# EFFICACY EVALUATION

## Data Sets Analyzed

[Intent to Treat Efficacy Data Sets]{.underline}

All patients who were randomized, received treatment with study device,
regardless of study completion, and had at least one post-treatment
efficacy evaluation were included in the ITT population. Treatment
assigned to the donor site at the time of randomization was used for all
listings, tables, analyses and graphs presented in this report.

All 82 patients enrolled in the study were included in the ITT
population.

######### Table 11.1.1: ITT, Per Protocol, and Safety Populations {#table-11.1.1-itt-per-protocol-and-safety-populations .unnumbered}

  ----------------------------------- -----------------------------------
  Intent-to-Treat                     82 (100%)

  Per Protocol                        74 (90.2%)

  Safety                              82 (100%)

  *Source: Section 14, Table C1*      
  ----------------------------------- -----------------------------------

[Per Protocol Efficacy Data Sets]{.underline}

These data sets were a subgroup of the ITT efficacy data sets, which
excluded patients with major protocol violations. Eligibility criteria
for this population were established at a Validity Meeting on 13
November 2000, prior to unblinding the study and consisted of the
following:

-   Exclusion for incomplete planimetry data. Incomplete planimetry was
    defined as not enough planimetry data to determine if the donor site
    was healed by the Day 28 study visit.

-   Exclusion for violation of inclusion or exclusion criteria or any
    other major protocol violation.

Patients were not excluded from the PP population for systemic
corticosteriod use before or during the study. The rationale for this
decision was that the matched pairs design of the study would render
both treatment sites equally vulnerable to any steroid effects on wound
healing.

Of 82 randomized patients, eight patients were excluded from the PP
population due to major protocol violations (See Section 10.2).

## Demographic and Baseline Characteristics

Table 11.2.1 summarizes the demographic characteristics of the 82
enrolled subjects.

The population randomized to treatment was composed of 63 males (76.8%)
and 19 (23.2%) females. Mean age of all patients was 31.7 years (range:
1 to 88 years). The population was 53.7% Caucasian, 24.4%
African-American, 15.9% Hispanic, 2.4% Asian/Pacific Islander and 3.7%
other.

Table 11.2.1: Demographics of All Randomized Subjects

+-----------------------------------+--------------+------------------+
| ####### Sex {#sex .unnumbered}    |              |                  |
+-----------------------------------+--------------+------------------+
| > Male                            | n (%)        | 63 (76.8)        |
+-----------------------------------+--------------+------------------+
| Female                            | n (%)        | 19 (23.2)        |
+-----------------------------------+--------------+------------------+
| **Race**                          |              |                  |
+-----------------------------------+--------------+------------------+
| > Caucasian                       | n (%)        | 44 (53.7)        |
+-----------------------------------+--------------+------------------+
| > African American                | n (%)        | 20 (24.4)        |
+-----------------------------------+--------------+------------------+
| > Hispanic                        | n (%)        | 13 (15.9)        |
+-----------------------------------+--------------+------------------+
| > Asian/Pacific Islander          | n (%)        | 2 (2.4)          |
+-----------------------------------+--------------+------------------+
| > Other                           | n (%)        | 3 (3.7)          |
+-----------------------------------+--------------+------------------+
| **Age** (years) (n=82)            | Mean (SD)    | 31.7 (21.3)      |
+-----------------------------------+--------------+------------------+
| **Height** (inches) (n=80)        | Mean (SD)    | 61.2 (13.7)      |
+-----------------------------------+--------------+------------------+
| **Weight** (pounds) (n=82)        | Mean (SD)    | 148.8 (70.6)     |
+-----------------------------------+--------------+------------------+
| *Source: Section 14, Table C6*    |              |                  |
+-----------------------------------+--------------+------------------+

Over 80% of the study population had medical histories relating to
dermatologic, endocrine/metabolic or neurologic disorders. Skin was the
only organ system that yielded abnormal findings on physical examination
in the majority of patients. (Section 14, Tables C10 and C11 provide
baseline summary data for medical history and screening physical exam,
respectively. Appendix 16.10, Listings 6 and 7 provide medical history
and physical exam data, respectively, for individual patients).

With regard to the severity of injuries at baseline, Table 11.2.2
presents descriptive statistics for protocol-specified injury severity
scales, daily caloric requirements, and percentage of total body surface
area (TBSA) burned of randomized subjects.

Table 11.2.2: Baseline Characteristics of Injury Severity

+---------------------------+------------------+-----------------------+
| ####### Daily caloric re  | N                | 82                    |
| quirement {#daily-caloric |                  |                       |
| -requirement .unnumbered} |                  |                       |
+---------------------------+------------------+-----------------------+
|                           | Mean (SD)        | 2383.9 (756.56)       |
+---------------------------+------------------+-----------------------+
|                           | Median           | 2379.5                |
+---------------------------+------------------+-----------------------+
|                           | Range            | 568-4400              |
+---------------------------+------------------+-----------------------+
|                           |                  |                       |
+---------------------------+------------------+-----------------------+
| Injury Severity Score     | N                | 50                    |
| (ISS)                     |                  |                       |
|                           |                  |                       |
| (subjects 15 years of     |                  |                       |
| age)                      |                  |                       |
+---------------------------+------------------+-----------------------+
|                           | Mean (SD)        | 14.6 (8.12)           |
+---------------------------+------------------+-----------------------+
|                           | Median           | 11.0                  |
+---------------------------+------------------+-----------------------+
|                           | Range            | 4-50                  |
+---------------------------+------------------+-----------------------+
|                           |                  |                       |
+---------------------------+------------------+-----------------------+
| Pediatric Trauma Score    | N                | 18                    |
| (PTS)                     |                  |                       |
|                           |                  |                       |
| (subjects \<15 years of   |                  |                       |
| age)                      |                  |                       |
+---------------------------+------------------+-----------------------+
|                           | Mean (SD)        | 8.9 (1.28)            |
+---------------------------+------------------+-----------------------+
|                           | Median           | 8.5                   |
+---------------------------+------------------+-----------------------+
|                           | Range            | 7-11                  |
+---------------------------+------------------+-----------------------+
|                           |                  |                       |
+---------------------------+------------------+-----------------------+
| Pediatric Glasgow Coma    | N                | 19                    |
| Score                     |                  |                       |
|                           |                  |                       |
| (subjects \<15 years of   |                  |                       |
| age)                      |                  |                       |
+---------------------------+------------------+-----------------------+
|                           | Mean (SD)        | 14.8 (0.92)           |
+---------------------------+------------------+-----------------------+
|                           | Median           | 15.0                  |
+---------------------------+------------------+-----------------------+
|                           | Range            | 11-15                 |
+---------------------------+------------------+-----------------------+
|                           |                  |                       |
+---------------------------+------------------+-----------------------+
| Percentage of TBSA Burned | \<10%            | 0 ( 0.0%)             |
+---------------------------+------------------+-----------------------+
|                           | 10 -- 20%        | 21 (26%)              |
+---------------------------+------------------+-----------------------+
|                           | 20 -- 40%        | 47 (57%)              |
+---------------------------+------------------+-----------------------+
|                           | \>40%            | 14 (17%)              |
+---------------------------+------------------+-----------------------+
|                           | Total            | 82 (100%)             |
+---------------------------+------------------+-----------------------+
| *Source: Section 14,      |                  |                       |
| Tables C7 and P10,        |                  |                       |
| Section 16.10 Listing 6*  |                  |                       |
+---------------------------+------------------+-----------------------+

The mean ISS and the mean PTS were 14.6 and 8.9, respectively, and the
mean Pediatric Glasgow Coma Score was 14.8. A mean caloric intake (2384
calories) indicates that the majority of patients were in a catabolic
state as a result of the severity of their injury. None of the
randomized subjects had less than 10% TBSA burned and 74% of subjects
had greater than 20% TBSA burned, as indicated in Figure 11.2.3.

######### Figure 11.2.3: Extent of Burn Injuries {#figure-11.2.3-extent-of-burn-injuries .unnumbered}

![](media/image1.wmf)

Routine laboratory data obtained at the screening visit are summarized,
descriptively, in Section 14, Table C12 and listed in Appendix 16.10,
Listing 36. A total of 55 subjects (82%) had anemia and 35 subjects
(52%) had elevated white cell counts. Over one third of the subjects
(27/76, 36%) had elevated glucose levels. Additionally, decreased mean
and median albumin levels (2.0 and 2.1g/dL, respectively, lower limit of
normal is 3.5 g/dL) indicate that the population, as a whole, was
malnourished. The screening laboratory results substantiate a patient
population that was seriously ill.

Results of baseline medical histories, injury severity ratings, burned
surface area, caloric intake, hematologic and chemistry parameters
describe a population that was severely burned, malnourished, and
debilitated. These factors indicate a possible predisposition to longer
healing times in the studied population.

The treatment groups were well balanced with respect to donor site
characteristics. Mean surface areas for the CCS and Biobrane L donor
sites were 94.4 and 94.3 cm^2^, respectively (p = 0.97). The mean
autograft thickness of both the CCS and Biobrane L donor sites was
0.0116 inches (Section 14, Table C9 and Appendix 6.10, Listing 18).

