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16.5 kD 146 amino acid protein
belongs to a family characterized by high affinity for heparin
pluripotent mitogen capable of stimulating migration and proliferation of a variety of cell types, e.g. EC and SMC
induces angiogenesis in vitro and in several animal models of myocardial and hindlimb ischemia
rFGF-2 well tolerated by intracoronary infusion in doses up to 36 mg/kg (ideal body weight) in Phase I
Dose not the optimal dose from CAD
Stable Intermittent Claudication
Phase II, Randomized, Multicenter, Double-blind, Placebo-controlled
Three arms: Placebo, one, or two intraarterial doses of rFGF-2 (days 1 and 30)
Major Endpoints at 90, 180 days.
180 patients total
Prior CABG ~35%
Prior PCI ~ 25%
All patients underwent contrast angiography within 3 months of enrollment.
Angiograms were evaluated by a core laboratory at the University of Michigan.
A diameter stenosis of 70% was considered significant.
Segments including bypass grafts were combined here to show segmental distribution of 70% stenosis.
The majority of patients had femoropopliteal stenosis although a large minority also had tibial artery disease.
A few patients had angiographic iliac artery stenosis that was judged hemodynamically insignificant.
Patients were also classified as having either multilevel angiographic disease on either side or having disease confined to a single anatomic level.
Again, the majority of patients had isolated femoropopliteal level stenoses, and a large minority had multilevel disease.  Very few had stenoses confined to the tibial artery territory.
Approximately one-third of patients had angiographically unilateral disease.
The next table summarizes patient follow-up. Safety follow-up to day 180 was available for 93% of patients. Peak walking time measurements at 90 and 180 days were available for 93% and 88% of the patients, respectively. Premature termination occurred in 14 subjects for the reasons shown, and 8 patients underwent revascularization. There were no differences among the treatment groups.
The percentage of subjects who experienced any adverse event was similar among the three study groups. The numbers of patients with the selected AEs summarized here were generally similar among treatment groups. Proteinuria and hypotension were infrequent but appeared to be more common in the FGF-2 groups.
About 20% of study subjects experienced a serious adverse event. The selected serious adverse events of particular interest summarized here did not differ among study groups.
The next two slides will show the main findings of the TRAFFIC study.
The primary efficacy analysis is shown here.
At 90 days, the relative PWT increased 14% in the placebo group, 34% in the SINGLE group, and 20% in the DOUBLE group. These relative changes are shown as a geometric mean (or log-transformed data).  This calculation was selected to attenuate the impact of large values. As clinicians, we think in terms of minutes of walking time, so I will switch formats.
This slide combines the % change shown before with the absolute change in PWT, as shown here in the yellow histograms. At 90 days, there was a 0.6 minute improvement in the placebo group, a 1.8 minute improvement in the SINGLE group, and a 1.5 minute improvement in the DOUBLE group. The overall ANOVA is intended to detect a difference among the three groups and showed a p=0.075. Therefore we cannot formally reject the null hypothesis at the conventional threshold p=0.05. However, the alternate prespecified analysis uses ANOVA of ranks, which may be more statistically conservative, and shows a p=0.035, for a difference among the three groups.
These p values are sufficiently low that pairwise analysis is appropriate.
Pairwise comparison of SINGLE vs placebo showed p=0.026, while comparison of DOUBLE vs placebo showed p=0.45.
Therefore in this phase II proof-of-concept trial, we interpret these findings to show that a single infusion of FGF-2 is associated with a significant improvement in PWT compared with placebo, and that DOUBLE infusion is not superior to SINGLE.    The likelihood that we are wrong, in falsely rejecting the null hypothesis, is somewhere between 3.5%-7.5%.
Please note that this study was powered to detect a 60s increase over placebo in SINGLE and a 90s increase over placebo in DOUBLE, with the assumption that DOUBLE was both safe and superior.  DOUBLE was not in fact superior to SINGLE and this may account for the borderline ANOVA findings (0.075)
We reviewed these data from multiple perspectives, and the statistical findings are essentially the same regardless central tendency measure selected (geometric vs arithmetic means).  
16 Subjects excluded from primary efficacy analysis at day 90
10 Subjects with no day 90 PWT or premature termination (3 placebo, 3 SINGLE, 4 DOUBLE)
6 Subjects revascularized (2 placebo, 1 SINGLE, 3 DOUBLE)
At 180 days, fewer patients were available for PWT assessment in all groups.
At 180 days, the PWT improvement was maintained essentially unchanged in both SINGLE and DOUBLE groups. However, there was a marked improvement in the placebo patients at 180 days compared with 90 days. Compared with placebo at 180 days, the SINGLE group remained superior, although the DOUBLE group did not. Other placebo-controlled claudication studies with serial exercise examinations have shown a progressive increase in placebo effect over time, although generally not to the degree shown here.  Moreover, one of the entry criteria for the study was reproducibility of paired baseline ETTs, so patients were selected for more-reproducible PWTs.
Responder data (using > 1 min definition) at day 180 are not available to me
Validated general assessment of QoL.
Two summary scores:  physical component summary score (PCSS), mental component summary score
MCSS showed almost no significant difference.
Only applied to evaluable patients.
In contrast, change in COT was not significantly different between groups.
This is suprising, since in other claudication trials, COT tracks closely with PWT, only with a higher degree of variability.
This observation tempers our favorable interpretation of this study.
Conversely, trends were favorable on the objective hemodynamic assessment of ankle-brachial SBP index.
All evaluable patients.
All evaluable patients.
Hypotension < SBP90 or drop 30% from baseline
Proteinuria 2, 6, 7