circumstance arising is expected to be quite low, and wili oe carefully studied in the primate 
model prior to beginning the clinical protocol. In any case, the environmental risk derived 
from the possible spread of AAV-CFTR vectors is likely to be minimal, particularly since 
both wild-type AAV and concurrent adenovirus functions are necessary for active 
replication. 
7.4 Management of Toxicities and Complications 
7.4.1 Dose Schedule Modification for Toxicity 
If no subject develops a grade 3 toxicity related to the tgAAVCF vector administration at 
any dose under study then the highest dose level will be considered to have been tolerated 
(Appendix B, common toxicity criteria). 
If one of two subjects develops a grade 3 toxicity related to the tgAAVCF vector 
administration at a vector dose level below the highest dose, then an additional two subjects 
will be evaluated at that dose level. If no more than one of the four subjects develops a 
grade 3 toxicity related to tgAAVCF vector administration at a vector dose level below the 
highest dose, then the next two patients will be treated at the next highest vector dose level. 
If two or more of the four subjects develop a grade 3 toxicity related to tgAAVCF vector 
administration at a dose level then the maximum tolerated dose (MTD) has been exceeded 
and at least four additional subjects will be evaluated at the next lower vector dose. 
The MTD will be defined as the dose level immediately below the dose level at which at 
least two subjects develop a grade 3 toxicity related to the tgAAVCF vector administration. 
If a subject develops a grade 4 toxicity related to the tgAAVCF vector administration, then 
vector administration will be discontinued immediately and the Clinical Affairs Department 
at Targeted Genetics Corporation will be notified immediately. The Principal Investigator, 
the Institutional Review Board, and Targeted Genetics Corporation will then review the 
data to consider whether to interrupt the study. 
7.4.2 Constitutional Symptoms 
a. Fever, chills, and temperature elevations >101°F may be managed with 
acetaminophen 650 mg p.o. q 4-6 hrs. All subjects that develop fever or chills will 
have blood and sputum cultures obtained. 
b. Hypoxemia, wheezing, or coughing may be managed with supplemental 
oxygen, bronchodilator nebulization, or other supportive therapy. 
7.5 Premature Discontinuation 
Subjects who do not complete the full schedule of vector administration and evaluation will 
be considered to have prematurely discontinued the study. The reasons for premature 
discontinuation (for example, voluntary withdrawal, toxicity, death) must be recorded on 
the case report form. A subject may re-enter the study after premature discontinuation only 
by approval of the Principal Investigator. Potential reasons for premature discontinuation 
include: 
1. Significant exacerbation of pre-existing disease 
Recombinant DNA Research, Volume 20 
[125] 
