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Huge Clinical trial in Lucknow contradicts earlier knowledge abt benefit of Vit A supplementation & deworming

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  • Anant Bhan
    The Lancet, Early Online Publication, 14 March 2013 doi:10.1016/S0140-6736(13)60600-5Cite or Link Using DOI This article can be found in the following
    Message 1 of 1 , Mar 19 10:52 PM
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      This article can be found in the following collection: Public Health

      DEVTA: results from the biggest clinical trial ever

      In developing countries health resources are short, so it is particularly important that science should inform policy. In The Lancet, a landmark trial12 tests two so-called magic bullets of the international health community's armoury: pre-school vitamin A supplementation, assumed to reduce child mortality by a quarter;3 and intestinal deworming, assumed to improve child nutrition, growth, and cognitive development.4
      Richard Peto and colleagues taught us in the 1980s to “ask an important question, and answer it reliably” with large, simple randomised trials testing the effects on mortality of practicable treatments for common conditions.5 DEVTA epitomises this vision. It is the biggest drug trial ever undertaken, with 2 million pre-school children in India consuming four tonnes of vitamin A and eight tonnes of albendazole over 5 years. It is a credit to all participating: the scientists in Lucknow and elsewhere, the field staff, the anganwadi workers, and the mothers and children. DEVTA is of staggering size, but the delay in publication is equally staggering, in view of the important policy implications for India and the rest of the developing world. Data collection was completed in 2006 and preliminary results for vitamin A (but not deworming) were presented at a meeting in Turkey in 2007, with the presentation available online.6 Then silence until now, punctuated only by calls from us and others for the team to publish.78Today, the authors reveal that neither intervention showed a significant effect on child mortality in their trial.
      Before DEVTA, the randomised evidence base showed that vitamin A reduced mortality by a quarter, based on 17 trials in 194 795 children.9 DEVTA, with ten times the number of children (although contributing only about twice as much information, because of cluster effects) estimates mortality reduction at 4%, with 95% CIs ranging from an 11% reduction to a 3% increase (p=0·22). On the basis of their meta-analysis, the trial authors propose that DEVTA attenuates the global estimates of mortality reduction by half. Their forest plot suggests heterogeneity, confirmed in a sensitivity analysis in the Cochrane review:9 so an alternative interpretation is that vitamin A does not affect child mortality in all settings all of the time. If we accept the authors’ analysis that this trial simply reduces the global estimate of benefit by half, the question still remains as to why the maximum estimated mortality reduction of 11% is so substantially different from the estimate of the other 17 trials.9 Since there is clear evidence of vitamin A deficiency in the study site, this finding is unexpected. Had access to preventive and curative health-care interventions improved, as in many developing countries? Perhaps—even in settings of low service access, there have been substantial reductions in mortality due to diarrhoea and the incidence of measles,10—13 probably the main routes to mortality benefit in earlier trials.9 The interpretation of these findings in the context of existing research needs further debate, but what is clear is that DEVTA creates uncertainty around this intervention—or at least uncertainty around the effect size that has been attributed to vitamin A up until now. There could be shifting effects in public health nutrition over time; also, controlled trials of vitamin A are probably worthwhile and ethically justified.
      For deworming, the results are also somewhat surprising. A community trial of deworming children in Lucknow, completed in 1994, estimated an average weight gain of almost a kilogram.7 When DEVTA was set up in nearby rural areas, it was reasonable to assume that such effects would translate into long-term health benefits, making the hypothesis that deworming might affect child mortality worth testing. Yet DEVTA shows no significant effect of deworming on pre-school mortality (mortality ratio 0·95, 95% CI 0·89—1·02, p=0·16). Furthermore, the annual compliance monitoring in selected centres did not even suggest an effect on weight, although worm loads were light. Indeed, in Lucknow, one early trial completed in 1994 did show big effects on weight, but subsequent trials did not; this outcome mirrors trends globally, with older trials in Kenya estimating big effects on weight, but more recent trials showing little or no effect.7 In the Cochrane review,7 for most studies, community deworming effects on growth and nutrition have been limited or absent, apart from in isolated communities where worm burdens were high. Although debate about deworming currently centres on whether the intervention affects educational achievement,14 DEVTA highlights the debate about whether deworming of populations can lead to substantial long-term developmental benefits in the absence of demonstrable health effects.
      Click to toggle image size
      Full-size image (121K) Amy Toensing/National Geographic Society/Corbis
      Why were the results of DEVTA so delayed? Was it because the trial found no evidence of effect?1516 The authors shared DEVTA vitamin A results with the research and policy community in 2008, and they state that “feelings ran high”. As a result, the authors wanted to do further checks to ensure they were not “discredited by a malicious attack on details”.14 Reading the authors’ narrative, it sounds an unnerving experience for them. Belief disconfirmation bias is a recognised phenomenon. When people are faced with evidence that disconfirms their beliefs they subject it to intense critical evaluation; but when exposed to confirming evidence they take the evidence at face value. This phenomenon means that people might reject good science because, put simply, they don't like the results; and this biased assimilation of evidence leads to polarisation of attitudes.17 The believers become more entrenched on one side, with the holders of the evidence on the other, and policies are thrown into confusion.
      In Hindi, DEVTA means deity or divine being, and the divine signals emanating from this trial should not be lost. No-one would want to waste money on exaggerated benefits, and just the size of DEVTA shakes beliefs in current global policies promoting vitamin A and deworming to the core. Ironically, the largest drug trial in the world hasn't settled the policy questions, but has generated uncertainties. As an international community of scientists participating in policy, we must ensure that this trial, now its results are published, doesn't polarise, but becomes part of open, public, transparent debates to ensure the best use of finite resources to contribute to the health of children in developing countries.18
      DEVTA is a courageous study, and a watershed for best practice in research to inform international development. The delays, the authors have countered, were in part to ensure integrity of the data and because their resources were limited. So funders should invest—and invest heavily—in such studies, and not shy away from funding big trials because DEVTA did not show a difference.
      And what can researchers learn from DEVTA? Undoubtedly, the fact that there was no apparent effect detected delayed publication. The best way to underline this lesson for us all is to modify the criteria of a good trial to: “Ask an important question, answer it reliably; and publish the results promptly, irrespective of the findings”.
      We declare that we have no conflicts of interest.

