Clinical trial NCT03212677: Safe and Effective Delivery of Supplemental Iron to Healthy Volunteers
Official title: Safe and Effective Delivery of Supplemental Iron to Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Iron
Lead sponsor: Tufts University
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2017-07-11
Enrollment: 226
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Iron deficiency-related anemia is the most common nutritional deficiency disorder in the world, mainly affecting children, women and older adults in underdeveloped countries. To combat iron deficiency, inorganic forms of iron (such as ferrous sulfate) are often used as an iron supplement. One big problem is that high levels of this kind of iron supplement produce negative health effects. This includes diarrhea, changes in the bacteria in the gut, as well as increased severity to malaria in young children in countries with high rates of that parasite.

Most forms of iron are not well absorbed and, therefore, pass through the intestine to be eliminated in the stool. This unabsorbed iron can be used by gut bacteria, disturbing the balance of healthful and potentially harmful bacteria in the colon, which can increase inflammation in the body.

In this study, the investigators are seeking to determine whether two new forms of iron cause fewer changes in the gut bacteria thus lowering inflammation while providing similar amounts of iron to the body. The findings from this research study are important because they will inform the development of safer treatments for iron deficiency.

Detailed description: The forms of iron currently available have serious adverse effects that limit their use in addressing prevalent iron deficiency. Iron-supplementation programs have been frustrated by the serious side effects of inorganic forms of iron, which, due to low enteric absorptive efficiency, must be given in relatively high levels (5-20 fold effective levels of heme-iron in foods). Those adverse effects include infectious diarrhea, changes in the gut microbiome and increased serious morbidity among iron-replete children in malaria-endemic areas. The underlying causes of these effects are thought to involve stress on the gut due to excess unabsorbed iron, which can be pro-oxidative and pro-inflammatory. In addition, unabsorbed, soluble iron can be used by the gut microbiome and favor the proliferation of pathogenic enteric bacteria which can contribute to the inflammatory response that leads to down-regulation of iron absorption. Lack of a safe and effective treatment leaves large numbers of children iron deficient, many with associated anemia. Thus, the burden of disease, which includes growth, cognitive and physical performance deficits as well as increased risk of infection, continues to climb in this age group.

The overall goal of this project is to generate evidence to support development of a modality of providing bioavailable iron that does not or produces less adverse effects in iron-replete individuals. The investigators will employ the commonly used iron supplement FeSO4 to compare with two novel forms of iron with features that suggest each may be a useful nutritional source of iron with fewer side effects than FeSO4. The first novel form of iron is a nanoparticulate formulation of iron hydroxide adipate tartrate (IHAT). The second novel form of iron is an organic fungal iron metabolite, Aspiron, which has recently been developed by using a food-grade Aspergillus oryzae cultured in iron-fortified media.

The investigators will evaluate these forms of iron using a randomized clinical trial approach that will robustly test the formal hypotheses and yield useful answers to the primary questions about the relative safety and efficacy of these novel forms of iron in iron-replete subjects. This study is divided to two phases. In Phase I, the investigators will determine of effects of form of low-dose, supplemental iron. Three forms of iron administered at the dose of 60 mg Fe/d will be evaluated against the primary outcomes of ex vivo malarial infectivity, bacterial proliferation potential (also assessed ex vivo) and gut inflammation, and other relevant outcomes in adults. In this protocol the investigators refer to this set of indicators as the "safety profile". The justification for providing 60 mg Fe/d is based on the World Health Organization (WHO) recommendation for daily supplementation for non-anemic, pregnant women with 30-60 mg Fe/d. In addition, the effects on those outcomes of ferrous sulfate administered daily (60 mg Fe/d) vs. weekly (420 mg Fe administered in one weekly dose) will be compared. There is great practical value in addressing this hypothesis of whether a weekly dose can be administered without adverse effects. Nested within this design will be a second comparative study of effects in iron-replete children and adults to validate the applicability of data obtained in adults to children.

For the forms of iron found to produce no adverse effects at the 60 mg Fe/d dose level, Phase II of the study will be conducted in which such forms will be tested at a higher, therapeutic dose of 120 mg Fe/d against the same outcomes.

Eligibility criteria: Inclusion Criteria:

* Age range: 50-80 years
* BMI range: 18-35
* Men and post-menopausal women (defined as no menses for \> 1year or S/P hysterectomy with bilateral oopherectomy)
* Typical bowel pattern: at least 1 stool every other day
* Willing to take iron and be randomized into study intervention group
* Willing to abstain from recreational drug use and consumption \> 2 alcoholic drinks per day during study participation
* Will not be undergoing colonoscopy in the 2 months before, or during the course of the study

Exclusion Criteria:

