Iron Supplementation and Side Effects

Study Overview
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Brief Summary
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The objective of this study is to examine patient-reported gastrointestinal side effects, as well as iron status indicators, inflammatory markers and oxidative stress following administration of ferrous sulfate and iron-enriched Aspergillus oryzae supplementation.

Detailed Description
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Iron deficiency anemia (IDA) afflicts more than 2 billion people globally, making it the most prevalent nutrient disorder, today. Inadequate dietary intake of iron results in consequences like cognitive decline, fatigue, abnormal growth and adverse pregnancy outcomes. These ramifications have associated burdens on economical progression due to decreased market productivity. Inorganic iron supplements like ferrous sulfate (FeSO4) are most commonly used to treat IDA, however known associated side effects occur, decreasing compliancy in individuals. Moreover, inorganic iron salts present a large bolus of iron to the intestinal lumen, resulting in non-transferrin bound iron which leads to systemic inflammation and further exacerbation of chronic diseases. Organic iron compounds have strong potential to be utilized for supplementation, however only under circumstances in which contain high absorbance. Seventeen subjects were randomized in a three-armed, double-blinded crossover design to examine the differences among three treatments (FeSO4, ASP-s and placebo). Outcomes will be to assess acute inflammatory proteins, oxidative stress, iron status indicators, non-transferrin bound iron and gastrointestinal-related side effects.

Official Title
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Assessment of Gastrointestinal Symptoms and Other Side Effects After Three Week Oral Ferrous Sulfate and Iron-enriched Aspergillus Oryzae Supplementation in Young Female Subjects

Conditions
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Iron Deficiency Anemia, Iron Overload

Intervention / Treatment
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* Dietary Supplement: Ferrous sulfate
* Dietary Supplement: Aspiron
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-40 Female BMI < 30 kg/m2 Nonsmoker Non pregnant Non lactating No food allergies to wheat or dairy No history of gastrointestinal diseases/disorders Willing to discontinue use of vitamin/mineral supplements No medications that interfere with iron absorption No blood or plasma donations during study period Exclusion Criteria: History of gastrointestinal diseases or disorders Donating blood or plasma two weeks prior to study period On medications interfering with iron absorption Food allergies to wheat or dairy Pregnant or lactating Smoker Anemic (< 120 g/L) Ferritin > 40 ug/L

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Three armed, cross-over, double blinded design. Fifteen subjects will be randomized to treatment FeSO4, ASP or placebo for two week per treatment. Following each treatment, will be a two week washout period whereby subjects will not consume a supplement. Baseline and final blood draws of each treatment will be collected, in addition to serum collection at 0h, 1h, 2h, 3h, 4h following one dose to determine NTBI concentration curve.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ferrous sulfate<br>Subjects will take a 65 mg Fe capsule of ferrous sulfate, once daily for 21 consecutive days. The first treatment capsule will be consumed with a semi-purified meal (egg albumin, sugar, vanilla, maltodextrose and corn oil) and will have blood drawn hours 0, 1, 2, 3, 4, 6 and 8 post consumption. Serum will be used to determine non-transerrin bound iron, serum iron and percent saturation. Throughout the treatment period, subjects are informed to consume the capsule with food and report symptoms in an online questionnaire. Following three weeks treatment, participants return for a blood draw and oxidative stress indicators are measured. A three week washout period with placebo treatment takes place between treatment crossover. | Dietary Supplement: Ferrous sulfate<br>* 65 mg Fe as ferrous sulfate<br>|
| Experimental: Aspiron<br>AspironTM which is an iron-enriched supplement will follow the same guidelines and protocol as ferrous sulfate arm. Equivalent 65 mg Fe per capsule will be administered to participants. | Dietary Supplement: Aspiron<br>* 65 mg Fe as iron-enriched koji culture, called AspironTM<br>* Other names: Aspergillus oryzae;|
| Placebo Comparator: Placebo<br>Participants will follow the same description for the other two experimental treatment groups. Capsules will be given to subjects in opaque formation, therefore will be unable to differentiate the iron supplements. | Other: Placebo<br>* Contains maltodextrin.<br>* Other names: Starch pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the serum iron curve over 8 hours | Serum iron concentrations (µM) measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h). | 0,1,2,3,4,6 and 8 hours | 
| Area under the NTBI curve over 8 hours | NTBI (µM) concentrations measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h). | 0,1,2,3,4,6 and 8 hours | 
| Area under the percent transferrin saturation curve over 8 hours | Percent transferrin (%) saturation concentrations measured over 8 hours following consumption of either Ultimine, FeSO4, or placebo capsules at baseline (0h). | 0,1,2,3,4,6 and 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in protein carbonyls | Change from baseline to 21 days of protein carbonyls (nmol/mL) oxidative stress after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in thiobarbituric acid reactive substances (TBARS) | Change from baseline to 21 days of TBARS (µM) oxidative stress after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in hepcidin | Change from baseline to 21 days of inflammatory status via hepcidin (ng/mL) after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in C-reactive protein | Change from baseline to 21 days of inflammatory status via C-reactive protein (mg/L) after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in serum ferritin | Change from baseline to 21 days of iron status through serum ferritin (µg/L) after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in hemoglobin | Change from baseline to 21 days of iron status through hemoglobin (g/dL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in hematocrit | Change from baseline to 21 days of iron status through hematocrit (%) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in soluble transferrin receptor (sTFR) | Change from baseline to 21 days of iron status through sTFR (ng/mL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in total iron binding capacity (TIBC) | Change from baseline to 21 days of iron status through TIBC (µg/dL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in glomerular filtration rate (eGFR) | Change from baseline to 21 days of kidney function through eGFR (mL/min/1.73m2) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in creatinine | Change from baseline to 21 days of kidney function through creatinine (mg/dL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in blood urea nitrogen (BUN) | Change from baseline to 21 days of kidney function through BUN (mg/dL) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in aspartate aminotransferase (AST) | Change from baseline to 21 days of kidney function through AST (U/L) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Change in alanine aminotransferase (ALT) | Change from baseline to 21 days of kidney function through ALT (U/L) production after taking either Ultimine, FeSO4, or placebo for 3 consecutive weeks. | Baseline and 21 days | 
| Gastrointestinal symptoms | Symptoms questionnaire was distributed 3 days/week over 3 weeks/treatment. Total survey per supplemental treatment included 9 surveys. Participants described how the supplement contributed to gastrointestinal distress, such as, constipation, diarrhea, fatigue, abdominal discomfort, nausea, headaches, and heartburn. | 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ferrous sulfate, non-transferrin bound iron, oral iron supplement, oral iron supplement side effects