Chronic Kidney Disease, Iron Deficiency Anaemia
Conditions
Keywords
Ferinject Iron Deficiency Anaemia Chronic Kidney Disease
Brief summary
Phase IIIb study to evaluate the long-term efficacy of ferric carboxymaltose (FCM) (using targeted ferritin levels to determine dosing) or oral iron in non-dialysis-dependent chronic kidney disease (NDD-CKD) subjects with iron deficiency anaemia (IDA).
Detailed description
After an initial screening period of up to 4 weeks, eligible subjects were randomised (1:1:2) to 1 of the following 3 treatment arms for a period of 52 weeks. 1. FCM regimen (maximum single intravenous doses of 1,000 mg of iron) targeting a ferritin level of 400-600 mcg/L. 2. FCM regimen (maximum single intravenous doses of 200 mg of iron) targeting a ferritin level of 100-200 mcg/L. 3. Daily oral iron with 200 mg iron/day (100 mg twice daily)
Interventions
DRUGFCM (Ferric carboxymaltose) high ferritin target
DRUGFCM (Ferric carboxymaltose) low ferritin target
Sponsors
American Regent, Inc.
ICON Clinical Research
Vifor Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 4 (MDRD-4) calculation. 3. NDD-CKD subjects with an eGFR loss ≤12 mL/min/1.73 m2/year and a predicted eGFR of ≥15 mL/min/1.73 m2 in 12 months. 4. Any single Hb between 9 and 11 g/dL within 4 weeks of randomisation. A value taken as part of routine medical care was used. 5. Any single serum ferritin \<100 mcg/L or \<200 mcg/L with TSAT \<20% within 4 weeks of randomisation. Measurements taken as part of routine medical care were used. 6. ESA naïve; no exposure to ESA in last 4 months prior to randomisation. 7. Females of childbearing potential must have had a negative pregnancy test, using any medically acceptable assessment, prior to randomisation. 8. Before any study specific procedure, the appropriate written informed consent must have been obtained.
Exclusion criteria
1. History of acquired iron overload. 2. Known hypersensitivity reaction to any component of ferrous sulphate or FCM. Subjects with hypersensitivity to other forms of iron were permitted to participate. 3. Documented history of discontinuing oral iron products due to significant gastrointestinal (GI) 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 (HIV)/acquired immunodeficiency syndrome or active hepatitis B or C virus infection. 9. Anaemia due to reasons other than iron deficiency (e.g., haemoglobinopathy). Subjects with treated Vitamin B12 or folic acid deficiency were permitted. 10. IV iron and/or blood transfusion in previous 30 days prior to screening (or during the screening period). 11. Oral iron therapy at doses \>100 mg/day dosing must have been discontinued at least 1 week prior to randomisation. If subject had received this therapy for \>3 months (at doses \>100 mg/day) then subject was not eligible. Ongoing use of multivitamins containing iron was permitted. 12. Immunosuppressive therapy that may have led to anaemia (e.g., cyclophosphamide, azathioprine, or mycophenolate mofetil). Steroid therapy was permitted. 13. Currently requiring renal dialysis. 14. Anticipated dialysis or transplant during the study. 15. Anticipated need for surgery that may have resulted in significant bleeding (\>100 mL). 16. Currently suffering from chronic heart failure New York Heart Association 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, would have made participation unacceptable. 20. Subject was not using adequate contraceptive precautions. 21. Subject of childbearing potential was evidently pregnant (e.g., positive human chorionic gonadotropin test) or was breast feeding. 22. Body weight \<35 kg. 23. Subject currently was enrolled in or had not yet completed at least 30 days since ending other investigational device or drug studies, or subject was receiving other investigational agent(s). 24. Subject would not be available for follow-up assessment. 25. Subject had any kind of disorder that compromised the ability of the subject to give written informed consent and/or to comply with study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Survival Analysis for Time to Other Anemia Therapy or Hb Trigger | Up to 1 year after baseline | Endpoint reported number of participants with/without events and was reached: * First time of initiation of additional or alternative anaemia management, * First time the subject reached the Hb trigger. 3 primary comparisons using a hierarchical step-down procedure on the log-rank test to preserve an alpha level of 0.05, performed in the following order: 1. FCM (high ferritin target) compared with oral iron. 2. FCM (high ferritin target) compared with FCM (low ferritin target). 3. FCM (low ferritin target) compared with oral iron. Sensitivity analyses of the primary endpoint were performed using the following alternative definitions of time to initiation of additional or alternative anaemia management: 1. Without taking into account the Hb trigger. 2. Taking into account the Hb trigger based on local laboratory data, instead of central laboratory data. 3. Taking into account the Hb trigger based on subjects with a complete set of Hb values from the central laboratory. |
