Diabetes Ther DOI 10.1007/s13300-017-0330-z ORIGINAL RESEARCH Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol Christoph Schindler . Andreas L. Birkenfeld . Markolf Hanefeld . Ulrike Schatz . Carsta Ko¨hler . Martin Gru¨neberg . Diethelm Tscho¨pe . Matthias Blu¨her . Christoph Hasslacher . Stefan R. Bornstein Received: October 11, 2017 Ó The Author(s) 2017. This article is an open access publication ABSTRACT deficiency) trial is a randomized, single-blind, proof-of-concept study with two treatment Introduction: HbA1c is the gold standard for arms. 140 men and women diagnosed with type glycemic control in pre-diabetes and diabetes. 2 diabetes and iron deficiency will receive either However, its validity has been questioned, placebo or ferric carboxymaltose (500 or especially in the presence of imbalanced iron 1000 mg) as intravenous infusions. The primary homeostasis. The CLEVER trial aims to evaluate outcome measure is the change in HbA1c level the relationship between iron deficiency and between baseline and after 12 weeks of treat- HbA1c (a biomarker for the diagnosis and ment. Secondary endpoints include change of therapeutic monitoring of type 2 diabetes) in a iron status and metabolic markers as well as randomized, placebo-controlled, multicenter treatment safety and tolerability. Furthermore, clinical trial. the potential clinical improvement in quality of Methods: The CLEVER (intravenous ferric Car- life and the reliability of HbA1c measurement in boxymaLtosE for improVement of mEtabolic patients with type 2 diabetes and iron defi- parameters in type 2 diabetes patients with iRon ciency will be investigated. Results: Both excessive iron and iron deficiency are associated with metabolic disorders; exces- Enhanced Content To view enhanced content for this sive iron is a risk factor for the development of article go to https://www.medengine.com/Redeem/ diabetes, whereas iron deficiency is associated 8DCCF06025616539. C. Schindler (&) M. Gru¨neberg Clinical Research Center Hannover and Center for Diabetes Center Herne, Herne, Germany Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany D. Tscho¨pe e-mail: [email protected] Herz- und Diabeteszentrum Nordrhein-Westfalen, Ruhr-Universita¨t Bochum, Bad Oeynhausen, A. L. Birkenfeld Á U. Schatz Á S. R. Bornstein Germany Medical Clinic and Policlinic III at the University Hospital Dresden, Dresden, Germany M. Blu¨her Department of Medicine at the University Hospital A. L. Birkenfeld Á M. Hanefeld Leipzig, Leipzig, Germany Centre for Metabolic Vascular Medicine, GWT-TUD, Dresden, Germany C. Hasslacher Diabetesinstitut Heidelberg and Department of C. Ko¨hler Clinical Studies, St. Josefskrankenhaus Heidelberg, Medical Consulting, GWT-TUD, Dresden, Germany Heidelberg, Germany Diabetes Ther with obesity and insulin resistance. It has been people that are diagnosed with pre-diabetes and suggested that iron increases insulin secretion diabetes and overtreatment when HbA1c is used in pancreatic beta-cells. CLEVER is the first as the primary indicator for glycemic control study to investigate the hypothesis that intra- [8–10]. venous substitution with ferric carboxymaltose The hypothesis to be tested in the CLEVER reduces HbA1c levels in patients with type 2 trial is that infusion of ferric carboxymaltose diabetes and iron deficiency, thereby improving (FCM) in patients with type 2 diabetes (T2DM) metabolic status and quality of life. and iron deficiency (ID) significantly reduces Clinical Trial Registration: ClinicalTrials.gov HbA1c, as has already been shown for other (NCT01513369). populations, e.g., nondiabetic people and Funding: GWT-TUD GmbH acts as sponsor of patients with type 1 diabetes. The reliability of the clinical trial. Financial support is provided HbA1c as an indicator for glycemic control will by Vifor Pharma. be assessed by the concomitant determination of fasting blood glucose and fructosamine. Keywords: FerinjectÒ; Ferric carboxymaltose; Moreover, the treatment of ID and metabolic HbA1c; Intravenous; Iron deficiency; Type 2 status improvement are expected to have an diabetes mellitus impact on the overall quality of life, which will be evaluated as a secondary endpoint. INTRODUCTION METHODS Iron influences glucose metabolism, and the link between iron metabolism and diabetes is Study Design well established [1, 2]. The relationship is bidi- rectional: iron affects glucose metabolism, and The CLEVER trial is designed as a multicenter, glucose metabolism interferes with several iron randomized, single-blind, proof-of-concept metabolic pathways. Whereas excessive iron study. Men and women with T2DM and ID are seems to be involved in the pathogenesis of randomized 1:1 to treatment with either FCM diabetes, iron