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S-1/A
PROTEON THERAPEUTICS INC filed this Form S-1/A on 10/07/2014
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    Use for hemodialysis.  Use was defined as use of the AVF for hemodialysis at any time without a previous intervention. Although the results were not statistically significant, there was a trend to more patients using the AVF for hemodialysis in the 30 microgram group (69%) compared with the placebo group (53%).
    Hemodynamically significant lumen stenosis.  Hemodynamically significant lumen stenosis, or narrowing of blood vessels, impairs AVF maturation and contributes to AVF patency loss. Hemodynamically significant stenosis was defined as a 50% or greater stenosis and a significant elevation in peak blood flow velocity across the stenosis detected by ultrasound. Ultrasounds were performed using a standard protocol and reviewed by a central reader masked to treatment assignment and AVF outcome. Although the results were not statistically significant, there was a trend to fewer patients with a hemodynamically significant stenosis in the patients receiving 10 micrograms (30%) and 30 micrograms (39%) of PRT-201 compared with the placebo group (51%) at 6 weeks. Detecting hemodynamically significant stenosis is technically challenging and often confounded by the performance of procedures, such as angioplasty to treat stenosis prior to the ultrasound examination.

    Safety and tolerability

        PRT-201 is administered topically at the vascular access and only acts locally. We have not observed systemic activity or toxicity in our preclinical animal studies, even following intravenous administration at very high multiples of the Phase 2 clinical trial doses. Safety evaluations in Phase 2 included ascertainment of adverse events, physical examinations, ultrasounds of the AVFs and nearby vessels, vital signs and laboratory studies. No significant safety signals were identified. In the trial, patients treated with PRT-201 reported adverse events, the most common of which are summarized in the following table, comparable to placebo. These events were consistent with the medical events experienced by CKD patients undergoing AVF placement surgery. The most common adverse events were AVF incision pain, venous stenosis, AVF thrombosis, steal syndrome and hypoesthesia. Serious adverse events, or SAEs, reported by the investigator as possibly drug-related occurred in two 10 microgram PRT-201 patients (both AVF thrombosis), and two 30 microgram patients (one chest pain and one swelling at the surgical incision). There were no SAEs reported by the investigator as possibly drug-related in the placebo group. There was one SAE reported by the investigator to be drug-related in the 10 microgram PRT-201 group (AVF maturation failure), and there were none in the other treatment groups.


Number and Proportion (%) of Patients with
Common Adverse Events
(1)

N (%)
  Placebo
N=51
  PRT-201
10 micrograms
N=51
  PRT-201
30 micrograms
N=49
 

Any adverse event

    42 (82 )   39 (77 )   43 (88 )

AVF thrombosis

    13 (26 )   8 (16 )   7 (14 )

Venous stenosis

    10 (20 )   7 (14 )   8 (16 )

Steal syndrome

    7 (14 )   2 (4 )   6 (12 )

Hypoesthesia

    7 (14 )   6 (12 )   6 (12 )

AVF incisional pain

    5 (10 )   9 (18 )   9 (18 )

AVF site complication

    5 (10 )   4 (8 )   4 (8 )

Nausea

    5 (10 )   1 (2 )   2 (4 )

Peripheral edema

    5 (10 )   0 (0 )   2 (4 )

Arterial stenosis

    4 (8 )   5 (10 )   0 (0 )

Paresthesia

    1 (2 )   1 (2 )   5 (10 )

Pain in extremity(2)

    0 (0 )   1 (2 )   5 (10 )

Note: None of the differences between groups were statistically significant.

(1)
Adverse events occurring in at least 10% of placebo or either PRT-201 treatment groups.

(2)
All but one unrelated to limb used in AVF surgery.

95