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P rospective Evaluation of R ifalazil Effect O n V ascular Symptoms of I ntermittent Clau d ication and Other EN dpoints in C hlamydia S E ropositive Patients.

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  1. Prospective Evaluation of Rifalazil Effect On Vascular Symptoms of Intermittent Claudication and Other ENdpoints in Chlamydia SEropositive Patients Michael R. Jaff; William R. Hiatt; Mark A. Creager; Lee Ann Campbell; Ray Lipicky;John Constant;Suzanne Cadden; Andrew Sternlicht; for the PROVIDENCE Investigators

  2. Disclosures • Jaff – Speakers Bureau: Bristol-Myers Squibb-Sanofi Aventis; Grant Support: ActivBiotics; Genzyme • Hiatt - Grant Support: Genzyme, Sanofi-Aventis, ActivBiotics, Sigma Tau Pharmaceuticals, DNAVEC, Biomarin, Cardium Therapeutics, KOWA; Speaker’s Bureau - Sanofi-Aventis, Otsuka • Creager- Grant Support: Sanofi-Aventis; Consultant - Genzyme, Sigma Tau, Sanofi-Aventis, ActivBiotics; Speakers Bureau – Bristol Myers Squibb-Sanofi Aventis • Campbell – Consultant: ActivBiotics • Lipicky – Consultant: ActivBiotics • Constant - Consultant: ActivBiotics • Cadden – Employee of ActivBiotics • Sternlicht – Employee of ActivBiotics

  3. Peripheral Artery Disease • Common disorder with significant morbidity/mortality • ~8-12 million Americans • High risk of cardiovascular events • Marked reduction in quality of life due to functional limitations from intermittent claudication • Very few effective treatment options for intermittent claudication

  4. C. pneumoniae and Atherosclerosis/PAD • C. pneumoniae is a common respiratory pathogen that can also infect vascular tissues • Different species from C. trachomatis which causes sexually transmitted diseases • Extensive clinical, lab and epidemiological studies demonstrate C. pneumoniae exacerbates atherosclerosis • Found in atherosclerotic plaque • Infection results in inflammatory response and exacerbates atherosclerosis in animals • Patients with PAD are ~15 times more likely to have vascular infection with C. pneumoniae than age-matched controls without PAD • In humans, high antibody titers to C. pneumoniae correlate with increased progression of PAD Sources: Wiesli P, et al., Circulation105:2646-52, 2002; Linares-Palomino JP, et al., J Vasc Surg40:359-66, 2004; Schulthess G, et al., Int J Cardiol, 112:249-250, 2005; Vainas T, et al., Eur J Vasc Endovasc Surg29:403-411, 2005; Gutierres J, et al., Thromb Haemost93:1153-60, 2005; Sander D, et al., Circulation109:1010-1015, 2004

  5. Antibiotic Therapy and Atherosclerosis • Prior large event-based studies of antibiotic therapy in CAD (WIZARD, PROVE-IT, ACES) were negative Trials in Non-Coronary Atherosclerosis Atherosclerosis 2005; 179: 103-110Circulation 2004; 109: 1010-15 Eur L Vasc Endovasc Surg; 2005; 29: 403-11 Atherosclerosis; 2007; Apr 4 (e-pub)

  6. Rifalazil – A Potent Anti-Chlamydial Antibiotic • Selective inhibitor of bacterial RNA polymerase B • Efficacious in C. pneumoniae infection-exacerbated rabbit atherosclerosis model • High potency against Chlamydia in humans • Single oral 25 mg dose eradicated C. trachomatis in Phase II trial • Well tolerated in > 650 patients • Lipophilic – high tissue penetration and intracellular accumulation • Oral administration, long half-life – once weekly dosing

  7. PROVIDENCE Trial • Hypothesis: Eight weeks of once weekly therapy with rifalazil (25 mg) improves peak walking time (PWT) on a graded treadmill compared with placebo • Multicenter, multinational, prospective, randomized, placebo-controlled trial of patients with intermittent claudication who are highly seropositive for C. pneumoniae

  8. Endpoints • Primary Endpoint: Change in Peak Walking Time (PWT) at 6 months • Robust, objective primary endpoint for claudication trials • Secondary Endpoints: • Change in PWT (2,3,6,12 months) • Change in Claudication Onset Time (2,3,6,12 months) • Walking Impairment and SF-36 Questionnaire (3,6,12 months) • Safety: Adverse Events

  9. Inclusion Criteria • Male/female between 40-80 years • C. pneumoniae titers (IgG antibody titer > 1:128) • Diagnosis of PAD • Symptoms of stable intermittent claudication for 6 months • Ankle-brachial index <0.90 • or 20% reduction on treadmill exercise testing • PWT between 1-12 minutes on Gardner treadmill protocol (2 mph, 2% increased grade every 2 min)

  10. Statistical Design • Intent to Treat population included all patients randomized with at least one baseline and one post-baseline treadmill visit • 2-sided equal variance t-test on log ratio PWT (6M/baseline) with LOCF • Significance assessed at an alpha = 0.05

  11. n=131 ITT 145 Rifalazil n=153 693 Patients with Stable I.C. 1° endpoint n=297 Placebo n=122 ITT 138 n=144 2 mos. 6 mos. 12 mos. 396 Excluded (201 due to absence of titer) Study Design

  12. Baseline Demographics

  13. Primary Endpoint:PWT* p=NS Δ16% Placebo Δ 20% Rifalazil PWT (sec) *Presented as Geometric Mean

  14. Secondary Endpoint: Log PWT Over Time p=NS

  15. Secondary Endpoint: Log COT Over Time p=NS

  16. Quality of Life Results

  17. Cardiovascular Serious Adverse Events

  18. Summary • PROVIDENCE study found no benefit of Rifalazil in patients with intermittent claudication • Study appropriately powered to detect 18% treatment effect • High degree of drug compliance and patient follow up at 6 months

  19. Conclusion • This well-powered and well-executed study provides a compelling argument that C. pneumoniae does not play a role in PAD that is modifiable by antibacterial therapy

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