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DARAD TRIAL: Doxycycline and Rifampicin for Alzheimer s disease

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DARAD TRIAL: Doxycycline and Rifampicin for Alzheimer s disease

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    1. DARAD TRIAL: Doxycycline and Rifampicin for Alzheimers disease DW Molloy BM Kucher A Cunje T Standish T Woo D Cowan M Rathbone S Jiang

    4. Alzheimers disease Neurodegenerative Disease Progressive Cognitive deterioration Declining ADLs Neuropsychiatric symptoms Behavioural Changes Most common presenting complaints: Loss of short term memory Aphasia, Apraxia, Agnosia, Impaired executive functioning

    5. Alzheimers disease Most common form of dementia (50%) Age 65 (2-3% clinical AD) 85 (25-50% clinical AD) Every five years after 65 probability of AD doubles In US: Seventh leading cause of death Third most expensive disease after heart disease and cancer (100 billion) $77,500/year for AD care

    6. AD Pathological Hallmarks Amyloid beta Physiological function not well understood Soluble 40 and 42 species Processing of APP Production is constitutive in most cell types Overproduction or inadequate clearance results in aggregation Tau Promotes microtubule assembly and stability (aids in axonal transport and synaptic function) Regulation by kinases/phosphatases Hyperphosphorylation of tau in response to oxidative stress, etc. Induces tau and microtubule aggregation (NFTs) Disassembly of microtubules (altered neuronal function)

    7. AD Pathomechanisms Amyloid beta (soluble and aggregate) Tau Inflammation (Cytokines) Proteolytic Enzymes (MMPs) Metal Ions Oxidative Stress Nitrosative (Nitric Oxide Synthase) Stress Infectious

    8. PATHOGENESIS OF ALZHEIMERS DISEASE

    9. Pathogenesis of Alzheimers disease - the amyloid hypothesis

    10. AD Pathomechanisms

    11. AD Pathomechanisms Amyloid beta (soluble and aggregate) Tau Inflammation (Cytokines) Proteolytic Enzymes (MMPs) Metal Ions Oxidative Stress Nitrosative (Nitric Oxide Synthase) Stress Infectious

    12. Alzheimers disease Treatment strategies very limited Epidemiological NSAIDS, prednisone, vitamin E, statins Symptomatic Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) NMDA receptor antagonists (memantine) Disease Modifying Immunization with amyloid beta (active and passive) Clioquinol (metal chelation) Beta and gamma secretase inhibitors

    13. Pathogenesis of Alzheimers disease - the amyloid hypothesis

    14. Therapeutic possibilities based on role of amyloid in Alzheimers disease

    15. Therapeutic possibilities based on role of amyloid in Alzheimers disease

    16. Therapeutic possibilities based on role of amyloid in Alzheimers disease

    17. Beta amyloid immunotherapy approaches

    19. Pharmacotherapy of Alzheimers disease up to 2006 No efficacy (or doubtful) Vasodilators Lecitihin/choline Nootropics Cholinergic agonists NSAIDs/steroids Oestrogen

    20. Disease Modifying Treatments Chlamydia and Alzheimers? Is there a role?

    21. Infectious Chlamydia Pneumoniae Isolated from AD brains (Balin et al., 1998; Gerard et al., 2005) Infection induced Alzheimer-like plaque formation in brain of BALB/c mice (Little et al., 2004)

    22. Doxycycline Antimicrobial Properties Tetracycline family Semi-synthetic (includes minocycline) derived from tetracycline natural products Broad spectrum Abx Gram(+) and gram(-) bacteria Atypical pathogens (Chlamydia and Borrelia) MOA bacteriostatic. Inhibit protein synthesis.

    23. Rifampicin Antimicrobial Properties Mainly used for treatment of mycobacterial infections including Tb, leprosy, and mycobacterial Avian complex (MAC) infections. MOA inhibits DNA-dependent RNA polymerase

    24. Study to Examine the Effect of the Antibiotics Rifampin and Doxycyline on Patients with AD Three months treatment Followed for one year Assessed at 3, 6, 12 months Measures of cognition, ADL, behaviour and mood Cognition was the primary outcome (Standardized Alzheimers Disease Assessment Scale cognitive subscale)

    34. Pilot RCT Key Results Scores over time decreased significantly less in antibiotic-treated group compared to placebo for following: 3 months: depression, behaviour, caregiver burden, ADLs 6 months: cognition (SADAS-cog) 12 months: cognition (SMMSE) No difference between groups for C. pneumoniae serology

    35. Pilot RCT What does this mean? Do these drugs delay progression of clinical impairment? Is it DOX, RIF or both? How do they work? Antimicrobial properties Infectious Nonantimicrobial properties

    36. Doxycycline Non-Antimicrobial Properties Anti-amyloidogenic Anti-inflammatory Anti-proteolytic (MMPs) Anti-oxidant Metal chelator Proposed use for acne, RA, cancer, periodontitis

    37. Indirect Evidence for Tetracyclines for AD Amyloid (Forloni et al., 2001; Familian et al., 2006; Ryu et al., 2004; Cardoso et al., 2003; 2006) Tau (Nil) Inflammation (IL-1beta, TNF-alpha, IL-4, IL-10) (Kloppenberg et al., 1974; Plewig et al., 1975; Martin et al., 1974; Esterley et al., 1978; Thong et al., 1979; Pruzanski et al., 1992; Brundula et al., 2002) Proteolytic Enzymes (MMP-2 and MMP-9) (Golub et al., 1983; 1991; 1994; 1998; Greenwald et al., 1988; 1992; 1994; Uitto et al., 1994; Liu et al., 2003; Petrinec et al., 1996; Pyo et al., 1997) Oxidative Stress (Topsakal et al., 2003; Fan et al., 2005; Morimoto et al., 2005; Lertvorachon et al., 2005; Kraus et al., 2005; Shimazawa et al., 2005; Ryu et al., 2005; Cai et al., 2006) Nitrosative Stress (Amin et al., 1996; 1997; Fan et al., 2005; Cai et al., 2006) Metal Ions (Uitto et al., 1975; Chin et al., 1975; Banerjee et al., 1976; Romankiewicz et al., 1976; Newman et al., 1976; Martin et al., 1979; Gugler et al., 1990; Zebrev et al., 1990; Zhu et al., 1990; Campbell et al., 1991; Carson et al., 1993; 1996; Schmidt et al., 2002; Sapadin et al., 2006) Infectious (Nil)

    38. Rifampicin Non-Antimicrobial Properties Anti-amyloidogenic Anti-inflammatory Anti-proteolytic Anti-oxidant Metal chelator

    39. Indirect Evidence for Rifampicin for AD Amyloid beta (Matsuzaki et al., 2007; Meier et al., 2006; Ono et al., 2002; 2004; 2005; Tomiyama et al., 1994; 1996; 1997) Tau (Nil) Inflammation (IL-1beta, TNF-alpha, IL-4, IL-10) (Brinkmann et al., 2005; Mlambo and Sigola, 2003; Ziglam et al, 2004; Lozano et al., 2002; Kurokohchi et al., 2004) Proteolytic Enzymes (MMP-2 and MMP-9) (Gotschall and Yu, 1995; Ben-Hur et al., 2006) Oxidative Stress (Kilic et al., 2004; Oida et al., 2006) Nitrosative Stress (Wanchu et al., 2002; Brinkman et al., 2005; Whiteman et al., 1997) Metal Ions (Sadeghi et al., 2006) Infectious (Nil)

    40. Current and Future Directions 1) Large RCT (DARAD) 500 patients treated for 12 months with: 1) Placebo, 2) DOX, 3) RIF, 4) DOX+RIF Clinical Outcomes at 0, 3, 6, 12 months Treatment time? DOX, RIF, BOTH? 2) Serum, CSF biomarkers and MRI Amyloid beta, tau, cytokines, MMPs, metal ions Pathomechanisms affected by treatment? MRI SWI imaging before and after 3) Age-matched controls Clinical outcomes and biomarkers Diagnostic tool? Screening test?

    41. Doxycycline And Rifampin for Alzheimers Disease (DARAD) A multi-centre, blinded, randomized controlled trial comparing different regiments of the antibiotics doxycycline and rifampin for treatment of Alzheimers Disease Funding: Canadian Institutes of Health Research (CIHR) Amount: $1.9 M Duration: 3.5 years Sites: 13 sites in... Hamilton (2), London, North Bay (2),Toronto (2), Barrie, Niagara Falls, Saint John, Peterborough, Halifax, Simcoe

    42. DARAD Protocol 500 patients with AD 4 treatment arms: Doxycycline + Rifampin Doxycycline + Placebo-Rifampin Placebo-Doxycycline + Rifampin Placebo-Doxycycline + Placebo-Rifampin

    43. DARAD Protocol (contd) 12 month treatment Assessment: Baseline, 3, 6, 9, 12 months Primary Outcome Measures: -SADAS-cog -Clinical Dementia Rating scale (CDR)

    44. Ethical Approval Research Ethics Board of HHS and McMaster approval received 14-Apr-06 Each site must receive local ethics board approval before entering patients

    45. Clinical Trial Application (CTA) to Therapeutic Products Directorate (TPD) of Health Canada Approval from TPD must be received to use approved/marketed drugs in condition for which they are not indicated Approved indications: Doxycycline (tetracycline) acne, infections, etc. Rifampin (anti-tuberculosis) Placebo composition must also be submitted

    46. International Clinical Trial Registry CIHR requires that the trial be registered with the International Standard Randomized Controlled Trial Registry (ISRCTN) Registering ensures that study results will be available to the medical/scientific community even if a journal does not publish it Example: a negative trial may not be perceived as interesting enough for a journal editor to publish but another investigator may decide to do that study, not knowing that its already been done and didnt work! OR negative results may be withheld to not damage financial, professional or academic interests See it at: www.controlled-trials.com #ISRCTN15039674

    47. Trial Committee Structure and Decision - Making

    48. DARAD Progress to Date 14 Centres in Canada 271 patients enrolled 145 completed 70 at baseline and 24 completed Medication is well tolerated

    50. CSF Study Add-on to antibiotic study Evidence that biomarkers in CSF may measure the changes in AD caused by the treatments CSF sample at beginning and end of study Separate consent

    51. Grants to Study CSF PSI Tau, amyloid in 100 patients with AD PSI- Pilot Study of 5 Inflammatory markers in 10 AD and 10 age-matched normal controls Will also study neurotransmitters and metalloproteinases

    52. DARAD IMAGING Susceptibility Weighted Imaging Dr. M. Noseworthy McMaster with Dr. Mohammed Warsi MRI using SWI will be used before and after for 100 subjects. Attempt to quantify changes in the images and hopefully correlate these changes with the clinical and biological markers in blood and CSF.

    59. SWI and Aging

    60. Subject # 7(each MIP is 16 mm thick)

    62. Thank You! DARAD is a collaborative project of many investigators and staff looking at the causes and treatment of Alzheimers disease. Thank you to all of them listed on the following slides!

    63. The DARAD Team #1 Hamilton Coordinating Centre (St. Peters) Investigators: D.W. Molloy (P.I.), G. Guyatt, A. Cunje, A. Moore; Staff: T. Standish, E. Almeida, P. Diloreto, B. MacMillan #2 London Parkwood Hosp. Investigator: M. Borrie; Coord. C. Nsiah #4 Saint John- St.Josephs Hosp. Investigator: P. Jarrett; Coord. P.Shea

    64. #5 Halifax QEII Health Sci. Investigator: C.MacKnight, K.Rockwood; Coord. J. Cross #6 Simcoe- Norfolk Investigator: R.Chivers; staff: C. Martinsen #9 Toronto Sunnybrook Investigator: S. Black; Coord. J.Lawrence #13 Hamilton St. Josephs Investigator: D. Cowan; Coord. G. Charles

    65. #15 Peterborough Kawartha Reg. Mem. Clin. Investigator: J. Ingram; Coord. S. Goldberg #16 Toronto Sunnybrook Investigator: N. Herrmann; Coord. R. Rajaram #17 Niagara Falls Greater Niagara Gen. Investigator: D. Cowan, W. Molloy; Staff C. Lam-Au, R. Panetta, S. Hawkey, C. Colangelo

    66. # 18 Kitchener New Vision Family Health Team. Investigator: M. Cescon; Coord. A. Horton # 20 North Bay Shemilt Clinic Investigator: R. Shemilt; Coord. J. Meyers #21 North Bay Northeast Mental Health Centre Investigator: G.McKercher; staff M. Bradshaw, D. Germain

    67. Biomarker Studies Team B. Kucher, W. Molloy, A. Cunje, D. Cowan Basic Research Team M. Rathbone, S. Jiang, W. Molloy, B. Kucher

    68. Imaging Studies Team M. Noseworthy, B. Kucher, A. Fatemi-Ardekani, D. Kumbhare, T.Standish, W. Molloy Film Jeremy Freiburger, Open Daily Films

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