DO-HEALTH / Vitamin D3 - Omega3 - Home Exercise - Healthy Ageing and Longevity Trial

Study Overview
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Brief Summary
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The European population is aging rapidly which poses a challenge on the individual, the European societies, and health care systems. Among the most promising public health interventions that may extend healthy life expectancy at older age are vitamin D, marine omega-3 fatty acids and physical exercise. However, their individual and combined effects have yet to be confirmed in a clinical trial. The broad aim of DO-HEALTH is to prolong healthy life expectancy in European seniors. The specific aim is to establish whether vitamin D, omega-3 fatty acids, and a simple home exercise program will prevent disease at older age. To achieve these aims, DO-HEALTH will enroll 2152 community-dwelling men and women who are 70 years and older, an age when chronic diseases increase substantially. The DO-HEALTH seniors will be recruited from 7 European cities (Zurich, Basel, Geneva, Toulouse, Berlin, Innsbruck and Coimbra) and will be randomized in a 2x2x2 factorial design trial to a simple home exercise program and/or vitamin D, and/or omega-3 fatty acids, over a 3 year period. This will allow to test the individual and the combined benefit of the interventions in the prevention of 5 primary endpoints: incident non-vertebral fractures; functional decline; systolic and diastolic blood pressure change; cognitive decline; and the rate of any infection. Key secondary endpoints include incidence of hip fractures, rate of falls, severity of pain in symptomatic knee osteoarthritis, gastro-intestinal symptoms, mental and oral health, quality of life, and mortality. All clinical endpoints will be supported by a large DO-HEALTH biomarker study to evaluate the effect of the interventions at the cellular level of multi-organ function. DO-HEALTH will further evaluate reasons why or why not seniors adhere to the 3 interventions, and will assess their cost-benefit in a health economic model based on documented health care utilization and observed incidence of chronic disease. website DO-HEALTH: http://do-health.eu/wordpress/

Detailed Description
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The 3 primary treatment comparisons are: 2000 IU vitamin D per day compared to placebo (controlling for the other treatment strategies) 1 g of omega-3 fatty acids (EPA+DHA, ratio 1:2, from marine algae) compared to placebo (controlling for the other treatment strategies) Home exercise program (muscle strength) of 30 minutes 3 times a week compared to a control exercise program (joint flexibility) 30 minutes 3 times a week Follow-up: DO-HEALTH seniors will be followed for 3 years, in-person, and in 3-monthly intervals (4 clinical visits and 9 phone calls) at the 7 recruitment centers. Study population: DO-HEALTH will enroll seniors age 70 years and older. To represent the largest part of the senior population, DO-HEALTH will recruit community-dwelling seniors. However, to represent also the pre-frail population at risk of institutionalization, at least 40% of seniors will be enrolled based on a fall with or without a fracture in the year before DO-HEALTH enrolment. Study Design: This is a randomized, double-blind, placebo-controlled, 2×2×2 factorial design clinical trial. Recruitment Centers: The trial will be performed at 7 recruitment centers located in 5 countries: Switzerland (University of Zurich, Basel University Hospital, Geneva University Hospital), France (University of Toulouse Hospital Centre), Germany (Charité Berlin), Portugal (University of Coimbra), and Austria (Innsbruck Medical University). Randomization: Stratified block randomization. Labeling of study intervention will be performed by a central randomization centre in Switzerland. Stratification variables: recruitment centre (7 centers), fall during previous 12 months (yes/no), gender, and age (70 - 84 and 85+). At least 40% of Seniors among those who fell or did not fall during the last year will be enforced at each of the 7 recruitment centers. Gender and age distribution will be monitored within each recruitment centre with the DO-HEALTH randomization software. If gross imbalance (less than 30% of fallers/non-fallers in a stratum) is detected within a centre, recruitment strategies for the centre will be adapted to boost recruitment of participants of underrepresented category. website DO-HEALTH: http://do-health.eu/wordpress/

Official Title
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Vitamin D3 - Omega3 - Home Exercise - Healthy Ageing and Longevity Trial (Acronym: DO-HEALTH)

Conditions
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Improve Healthy Ageing in Seniors; Prevent Disease at Older Age

Intervention / Treatment
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* Drug: Vitamin D3
* Drug: Omega 3 fatty acids
* Procedure: Strength Home Exercise
* Procedure: Flexibility Home Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 70 years or older Mini Mental State Examination Score of at least 24 Living in the community Sufficiently mobile to come to the study centre Able to walk 10 meters with or without a walking aid and able to get in and out of a chair without help Able to swallow study capsules Able and willing to participate, sign informed consent (including consent to analyze all samples until drop-out or withdrawal) and cooperate with study procedures Exclusion criteria: Consumption of more than 1000 IU vitamin D/day in the 36 months prior to enrollment, or a bolus of 300'000 IU or more in the last 12 month prior to enrollment, and/ or unwillingness to limit vitamin D intake to the current standard of 800 IU/day of vitamin D during the course of the trial. Provision 1: an individual who consumed an average vitamin D dose between 1000 and 2000 IU vitamin D/day in the 3 months prior to enrollment, may be enrolled after a 3-month wash-out period where the maximum daily intake is limited to 800 IU vitamin D. Provision 2: an individual who consumed an average vitamin D dose higher than 2000 IU/day in the 3 months prior to enrollment, may be enrolled after a 6-month wash-out period where the maximum daily intake is limited to 800 IU vitamin D. Unwillingness to limit calcium supplement dose to 500 mg per day for the duration of the trial Taking omega-3 fat supplements in the 3 month prior to enrolment and unwilling to forgo their use for the duration of the trial Use of any active vitamin D metabolite (i.e. Rocaltrol, alphacalcidiol), PTH treatment (i.e. Teriparatide), or Calcitonin at baseline and unwillingness to forego these treatments during the course of the trial Current or recent (previous 4 months) participation in another clinical trial, or plans of such participation in the next 3 years (corresponding to DO-HEALTH length) Presence of the following diagnosed health conditions in the last 5 years: history of cancer (except non-melanoma skin cancer); myocardial infarction, stroke, transient ischemic attack, angina pectoris, or coronary artery intervention Severe renal impairment (creatinine clearance = 15 ml/min) or dialysis, hypercalcaemia (> 2.6 mmol/l) Hemiplegia or other severe gait impairment History of hypo- or primary hyperparathyroidism Severe liver disease History of granulomatous diseases (i.e. tuberculosis, sarcoidosis) Major visual or hearing impairment or other serious illness that would preclude participation Living with a partner who is enrolled in DO-HEALTH (i.e. only one person per household can be enrolled) Living in assisted living situations or a nursing home Temporary exclusion: acute fracture in the last 6 weeks Epilepsy and/or use of anti-epileptic drugs Individuals who fell more than 3 times in the last month Osteodystrophia deformans (M. Paget, Paget's disease) For study centers in Germany only: persons who are institutionalized / in prison by court order (§40, Abs. 1, Art. 4, Gesetz über den Verkehr mit Arzneimitteln).