Countries
Australia, Austria, Belgium, Czechia, Denmark, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Portugal, Romania, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FCM (High Ferritin Target Ferric carboxymaltose (FCM) (Ferinject / Injectafer) targeting ferritin level of 400 - 600 mcg/L | 153 |
| FCM (Low Ferritin Target) Ferric carboxymaltose (FCM) (Ferinject / Injectafer) targeting ferritin level of 100 - 200 mcg/L | 152 |
| Oral Iron Ferrous sulphate 100 mg iron twice daily, continuous | 308 |
| Total | 613 |
Baseline characteristics
| Characteristic | FCM (High Ferritin Target | FCM (Low Ferritin Target) | Oral Iron | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 112 Participants | 103 Participants | 216 Participants | 431 Participants |
| Age, Categorical Between 18 and 65 years | 41 Participants | 49 Participants | 92 Participants | 182 Participants |
| Age, Continuous | 69.46 years STANDARD_DEVIATION 12.643 | 68.19 years STANDARD_DEVIATION 13.264 | 69.31 years STANDARD_DEVIATION 13.404 | 69.07 years STANDARD_DEVIATION 13.172 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 9 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 7 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 149 Participants | 144 Participants | 291 Participants | 584 Participants |
| Region of Enrollment Australia | 15 participants | 16 participants | 31 participants | 62 participants |
| Region of Enrollment Austria | 2 participants | 2 participants | 4 participants | 8 participants |
| Region of Enrollment Belgium | 3 participants | 3 participants | 4 participants | 10 participants |
| Region of Enrollment Czech Republic | 16 participants | 15 participants | 31 participants | 62 participants |
| Region of Enrollment Denmark | 1 participants | 1 participants | 2 participants | 4 participants |
| Region of Enrollment France | 1 participants | 0 participants | 3 participants | 4 participants |
| Region of Enrollment Germany | 26 participants | 25 participants | 49 participants | 100 participants |
| Region of Enrollment Greece | 28 participants | 28 participants | 55 participants | 111 participants |
| Region of Enrollment Italy | 10 participants | 10 participants | 19 participants | 39 participants |
| Region of Enrollment Netherlands | 4 participants | 4 participants | 8 participants | 16 participants |
| Region of Enrollment Norway | 0 participants | 1 participants | 4 participants | 5 participants |
| Region of Enrollment Poland | 11 participants | 11 participants | 20 participants | 42 participants |
| Region of Enrollment Portugal | 2 participants | 2 participants | 5 participants | 9 participants |
| Region of Enrollment Romania | 2 participants | 2 participants | 4 participants | 8 participants |
| Region of Enrollment Spain | 4 participants | 4 participants | 10 participants | 18 participants |
| Region of Enrollment Sweden | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Turkey | 7 participants | 7 participants | 15 participants | 29 participants |
| Region of Enrollment United Kingdom | 17 participants | 18 participants | 36 participants | 71 participants |
| Region of Enrollment United States | 4 participants | 3 participants | 7 participants | 14 participants |
| Sex: Female, Male Female | 91 Participants | 98 Participants | 192 Participants | 381 Participants |
| Sex: Female, Male Male | 62 Participants | 54 Participants | 116 Participants | 232 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 126 / 154 | 129 / 150 | 255 / 312 |
| serious Total, serious adverse events | 39 / 154 | 36 / 150 | 59 / 312 |
Outcome results
Primary
Kaplan-Meier Survival Analysis for Time to Other Anemia Therapy or Hb Trigger
Endpoint reported number of participants with/without events and was reached: * First time of initiation of additional or alternative anaemia management, * First time the subject reached the Hb trigger. 3 primary comparisons using a hierarchical step-down procedure on the log-rank test to preserve an alpha level of 0.05, performed in the following order: 1. FCM (high ferritin target) compared with oral iron. 2. FCM (high ferritin target) compared with FCM (low ferritin target). 3. FCM (low ferritin target) compared with oral iron. Sensitivity analyses of the primary endpoint were performed using the following alternative definitions of time to initiation of additional or alternative anaemia management: 1. Without taking into account the Hb trigger. 2. Taking into account the Hb trigger based on local laboratory data, instead of central laboratory data. 3. Taking into account the Hb trigger based on subjects with a complete set of Hb values from the central laboratory.