## Measurements of Treatment Compliance

Not applicable

## Efficacy Results 

There was a clinically meaningful and statistically significant shorter
time to 100% wound closure with CCS when compared to Biobrane-L. This
finding was observed in three different methods of assessments (i.e.,
planimetric, photographic, and investigator assessments); evaluated with
three different statistical metrics (i.e., mean, median, and
Kaplan-Meier estimates) in two protocol specified populations (i.e.,
Intent-to-Treat and Per Protocol). The difference was also clinically
and statistically significant in all subgroups where the patient numbers
were greater than five (i.e., age, race, gender, percentage of total
body surface area burned, and donor skin size).

**Figure 11.4.1: Median Days to 100% Wound Closure**

**ITT Population**

![](media/image2.wmf)

In this section we present these findings in detail. We will use
Kaplan-Meier curves to depict the percentage of donor sites completely
healed over time. We also present the rate of wound closure as well as
the percentage of donor sites completely healed by day 32 using the
three methods of assessment and the two different populations.
Additionally, using planimetry data we will demonstrate that in the
first 16 days after donor skin harvest (i.e., 50% of the duration to day
32) the rate of wound closure at CCS-treated donor sites was nearly 70%
faster of that of the Biobrane-L-treated sites.

**Figure 11.4.2: Mean Days to 100% Wound Closure**

**ITT Population**

![](media/image3.wmf)

###  {#section .unnumbered}

### Primary Efficacy Parameter

Primary efficacy data (i.e., time to 100% wound closure) are presented
in Table 11.4.3 for the ITT and PP populations and the three methods of
assessment.

######### Table 11.4.3: Median and Mean Days to 100% Wound Closure {#table-11.4.3-median-and-mean-days-to-100-wound-closure .unnumbered}

<table>
<colgroup>
<col style="width: 17%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 3%" />
<col style="width: 6%" />
<col style="width: 13%" />
<col style="width: 12%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4">Median Days to Wound Closure*</td>
<td></td>
<td colspan="4">Mean (SD) Days to Wound Closure</td>
</tr>
<tr class="even">
<td></td>
<td>Source</td>
<td>CCS</td>
<td>BIO</td>
<td>p-value**</td>
<td></td>
<td>Source</td>
<td>CCS</td>
<td>BIO</td>
<td>p-value+</td>
</tr>
<tr class="odd">
<td>Investigator ITT</td>
<td>E18.3</td>
<td>12.0</td>
<td>16.0</td>
<td>&lt;0.0001</td>
<td></td>
<td>E18.1</td>
<td>13.2(4.87)</td>
<td>18.4(7.86)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="even">
<td>Investigator PP</td>
<td>E19.3</td>
<td>12.0</td>
<td>16.0</td>
<td>&lt;0.0001</td>
<td></td>
<td>E19.1</td>
<td>12.9(4.16)</td>
<td>17.9(7.51)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="odd">
<td>Planimetric ITT</td>
<td>E1.3</td>
<td>12.0</td>
<td>17.0</td>
<td>&lt;0.0001</td>
<td></td>
<td>E1.1</td>
<td>13.7(5.83)</td>
<td>19.3(8.37)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="even">
<td>Planimetric PP</td>
<td>E2.3</td>
<td>12.0</td>
<td>16.0</td>
<td>&lt;0.0001</td>
<td></td>
<td>E2.1</td>
<td>13.4(5.14)</td>
<td>18.7(8.02)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="odd">
<td>Photographic ITT</td>
<td>E9.3</td>
<td>15.0</td>
<td>22.0</td>
<td>0.0006</td>
<td></td>
<td>E9.1</td>
<td>18.0(7.12)</td>
<td>22.4(8.48)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="even">
<td>Photographic PP</td>
<td>E10.3</td>
<td>15.0</td>
<td>21.0</td>
<td>0.0009</td>
<td></td>
<td>E10.1</td>
<td>17.8(6.64)</td>
<td>22.1(8.25)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="odd">
<td colspan="10"><p>*Kaplan-Meier estimates of the median days to 100%
wound closure +Paired t-test</p>
<p>**Log-Rank test of the difference between median healing times</p>
<p><em>Source: Section 14, tables specified above</em></p></td>
</tr>
</tbody>
</table>

[ITT Population]{.underline}

As specified in the protocol, the primary endpoint is 100% wound closure
using photographic assessments. Figures 11.4.1 and 11.4.2 depict the
median and mean times, respectively, to 100% wound closure across all
three methods of assessment, photographic, planimetric, and
investigator. For the ITT population and median days to healing using
photographic assessment, CCS treated sites healed seven days faster than
the Biobrane-L treated sites (15 days vs. 22 days, respectively); this
was statistically significant with p-value=0.0006. For mean days to
healing by photographic assessment, CCS treated sites in the ITT
population healed four days faster than the Biobrane-L treated sites (18
days vs. 22 days, respectively), also statistically significant
(p\<0.0001).

