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Evaluation of Rifalazil Effects on Vascular Symptoms of Intermittent Claudication in C. pneumoniae Seropositive Patients

Explore the impact of Rifalazil on vascular symptoms in patients with intermittent claudication and C. pneumoniae infection. The study investigates the antibiotic’s efficacy, safety, and potential benefits on walking performance and quality of life.

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Evaluation of Rifalazil Effects on Vascular Symptoms of Intermittent Claudication in C. pneumoniae Seropositive 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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