Dataset Information

Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation.

ABSTRACT:

Background

Research waste can occur when trials are conducted in the wrong populations. Vitamin D deficient populations are most likely to benefit from vitamin D supplementation. We investigated waste attributable to randomised controlled trials (RCTs) of supplementation in populations that were not vitamin D deficient.

Methods

In December 2015, we searched Pubmed, recent systematic reviews, and three trial registries for RCTs of vitamin D with clinical endpoints in adults, and 25-hydroxvitamin D (25OHD) survey data relevant to large (N ≥ 1000) RCTs. We investigated the proportion of RCTs that studied vitamin D deficient populations, temporal trends in baseline 25OHD, and whether investigators in large RCTs considered relevant 25OHD survey data or systematic reviews in their trial justifications.

Results

Of 137 RCTs of vitamin D with clinical endpoints, 118 (86%) reported baseline mean/median 25OHD, which was < 25, 25-49, 50-74, and ≥ 75 nmol/L in 12 (10%), 62 (53%), 36 (31%), and 8 (7%) RCTs, respectively. In 70% of RCTs, baseline 25OHD was > 40 nmol/L. Baseline 25OHD increased over time. Before 2006, 38%, 62%, 0% and 0% of RCTs had baseline 25OHD < 25, 25-49, 50-74, and ≥ 75 nmol/L respectively; in 2011-15, the respective proportions were 9%, 49%, 37%, and 6%. Of 12 RCTs with baseline 25OHD < 25 nmol/L, 8 had neutral findings. Of 25 large RCTs (18 completed, 7 ongoing), 1 was undertaken in a vitamin D deficient population, 3 in vitamin D insufficient populations, and 17 had, or probably will have, baseline 25OHD > 40 nmol/L. 44% (8/18) of large completed RCTs cited relevant prior population 25OHD data, and only 3/10 (30%) relevant prior systematic reviews.

Conclusions

Up to 70% of RCTs of vitamin D with clinical endpoints, 71% of large completed RCTs, and 100% of ongoing large RCTs could be considered research waste because they studied cohorts that were not vitamin D deficient.

SUBMITTER: Bolland MJ

PROVIDER: S-EPMC6171194 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation.

Bolland Mark J MJ Grey Andrew A Avenell Alison A

BMC medical research methodology 20181003 1

<h4>Background</h4>Research waste can occur when trials are conducted in the wrong populations. Vitamin D deficient populations are most likely to benefit from vitamin D supplementation. We investigated waste attributable to randomised controlled trials (RCTs) of supplementation in populations that were not vitamin D deficient.<h4>Methods</h4>In December 2015, we searched Pubmed, recent systematic reviews, and three trial registries for RCTs of vitamin D with clinical endpoints in adults, and 25 ...[more]

PMID: 30285729

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Project description:BackgroundResearch waste is estimated to be very common, but assessments of its prevalence and scope are rare. As an example, we assessed research waste in clinical research on calcium intake (assessing study design and endpoint type) and vitamin D supplementation (assessing endpoint type).MethodsWe examined 404 randomised controlled trials (RCTs) and observational studies of calcium intake (diet or supplements) and bone mineral density (BMD) or fracture, and 547 RCTs of vitamin D supplements, and assessed the proportion of studies that used surrogate or clinical endpoints. For studies with BMD or fracture as an endpoint, we estimated when the 'tipping' point occurred indicating the need for RCTs with fracture as an endpoint (based on cumulative meta-analyses of BMD RCTs, and chronological review of observational studies), and whether each study published at least 5y after the tipping point was novel, added new clinical knowledge or was research waste.ResultsObservational studies of calcium intake and BMD or fracture outnumbered RCTs by 3.3-4.5 times. For both calcium intake and vitamin D supplements, studies using surrogate endpoints outnumbered studies using clinical endpoints by 1.6-3 times. Of 41 RCT publications of calcium intake and BMD or fracture published at least 5y after the tipping point in 1994, we considered that 19 (46%) lacked novelty, another 13 (32%) added no new clinical knowledge, and 30 (73%) were research waste. Of 204 observational study publications of calcium intake and BMD or fracture, 197 (96%) lacked novelty, another 5 (2%) added no new clinical knowledge, and 202 (99%) were research waste. Of 39 RCTs of vitamin D supplementation and BMD or fracture published at least 5y after the tipping point in 1999, 14 (36%) lacked novelty, another 13 (33%) added no new clinical knowledge, and 27 (69%) were research waste.ConclusionsA high proportion of studies of calcium intake since 2000 (95%) and trials of vitamin D supplements since 2005 (69%) on BMD or fracture represent research waste.

