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

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

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

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

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

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

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

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

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)

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

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

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

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

Secondary Endpoint: Log PWT Over Time

p=NS

Secondary Endpoint: Log COT Over Time

p=NS

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

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

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

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