deficiency has been linked with or placebo (0.9% NaCl solution) administered as obesity and insulin resistance. However, the an intravenous drip infusion over 30 min. The crosstalk between iron and energy metabolism aim of the study is to investigate a systematic as well as pathophysiological processes such as influence of ID on HbA1c. Participants will also inflammation, peripheral ischemia, and be monitored for the occurrence of treat- hypoxia is still not fully understood [3]. ment-emergent adverse events and overall Although the HbA1c value is well established health status. After confirming eligibility at the as a biomarker for the diagnosis of diabetes and screening visit (V1a), participants will enter the for monitoring the treatment of diabetes, its treatment phase, consisting of three visits. At reliability, especially under conditions of an visit 1b, baseline data for iron and metabolic altered iron homeostasis, has been challenged. status and quality of life will be recorded, and HbA1c levels appear to be affected by iron sta- the first dose of the study medication will be tus, as several studies have demonstrated administered. FCM (FerinjectÒ, Vifor Pharma increased values under conditions of iron Deutschland GmbH) will be dosed at 500 or depletion and iron deficiency anemia (IDA) in 1000 mg, depending on the individual body both type 1 diabetic and nondiabetic popula- weight and hemoglobin level (Fig. 1). This will tions [4–7]. On the other hand, iron substitu- be followed by an observation period of 30 min tion therapy results in a significant drop in to monitor the tolerability of the infusion. Iron HbA1c values [5–7]. There is evidence that status will be assessed based on the following iron-associated elevations and reductions in laboratory parameters: ferritin, transferrin, HbA1c do not properly reflect glycemic status, transferrin saturation (TSAT), soluble transferrin resulting in a spuriously exaggerated number of receptor (sTFR), serum iron, hemoglobin, mean Diabetes Ther corpuscular volume, mean corpuscular hemo- accordance with the ethical standards of the globin, % hypochromic cells, reticulocyte responsible committee on human experimen- hemoglobin content, and hepcidin. HbA1c, tation (institutional and national) and with the fasting blood glucose, and fructosamine as well Helsinki Declaration of 1964, as revised in 2013. as the insulin dosage used will serve as markers Informed consent was obtained from all to assess the metabolic status. Overall health patients for being included in the study. status and quality of life (QoL) will be evaluated by the Euro-QoL (EQ5D) questionnaire. In Study Population accordance with the summary of product char- acteristics (SmPC) and the study protocol, par- Men and women 18 years or older and diag- ticipants will receive a second dose of study nosed with T2DM as well as ID (defined as medication at visit 2a, which is scheduled for serum ferritin\150 ng/mL or transferrin satu- 4 weeks after the first dose. In cases where iron ration\25% if hemoglobin\14 g/dL; or serum deficiency persists, a third dose will be admin- ferritin\100 ng/mL or transferrin satura- istered approximately 5 days after the second tion\20% if hemoglobin C 14 g/dL and B 15 g/ dosing (visit 2b). Finally, primary and secondary dL) are eligible for inclusion in the CLEVER outcome parameters will be assessed at the trial. HbA1c values between 48 and end-of-study visit scheduled for 8 weeks after 69 mmol/mol (6.5% and 8.5%) were defined for the application of the final dose of study med- inclusion in the study based on data from ication. The visit schedule, including study-re- El-Agouza et al. [7], who showed that HbA1c lated actions/measures, is shown in Table 1. values of nondiabetic people treated with iron This trial is registered under the US National were reduced from 6.15% ± 0.62% to Institutes of Health ClinicalTrials.gov identifier 5.25% ± 0.45%. Consequently, it was hypothe- NCT01513369. All procedures followed were in sized that people with T2DM will demonstrate a Fig. 1 CLEVER study design. #Defined as *Control parameter: ferritin and transferrin saturation. HbA1c C 48 mmol/mol (6.5%) and\69 mmol/mol **If still iron deficient at V2a [serum ferritin\150 ng/mL (8.5%). ##Defined as serum ferritin\150 ng/mL or or transferrin saturation\25%], an additional dose of transferrin saturation\25% if hemoglobin\14 g/dL or 500 mg ferric carboxymaltose is given at V2b, otherwise it serum ferritin\100 ng/mL or transferrin satura- is not tion\20% if hemoglobin C 14 g/dL and B 15 g/dL. Diabetes Ther Table 1 Visit schedule and study-related actions/measures Visit 1a 1b 2a (2b)* 3 Week 0 Week 1 Week 5 Week 5 Week 13 Day 0 Day 7 – – 14 days – 14 days