7502 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 288177 0
Commercial sector/Industry
Name [1] 288177 0
Novartis
(Investigator initiated study)
Country [1] 288177 0
Australia
Primary sponsor type
Individual
Name
Deborah H Yates
Address
Dept Thoracic Medicine
St Vincent's Hospital
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 286900 0
Other
Name [1] 286900 0
Holdsworth House Medical Practice (HHMP),
Address [1] 286900 0
32A Oxford St
Darlinghurst
NSW 2010
Country [1] 286900 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290090 0
University of New South Wales HREC
Ethics committee address [1] 290090 0
High St, Kensington NSW 2052
Ethics committee country [1] 290090 0
Australia
Date submitted for ethics approval [1] 290090 0
Approval date [1] 290090 0
31/07/2013
Ethics approval number [1] 290090 0
HREC Ref: # HC13202

Summary
Brief summary
Lymphangioleiomyomatosis (LAM) is a rare lung disease restricted to adult women. This may occur either sporadically (s-LAM) or in association with tuberous sclerosis (TSC-LAM). The lungs of patients with LAM are infiltrated by smooth muscle cells (LAM cells).There is a very limited evidence base for treatment of LAM and it is only recently that the first randomised trials have been initiated. The LAM clinic at St Vincent’s follows the largest number of women with LAM in Australia, currently approximately 40 patients. The first ever trial into the efficacy of doxycycline in LAM was completed at St Vincent’s LAM clinic, and this new study aims to assist the breathlessness associated with this disease and evaluate the mechanisms underlying this.
Indacaterol is a novel, inhaled, once-daily, ultra-long-acting beta 2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). Bronchodilator agents are frequently prescribed in LAM but have never been the subject of a clinical trial. Long acting beta2-agonists have been described as having anti-proliferative effects on smooth muscle in vitro as well as in vitro, but these agents have not yet been investigated in LAM. It is theoretically possible that women with LAM will respond clinically, and it is also possible that indacaterol might have a beneficial effect within the airway. This trial will evaluate indacaterol in LAM using a classical study design ie. a double blind placebo controlled trial, in 15 women with LAM.
Trial website
www.holdsworthhouse.com.au
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 43906 0
A/Prof Deborah Yates
Address 43906 0
Dept Thoracic Medicine, St Vincent's Hospital, Victoria St, Darlinghurst, NSW 2010
Country 43906 0
Australia
Phone 43906 0
61-2-8382-2330
Fax 43906 0
61-2-83822359
Email 43906 0
[email protected]
Contact person for public queries
Name 43907 0
Trina Vincent
Address 43907 0
Holdsworth House Medical Practice
Suite 1, Level 2, 32A Oxford St, Darlinghurst NSW 2010
Country 43907 0
Australia
Phone 43907 0
61-2- 8032- 1044
Fax 43907 0
61-2- 9331-5705
Email 43907 0
[email protected]
Contact person for scientific queries
Name 43908 0
Deborah H Yates
Address 43908 0
Dept Thoracic Medicine, St Vincent's Hospital, Victoria St, Darlinghurst, NSw 2010
Country 43908 0
Australia
Phone 43908 0
61-2-8382-2330
Fax 43908 0
61-2-8382-2359
Email 43908 0
[email protected]

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