Clinical trial NCT01745263: DO-HEALTH / Vitamin D3 - Omega3 - Home Exercise - Healthy Ageing and Longevity Trial
Official title: Vitamin D3 - Omega3 - Home Exercise - Healthy Ageing and Longevity Trial (Acronym: DO-HEALTH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Improve Healthy Ageing in Seniors; Prevent Disease at Older Age
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Recruitment Partners
name: University of Geneva, Switzerland
name: University of Basel
name: University Hospital, Toulouse, France (Prof. Bruno Vellas, MD)
name: Charite University, Berlin, Germany
name: Medical University Innsbruck
name: University of Coimbra, Portugal (Prof. José daSilva, MD)
name: Other University Partners
name: University of Sheffield
name: University of Manchester, UK (Prof. David Felson, MD MPH)
name: Max Rubner University, Germany (Prof. Bernhard Watzl, PhD)
name: Technische Universität Dresden
name: Impact Partner
name: International Osteoporosis Foundation (IOF; Prof. John Kanis, MD)
name: SME Partners
name: Ferrari Data Solution
name: Gut Pictures, Switzerland (Benno Gut; animated exercise video)
name: NOVAMEN, France (Sandrine Rival; logistic management partner)
name: Pharmalys, UK (Marieme Ba; monitoring partner)
name: Industry Partners
name: DSM Nutritional Products (Dr. Elisabeth Stöcklin PhD, Dr. Manfred Eggersdorfer PhD)
name: Nestlé (Michaela Höhne PhD, Irène Corthesy PhD)
name: Roche Diagnostics GmbH
name: European Commission
name: Further collaborators and advisors at website do-health.eu
First posted: 2012-12-10
Enrollment: 2157
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

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/

Eligibility criteria: 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").

Primary outcomes:
measure: Bone: Incident non-vertebral fractures over 36 months
timeFrame: over 36 months
measure: Muscle: Functional decline (lower extremity function)
timeFrame: Baseline, 12, 24 and 36 months
measure: Cardio-vascular: Systolic and diastolic blood pressure change
timeFrame: Baseline, 12, 24 and 36 months
measure: Brain: Cognitive decline
timeFrame: Baseline, 12, 24 and 36 months
measure: Immunity: Rate of any infections
timeFrame: Baseline, and every 3 months up to 36 months
Secondary outcomes:
measure: Bone: Incident hip fractures
timeFrame: 36 months
measure: Bone: Incident total fractures
timeFrame: 36 months
measure: Bone: Incident vertebral fractures
timeFrame: 36 months
measure: Bone: Bone mineral density decrease at the lumbar spine and hip
timeFrame: Baseline, 12, 24, and 36 months
measure: Muscle: Rate of falls
timeFrame: Assessed every 3 months over 36 months
measure: Muscle: reaction time and grip strength
timeFrame: Baseline, 12,24,36 months
measure: Muscle: Muscle mass decrease at upper and lower extremities
timeFrame: Baseline, 12,24,36 months
measure: Muscle: Dual tasking 10-meter gait speed
timeFrame: Baseline, 12,24 and 36 months
measure: Muscle/Bone: musculoskeletal pain
timeFrame: Baseline, 12,24, and 36 months
measure: Cardio-vascular: Incident Hypertension
timeFrame: 36 months
measure: Brain: mental health decline
timeFrame: Baseline, 12,24, and 36 months
measure: Brain: Incident Depression
timeFrame: 36 months
measure: Brain/Muscle: Dual tasking gait variability
timeFrame: Baseline, 12, 24 and 36 months
measure: Immunity: Rate of upper respiratory infections / rate of flu-like illness
timeFrame: 36 months
measure: Immunity: Incident severe infections that lead to hospital admission
timeFrame: 36 months
measure: Cartilage/Bone: Severity of knee pain in participants with symptomatic knee osteoarthritis
timeFrame: Baseline, 12, 24 and 36 months
measure: Cartilage/Bone: Rate of knee buckling
timeFrame: Baseline, 12,24,36 months
measure: Cartilage/Bone: NSAID use / number of joints with pain
timeFrame: Baseline, 12, 24, 36 months
measure: Dental: Decline in oral health
timeFrame: Baseline, 12,24 and 36 months
measure: Dental: Tooth loss
timeFrame: 36 months
measure: Gastro-Intestinal: rate of GI symptoms
timeFrame: Baseline, 12, 24 and 36 months
measure: Glucose-Metabolic: Change in fasting glucose, insulin levels (QUICKI, HOMA index)
timeFrame: Baseline, 12,24,36 months
measure: Glucose-Metabolic: Body composition
timeFrame: Baseline, 12, 24, 36 months
measure: Kidney: Decline in kidney function
timeFrame: Baseline, 12, 24, and 36 months
measure: Global Health: Quality of life
timeFrame: Every 6 months
measure: Global Health: Incident disability regarding activities of daily living
timeFrame: Baseline, 12, 24 and 36 months
measure: Global Health: Incident nursing home admission
timeFrame: 36 months
measure: Global Health: Mortality
timeFrame: 36 months
Other outcomes:
measure: Biomarker endpoints
timeFrame: Baseline, 12, 24, and 36 months
measure: Bone: Incident repeat fractures
timeFrame: 36 months
measure: BONE: Functional recovery after long bone fracture
timeFrame: 36 months
measure: Muscle: Incident sarcopenia / incident frailty / decline in physical function
timeFrame: 36 months
measure: Cardio-vascular: Major cardio-vascular events
timeFrame: 36 months
measure: Brain: incident dementia
timeFrame: 36 months
measure: Immunity: Incident cancer / rate of implant infections / rate of gastro-intestinal infections
timeFrame: 36 months
measure: Cartilage/bone: Incident osteoarthritis
timeFrame: Baseline, 12, 24, and 36 months
measure: Adherence laboratory
timeFrame: Baseline, 12, 24, and 36 months
Locations:
city: Innsbruck
country: Austria
facility: University of Innsbruck
city: Toulouse
country: France
facility: University of Toulouse - Centre de Recherche - Gérontopôle Hôpital La Grave
city: Berlin
country: Germany
facility: Charité Berlin
city: Coimbra
country: Portugal
facility: University of Coimbra - Clínica Universitária de Reumatologia
city: Zurich
country: Switzerland
facility: Centre on Aging and Mobility, University of Zurich and City Hospital Waid
state: ZH
city: Basel
country: Switzerland
facility: Basel University
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève
Study officials:
affiliation: "Centre on Aging and Mobility" University of Zurich, University Hospital Zurich and City Hospital Waid.
name: Heike Bischoff Ferrari, Prof MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bischoff-Ferrari HA, Willett WC, Manson JE, Dawson-Hughes B, Manz MG, Theiler R, Braendle K, Vellas B, Rizzoli R, Kressig RW, Staehelin HB, Da Silva JAP, Armbrecht G, Egli A, Kanis JA, Orav EJ, Gaengler S. Combined Vitamin D, Omega-3 Fatty Acids, and a Simple Home Exercise Program May Reduce Cancer Risk Among Active Adults Aged 70 and Older: A Randomized Clinical Trial. Front Aging. 2022 Apr 25;3:852643. doi: 10.3389/fragi.2022.852643. eCollection 2022.
citation: de Godoi Rezende Costa Molino C, Chocano-Bedoya PO, Sadlon A, Theiler R, Orav JE, Vellas B, Rizzoli R, Kressig RW, Kanis JA, Guyonnet S, Lang W, Egli A, Bischoff-Ferrari HA; DO-HEALTH Research Group. Prevalence of polypharmacy in community-dwelling older adults from seven centres in five European countries: a cross-sectional study of DO-HEALTH. BMJ Open. 2022 Apr 29;12(4):e051881. doi: 10.1136/bmjopen-2021-051881.
citation: Schietzel S, Chocano-Bedoya PO, Sadlon A, Gagesch M, Willett WC, Orav EJ, Kressig RW, Vellas B, Rizzoli R, da Silva JAP, Blauth M, Kanis JA, Egli A, Bischoff-Ferrari HA. Prevalence of healthy aging among community dwelling adults age 70 and older from five European countries. BMC Geriatr. 2022 Mar 2;22(1):174. doi: 10.1186/s12877-022-02755-8.
citation: 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.