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

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ClinicalTrials.gov Identifier: NCT01745263
Recruitment Status : Completed
First Posted : December 10, 2012
Last Update Posted : August 9, 2018
Sponsor:
Collaborators:
Recruitment Partners
University of Geneva, Switzerland
University of Basel
University Hospital, Toulouse, France (Prof. Bruno Vellas, MD)
Charite University, Berlin, Germany
Medical University Innsbruck
University of Coimbra, Portugal (Prof. José daSilva, MD)
Other University Partners
University of Sheffield
University of Manchester, UK (Prof. David Felson, MD MPH)
Max Rubner University, Germany (Prof. Bernhard Watzl, PhD)
Technische Universität Dresden
Impact Partner
International Osteoporosis Foundation (IOF; Prof. John Kanis, MD)
SME Partners
Ferrari Data Solution
Gut Pictures, Switzerland (Benno Gut; animated exercise video)
NOVAMEN, France (Sandrine Rival; logistic management partner)
Pharmalys, UK (Marieme Ba; monitoring partner)
Industry Partners
DSM Nutritional Products (Dr. Elisabeth Stöcklin PhD, Dr. Manfred Eggersdorfer PhD)
Nestlé (Michaela Höhne PhD, Irène Corthesy PhD)
Roche Diagnostics
Funding within Framework 7 research program of the European Commission (project 278588)
Further collaborators and advisors at website do-health.eu
Information provided by (Responsible Party):
Heike Bischoff-Ferrari, University of Zurich

