A Double Blind Randomised Placebo-controlled Trial to Assess the Role of Iron Repletion in Glucose Homeostasis.

Study Overview
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Brief Summary
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In this study the investigators aim at addressing potential relationships between iron stores and glucose homeostasis. Iron (i.e. Ferric Carboxymaltose) will be perfused to pre-menopausal, iron-deficient non-anaemic women suffering from a chronic fatigue syndrome and parameters related to glucose homeostasis, parameters related to metabolic syndrome and inflammation will be measured before and after the intervention.

Official Title
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A Double Blind Randomised Placebo-controlled Trial to Assess the Effect of a Single Administration of Ferric Carboxymaltose of 1000 mg Iron on Glucose Homeostasis, in Iron-deficient Non-anaemic Women of Childbearing Age.

Conditions
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Iron-deficiency, Iron Toxicity, Glucose Metabolism Disorders (Including Diabetes Mellitus), Metabolic Side Effects of Drugs, Metabolic Disorder, Glucose, Safety Issues

Intervention / Treatment
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* Drug: Ferric Carboxymaltose
* Drug: 0.9% sodium chloride solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal women. Negative pregnancy test. Adequate contraception during the study period and for 1 month following study completion. Overt or relative iron deficiency at screening defined as follows: Serum ferritin <50 ng/mL AND transferrin saturation <20%, OR Serum ferritin <30 ng/mL. - Serum C-reactive protein: <5 mg/L if not on oral contraception, OR <20 mg/L if use of oral contraception Intolerance to oral iron formulations, or lack of efficacy of oral iron formulations. Minimum total score of 5 on the Visual analogic scale of fatigue. Normal levels of vitamin B12 and folic acid at screening. Availability and willingness to complete all study visits and procedures per protocol. Ability to sign an informed consent. Exclusion Criteria: Age <18 years. Menopause (defined as an amenorrhea of at least 12 months). Irregularly menstruating women (menstrual cycle outside a range of 24-38 days in duration) or experiencing overt metrorrhagia (simple spotting not being an exclusion criteria). Body mass index <18.5 kg/m2 or >30 kg/m2. Diabetes, defined as subjects with HbA1c ≥ 6.5 % and/or with fasting blood glucose levels ≥ 7 mmol/l and/or with a history of diabetes and/or by the use of anti-diabetic drugs. Hb level <117 g/L or known haemoglobinopathy or haemochromatosis. Blood transfusion within the last 12 weeks. Intake of iron preparations 4 weeks prior to screening. Known hypersensitivity to FCM or to any other iron preparation. Suspicion of major depressive disorder based on Patient Health Questionnaire. Known chronic inflammatory disease, including human immunodeficiency virus, hepatitis B or hepatitis C virus infection. Active malignancy. Decreased renal function (estimated glomerular filtration rate using the CKD-EPI equation<60 ml/min/1.73m2). Liver dysfunction (aspartate aminotransferase and alanine aminotransferase > 3-fold upper limit). Angina (Class IV). Asthma. Documented sleep apnoea. Important recent weight loss (>10% within the past month). Thyroid dysfunction (thyroid stimulating hormone >4 µU/mL). Reported weekly alcohol consumption > 14 standard drinks. Drug abuse (any drug consumption reported in the past 12 months).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind randomised placebo-controlled, parallel group comparative inferiority study with open-label extension divided in two parts: A first randomised and double-blind part in which FCM or placebo will be administered at baseline and post-baseline parameters assessed. A second non-randomised, non-blinded open-label extension part starting at the end of part 1, in which participants randomised to the placebo group will receive a FCM injection and post-baseline parameters assessed.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ferric carboxymaltose arm<br>Ferric carboxymaltose (FCM), 1000 mg iron element will be administered once by drip infusion (Intravenous route). FCM will be diluted in 250 mL of a commercially available sterile 0.9% sodium chloride solution prior to administration. Infusion time will be 15 minutes. | Drug: Ferric Carboxymaltose<br>* Ferric Carboxymaltose 1000 mg iron element will be diluted in 250 mL of a commercially available sterile 0.9% sodium chloride solution.<br>|
| Placebo Comparator: Placebo arm<br>A commercially available sterile, 250 mL, 0.9% sodium chloride solution will be administered by drip infusion (Intravenous route). Infusion time will be 15 minutes. At the end of the randomised part of the study, participants initially randomised to the placebo group will be included in a non-blinded open-label extension part and receive a FCM 1000 mg injection. | Drug: 0.9% sodium chloride solution<br>* 250 mL of a commercially available sterile 0.9% sodium chloride solution.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in glucose homeostasis status, assessed by a dynamic two-step hyperglycaemic clamp investigation. | two-step hyperglycaemic clamp investigation | at 28 days of the injection of the Investigation Product | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in ultrasensitive C-reactive protein (hs-CRP) levels at 14 days | plasma hs-CRP levels | at 14 days of the injection of the Investigation Product | 
| Change from baseline in ultrasensitive C-reactive protein (hs-CRP) levels at 28 days | plasma hs-CRP levels | at 28 days of the injection of the Investigation Product | 
| Change from baseline in interleukin-6 (IL-6) levels at 14 days | plasam IL-6 levels | at 14 days of the injection of the Investigation Product | 
| Change from baseline in interleukin-6 (IL-6) levels at 28 days | plasam IL-6 levels | at 28 days of the injection of the Investigation Product | 
| Change from baseline in adiponectin levels at 14 days | adiponectin | at 14 days of the injection of the Investigation Product | 
| Change from baseline in adiponectin levels at 28 days | adiponectin | at 28 days of the injection of the Investigation Product | 
| Change from baseline in interleukin-1beta levels at 14 days | IL-1b | at 14 days of the injection of the Investigation Product | 
| Change from baseline in interleukin-1beta levels at 28 days | IL-1b | at 28 days of the injection of the Investigation Product | 
| Change from baseline in blood pressure levels at 14 days | systolic and diastolic blood pressure | at 14 days of the injection of the Investigation Product | 
| Change from baseline in blood pressure levels at 28 days | systolic and diastolic blood pressure | at 28 days of the injection of the Investigation Product | 
| Change from baseline in the plasma lipid profile level at 14 days | plasma total- and HDL-cholesterol and plasam triglycerides | at 14 days of the injection of the Investigation Product | 
| Change from baseline in the plasma lipid profile level at 28 days | plasma total- and HDL-cholesterol and plasam triglycerides | at 28 days of the injection of the Investigation Product | 
| Change from baseline in the Homeostasis Model Assessment (HOMA-2) index at 14 days | Calculated Homeostasis Model Assessment (HOMA-2) index | at 14 days of the injection of the Investigation Product | 
| Change from baseline in the Homeostasis Model Assessment (HOMA-2) index at 28 days | Calculated Homeostasis Model Assessment (HOMA-2) index | at 28 days of the injection of the Investigation Product | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolomics, Transcriptomics, Ironomics