Methodological considerations in D-health cancer mortality results - authors' reply

No description availabl

The effect of vitamin D supplementation on acute respiratory tract infection in older Australian adults: an analysis of data from the D-Health Trial.

BACKGROUND: Observational studies have linked vitamin D deficiency with acute respiratory tract infection, but results from randomised controlled trials are heterogeneous. We analysed data from the D-Health Trial to determine whether supplementing older Australian adults, recruited from the general population, with monthly doses of vitamin D reduced the risk, duration, and severity of acute respiratory tract infections. METHODS: We used data from the D-Health Trial, a randomised, double-blind, placebo-controlled trial of monthly vitamin D supplementation, for which acute respiratory infection was a pre-specified trial outcome. Participants were supplemented and followed for up to 5 years. The trial was set within the Australian general population, using the Commonwealth Electoral Roll as the sampling frame, but also allowing some volunteers to participate. Participants were men and women aged 60 to 79 years (with volunteers up to age 84 years). Participants were randomly assigned to receive either vitamin D or placebo (1:1) using computer-generated permuted block randomisation, which was stratified by age, sex, and state. This was an automated process and the assignment list was not visible to study staff or investigators. Active and placebo gel capsules, identical in appearance to ensure masking, were labelled A and B and the code was not available to study staff or investigators. Participants were asked to report occurrence of acute respiratory symptoms over the previous month via annual surveys, and a subset of participants completed 8-week respiratory symptom diaries in winter. As part of our process to maintain blinding, a random sample of participants was selected for analysis of survey data and a separate sample selected for analysis of diary data. Blood samples were obtained from a random sample of participants (about 450 per group per year) and serum 25-hydroxy vitamin D (25[OH]D) concentrations were measured to monitor adherence. We used regression models to estimate odds ratios (OR), rate ratios, and rate differences. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763. FINDINGS: Between Jan 13, 2014, and May 26, 2015, 421 207 invitations were sent, 40 824 people were interested in participating, and 21 315 participants were recruited and randomised. Of the 16 000 participants selected for potential analysis of survey data, 15 373 were included in the analysis; 295 in the vitamin D group and 332 in the placebo group who were missing data for all five annual surveys were excluded from the analysis. Of the 3800 selected for potential analysis of diary data, 3070 were invited to complete the diaries because 730 had already withdrawn. 2598 people were included in the analysis; 218 people in the vitamin D group and 254 in the placebo group were missing data and were therefore excluded from the analysis. In blood samples collected from randomly sampled participants throughout the trial, the mean serum 25(OH)D concentration was 114·8 (SD 30·3) nmol/L in the vitamin D group and 77·5 (25·2) nmol/L in the placebo group. Vitamin D supplementation did not reduce the risk of acute respiratory tract infection (survey OR 0·98, 95% CI 0·93 to 1·02; diary OR 0·98, 0·83 to 1·15). Analyses of diary data showed reductions in the overall duration of symptoms and of severe symptoms, but these were small and unlikely to be clinically significant. INTERPRETATION: Monthly bolus doses of 60 000 IU of vitamin D did not reduce the overall risk of acute respiratory tract infection, but could slightly reduce the duration of symptoms in the general population. These findings suggest that routine vitamin D supplementation of a population that is largely vitamin D replete is unlikely to have a clinically relevant effect on acute respiratory tract infection. FUNDING: National Health and Medical Research Council

The effect of vitamin D supplementation on risk of keratinocyte cancer: an exploratory analysis of the D-Health randomized controlled trial

Background: Vitamin D may play a role in prevention of keratinocyte cancer (KC), but observational studies examining the association between serum 25-hydroxy vitamin D concentration and KC are largely uninformative because sun exposure causes both KC and vitamin D production. There is scant evidence from clinical trials of supplementary vitamin D. Objectives: To examine the effect of vitamin D supplementation on the risk of developing KC. Methods: We used data from the D-Health Trial, a randomized placebo-controlled trial of vitamin D supplementation (60 000 international units monthly for 5 years) among Australians aged >=60 years. KC outcomes were captured through linkage to a national administrative dataset for those who consented (N=20 334; 95%). We used negative binomial regression to analyse the incidence of KC excisions and the incidence of actinic lesions treated using cryotherapy or serial curettage, and flexible parametric survival models for analysis of time to first KC excision. Results: Randomization to vitamin D supplementation did not reduce the incidence of KC lesions treated by excision [incidence rate ratio (IRR) 1.04; 95% confidence interval (CI) 0.98-1.11], the incidence of actinic lesions treated using other methods (IRR 1.01; 95% CI 0.95-1.08) or time to first histologically confirmed KC excision (hazard ratio 1.02; 95% CI 0.97-1.08). However, in subgroup analysis vitamin D increased the incidence of KC excisions in adults aged ≥ 70 years (IRR 1.13, 95% CI 1.04-1.23; P-value for interaction = 0.01). Conclusions: Vitamin D supplementation did not reduce the incidence of KC or other actinic lesions. What is already known about this topic? Laboratory studies have suggested possible protective effects of vitamin D on skin cancer. Observational studies investigating the association between vitamin D and risk of keratinocyte cancer are largely uninformative as ultraviolet radiation both causes skin cancer and is the primary source of vitamin D. The evidence from randomized controlled trials of vitamin D is limited and inconclusive. What does this study add? This population-based, randomized controlled trial suggests that supplementing older adults with a high monthly dose of vitamin D for 5 years does not affect the incidence of keratinocyte cancer.</p

A randomized placebo-controlled trial of vitamin D supplementation for reduction of mortality and cancer: statistical analysis plan for the D-Health Trial

Background: Many observational studies have reported an association between vitamin D and non-skeletal health outcomes. The D-Health Trial was launched to determine if supplementing the older population with high monthly doses of Vitamin D can prevent cancer and premature mortality. The intervention is ongoing but here we provide a detailed statistical analysis plan for the primary and secondary outcomes of the D-Health Trial. Methods/Design: The D-Health Trial is a double-blind, randomized, placebo-controlled trial. Between February 2014 and May 2015, 21,315 people were randomized in a 1:1 ratio to receive monthly doses of either 60,000 IU of cholecalciferol (vitamin D3) or placebo for five years. The primary outcome is all-cause mortality and the secondary outcomes are total cancer incidence and colorectal cancer incidence. These will be ascertained via linkage to death and cancer registries. The primary analysis for each outcome will follow an intention-to-treat approach; we will use flexible parametric survival models to investigate the association between supplementation and time to an event. We describe in detail sophisticated secondary analyses that consider non-compliance and contamination due to off-study supplementation. Conclusions Publication of this statistical analysis plan in advance of the intervention's completion, and adherence to it, will avoid data-driven analyses of the primary and secondary outcomes and ensure robust reporting of outcomes.</p

The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality

Background: The effect of supplementing unscreened adults with vitamin D3 on mortality is unclear. We aimed to determine whether monthly doses of vitamin D3 influenced mortality in older Australians. Methods: We did a randomised, double-blind, placebo-controlled trial of oral vitamin D3 supplementation (60 000 IU per month) in Australians 60 years or older who were recruited across the country via the Commonwealth electoral roll. Participants were randomly assigned (1:1), using automated computer-generated permuted block randomisation, to receive one oral gel capsule of either 60 000 IU vitamin D3 or placebo once a month for 5 years. Participants, staff, and investigators were blinded to study group allocation. The primary endpoint was all-cause mortality assessed in all participants who were randomly assigned. We also analysed mortality from cancer, cardiovascular disease, and other causes. Hazard ratios (HRs) and 95% CIs were generated using flexible parametric survival models. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763. Findings: Between Feb 14, 2014, and June 17, 2015, we randomly assigned 21 315 participants, including 10 662 to the vitamin D group and 10 653 to the placebo group. In 4441 blood samples collected from randomly sampled participants (N=3943) during follow-up, mean serum 25-hydroxy-vitamin D concentrations were 77 (SD 25) in the placebo group and 115 (SD 30) nmol/L in the vitamin D group. Following 5 years of intervention (median follow-up 5·7 years [IQR 5·4-6·7]), 1100 deaths were recorded (placebo 538 [5·1%]; vitamin D 562 [5·3%]). 10 661 participants in the vitamin D group and 10 649 participants in the placebo group were included in the primary analysis. Five participants (one in the vitamin D group and four in the placebo group) were not included as they requested to be withdrawn and their data to be destroyed. The HR of vitamin D3 effect on all-cause mortality was 1.04 [95% CI 0·93 to 1·18]; p=0·47)and the HR of vitamin D3 effect on cardiovascular disease mortality was 0·96 (95% CI 0·72 to 1·28; p=0·77). The HR for cancer mortality was 1·15 (95% CI 0·96 to 1·39; p=0·13) and for mortality from other causes it was 0·83 (95% CI 0·65 to 1·07; p=0·15). The odds ratio for the per-protocol analysis was OR 1·18 (95% CI 1·00 to 1·40; p=0·06). In exploratory analyses excluding the first 2 years of follow-up, those randomly assigned to receive vitamin D had a numerically higher hazard of cancer mortality than those in the placebo group (HR 1·24 [95% CI 1·01-1·54]; p=0·05). Interpretation: Administering vitamin D3 monthly to unscreened older people did not reduce all-cause mortality. Point estimates and exploratory analyses excluding the early follow-up period were consistent with an increased risk of death from cancer. Pending further evidence, the precautionary principle would suggest that this dosing regimen might not be appropriate in people who are vitamin D-replete.</p

Vitamin D Supplementation and the Incidence of Cataract Surgery in Older Australian Adults

Purpose: Observational studies suggest that higher serum 25-hydroxy vitamin D (25(OH)D) concentration may be associated with lower risk of cataract. However, no randomized controlled trials have assessed the effect of vitamin D supplementation on the incidence of cataract. We aimed to assess whether vitamin D supplementation reduces the incidence of cataract surgery. Design: We conducted an ancillary study of the D-Health Trial, a randomized, double-masked, placebo-controlled trial of monthly vitamin D conducted from 2014 through 2020 within the Australian general population. Participants: We invited 421 207 men and women 60 to 84 years of age to participate; including an additional 1896 volunteers, 40 824 expressed interest. Those with hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis or those who were taking more than 500 international units (IU) supplemental vitamin D per day were excluded. A total of 21 315 were randomized, and 1390 participants did not fulfil the eligibility criteria for this analysis (linked data available, no cataract within first 6 months), leaving 19 925 included. The median follow-up was 5 years. Methods: Participants took 60 000 IU of vitamin D3 (n = 10 662) or placebo (n = 10 653) orally once per month for a maximum of 5 years. Main outcome measures: The primary outcome for this analysis was the first surgical treatment for cataract, ascertained through linkage to universal health insurance records and hospital data. Results: Among 19 925 participants eligible for this analysis (mean age, 69.3 years; 46% women) 3668 participants (18.4%) underwent cataract surgery during follow-up (vitamin D: n = 1841 [18.5%]; placebo: n = 1827 [18.3%] ). The incidence of cataract surgery was similar between the two groups (incidence rate, 41.6 and 41.1 per 1000 person-years in the vitamin D and placebo groups, respectively; hazard ratio, 1.02; 95% confidence interval, 0.95-1.09). In prespecified subgroup analyses, the effect of vitamin D supplementation on the incidence of cataract surgery was not modified by age, sex, body mass index, predicted serum 25(OH)D concentration, or ambient ultraviolet radiation. Conclusions: Routinely supplementing older adults who live in an area with a low prevalence of vitamin D deficiency with high-dose vitamin D is unlikely to reduce the need for cataract surgery.</p

The effect of vitamin D supplementation on pain: an analysis of data from the D-Health randomized controlled trial

Observational studies suggest that 25-hydroxy vitamin D (25(OH)D) concentration is inversely associated with pain. However, findings from intervention trials are inconsistent. We assessed the effect of vitamin D supplementation on pain using data from a large, double-blind, population-based, placebo-controlled trial (the D-Health Trial). 21,315 participants (aged 60-84 years) were randomly assigned to a monthly dose of 60,000 IU vitamin D3 or a matching placebo. Pain was measured using the 6-item Pain Impact Questionnaire (PIQ-6), administered 1, 2 and 5 years after enrollment. We used regression models (linear for continuous PIQ-6 score and log-binomial for binary categorizations of the score, namely 'some or more pain impact' and 'presence of any bodily pain') to estimate the effect of vitamin D on pain. We included 20,423 participants who completed ≥1 PIQ-6. In blood samples collected from 3943 randomly selected participants (∼800 per year) the mean (SD) 25(OH)D concentrations were 77 (SD 25) and 115 (SD 30) nmol/L in the placebo and vitamin D groups, respectively. Most (76%) participants were predicted to have 25(OH)D concentration >50 nmol/L at baseline. The mean PIQ-6 was similar in all surveys (∼50.4). The adjusted mean difference in PIQ-6 score (vitamin D cf placebo) was 0.02 (95% CI, -0.20 to 0.25). The proportion of participants with some or more pain impact and with presence of bodily pain was also similar between groups (both prevalence ratios 1.01, 95% CI 0.99 to 1.03). In conclusion, supplementation with 60,000 IU of vitamin D3 per month had negligible effect on bodily pain