Project description:Scientific interest in possible extraskeletal effects of vitamin D first appeared in the 1930s soon after the structure of vitamin D was characterized, and increased in the 1980s with the development of assays of 25-hydroxyvitamin D status as a marker of vitamin D status, which in observational epidemiological studies was shown to be inversely associated with many nonskeletal diseases. This resulted in the start of seven large randomized controlled trials (n > 2000 participants in each) of vitamin D supplementation giving higher doses than previously used. The intervention periods in these trials collectively started in 2009 and continued to 2020. They have recruited participants, mostly of both sexes and over the age of 50 years, from many countries and have given either daily or monthly doses of vitamin D. Collectively, the trials have a wide range of outcomes with the main focus on the prevention of cancer, cardiovascular disease, and fractures, besides many other outcomes. The findings of four trials have been published, and they have shown that vitamin D supplementation does not prevent hard-disease endpoints, such as cardiovascular disease, cancer, fractures, or falls, aside from a possible beneficial effect against cancer mortality. In contrast, beneficial effects were seen for intermediate outcomes such as BMD of spine and hips, arterial function, and lung function, especially in people with vitamin D deficiency. The finding of a benefit primarily in people with vitamin D deficiency, if confirmed by the other trials, would support a population approach to preventing vitamin D deficiency using fortification rather than the high-risk approach of screening for deficiency combined with supplementation. The findings on other outcomes from the three published trials, along with the findings from the four unpublished trials, are expected within the next 2 to 3 years to clarify the role of vitamin D supplementation in preventing nonskeletal disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Project description:BackgroundThe achievement of target 25-hydroxyvitamin D [25(OH)D] concentrations in pregnancy may be altered by maternal obesity.ObjectiveThe authors examined the effects of maternal supplementation of 10 μg compared with 20 μg vitamin D3/d on maternal and umbilical cord 25(OH)D. The secondary aim was to investigate the influence of maternal BMI (in kg/m2) on the response of the primary outcomes.MethodsThe authors performed a 2-arm parallel double-blind randomized trial with 240 pregnant women recruited throughout the year in Northern Ireland. Women were stratified by BMI to receive 10 or 20 µg vitamin D3/d from 12 gestational wk (GW) until delivery. Maternal blood samples collected at 12, 28, and 36 GW and from the umbilical cord were analyzed for total serum 25(OH)D. A total of 166 women completed the study.ResultsMean ± SD 25(OH)D at 36 GW was 80.8 ± 28.2 compared with 94.4 ± 33.2 nmol/L (P < 0.001) (10 compared with 20 µg vitamin D3/d, respectively). In those classified with 25(OH)D <50 nmol/L at baseline and assigned 10 µg vitamin D3/d, mean 25(OH)D concentrations remained <50 nmol/L at 36 GW, whereas those <50 nmol/L at baseline and assigned 20 µg vitamin D3/d, had mean 25(OH)D concentrations ≥50 nmol/L at 28 and 36 GW. In women with obesity and 25(OH)D <50 nmol/L at baseline, the related mean umbilical cord 25(OH)D was deficient (<25 nmol/L) in both treatment groups, whereas those with obesity and 25(OH)D ≥50 nmol/L at baseline had an average umbilical cord 25(OH)D between 25 and 50 nmol/L in both treatment groups.ConclusionsSupplementation of 20 µg vitamin D3/d is needed to attain maternal and umbilical cord 25(OH)D concentrations ≥50 nmol/L on average, in those who start pregnancy with low 25(OH)D concentrations (<50 nmol/L). Under current recommendations, women with obesity and low 25(OH)D in early pregnancy are particularly vulnerable to maintaining a low 25(OH)D concentration throughout pregnancy and having an infant born with deficient 25(OH)D concentrations. This trial was registered at ClinicalTrials.gov as NCT02713009.

Project description:BackgroundThe extent and the progression of vascular calcification (VC) are independent predictors of cardiovascular risk in the haemodialysis population. Vitamin K is essential for the activation of matrix gla protein (MGP), a powerful inhibitor of tissue calcification. Functional vitamin K deficiency may contribute to the high VC burden in haemodialysis patients. In addition, haemodialysis patients are frequently treated with vitamin K antagonists, mainly to prevent stroke in atrial fibrillation, potentially compounding the cardiovascular risk in these already vulnerable patients. New oral anticoagulants (NOACs) are valuable alternatives to vitamin K antagonists in the general population, but their use in dialysis has been encumbered by substantial renal clearance. However, a recent pharmacokinetic study provided information on how to use rivaroxaban in haemodialysis patients.MethodsWe conduct a randomized, prospective, multicentre, open-label interventional clinical trial that will include 117 chronic haemodialysis patients with non-valvular atrial fibrillation, treated with or candidates for treatment with vitamin K antagonists. Patients will be randomized to a vitamin K antagonist titrated weekly to an international normalized ratio between 2 and 3, a daily dose of rivaroxaban of 10 mg, or a daily dose of rivaroxaban 10 mg with a thrice weekly supplement of 2000 µg vitamin K2. Cardiac computed tomography, pulse wave velocity (PWV) measurements and MGP sampling will be performed at baseline, 6 months, 12 months and 18 months. Primary endpoints include progression of coronary artery and thoracic aorta calcification and changes in PWV. Secondary endpoints are progression of aortic and mitral valve calcification, all-cause mortality, major adverse cardiovascular events, stroke and bleeding. The ClinicalTrials.gov database was searched to retrieve related trials.ResultsSeven trials, three of which are performed in the haemodialysis population, evaluate whether pharmacological doses of vitamin K1 or K2 retard progression of VC. Five studies compare the effect of warfarin and NOACs on progression of VC, the present study being the only conducted in the dialysis population.ConclusionVitamin K deficiency may be a modifiable cardiovascular risk factor in the haemodialysis population. Conversely, vitamin K antagonists may aggravate VC burden in haemodialysis patients. Several ongoing trials may provide an answer to these questions in the near future.

Dataset Information

Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation.

Background

Methods

Results

Conclusions

Publications

Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation.

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