Clinical Trials Register

Summary
EudraCT Number:	2017-001094-16
Sponsor's Protocol Code Number:	PROACT
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2017-05-10
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2017-001094-16

A.3

Full title of the trial

Preventing cardiac damage in patients treated for breast cancer and lymphoma: a phase 3
Randomised, Open label, blinded endpoint, trial of enalapril to prevent
Anthracycline-induced CardioToxicity (PROACT).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Can the heart drug enalapril prevent heart damage in patients with newly diagnosed breast cancer and lymphoma receiving chemotherapy?

A.3.2

Name or abbreviated title of the trial where available

Preventing Cardiotoxicity in Patients with Breast Cancer: PROACT

A.4.1

Sponsor's protocol code number

PROACT

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03265574

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	South Tees NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	National Institute for Health Research
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Newcastle Clinical Trials Unit
B.5.2	Functional name of contact point	Robbie Brown
B.5.3	Address:
B.5.3.1	Street Address	James Cook University Hospital
B.5.3.2	Town/ city	Middlesbrough
B.5.3.3	Post code	TS4 3BW
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01642854638
B.5.6	E-mail	nctu.tees@newcastle.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Enalapril Maleate
D.3.2	Product code	Enalapril
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Enalapril Maleate
D.3.9.1	CAS number	76095-16-4
D.3.9.2	Current sponsor code	Enalapril
D.3.9.3	Other descriptive name	Enalapril
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2.5 to 10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prevention of cardiotoxicity

E.1.1.1

Medical condition in easily understood language

damage to the heart caused by chemotherapy drugs being used to treat patients with breast cancer and non-Hodgkin lymphoma

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10048610
E.1.2	Term	Cardiotoxicity
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To understand if a commonly used heart drug called enalapril can stop patients who are receiving chemotherapy for their breast cancer or non-Hodgkin lymphoma from getting heart damage.

This will be measured by testing blood samples taken and comparing the levels of a marker in the blood (called troponin T).

E.2.2

Secondary objectives of the trial

Secondary objectives will concentrate on understanding the effectiveness of enalapril in preventing cardiotoxicity. They include important measures of heart function which relate directly to patients:

• heart function will be assessed by heart scans (called echocardiograms), at baseline and following completion of chemotherapy;

• presence or absence of markers in the blood (called cardiac troponin I) at any time during chemotherapy and one month after the last dose of chemotherapy;

• whether patients take the enalpril as prescribed;

• side effects of enalapril;

• any anxiety or distress related to trial participation.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Adult patients with histopathologically* confirmed breast carcinoma who have received surgery for their breast cancer;
• Planned to receive 6 cycles of EC 90 (total planned dose 540 mg/m2 epirubicin) or FEC 75 (total planned dose 450 mg/m2 epirubicin) adjuvant chemotherapy regimen;
OR
• Adult patients with histopathologically confirmed non-Hodgkin lymphoma planned to receive 6 cycles of R-CHOP or CHOP (total planned dose 300mg/m2 doxorubicin) chemotherapy
AND
• Written informed consent.
*Patients with HER2+ breast cancer are eligible for inclusion.

E.4

Principal exclusion criteria

• Positive baseline cardiac troponin T (≥14ng/L);
• known contraindication to ACE inhibitor e.g. renal artery stenosis, severe aortic stenosis;
• are taking, or have a previous intolerance to ACEI (e.g. angioedema);
• patient already taking other agents acting on the renin-angiotensin-aldosterone system e.g. Aliskiren, angiotensin receptor blockers (ARBs), Entresto (sacubitril/valsartan), spironolactone, eplerenone;
• LVEF <50%*;
• estimated GFR < 30 mL/min/1.73m2 at baseline;
• hyperkalaemia defined as serum potassium ≥5.5mmol/L;
• symptomatic hypotension, or Systolic Blood Pressure <100mmHg;
• poorly-controlled hypertension (Blood Pressure >160/100mmHg**, or ambulatory BP of 150/95mmHg);
• previous myocardial infarction;
• known metastatic breast cancer;
• previous exposure to anthracycline chemotherapy;
• are pregnant or breastfeeding;
• previous Herceptin treatment or planned Herceptin treatment within four weeks following anthracycline chemotherapy;
• for patients of childbearing potential: refusal to use adequate contraception throughout the trial;***
• any other invasive cancer diagnosed and treated in the past 5 years;
• symptomatic or severe asymptomatic radiation-induced cardiac disease;
• participation in other interventional medicinal trials in the past 6 months;
• judgement by the investigator that the patient has a prognosis of < 1 year or are unlikely to complete 6 cycles of chemotherapy.
• judgement by the investigator that the patient is high risk for tumour lysis syndrome (applicable only to NHL patients).
• judgement by the Investigator that the patient should not participate in the study, for example, if the patient is unlikely to comply with study procedures, restrictions, and requirements.

*<50% as defined by Simpson’s biplane method; if absolute measurements are not possible, then a visually normal assessment of LVEF is acceptable for inclusion.

**White coat hypertension is more common, and should be ruled out by an ambulatory blood pressure monitor

***Female patients between the ages of 18 and 50 will receive a pregnancy test at baseline.

Adequate methods of contraception are those that can achieve a failure rate of less than 1% per year when used consistently and correctly, such methods include:
• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation
o oral
o intravaginal
o transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation
o oral
o injectable
o implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomy/vasectomised partner
• true sexual abstinence (refraining from heterosexual intercourse during the entire period of study treatment)

E.5 End points

E.5.1

Primary end point(s)

The primary outcome of PROACT is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and one month after the last dose of anthracycline.

E.5.1.1

Timepoint(s) of evaluation of this end point

Any time during anthracycline treatment and one month after the last dose of anthracycline.

E.5.2

Secondary end point(s)

Secondary outcomes will focus on the effectiveness of enalapril in preventing cardiotoxicity. These include important measures of cardiac function which relate directly to patient outcomes:
• cardiac function assessed by echocardiogram, including global longitudinal strain (GLS), and measurements of left ventricular ejection fraction (LVEF), at baseline and following completion of anthracycline chemotherapy;
• cardiac troponin I release at any time during adjuvant chemotherapy and one month after the last dose of epirubicin;
• adherence to enalapril;
• side effects of enalapril;
• adverse events;
• any anxiety or distress related to trial participation.

E.5.2.1

Timepoint(s) of evaluation of this end point

Cardiac function by echocardiogram will be assessed 4 weeks after the final cycle of chemotherapy.
Cardiac troponin levels will be assessed at day 1 of each cycle from the second cycle of chemotherapy until study completion (4 weeks following the last cycle of chemotherapy.
Adherence, adverse event reporting and general patient safety assessments will take place from first drug intake, at each titration visit and day 1 of each cycle until the trial completion visit (4 weeks after completion of chemotherapy).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1