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Trial registered on ANZCTR


Registration number
ACTRN12612001300864
Ethics application status
Approved
Date submitted
30/11/2012
Date registered
17/12/2012
Date last updated
17/12/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
Development of an Effective Treatment for Cheyne-Stokes Respiration
Scientific title
The effect of inspired carbon dioxide on Cheyne Stokes Respiration in Heart Failure Patients
Secondary ID [1] 280856 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cheyne-Stokes Respiration 286922 0
Condition category
Condition code
Respiratory 287253 287253 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each patient will be randomised on the first night of study to receive treatment with either 1-3% carbon dioxide or air. At the start of the night, the starting condition is that the patient will breathe from a circuit delivering air via a Douglas bag. The circuit will contain a 4-way Hans-Rudolph valve so that the patient can be switched rapidly to the test gas as desired. Once the first apnea is evident from the patient's ventilatory airflow signal, and from mask pressure and abdominal and chest respibands, the valve will be switched to a circuit delivering the test gas via another Douglas bag. The test gas will be continued for 10 minutes before the valve will be used to switch the patient back to the air supply. On the appearance of another apnea the valve will be used to switch the patient to the test gas for a further 10 minutes. This process will be repeated for the entire study night.
One week or more following the first arm of the study, the patient will enter the second arm in which the alternate test gas will be applied for 10 minutes once an apnea is observed. Patients will be studied as soon as practicable following the on e week washout period with a maximum of four weeks between studies.
Intervention code [1] 285283 0
Treatment: Other
Comparator / control treatment
The patient will breathe air as the standard inspired gas throughout the study, but will switch to the intervention ( 1-3% carbon dioxide or air) whenever an apnoea is observed. The intervention will then continue for periods of 10 minutes, followed by a return to air until the next apnea is observed when once again the intervention gas will be switched on. The exposure to the intervention will depend upon the frequency of apnea during the night.
Control group
Placebo

Outcomes
Primary outcome [1] 287533 0
Cessation of Cheyne-Stokes Respiration as measured by reduction in central apnoea index and central apnoea-hypopnoea index during the study period.
Timepoint [1] 287533 0
Measured at time of intervention
Primary outcome [2] 287534 0
Change in apnoea index and apnoea-hypopnea index (as defined by American Academy of Sleep Medicine(AASM)).
Timepoint [2] 287534 0
Measured across total sleep time of study
Primary outcome [3] 287535 0
Improvement in sleep architecture as measured by total sleep, percentage slow wave sleep and percentage rapid eye movement sleep as measured during the sleep study using AASM criteria.
Timepoint [3] 287535 0
Measured across total sleep time of study
Secondary outcome [1] 298346 0
pro-brain natriuretic peptide in blood
Timepoint [1] 298346 0
measured at start of night of study and in the morning
Secondary outcome [2] 298347 0
markers of inflammation including Urine analysis for Catecholamines (Epinephrine, Norepinephrine and Dopamine), Creatinine and renal electrolytes - Na, K, Cl, BUN, uric acid. Serum or Plasma analysis for NTpro-BNP, Troponin I and C-Reactive Protein, ST2, IL-6, cystatin C, hs-CRP, galectin-3, copeptin, sIL-6R, IL-18, and TNFalpha.
Timepoint [2] 298347 0
measured at start of night of study and in the morning
Secondary outcome [3] 298650 0
work of breathing as calculated conventionally using the Campbell diagram
Timepoint [3] 298650 0
Measured across total sleep time in the study

Eligibility
Key inclusion criteria
Heart failure as measured by an ejection fraction <45%
able to provide informed consent
Minimum age
35 Years
Maximum age
100 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded unless their lung function is >70% predicted. Patients will be stable, with no hospitalisation over the preceding 4 weeks. Exclusion criteria will include significant renal, neurologic or respiratory disease.
The patients are required to be in a stable health condition with no changes in treatment between the study nights.

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)
Patients referred by their doctors for routine polysomnography will be made aware of the study on their first contact, either by phone or in person, with the sleep physician. On the day of their diagnostic sleep study, patients have a lung function assessment made during the afternoon. At that time, they will have the study explained to them, they will be provided with a Patient Information and Consent Form to read, and they will be invited to participate. Any questions they have about the study will be answered.

Allocation will be concealed from the patient and those analysing the data. It will not be concealed from those performing the randomisation who will also implement the selected intervention on the night of the studies. Administration of air versus carbon dioxide will be performed from an adjoining room with the patient unaware of the provided gas.

