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Trial registered on ANZCTR


Registration number
ACTRN12616000781448
Ethics application status
Approved
Date submitted
11/05/2016
Date registered
15/06/2016
Date last updated
8/04/2019
Date data sharing statement initially provided
8/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Can use of N-acetylcysteine and Ramipril improve clinical outcomes in Tako Tsubo Cardiomyopathy (TTC) patients? A randomised controlled trial.
Scientific title
Can use of N-acetylcysteine and Ramipril improve clinical outcomes in Tako Tsubo Cardiomyopathy (TTC) patients?
Secondary ID [1] 289188 0
Nil known
Universal Trial Number (UTN)
Trial acronym
NACRAM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Takotsubo Cardiomyopathy 298745 0
Condition category
Condition code
Cardiovascular 298789 298789 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Placebo controlled trial in a 2 by 2 factorial design, studying the effects of N-acetylcystein (NAC) and Ramipril on the severity and recovery of patients with TTC. NAC component involve 24 hours of intravenous infusion of 10g of NAC/placebo, and the Ramipril component involves 10mg daily of encapsulated ramipril tablet/encapsulated placebo tablet for a duration of 3 months.
Each arm of the study is as per the following:
Arm 1: 24 hours of intravenous infusion of 10g of NAC at baseline and daily 10mg Ramipril for a duration of 3 months Arm 2: 24 hours of intravenous infusion of placebo at baseline and daily 10mg Ramipril for a duration of 3 months Arm 3: 24 hours of intravenous infusion of 10g of NAC at baseline and daily 10mg placebo for a duration of 3 months Arm 4: 24 hours of intravenous infusion of placebo at baseline and daily 10mg placebo for a duration of 3 months
Adherence monitoring will be done by drug tablet return.
Intervention code [1] 294724 0
Treatment: Drugs
Comparator / control treatment
NAC component: placebo will be 50mL of 0.9% sodium chloride.
Ramipril: placebo will be placebo capsules made by Pharmaceutical Packaging Professionals
Control group
Placebo

Outcomes
Primary outcome [1] 298262 0
NAC component: the change in myocardial oedema scores on T2W signalling on MRI
Timepoint [1] 298262 0
MRI to be done within 24 hours of completion of NAC/placebo infusion
Primary outcome [2] 298295 0
Ramipril component: the change in left ventricular function based on global longitudinal strain on echocardiography after 3 months
Timepoint [2] 298295 0
Echocardiography to be performed during the acute attack and again after 3 months of ramipril/placebo
Secondary outcome [1] 323814 0
Plasma NT-proBNP concentrations on commercially available assays
Timepoint [1] 323814 0
24 hours NAC/placebo infusion and after 3 months of ramipril/placebo therapy.
Secondary outcome [2] 323815 0
Plasma hsCRP concentrations on commercially available assays
Timepoint [2] 323815 0
24 hours NAC/placebo infusion and after 3 months of ramipril/placebo therapy.
Secondary outcome [3] 323816 0
Plasma normetanephrine concentrations on commercially available assays
Timepoint [3] 323816 0
24 hours NAC/placebo infusion
Secondary outcome [4] 323818 0
Quality of life scores based on the SF36 Questionnaire that patients will fill up on follow up
Timepoint [4] 323818 0
After 3 months of ramipril/placebo therapy.

Eligibility
Key inclusion criteria
i) Acute episodes of TTC
ii) Provisional diagnosis of TTC will be based on:-
(a) Symptoms of chest pain and/or dyspnoea
(b) Elevation of NT-proBNP levels
(c) Demonstration of regional wall motion abnormality within LV consistent with TTC via ventriculography or echocardiography. Echocardiography will be performed on all patients, irrespective of whether or not they undergo initial cardiac catheterisation, within 48 hours of admission. Data will be archived for later blinded analysis.
iii) Definitive diagnosis of TTC will require demonstration of myocardial oedema on cardiac MRI, and exclusion of myocardial infarction by cardiac MRI or exclusion of relevant coronary artery disease by angiography. The difference in diagnostic criteria reflects the fact that exclusion of myocardial infarction (usually by coronary angiography) may not be performed on admission in all presumptive NAC patients in the absence of ST-segment elevation electrocardiogram.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
For NAC component:
(a) Delay beyond 24 hours post onset of symptoms before making presumptive diagnosis:- in all cases NAC infusion must begin within 24 hours of onset of symptoms.
(b) Simultaneous administration of long-acting nitrates or intravenous glyceryl trinitrate (GTN). If the patient had been commenced on intravenous GTN on presentation, this should be immediately ceased. Patients can be invited to participate in the trial upon cessation of intravenous GTN.
(c) Previous adverse reaction to NAC.
(d) Patients with any contraindications to Cardiac MRI.

ii) For Ramipril component
(a) Previous adverse reaction to ACE inhibitors.
(b) Current therapy with ACE inhibitor or angiotensin receptor blocker.
(c) Severe renal functional impairment: calculated creatinine clearance <30mL/min.

