The FIND-CKD Study Background Study design (Results)

Transcription

1 The FIND-CKD Study Background Study design (Results)

2 The FIND-CKD Study An open-label, multicentre, randomized, 3 arm study comparing the 12-month efficacy and safety of Ferric carboxymaltose (FCM, Ferinject /Injectafer ) using higher or lower ferritin targets versus oral iron in patients with Iron deficiency, anaemia and Non-Dialysis dependent Chronic Kidney Disease not receiving an erythropoiesis-stimulating agent

3 Rationale for the FIND-CKD Study Attempts to normalise Hb with ESA therapy in patients with CKD are associated with an increased risk of stroke, venous thromboembolism, and possibly death especially if patients are relatively unresponsive to high-dose ESA In response, the use of ESAs in CKD patients has declined and the use of iron therapy has increased In contrast to dialysis patients, the evidence base supporting optimum iron management in ND-CKD is woefully inadequate There is a need for more robust clinical trials of iron therapy with longer follow-up in patients with ND-CKD

4 FIND-CKD Study Design Screening (up to 4 weeks) ND-CKD No ESA (last 4 months) Hb 9 11 g/dl Ferritin <100 ng/ml or <200 ng/ml + TSAT <20% Rescreening permitted R FCM: high ferritin (ferritin target ng/ml) FCM: low ferritin (ferritin target ng/ml) Visits: Every 2 weeks (Weeks 0 8), then every 4 weeks (Weeks 8 52). Dosing every 4 weeks No ESA or other anaemia management (Weeks 0 8) Oral iron, ferrous sulfate (200 mg iron/day) anaemia management per standard local practice Central labs at week 0, 4, 8, 12, 24, 36 and 52. Local labs will be used for dosing determination (ferritin) and assessing requirements for anaemia management End of study Week 56 (or 4 weeks after last dose of study drug)

5 FIND-CKD Study Design Screening (up to 4 weeks) ND-CKD No ESA (last 4 months) Hb 9 11 g/dl Ferritin <100 ng/ml or <200 ng/ml + TSAT <20% Rescreening permitted R FCM: high ferritin (ferritin target ng/ml) FCM: low ferritin (ferritin target ng/ml) Visits: Every 2 weeks (Weeks 0 8), then every 4 weeks (Weeks 8 52). Dosing every 4 weeks No ESA or other anaemia management (Weeks 0 8) Oral iron, ferrous sulfate (200 mg iron/day) anaemia management per standard local practice Central labs at week 0, 4, 8, 12, 24, 36 and 52. Local labs will be used for dosing determination (ferritin) and assessing requirements for anaemia management End of study Week 56 (or 4 weeks after last dose of study drug)

6 Inclusion Criteria 18 years ND-CKD egfr 60 ml/min/1.73m 2 (MDRD-4) egfr loss 12 ml/min/1.73m 2 /year Predicted egfr 15 ml/min/1.73m 2 in 12 months Any single Hb level between 9 and 11 g/dl within 4 weeks of randomization Any single serum ferritin <100 µg/l (or <200 µg/l with TSAT <20%) within 4 weeks of randomization No exposure to ESA therapy in last 4 months prior to randomization

7 Key Exclusion Criteria Documented history of discontinuing oral iron products due to significant gastrointestinal distress TSAT > 40% at screening CRP > 20 mg/l; known active infection or malignancy IV iron and/or blood transfusion within 30 days prior to screening or during screening period Chronic liver disease or history of alcohol abuse Receipt of oral iron therapy (>100 mg/day) for >3 months

8 Study Treatment High Ferritin FCM Low Ferritin FCM Oral iron Target Serum ferritin µg/l Serum ferritin µg/l Day mg iron* 200 mg iron Ferrous sulfate 200 mg iron/day Weeks 4 52 Serum ferritin Iron dose*** <200 µg/l 1000 mg iron every 4 weeks to week 48** 200 to 500 mg iron <400 µg/l every 4 weeks to week µg/l No iron Serum ferritin Iron dose*** <100 µg/l 200 mg iron every 4 weeks to week µg/l No iron * Patients 66 kg: 500 mg iron on Days 0 and 7 ** Patients 66 kg: 500 mg iron on day of visit and 500 mg iron one week later *** No administration if TSAT level 40% Oral iron was withheld if ferritin >200 µg/l and restarted if/when ferritin <100 µg/l The last dose of FCM was administered at Week 48, and the last dose of oral iron was administered at week 52

