# SAFETY EVALUATION

## Extent of Exposure

The designated wound sites received a single application of the control
dressing or the investigational dressing. Wounds assigned to the control
dressing received Biobrane-L coverage. Removal of the outer dressing
layers on the Biobrane-L site was generally performed after the initial
24-48 hours following surgery. The timing of Biobrane-L removal was
expected to be variable from patient to patient, however attempts to
peel Biobrane-L from newly formed epidermis generally began between the
7^th^ and 10^th^ post operative days. Those areas where Biobrane-L
separated easily from the underlying donor surface were trimmed back.
Those areas where Biobrane-L remained adherent to the test site despite
soaking were considered non-epithelialized and open.

Wounds assigned to the investigational treatment received the CCS for
coverage. The outer dressing layers over the CCS test site remained
undisturbed during the initial 72-hour postoperative period. On the
third post-operative day, the outer layers were taken down to allow
inspection of the CCS backing surface overlying the treatment site. The
backing material was left in place at this time and gentle normal saline
irrigation of the area was permitted to remove any exudate or debris
that was adherent to the backing material. Thereafter removal and
replacement of the outer dressing wrap on the CCS was permitted every
48-72 hours until Day 7, at which time attempts were made to remove the
backing to allow the first direct visual assessment of the donor
treatment site.

## Adverse Events

### Brief Summary of Adverse Events

Of the 82 patients enrolled in the study, 64 (78.0%) had at least one
adverse event. Overall, most of the adverse events were mild to moderate
in severity, however there were three fatalities that were not related
to donor site treatment. Sepsis, multiple organ system failure and
dyspnea were the events associated with fatal outcomes. Serious adverse
events without donor site involvement were reported by 23 (28%) of the
patients. There were no serious adverse events involving the donor
sites. There were 12 adverse events involving the CCS site and 13
adverse events involving the Biobrane-L site. All of the adverse events
with donor site involvement were mild to moderate in severity.

### Display of Adverse Events

Table 12.2.1 lists the adverse events without donor site involvement
that had an incidence of [\>]{.underline} 5.0 % in one or more severity
categories. Table 12.2.2 lists the adverse events without donor site
involvement that had an incidence of \< 5.0% in all severity categories.
Most of the adverse events were considered unlikely to be related to the
study treatment. No severe, life threatening, or fatal adverse events
occurred at an incidence of [\>]{.underline} 5.0%.

+----------------------------+------+------+------+------+------+------+
| **Table 12.2.1: Adverse    |      |      |      |      |      |      |
| Events with an Incidence   |      |      |      |      |      |      |
| [\>]{.underline} 5.0% by   |      |      |      |      |      |      |
| Severity**                 |      |      |      |      |      |      |
+============================+======+======+======+======+======+======+
|                            | Mild |      | Se   |      | Life |      |
|                            | to   |      | vere |      | Thr  |      |
|                            | Mode |      |      |      | eate |      |
|                            | rate |      | N=82 |      | ning |      |
|                            |      |      |      |      | /    |      |
|                            | N=82 |      |      |      | F    |      |
|                            |      |      |      |      | atal |      |
|                            |      |      |      |      |      |      |
|                            |      |      |      |      | N=82 |      |
+----------------------------+------+------+------+------+------+------+
| Body System                | n    | \%   | n    | \%   | n    | \%   |
|                            |      |      |      |      |      |      |
| > Preferred Term           |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Body As A Whole - General  |      |      |      |      |      |      |
| Disorders                  |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Fever                      | 8    | 9.8  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Gastro-Intestinal System   |      |      |      |      |      |      |
| Disorders                  |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Constipation               | 16   | 19.5 | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Nausea                     | 8    | 9.8  | 1    | 1.2  | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Vomiting                   | 9    | 11.0 | 1    | 1.2  | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Metabolic And Nutritional  |      |      |      |      |      |      |
| Disorders                  |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Hyperglycaemia             | 5    | 6.1  | 1    | 1.2  | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Hypernatraemia             | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Platelet,Bleeding &        |      |      |      |      |      |      |
| Clotting Disorders         |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Thrombocythaemia           | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Psychiatric Disorders      |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Agitation                  | 6    | 7.3  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Anxiety                    | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Insomnia                   | 12   | 14.6 | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Red Blood Cell Disorders   |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Anaemia                    | 11   | 13.4 | 1    | 1.2  | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Reproductive Disorders,    |      |      |      |      |      |      |
| Female (N=19)              |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Vaginal Haemorrhage (N=19) | 1    | 5.3  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Respiratory System         |      |      |      |      |      |      |
| Disorders                  |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Atelectasis                | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Pharyngitis                | 8    | 9.8  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Skin And Appendages        |      |      |      |      |      |      |
| Disorders                  |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Pruritus                   | 8    | 9.8  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Body System Unclassified   |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Relaxation Of Scar         | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| *Source: Section 14 Tables |      |      |      |      |      |      |
| S10-A and S10-B*           |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+

+-----------------------------+------+------+------+-----+------+----+
| **Table 12.2.2: Adverse     |      |      |      |     |      |    |
| Events with an Incidence \< |      |      |      |     |      |    |
| 5.0% by Severity**          |      |      |      |     |      |    |
+=============================+======+======+======+=====+======+====+
| []{.mark}                   | Mild |      | Se   |     | Life |    |
|                             | to   |      | vere |     | Thr  |    |
|                             | Mode |      |      |     | eate |    |
|                             | rate |      | N=82 |     | ning |    |
|                             |      |      |      |     | /    |    |
|                             | N=82 |      |      |     | F    |    |
|                             |      |      |      |     | atal |    |
|                             |      |      |      |     |      |    |
|                             |      |      |      |     | N=82 |    |
+-----------------------------+------+------+------+-----+------+----+
| Body System/Preferred Term  | n    | \%   | n    | \%  | n    | \% |
+-----------------------------+------+------+------+-----+------+----+
| Application Site Disorders  |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Cellulitis                  | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Autonomic Nervous System    |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypertension                | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypertension Aggravated     | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypotension                 | 0    | 0.0  | 0    |     | 1    | 1  |
|                             |      |      |      |     |      | .2 |
+-----------------------------+------+------+------+-----+------+----+
| Sweating Increased          | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Tachycardia                 | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Tachycardia Ventricular     | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Body As A Whole - General   |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Abdominal Pain              | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Crying Abnormal             | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypothermia                 | 1    | 1.2  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Multiple Organ Failure      | 0    | 0.0  | 0    |     | 1    | 1  |
|                             |      |      |      |     |      | .2 |
+-----------------------------+------+------+------+-----+------+----+
| Oedema                      | 3    | 3.7  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Pain                        | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Scar                        | 2    | 2.4  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Cardiovascular Disorders,   |      |      |      |     |      |    |
| General                     |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypertension                | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypertension Aggravated     | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypotension                 | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Centr & Periph Nervous      |      |      |      |     |      |    |
| System Disorders            |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Brain Stem Disorder         | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Convulsions                 | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Dizziness                   | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Dysphonia                   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Headache                    | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hyperreflexia               | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypoaesthesia               | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Muscle Contractions         | 1    | 1.2  | 0    |     | 0    |    |
| Involuntary                 |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Neuropathy                  | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Neuropathy Peripheral       | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Paralysis                   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Stupor                      | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Collagen Disorders          |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Collagenosis                | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Gastro-Intestinal System    |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Achalasia Cardiae           | 0    | 0.0  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Anorexia                    | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Diarrhoea                   | 4    | 4.9  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Dyspepsia                   | 4    | 4.9  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Dysphagia                   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Tooth Ache                  | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Heart Rate And Rhythm       |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Cardiac Arrest              | 0    | 0.0  | 0    |     | 1    | 1  |
|                             |      |      |      |     |      | .2 |
+-----------------------------+------+------+------+-----+------+----+
| Fibrillation Ventricular    | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Metabolic And Nutritional   |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| A/G Ratio Abnormal          | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Dehydration                 | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Gout                        | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hyperchloraemia             | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hyperkalaemia               | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hyperlipaemia               | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypermagnesaemia            | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Metab/Nutritional Disord    |      |      |      |     |      |    |
| (continued)                 |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Hyperphosphataemia          | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypocalcaemia               | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypochloraemia              | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypoglycaemia               | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypokalaemia                | 3    | 3.7  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypophosphataemia           | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Musculo-Skeletal System     |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Back Pain                   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Bone Development Abnormal   | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Dystonia                    | 0    | 0.0  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Myalgia                     | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Myo Endo Pericardial &      |      |      |      |     |      |    |
| Valve Disorders             |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Mitral Insufficiency        | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Neoplasm                    |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Neoplasm Nos                | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Platelet,Bleeding &         |      |      |      |     |      |    |
| Clotting Disorders          |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Thrombocytopenia            | 3    | 3.7  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Thrombophlebitis Deep       | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Psychiatric Disorders       |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Confusion                   | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Depression                  | 3    | 3.7  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Red Blood Cell Disorders    |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Bilirubinaemia              | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Reproductive Disorders,     |      |      |      |     |      |    |
| Male (n=63)                 |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Hernia Inguinal (n=63)      | 1    | 1.6  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Resistance Mechanism        |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Healing Impaired            | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Infection                   | 4    | 4.9  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Infection Aggravated        | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Pneumonia                   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Sepsis                      | 2    | 2.4  | 1    | 1.2 | 2    | 2  |
|                             |      |      |      |     |      | .4 |
+-----------------------------+------+------+------+-----+------+----+
| Respiratory System          |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Aspiration                  | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Coughing                    | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Dyspnoea                    | 0    | 0.0  | 3    | 3.7 | 1    | 1  |
|                             |      |      |      |     |      | .2 |
+-----------------------------+------+------+------+-----+------+----+
| Haemoptysis                 | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Respiratory System          |      |      |      |     |      |    |
| Disorders (continued)       |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Hypoxia                     | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Larynx Oedema               | 0    | 0.0  | 0    |     | 1    | 1  |
|                             |      |      |      |     |      | .2 |
+-----------------------------+------+------+------+-----+------+----+
| Pleural Effusion            | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Pneumonia                   | 0    | 0.0  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Pneumothorax                | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Pulmonary Collapse          | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Pulmonary Congestion        | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Pulmonary Infiltration      | 3    | 3.7  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Pulmonary Oedema            | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Respiratory Insufficiency   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Sinusitis                   | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Stridor                     | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Secondary Terms             |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Ectropion                   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Medication Error            | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Surgical Intervention       | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Skin And Appendages         |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Dermatitis Fungal           | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Rash                        | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Skin Malformation           | 2    | 2.4  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Urinary System Disorders    |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Dysuria                     | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Renal Failure Acute         | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Urinary Retention           | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Urinary Tract Infection     | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Vascular (Extracardiac)     |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Haematoma                   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Haemorrhoids                | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Vascular Disorder           | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Vein Disorder               | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Vision Disorders            |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Eye Abnormality             | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| White Cell And Res          |      |      |      |     |      |    |
| Disorders                   |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Leucopenia                  | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Leukocytosis                | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Lymphoedema                 | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Body System Unclassified    |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+
| Entropion/Ectrop Rep Nec    | 0    | 0.0  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Ext Fix Dev-Metacar/Carp    | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Finger Amputation           | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Full-Thick Skin Graft Nec   | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Heterograft To Skin         | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Lid Reconst W Skin Graft    | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Lid Reconstr W Graft Nec    | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Other Local Destruc Skin    | 3    | 3.7  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Other Pleural Incision      | 0    | 0.0  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Rehabilitation Nec          | 3    | 3.7  | 1    | 1.2 | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Remove Impltd Device Nos    | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Rotator Cuff Repair         | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Skin Repair & Plasty Nec    | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Skin Suture Nec             | 2    | 2.4  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| Tot Nasal Reconstruction    | 1    | 1.2  | 0    |     | 0    |    |
+-----------------------------+------+------+------+-----+------+----+
| *Source: Section 14 Tables  |      |      |      |     |      |    |
| S10-A and S10-B*            |      |      |      |     |      |    |
+-----------------------------+------+------+------+-----+------+----+