      References

      1 Awasthi SPeto RRead SClark SPande VBundy Dthe DEVTA (Deworming and Enhanced Vitamin A) teamVitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial.Lancet 2013published online March 14. http://dx.doi.org/10.1016/S0140-6736(12)62125-4.
      2 Awasthi SPeto RRead SRichards SMPande VBundy Dthe DEVTA (Deworming and Enhanced Vitamin A) teamPopulation deworming every 6 months with albendazole in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial.Lancet 2013published online March 14. http://dx.doi.org/10.1016/S0140-6736(12)62126-6.
      3 UNICEFVitamin A supplementation: a decade of progressNew York, NY: UNICEF, 2007.
      4 WHODeworming to combat the health and nutritional impact of soil-transmitted helminths. Biological, behavioural and contextual rationalehttp://www.who.int/elena/titles/bbc/deworming/en/index.html(accessed Feb 13, 2013).
      5 Yusuf SCollins RPeto RWhy do we need some large, simple randomized trials?Stat Med 19843409-422CrossRef |PubMed
      6 Awasthi SPeto RRead SBundy D, et alSix-monthly vitamin A from 1 to 6 years of age. DEVTA: cluster randomised trial in 1 million children in North Indiahttp://www.micronutrientforum.org/meeting2007/Tuesday/T1445%20Awasthi.pdf(accessed March 8, 2013).
      7 Taylor-Robinson DCMaayan NSoares-Weiser KDonegan SGarner PDeworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performanceCochrane Database Syst Rev 201211:CD000371PubMed
      8 Yngve AMargetts BSachdev HPGuidance on publishing results and how we operate evidence-based policyPublic Health Nutr200811655-656PubMed
      9 Imdad AHerzer KMayo-Wilson EYakoob MYBhutta ZAVitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of ageCochrane Database Syst Rev 201012CD008524PubMed
      10 Murray CJVos TLozano R, et alDisability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990—2010: a systematic analysis for the Global Burden of Disease Study 2010Lancet 20123802197-2223Summary | Full Text |PDF(1135KB) CrossRef | PubMed
      11 Liu LJohnson HLCousens S, et alfor the Child Health Epidemiology Reference Group of WHO and UNICEFGlobal, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000Lancet 2012379:2151-2161Summary | Full Text | PDF(721KB) CrossRef | PubMed
      12 Lozano RNaghavi MForeman K, et alGlobal and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010Lancet 20123802095-2128Summary | Full Text |PDF(1201KB) CrossRef | PubMed
      13 The Million Death Study CollaboratorsCauses of neonatal and child mortality in India: a nationally representative mortality surveyLancet 20103761853-1860Summary | Full Text | PDF(704KB) CrossRef | PubMed
      14 Hawkes NDeworming debunkedBMJ 2012346e8558PubMed
      15 Chalmers IGlasziou PGodlee FAll trials must be registered and the results publishedBMJ 2013346f105PubMed
      16 Godlee FTimely publication of all trial results may mean less overtreatmentBMJ 2013346f159PubMed
      17 Lord CGRoss LLepper MRBiased assimilation and attitude polarization: the effects of prior theories on subsequently considered evidenceJ Pers Soc Psychol 1979372098CrossRef | PubMed
      18 Karlan DFiennes CDevelopment controversy a sign of sophistication. Stanford Social Innovation Review.http://www.ssireview.org/blog/entry/development_controversy_a_sign_of_sophistication(accessed Jan 21, 2013).
      a Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK
      b Department of Public Health and Policy, University of Liverpool, Liverpool, UK
      c Sitaram Bhartia Institute of Science and Research, New Delhi, India
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