9 Primary Endpoint Time to initiation of other anaemia management or occurrence of haemoglobin (Hb) trigger Other anaemia management was specified as ESAs, blood transfusion, or use of an alternative iron therapy (i.e. product, dosing schedule, or total dose different from study drug) Hb trigger was specified as two consecutive Hb values <10 g/dl on or after week 8, without an increase of 0.5 g/dl between consecutive values

10 Analysis of Primary Endpoint ITT population Kaplan-Meier survival analyses (log-rank test) Patients who did not meet the primary endpoint were censored at the time of study completion or discontinuation Up to three primary comparisons were made using a hierarchical step-down procedure: i. High ferritin FCM versus oral iron (if sig -> ii.) ii. iii. High ferritin FCM versus low ferritin FCM (if sig. -> iii.) Low ferritin FCM versus oral iron Supportive analysis: hazard ratios and 95% CI values (Cox proportional hazards modeling)

11 Key Secondary Endpoints Percentage of patients requiring blood transfusion Cumulative ESA doses over the study period Percentage of patients with a Hb increase 1 g/dl Change in hematologic and iron indices from baseline to end of study Change in egfr (MDRD-4) from baseline to end of study Percentage of patients requiring dialysis Percentage of patients discontinuing study drug due to intolerance Change in health-related quality of life (SF-36)

12 Study population Assessed for eligibility (n=938) Randomized (n=626) Excluded (n=312) Physician decision (n=5) Contravened eligibility criteria (n=269) Lack of consent (n=31) Other (n=7) Allocated to high-ferritin FCM (n=155) Allocated to low-ferritin FCM (n=154) Allocated to oral iron (n=317)

13 FIND-CKD 20 Countries 193 Active Sites Norway 1 site Sweden 1 site Denmark 4 sites Australia 14 sites United States of America 4 sites United Kingdom 30 sites France 5 sites Netherlands 6 sites Belgium 6 sites Germany 18 sites Switzer land 1 site Czech Republic 19 sites Austria 2 sites Poland 16 sites Romania 4 sites Portugal 6 sites Spain 11 sites Italy 17 sites Greece 21 sites Turkey 7 sites

14 Study Steering Committee Iain Macdougall, United Kingdom (Lead Investigator) Andreas Bock, Switzerland Fernando Carrera, Portugal Kai-Uwe Eckardt, Germany Carlo Gaillard, Netherlands Simon Roger, Australia David Van Wyck, United States

15 What Makes FIND-CKD Unique? It is the largest and longest trial ever conducted evaluating IV versus oral iron in patients with ND-CKD It is the largest and longest study ever conducted evaluating IV iron in patients with ND-CKD not receiving ESA therapy The primary endpoint was not a change in Hb level All the major clinical trials evaluating ESA therapy have failed to meet their primary endpoint (NHT, CREATE, CHOIR, TREAT)

16 Oral versus IV Iron Studies Patient Numbers

17 Oral versus IV Iron Studies Study Period

18 Example: Quinibi et al. 255 patients with GFR < 45, Hb < 11, TSAT < 25, Ferritin < 300 Randomized to FCM 1000 to 2000 mg i.v. until Ferr>500 or TSAT > 30) or 3 x 325 oral FeSO4 for 8 wks (195 mg elemental Fe+/d = 10'920 mg in 8 weeks) Ferritin Hb Difference: 0.44 g/dl Quinibi, Nephrol Dial Transplant 26: , 2011

19 What Makes FIND-CKD Unique? It is the largest and longest trial ever conducted evaluating IV versus oral iron in patients with ND-CKD It is the largest and longest study ever conducted evaluating IV iron in patients with ND-CKD not receiving ESA therapy The primary endpoint was not a change in Hb level All the major clinical trials evaluating ESA therapy have failed to meet their primary endpoint (NHT, CREATE, CHOIR, TREAT)

20 Results unfortunately currently embargoed by Vifor: publication policy reasons

21 Thank you!