A Phase III, Randomized, Comparative, Open-label Study of Intravenous Iron Isomaltoside 1000 (Monofer) Administered as Maintenance Therapy by Single or Repeated Bolus Injections in Comparison with Intravenous Iron Sucrose in Subjects with Stage 5 Chronic Kidney Disease on Dialysis Therapy (CKD-5D).

Study Title

A Phase III, Randomized, Comparative, Open-label Study of Intravenous Iron Isomaltoside 1000 (Monofer®) Administered as Maintenance Therapy by Single or Repeated Bolus Injections in Comparison with Intravenous Iron Sucrose in Subjects with Stage 5 Chronic Kidney Disease on Dialysis Therapy (CKD-5D).

|Study Design

Prospective, Open-label, Randomized, Comparative, Multi-centre, Non-inferiority Study with Three Treatment Groups:

A.                 Iron isomaltoside 1000 (Monofer®)

• administered as 500 mg intravenous single bolus injections (A1)
• administered as 500 mg fractionated (100mg+200mg+200mg) intravenous bolus injection (A2)

B.                 Iron sucrose administered as 500 mg fractionated (100mg+200mg+200mg) intravenous bolus injection (B)

|Background

Therapy for Iron Deficiency Anaemia (IDA) includes treatment of its underlying cause and restoration of normal haemoglobin concentrations and iron stores. Iron replacement can be accomplished by the oral or intravenous routes.

Currently, parenteral iron is widely used in subjects with anaemia associated with chronic kidney disease treated with haemodialysis and Erythropoiesis Stimulating Agents (ESA’s, i.e. epoetin or darbepoetin). Studies have shown that parenteral iron therapy may be superior to oral supplementation in such subjects.

Iron is also proposed to play a role in the pathophysiology of Restless Legs Syndrome (RLS). RLS symptoms seem to appear in many conditions with iron deficiency and thus likely also in subjects with chronic kidney disease. In the present study information as to occurrence of such symptoms in CKD-5D subjects and treatment effects of intravenous (IV) iron will be obtained.

Several different parenteral iron preparations have been synthesized and marketed. The currently available parenteral iron preparations are generally considered equally efficacious but vary in molecular size, degradation kinetics, bioavailability, toxicology and adverse drug event profiles. Iron isomaltoside 1000 (Monofer®) solution for injection/infusion is a formulation with strongly bound iron-carbohydrate. This enables a controlled and slow release of bioavailable iron to the iron-binding proteins, with little risk of free iron toxicity. This makes it possible to administer iron isomaltoside 1000 (Monofer®) in relatively high doses by rapid intravenous infusion or bolus injection. Iron isomaltoside 1000 (Monofer®) consists predominantly of 3-5 glucose units, which have very low immunological activity; therefore it does not require a test dose.

This randomized, open label study is planned to compare the efficacy and further ascertain the safety of intravenous iron isomaltoside 1000 (Monofer®) administered by single or repeated bolus injections in comparison to IV iron sucrose in subjects with CKD-5D.

|Objectives

The primary objective of the study is:

• To demonstrate that intravenous iron isomaltoside 1000 (Monofer®) is non-inferior to IV iron sucrose determined as ability to maintain Hb in subjects with CKD-5D who are on maintenance iron therapy

The secondary objectives are:

• To obtain safety reassurance with the use of iron isomaltoside 1000 (Monofer®) for the maintenance of Haemoglobin in subjects with CKD-5D who are on maintenance iron therapy
• To evaluate the safety of intravenous iron isomaltoside 1000 (Monofer®) in comparison with iron sucrose administered intravenously in patients with CKD-5D
• To compare iron related hematological parameters (haemoglobin (Hb), Transferrin Saturation (TfS), serum iron, serum ferritin levels and reticulocyte count)
• To assess subjects who discontinue study due to lack of response or intolerance
• Assess changes in Quality of Life (QoL) by Linear Analog Scale Assessment (LASA)
• Assess Restless Legs Syndrome (RLS) symptoms and change in these symptoms during the study

|End Points

The primary endpoint of the study is:

1.       Change in Hb concentrations from baseline to week 6.

The secondary end points are:

1.       Change in Hb concentration from baseline to week 2 and 4.

2.       Safety laboratory assessments at baseline, and 1, 2, 4 and 6 weeks.

3.       Change in concentrations of serum iron, TfS, serum ferritin and reticulocyte count from baseline to week 1, 2, 4 and 6.

