Clinical Trials Register

Summary
EudraCT Number:	2020-005176-35
Sponsor's Protocol Code Number:	ESR-19-20262
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-11-05
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

Sweden - MPA

A.2

EudraCT number

2020-005176-35

A.3

Full title of the trial

OPtimizing Aldosterone Receptor Antagonist Therapy by Sodium Zirconium Cyclosili-cate in Heart Failure (OPRA-HF)

A.3.1

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

Optimizing medical therapy in patients with heart failure

A.3.2

Name or abbreviated title of the trial where available

OPRA-HF

A.4.1

Sponsor's protocol code number

ESR-19-20262

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	Sahlgrenska University Hospital
B.1.3.4	Country	Sweden
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	AstraZeneca
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sahlgrenska University Hospital
B.5.2	Functional name of contact point	Michael Fu
B.5.3	Address:
B.5.3.1	Street Address	Diagnosvägen 11
B.5.3.2	Town/ city	Gothenburg
B.5.3.4	Country	Sweden
B.5.6	E-mail	Michael.fu@vgregion.se

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.2.1.1.1	Trade name	Lokelma
D.2.1.1.2	Name of the Marketing Authorisation holder	Astrazeneca
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	lokelma
D.3.2	Product code	V03AE10
D.3.4	Pharmaceutical form	Powder and solvent for oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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
D.8.3	Pharmaceutical form of the placebo	Powder for oral suspension
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart failure

E.1.1.1

Medical condition in easily understood language

Heart failure is a serious condition, it means that the heart isn’t pumping as well as it should be and it requires seeking timely medical attention

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

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 demonstrate the efficacy and safety of Sodium Zirconium Cyclosilicate (SZC) in optimizing MRA in symptomatic patients with heart failure

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

For inclusion in the study subjects should fulfil the following criteria:
1. Obtain signed informed consent prior to any study specific procedures
2. >18 yrs, irrespective of sex
3. LVEF ≤ 40%, with echocardiography within last 2 years
4. NYHA II-IV
5. Stable heart failure as judged by local Investigator. Patients may be enrolled as an outpatient or in-hospital at, or close to, the time of hospital discharge
6. On optimal treatment with GDMT (Guideline-Directed Medical Treatment including ACE/ARB/ARNI and beta blockers) as per physician´s judgement
7. AND one of followings:
(1) Prior hyperkalemia due to MRA therapy and current S-K ≤ 5.0 mmol/L;
(2) Risk of hyperkalemia as indicated by eGFR 30-45 ml/min/1.73m2 and S-K 4.5-5.0 mmol/L;
(3) Mild hyperkalemia (S-K 5.1-5.5 mmol/L) and MRA below target dose (target doses for spironolactone: 25-50 mg daily, and for eplerenone: 50 mg daily)

E.4

Principal exclusion criteria

Subjects should not enter the study if any of the following exclusion criteria are ful-filled:
1. Symptomatic hypotension (< 90/60 mmHg)
2. eGFR < 30 ‎ml/min/1,73 m2 (modified MDRD formula)
3. HF due to restrictive cardiomyopathy, hypertrophic (obstructive) cardiomy-opathy or primary valvular disease
4. Current/recent (within 3 months) hospitalization due to myocardial infarc-tion, unstable angina pectoris, coronary revascularization (percutaneous cor-onary intervention or coronary artery bypass grafting), or other interventions (valvular repair/replacement, cardiac transplantation or implantation of a ven-tricular assistance device)
5. Ongoing or planned dialysis
6. Prior history of hypersensitivity (other than hyperkalemia) to a MRA, or SZC
7. Advanced malignancy requiring treatment
8. History of QT prolongation associated with other medications that required discontinuation of that medication.
9. Congenital long QT syndrome.
10. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymp-tomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted
11. QTc(f) > 550 msec
12. Currently pregnant (confirmed with positive pregnancy test) or planned pregnancy or breast-feeding
13. Can not sign informed consent.

E.5 End points

E.5.1

Primary end point(s)

To demonstrate the efficacy of Sodium Zir-conium Cyclosilicate (SZC) on optimizing MRA in heart failure, SZC vs Placebo.

E.5.1.1

Timepoint(s) of evaluation of this end point

at the end of study

E.5.2

Secondary end point(s)

1.To determine the efficacy of SZC when com-pared to placebo in maintaining achieved MRA-dose after run-in period, SZC vs Placebo;

2.To determine the impact of MRA-optimization by SZC in QoL-parameters, SZC vs Placebo;

3.To determine the estimated treatment persisten-cy of highest tolerable dose (25-50 mg daily) of MRA, SZC vs Placebo;

4. To evaluate the safety and tolerability of SZC when compared to placebo as assessed by differ-ences in percent (%) between the two groups in pre-specified safety endpoints (occurring at any point during the study)

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of study

and throughtout the study for safety endpoint

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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.8.6 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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

130

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

230

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

To restore the original dose of minerocorticoid receptor antagonist (MRA) until dose before Run-in i.e returning the subject to their baseline (Run-in) MRA dose;

Above procedure is carried out by a physical visit consisting of following steps
1) Information about detailed planning of continuous follow-up after the end of study
2) Information that investigator will send referral to patient´s ordinarie physi-cian/Clinic/Outpatient Clinic for continuous follow-up

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-01-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-14

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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