Proton Pump Inhibition for Secondary Hemochromatosis in Hereditary Anemia, a Phase III Placebo Controlled Randomized Cross-over Trial in Progress
Authors: Van Vuren Annelies J. , Biemond Bart J. , Kerkhoffs Jean-Louis , Schols Saskia E.M. , Rijneveld A. W. , Nur Erfan , van Wijk Richard , Leiner Tim , Marx Joannes J.M. , van Beers Eduard J. 
Published: February 2020

Background: Iron overload is an emerging and underestimated problem in management of patients with hereditary anemia characterized by chronic hemolysis or ineffective erythropoiesis in the absence of regular red cell transfusions. Liver iron overload was present in 65% of the patients with hereditary hemolytic anemia who were never transfused. (Van Straaten et al., Br J Haematol. 2018) Iron-loading results from inadequately high intestinal iron absorption in response to low hepcidin and ultimately leads to iron overload in liver and other organs.
Iron chelation treatment is recommended, however drug-related toxicity is considerable, and treatment with iron chelators is expensive. Alternative treatment options for anemic patients not tolerating iron chelating agents are not available.
For adequate iron absorption, a low luminal pH is required to solubilize dietary iron salts, and to promote the reduction of dietary Fe(III) to Fe(II) by ferriredutases as only Fe(II) can be absorbed. Proton pump inhibitors (PPI) block gastric acid secretion and thereby impede iron absorption.
No studies are available that quantify effects of PPIs on dietary iron absorption in human. However, PPIs have shown to minimize phlebotomy requirements in patients with hereditary hemochromatosis. (Vanclooster et al., Gastroenterology. 2017)
Here we report the design of the currently ongoing PPI SHINE AGAIN study that evaluates the efficacy and safety of PPI treatment in patients with non-transfusion dependent hereditary anemias.
Methods: The PPI SHINE AGAIN is a phase 3, multicentre, randomized, placebo-controlled, cross-over clinical trial (Netherlands Trial Register, identifier [NL6659]). Transfusion independent adults with a form of hemolytic or dyserythropoietic anemia and mild to moderate iron overload are randomized in a 1:1 ratio to start with either esomeprazole 40 mg (administered orally BID) or placebo. Mild to moderate iron overload is defined as baseline liver iron content (LIC) of 3-15 mg Fe/g dry weight as measured by T2* MRI (MRQuantif Software Université de Rennes, https://imagemed.univ-rennes1.fr/en/mrquantif/quantif.php) without or on stable iron chelation therapy with no expected dose adjustments over the next 2 years. Additional criteria included baseline Hb ≤ 11.3 g/dL, expected to receive less than 4 red cell transfusions in the following 12 months, and no phlebotomies. The trial consists of two treatment periods of 12 months each (Figure), directly starting after baseline MRI.
The primary study end-point is effectiveness of PPI treatment defined as difference in delta LIC after one-year treatment with esomeprazole compared to one-year treatment with placebo. Key secondary endpoints include tolerability, quality of life (assessed by EQ5D-5L questionnaire) and cost-effectiveness (assessed by iMTA Productivity Cost Questionnaire and iMTA Medical Consumption Questionnaire).
Inclusion in the PPI SHINE AGAIN was completed in April 2019. Thirty patients are enrolled (non-transfusion dependent β-thalassemia n=10; pyruvate kinase deficiency n=8; congenital dyserythropoietic anemia n=3; sideroblastic anemia n=3; SCD n=2; HbH disease n=2; hereditary elliptocytosis n=1; G6PD deficiency n=1) with a median age of 44 years (IQR 28, 54). Results are expected Q3 2020. The trial is funded by ZonMW, The Netherlands Organization for Health and Research Development, and by the Innovatiefonds Zorgverzekeraars.

Disclosures
Nur: Novartis Pharmaceuticals: Consultancy. van Wijk:Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding.