Alzheimer's disease--input of vitamin D with mEmantine assay (AD-IDEA trial): study protocol for a randomized controlled trial.
ABSTRACT: Current treatments for Alzheimer's disease and related disorders (ADRD) are symptomatic and can only temporarily slow down ADRD. Future possibilities of care rely on multi-target drugs therapies that address simultaneously several pathophysiological processes leading to neurodegeneration. We hypothesized that the combination of memantine with vitamin D could be neuroprotective in ADRD, thereby limiting neuronal loss and cognitive decline. The aim of this trial is to compare the effect after 24 weeks of the oral intake of vitamin D3 (cholecalciferol) with the effect of a placebo on the change of cognitive performance in patients suffering from moderate ADRD and receiving memantine.The AD-IDEA Trial is a unicentre, double-blind, randomized, placebo-controlled, intent-to-treat, superiority trial. Patients aged 60 years and older presenting with moderate ADRD (i.e., Mini-Mental State Examination [MMSE] score between 10-20), hypovitaminosis D (i.e., serum 25-hydroxyvitamin D [25OHD] < 30 ng/mL), normocalcemia (i.e., serum calcium < 2.65 mmol/L) and receiving no antidementia treatment at time of inclusion are being recruited. All participants receive memantine 20 mg once daily -titrated in 5 mg increments over 4 weeks- and each one is randomized to one of the two treatment options: either cholecalciferol (one 100,000 IU drinking vial every 4 weeks) or placebo (administered at the same pace). One hundred and twenty participants are being recruited and treatment continues for 24 weeks. Primary outcome measure is change in cognitive performance using Alzheimer's Disease Assessment Scale-cognition score. Secondary outcomes are changes in other cognitive scores (MMSE, Frontal Assessment Battery, Trail Making Test parts A and B), change in functional performance (Activities of Daily Living scale, and 4-item Instrumental Activities of Daily Living scale), posture and gait (Timed Up & Go, Five Time Sit-to-Stand, spatio-temporal analysis of walking), as well as the between-groups comparison of compliance to treatment and tolerance. These outcomes are assessed at baseline, 12 and 24 weeks, together with the serum concentrations of 25OHD, calcium and parathyroid hormone.The combination of memantine plus vitamin D may represent a new multi-target therapeutic class for the treatment of ADRD. The AD-IDEA Trial seeks to provide evidence on its efficacy in limiting cognitive and functional declines in ADRD.ClinicalTrials.gov number, NCT01409694.
Project description:The role vitamin D intake/production plays in sarcoidosis-associated hypercalcaemia is uncertain. However, authoritative reviews have recommended avoiding sunlight exposure and vitamin D supplements, which might lead to adverse skeletal outcomes from vitamin D insufficiency. We investigated the effects of vitamin D supplementation on surrogate measures of skeletal health in patients with sarcoidosis and vitamin D insufficiency.Randomised, placebo-controlled trial.Clinical research centre.27 normocalcaemic patients with sarcoidosis and 25-hydroxyvitamin D (25OHD) <50 nmol/L.50 000 IU weekly cholecalciferol for 4 weeks, then 50 000 IU monthly for 11 months or placebo.The primary endpoint was the change in serum calcium over 12 months, and secondary endpoints included measurements of calcitropic hormones, bone turnover markers and bone mineral density (BMD).The mean age of participants was 57 years and 70% were women. The mean (SD) screening 25OHD was 35 (12) and 38 (9) nmol/L in the treatment and control groups, respectively. Vitamin D supplementation increased 25OHD to 94 nmol/L after 4 weeks, 84 nmol/L at 6 months and 78 nmol/L at 12 months, while levels remained stable in the control group. 1,25-Dihydroxy vitamin D levels were significantly different between the groups at 4 weeks, but not at 6 or 12 months. There were no between-groups differences in albumin-adjusted serum calcium, 24 h urine calcium, markers of bone turnover, parathyroid hormone or BMD over the trial. One participant developed significant hypercalcaemia after 6 weeks (total cholecalciferol dose 250 000 IU).In patients with sarcoidosis and 25OHD <50 nmol/L, vitamin D supplements did not alter average serum calcium or urine calcium, but had no benefit on surrogate markers of skeletal health and caused one case of significant hypercalcaemia.This trial is registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). The registration number is ACTRN12607000364471, date of registration 5/7/2007.
