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Trial registered on ANZCTR


Registration number
ACTRN12616000940471
Ethics application status
Approved
Date submitted
22/01/2016
Date registered
15/07/2016
Date last updated
15/07/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase II Feasibility study to determine the efficacy and dose-response of a single enteral dose of Ivabradine to reduce participant heart rate in patients admitted to the intensive care unit with sepsis and sinus tachycardia
Scientific title
Ivabradine in Sepsis for Heart Rate, Benefits and Disadvantages trial (IS-HR-BAD)
Secondary ID [1] 289632 0
Nil Known
Universal Trial Number (UTN)
U1111-1178-8141
Trial acronym
IS-HR-BAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sepsis 297394 0
tachycardia 297395 0
Condition category
Condition code
Infection 297584 297584 0 0
Other infectious diseases
Cardiovascular 297585 297585 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single dose enteral ivabradine (initially 5mg, however dose response will be reviewed after first 5 patients and dose may be increased to 10mg if inadequate response). Administered via oral/ nasogastric route. Dose will be administered under the supervision of study staff to ensure adherence.
Intervention code [1] 293697 0
Treatment: Drugs
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 297129 0
Heart rate, assessed by continuous ECG monitoring with supplimentary confirmation from pulse oximetry, arterial line and Vigileo.
Timepoint [1] 297129 0
Continuously monitored with hourly timepoints for data collection from time of ivabradine administration to 12 hours post administration
Secondary outcome [1] 320108 0
Haemodynamics from arterial line: (MAP, stroke volume, cardiac output)
Timepoint [1] 320108 0
Continuously assessed by waveform analysis of arterial line by attached continuous cardiac output monitor, with hourly timepoints for data collection from time of ivabradine administration to 12 hours post administration
Secondary outcome [2] 320109 0
plasma Lactate
Timepoint [2] 320109 0
Blood sampling from time of ivabradine administration to 12 hours post administration at time 0, 3 hours, 6 hours and 12 hours)
Secondary outcome [3] 320110 0
Non cardiovascular organ function (urine output, renal and liver biochemistry, paO2/FiO2 ratio)
Timepoint [3] 320110 0
Hourly urine output from time of ivabradine administration to 12 hours post administration from IDC output.
Renal and liver biochemistry with blood sample at time of ivabradine administration and 12 hours post administration.
PaO2/FiO2 from time of ivabradine administration to 12 hours post administration at time 0, 3 hours, 6 hours and 12 hours (PaO2 from blood gas results).
Secondary outcome [4] 320111 0
Significant adverse events:
Bradycardia assessed by continuous ECG, arterial line and pulse oximeter readings
Hypotension, assessed by continuous arterial line pressures,
Low cardiac output, assessed by continuous cardiac output monitor and serum lactate,
Timepoint [4] 320111 0
over 12 hours

Eligibility
Key inclusion criteria
1. Age greater than or equal to 18 years of age;
2. Presumed diagnosis of sepsis on intravenous antibiotics;
3. A heart rate of >100/min in sinus rhythm;
4. The requirement for vasopressor infusion to maintain a mean arterial pressure > 65mmHg despite adequate fluid resuscitation (defined by a central venous pressure > 8mmHg);
5. Informed consent is obtained from the patient or surrogate decision maker;
6. The patient is anticipated to require ICU care beyond the next calendar day; and
7. Presence of an indwelling urinary catheter (IDC) and arterial line
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pacemaker in situ; or
2. Use of a beta blocker within the last 48 hours; or
3. History of rhythm disturbance or bradycardia; or
4. Concurrent use of inhibitors of CYP3A4 (macrolide antibiotics, azole antifungals) that interact with the metabolism of ivabradine; or
5. Inability to administer enteral medication; or
6. Severe hepatic dysfunction – defined as an AST or ALT > 5 x upper limit of normal (ULN), or and AST or ALT > 3 x ULN with an associated total bilirubin > 2 x ULN; or
7. Pregnancy; or
8. Breast-feeding mothers; or
9. Inability to complete the monitoring period in ICU following ivabradine administration; or
10. Patient not expected to survive next 24-48 hours and/or clinician not committed to ongoing life support

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Statistical considerations:

Enrollment will consist of a 20 patient cohort.
Data from Morelli et al (JAMA 2015) demonstrate that the median heart rate in a similar patient cohort was 114/min at baseline, with a decrease to 85/min following esmolol infusion. In 2014, ~280 patients were admitted to the Alfred ICU with a ‘sepsis’ related diagnosis (not specifically requiring vasopressor infusion). The mean maximum HR was ~100/min on admission, with a standard deviation of 25/min.
Therefore, with an anticipated mean heart rate of 110 +/- 25/min at baseline, and a type-1 error of 0.05, a 20 patient cohort provides 80% power to detect an absolute reduction in mean heart rate of 15/min following study drug administration.
Analysis will primarily be conducted using SPSS version 22 (Chicago, IL, USA).

