Recombinant DNA Advisory Committee- 9/12-13/94 
the investigators determined the ability of the VEGF plasmid DNA to bind to the 
hydrogel polymer coating of the angioplasty balloon. 
The investigators now propose to study 12 patients with claudication at rest or non-healing 
ischemic ulcers. Such patients are not candidates for non-surgical or surgical re- 
vascularization. The patients will have the VEGF plasmid DNA introduced by arterial 
catheterization with the balloon catheter being expanded for one minute. The maximal 
calculated dose of the plasmid DNA will be 1.07 mg. The endpoint of the study will be a 
decrease in the amount of pain at rest and/or healing of the ulcers. Secondary endpoints 
will be based on arteriorography that will be done to patients before and after gene 
transfer. Other physiologic measurements are being explored as surrogate endpoints. 
Dr. Parkman raised several questions in his critique. Most of them have been 
satisfactorily answered by the investigators in their written response. The arteriograms 
were scored by more than one blinded observer, and consistent differences between 
control and treated animals were observed. The investigators provided copies of all 
arteriograms, and Dr. Parkman agreed with the investigators’ assessment about 
improvement of blood flow. Dr. Parkman said that this protocol is very good, and he did 
not agree with all the criticisms made by Dr. Dzau in his written review. The investigators 
require the patients to keep a diary for pain medication but the baseline is not well 
defined. Dr. Parkman suggested the diary be kept for a month’s period before treatment 
to define a baseline for pain relief. The diary will record a pain scale, and Dr. Parkman 
suggested a period of 1 month before and 1 or 2 months after gene transfer. 
Review-Dr. Dzau (presented by Dr. Parkman) 
Dr. Walters called on Dr. Parkman to present a written review by Dr. Dzau in his 
absence. Dr. Dzau raised several issues, and the investigators have provided a detailed 
response to each question. Dr. Parkman said that most of the concerns have been 
addressed. Three major issues raised by Dr. Dzau were: (1) What is the imperative 
rationale for doing gene transfer rather than simple infusion of VEGF peptide? (2) The 
statement, "not satisfactory candidates for nonsurgical and surgical revascularization", in 
the Selection of Patients, must be clinically defined. (3) Is this protocol a Phase I study 
for safety or a therapeutic trial? If it is a efficacy study, a control group of patients should 
be included. On the matter of the control group in the study, Dr. Parkman said that this 
is a Phase I study using pain relief as an endpoint. The primary objective is to look for 
untoward effects. His suggestion of keeping a diary for pain and medication is to use each 
individual as his/her own control. In his opinion, it is better than a control group of 
patients in this study. On the question of exclusion criteria, the investigators have now 
listed the entities in the Exclusion Criteria of the protocol. Dr. Parkman commented that 
there are patients who are candidates for surgical intervention who are in fact potential 
candidates for gene transfer. 
Review-Dr. Motulsky 
Dr. Motulsky said this new approach using gene therapy is very exciting for PAD. This 
Recombinant DNA Research, Volume 20 
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