Project description:To assess vitamin D status and the influences of race, sun exposure and dietary vitamin D intake on vitamin D levels, and to evaluate two vitamin D repletion regimens in extremely obese patients awaiting bariatric surgery.A cross-sectional analysis of dietary vitamin D, sun exposure, PTH [intact (iPTH) and PTH(1-84)] and 25-hydroxyvitamin D (25OHD; differentiated 25OHD2 and 25OHD3) in 56 obese [body mass index (BMI) > 35 kg/m(2)] men and women (age 20-64 years). In a pilot clinical trial, 27 subjects with 25OHD levels < 62 nmol/l were randomized to receive ergocalciferol or cholecalciferol for 8 weeks.Serum 25OHD was low (mean 45 +/- 22 nmol/l) and was inversely associated with BMI (r = -0.36, P < 0.01). Each BMI increase of 1 kg/m(2) was associated with a 1.3 nmol/l decrease in 25OHD (P < 0.01). BMI, sun exposure, African American race and PTH predicted 40% of the variance in 25OHD (P < 0.0001). Serum 25OHD significantly increased at 4 and 8 weeks in both treatment groups (P < 0.001), whereas PTH(1-84) declined significantly in subjects treated with cholecalciferol (P < 0.007) and tended to decrease following ergocalciferol (P < 0.09).In severely obese individuals, those who are African American, have higher BMI and limited sunlight exposure are at greatest risk for vitamin D insufficiency. These demographic factors can help to identify at-risk patients who require vitamin D repletion prior to bariatric surgery. Commonly prescribed doses of ergocalciferol and cholecalciferol are effective in raising 25OHD. Further investigation is needed to evaluate whether these regimens have differential effects on PTH, and to determine the optimal regimen for vitamin D repletion in the extremely obese patient.
Project description:OBJECTIVE:To evaluate the safety and efficacy of cholecalciferol in patients with relapsing-remitting MS (RRMS). METHODS:In this double-blind, placebo-controlled parallel-group, 2-year study, 181 patients with RRMS were randomized 1:1. Key inclusion criteria were a low serum 25-hydroxy vitamin D (25OHD) concentration (<75 nmol/L), a treatment with interferon beta-1a 44 ?g (SC 3 times per week) 4 months ± 2 months before randomization, and at least one documented relapse during the previous 2 years. Patients received high-dose oral cholecalciferol 100,000 IU or placebo every other week for 96 weeks. Primary outcome measure was the change in the annualized relapse rate (ARR) at 96 weeks. Secondary objectives included safety and tolerability of cholecalciferol and efficacy assessments (ARR, MRI parameters, and Expanded Disability Status Scale [EDSS]). RESULTS:The primary end point was not met. In patients who completed the 2-year follow-up (45 with cholecalciferol and 45 with placebo), all efficacy parameters favored cholecalciferol with an ARR reduction (p = 0.012), less new hypointense T1-weighted lesions (p = 0.025), a lower volume of hypointense T1-weighted lesions (p = 0.031), and a lower progression of EDSS (p = 0.026). The overall rate of adverse events was well balanced between groups. CONCLUSIONS:Although the primary end point was not met, these data suggest a potential treatment effect of cholecalciferol in patients with RRMS already treated with interferon beta-1a and low serum 25OHD concentration. Together with the good safety profile, these data support the exploration of cholecalciferol treatment in such patients with RRMS. CLINICALTRIALSGOV IDENTIFIER:NCT01198132. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for patients with RRMS and low serum 25OHD, cholecalciferol did not significantly affect ARRs.
Project description:The Maternal Vitamin D Osteoporosis (MAVIDOS) trial reported higher total body bone mineral content in winter-born infants of mothers receiving vitamin D supplementation [1000 IU/day cholecalciferol] compared with placebo from 14 weeks gestation until delivery. This sub-study aimed to determine whether antenatal vitamin D supplementation altered postnatal bone formation in response to mechanical stimulation. Thirty-one children born to MAVIDOS participants randomised to either placebo (n=19) or cholecalciferol (n=12) were recruited at age 4-5 years. Children received whole body vibration (WBV) for 10 minutes on 5 consecutive days. Fasting blood samples for bone homeostasis, 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and bone turnover markers (Pro-collagen Type 1 N-terminal propeptide, P1NP; Cross-linked C-telopeptide of Type I Collagen, CTX) were collected pre-WBV and on day 8 (D8). Mean changes (D) in P1NP (ng/ml) between baseline and D8 in the vitamin-D intervention and placebo groups were 40.6 and -92.6 respectively and mean changes (?) in CTX (ng/ml) were 0.034 (intervention) and -0.084 (placebo) respectively. Between-group DP1NP difference was 133.2ng/ml [95% CI 0.4, 266.0; p=0.049] and ?CTX 0.05ng/ml (95% CI -0.159, 0.26ng/mL; p=0.62). Antenatal vitamin-D supplementation resulted in increased P1NP in response to WBV, suggesting early life vitamin D supplementation increases the anabolic response of bone to mechanical loading in children.