Results of ITT planimetric assessments support those obtained by
photography (i.e., median and mean days to healing for CCS were 12 and
14 days, respectively, while those of Biobrane-L were 17 and 19 days,
respectively). These differences reflect a five-day shorter time to
healing with CCS and are statistically significant (p=\<0.0001).

Results of the ITT investigator assessment also support those obtained
by photography; i.e., median and mean days to healing for CCS were 12
and 13 days, respectively, while those of Biobrane-L were 16 and 18
days, respectively, reflecting a four- to five-day shorter time to
healing with CCS that is statistically significant (p\<0.0001).

[Per Protocol Population]{.underline}

Figure 11.4.3 depicts the photographic, planimetric and investigator
assessments of time to 100% wound closure for the PP population. Results
obtained with this population closely resemble those of the ITT
population with statistically significant differences in time to wound
closure for all three assessment methods.

**Figure 11.4.3: Median Days to 100% Wound Closure**

**Per Protocol Population**

(Investigator, Planimetric, Photographic Assessments)

![](media/image4.wmf)

For the photographic assessment, CCS treated sites healed six days
faster than the Biobrane-L treated sites (15 days vs. 21 days,
respectively), a statistically significant difference (p = 0.0009). Mean
time to healing was 18 vs. 22 days, respectively (p\<0.0001).

Results of planimetric and investigator assessments were similar to the
photographic assessment with CCS treated sites requiring only 12 days to
wound closure (median time) while Biobrane-L treated sites required 16
days, again, reflecting a statistically significant difference between
the two treatments (p\<0.0001) for both assessments. Mean time to
healing by planimetry was 13 vs. 19 days, respectively (p\<0.0001). Mean
time to healing according to investigators assessment was 13 vs. 18
days, respectively (p\<0.0001).

[Kaplan-Meier Presentation]{.underline}

![](media/image5.wmf){width="5.927083333333333in" height="3.46875in"}To
depict the time to wound closure in more detail, the Kaplan-Meier (K-M)
curve waas employed. Figure 11.4.4 is the K-M curve for time to 100%
wound closure based on investigator assessments for the ITT population.
The horizontal axis presents days and the vertical axis presents
percentage of patients healed. To explain this graph, we draw an arrow
at 80% on the vertical axes (percent of patients healed) and
demonstrated its associated time to healing on the horizontal axes for
CCS (15 days) and for Biobrane-L (26 days).

Figures 11.4.5 and 11.4.6 depict K-M curves for the planimetric and
photographic assessments, respectively, in the ITT population. Results
from all three methods of assessment indicate the superior healing power
of CCS as compared to Biobrane-L in terms of time of healing. By
planimetric assessment, 80% of all CCS donor sites achieved complete
closure by day 15 as compared to day 28 for complete closure of 80% of
the Biobrane-L sites. Per photographic assessment, 80% of all CCS donor
sites achieved complete closure by day 22 as compared to day 29 for the
Biobrane-L donor sites.

![](media/image6.wmf){width="5.9375in" height="3.46875in"}

![](media/image7.wmf){width="5.9374015748031495in"
height="3.4688976377952754in"}

[Percentage of Donor Sites Healed by Day 32]{.underline}

Figures 11.4.7 and 11.4.8 depict the percentage of donor sites
completely healed by day 32 for the ITT and PP populations,
respectively, as assessed by investigator, planimetry, and photography.
The percentage of CCS donor sites completely healed by day 32 was
significantly higher (p\<0.05) than those of Biobrane-L for all
assessment methods and both populations.

**Figure 11.4.7: Percentage of Sites Completely Healed by Day 32**

![](media/image8.wmf)

For the ITT population, CCS and Biobrane-L donor sites completely healed
on day 32 were 96.3% and 86.6%, respectively, (p=0.0047) according to
investigator assessment; 92.7% and 80.5%, respectively, (p=0.0039)
according to planimetry; and 85.4% and 61.0%, respectively, (p=\<0.000)
by photography.

Similar results and significance levels were obtained with the PP
population, as depicted in Figure 11.4.8.

**Figure 11.4.8: Percentage of Sites Completely Healed by Day 32**

![](media/image9.wmf)**Per Protocol Population**

[Time to 95% and 98% Wound Closure]{.underline}

Kaplan-Meier estimates of median time to 95% and 98% wound closure, as
assessed by planimetry, were also conducted. Figures 11.4.9 and 11.4.10,
respectively, depict these median times for the ITT population.

Median times to 95% wound closure were 10 days for CCS and 13 Days for
Biobrane-L; 98% wound closure was achieved in 11 days for CCS and 15
days for Biobrane-L sites.

> ![](media/image10.wmf){width="4.4in" height="3.204724409448819in"}