prospective evaluation of rifalazil effect on vascular symptoms of intermittent claudication and...
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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
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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
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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
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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., Circulation 105:2646-52, 2002; Linares-Palomino JP, et al., J Vasc Surg 40:359-66, 2004; Schulthess G, et al., Int J Cardiol, 112:249-250, 2005; Vainas T, et al., Eur J Vasc Endovasc Surg 29:403-411, 2005; Gutierres J, et al., Thromb Haemost 93:1153-60, 2005; Sander D, et al., Circulation 109:1010-1015, 2004
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Antibiotic Therapy and Atherosclerosis
Prior large event-based studies of antibiotic therapy in CAD (WIZARD, PROVE-IT, ACES) were negative
Trial N AntibioticCourse/
ObservationPrimary EP Results
Krayenbuehl et al 100 Roxithromycin 30 d/2.5 yr
No. of PAD interventions;Walking distance
p<0.05
Sander et al 272 Roxithromycin 30 d/2 yr Change in carotid IMT p<0.01
Vainas et al 509 Azithromycin 30 d/2 yr CV Events NS
Joensen et al
507 Roxithromycin 30 d/2 yr CV Events NS
Atherosclerosis 2005; 179: 103-110Circulation 2004; 109: 1010-15 Eur L Vasc Endovasc Surg; 2005; 29: 403-11 Atherosclerosis; 2007; Apr 4 (e-pub)
Trials in Non-Coronary Atherosclerosis
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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
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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
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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
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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)
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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
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Study Design
2 mos. 6 mos. 12 mos.
1° endpointn=297
n=131
n=122
n=153
n=144
Rifalazil
Placebo
693 Patients with
Stable I.C.
396 Excluded(201 due to
absence of titer)
ITT 145
ITT 138
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Baseline DemographicsVariable Rifalazil
(n=145) Placebo (n=138) P-value
Age (yrs) 66.6 ± 8.0 64.1 ± 8.7 0.01
Male/Female 118 / 27 109 / 29 NS
BMI 27.7 ± 5.3 27.3 ± 4.6 NS
Caucasian/Black/Other
133 / 6 / 6 126 / 10 / 2 NS
Diabetes /No diabetes
43 / 102 32 / 106 NS
Smoking (None / former / current)
17 / 78 / 50 21 / 60 / 57 NS
Ankle-Brachial Index (Baseline)
0.63 ± 0.17 0.63 ± 0.15 NS
Chlamydia Titer (<1:512 / ≥1:512)
77 / 68 86 / 52 NA
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Primary Endpoint:PWT*
0
50
100
150
200
250
300
350
Baseline 6 Months
Rifalazil(n=145)Placebo(n=138)P
WT
(se
c)
p=NS
*Presented as Geometric Mean
Δ 16% PlaceboΔ 20% Rifalazil
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Secondary Endpoint: Log PWT Over Time
p=NS
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Secondary Endpoint: Log COT Over Time
p=NS
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Quality of Life Results
Variable Rifalazil Placebo P Value
W. I. Q.
Baseline
29.4 ± 23.3 29.9 ± 22.7
W.I.Q.
6 Months
35.7 ± 26.3 39.2 ±27.1 NS
SF 36 Physical Functioning Score
Baseline
47.5 ± 17.8 50.8 ± 18.0
SF 36 Physical Functioning Score
6 Months
51.5 ± 17.4 51.9 ± 17.4 NS
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Cardiovascular Serious Adverse Events
Type of Event Rifalazil Placebo
Cardiac (MI, AP, Dysrhythmias,CHF)
7 8
Vascular (PAD, Revasc,Amputations, DVT)
9 10
Mortality 3 1
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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
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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