Unethical to restrict Vitamin D to half of the asthmatic children in RCT – June 2018

Administration of placebo vitamin D to non-consenting children

Lancet Respirtory Medicine, Volume 6, No. 6, e23–e24, June 2018,
Correspondence – Bruce L Davidson, Bruce L Davidson
https://doi.org/10.1016/S2213-2600(18)30198-X

I believe there are multiple important problems with David Jolliffe and colleagues' meta-analysis of vitamin D for asthma.1 The inclusion criteria presented are “double-blind, placebo-controlled randomised controlled trials of supplementation with vitamin D3 or vitamin D2 in patients with asthma”; however, the meta-analysis includes the study by Jensen and colleagues,2 in which control participants received vitamin D every day for almost 6 months. Despite the required Correction, in my opinion the meta-analysis 1 contains further misstatements.
Worse, it promotes the unnerving view that experimenters on human beings can withhold recommended minimal nutrition supplements from possibly nutritionally deficient, non-consenting children.

One misstatement that is repeated is that the selected studies are placebo controlled. This is stated twice in the Summary, in the Methods, twice in “Research in context”, and in the Results and Discussion. The Correction addresses the Results section only. To be clear: during 6 months of observation for clinical events, Dr Jensen's control participants received one placebo injection followed by 400 IU of vitamin D every day for 5 months and 29 days, 72 800 units of oral vitamin D altogether, compared with 172 800 units for the active treatment group.2 The authors' first Cochrane Group publication,3 which called Dr Jensen's 22-patient study 2 the only high-quality placebo-controlled study in children for the primary outcome, reviewed and excluded multiple studies like ours 4 for not being placebo controlled. Control group vitamin D dosing of Dr Jensen's patients is plainly described in the meta-analysis' table 1. Moreover, regarding the supposed placebo dosing, Dr Jensen's study publication itself states, “The investigators initially believed it was unethical to not provide vitamin D to the control group, who were suspected to have low serum 25(OH) D levels at recruitment; thus, all participants, irrespective of group assignment, were provided with Pediavit D400 (Euro-Pharm International Canada, Montreal, QC, Canada) and instructed to take 1 mL daily (400 IU vitamin D3) during the study. Adherence was assessed by weighing the bottles before dispensation and at their return at each clinic visit.”
Placebo has a definition: “an inert substance, with no therapeutic effect”. Two other North American clinical trial reports of paediatric vitamin D treatment 4, 5 have nearly the same statement declaring placebo dosing unethical and gave the exact same daily dose. It is unclear how the authors of the meta-analysis can reconcile inclusion of a study that administered 400 IU per day for 182 of 183 study days to both study groups with the repeated statement that this review is of placebo-controlled studies. The authors seem to have chosen a particular non-placebo controlled study for inclusion, dismissing the others.

The authors' meta-analyses 1, 3 only included double-blind studies, rating double-blinding higher quality 3 than other designs. This is not true for hard outcomes and would be news to the pioneering clinicians around the globe who proved the life-saving benefit, now used worldwide, of oral rehydration therapy for infant diarrhoea (studied unblinded vs intravenous fluid replacement),6 as well as oral anticoagulant (frequently studied unblinded—eg, vs aspirin)7 therapy to prevent stroke in adults with atrial fibrillation.

The Article also claims to be unique in investigating whether the effect of vitamin D on the risk of asthma exacerbation varies according to baseline concentrations. However, our trial found that benefit was restricted to children with the lowest baseline concentrations. This trial was published in abstract form in 2015 8 and cited in the author's Cochrane review in 2016, 3 and published in final article form in 2017,4 several months before The Lancet Respiratory Medicine Article—and we obtained our hypothesis about baseline vitamin D concentrations from the published work of yet other, prior researchers.

In my opinion, far worse than these misstatements, the authors promote and endorse the legitimacy of placebo-controlled studies for suspected or known vitamin D deficient, and by extension applicable to other nutritionally deficient, children.
First, children aged 2–14 years cannot give voluntary informed consent. What child would provide informed consent to skipping maintenance vitamin D supplementation for 6 months during these crucial years and risking subsequent bone and muscle health?
What adult would? What risks were stated in the consent forms for these placebo-controlled studies?

They seem to finesse this problem, knowing some patients with asthma will have deficient baseline concentrations, by taking the blood at baseline but not measuring the concentrations until later. Nearly every inhaled glucocorticoid treatment causes systemic glucocorticoid exposure, placing such children with asthma in a higher-risk group for reduced bone mass and increased fragility,9 noted in the package insert of every glucocorticoid inhaler.

The US National Heart, Lung, and Blood Institute has required principal investigator Dr Juan Celedon to make multiple revisions in an Otsuka Pharma/Pharmavite co-sponsored placebo-controlled trial of vitamin D in children with asthma.10 The two lead authors of the current American Academy of Pediatrics clinical guidance 9 on bone health, Dr Neville Golden and Dr Steven Abrams, each have stated they consider placebo control unethical for such paediatric studies. Dr Golden was further quoted: “They could definitely get a valuable result” without using a no-dose comparator group,10 as we did.4
Withholding consensus-recommended nutrients from non-consenting children seems artefactual, not scientifically necessary, and not a marker of high quality. It is not the new normal.

I declare no competing interests.

References

1. Jolliffe, DA, Greenberg, L, Hooper, RL et al. Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med. 2017; 5: 881–890
2. Jensen, ME, Mailhot, G, Alos, N et al. Vitamin D intervention in preschoolers with viral-induced asthma (DIVA): a pilot randomised controlled trial. Trials. 2016; 17: 353
3. Martineau, AR, Cates, CJ, Urashima, M et al. Vitamin D for the management of asthma. (CD011511.)Cochrane Database Syst Rev. 2016; 9
4. Alansari, K, Davidson, BL, Yousef, KI, Mohamed, ANH, and Alattar, I. Rapid vs maintenance vitamin D supplementation in deficient children with asthma to prevent exacerbations. Chest. 2017; 152: 527–536
5. Aglipay, M, Birken, CS, Parkin, PC et al. Effect of high-dose vs standard-dose wintertime vitamin D supplementation on viral upper respiratory tract infection in young healthy children. JAMA. 2017; 318: 245–254
6. Hirschhorn, N, Kinzie, JL, Sachar, DB et al. Decrease in net stool output in cholera during intestinal perfusion with glucose-containing solutions. N Engl J Med. 1968; 279: 176–181
7. Hart, RG, Pearce, LA, and Aguilar, MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007; 146: 857–867
8. Alansari, K, Alattar, M, Ibrahim, KY, Davidson, BL, Elnair, MB, and Mohamed, AN. A randomized trial of vitamin D to reduce pediatric asthma exacerbations. Am J Respir Crit Care Med. 2015; 191: A2621
9. Golden, NH, Abrams, SA, and Committee on Nutrition. Clinical report: optimizing bone health in children and adolescents. Pediatrics. 2014; 134: e1229–e1243
10. Hamill, SD. Complaint that Pitt kids' study on vitamin D and asthma is ‘unethical’ leads to changes. Pittsburgh Post-Gazette.
11. http://www.post-gazette.com/news/health/2017/11/01/Complaints-that-Pitt-kids-study-on-vitamin-D-and-asthma-is-unethical-lead-to-changes-NIH-NHLBI-Celedon-Davidson-Vit-D-

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