Project description:BACKGROUND:Subjects with atopic dermatitis (AD) have defects in antimicrobial peptide (AMP) production possibly contributing to an increased risk of infections. In laboratory models, vitamin D can alter innate immunity by increasing AMP production. OBJECTIVE:To determine if AD severity correlates with baseline vitamin D levels, and to test whether supplementation with oral vitamin D alters AMP production in AD skin. METHODS:This was a multi-centre, placebo-controlled, double-blind study in 30 subjects with AD, 30 non-atopic subjects, and 16 subjects with psoriasis. Subjects were randomized to receive either 4000 IU of cholecalciferol or placebo for 21 days. At baseline and day 21, levels of 25-hydroxyvitamin D (25OHD), cathelicidin, HBD-3, IL-13, and Eczema Area and Severity Index (EASI) and Rajka-Langeland scores were obtained. RESULTS:At baseline, 20% of AD subjects had serum 25OHD below 20 ng/mL. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI, but not AD severity. After 21 days of oral cholecalciferol, mean serum 25OHD increased, but there was no significant change in skin cathelicidin, HBD-3, IL-13 or EASI scores. CONCLUSIONS:This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD, and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels. Given the molecular links between vitamin D and immune function, further study of vitamin D supplementation in subjects with AD is warranted.
Project description:BACKGROUND:A large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer's disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome. METHODS:Randomized patients (N?=?2045) were divided into subgroups based on memantine use. Analyses included demographic and clinical characteristics (age, nursing home placement, Mini-Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD) scores) and mortality endpoints. RESULTS:Overall, 496 (24.3 %) patients were memantine users and were older (mean (SD), 74.0 (8.76) vs 72.8 (8.76), p?=?0.008), with lower MMSE scores (18.2 (4.16) vs 19.2 (4.02), p?<?0.0001) and DAD scores (58.0 (23.49) vs 62.5 (20.52), p?<?0.0001) than nonusers. Mortality rates (per 100 patient-years) in memantine nonusers (n?=?1549) were lower for galantamine (1.39) vs placebo-treated patients (4.15). In memantine users, mortality rates were similar for placebo-treated (4.49) and galantamine-treated patients (5.57). In memantine nonusers at 24 months, the decline in MMSE scores (effect size (95 % CI) 0.25 (0.14; 0.36)) and DAD scores (0.17 (0.06; 0.28)) from baseline was lower in galantamine patients vs placebo patients. The absence of these benefits in memantine users could not be explained by baseline age, MMSE, or DAD scores. CONCLUSION:This post-hoc analysis shows that the beneficial effects of galantamine at 2 years post treatment were not observed in patients who had been placed on background memantine. The reasons for memantine treatment and the possibility of interaction between memantine and galantamine merit further investigation. TRIAL REGISTRATION:ClinicalTrials.gov NCT00679627 . Registered 15 May 2008.
Project description:BACKGROUND:Vitamin D3 fortified food may improve serum vitamin D level, suggesting that the prevention of adverse consequences of hypovitaminosis D is possible with food fortification. The aim of this randomized controlled trial (RCT) was to examine the effects of vitamin D and calcium fortified yogurt on spatiotemporal gait parameters, cognitive performance, handgrip strength, and serum 25OHD levels in healthy older females. METHODS:Forty older community-dwelling females were recruited in a single-blind, randomized, controlled, superiority clinical trial in two parallel groups (20 participants in the intervention group and 20 in the control group) with intent-to-treat. The intervention group took fortified yogurts daily (i.e., 400 UI of vitamin D3 and 800 mg calcium) for 3 months. The non-fortified yogurts contained similar proteins, carbohydrates and lipids, as well as a lower dose of calcium (300 mg) and no vitamin D3 supplementation. Spatiotemporal gait parameters (mean value and coefficient of variation) were assessed using a computerized walkway. Handgrip strength was measured with hydraulic dynamometers. Cognitive performances, including global cognitive functioning assessed with the Mini Mental Status Examination (MMSE) were recorded. All the outcomes were assessed at baseline and at the end of follow-up. The primary outcome was the coefficient of variation of stride time. RESULTS:The intervention group maintained its global cognitive performance and serum 25OHD concentrations, whereas these outcomes decreased (i.e., worst performance) in the control group. The changes in the MMSE score (p = 0.022) and serum 25OHD concentrations were different (p ? 0.001) with better values reported in the intervention group compared to the control group. There was no significant change in gait parameters (p ? 0.518) and handgrip strength (p ? 0.600). CONCLUSIONS:Fortified yogurts with vitamin D (i.e., 200 IU) and calcium (i.e., 400 mg) twice a day maintained global cognitive performance and vitamin D status in older females, but not gait performances, signifying that they mainly prevent hypovitaminosis D-related extra-skeletal disorders.
