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Treatment with iron chelators is hampered by important side\u2010effects, high costs, and the lack of availability in many countries with a high prevalence of hereditary anemias. In this phase III randomized placebo\u2010controlled trial, we assigned adults with non\u2010transfusion\u2010dependent hereditary anemias with mild\u2010to\u2010moderate iron overload to receive esomeprazole (at a dose of 40\u2009mg twice daily) or placebo for 12\u2009months in a cross\u2010over design. The primary end point was change of liver iron content measured by MRI. A total of 30 participants were enrolled in the trial. Treatment with esomeprazole resulted in a statistically significant reduction in liver iron content that was 0.55\u2009mg Fe\/g dw larger than after treatment with placebo (95%CI [0.05 to 1.06]; <jats:italic>p<\/jats:italic>\u00a0=\u20090.03). Median baseline liver iron content at the start of esomeprazole was 4.99 versus 4.49\u2009mg Fe\/g dw at start of placebo. Mean delta liver iron content after esomeprazole treatment was \u22120.57 (SD 1.20) versus \u22120.11\u2009mg Fe\/g dw (SD 0.75) after placebo treatment. Esomeprazole was well tolerated, reported adverse events were mild and none of the patients withdrew from the study due to side effects. In summary, esomeprazole resulted in a significant reduction in liver iron content when compared to placebo in a heterogeneous group of patients with non\u2010transfusion\u2010dependent hereditary anemias. From an international perspective this result can have major implications given the fact that proton pump inhibitors may frequently be the only realistic therapy for many patients without access to or not tolerating iron chelators.<\/jats:p>","DOI":"10.1002\/ajh.26581","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T19:58:57Z","timestamp":1651003137000},"page":"924-932","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Proton pump inhibition for secondary hemochromatosis in hereditary anemia: a phase <scp>III<\/scp> placebo\u2010controlled randomized cross\u2010over clinical trial"],"prefix":"10.1002","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4258-3836","authenticated-orcid":false,"given":"Annelies","family":"van Vuren","sequence":"first","affiliation":[{"name":"Center for Benign Haematology Thrombosis and Haemostasis, Van Creveldkliniek, University 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