Clinical Trials Register

Summary
EudraCT Number:	2018-005030-38
Sponsor's Protocol Code Number:	PAT-CR-302
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-06-10
Trial results	View 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

Belgium - FPS Health-DGM

A.2

EudraCT number

2018-005030-38

A.3

Full title of the trial

A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal, Parallel Group Study of Patiromer for the Management of Hyperkalemia in Subjects Receiving Renin-Angiotensin-Aldosterone System Inhibitor (RAASi) Medications for the Treatment of Heart Failure (DIAMOND)

A.3.1

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

A placebo controlled Study of Patiromer for the Management of high potassium serum levels in Subjects Receiving a certain group of medications called Renin-Angiotensin-Aldosterone System Inhibitor for treatment of Heart failure.

A.3.2

Name or abbreviated title of the trial where available

DIAMOND

A.4.1

Sponsor's protocol code number

PAT-CR-302

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03888066

A.5.4

Other Identifiers

Name:

IND number

Number:

075615

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	Vifor Pharma, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Vifor Pharma, Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Vifor Pharma, Inc
B.5.2	Functional name of contact point	DIAMOND Clinical Study Team
B.5.3	Address:
B.5.3.1	Street Address	200 Cardinal Way
B.5.3.2	Town/ city	Redwood City
B.5.3.3	Post code	94063 (CA)
B.5.3.4	Country	United States
B.5.4	Telephone number	+41 588 518 000
B.5.6	E-mail	Diamond_Information@viforpharma.com

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	Veltassa®
D.2.1.1.2	Name of the Marketing Authorisation holder	Vifor Fresenius Medical Care Renal Pharma France for Europe and Vifor Pharma, Inc. for USA
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Patiromer
D.3.2	Product code	RLY5016
D.3.4	Pharmaceutical form	Oral suspension
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	Patiromer for oral suspension
D.3.9.2	Current sponsor code	RLY5016
D.3.9.3	Other descriptive name	PATIROMER
D.3.9.4	EV Substance Code	SUB182272
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	8.4
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	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

Management of hyperkalemia due to renin-angiotension-aldosterone system medications in patients treated for heart failure.

E.1.1.1

Medical condition in easily understood language

Serum potassium levels increase in patients with heart failure.

E.1.1.2

Therapeutic area

Not possible to specify

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10005725
E.1.2	Term	Blood potassium increased
E.1.2	System Organ Class	10022891 - Investigations

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 assess the effects of patiromer on serum K+ in HF patients compared with placebo

E.2.2

Secondary objectives of the trial

Not applicable.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject provides written informed consent prior to study participation
2. Age at least 18 years or greater
3. Current New York Heart Association (NYHA) Class II–IV HF
4. Left ventricular ejection fraction ≤40%, measured by any echocardiographic, radionuclide, magnetic resonance imaging (MRI), angiographic, or computerized tomography method in the last 12 months without subsequent measured ejection fraction ≥40% during this interval)
5. Receiving any dose of a beta blocker (BB) for the treatment of HF or unable to
tolerate beta-blocker (reason documented)
6.eGFR ≥30 mL/min/1.73 m2 at Screening (based on a single local laboratory analysis of serum creatinine and calculation using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; see Section 9.2 of the protocol)
7. Hyperkalemia at Screening (defined by 2 local serum K+ values of >5.0 mEq/L each obtained from a separate venipunctures, e.g., one in
each arm or 2 separate venipunctures in the same arm) while receiving ACEi/ ARB/ ARNi/ and/or MRA
OR
Normokalemia at Screening (defined by 2 local serum K+ ≥4.0-≤5.0 mEq/L each obtained from a separate venipuncture, e.g., one in each
arm or two separate venipunctures in the same arm) but with a history of hyperkalemia documented by a usual care serum K+ measurement
>5.0 mEq/L while on RAASi treatment in the 12 months prior to Screening leading to a subsequent and permanent dose decrease or discontinuation of one or more RAASi medications
8. Females of child-bearing potential must be non-lactating, must have a negative
pregnancy test at Screening, and must agree to continue using contraception (see Section 9.8 of the protocol) throughout the study and for 4 weeks after study completion
9. With hospitalization for HF or equivalent (e.g., emergency room or outpatient visit for worsening HF during which the subject received
intravenous medications for the treatment of HF) within the last 12 months before Screening
a) Without atrial fibrillation at Screening, brain natriuretic peptide (BNP*) level must be greater than 600 pcg/mL (71 pmol/L)
b) With atrial fibrillation at Screening, BNP level must be greater than 300 pcg/mL (35 pmol/L) or NT-proBNP must be greater than 150 pcg/mL (18 pmol/L) or Nterminal pro b-type BNP (NT-proBNP) must be greater than 600 pcg/mL (71 pmol/L)
OR
Without hospitalization for HF or equivalent (e.g., emergency room or outpatient visit for worsening HF during which the subject received
intravenous medications for the treatment of HF) within the last 12 months before Screening
a) Without atrial fibrillation at Screening, BNP level must be greater than 300 pcg/mL (35 pmol/L) or NT-proBNP must be greater than 1,200
pcg/mL (142 pmol/L)
b) With atrial fibrillation at Screening, BNP level must be greater than 600 pcg/mL (71 pmol/L) or NT-proBNP must be greater than 2400
pcg/mL (284 pmol/L)
*For subjects treated with ARNi (sacubitril/valsartan) in the previous 4 weeks before Screening, only NT-proBNP values are to be considered.