There were 12 mild to moderate adverse events involving the CCS treated
donor sites and 13 mild to moderate adverse events involving the
Biobrane-L treated donor sites. The events for each treatment, the
severity of the event and its frequency are presented in Table 12.2.3

Table12.2.3: Adverse Events With Donor Site Involvement

<table style="width:100%;">
<colgroup>
<col style="width: 33%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3"><strong>Adverse Event</strong></td>
<td colspan="4"><strong>CCS (n=82)</strong></td>
<td colspan="5"><strong>Biobrane-L (n=82)</strong></td>
</tr>
<tr class="even">
<td colspan="2"><strong>Mild</strong></td>
<td colspan="2"><strong>Moderate</strong></td>
<td colspan="2"><strong>Mild</strong></td>
<td colspan="3"><strong>Moderate</strong></td>
</tr>
<tr class="odd">
<td><p id="n" class="heading unnumbered">n</p></td>
<td><strong>%</strong></td>
<td><p id="n-1" class="heading unnumbered">n</p></td>
<td><strong>%</strong></td>
<td><p id="n-2" class="heading unnumbered">n</p></td>
<td><strong>%</strong></td>
<td colspan="2"><p id="n-3" class="heading unnumbered">n</p></td>
<td><strong>%</strong></td>
</tr>
<tr class="even">
<td><strong>Application site reaction</strong></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><strong>Pain</strong></td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td colspan="2">2.4</td>
</tr>
<tr class="even">
<td><p id="infection" class="heading unnumbered">Infection</p></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><strong>Surgical Site Reaction</strong></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td><strong>Bullous Eruption</strong></td>
<td>0</td>
<td></td>
<td>0</td>
<td></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><strong>Pruritus</strong></td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td>2.4</td>
<td>3</td>
<td colspan="2">3.7</td>
</tr>
<tr class="even">
<td><strong>Rash Pustular</strong></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td></td>
<td>0</td>
<td></td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="10"><em>Source: Section 16.10, Listing 30</em></td>
</tr>
</tbody>
</table>

### Analysis of Adverse Events

Most of the adverse events reported in this study were mild to moderate
in severity and not associated with the donor site. The most frequent
adverse events (i.e., 5.0%) were constipation (19.5%), insomnia (14.6%),
anemia (13.4%), vomiting (11.0%), fever (9.8%), nausea (9.8%),
pharyngitis (9.8%), pruritus (9.8%), agitation (7.3%), hyperglycemia
(6.1%), hypernatremia (6.1%), thrombocythemia (6.1%), anxiety (6.1%),
atelectasis (6.1%), relaxation of scar (6.1%), and vaginal hemorrhage in
females (5.3%). All adverse events occurring at a frequency of 5.0% were
mild to moderate in severity.

Both donor site treatments were well tolerated. There were no serious
adverse events associated with the donor sites. Of the adverse events
reported for the donor site, all were mild to moderate in severity.
There were 12 adverse events associated with the CCS donor site and 13
associated with the Biobrane-L donor site, however all events associated
with CCS sites were judged to be unrelated to treatment. One event of
pruritus at a Biobrane-L site was judged likely to be related to
treatment.

### Listing of Adverse Events by Patient

Listing 30 in Appendix 16.10 shows all adverse events for each patient.

## Deaths, Other Serious Adverse Events, and Other Significant Adverse Events.

### Deaths

Three patients died during the study. None of the deaths were considered
related to the study treatment. Narratives describing the events
experienced by the patients that died are provided in Section 12.3.3.

### Other serious adverse events

Table 12.3.1 summarizes the serious adverse events reported during the
study. The total number of subjects reporting one or more serious
adverse events was 24. All of the serious adverse events were considered
unlikely to be related to study treatment. There were no serious adverse
events involving the donor sites.

+-----------------------------------------------------+----+-----------+
| Table 12.3.1: Serious Adverse Events                |    |           |
+=====================================================+====+===========+
| **Body System**                                     | *  | **%**     |
|                                                     | *n |           |
| > **Preferred Term**                                | ** |           |
+-----------------------------------------------------+----+-----------+
| Application Site Disorders                          |    |           |
+-----------------------------------------------------+----+-----------+
| Cellulitis                                          | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Autonomic Nervous System Disorders                  |    |           |
+-----------------------------------------------------+----+-----------+
| Hypotension                                         | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Body As A Whole - General Disorders                 |    |           |
+-----------------------------------------------------+----+-----------+
| Multiple Organ Failure                              | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Scar                                                | 3  | 3.7       |
+-----------------------------------------------------+----+-----------+
| Centr & Periph Nervous System Disorders             |    |           |
+-----------------------------------------------------+----+-----------+
| Brain Stem Disorder                                 | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Convulsions                                         | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Neuropathy                                          | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Gastro-Intestinal System Disorders                  |    |           |
+-----------------------------------------------------+----+-----------+
| Achalasia Cardiae                                   | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Heart Rate And Rhythm Disorders                     |    |           |
+-----------------------------------------------------+----+-----------+
| Cardiac Arrest                                      | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Musculo-Skeletal System Disorders                   |    |           |
+-----------------------------------------------------+----+-----------+
| Bone Development Abnormal                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Red Blood Cell Disorders                            |    |           |
+-----------------------------------------------------+----+-----------+
| Anaemia                                             | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Resistance Mechanism Disorders                      |    |           |
+-----------------------------------------------------+----+-----------+
| Healing Impaired                                    | 2  | 2.4       |
+-----------------------------------------------------+----+-----------+
| Infection Aggravated                                | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Sepsis                                              | 3  | 3.7       |
+-----------------------------------------------------+----+-----------+
| Respiratory System Disorders                        |    |           |
+-----------------------------------------------------+----+-----------+
| Dyspnoea                                            | 4  | 4.9       |
+-----------------------------------------------------+----+-----------+
| Larynx Oedema                                       | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Pneumonia                                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Pneumothorax                                        | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Secondary Terms                                     |    |           |
+-----------------------------------------------------+----+-----------+
| Ectropion                                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Skin And Appendages Disorders                       |    |           |
+-----------------------------------------------------+----+-----------+
| Skin Malformation                                   | 3  | 3.7       |
+-----------------------------------------------------+----+-----------+
| Urinary System Disorders                            |    |           |
+-----------------------------------------------------+----+-----------+
| Renal Failure Acute                                 | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Vascular (Extracardiac) Disorders                   |    |           |
+-----------------------------------------------------+----+-----------+
| Haematoma                                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| White Cell And Res Disorders                        |    |           |
+-----------------------------------------------------+----+-----------+
| Lymphoedema                                         | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Body System Uncategorized                           |    |           |
+-----------------------------------------------------+----+-----------+
| Entropion/Ectrop Rep Nec                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Lid Reconst W Skin Graft                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Lid Reconstr W Graft Nec                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Tot Nasal Reconstruction                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Other Pleural Incision                              | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Ext Fix Dev-Metacar/Carp                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Remove Impltd Device Nos                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Rotator Cuff Repair                                 | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Finger Amputation                                   | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Other Local Destruc Skin                            | 3  | 3.7       |
+-----------------------------------------------------+----+-----------+
| Skin Suture Nec                                     | 2  | 2.4       |
+-----------------------------------------------------+----+-----------+
| Full-Thick Skin Graft Nec                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Heterograft To Skin                                 | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Relaxation of Scar                                  | 4  | 4.9       |
+-----------------------------------------------------+----+-----------+
| Skin Repair & Plastic NEC                           | 2  | 2.4       |
+-----------------------------------------------------+----+-----------+
| Rehabilitation NEC                                  | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| *Source: Section 14, Tables S6-A and S6-B*          |    |           |
+-----------------------------------------------------+----+-----------+

