PITTSBURGH--A federally funded, University of Pittsburgh research project, testing whether children with asthma attacks benefit from high doses of vitamin D, will be altered following complaints from an outside researcher to federal officials that the study was "unethical."
Bruce Davidson, a pulmonary and critical care researcher in Seattle who helped perform a similar study with children in Qatar, was bothered that the study run by Pitt out of Children's Hospital of Pittsburgh of UPMC and three other U.S. sites was proposing to give half of the 400 participants who already have low vitamin D levels, a placebo with no vitamin D for a year.
"It is unethical to treat children known to be deficient in vitamin D with placebo," Davidson wrote in a letter in August to the National Heart, Lung and Blood Institute, a division of the National Institutes of Health. The NIH is providing $2.3 million in funding over three years and is overseeing the study, which is still recruiting participants 6 to 13 years-old and has not yet begun.
In conversations with nine experts on bioethics, vitamin D, bone health and asthma -- none of whom were involved in the study -- the Pittsburgh Post-Gazette found that not all of them agree with Davidson that using a no-dose placebo is unethical.
By using a no-dose placebo and comparing it to a high dose of 4,000 international units a day, the study's results "hopefully will be black and white" about what works and what doesn't, said Michael Holick, an expert on vitamin D and its effects on humans. "Whereas, if you gave the (control group) kids 600 units (a day) the answers would be gray."
But some prominent experts do agree with Davidson, arguing that all of the participants should at least be given a maintenance dose of vitamin D to ensure their health and development.
"If I was on an (Institutional Review Board that needs to approve such studies at Pitt) I would have recommended that the control group get a maintenance dose" instead of a placebo, Neville Golden, a professor of pediatrics at Stanford University and an expert on bone health in children, said in an interview. "They could definitely get a valuable result" without using a no-dose placebo.
With experts divided, Davidson's concern was enough that the NHLBI convened its Data Safety Monitoring Board and investigated the issues he brought up, which included that the study would likely involve a significant percentage -- if not a majority -- of minority children. Blacks are more likely to have asthma for a variety of reasons, and low levels of vitamin D than white children because their darker skin makes it harder to produce vitamin D from the sun.
"When issues are raised, we take them very, very seriously," James Kiley, director of the NHLBI's division of Lung Diseases, where the study is overseen, said in an interview. "There are a number of things that will be done as a result of Dr. Davidson's concerns."
"We want to make sure that all the trials are safe and ethical," Kiley said.
Changes will be made to the inclusion and exclusion criteria for the study -- which determines which children are eligible to participate -- as well as the consent form that families are given before agreeing to participate, he said.
How families are updated during the yearlong study also will be changed, he said, and there will be additional monitoring of the study by the NHLBI.
Exactly what the specific changes will be is not known, however. The monitoring board made recommendations to Pitt and its lead investigator, researcher Juan Celedon, director of the Pediatric Asthma Center at Children's.
"Dr. Celedon started making some changes (to the study) almost as soon as Dr. Davidson came to us" with his concerns this past summer, Kiley said.
Celedon, Pitt and Children's declined to answer questions about the study beyond an emailed statement from Children's spokesman Marc Lukasiak that said, in part, that the "health and safety of our trial participants is our top concern."
Reached by phone, Richard Guido, the chairman of Pitt's IRB, which ultimately will have to approve any changes to the study, said he had no comment.
Celedon began the study in 2014 with a smaller pilot of 24 children in Pittsburgh that did not use a no-dose placebo, and instead used a maintenance dose of 200 units a day. Children's has dubbed the larger study the "Vit-D-Kids" asthma study and undertaken an advertising campaign to recruit participants, which is still ongoing.
Media representatives at all three other sites that are also recruiting children for the study -- St. Louis Children's Hospital, Boston Children's Hospital and UCSF Benioff's Children's Hospital in San Francisco -- did not make their lead investigators available to answer questions and referred the Post-Gazette back to Celedon and Pitt.
That lack of transparency is nothing new to Davidson, who also was rebuffed by Pitt, Celedon and representatives from all three sites when he began raising questions about the study's format this past summer.
The fact that everyone involved but the federal government refuses to discuss the case "is wrong," Davidson said.
"The research is public, and publicly funded, and the hospitals advertise it on their web sites and they say, 'Call us if you have questions,'" he said. "I imagine (they won't answer questions because) they're embarrassed about it."
Davidson's attention was drawn to Celedon's study this summer because he and several colleagues in Qatar earlier this year finished the analysis of their own study -- published in the journal Chest in September -- examining the effects of vitamin D on children with asthma who had low levels of vitamin D.
But in their study -- which looked at whether an initial, very high dose of vitamin D was better than daily supplementation -- they decided it was not acceptable to use a no-dose placebo.
"Since the American Academy of Pediatrics had recommended a minimum daily intake of 400 International Units, we did not consider a nonsupplemental (placebo) control group appropriate," he and his colleagues wrote in the journal article.
Research into the effects that healthy levels of vitamin D have on a variety of chronic diseases -- not just asthma, but cancer, heart disease, multiple sclerosis, the common cold and others -- has been a hot topic for much of the last decade.
The working theory is that vitamin D helps with asthma and other conditions by boosting the immune system, helping the body fight back. Persistently low levels of vitamin D in kids can rarely result in rickets, a softening of the bones, but can lead to other health issues.
Multiple studies in recent years have examined whether vitamin D helps reduce asthma attacks in adults and children. None of them, however, focused solely on participants with low levels of vitamin D like Celedon is now doing -- which is a big reason why even those researchers who object to giving a no-dose placebo to kids would like there to be changes made so his study can go forward.
"I think it's a particularly important trial because kids are underrepresented in clinical trials on this," said Adrian Martineau, a professor of respiratory disease and infection at Queen Mary University of London, and lead author on a journal article last year that looked at all the major published studies involving vitamin D and asthma.
Many of the results of previous studies show that boosting vitamin D tends to help those who have low levels of vitamin D the most.
But Alan Fleischman, a bioethicist and professor of pediatrics at the Albert Einstein College of Medicine in New York, said even though giving kids known to have low levels of vitamin D a supplement would help them, it is not unethical under federal regulations to give them a no-dose placebo.
"A placebo trial is ethical when children aren't being asked to give up something," he said. Giving them a placebo "does not increase risk to children who don't get an active drug."
That may be OK under the regulations, Davidson said, but particularly when it comes to doing research involving children "you're never supposed to abandon the standard of care."
Doing otherwise, he said, "is taking advantage of kids."
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