| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Iron deficiency anaemia in subjects with non-dialysis-dependent chronic kidney disease |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10022972 |
| E.1.2 | Term | Iron deficiency anaemia |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the long-term efficacy of FCM (using targeted ferritin levels to determine dosing) or oral iron to delay and/or reduce erythropoiesis stimulating agent (ESA) use and/or other anaemia management options in NDD-CKD subjects with iron deficiency anaemia (IDA). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the potential to reduce ESA requirement for subjects receiving FCM (using targeted ferritin levels to determine dosing) or oral iron.
To evaluate the long-term safety and tolerability of Ferinject and oral iron in the treatment of NDD-CKD subjects with IDA.
To evaluate the health resource utilisation, quality of life (QoL) effects and economic burden of the treatment of NDD-CKD subjects with IDA. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. At least 18 years of age.
2. NDD-CKD subjects with an estimated glomerular filtration rate (eGFR) ≤60 ml/min/1.73 m2 using modification of diet in renal disease (MDRD) calculation.
3. NDD-CKD subjects with an eGFR loss ≤12 ml/min/1.73 m2 per year (based on at least 2 values over at least 4 weeks prior to randomisation, ideally 3 values over at least 3 months) and a predicted eGFR ≥15 ml/min/1.73 m2 in 12 months (based on previous eGFR loss). If more than 3 eGFR values are available in the 2-year time period prior to randomisation, the predicted loss should be calculated using 3 appropriately representative values (which will also be recorded in the case report form (CRF)). If this predicted eGFR decline is ≤12 ml/min/1.73 m2 per year then subject may be included.(*)
4. Hb between 9 and 11 g/dL within 4 weeks of randomisation. Note: A value taken as part of routine medical care may be used.
5. Serum ferritin <100 mcg/L or <200 mcg/L with TSAT <20% within 4 weeks of randomisation. Note: Measurements taken as part of routine medical care may be used.
6. ESA naïve (no exposure in last 4 months prior to randomisation).
7. Females of child-bearing potential must have a negative pregnancy test prior to randomisation.
8. Before any study-specific procedure, the appropriate written informed consent must be obtained.
(*) Criterion number 3 is aimed to minimise the likelihood that study
participants go on to terminal renal failure (eGFR <15 ml/min/1.73 m2)
during the study. |
|
| E.4 | Principal exclusion criteria |
1. History of acquired iron overload.
2. Known hypersensitivity reaction to any component of ferrous sulphate or FCM. Note: subjects with hypersensitivity to other forms of iron will be permitted to participate.
3. Documented history of discontinuing oral iron products due to significant gastrointestinal distress.
4. Screening TSAT >40%.
5. Known active infection, C-reactive protein >20 mg/l, clinically significant overt bleeding, active malignancy (i.e., clinical evidence of current malignancy or not in stable remission for at least 5 years since completion of last treatment with exception of basal cell or squamous cell carcinoma of the skin, and cervical intraepithelial neoplasia).
6. History of chronic alcohol abuse (alcohol consumption >40 g/day).
7. Chronic liver disease and/or screening alanine transaminase or aspartate transaminase above 3 times the upper limit of the normal range.
8. Active human immunodeficiency virus/acquired immunodeficiency syndrome, hepatitis B virus or hepatitis C virus infection.
9. Anaemia due to reasons other than iron deficiency (e.g., haemoglobinopathy). Subject with treated Vitamin B12 or folic acid deficiency are permitted.
10. Intravenous iron and/or blood transfusion in previous 30 days prior to screening.
11. Oral iron therapy at doses >100 mg/day in previous 1 week prior to randomisation and/or patients who have been continuously treated with >100 mg/day of oral iron for the last 3 months. Upon randomisation the oral iron therapy must be discontinued. Note: Ongoing use of multivitamins containing iron are permitted.
12. Immunosuppressive therapy that may lead to anaemia e.g., cyclophosphamide, azathioprine, mycophenolate mofetil, etc. Note: Steroid therapy is permitted.
13. Currently requiring renal dialysis.
14. Anticipated dialysis or transplant during the study.
15. Anticipated need for surgery that may result in significant bleeding (>100 ml).
16. Currently suffering from chronic heart failure New York Heart Association (NYHA) Class IV.
17. Poorly controlled hypertension (>160 mmHg systolic pressure or >100 mmHg diastolic pressure).
18. Acute coronary syndrome or stroke within the 3 months prior to screening.
19. Currently suffering from concomitant, severe psychiatric disorders or other conditions which, in the opinion of the Investigator, make participation unacceptable.
20. Subject is not using adequate contraceptive precautions. Adequate contraceptive precautions are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intra-uterine devices, sexual abstinence or vasectomised partner. Non-childbearing potential includes being surgically sterilised at least 6 months prior to the study or post menopausal, defined as amenorrhea for at least 12 months.
21. Subject of child-bearing potential is evidently pregnant (e.g., positive human chorionic gonadotropin test) or is breast feeding.
22. Body weight <35 kg.
23. Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(ies), or subject is receiving other investigational agent(s).
24. Subject will not be available for follow-up assessment.
25. Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
• Time to the initiation of other anaemia management (e.g., ESA or transfusion) using Kaplan-Meier survival analyses.
Secondary Endpoints:
• Cumulative ESA requirement over the study period.
• Percentage of subjects requiring transfusion at anytime during the study.
• Cumulative iron requirements and number of iron administrations over the study period.
• Percentage of subjects with an increase of Hb ≥1 g/dL prior to any other anaemia management (e.g., ESA or transfusion).
• Value change from baseline to end of study (for each visit) for the following parameters:
− Haematological and iron parameters.
− eGFR as calculated with the MDRD formula.
• Percentage of subjects requiring dialysis at anytime during the study.
• Change in health-related QoL over the study period using the SF-36.
• Health resource utilisation over the study period calculated direct, indirect and total costs from 2 perspectives (payer’s and societal perspective).
• Cost effectiveness of treatment options using relevant effectiveness parameters.
• Percentage of subjects discontinuing the study drug due to intolerance. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 230 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| At week 56 (or 4 weeks after last dose of study medication if subject is withdrawn early) all assessments per Schedule of Events should be completed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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