Tracking Information
First Submitted Date  ICMJE December 6, 2012
First Posted Date  ICMJE December 10, 2012
Last Update Posted Date August 9, 2018
Actual Study Start Date  ICMJE December 20, 2012
Actual Primary Completion Date November 17, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 21, 2018)
  • Bone: Incident non-vertebral fractures over 36 months [ Time Frame: over 36 months ]
    Confirmed by medical and/or x-ray reports
  • Muscle: Functional decline (lower extremity function) [ Time Frame: Baseline, 12, 24 and 36 months ]
    Measured with the SPPB (short physical performance test battery)
  • Cardio-vascular: Systolic and diastolic blood pressure change [ Time Frame: Baseline, 12, 24 and 36 months ]
    Standardized blood pressure assessment in sitting position
  • Brain: Cognitive decline [ Time Frame: Baseline, 12, 24 and 36 months ]
    Montreal Cognitive Assessment (MoCA)
  • Immunity: Rate of any infections [ Time Frame: Baseline, and every 3 months up to 36 months ]
    3-monthly incident infection protocol
Original Primary Outcome Measures  ICMJE
 (submitted: December 6, 2012)
  • medical records and x-ray reports [ Time Frame: 36 months ]
    incidence of non-vertebral fractures
  • Short Physical Performance Battery [ Time Frame: Baseline, 12, 24 and 36 months ]
    Functional decline (lower extremity function)
  • Systolic and diastolic blood pressure change [ Time Frame: Baseline, 12, 24 and 36 months ]
  • Montreal Cognitive Assessment (MoCA) [ Time Frame: Baseline, 12, 24 and 36 months ]
    Cognitive decline
  • infection questionnaire [ Time Frame: at baseline, and every 3 months up to 36 months ]
    rate of any infection
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 21, 2018)
  • Bone: Incident hip fractures [ Time Frame: 36 months ]
    Based on medical records and/or x-ray reports
  • Bone: Incident total fractures [ Time Frame: 36 months ]
    Combined non-vertebral and vertebral fractures among subgroup of 1502 participants with DXA vertebral morphometry assessment
  • Bone: Incident vertebral fractures [ Time Frame: 36 months ]
    Based on DXA vertebral morphometry among subset of 1502 participants
  • Bone: Bone mineral density decrease at the lumbar spine and hip [ Time Frame: Baseline, 12, 24, and 36 months ]
    Assessed in a subset of 1502 participants with DXA measurements
  • Muscle: Rate of falls [ Time Frame: Assessed every 3 months over 36 months ]
    Any low trauma fall, injurious fall
  • Muscle: reaction time and grip strength [ Time Frame: Baseline, 12,24,36 months ]
    Reaction time will be assessed with the repeated sit-to-stand test; grip strength will be assessed with the Martin Vigorimeter
  • Muscle: Muscle mass decrease at upper and lower extremities [ Time Frame: Baseline, 12,24,36 months ]
    Subset of 1502 participants with DXA measurements
  • Muscle: Dual tasking 10-meter gait speed [ Time Frame: Baseline, 12,24 and 36 months ]
  • Muscle/Bone: musculoskeletal pain [ Time Frame: Baseline, 12,24, and 36 months ]
    Assessed with the McGill questionnaire
  • Cardio-vascular: Incident Hypertension [ Time Frame: 36 months ]
  • Brain: mental health decline [ Time Frame: Baseline, 12,24, and 36 months ]
    Assessed with Geriatric Depression Scale
  • Brain: Incident Depression [ Time Frame: 36 months ]
  • Brain/Muscle: Dual tasking gait variability [ Time Frame: Baseline, 12, 24 and 36 months ]
    Subset of 250 participants
  • Immunity: Rate of upper respiratory infections / rate of flu-like illness [ Time Frame: 36 months ]
    Assessed with infection protocol every 3 months
  • Immunity: Incident severe infections that lead to hospital admission [ Time Frame: 36 months ]
  • Cartilage/Bone: Severity of knee pain in participants with symptomatic knee osteoarthritis [ Time Frame: Baseline, 12, 24 and 36 months ]
    Assessed with the KOOS questionnaire. Knee OA assessment with modified ACR criteria.
  • Cartilage/Bone: Rate of knee buckling [ Time Frame: Baseline, 12,24,36 months ]
    Questionnaire-based.
