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1 Clinical Trial Details (PDF Generation Date :- Mon, 29 Jan :46:37 GMT) CTRI Number Last Modified On 28/05/2012 Post Graduate Thesis Type of Trial Type of Study Study Design Public Title of Study Scientific Title of Study CTRI/2011/05/ [Registered on: 16/05/2011] - Trial Registered Prospectively No Interventional Drug Randomized, Parallel Group, Active Controlled Trial To demonstrate that intravenous iron isomaltoside 1000 (Monofer) is equivalent to IV iron sucrose determined as ability to maintain the iron level to certain limits in patients already on iron therapy with CKD-5D who are on maintenance iron therapy 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). Secondary IDs if Any Secondary ID Identifier Details of Principal Investigator or overall Trial Coordinator (multi-center study) Details Contact Person (Scientific Query) Details Contact Person (Public Query) P Monofer CKD 03 Name Designation Affiliation Protocol Number Details of Principal Investigator Dr Jatin Kothari Consultant Nehrologist and Transplant Physician P. D. Hinduja National Hospital and Research Center Address P. D. Hinduja National Hospital and Research Center, Veer Savarkar Marg, Mahim, City: Mumbai State: Mumbai Postal Code: Country: India Mumbai MAHARASHTRA India Phone Fax Name Designation Affiliation Address jatin_kothari@yahoo.com Details Contact Person (Scientific Query) Dr Sumbul Siddiqui Medical Monitor Max Neeman International Phone Fax Name Designation Affiliation Address Max Neeman International, Max House, 1st Floor 1, Dr. Jha Marg, Okhla Phase-III, New Delhi South DELHI India ssiddiqui@neemanasia.com Details Contact Person (Public Query) Dr Shariq Anwar Director of Operations Max Neeman International Max Neeman International, Max House, 1, Dr. Jha Marg, Okhla Phase-III, New Delhi South page 1 / 14

2 Source of Monetary or Material Support Primary Sponsor Details of Secondary Sponsor Countries of Recruitment Sites of Study DELHI India Phone Fax Source of Monetary or Material Support > Pharmacosmos A/S Roervangsvej 30, DK-4300 Holbaek Name Primary Sponsor Details Lars Christensen MD Address Chief Executive Officer Pharmacosmos A/S Roervangsvej 30, DK-4300 Holbaek Type of Sponsor Name Max Neeman International List of Countries Denmark India Norway Sweden Switzerland United Kingdom United States of America Name of Principal Investigator Dr Rajesh Kumar Pharmaceutical industry-global Address Max Neeman International, 1 Dr. Jha Marg, Okhla III City: New Delhi State: Delhi Postal Code: Name of Site Site Address Phone/Fax/ Apex Kidney Care Pvt. Ltd. 3rd Floor, Abhishek Commercial Complex, S.V Road, Malad (w), Mumbai Maharashtra, India Mumbai MAHARASHTRA Dr V L Gupta Ashwini Kidney Care Ashwini Kidney and Dialysis Centre, 301 / B, Neeti Gaurav Complex 21, Central Peth, Nagpur , Maharashtra-India Nagpur MAHARASHTRA Dr Hussaini Shaista Care Hospital Exhibition Road, Nampally, Hyderabad ,Andhra Pradesh, India Hyderabad ANDHRA PRADESH Dr Vikas Makkar Dayanand Medical College and Hospital New Tagore Nagar, Civil Lines, Ludhiana, Punjab, India Ludhiana PUNJAB rajkbasudeo@yahoo.co m Vlgupta14@rediffmail.c om shaistamhussaini@gma il.com vikas_makkar@rediffm ail.com page 2 / 14