Project description:Epidemiological evidence suggests that circulating 25-hydroxyvitamin D (25OHD) levels are inversely associated with hemoglobin (Hb) levels and anemia risk. We evaluated whether vitamin D supplementation improves Hb levels and reduces anemia risk in hypertensive patients. Two hundred patients with 25OHD levels <75?nmol/L who attended the Styrian Vitamin D Hypertension Trial were included, of whom 188 completed the trial. Patients randomly received 2800?IU vitamin D3 daily or a matching placebo for eight weeks. Initially, the prevalence of anemic status (Hb levels <12.5?g/dL) and deficient 25OHD levels (<30?nmol/L) was 6.5% and 7.5%, respectively. All anemic patients had 25OHD levels >50?nmol/L. The mean (95% confidence interval) vitamin D effect on Hb levels was 0.04 (-0.14 to 0.22) g/dL (P = 0.661). Moreover, vitamin D treatment did not influence anemic status significantly (P > 0.999). Likewise, vitamin D had no significant effect on Hb levels in the subgroups of anemic patients or in patients with initial 25OHD levels <30?nmol/L. In conclusion, a daily vitamin D supplement of 2800?IU for eight weeks did not improve Hb levels or anemic status in hypertensive patients. Future trials should focus on anemic patients with deficient 25OHD levels (e.g., <30?nmol/L). This trial is registered with clinicaltrials.gov [NCT02136771].
Project description:Iron and vitamin D deficiencies are common during pregnancy. Our aim was to identify whether antenatal vitamin D? supplementation affects iron status (via hepcidin suppression) and/or inflammation. Using a subset of the UK multicenter Maternal Vitamin D Osteoporosis Study (MAVIDOS)-a double-blinded, randomized, placebo-controlled trial (ISRCTN82927713; EudraCT2007-001716-23)-we performed a secondary laboratory analysis. Women with blood samples from early and late pregnancy (vitamin D? (1000 IU/day from ~14 weeks gestation n = 93; placebo n = 102) who gave birth in the springtime (March?May) were selected as we anticipated seeing the greatest treatment group difference in change in 25-hydroxyvitamin D (25OHD) concentration. Outcomes were hepcidin, ferritin, C-reactive protein, and ?1-acid glycoprotein concentration in late pregnancy (25OHD concentration was measured previously). By late pregnancy, 25OHD concentration increased by 17 nmol/L in the vitamin D? group and decreased by 11 nmol/L in the placebo group; hepcidin, ferritin, and inflammatory markers decreased but no treatment group differences were seen. In late pregnancy, positive relationships between 25OHD and hepcidin and 25OHD and ferritin in the placebo group were observed but not in the treatment group (group × 25OHD interaction, p < 0.02). Vitamin D? supplementation had no effect on hepcidin, ferritin, or inflammatory status suggesting no adjunctive value of vitamin D? in reducing rates of antenatal iron deficiency.
Project description:BACKGROUND:Maternal vitamin D status has been associated with bone mass of offspring in many, but not all, observational studies. However, maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a randomised controlled trial. We aimed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content (BMC) at birth than those of mothers who had not received supplementation. METHODS:The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicentre, double-blind, randomised, placebo-controlled trial that recruited pregnant women from three study sites in the UK (Southampton, Oxford, and Sheffield). Eligible participants were older than 18 years, with a singleton pregnancy, gestation of less than 17 weeks, and a serum 25-hydroxyvitamin D (25[OH]D) concentration of 25-100 nmol/L at 10-17 weeks' gestation. P'articipants were randomly assigned (1:1), in randomly permuted blocks of ten, to either cholecalciferol 1000 IU/day or matched placebo, taken orally, from 14 weeks' gestation (or as soon as possible before 17 weeks' gestation if recruited later) until delivery. Participants and the research team were masked to treatment allocation. The primary outcome was neonatal whole-body BMC, assessed within 2 weeks of birth by dual-energy x-ray absorptiometry (DXA), analysed in all randomly assigned neonates who had a usable DXA scan. Safety outcomes were assessed in all randomly assigned participants. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007-001716-23. FINDINGS:Between Oct 10, 2008, and Feb 11, 2014, we randomly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day. 370 (65%) neonates in the placebo group and 367 (65%) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint. Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo (61·6 g [95% CI 60·3-62·8] vs 60·5 g [59·3-61·7], respectively; p=0·21). We noted no significant differences in safety outcomes, apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group (96 [17%] of 569 mothers in the placebo group vs 65 [12%] of 565 mothers in the cholecalciferol group; p=0·01). No adverse events were deemed to be treatment related. INTERPRETATION:Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited. FUNDING:Arthritis Research UK, Medical Research Council, Bupa Foundation, and National Institute for Health Research.