Phase II RCT of High-dose Vitamin D Supplements in Older Adults
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 180
- 试验地点
- 2
- 主要终点
- Correction of VitD insufficiency
研究概览
简要总结
This Phase II randomized clinical trial aims to test if supplementation with high dose oral vitamin D will successfully correct vitamin D insufficiency, compared to treatment with standard (RDA) dose vitamin D in a diverse community-based elderly cohort. The effect of high-dose vs. standard-dose vitamin D on altering cognitive trajectories will also be assessed and data will be expected to be used in designing a potential definitive Phase III trial in elderly groups at risk for dementia. A total of 180 elderly persons with longitudinal biomarkers, neuropsychological testing and brain MRI scans will be enrolled, with 152 (~50 with MCI, 50 with mild AD and 50 with no cognitive impairment) expected to complete the 3½-year study. One-half of each diagnostic group will be randomized to treatment with high-dose vitamin D3 (4,000 IU daily) or to standard dose Vitamin D (600 IU capsule daily + ~200 IU dietary = ~800 IU total/day). Longitudinal MRI analyses will provide an estimate of the treatment effect size on brain atrophy rate. Vitamin D receptor genotype polymorphisms and their impact on response to oral supplementation will also be examined. If vitamin D supplementation improves cognitive outcome, this could have a large impact on the public health, since low vitamin D status is a common, readably treatable condition which may provide a novel window to prevent dementia and AD. Furthermore, the higher prevalence of AD and dementia in African Americans and Latinos could be partially attributable to vitamin D insufficiency.
详细描述
- General Design This Phase 2 randomized clinical trial of high-dose vs. standard dose Vitamin D (VitD) supplementation aims to prove feasibility of the intervention in a diverse community-recruited cohort and to provide an estimate of the effect sizes of treatment on cognitive change and brain MRI volumetric measures as the main outcomes. We will study 180 elderly participants (approximately 60 with MCI, 60 with mild AD and 60 with No Cognitive Impairment) with longitudinal neuropsychological testing and brain MRI scans over a 3½ year study period. One-half of each diagnostic group will be randomized to treatment with high-dose (4,000 IU p.o. daily) vitamin D3 (n=90) or to standard dose vitamin D3 treatment (n=90 who will receive 600 IU vitamin D3 daily). The choice of the low-dose amount of vitamin D3 was determined by the goal to meet the Institute of Medicine (IOM) RDA recommendation of 800 IU/day for older adults (age >71y) from all sources, including both diet and supplements. The estimated average dietary intake of VitD by older adults is ~200 IU/day. Thus, the combined intake of VitD from diet and the low-dose supplement in our study will be approximately the RDA (i.e. 800 IU/day). Blood will be collected every 6 months (except month 30) for VitD levels along with other clinical labs.
This study aims to test if supplementation with high dose oral VitD (4,000 IU) will successfully correct VitD insufficiency, compared to treatment with standard RDA dose VitD (~800 IU total intake, as recommended by the IOM for those >age 71) in a diverse community-based cohort with serum VitD levels <20 ng/ml at study entry. The primary aims are to prove feasibility of the intervention, and the effectiveness of high-dose VitD in correcting VitD insufficiency in this diverse old cohort. Our primary outcome will be correction of VitD insufficiency in all subjects treated with 4,000 IU daily. Secondary aims are to provide an estimate of the effect sizes of treatment on cognitive change (executive function and global), and to gather preliminary data relevant to the evidence for moving forward with a potential definitive Phase III study in elderly groups at risk for dementia. Additional analyses will test if correction of VitD insufficiency correlates with changes in key biomarkers measured in blood and urine. Longitudinal MRI analyses will provide an estimate of the treatment effect size on brain atrophy rate. We will also examine VitD receptor genotype polymorphisms and their impact on response to oral supplementation. 2. Schedule of Visits Screening Visit (Visit 1). Elderly participants with a prior diagnosis of either No Cognitive Impairment, MCI, or mild AD, will be screened for potential study entry. Informed consent will be obtained before any study procedures are conducted. The following assessments will be done at screen (before Visit 2): MOCA, GDS, CDR, screening labs, then brain MRI for those who remain eligible. Blood and urine screening lab results will be reviewed by the investigator or designee for assessment of eligibility. Patients who do not meet all inclusion criteria or who meet any exclusion criteria will be discontinued from the study. Up to 45 days are allowed for completion of Visit 1 screening procedures, assessments, and evaluation of results from laboratory tests and Brain MRI.