Patients with severe renal function impairment (calculated creatinine clearance <30mL/min) will be excluded from Gadolinium administration during MRI imaging due to its association with nephrogenic systemic sclerosis in this population.
Patients who are unable to provide informed consent will be excluded from the study.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Factorial
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
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)
SA
Recruitment hospital [1] 5789 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [2] 5790 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 5791 0
Lyell McEwin Hospital - Elizabeth Vale

Funding & Sponsors
Funding source category [1] 293569 0
Hospital
Name [1] 293569 0
Cardiology Department, Queen Elizabeth Hospital
Address [1] 293569 0
28 Woodville Road, Woodville South, 5011 SA, Australia
Country [1] 293569 0
Australia
Primary sponsor type
Hospital
Name
Cardiology Department, Queen Elizabeth Hospital
Address
28 Woodville Road, Woodville South, 5011 SA, Australia
Country
Australia
Secondary sponsor category [1] 292391 0
None
Name [1] 292391 0
-
Address [1] 292391 0
-
Country [1] 292391 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295015 0
Human Research Ethics Committee (TQEH/LMH/MH)
Ethics committee address [1] 295015 0
Human Research Ethics Committee (TQEH/LMH/MH)
The Queen Elizabeth Hospital
Ethics: DX465101
Ground Floor, Basil Hetzel Institute
28 Woodville Road
WOODVILLE SOUTH SA 5011
Ethics committee country [1] 295015 0
Australia
Date submitted for ethics approval [1] 295015 0
12/11/2015
Approval date [1] 295015 0
21/12/2015
Ethics approval number [1] 295015 0
HREC /15/TQEH/249; CALHN Reference number: Q20151122

Summary
Brief summary
Stress cardiomyopathy (Tako-Tsubo Cardiomyopathy; TTC) was once thought to be a relatively rare form of transient regional cardiac dysfunction, occurring largely in ageing women. Given the apparently benign course of this condition, little attention has been directed until recently to its cause, or to appropriate treatment. However, it is now apparent that TTC is neither rare nor benign and accounts for about 10% of “heart attacks” in women. Our studies have led to expedited diagnosis, and have delineated a number of aspects of the natural history of TTC. Specifically, attacks, presenting usually as episodes of chest pain and/or breathlessness, TTC actually represents a form of catecholamine-triggered myocardial(heart muscle) inflammation of varying severity, which may engender lethal arrhythmias (abnormal heart rhythms), However the main cause of death post hospital admission is the development of severe hypotension (low blood pressure), which causes death in 2 – 3% of cases. The recovery is slow, due to persistent inflammation and energetic impairment within myocardium (heart muscle), and is associated with prolonged impairment of quality of life. There is also a substantial risk of recurrence.
Furthermore, we have data from post-mortem studies and from a rat model of TTC developed in our laboratory that the myocardial inflammation is associated with increased nitrosative stress.

Currently, there has not been an established treatment for TTC. We wish to test the hypotheses that agents that limit nitrosative stress (such as NAC and ramipril) might:-
(i) Reduce the severity of inflammation and associated myocardial energetic impairment in TTC, and
(ii) Accelerate recovery from TTC
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65794 0
Prof John D Horowitz
Address 65794 0
Cardiology Department,
The Queen Elizabeth Hospital,
28 Woodville Road, Woodville South, 5011 SA
Country 65794 0
Australia
Phone 65794 0
+61882226000
Fax 65794 0
Email 65794 0
john.horowitz@adelaide.edu.au
Contact person for public queries
Name 65795 0
Prof John D Horowitz
Address 65795 0
Cardiology Department,
The Queen Elizabeth Hospital,
28 Woodville Road, Woodville South, 5011 SA
Country 65795 0
Australia
Phone 65795 0
+61882226000
Fax 65795 0
Email 65795 0
john.horowitz@adelaide.edu.au
Contact person for scientific queries
Name 65796 0
Prof John D Horowitz
Address 65796 0
Cardiology Department,
The Queen Elizabeth Hospital,
28 Woodville Road, Woodville South, 5011 SA
Country 65796 0
Australia
Phone 65796 0
+61882226000
Fax 65796 0
Email 65796 0
john.horowitz@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
At this stage, we feel there is no need for IPD to be made available. However, if circumstances change, this could be negotiated upon completion of the trial, ie January 2021, by contacting the principal investigator by email on john.horowitz@adelaide.edu.au
What supporting documents are/will be available?
Study protocol
Attachments/websites
Type [1] 1804 0
Study protocol
URL/details/comments [1] 1804 0
Summary results
No Results