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Trial registered on ANZCTR


Registration number
ACTRN12611000216910
Ethics application status
Approved
Date submitted
22/06/2010
Date registered
28/02/2011
Date last updated
26/02/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Chronotherapy (timed ingestion of medicine) for high blood pressure in patients with obstructive sleep apnoea (OSA)
Scientific title
A double-blinded, randomised, placebo-controlled, crossover study to assess the efficacy of morning or bed-time Perindopril (10mg) to treat hypertension in adult patients with Obstructive Sleep Apnoea
Secondary ID [1] 252070 0
n/a
Universal Trial Number (UTN)
Trial acronym
CH-OSA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertension 257610 0
Obstructive Sleep Apnoea 257663 0
Condition category
Condition code
Cardiovascular 257785 257785 0 0
Hypertension
Respiratory 257786 257786 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following screening, patients on Angiotensin Converting Enzyme Inhibitors (ACE-i) or Angiotensin Receptor Blockers (ARBs) will undertake a washout period of 3 weeks.

All patients will then undergo a run-in period with perindopril 10mg (morning dose) to ensure medication tolerability. The run in period will be 1 week for those previously taking ACE-i, 2 weeks for those previously on ARBs, and 4 weeks for all patients.

Patients will then be randomised to one of two anti-hypertensive treatment orders for 6 weeks and then cross over to the alternative order. The two treatment orders are.

Treatment Order 1: Perindopril 10 mg morning dose and placebo bedtime dose
Treatment Order 2: Placebo morning dose and Perindopril 10mg bedtime dose

There is no washout period between the two treatment orders.

Following completion of both treatment orders, patients will continue with their last allocated anti-hypertensive treatment order (1 or 2) and also receive Continous Positive Airway Pressure (CPAP) treatment in an open label design for 8 weeks. CPAP will be delivered via a nasal mask and the pressure will be individually titrated during an in-laboratory pressure determination study prior to commencement of 8 weeks CPAP therapy. The pressure will be titrated to a level that fully prevents apnoeas and hypopneas and normalizes breathing during sleep. During the 8 weeks of CPAP treatment, patients will be encouraged to use the device every night for the entire sleep period.
Intervention code [1] 256695 0
Treatment: Drugs
Intervention code [2] 256696 0
Treatment: Devices
Comparator / control treatment
The placebo pill will be produced by the same manufacturer (Servier) as the active drug. The placebo tablet will be identical to the active tablet except that the active ingredient will not be added
Control group
Placebo

Outcomes
Primary outcome [1] 258656 0
Nigh time systolic blood pressure (determined from 24-hour ambulatory blood pressure monitoring (ABPM) in Obstructive Sleep Apnoea patients.
Timepoint [1] 258656 0
Baseline (week 0), visit 5 (End of Treatment Arm 1,week 10) visit 6 (End of Treatment Arm 2,week 16) Visit 7 (End of CPAP Arm week 24)
Secondary outcome [1] 264632 0
Examine the changes in other Blood Pressure indices (24 hour, daytime, night time and office Blood Pressure) and, arterial stiffness and central Blood Pressure (using Pulse Wave Analysis).
Timepoint [1] 264632 0
Baseline (week 0), visit 5 (End of Treatment Arm 1, week 10) visit 6 (End of Treatment Arm 2, week 16) Visit 7 (End of CPAP Arm, week 24)
Secondary outcome [2] 302304 0
Explanatory/Efficacy outcome: Pharmacokinetics. The phramocokinetics of the study drug perindopril will be investigated over a 24 hour period in a small subgroup of patients. This will help explain any differences in antihypertensive effects observed between a morning and evening dose before and after the addition of CPAP treatment for sleep apnoea.
Timepoint [2] 302304 0
Pharmacokinetics will be examined across 24 hours at the end of the drug treatment arm (6 weeks morning versus 6 weeks evening dose) and then after 2 months treatment with CPAP.

Eligibility
Key inclusion criteria
The maximum age is 65 years as stated below. This amendment was approved by the ethics committee on 01/06/2011.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Pregnancy.
Abnormal renal function or chronic kidney disease indicated by any of
1. raised creatinine (>110umol/L)
2. raised potassium (>5.0 mmol/L)
3. low eGFR (<60ml/min/1.73m2)
Severe hypertension (SBP>=180 and/or DBP>=110)
Drug resistant hypertension defined as taking more than 3 classes of BP medication
Normal Office BP (< 140/90 mmHg) whilst taking anti-hypertensive medication that does not include an ACE or ARB.
ACE Inhibitor intolerance (based on the opinion of participants and study physicians) indicated by the development of new cough or symptoms of hypotension (dizziness).
Unwilling to undergo washout of ACE or ARB medication.
Shift workers who rotate to night shift.
Poorly controlled diabetes defined as Glycosolated Haemoglobin (HbA1c) >=8.
Unstable Angina / Heart Failure (NYHA Class III and IV)/ Stroke.
Recent (< 6 months) AMI or Revascularisation Procedure.
Significant Arrhythmia or Atrial Fibrillation.
Cognitive impairment / Psychiatric disorder / Physically unable to participate.
Recent OSA treatment with Mandibular Advancement Splint or CPAP exposure (within 3 months of screening) or prior refusal of CPAP treatment.
Severe OSA (minimum oxygen saturation < 65% or RDI > 80) or excessively sleepy patients at increased risk for driving-related accidents requiring immediate treatment.
More than 20% of AHI with central apnoeas.

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)
After informed and written consent, patients will be sequentially enrolled according to a randomised list generated via a computer program by a third party who had no involvement in the trial. The outcome of which will result in sequentially numbered drug packs being distributed to sequentially enrolled subjects. Each subject will be randomised to one of the two treatment orders:
1. Perindopril morning and Placebo evening or
2. Placebo morning and Perindopril evening and then crossing over to the alternative order.
This final order will continue with an additional arm of CPAP treatment in OSA patients.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The treatment sequence was according to a randomised, block design. It was computer generated using a SAS program utilising the RANUNI function and a random seed.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

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
Recruitment hospital [1] 895 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 4601 0
Royal Prince Alfred Hospital - Camperdown

Funding & Sponsors
Funding source category [1] 257164 0
Government body
Name [1] 257164 0
National Health and Medical Research Council NHMRC
Address [1] 257164 0
Level 1, 16 Marcus Clarke St Canberra ACT 2601
Country [1] 257164 0
Australia
Primary sponsor type
Individual
Name
Dr C Phillips - Principle Investigator
Address
Dept Respiratory & Sleep Medicine Level 8, Acute Services Building, Royal North Shore Hospital St Leonards NSW 2065
Country
Australia
Secondary sponsor category [1] 256419 0
None
Name [1] 256419 0
Address [1] 256419 0
Country [1] 256419 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259205 0
Hawkesbury Ethics Review Committee of Northern Sydney Central Coast Health
Ethics committee address [1] 259205 0
Research Office Level 2, Building 51, Royal North Shore Hospital, Pacific Hwy, ST Leonards NSW 2065
Ethics committee country [1] 259205 0
Australia
Date submitted for ethics approval [1] 259205 0
16/03/2010
Approval date [1] 259205 0
30/06/2010
Ethics approval number [1] 259205 0
HREC/10/HARBR/51

Summary
Brief summary
The aim of the study is to investigate the efficacy of chronotherapy (altering ingestion time of study medication Perindopril) to improve and provide a better overall control of hypertension in patients with Obstructive Sleep Apnoea.
Trial website
www.woolcock.org.au
Trial related presentations / publications
n/a
Public notes

Contacts
Principal investigator
Name 31315 0
Dr Craig Phillips
Address 31315 0
Dept Respiratory & Sleep Medicine, Level 8, Acute Services Building, Royal North Shore Hospital, St Leonards NSW 2065, Australia
Country 31315 0
Australia
Phone 31315 0
+61 2 94632936
Fax 31315 0
Email 31315 0
craig.phillips@sydney.edu.au
Contact person for public queries
Name 14562 0
Dr Yasmina Djavadkhani
Address 14562 0
The Woolcock institute of medical research
431 Glebe Point Rd Glebe NSW 2037
Country 14562 0
Australia
Phone 14562 0
+61291140414
Fax 14562 0
+61 2 91140011
Email 14562 0
chosa@woolcock.org.au
Contact person for scientific queries
Name 5490 0
Dr Craig Phillips
Address 5490 0
The Woolcock institute of medical research
431 Glebe Point Rd Glebe NSW 2037
Country 5490 0
Australia
Phone 5490 0
+61 2 91140301
Fax 5490 0
+61 2 91140011
Email 5490 0
craig.phillips@sydney.edu.au

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