Baseline Visit (Visit 2). The treatment period is a double-blind phase beginning at Visit 2, with treatment duration of 3½ years from baseline to the final 42 month visit. Patients who meet entry criteria will be enrolled and randomized to high-dose VitD 4,000 IU p.o. daily or standard dose VitD (600 IU daily). Randomization will be stratified by diagnosis and race, such that 50% of each diagnostic subgroup will be randomized to the high-dose treatment arm.
Assessments to be performed at the Baseline visits are: additional neuropsychological tests including the SENAS and ADAS-Cog, the ECog which has sections completed by the participant and the informant. Blood samples drawn at the Screening or Baseline visit will be sent for measurements of parathyroid hormone (PTH) level and genotyping to include polymorphisms of the VitD receptor for all enrolled subjects.
Telephone Check-Ins at Months 1 and 30. Brief telephone calls will be made to all enrolled participants at Month 1 & Month 30 to check on compliance with the study medication.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Participants receive identically appearing capsules which contain either 4,000 IU (high-dose) or 600 IU (standard-dose) of vitamin D3.
入排标准
- 年龄范围
- 65 Years 至 90 Years（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion criteria for this study are: 1) Age 65-90; 2) Low Vitamin D status, defined by a serum 25-OHD <20 ng/ml, as measured by competitive immunoassay at the Screening visit; 3) Fluent in either English or Spanish; 4) Willingness to be randomized to high-dose vs. standard dose vitamin D; 5) Education adjusted scores between 12-30 on the Montreal Cognitive Assessment (MOCA) at baseline; 6) A consensus clinical diagnosis of No Cognitive Impairment, Mild Cognitive Impairment, or mild AD dementia.
- •In order to be included in the No Cognitive Impairment (NC) subgroup, an individual must show no significant cognitive impairment on the baseline neuropsychological tests. Diagnoses are made by a comprehensive case conference review, including investigators from both sites, resulting in a consensus diagnosis made according to current research criteria. We will also require a minimum MOCA score of 23 or above for those with education >12 y, or MOCA >20 (uncorrected score) for those with education <12 years. These subjects are expected to mostly have CDR global scores of 0, but we will not exclude CDR=0.5, as long as Peterson criteria (Petersen, Journal of Internal Medicine 2004) for MCI (amnestic or non-amnestic) are not met and the CDR-Sum of Boxes is <1.
- •Similarly, we will not exclude elderly with subjective memory complaints from the NC group.
- •In order to be included in the Mild Cognitive Impairment (MCI) subgroup, a participant will need to meet research criteria for amnestic MCI, either single-domain or multiple-domain (McKhann et al, Neurology 1984). Thus, participants with amnestic MCI will have standardized memory scores >1.5 SDs below average, and if cognitive scores in other cognitive domains are also >1.5 SDs below average they will be classified as multiple-domain amnestic MCI. All MCI participants will be required to have a global CDR=0.
- •In addition, we will require a minimum MOCA score of >20 for those with education >12 y, or MOCA >17 (uncorrected score) for those with education <12 years.
- •In order to be included in the Mild AD dementia subgroup, a participant will need to meet research criteria for probable or possible AD (McKhann et al, Neurology 1984). A global CDR score of 1 will be required (mild dementia). In addition, we will require a minimum MOCA score of >15 at entry for those with education >12 y, or MOCA >12 (uncorrected score) for those with education <12 y. AD therapies will be allowed (e.g. donepezil, memantine) as long as doses have been stable for >6 weeks, and no changes in doses or CNS active medications are planned while participating in this trial.
