ANZCTR - Registration

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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

1/03/2023

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]

Nil known

Universal Trial Number (UTN)

Trial acronym

NACRAM

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Takotsubo Cardiomyopathy

Condition category

Condition code

Cardiovascular

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]

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]

NAC component: the change in myocardial oedema scores on T2W signalling on MRI

Timepoint [1]

MRI to be done within 24 hours of completion of NAC/placebo infusion

Primary outcome [2]

Ramipril component: the change in left ventricular function based on global longitudinal strain on echocardiography after 3 months

Timepoint [2]

Echocardiography to be performed during the acute attack and again after 3 months of ramipril/placebo

Secondary outcome [1]

Plasma NT-proBNP concentrations on commercially available assays

Timepoint [1]

24 hours NAC/placebo infusion and after 3 months of ramipril/placebo therapy.

Secondary outcome [2]

Plasma hsCRP concentrations on commercially available assays

Timepoint [2]

24 hours NAC/placebo infusion and after 3 months of ramipril/placebo therapy.

Secondary outcome [3]

Plasma normetanephrine concentrations on commercially available assays

Timepoint [3]

24 hours NAC/placebo infusion

Secondary outcome [4]

Quality of life scores based on the SF36 Questionnaire that patients will fill up on follow up

Timepoint [4]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/07/2016

Actual

31/08/2016

Date of last participant enrolment

Anticipated

1/07/2023

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

100

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

The Queen Elizabeth Hospital - Woodville

Recruitment hospital [2]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [3]

Lyell McEwin Hospital - Elizabeth Vale

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Cardiology Department, Queen Elizabeth Hospital

Address [1]

28 Woodville Road, Woodville South, 5011 SA, Australia

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Human Research Ethics Committee (TQEH/LMH/MH)

Ethics committee address [1]

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]

Australia

Date submitted for ethics approval [1]

12/11/2015

Approval date [1]

21/12/2015

Ethics approval number [1]

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

Prof John D Horowitz

Address

Cardiology Department,
The Queen Elizabeth Hospital,
28 Woodville Road, Woodville South, 5011 SA

Country

Australia

Phone

+61882226000

Fax

[email protected]

Contact person for public queries

Name

John D Horowitz

Address

Cardiology Department,
The Queen Elizabeth Hospital,
28 Woodville Road, Woodville South, 5011 SA

Country

Australia

Phone

+61882226000

Fax

[email protected]

Contact person for scientific queries

Name

John D Horowitz

Address

Cardiology Department,
The Queen Elizabeth Hospital,
28 Woodville Road, Woodville South, 5011 SA

Country

Australia

Phone

+61882226000

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 [email protected]

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
1804	Study protocol					370684-(Uploaded-05-04-2019-16-26-19)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	The N-AcetylCysteine and RAMipril in Takotsubo Syndrome Trial (NACRAM): Rationale and design of a randomised controlled trial of sequential N-Acetylcysteine and ramipril for the management of Takotsubo Syndrome.	2020	https://dx.doi.org/10.1016/j.cct.2019.105894
Dimensions AI	Takotsubo Syndrome: Pathophysiology, Emerging Concepts, and Clinical Implications	2022	https://doi.org/10.1161/circulationaha.121.055854

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically