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The Role of the "Inflammatory/ Pathogen Burden" for Cardiac Ageing (AntiCardAgeing)

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ClinicalTrials.gov Identifier: NCT01045512
Recruitment Status : Terminated (unsufficient recruitment)
First Posted : January 11, 2010
Last Update Posted : January 28, 2015
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Martin-Luther-Universität Halle-Wittenberg

Tracking Information
First Submitted Date  ICMJE January 8, 2010
First Posted Date  ICMJE January 11, 2010
Last Update Posted Date January 28, 2015
Study Start Date  ICMJE October 2009
Actual Primary Completion Date September 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 8, 2010)
reduced narrowing of heart rate variability (measured by SDNN of a standardised 20 minute- resting-ecg) via lowering inflammatory/ pathogen burden by anti-inflammatory measures (standardized physical activity and statin administration) [ Time Frame: 24 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01045512 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 8, 2010)
  • quality of life [ Time Frame: 24 months ]
  • inflammatory parameters [ Time Frame: 24 months ]
  • major adverse cardiac events (MACE)including death, non lethal myocardial infarction and hospitalisation for cardiovascular reason [ Time Frame: 24 month ]
  • inflammatory parameters in vaccinated and unvaccinated probands [ Time Frame: 24 months ]
  • heart rate variability in vaccinated and unvaccinated probands [ Time Frame: 24 month ]
  • evidence of reduced narrowing of heart rate variability (measured by SDNN of a 24-hours-holter-ecg) via lowering inflammatory/ pathogen burden by anti-inflammatory measures (standardized physical activity and statin administration) [ Time Frame: 24 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Role of the "Inflammatory/ Pathogen Burden" for Cardiac Ageing
Official Title  ICMJE The Role of the "Inflammatory/ Pathogen Burden" for Cardiac Ageing
Brief Summary

In the elderly a chronic basal systemic inflammation prevails - which is evident by enhanced CRP or IL-6 plasma concentrations - and by compromised defense mechanisms against invading microbes. These alterations belong to the physiological ageing process of the immune system (immunosenescence) and are regarded as an inflammatory response towards lifelong antigen stress ("inflammatory/pathogen burden"). This lifelong antigen stress evokes an age-dependent basal inflammatory activation of innate immunity as well as a wasting of specific immunity: it is supposed that in the course of life-time due to a multitude of infectious/inflammatory events ("multiple hits") an inflammatory stress prevails or "inflammatory/pathogen burden" accumulates, which substantially contributes to an enhancement of the inflammatory parameters of natural immune response. Such enhanced inflammatory parameters characterize persons at increased risk of degenerative diseases like atherosclerosis or coronary heart disease. The risk is the higher, the higher the "pathogen burden". An impact of the inflammatory load on cardiac ageing has not yet been described.

"CARDIAC AGEING", REFLECTED BY A NARROWING OF HEART RATE VARIABILITY: The physiological ageing process of the heart goes along with a narrowing of heart rate variability as shown by various groups, including our own. Arguments in favour of a causal relationship between inflammation and cardiac ageing come from an experimental study with healthy human volunteers who had received a low dose of endotoxin: such a proinflammatory stimulus leads to a reversible narrowing of heart rate variability (7). Also in senescence heart rate variability steadily declines, paralleled by a steady increase of basal inflammatory activity.

The reduction of heart rate variability also is regarded as a sensitive parameter of autonomic dysfunction, which contributes to the compromise of cardiac reserve in old age. Apart from typical morphological features and functional deterioration, e.g. diastolic dysfunction, the senescent heart is typically characterized by a narrowed heart rate variability. Efforts have been made to estimate the cardiac age of an individual by this compromised heart rate variability, which may be divergent to the biological age. In recent years diverse approaches were proposed to measure cardiac age on the basis of heart rate variability. The published mathematical formulae were mostly validated with small patient groups and have presently not entered clinical practice. Still heart rate variability is an accepted surrogate parameter of cardiac ageing and is amenable by therapeutic measures, e.g. beta-blockade.

The interaction between autonomic nervous system and inflammation is bilateral: thus vagal stimulation can improve heart rate variability and at the same time evoke anti-inflammatory action: this "cholinergic anti-inflammatory" reflex could make the basis for pharmacological interventions to confine overwhelming inflammatory response syndromes. The afferent vagal nerve, on the other hand, can be stimulated by inflammatory mediators and toxins (endotoxin, Interleukin-1), thus activating the efferent vagus to release acetylcholine, which can bind to a nicotinergic acetylcholine receptor on macrophages and thus interrupt cytokine release and limit the rise in the blood levels of proinflammatory cytokines (TNF, IL-6). The biological meaning of this reflex is to localise inflammatory reactions in the organism and prevent a spill of cytokines to the circulation. A functioning autonomic nervous system is thus mandatory to prevent overshooting of inflammatory response to infection and non-infectious stimuli. The link between cardiac ageing and autonomic dysfunction gives another argument in favour of the notion that autonomic dysfunction and pathogen/inflammatory load could be factors promoting cardiac ageing. This, on the other hand, implies the chance of slowing down the cardiac ageing process by successfully modulating the extent of autonomic dysfunction and the scope of "pathogen/inflammatory burden".

THE NEED FOR A TRIAL:

A possible causal relationship between basal inflammatory activation and cardiac ageing has not been established. This is the issue of the project proposal. In this trial the investigators strive to lower the "pathogen/ inflammatory load" by simple and safe measures. The investigators therefore chose treatment with statins, standardised physical training (both parameters of heart function and heart rate variability could thus be improved) and vaccinations against influenza and pneumococci to prevent a further enhanced "pathogen/ inflammatory burden".

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Aging
  • Inflammation
Intervention  ICMJE Drug: fluvastatin
40-80mg once daily
Study Arms  ICMJE
  • Active Comparator: statins, standardised physical training
    Intervention: Drug: fluvastatin
  • No Intervention: to continue with current lifestyle
Publications * Not Provided

*   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 Terminated
Actual Enrollment  ICMJE
 (submitted: January 27, 2015)
96
Original Estimated Enrollment  ICMJE
 (submitted: January 8, 2010)
400
Actual Study Completion Date  ICMJE September 2014
Actual Primary Completion Date September 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • age 60-75
  • physical activity less than 3 times a week
  • written informed consent

Exclusion Criteria:

  • heart disease requiring treatment
  • treatment with beta-receptor-antagonists
  • treatment with statins
  • treatment with immunosuppressive drugs
  • treatment with anti- inflammatory drugs
  • underlying hematological disease
  • alcohol abuse, drug abuse
  • diabetes mellitus
  • study participation within past 30 days
  • known intolerance to active agent or any other component of the drug
  • active liver disease or unexplained persistent elevation of serum levels of transaminases or cholestasis
  • existing myopathy
  • pregnancy or nursing period
  • absence of an ophthalmological examination within 12 month prior inclusion
  • known cataract
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01045512
Other Study ID Numbers  ICMJE KKSH-38
2007-003003-12 ( Registry Identifier: EudraCT )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Martin-Luther-Universität Halle-Wittenberg
Study Sponsor  ICMJE Martin-Luther-Universität Halle-Wittenberg
Collaborators  ICMJE Novartis
Investigators  ICMJE
Study Chair: Ursula Müller-Werdan, Prof.Dr.med. Martin-Luther-University Halle-Wittenberg, Medical Faculty
PRS Account Martin-Luther-Universität Halle-Wittenberg
Verification Date January 2015

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