4.       Number of subjects in each randomization group who discontinue study because of lack of response or intolerance of investigational drugs.

5.       Change in total QoL score (LASA) from baseline to week 4 and 6.

6.       Change in RLS symptoms (CH-RLSq score) from baseline to week 6 in subjects with RLS symptoms at baseline.

7.       Number of subjects who experience any Adverse Drug Reaction (ADR) including any Suspected Unexpected Serious Adverse Reaction (SUSAR).

All blood samples will be drawn immediately pre-dialysis. Intravenous iron will be administered during dialysis, at least 30 minutes after the start and at least 1 hour before the end of dialysis.

It is also recommended (but not mandatory) that blood samples for the individual subject are drawn at the same time of the day at all visits as much as possible, as this will reduce any diurnal fluctuation of the parameters.

All laboratory parameters are analyzed at a central laboratory (except urine pregnancy test).

|Study Duration and Number of Visits

Total duration of the study is 13 months and 2 weeks, which includes 12 months as enrolment period and 6 weeks treatment period. Individual subject duration of the study will be 6-8 weeks. Each subject will make a total of 6 visits during the study.

|Subject Population

Inclusion Criteria:

Subjects with a diagnosis of CKD-5D, in dialysis therapy for at least 90 days prior to inclusion, will be included if they meet all of the following criteria:

1. Men or women, aged 18 years or greater.
2. Subjects diagnosed with CKD-5D and in haemodialysis therapy for at least 90 days.
3. Life expectancy beyond 12 months by Principal Investigator’s judgement.
4. Willingness and ability to participate after Informed Consent.
5. Hb concentrations between 10.0 g/dL and 12.5 g/dL both at Screening Visit 1a and at Screening Visit 1b (screening Visit 1a and Visit 1b must be separated by at least 1 week).
6. Serum ferritin < 800 ng/mL.
7. Transferrin Saturation < 35%.
8. Subjects receiving ESA treatment with dose stable for the previous 4 weeks prior to screening.
9. Subjects receiving no IV iron or an average of no more than 100 mg/week for the previous 4 weeks.

Exclusion Criteria:

1. Anaemia caused primarily by factors other than renal related anaemia.
2. Iron overload or disturbances in utilization of iron (e.g. haemochromatosis and haemosiderosis).
3. Patients currently undergoing treatment with immunosuppresives.
4. Difference of  Hb ≥ 1.0 g/dL between screening (Visits 1a and 1b)  .

5.       Patients with a history of multiple allergies.

6. Decompensated liver cirrhosis [Alanine Aminotransferase (ALT) > 3 times normal] or history of Hepatitis B or C.
7. Active acute or chronic infections (assessed by clinical judgement), supplied with White Blood Cells (WBC) and C - reactive protein (CRP).
8. Rheumatoid arthritis with symptoms or signs of active joint inflammation.
9. Pregnancy or nursing. [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 for at least 5 times plasma biological half-life of the investigational medicinal product: Contraceptive pills, Intrauterine Devices (IUD), contraceptive depot injections (prolonged-release gestagen), subdermal implantation, vaginal ring, and transdermal patches]
10. Blood transfusion within the previous 12 weeks.
11. Planned elective surgery in the next 8 weeks.
12. Participation in any other clinical trial within the past 30 days, or if longer, where the study drug has not passed five half-lives prior to screening.
13. Untreated Vitamin B12 or folate deficiency.
14. Any other medical condition that, in the opinion of Principal Investigator, may cause the subject to be unsuitable for the completion of the study or place the subject at potential risk from being in the study. Examples include Uncontrolled Hypertension, Unstable Ischemic Heart Disease or Uncontrolled Diabetes Mellitus.

| Drug Dosage and Formulation

Drug dosage and formulation is as follows:

A1:       Group iron isomaltoside 1000 (Monofer®) – 500 mg intravenous single bolus injection

Iron isomaltoside 1000 (Monofer®) is administered undiluted in a single dose of 500mg as IV bolus over approximately 2 minutes at baseline.

A2:       Group iron isomaltoside 1000 (Monofer®) – 500 mg fractionated (100mg+200mg+200mg) intravenous bolus injections

Iron isomaltoside 1000 (Monofer®) is administered undiluted in doses of 100mg at baseline, 200mg at week 2 and 200 mg at week 4 as fractionated IV bolus injections over approximately 2 minutes.

