The 23-month-old, who was being treated at Alder Hey Children’s Hospital in Liverpool died at 2.30am, Kate James and Thomas Evans said on Facebook.
The youngster was at the centre of a legal battle over his treatment that touched hearts around the world.
The post on Facebook said: “Our baby boy grew his wings tonight at 2:30 am. We are heart broken. Thank you everyone for all your support.”
Evans, 21 and James, 20, had fought to take their son to a foreign hospital for treatment for a degenerative medical condition, but lost a final court appeal on Wednesday.
His parents said that the youngster had defied doctors’ expectations and they took their case to the Court of Appeal, but the application to take him abroad was rejected.
Tom Evans said their lives had been “turned upside down” by the “intense focus” his case had received.
“Our little family along with Alder Hey has become the centre of attention for many people around the world and it has meant we have not been able to live our lives as we would like,” he said.
The attention and emotion garnered by Alfie’s plight and his parents’ determined public campaign to get the treatment they believed he needed led to high tensions between supporters and staff at Alder Hey.
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