排除标准
- •Exclusion criteria (for all participants) are: 1) Lacks adequate vision, hearing, or literacy to complete the required psychometric tests (e.g. severe bilateral deafness despite use of hearing aids, or visual acuity poorer than 20/100 in both eyes); 2) Hepatic insufficiency, defined by either albumin <3.3 g/dL or by a value >2X the upper limit of normal (ULN) in either alanine aminotransaminase (ALT/SGPT) or bilirubin, or >3X the ULN for aspartate aminotransaminase (AST/SGOT); 3) Renal insufficiency, defined by either serum creatinine >1.7 mg/dL or glomerular filtration rate <40 mL/min/1.73 m2; (calculated per CKD-EPI formula). 4) Hypercalcemia, defined by serum calcium level >2 standard deviations above the mean. Corrected Calcium mg/dL = [0.8*(4.0g/dL - Patients Albumin g/dL)] + Serum Calcium mg/dL (X of 8.6-10.5 is in normal range; formula accurate only if Albumin is in 3.2-4.6 range). 5) Current serious or unstable medical illnesses including cardiovascular (e.g. unstable ischemic cardiovascular disease), hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the participant being able to safely take high-dose vitamin D for the 3.5 year study duration; or has a life expectancy of <4 years; 6) History of recurrent renal stones; 7) Unable to undergo MRI scanning (e.g. pacemaker, metallic implants, severe claustrophobia); 8) Subjects with a history of osteoporosis will be excluded if the Screening serum 25-OHD level is < 12 ng/ml. 9) History of chronic psychiatric illness (e.g. schizophrenia, bipolar disorder), any episode of major depression within last 2 years, or current GDS > 6, any recent suicide attempts or suicidal ideation; 10) history within the last 5 years of a serious infectious disease affecting the brain (including neurosyphilis, meningitis, or encephalitis), or head trauma resulting in protracted loss of consciousness (>10 minutes) or any persistent cognitive deficit; 11) History of chronic alcohol or drug abuse/dependence as defined by DSM-IV, within the past 5 years; 12) History within the last 5 years of a primary or recurrent malignant disease with the exceptions of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or non-metastatic prostate cancer with a normal prostate-specific antigen post-treatment; 13) Does not have good venous access, such that multiple blood draws would be precluded; 14) Regular use of any of these CNS active medications: benzodiazepines, antipsychotics, narcotics, cholinesterase inhibitors, memantine or anti-epileptic drugs. Stable doses of SSRIs or SNRI anti-depressants will be allowed, and included persons will be discouraged to change the doses of any potentially CNS active medication throughout the 3.5-year study. 15) Those who plan to change their dosage of any vitamin supplement during the duration of the study may be discontinued from the clinical trial. Changes in vitamin supplement dosing (e.g. vitamin B12) will only be allowed if a specific deficiency has been found. If participants are taking vitamin D supplementation (e.g. in a daily multi-vitamin) at the time of screening, they should continue on this same dose of vitamin supplementation throughout the duration of the randomized clinical trial. 16) Current participation in any clinical trial involving experimental AD therapies (anti-amyloid, anti-tau, etc.). 17) Female subjects who are pregnant or plan to become pregnant during participation in this trial. 18) Inability to swallow oral capsules.
- •We will not exclude subjects with stable coronary artery disease or vascular risk factors such as diabetes or hypertension, who otherwise meet our inclusion/exclusion criteria. We will allow inclusion of participants with prior TIA or prior history of one stroke, but will exclude those with past history of multiple strokes. We will allow participants with up to two incidental infarcts on structural MRI, because the presence of cerebrovascular disease is very common in any representative sample of U.S. elderly persons, and may be an important contributor to dementia and age-associated cognitive decline. We will not exclude those with severe white matter (WM) hyperintensities, for similar reasons.
结局指标
主要结局
Correction of VitD insufficiency
时间窗: Expect vitamin D levels to correct by 1-2 month on treatment
Correction of VitD insufficiency in all subjects treated with high dose VitD (defined as serum 25-hydroxyvitamin D ≥ 20.0 ng/ml)
SENAS Executive Function Composite Score
时间窗: 3.5 years
Change in SENAS executive function score from Baseline Visit to last Visit (month 42)
次要结局
- Evaluate effect of VitD on Cognitive Change(3.5 years)