E.4

Principal exclusion criteria

1. Current acute decompensated HF within 4 weeks before Screening. Subjects with a discharge from a hospitalization for acute decompensation of HF longer than 4 weeks before Screening may be included
2. Symptomatic hypotension or systolic blood pressure <90 mmHg
3. Significant primary aortic or mitral valvular heart disease (except secondary mitral regurgitation due to left ventricular dilatation)
4. Heart transplantation or planned heart transplantation (i.e., currently on a heart transplant waiting list) during the study period
5. Diagnosis of peripartum or chemotherapy-induced cardiomyopathy or acute myocarditis in the previous 12 months
6. Implantation of a cardiac resynchronization therapy device in the previous 4 weeks before Screening
7. Restrictive, constrictive, hypertrophic, or obstructive cardiomyopathy
8. Untreated ventricular arrhythmia with syncope in the previous 4 weeks
9. History of, or current diagnosis of, a severe swallowing disorder, moderate-to-severe gastroparesis, or major gastrointestinal (GI)
surgery (e.g., bariatric surgery or large bowel resection)
10. A major CV event within 4 weeks prior to Screening, including acute myocardial infarction, stroke (or transient ischemic attack), a lifethreatening
atrial or ventricular arrhythmia, or resuscitated cardiac arrest
11. Note: This exclusion criterion is included in the new Inclusion Criterion 9
12. Liver enzymes (alanine aminotransferase, aspartate aminotransferase) >5 times upper limit of normal at Screening based on
the local laboratory
13. Diagnosis or treatment of a malignancy in the past 2 years, excluding non-melanoma skin cancer and carcinoma in situ of the cervix, prostate
cancer with Gleason score <7, or a condition highly likely to transform into a malignancy during the study
14. Presence of any condition (e.g., drug/alcohol abuse; acute illness), in the opinion of the Investigator, that places the subject at undue risk,
or prevents complete participation in the trial procedures, or potentially jeopardizes the quality of the study data
15. Use of any investigational product for an unapproved indication within 4 weeks prior to Screening or currently enrolled in any other type
of medical research judged not to be scientifically or medically compatible with this study
16. Known hypersensitivity to patiromer (RLY5016) or its components
17. Note: This exclusion criterion is modified and partially incorporated in Exclusion Criterion 18
18. Subjects currently being treated with or having taken any one of the
following medications in the 7 days prior to Screening: sodium or
calcium polystyrene sulfonate or sodium zirconium cyclosilicate, or patiromer
19. An employee, spouse, or family member of the Sponsor (Vifor Pharma), investigational site or the Contract Research Organization
(CRO)

E.5 End points

E.5.1

Primary end point(s)

Changes in serum K+ levels from Baseline

E.5.1.1

Timepoint(s) of evaluation of this end point

See endpoint description.

E.5.2

Secondary end point(s)

1. Hyperkalemia events: The time to the first event of hyperkalemia with a serum K+ value >5.5 mEq/L as per the measured values from the central or local laboratories is analyzed using a Cox proportional hazards regression model. The event probabilities will be estimated using the
Aalen- Johansen estimator of the cumulative incidence function accounting for competing events such as death.
2. Durable enablement to stay on the MRA target dose (of 50 mg spironolactone or eplerenone): The time to the event of reduction of the
MRA dose below target is analyzed using a Cox proportional hazards regression model. The event probabilities will be estimated using Aalen- Johansen estimator of the cumulative incidence function accounting for competing events such as death.
Note: Discontinuation of the target dose for at least 14 days (or less if at the EoS) is required to confirm this endpoint.
3. Investigator reported AEs of hyperkalemia (first and recurrent) are analyzed using a negative binomial regression with the logarithm of the
individual follow-up time as offset. A joint frailty model of the total (first and recurrent) hyperkalemia events and time to death as
terminating event. If all- cause mortality is substantial in number and differential between the treatment groups, then the joint frailty model would
become the main analysis approach. Note: For analyses based upon the negative binomial distribution, the subject level count data will be modeled as
function of treatment with the natural log of the subject level follow up time taken into account in the estimation of the event rate.
4. Hyperkalemia-related hard outcomes are analyzed using the Win Ratio approach with the following hierarchical components (all assessed
during comparable follow-up times):
1. Time to CV death
2. Total number of CV hospitalizations
3. Total number of hyperkalemia toxicity events with serum K+ >6.5
mEq/L
4. Total number of hyperkalemia toxicity events with serum K+ >6.0-
6.5 mEq/L
5. Total number of hyperkalemia toxicity events with serum K+ >5.0-
6.0 mEq/L
5. RAASi Use Score which will be analyzed using the Win Ratio approach for each pair of patients at the end of the comparable follow
up period that is appropriate for that pair of patients with the following additive components. Points are accumulated from two components at the
respective time for each patient in each comparison:
Component A:
•If during the follow-up (to the respective end of follow-up in the
comparison) there was a death, the subject is assigned 0 points
•If during the follow-up (to the respective end of follow-up in the
comparison) there was a CV hospitalization, but the subject is alive at
the end of
that follow-up, the subject is assigned 1 point
•If during the follow-up (to the respective end of follow-up in the
comparison) there was no CV hospitalization and the subject is alive at
the end
of that follow-up, the subject is assigned 2 points
Component B:
Further points are collected for the treatment status at the respective
end of follow-up in the comparison:
•For ACEi/ARB/ARNi use: >50% of the target dose = 2 points
•For ACEi/ARB/ARNi use: >0 and up to 50% of the target dose = 1 point
•For MRA use: >50% of the target dose = 2 points
•For MRA use: >0 and up to 50% of the target dose = 1 point
•For beta-blocker use: >50% of the target dose = 2 points
•For beta-blocker use: >0 and up to 50% of the target dose = 1 point
In summary, each subject in each comparison can have 0-8 points (sum
of Components A and B) and all subjects are compared using this score
at the respective appropriate follow-up time point.
The regression analyses will be adjusted for geographic region as the
stratification factor of the randomization and relevant baseline
characteristics of the subjects.
Other Secondary End Points
• Durable enablement to stay on the target dose of ACE/ARB/ARNi
Note: Discontinuation of the target dose for at least 14 days (or less if at
the EoS) is required to confirm this endpoint
• Durable hyperkalemia-free enablement to stay on the MRA target
dose (days on 50 mg MRA without presence of hyperkalemia)
• Hyperkalemia toxicity events with serum K+ >6.5 mEq/L
• Hyperkalemia toxicity events with serum K+ >6.0-6.5 mEq/L
• Emergency treatment for hyperkalemia (hospitalization or emergency
room)
• Total number of hyperkalemia toxicity events with serum K+ >5.0-6.0
mEq/L
• KCCQ questionnaire - OSS, CSS and TSS
• Investigator reported events of hyperkalemia (recurrent events)
• Proportion of subjects on =50% of target dose of ACEi, ARB, or ARNi
and =50% of target dose of MRA at the EoS Visit
• Time to first occurrence of CV death or CV hospitalization

E.5.2.1

Timepoint(s) of evaluation of this end point

See endpoint description.

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)

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

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

Yes

E.8.1.7.1

Other trial design description

Single blind during Run-in phase and double blind during treatment phase

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

242

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Brazil

Georgia

Israel

Mexico

Russian Federation

Serbia

Ukraine

United States

Belgium

Bulgaria

France

Germany

Italy

Netherlands

Poland

Spain

Sweden

United Kingdom

Czechia

Argentina

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

The common EoS will occur when 820 subjects have completed the Week 6 visit

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

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:

286

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

590

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Illiterate or blinded patients.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

757

F.4.2.2

In the whole clinical trial

878

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)

None.

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

2020-03-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-03-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-09-02

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