Clinical Trials Register

Summary
EudraCT Number:	2014-004133-16
Sponsor's Protocol Code Number:	IH141
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-02-17
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

UK - MHRA

A.2

EudraCT number

2014-004133-16

A.3

Full title of the trial

Exploratory multicentre prospective double blinded randomised controlled pilot study of the effect of intravenous iron supplementation(Monofer)in iron deficient but not anaemic patients with Chronic Kidney Disease stages 3b or worse on functional status and cardiac structure and function.

A.3.1

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

The Iron and Heart Trial

A.3.2

Name or abbreviated title of the trial where available

Iron and Heart Trial

A.4.1

Sponsor's protocol code number

IH141

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	Hull and east Yorkshire Hospitals 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	Kidney Research UK
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	Hull and East Yorkshire Hospitals Trust
B.5.2	Functional name of contact point	Professor Sunil Bhandari
B.5.3	Address:
B.5.3.1	Street Address	Renal Dept, Hull Royal Infirmary, Anlaby Road
B.5.3.2	Town/ city	Hull
B.5.3.3	Post code	HU3 2JZ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01482605260
B.5.5	Fax number	01482605256
B.5.6	E-mail	sunil.bhandari@hey.nhs.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.2.1.1.1	Trade name	Monofer
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmacosmos A/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Monofer 100mg/ml
D.3.4	Pharmaceutical form	Solution for infusion in administration system
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	iron(iii)isomaltoside 1000
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Kidney Disease stages 3b to 5 with iron deficiency

E.1.1.1

Medical condition in easily understood language

Chronic Kidney Disease

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 determine whether IV iron supplementation in iron deficient non-anaemic CKD patients improves physical and functional status assessed by the 6MWT and questionnaires (KDQoL and MLHF).

E.2.2

Secondary objectives of the trial

Improvement in cardiac structure and function. Monitoring of physiological aspects using pulse oximetry and cardiac harness for heart and respiratory rate.

Change in New York Heart association functional classification (NYHA)

To investigate cardiac iron loading based on MRI using T2* in a small cohort of patients in a single centre (10 patients)

To observe improvement in renal function as assessed with eGFR

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

In a separate sub-study, to be performed at Hull and East Yorkshire Hospitals NHS Trust 10 patients will undergo T2* imaging of the heart to assess iron loading of the heart immediately after iron infusion. This is not to examine Monofer® as a tracer substance but direct loading into cardiac myoctyes. Each patient’s baseline data will serve as a control.

E.3

Principal inclusion criteria

Stage of CKD will be calculated by the 4 point MDRD equation. Patients must have a stable eGFR, as defined by <20% variation in eGFR in the preceding 3 months. It is estimated that approximately 30% of patients will have underlying ischaemic heart disease and be on aspirin therapy, which may contribute to iron deficiency. In both groups, BP will be controlled in participants in the trial to the target pressures outlined by the NICE Hypertension guideline (clinical guideline number 127) and NICE CKD guideline (clinical guideline number 73) (21, 22). The standard blood pressure targets will be used (<140/85mmHg)

Patients with established CKD (Stages 3b-5) (eGFR using MDRD <45ml/min/1.73m2), not on dialysis.

Clinically stable (principal investigator’s judgement)

Resting BP ≤ 160/90mmHg when measured in accordance with British Hypertension Society guidelines.

Men and women aged 18-80 years

Able to give a written and signed informed patient consent

Serum ferritin level less than 100 µg/L AND/OR transferrin saturation ≤20%

Patient must be in sinus rhythm to allow for accurate echo measurements

Haemoglobin greater or equal to 110g/L up to and including 150g/L

If deemed necessary all patients will have had faecal occult blood testing (FOBs) carried out as part of national recommendations to exclude bowel pathology.

E.4

Principal exclusion criteria

Pregnancy or breast feeding (To avoid pregnancy, women have to be postmenopausal, (at least 12 months must have elapsed since last menstruation), surgically sterile, or women of child bearing potential must use one of the following contraceptives during the whole study period and after the study has ended: Contraceptive pills, intrauterine devices (IUD) contraceptive depot injections (prolonged release gestagen), subdermal implantation, vaginal ring and transdermal patches.

Age < 18 years

Known allergy to iron therapy

Haemochromatosis or history of acquired iron overload

Parenteral iron therapy within the previous 6 weeks

Inability to co-operate with study protocol

CRP > 50 mg/L

Active infection

Symptomatic ischaemic heart disease

Current therapy with ESA agents

Patients with atrial fibrillation

Patients with potential confounding factors - cancer, (with exception of basal cell or squamous cell carcinoma of the skin, and cervical intraepithelial neoplasia)

Patients who are unable or do not wish to give consent.

Patients being investigated for potential blood loss

Patients who have received blood transfusions

Patients with known haemoglobinopathy, myelodysplasia, myeloma,

Patients with musculoskeletal disease, who the investigator deems unable to carry out the 6MWT.

Patients who have been involved in another medicinal trial (CTIMP) within the past four weeks

E.5 End points

E.5.1

Primary end point(s)

To compare the effect of IV iron versus placebo on changes in physical function based on a 6-minute walk test and qualitative questionnaires in iron deficient non-anaemic chronic kidney disease patients.

E.5.1.1

Timepoint(s) of evaluation of this end point

Difference in the co analysis of a 6-minute walk test and questionnaires (KDQoL and Minnesota Living and Heart Failure Questionnaire (MLHF) patient quality of life and wellbeing) between experimental and placebo groups (Group 1) and control groups (Groups 2 and 3).

E.5.2

Secondary end point(s)

Speckle tracking Echo parameters of cardiac function after 6MWT
Hospitalisation rates from any cause in each group will be noted
All-cause death and a composite of non-fatal myocardial infarction, stroke, and hospitalisation for heart failure
All-cause mortality will be recorded
Cardiovascular events, stroke, non-fatal myocardial infarction will be recorded
Change in New York Heart association functional classification (NYHA)
Thrombotic episodes
Restless leg syndrome questionnaire

E.5.2.1

Timepoint(s) of evaluation of this end point

n/a

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

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.8.3

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

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

At the end of the trial a declaration form will be submitted by the Chief Investigator to the MHRA, REC and HEY R&D within 90 days from completion of the trial and within 15 days if the trial is discontinued prematurely. A summary of the trial final report will be submitted by the Chief Investigator to the MHRA, REC and HEY R&D within 1 year of the end of the study.

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