  • Cartilage/Bone: NSAID use / number of joints with pain [ Time Frame: Baseline, 12, 24, 36 months ]
    Assessed by questionnaire and homunculus figure
  • Dental: Decline in oral health [ Time Frame: Baseline, 12,24 and 36 months ]
    Assessed with questionnaire.
  • Dental: Tooth loss [ Time Frame: 36 months ]
    Assessed by tooth count at every clinical visit
  • Gastro-Intestinal: rate of GI symptoms [ Time Frame: Baseline, 12, 24 and 36 months ]
    Assessed with ROME III questionnaire.
  • Glucose-Metabolic: Change in fasting glucose, insulin levels (QUICKI, HOMA index) [ Time Frame: Baseline, 12,24,36 months ]
    Laboratory measures at the Central DO-HEALTH Laboratory (Institute of Clinical Chemistry at the University Hospital Zurich)
  • Glucose-Metabolic: Body composition [ Time Frame: Baseline, 12, 24, 36 months ]
    Subset of 1502 participants with DXA measurements
  • Kidney: Decline in kidney function [ Time Frame: Baseline, 12, 24, and 36 months ]
    Blood creatinine levels and estimated glomerular filtration rate
  • Global Health: Quality of life [ Time Frame: Every 6 months ]
    Assessed with questionnaire (EuroQuol).
  • Global Health: Incident disability regarding activities of daily living [ Time Frame: Baseline, 12, 24 and 36 months ]
    Assessed with HAQ-PROMIS questionnaire
  • Global Health: Incident nursing home admission [ Time Frame: 36 months ]
  • Global Health: Mortality [ Time Frame: 36 months ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: June 21, 2018)
  • Biomarker endpoints [ Time Frame: Baseline, 12, 24, and 36 months ]
  • Bone: Incident repeat fractures [ Time Frame: 36 months ]
    Any repeat non-vertebral fractures in all participants, vertebral fractures and total fractures among subset of 1502 seniors with yearly DXA measurements
  • BONE: Functional recovery after long bone fracture [ Time Frame: 36 months ]
  • Muscle: Incident sarcopenia / incident frailty / decline in physical function [ Time Frame: 36 months ]
    Incident sarcopenia (among subset of 1502 seniors with yearly DXA measurements), incident frailty (questionnaire), decline in physical activity (questionnaire)
  • Cardio-vascular: Major cardio-vascular events [ Time Frame: 36 months ]
    Major cardiovascular events as a composite endpoint (any event: myocardial infarction, stroke, revascularization procedures of CABG and PCI, incident congestive heart disease, cardiovascular mortality); individual endpoints: myocardial infarction, stroke, incident congestive heart disease, and cardiovascular mortality (assessed every 3 months over 36 months)
  • Brain: incident dementia [ Time Frame: 36 months ]
  • Immunity: Incident cancer / rate of implant infections / rate of gastro-intestinal infections [ Time Frame: 36 months ]
    Incident cancer (any cancer, gastro-intestinal, breast cancer in women, prostate cancer in men); rate of implant infections after total hip or knee replacement (due to fracture or osteoarthritis); rate of gastro-intestinal infections
  • Cartilage/bone: Incident osteoarthritis [ Time Frame: Baseline, 12, 24, and 36 months ]
    Incident symptomatic knee osteoarthritis; incident symptomatic hip osteoarthritis, incident symptomatic hand osteoarthritis; composite endpoint: incident symptomatic knee, hip or hand osteoarthritis; severity of hip pain in those with prevalent symptomatic hip osteoarthritis, severity of hand pain in those with prevalent symptomatic hand osteoarthritis
  • Adherence laboratory [ Time Frame: Baseline, 12, 24, and 36 months ]
    Serum 25(OH)D concentrations (measured both by an automated assay and HPLCMS/MS) and plasma PUFA concentrations (EPA, AA, DPA, DHA; measured by a sensitive and selective assay based on gas chromatography coupled to mass spectrometry detection (GC-MS)) in all participants
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE DO-HEALTH / Vitamin D3 - Omega3 - Home Exercise - Healthy Ageing and Longevity Trial
Official Title  ICMJE Vitamin D3 - Omega3 - Home Exercise - Healthy Ageing and Longevity Trial (Acronym: DO-HEALTH)
Brief Summary