Data will be presented in text and tabulated formats. We will develop a prospective data analysis plan that will be ratified by the investigators prior to analysis. This will include (but not be limited to) the following sections:
a. Patient demographics
b. Physiological and biochemical derangements and ICU supports prior to enrolment
c. Changes in haemodynamics and intensive Care supports following administration of a single dose of enteric ivabradine
Descriptive statistics will be used to describe overall cases (n) and proportions (%). Distributed data will be described according to the median and inter-quartile range (IQR). Inferential statistics will involve the Mann-Whitney U test for distributed data and the chi-sq / Fischer’s exact test for categorical data.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
2/03/2016
Date of last participant enrolment
Anticipated
31/01/2017
Actual
Date of last data collection
Anticipated
31/01/2018
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5110 0
The Alfred - Prahran

Funding & Sponsors
Funding source category [1] 292743 0
Charities/Societies/Foundations
Name [1] 292743 0
The Alfred Research Trust: Alfred Small Projects Grants
Country [1] 292743 0
Australia
Primary sponsor type
Individual
Name
A/Prof Andrew Udy,
Address
c/o: A/Prof Andrew Udy,
The Alfred hospital, 55 Commercial Rd, Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 291474 0
Individual
Name [1] 291474 0
Dr Thomas Rozen
Address [1] 291474 0
c/o: A/Prof Andrew Udy,
The Alfred hospital, 55 Commercial Rd, Melbourne VIC 3004
Country [1] 291474 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294228 0
Alfred HREC
Ethics committee address [1] 294228 0
The Alfred hospital, 55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 294228 0
Australia
Date submitted for ethics approval [1] 294228 0
21/09/2015
Approval date [1] 294228 0
04/11/2015
Ethics approval number [1] 294228 0
Alfred HREC: 482/15

Summary
Brief summary
Severe infection (sepsis) represents a common reason for admission to the ICU, often involving older people with multiple medical problems. These patients often have a prolonged hospital stay, complicated by multi-organ dysfunction leading to greater morbidity and mortality. Typically, patients have a high cardiac output, low resistance circulation, with rapid heart rates and low blood pressures requiring infusions of medications to increase blood pressure. There is an emerging body of evidence that elevated heart rates in sepsis contributes to morbidity in some people and can cause numerous complications including myocardial infarction, stress cardiomyopathy, immunosuppression and insulin resistance. Elevated heart rates may limit the time for the heart to fill between contractions, and at high rates may actually reduce the cardiac output. Controlling heart rate could therefore be beneficial.
While the drug class beta-blockers are traditionally used, they have the potential to reduce blood pressure which may worsen the clinical state. Ivabradine is currently used in heart failure patients to prevent elevated heart rates, and acts via a novel receptor to reduce heart rates without impacting on contractility. The use of ivabradine in the septic population is highly novel and previously untested.
This study aims to evaluate if a single dose of ivabradine is effective at reducing heart rate in septic patients, without escalation of ICU supports.
Trial website
n/a
Trial related presentations / publications
n/a
Public notes
Attachments [1] 735 735 0 0
/AnzctrAttachments/369980-Protocol (version 6) ISHRBAD 5-1-16 final.doc

Contacts
Principal investigator
Name 62978 0
Dr Thomas Rozen
Address 62978 0
Royal Children's Hospital
50 Flemington Rd, Parkville VIC 3052
Country 62978 0
Australia
Phone 62978 0
+61419331973
Fax 62978 0
Email 62978 0
[email protected]
Contact person for public queries
Name 62979 0
Andrew Udy
Address 62979 0
Alfred Hospital,
55 Commercial Rd, Prahran VIC 3181
Country 62979 0
Australia
Phone 62979 0
+61390762000
Fax 62979 0
Email 62979 0
[email protected]
Contact person for scientific queries
Name 62980 0
Andrew Udy
Address 62980 0
Alfred Hospital,
55 Commercial Rd, Prahran VIC 3181
Country 62980 0
Australia
Phone 62980 0
+61390762000
Fax 62980 0
Email 62980 0
[email protected]

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