* Any major illness or condition that may interfere with study outcomes at the discretion of the study MD
* Personal history of G-6-P (glucose-6-phosphate dehydrogenase) deficiency
* Diabetes Type 1 \& Type 2 or use of any pharmacological treatment for diabetes
* Endocrine disorders including diabetes, unstable thyroid disease (dose adjustment of thyroid replacement in the past 6 months), adrenal disease, pheochromocytoma or parathyroid disease
* Recent history of inflammatory diseases (for example: rheumatoid arthritis, lupus)
* Use tumor necrosis factor (TNF) blockade medication, methotrexate, or other immune-modulating drugs
* Steroid use (except for non-prescription topical and nasal steroids, e.g. Flonase)
* If participant is on hormone replacement therapy with estrogen, testosterone or growth hormone, has the dosage regimen changed in the past month, or expected to change during course of study
* History of myocardial infarction, stroke or transient ischemic attack (TIA), coronary artery bypass graft, stenosis \>50% diagnosed within the past 1 year or acute unstable cardiovascular disease.
* Clotting/bleeding disorders or ongoing anticoagulant use: coumadin (warfarin), Eliquis, Xarelto, Pradaxa
* GI diseases, conditions or medications known to influence GI absorption including active peptic ulcer disease or inflammatory bowel disease (such as ulcerative colitis, Crohn's disease), pancreatic insufficiency, celiac disease, malabsorption disorders (other than lactose intolerance)
* Hx of stomach or bowel resection (other than appendectomy), gastric bypass or other bariatric weight loss procedure
* Regular use (\> 2 times per week) of acid lowering medication: antacids, proton pump inhibitors (PPI), H2 blockers
* History of eating disorder anorexia, bulimia or binge-eating in the past 5 years
* Actively undergoing dialysis
* Inadequately controlled hypertension (HTN) @ the discretion of study MD or Registered Nurse
* Certain psychiatric disorders including schizophrenia, bipolar major depression or psychosis (depression OK, if stable on treatment regimen for \> 6 months)
* Immunodeficiency condition, HIV or AIDS
* Cancer of any type (except for non-melanoma skin) in past year
* Actively using cancer chemotherapeutic agents
* Regular use of acetylsalicylic acid (ASA); NSAIDs; Cox-2 inhibitors. However, infrequent NSAID use (not on a regular scheduled basis) allowed if able to hold NSAIDs x 72 hours prior to all blood draws
* Infection or febrile illness within 2wks prior to study or study blood draws, may rescheduled \>2wks after resolution of symptoms
* Hx of malaria; or vaccination or treatment for malaria, or antimalarial prophylaxis in past 3 months
* Seizure disorders (OK if well managed with medication: no seizure activity x 3 yrs)
* Hx splenectomy
* Chronic liver disease such as hepatitis B, C or cirrhosis
* Use of fiber supplements, laxatives or stool softeners, unless willing to maintain consistent dose for 2 weeks prior to entry and for duration of study
* Colonoscopy procedure or prep within 2 months prior to or during study
* Antibiotic use (including dental prophylaxis use within 3 months prior to or during study participation). Non-prescription topical antibiotics OK.
* If using probiotic or prebiotic foodstuffs or pills/capsules, will dosage regimen change during course of study?
* Inability to deliver stool sample to center within 18 hours of bowel movement
* Alcohol use on average \> 2 servings/day or \> 14 servings/wk (Serving size: 12oz beer/4oz wine/2oz hard liquor) or self-reported binge drinking
* Current use of iron supplement or other nutritional supplements containing iron
* Use of dietary supplements containing vitamins (except Ca+, Vit D), minerals, herbal other plant-based preparations, fish oil supplements (including cod liver oil) or homeopathic remedies x 2 weeks prior to or during study. If individual wishes to participate, must stop these supplements \>2 weeks prior to study.
* Inadequate venous access or history of a bilateral mastectomy with nodal dissection
* Participation in other research study during the same time period
* No social security number (required for stipend payment)
* Iron saturation outside of normal range
* Hemoglobin (Hgb) \< 11.7 (females) \< 13.2 (males)
* Serum creatinine \> 1.5 mg/dl
* Fasting blood sugar \>126 mg/dL
* Serum glutamic oxaloacetic transaminase (SGOT) \> 1.5x upper range of normal
* Serum glutamic-pyruvic transaminase (SGPT) \> 1.5x upper range of normal mg/dl in absence of benign cause, i.e.: Gilbert's syndrome

Primary outcomes:
measure: Malaria infectivity
timeFrame: 4 weeks
measure: Bacterial proliferation potential
timeFrame: 4 weeks
measure: Fecal calprotectin
timeFrame: 4 weeks
Secondary outcomes:
measure: Biochemical markers of systemic inflammation, such as plasma cytokines
timeFrame: 4 weeks
measure: Biochemical markers of intestinal inflammation, such as fecal cytokines
timeFrame: 4 weeks
measure: Intestinal microbiome
timeFrame: 4 weeks
measure: Fecal short chain fatty acids
timeFrame: 4 weeks
measure: Biochemical markers of redox stress, such as F2α-isoprostanes
timeFrame: 4 weeks
measure: Biochemical markers of iron status, such as ferritin
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
Study officials:
affiliation: Tufts Univeristy
name: Simin N Meydani, DVM, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tufts University
name: Gerald F Combs, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lewis ED, Wu D, Mason JB, Chishti AH, Leong JM, Barger K, Meydani SN, Combs GF. Safe and effective delivery of supplemental iron to healthy older adults: The double-blind, randomized, placebo-controlled trial protocol of the Safe Iron Study. Gates Open Res. 2021 Feb 9;3:1510. doi: 10.12688/gatesopenres.13039.2. eCollection 2019.