People assessing and analysing data will not be told of the intervention provided during each individual study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Order of treatment (sham or carbon dioxide) is randomised for each patient with the toss of a coin.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
None
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/01/2013
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
45
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 308 0
The Alfred - Prahran
Recruitment hospital [2] 309 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 5545 0
3004
Recruitment postcode(s) [2] 5546 0
3168

Funding & Sponsors
Funding source category [1] 285640 0
Government body
Name [1] 285640 0
National Health and Medical Research Council
Country [1] 285640 0
Australia
Primary sponsor type
Individual
Name
Dr Philip Berger
Address
Ritchie Centre
Level 5, Block B
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country
Australia
Secondary sponsor category [1] 284475 0
Individual
Name [1] 284475 0
Professor Matthew Naughton
Address [1] 284475 0
Department of Allergy, Immunology and Respiratory Medicine
The Alfred
Commercial Road
Melbourne
Victoria 3004
Country [1] 284475 0
Australia
Other collaborator category [1] 276940 0
Individual
Name [1] 276940 0
Dr Garrun Hamilton
Address [1] 276940 0
Department Respiratory and Sleep Medicine
Level 2, Block B
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country [1] 276940 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287640 0
Southern Health Human research and Ethics Committee
Ethics committee address [1] 287640 0
Level 4
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Ethics committee country [1] 287640 0
Australia
Date submitted for ethics approval [1] 287640 0
11/02/2012
Approval date [1] 287640 0
11/04/2012
Ethics approval number [1] 287640 0
12031B
Ethics committee name [2] 287641 0
The Alfred Hospital human Research and Ethics Committee
Ethics committee address [2] 287641 0
Alfred Health
55 Commercial Road
Melbourne
Victoria 3004
Ethics committee country [2] 287641 0
Australia
Date submitted for ethics approval [2] 287641 0
Approval date [2] 287641 0
11/04/2012
Ethics approval number [2] 287641 0
44/12

Summary
Brief summary
As many as half of all patients with heart failure exhibit Cheyne-Stokes respiration (CSR), a form of disordered breathing in which short periods (approx 30 sec) of regular breathing alternate with periods during which breathing stops (apnea). Patients with heart failure and CSR have a markedly poorer outcome compared to heart failure patients whose breathing is normal during sleep. While the reasons for the differential outcome are not fully known, it is likely that the direct consequences of CSR, which include increased sympathetic activity and frequent declines in blood oxygen level, contribute to impairment of cardiac function. When effective treatment causes CSR to revert to a continuous breathing pattern, the available evidence shows that patient condition and survival improve. However, the current front-line therapy, continuous positive airway pressure (CPAP) ameliorates CSR in only 50% of heart failure patients. We plan to use a novel loop gain theory developed in our laboratory that enables us to calculate a precise level of inspired CO2 for each patient that will convert CSR into a continuous pattern.

The work planned in this program will employ a manual method to deliver an optimised CO2 treatment for each patient during the night whenever the patient begins to exhibit CSR. In order to carry out our study, we will recruit patients with heart failure and suspected CSR for overnight sleep studies which involve measurement of respiratory, cardiovascular and sleep variables. Based upon our studies over the past two years in such patients, carried out at the Alfred and Monash Medical Centre, CO2 treatment will restore continuous breathing in all patients. In the current study we will determine how termination of CSR affects patients in terms of respiratory and cardiovascular function, as well as sleep architecture and quality (duration of sleep and time in its various stages). We anticipate that our proposed study will show that restricting the time a patient spends breathing with a periodic pattern while asleep will provide an acute benefit and justify a major program of device development to translate our technique into a home-based device for overnight patient use. Success in our program has the potential to benefit many of the approximately 25 million people world-wide with congestive heart failure, a condition that remains one of the leading causes of morbidity and mortality in the western world and now constitutes the leading cause of hospitalisation in developed countries.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34444 0
Dr Philip Berger
Address 34444 0
Ritchie Centre
Level 5, Block B
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country 34444 0
Australia
Phone 34444 0
+61395945477
Fax 34444 0
+61395946811
Email 34444 0
[email protected]
Contact person for public queries
Name 17691 0
Elizabeth Skuza
Address 17691 0
Ritchie Centre
Level 5, Block B
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country 17691 0
Australia
Phone 17691 0
+61395945398
Fax 17691 0
+61395946811
Email 17691 0
[email protected]
Contact person for scientific queries
Name 8619 0
Philip Berger
Address 8619 0
Ritchie Centre
Level 5, Block B
Monash Medical Centre
246 Clayton Road
Clayton
Victoria 3168
Country 8619 0
Australia
Phone 8619 0
+61395945477
Fax 8619 0
+61395946811
Email 8619 0
[email protected]

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