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

The 3 primary treatment comparisons are:

  1. 2000 IU vitamin D per day compared to placebo (controlling for the other treatment strategies)
  2. 1 g of omega-3 fatty acids (EPA+DHA, ratio 1:2, from marine algae) compared to placebo (controlling for the other treatment strategies)
  3. 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/

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Improve Healthy Ageing in Seniors; Prevent Disease at Older Age
Intervention  ICMJE
  • Drug: Vitamin D3
    2000 IU/d
    Other Name: Cholecalciferol
  • Drug: Omega 3 fatty acids

    Ratio EPA:DHA = 1:2

    1 g/d

    Other Name: Eicosapentaenoic acid AND Docosahexaenoic acid
  • Procedure: Strength Home Exercise
  • Procedure: Flexibility Home Exercise
Study Arms  ICMJE
  • Active Comparator: VitD-Omega3-StrengthExercise
    Vitamin D3 (2000 IU/d); Omega-3 fatty acids (1 g/d); Strength Home Exercise (3*30 minutes/week)
    Interventions:
    • Drug: Vitamin D3
    • Drug: Omega 3 fatty acids
    • Procedure: Strength Home Exercise
  • Active Comparator: VitD-Omega3-FlexibilityExercise
    Vitamin D3 (2000 IU/d); Omega-3 fatty acids (1 g/d); Flexibility Home Exercise (3*30 minutes/week)
    Interventions:
    • Drug: Vitamin D3
    • Drug: Omega 3 fatty acids
    • Procedure: Flexibility Home Exercise
  • Active Comparator: Placebo-Omega3-StrengthExercise
    Placebo Vitamin D3; Omega-3 fatty acids (1 g/d); Strength Home Exercise (3*30 minutes/week)
    Interventions:
    • Drug: Omega 3 fatty acids
    • Procedure: Strength Home Exercise
  • Active Comparator: Placebo-Omega3-FlexibilityExercise
    Placebo Vitamin D3; Omega-3 fatty acids (1 g/d); Flexibility Home Exercise (3*30 minutes/week)
    Interventions:
    • Drug: Omega 3 fatty acids
    • Procedure: Flexibility Home Exercise
  • Active Comparator: VitD-Placebo-StrengthExercise
    Vitamin D3 (2000 IU/d); Placebo Omega-3 fatty acids; Strength Home Exercise (3*30 minutes/week)
    Interventions:
    • Drug: Vitamin D3
    • Procedure: Strength Home Exercise
  • Active Comparator: VitD-Placebo-FlexiblityExercise
    Vitamin D3 (2000 IU/d); Placebo Omega-3 fatty acids; Flexibility Home Exercise (3*30 minutes/week)
    Interventions:
    • Drug: Vitamin D3
    • Procedure: Flexibility Home Exercise
  • Active Comparator: Placebo-Placebo-StrengthExercise
    Placebo Vitamin D3; Placebo Omega-3 fatty acids; Strength Home Exercise (3*30 minutes/week)
    Intervention: Procedure: Strength Home Exercise
  • Sham Comparator: Placebo-Placebo-FlexibilityExercise
    Placebo Vitamin D3; Placebo Omega-3 fatty acids; Flexibility Home Exercise (3*30 minutes/week)
    Intervention: Procedure: Flexibility Home Exercise
Publications * Bischoff-Ferrari HA, Vellas B, Rizzoli R, Kressig RW, da Silva JAP, Blauth M, Felson DT, McCloskey EV, Watzl B, Hofbauer LC, Felsenberg D, Willett WC, Dawson-Hughes B, Manson JE, Siebert U, Theiler R, Staehelin HB, de Godoi Rezende Costa Molino C, Chocano-Bedoya PO, Abderhalden LA, Egli A, Kanis JA, Orav EJ; DO-HEALTH Research Group. Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial. JAMA. 2020 Nov 10;324(18):1855-1868. doi: 10.1001/jama.2020.16909.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 8, 2018)
2157
Original Estimated Enrollment  ICMJE
 (submitted: December 6, 2012)
2152
Actual Study Completion Date  ICMJE January 19, 2018
Actual Primary Completion Date November 17, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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").
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 70 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   France,   Germany,   Portugal,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01745263
Other Study ID Numbers  ICMJE KEK-ZH-2012-0249
DO-HEALTH ( Other Grant/Funding Number: European Commission (project number 278588) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Heike Bischoff-Ferrari, University of Zurich
Study Sponsor  ICMJE University of Zurich
Collaborators  ICMJE
  • Recruitment Partners
  • University of Geneva, Switzerland
  • University of Basel
  • University Hospital, Toulouse, France (Prof. Bruno Vellas, MD)
  • Charite University, Berlin, Germany
  • Medical University Innsbruck
  • University of Coimbra, Portugal (Prof. José daSilva, MD)
  • Other University Partners
  • University of Sheffield
  • University of Manchester, UK (Prof. David Felson, MD MPH)
  • Max Rubner University, Germany (Prof. Bernhard Watzl, PhD)
  • Technische Universität Dresden
  • Impact Partner
  • International Osteoporosis Foundation (IOF; Prof. John Kanis, MD)
  • SME Partners
  • Ferrari Data Solution
  • Gut Pictures, Switzerland (Benno Gut; animated exercise video)
  • NOVAMEN, France (Sandrine Rival; logistic management partner)
  • Pharmalys, UK (Marieme Ba; monitoring partner)
  • Industry Partners
  • DSM Nutritional Products (Dr. Elisabeth Stöcklin PhD, Dr. Manfred Eggersdorfer PhD)
  • Nestlé (Michaela Höhne PhD, Irène Corthesy PhD)
  • Roche Diagnostics
  • Funding within Framework 7 research program of the European Commission (project 278588)
  • Further collaborators and advisors at website do-health.eu
Investigators  ICMJE
Principal Investigator: Heike Bischoff Ferrari, Prof MD "Centre on Aging and Mobility" University of Zurich, University Hospital Zurich and City Hospital Waid.
PRS Account University of Zurich
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP