Discontinuing for lack of efficacy (LOE)/adverse events (AE) at one year, excluding deaths.

\*\* Number of explants through August 1996, excluding deaths.

†† All deaths occurred by the long-term follow-up closing date of August 1996.

**Table 2.** Principal Efficacy and Safety Results [13]

#### **3. Regulatory approvals**

For the HIGH Group, a 30 Hz stimulation frequency was chosen based on the Woodbury rat studies [11] (Woodbury DM, 1990) and safety concerns by Agnew [12] (Agnew WF, 1990) that continuous stimulation at frequencies above 50 Hz might induce nerve damage, although the studies had shown that a 4-hour ON and 4-hour OFF at 50 HZ did not cause any damage. The E05 study used 20 Hz instead of 30 Hz. The 30 seconds ON and 5 minutes OFF was chosen as a compromise to extend battery life and achieve a 10% probability of stimulation during a

Results: The primary efficacy endpoint (percent reduction in seizure rate) was measured over 12 weeks as shown in Table 2. [13] (Cyberonics, 2013) Adverse events were assessed at each

**Principal Efficacy Results**

**No. of patients in efficacy analysis** 10 5 116 114 196 441

**Difference in mean (high/low)** - - - 17%§ (3%/31%) 13%|| (2%/23%) -

**Principal Safety Results Through Long-term Follow Up Exposure (pt-yr)** 45 20 245 456 135 901 **SAEs¶ (high/low)** 9%/ - 0%/ - 6%/ - 5%/0% 7%/9% - **Discontinued (LOE/AE)#** 0/1 0/0 2/3 0/2 1/3 3/9 **No. of explants\*\*** 2 2 15 9 5 33 **Deaths: SUDEP/total††** 0/0 0/0 3/4 0/3 1/2 4/9

**Median reduction in seizures/day** 32%\* 48% 22%\* 23% high\*/ 6%

**Mean reduction in seizures/day** 24%‡ 40% 7%‡ 24% high‡/ 6%

**% with >50% response** 30% 50% 29% 30% high/ 14%

All patients in efficacy analyses in all VNS clinical studies, N=441 [13]

§ P ≤ 0.02, by Wilcoxon rank sum; P ≤ 0.02, by Student's *t-test.*

\*\* Number of explants through August 1996, excluding deaths.

**Table 2.** Principal Efficacy and Safety Results [13]


†† All deaths occurred by the long-term follow-up closing date of August 1996.