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: VitD-Omega3-StrengthExercise<br>Vitamin D3 (2000 IU/d); Omega-3 fatty acids (1 g/d); Strength Home Exercise (3*30 minutes/week) | Drug: Vitamin D3<br>* 2000 IU/d<br>* Other names: Cholecalciferol;Drug: Omega 3 fatty acids<br>* Ratio EPA:DHA = 1:2 1 g/d<br>* Other names: Eicosapentaenoic acid AND Docosahexaenoic acid;Procedure: Strength Home Exercise<br> <br> |
| Active Comparator: VitD-Omega3-FlexibilityExercise<br>Vitamin D3 (2000 IU/d); Omega-3 fatty acids (1 g/d); Flexibility Home Exercise (3*30 minutes/week) | Drug: Vitamin D3<br>* 2000 IU/d<br>* Other names: Cholecalciferol;Drug: Omega 3 fatty acids<br>* Ratio EPA:DHA = 1:2 1 g/d<br>* Other names: Eicosapentaenoic acid AND Docosahexaenoic acid;Procedure: Flexibility Home Exercise<br> <br> |
| Active Comparator: Placebo-Omega3-StrengthExercise<br>Placebo Vitamin D3; Omega-3 fatty acids (1 g/d); Strength Home Exercise (3*30 minutes/week) | Drug: Omega 3 fatty acids<br>* Ratio EPA:DHA = 1:2 1 g/d<br>* Other names: Eicosapentaenoic acid AND Docosahexaenoic acid;Procedure: Strength Home Exercise<br> <br> |
| Active Comparator: Placebo-Omega3-FlexibilityExercise<br>Placebo Vitamin D3; Omega-3 fatty acids (1 g/d); Flexibility Home Exercise (3*30 minutes/week) | Drug: Omega 3 fatty acids<br>* Ratio EPA:DHA = 1:2 1 g/d<br>* Other names: Eicosapentaenoic acid AND Docosahexaenoic acid;Procedure: Flexibility Home Exercise<br> <br> |
| Active Comparator: VitD-Placebo-StrengthExercise<br>Vitamin D3 (2000 IU/d); Placebo Omega-3 fatty acids; Strength Home Exercise (3*30 minutes/week) | Drug: Vitamin D3<br>* 2000 IU/d<br>* Other names: Cholecalciferol;Procedure: Strength Home Exercise<br> <br> |
| Active Comparator: VitD-Placebo-FlexiblityExercise<br>Vitamin D3 (2000 IU/d); Placebo Omega-3 fatty acids; Flexibility Home Exercise (3*30 minutes/week) | Drug: Vitamin D3<br>* 2000 IU/d<br>* Other names: Cholecalciferol;Procedure: Flexibility Home Exercise<br> <br> |
| Active Comparator: Placebo-Placebo-StrengthExercise<br>Placebo Vitamin D3; Placebo Omega-3 fatty acids; Strength Home Exercise (3*30 minutes/week) | Procedure: Strength Home Exercise<br> <br> |
| Sham Comparator: Placebo-Placebo-FlexibilityExercise<br>Placebo Vitamin D3; Placebo Omega-3 fatty acids; Flexibility Home Exercise (3*30 minutes/week) | Procedure: Flexibility Home Exercise<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone: Incident non-vertebral fractures over 36 months | Confirmed by medical and/or x-ray reports | over 36 months | 
| Muscle: Functional decline (lower extremity function) | Measured with the SPPB (short physical performance test battery) | Baseline, 12, 24 and 36 months | 
| Cardio-vascular: Systolic and diastolic blood pressure change | Standardized blood pressure assessment in sitting position | Baseline, 12, 24 and 36 months | 
| Brain: Cognitive decline | Montreal Cognitive Assessment (MoCA) | Baseline, 12, 24 and 36 months | 
| Immunity: Rate of any infections | 3-monthly incident infection protocol | Baseline, and every 3 months up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone: Incident hip fractures | Based on medical records and/or x-ray reports | 36 months | 
| Bone: Incident total fractures | Combined non-vertebral and vertebral fractures among subgroup of 1502 participants with DXA vertebral morphometry assessment | 36 months | 
| Bone: Incident vertebral fractures | Based on DXA vertebral morphometry among subset of 1502 participants | 36 months | 
| Bone: Bone mineral density decrease at the lumbar spine and hip | Assessed in a subset of 1502 participants with DXA measurements | Baseline, 12, 24, and 36 months | 
| Muscle: Rate of falls | Any low trauma fall, injurious fall | Assessed every 3 months over 36 months | 
| Muscle: reaction time and grip strength | Reaction time will be assessed with the repeated sit-to-stand test; grip strength will be assessed with the Martin Vigorimeter | Baseline, 12,24,36 months | 
| Muscle: Muscle mass decrease at upper and lower extremities | Subset of 1502 participants with DXA measurements | Baseline, 12,24,36 months | 
| Muscle: Dual tasking 10-meter gait speed |  | Baseline, 12,24 and 36 months | 
| Muscle/Bone: musculoskeletal pain | Assessed with the McGill questionnaire | Baseline, 12,24, and 36 months | 
| Cardio-vascular: Incident Hypertension |  | 36 months | 
| Brain: mental health decline | Assessed with Geriatric Depression Scale | Baseline, 12,24, and 36 months | 
| Brain: Incident Depression |  | 36 months | 
| Brain/Muscle: Dual tasking gait variability | Subset of 250 participants | Baseline, 12, 24 and 36 months | 
| Immunity: Rate of upper respiratory infections / rate of flu-like illness | Assessed with infection protocol every 3 months | 36 months | 
| Immunity: Incident severe infections that lead to hospital admission |  | 36 months | 
| Cartilage/Bone: Severity of knee pain in participants with symptomatic knee osteoarthritis | Assessed with the KOOS questionnaire. Knee OA assessment with modified ACR criteria. | Baseline, 12, 24 and 36 months | 
| Cartilage/Bone: Rate of knee buckling | Questionnaire-based. | Baseline, 12,24,36 months | 
| Cartilage/Bone: NSAID use / number of joints with pain | Assessed by questionnaire and homunculus figure | Baseline, 12, 24, 36 months | 
| Dental: Decline in oral health | Assessed with questionnaire. | Baseline, 12,24 and 36 months | 
| Dental: Tooth loss | Assessed by tooth count at every clinical visit | 36 months | 
| Gastro-Intestinal: rate of GI symptoms | Assessed with ROME III questionnaire. | Baseline, 12, 24 and 36 months | 
| Glucose-Metabolic: Change in fasting glucose, insulin levels (QUICKI, HOMA index) | Laboratory measures at the Central DO-HEALTH Laboratory (Institute of Clinical Chemistry at the University Hospital Zurich) | Baseline, 12,24,36 months | 
| Glucose-Metabolic: Body composition | Subset of 1502 participants with DXA measurements | Baseline, 12, 24, 36 months | 
| Kidney: Decline in kidney function | Blood creatinine levels and estimated glomerular filtration rate | Baseline, 12, 24, and 36 months | 
| Global Health: Quality of life | Assessed with questionnaire (EuroQuol). | Every 6 months | 
| Global Health: Incident disability regarding activities of daily living | Assessed with HAQ-PROMIS questionnaire | Baseline, 12, 24 and 36 months | 
| Global Health: Incident nursing home admission |  | 36 months | 
| Global Health: Mortality |  | 36 months |