B:         Group iron sucrose – 500 mg fractionated (100mg+200mg+200mg) IV bolus injections

Iron sucrose is administered undiluted in doses of 100mg at baseline, 200mg at week 2 and 200 mg at week 4 as fractionated IV bolus injections over approximately 2 minutes.

All blood samples will be drawn immediately pre-dialysis. Intravenous iron will be administered during dialysis, at least 30 minutes after the start and at least 1 hour before the end of dialysis.

No test dose is administered for either agent.

|Prohibited Concomitant Medication and Therapy

1. Blood transfusion.
2. Any iron supplementation other than investigational drugs.

|Safety Assessments and Reporting

1.       Adverse Events (AEs) will be collected and evaluated for relation to study drug, seriousness, and expectedness (Investigators Brochure as reference document). They will be reported to authorities and followed-up according to international and local regulatory guidelines (requirements).

2.       Vital signs, standard safety hematology and biochemical laboratory parameters (e.g. electrolytes, leucocytes, phosphate, blood glucose and transaminases).

|Statistical Analysis

The sample size calculation is based on comparison between absolute change in haemoglobin from baseline to week 6 between Groups A and B. The non-inferiority margin is set to 0.5 g/dL. This margin is in line with previous studies and regarded as clinically relevant. A two-sided significance level of 0.05 is used and the power is set to 80%.

The following table shows the number of subjects needed per randomized treatment group in order to demonstrate non-inferiority with a margin of 0.5 g/dL when using a 2:1 randomization for different standard deviations.

|SD of change in Hb (g/dL)

Number of subjects per group

[iron isomaltoside 1000 (Monofer®)/iron sucrose]

| --- | --- | |1.25

150/75

|1.5

214/107

|1.75

290/145

|2.0

380/190

|2.25

480/240

Based on available literature and previous studies with iron isomaltoside 1000 (Monofer®), the Standard Deviation (SD) in change in haemoglobin is approximately 1.5 g/dL. Based on this, a total of 321 subjects should be included in the efficacy analyses (i.e. provide post-randomization haemoglobin measurements).

Few drop-outs are expected during the first week. As the study is designed to demonstrate non-inferiority, both the analysis of the Full Analysis Set and the Per Protocol Analysis Set should lead to similar conclusions, and therefore analysis for both analysis sets needs to be powered properly. With approximately 10% (anticipated) of subjects to have major protocol violations, a total of 351 subjects will be randomized [234 to Group A (A1:117 and A2:117) and 117 to Group B].

The primary efficacy data will be calculated using sample number, mean, standard deviation, minimum, maximum and 95% confidence Interval. ANCOVA mixed model with repeated measures will be used to compare the average change in Hb concentration from baseline to end of the study visit with the use of treatment, visit, Treatment*Visit interactions, country and stratum as factors and baseline values as covariates. Visit*Treatment estimate at week 6 will be used as estimate model. All tests will be two-tailed and significance level will be 0.05.

Summary tables and descriptive statistics will be done for demographics, efficacy and safety variable. Comparison to baseline analysis of treatment effects between Groups A and B with relevant test will be detailed in a Statistical Analysis Plan (SAP).

Efficacy Assessments

1. Hb concentration.
2. Concentrations of serum ferritin, serum iron, TfS and reticulocyte count.
3. Change in Quality of Life (QoL).
4. Change in RLS symptoms, if these are present in the participating subject.

|Participating Countries

USA, UK, Norway or Denmark, Sweden, Switzerland and India.

|Ethical Aspects

The study will follow ICH-GCP Guidelines and the Helsinki Declaration and local regulatory requirements.

All subjects will provide informed consent before any study related activity is performed.

The protocol will be submitted to relevant authorities (National Regulatory Authority, Ethics Committee, Medical Agencies, and Data Protection Agencies) according to local regulatory requirements prior to study initiation.

|Study Monitoring

In accordance with applicable regulations and ICH-GCP guidelines, monitors (CRAs) will contact the selected sites prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities as per regulatory, ethical, and Pharmacosmos A/S requirements.

During study conduct and at close-out a qualified monitor (CRA) will monitor the site activities to ensure that the study is consistent with the demands of the protocol. This will include, but not limited to the following:

1.                   Safety and rights of subjects are being protected.

2.                   Study is conducted in accordance with the currently approved protocol and any other study agreements, ICH-GCP guidelines, and all applicable regulatory requirements.

3.                   Data is authentic, accurate, and complete.