Potential of Prebiotic Galacto-oligosaccharides in Improving Efficacy and Safety of Oral Iron Supplementation in HIV-infected Children

Study Overview
=================
Brief Summary
-----------------
The objectives of this randomized controlled trial in virally suppressed HIV-positive children with anemia and/or depleted iron stores are to determine the effect of prebiotic galacto-oligosaccharides (GOS) as adjunct treatment to 12 weeks of oral iron supplementation on: iron status measured by conventional iron status biomarkers, fractional absorption of iron (fraction of total body iron per day, measured as Kabs, the slope of 57Fe isotopic dilution) and mean total amount of iron absorbed each day (mg Fe/day, calculated as Kabs x mean total body iron), systemic and gut inflammation, as well as gut mucosal integrity, gut microbiome composition, and adverse effects and gastrointestinal side-effects.

Detailed Description
-----------------
Iron deficiency anemia (IDA) in childhood can impair growth and cognition, as well as reduce school performance. Furthermore, anemia frequently complicates pediatric HIV infection and predicts disease progression and mortality. However, there is no international consensus on the treatment of ID and IDA in HIV-infected children, because of concerns around the efficacy and safety of oral iron supplements. Recent studies have suggested that oral iron supplements may increase gut inflammation in African children. This could be particularly detrimental in HIV-infected children, who may have gut immune activation, enteropathy and adverse shifts in the gut microbiome. Previous stable iron isotope studies from the ETH Laboratory of Human Nutrition showed that the consumption of prebiotic galacto-oligosaccharides (GOS) together with supplemental doses of iron can increase iron absorption. In Kenyan infants, we further showed that the addition of GOS to an iron-containing micronutrient powder mitigated the adverse effects of iron on the gut microbiome. Thus, we hypothesize that providing GOS as adjunct treatment to oral iron supplementation will improve efficacy (iron absorption and iron status), reduce systemic and gut inflammation, improve mucosal integrity, and mitigated iron-induced alterations in the gut microbiome, adverse events and gastrointestinal side-effects in virally suppressed HIV-infected children.

Official Title
-----------------
Improving Efficacy and Safety of Oral Iron Supplementation in HIV-infected Children by Providing Prebiotic Galacto-oligosaccharides as Adjunct Treatment: A Randomized Controlled Trial

Conditions
-----------------
Iron Deficiency, HIV

Intervention / Treatment
-----------------
* Dietary Supplement: Galacto-oligosaccharides
* Other: Maltodextrin
* Dietary Supplement: Ferrous fumarate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 10-15 years at baseline; Mild to moderate micro- and normocytic anaemia defined as Hb ≥8.0 and <11.5 / 12 g/dL (children 10-11 / 12-15 years) plus mean corpuscular volume ≤91.5 fL and/or iron deficiency defined as ferritin <30 µg/L or sTfR >8.3 mg/L; Body-Mass-Index-for-age Z-scores (BAZ) -3 to 2 SD of reference population; HIV criteria: HIV RNA viral load <50 copies/mL (measured as part of routine care); Willingness of caregiver to participate in the study; Caregiver speaks English, Afrikaans or isiXhosa; The informed consent form has been read and signed by the caregiver (or has been read out to the caregiver in case of illiteracy) plus assent needs to be obtained from the child; Residence in the study area for the period of the study. Exclusion Criteria: Child received iron supplements or antibiotic treatment 3 months prior to study start; Acute illness or other conditions that in the opinion of the PI or co-researchers would jeopardize the safety or rights of a participant in the trial or would render the participant unable to comply with the protocol; Participants taking part in other studies involving medical or physical interventions.

Ages Eligible for Study
-----------------
Minimum Age: 10 Years
Maximum Age: 15 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50 mg oral iron as ferrous fumarate (FeFum) with 7.5 g galacto-oligosaccharides<br> | Dietary Supplement: Galacto-oligosaccharides<br>* Prebiotic galacto-oligosaccharides (GOS)<br>* Other names: Prebiotic;Dietary Supplement: Ferrous fumarate<br>* 50 mg iron as ferrous fumarate<br>|
| Placebo Comparator: 50 mg oral iron as ferrous fumarate (FeFum) with 7.5 g maltodextrin<br> | Other: Maltodextrin<br>* Maltodextrin (placebo)<br>Dietary Supplement: Ferrous fumarate<br>* 50 mg iron as ferrous fumarate<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Iron status: Serum Ferritin (ug/L) (SF) | Change in SF concentrations over the study period of 12 weeks | 0, 6, 12 weeks | 
| Iron status: Soluble Transferrin Receptor (mg/L) (sTfR) | Change in sTfR concentrations over the study period of 12 weeks | 0, 6, 12 weeks | 
| Iron status: Transferrin saturation (%) (Tsat) | Change in Tsat concentrations over the study period of 12 weeks | 0, 6, 12 weeks | 
| Iron status: Hemoglobin (g/dL) (Hb) | Change in Hb concentrations over the study period of 12 weeks | 0, 6, 12 weeks | 
| Fractional iron absorption | Fractional absorption of iron will be determined by measuring Kabs, the slope of 57Fe isotopic dilution over the study period. From this value, mean total amount of iron absorbed each day (mg Fe/day, calculated as Kabs x mean total body iron) can be estimated. | 0, 6, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic inflammation: C-reactive protein (mg/L) (CRP) | Change in CRP concentrations over the study period of 12 weeks | 0, 6, 12 weeks | 
| Systemic inflammation: Alpha-1-acid glycoprotein (g/L) (AGP) | Change in AGP concentrations over the study period of 12 weeks | 0, 6, 12 weeks | 
| Hepcidin (nM) | Change in hepcidin concentrations over the study period of 12 weeks | 0, 6, 12 weeks | 
| Gut inflammation: Intestinal fatty acids binding protein (ng/ml) (IFABP) | Change in IFABP concentrations from baseline (0 weeks) to endpoint (12 weeks) | 0 and 12 weeks | 
| Gut inflammation: Fecal calprotectin (µg/g) | Change in fecal calprotectin concentrations from baseline (0 weeks) to endpoint (12 weeks) | 0 and 12 weeks | 
| Gut inflammation: Myeloperoxidase (µg /mL) (MPO) | Change in MPO concentrations from baseline (0 weeks) to endpoint (12 weeks) | 0 and 12 weeks | 
| Gut microbiome composition | Change in gut microbiome composition from baseline (0 weeks) to endpoint (12 weeks) | 0 and 12 weeks | 
| Fecal pH | Change in fecal pH from baseline (0 weeks) to endpoint (12 weeks) | 0 and 12 weeks | 
| HIV viral load (copies/ml) | Change in HIV viral load from baseline (0 weeks) to endpoint (12 weeks) | 0 and 12 weeks | 
| Gastrointestinal and respiratory symptoms | Self-reported gastrointestinal and respiratory symptoms assessed using a symptoms diary over the study period of 12 weeks | 12 weeks |