Time frame: Up to 1 year after baseline
Population: The Full Analysis Set (FAS) was used for the primary endpoint analysis, which consisted of all subjects randomised to treatment, received at least 1 dose of study treatment or, according to the protocol, were not treated due to ferritin value \<100 mcg/L, and attended at least 1 post-baseline visit with at least 1 non-missing assessment available.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| FCM (High Ferritin Target) | Kaplan-Meier Survival Analysis for Time to Other Anemia Therapy or Hb Trigger | Number of patients with events | 36 participants | 7.65 |
| FCM (High Ferritin Target) | Kaplan-Meier Survival Analysis for Time to Other Anemia Therapy or Hb Trigger | Number of patients without events | 117 participants | — |
| FCM (Low Ferritin Level) | Kaplan-Meier Survival Analysis for Time to Other Anemia Therapy or Hb Trigger | Number of patients with events | 49 participants | 9.47 |
| FCM (Low Ferritin Level) | Kaplan-Meier Survival Analysis for Time to Other Anemia Therapy or Hb Trigger | Number of patients without events | 103 participants | — |
| Oral Iron | Kaplan-Meier Survival Analysis for Time to Other Anemia Therapy or Hb Trigger | Number of patients with events | 98 participants | 7.71 |
| Oral Iron | Kaplan-Meier Survival Analysis for Time to Other Anemia Therapy or Hb Trigger | Number of patients without events | 210 participants | — |
Comparison: FCM (Ferinject / Injectafer) targeting high ferritin level (400 - 600 mcg/L) compared with Oral Iron (Ferrous sulphate 100 mg iron twice daily).~Three primary comparisons using a hierarchical step-down procedure on the log-rank test to preserve the overall alpha level of 0.05, performed in the following order:~1. FCM (high ferritin target) compared with oral iron.~2. FCM (high ferritin target) compared with FCM (low ferritin target).~3. FCM (low ferritin target) compared with oral iron.p-value: 0.02695% CI: [0.44, 0.95]Log Rank
Comparison: FCM (Ferinject / Injectafer) targeting high ferritin level (400-600mcg/L) compared with FCM targeting low ferritin level (100 - 200 mcg/L).~Three primary comparisons using a hierarchical step-down procedure on the log-rank test to preserve the overall alpha level of 0.05, performed in the following order:~1. FCM (high ferritin target) compared with oral iron.~2. FCM (high ferritin target) compared with FCM (low ferritin target).~3. FCM (low ferritin target) compared with oral iron.p-value: 0.08295% CI: [0.45, 1.05]Log Rank
Comparison: Sensitivity analysis of the primary endpoint. Time to initiation of additional or alternative anaemia management without taking into account the Hb trigger.~FCM (Ferinject / Injectafer) targeting high ferritin level (400 - 600 mcg/L) compared with Oral Iron (Ferrous sulphate 100 mg iron twice daily).p-value: 0.0295% CI: [0.39, 0.93]Log Rank
Comparison: Sensitivity analysis of the primary endpoint. Time to initiation of additional or alternative anaemia management taking into account the Hb trigger based on local laboratory data, instead of central laboratory data.~FCM (Ferinject / Injectafer) targeting high ferritin level (400 - 600 mcg/L) compared with Oral Iron (Ferrous sulphate 100 mg iron twice daily).p-value: 0.00895% CI: [0.43, 0.88]Log Rank
Comparison: Sensitivity analysis of the primary endpoint. Time to initiation of additional or alternative anaemia management taking into account the Hb trigger based on subjects with a complete set of Hb values from central laboratory.~FCM (Ferinject / Injectafer) targeting high ferritin level (400 - 600 mcg/L) compared with Oral Iron (Ferrous sulphate 100 mg iron twice daily)p-value: 0.1295% CI: [0.45, 1.1]Log Rank