3 Dr Sonal Dalal Dr Dhananjay Kumar Sinha Dr H L Trivedi Dr Georgy Nainan Dr Jatin Kothari Dr Dhananjai Agarwal Dr Atul Sajgure HCG Medi-Surge Hospitals Heritage Hospitals Limited, Mithakali,Ellis Bridge, Ahmedabad Gujarat, India Ahmadabad GUJARAT Heritage Hospitals Limited, Lanka, Varanasi Varanasi UTTAR PRADESH Institute of Kidney Civil Hospital Campus, Diseases and Research Ahmedabad, Gujarat, Centre (IKDRC) India Ahmadabad GUJARAT P V S Memorial Hospital P. D. Hinduja National Hospital and Research Center S M S Medical College and Hospital Sahyadri Speciality Hospital Cochin, Kozhikode Kerala:682017, India Kozhikode KERALA P. D. Hinduja National Hospital and Research Center,Veer Savarkar Marg, Mahim, Mumbai Maharashtra, India. Mumbai MAHARASHTRA Jawaharlal Nehru Marg, Jaipur India Jaipur RAJASTHAN Sahyadri Speciality Hospital, 30C Erandwane, Karve Road,Pune: Maharashtra, India Pune MAHARASHTRA sonalsanjiv@yahoo.co m dksinha15@rediffmail.c om drhtrivedi@yahoo.com drgkn@yahoo.com jatin_kothari@yahoo.co m dhananjaynephro@gma il.com atulsajgure@yahoo.co m Dr Kamal Goplani Shalby Hospitals Shalby Hospitals, Opp. Karnavati Club, S.G Highway, Ahmedabad-3 kamal.goplani@shalby Gujarat, India org Ahmadabad GUJARAT Dr Dinesh Khullar Dr Gokulnath Sir, Ganga Ram Hospital St. Johns Medical College and Hospital Sir Ganga Ram Hospital, Sir Ganga Hospital Marg, Rajinder Nagar, New Delhi New Delhi DELHI St. Johns Medical College and Hospital, Kormangala, Bangalore Karnataka, India Bangalore KARNATAKA drdineshkhullar@gmail. com nephro@hotmail.com page 3 / 14

4 Details of Ethics Committee Dr Deodatta S Chafekar Supreme Kidney Care Supreme Kidney Care, OM Chambers, Sadhu Waswani Road, Opposite Mico Circle, Nasik Nashik MAHARASHTRA nchafy@hotmail.com Name of Committee Approval Status Date of Approval Is Independent Ethics Committee? Care Hospital, Ethics Committee, Road No1,Banjara Hills, Hyderabad , A.P.India Approved 08/05/2011 No Central India Medical Research Ethics Committee, Dr. S. M. Patil Hospital, 2nd floor, Yugdharma Complex, Ramdaspeth, Nagpur-10, Maharashtra, India Approved 30/04/2012 No Dayanand Medical College and Hospital, New Tagore Nagar, Civil Lines, Ludhiana, India Ethics Committee of the SMS Medical college, Jaipur Ethics Committee, Sir Ganga Ram Hospital, Sir Ganga Ram Hospital Marg, Rajinder Nagar, New Delhi , India Approved 15/11/2011 No Approved 15/07/2011 No Approved 17/05/2012 No HCG Medi-Surge Hospitals, Ethics Committee, Mithakali, Ellis Bridge,Ahmedabad ,Gujarat,India Approved 26/03/2011 No Heritage hospital Ethics Approved 29/03/2012 No Committee, Heritage Hospital Limited, Lanka, Varansi Independent Ethics Committee, Dpt. Of clinical pharmacology, BYL Nair Hospital & TN Medical College, old RMO Building,5th floor, Bombay Central, Mumbai, Approved 20/07/2011 Yes Institute of Kidney Diseases and Research Centre (IKDRC), Ethics Committee, Civil Hospital Campus, Approved 10/02/2011 No page 4 / 14

5 Regulatory Clearance Status from DCGI Health Condition / Problems Studied Intervention / Comparator Agent Ahmedabad National Health & Education Society, Clinical Research and Ethics Committee, P.D. Hinduja National Hospital & Medical Research centre, Veer Savarkar Marg, Mahim, Mumbai PVS Memorial Hospital, Ethics Committee, Cochin,Kerala:682017,India Sahyadri Speciality Hospital, Ethics Committee, 30C,Erandwane,Karve Road, Pune , India Approved 13/05/2011 No Approved 17/05/2011 No Approved 31/03/2011 No Shalby Hospitals, Opp. Karnavati Club, Ethics Committee, S.G. Highw ay,ahmedabad , Gujrat,India Approved 28/04/2011 No Shatabdi Hospital Ethics Committee, Shatabdi Super Speciality Hospital, Suyojit City Centre, Opp. Mahamarg Bus Stand, Mumbai Naka Mashik St. Johns Medical College and Hospital, Kormangala, Banglore ,India Status Approved 20/04/2012 No Approved 06/07/2011 No Date Approved/Obtained 03/05/2011 Health Type Condition Patients Chronic Kidney Disease (Stage 5) Type Name Details Intervention Comparator Agent Intravenous Iron Isomaltoside 1000 (Monofer) Intravenous Iron Sucrose (Venofer) Arm A1- Single dose of 500 mg iv bolus of Monofer to be given in visit 2( Randomization/ Baseline) Arm A2- Dosing to be done as: i. Visit 2 (Baseline)- Single dose of 100 mg iv bolus of Monofer ii.visit 4( wk 2)- Single dose of 200 mg iv bolus of Monofer iii. Visit 5( wk 4)- Single dose of 200 mg iv bolus of Monofer. Arm B- Dosing to be done as: i.visit 2 (Baseline)- Single dose of 100 mg iv bolus Iron Sucrose ii. Visit 4( wk 2)- Single dose of page 5 / 14

6 Inclusion Criteria Age From Age To Gender Details Year(s) Year(s) Both Inclusion Criteria 200 mg iv bolus Iron Sucrose iii.visit 5( wk 4)- Single dose of 200 mg iv bolus Iron Sucrose. 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 Investigators 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 Details 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. 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 page 6 / 14

7 being in the study. Examples include Uncontrolled Hypertension, Unstable Ischemic Heart Disease or Uncontrolled Diabetes Mellitus. Method of Generating Random Sequence Method of Concealment Blinding/Masking Computer generated randomization Centralized Not Applicable Primary Outcome Outcome Timepoints To demonstrate that intravenous iron Baseline to week 6. 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. Secondary Outcome Outcome Timepoints Target Sample Size Phase of Trial Phase 3 Date of First Enrollment (India) Date of First Enrollment (Global) Estimated Duration of Trial Recruitment Status of Trial (Global) Recruitment Status of Trial (India) Publication Details Brief Summary 1. Obtain safety reassurance with Monofer for 1, 2, 4 and 6 weeks Hb maintenance in CKD5D subjects on maintenance iron therapy 2. evaluate safety of iv Monofer in comparison to iv iron sucrose in CKD5D patients. 3.compare hematological parameters Hb, TfS, serum iron, ferritin, reticulocyte count 4.assess subjects discontinuing due to lack of response/intolerance 5.Assess changes in QOL by LASA. 6. Assess RLS symptoms and change.7.assess No. of subjects experiencing ADR including any SUSAR. Total Sample Size=351 Sample Size from India=150 20/05/ /05/2011 Years=1 Months=1 Days=14 Open to Recruitment Open to Recruitment 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 page 7 / 14

8 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: page 8 / 14

9 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 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 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 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. page 9 / 14

10 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: Exclusion 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. 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. page 10 / 14

11 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 B 12 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. page 11 / 14

12 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 page 12 / 14

13 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] / / / / /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 Summary tables and descriptive statistics will be done for demographics, efficacy and page 13 / 14

14 Powered by TCPDF ( REF/2011/05/ 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. page 14 / 14