### Narratives of Deaths, Other Serious Adverse Events and Certain Other Significant Adverse Events

#### Deaths

[Patient 01-008]{.underline}

Patient 01-008, a 42-year old male experienced multiple adverse events.
His relevant medical history includes a 43% total body surface area burn
injury, septic shock and gram-negative septicemia with E. coli
organisms. Antibiotic therapy was adjusted and continued. On June 1,
1999 he underwent excision and grafting of the burn injury, at which
time the investigational device was placed on the donor sites. On the
day of surgery, the patient became hemodynamically unstable and required
support with appropriate pressors. He also developed adult respiratory
distress syndrome (ARDS) and ventilator changes were made. On June 2,
1999, the patient was documented as having non-oliguric renal failure
and drug therapy was initiated. On June 6, 1999, the patient remained
critically ill but was post-E. coli septic shock. On June 14, 1999, the
condition worsened and the patient required hemodialysis. The patient
was noted to have a worsening right side pneumothorax and required a
chest tube to reinflate the lung. Patient remained stable before and
after the insertion of the chest tube. On June 16, 1999 symptoms were
resolving but ARDS continued.

On June 24, 1999, the patient died due to multi-system organ failure. At
the time of death, the patient had grown more hemodynamically unstable
and experienced full cardio-pulmonary arrest the morning of his death.
Over the ten days prior to his death, the patient's condition had
declined due to multi-system organ failure from burn wound septic shock
mediated initially by E. coli and subsequently complicated by a wound
fungemia. These serious adverse events were judged to be unrelated to
the investigational device (CCS) by both the Investigator and the Ortec
Medical Director.

[Patient 15-007]{.underline}

Patient 15-007, a 76-year-old female developed respiratory distress
evidenced by shortness of breath. The event, which occurred on March 1,
2000, was considered severe. The patient was subsequently intubated to
secure her airway and prevent respiratory failure. Her relevant medical
history includes a 15% TBSA burn injury as well as excision and grafting
on February 23, 2000 at which time the investigational device was placed
on the donor sites. She then developed bacterial sepsis, which was
considered fatal on March 10, 2000. Her condition began to deteriorate
as evidenced by hypotension, and decreasing urine output. Upon family
request, all aggressive supportive measures were terminated. These
adverse events were considered by the Investigator to be unlikely
related to the study device (CCS). The adverse event was reviewed by
Ortec's Medical Director and determined to be unrelated to the study
device.

[Patient 15-009]{.underline}

Patient 15-009, a 37-year-old female suffered a cardiac arrest, on March
10, 2000, which was considered life threatening. She was successfully
resuscitated and upon family request, all medications were discontinued
and she was placed on minimal ventilator settings. She also suffered
acute respiratory distress syndrome (ARDS) which was considered fatal.
Her relevant medical history includes 65% TBSA burn injury as well as
excision and grafting on March 3, 2000 at which time the investigational
device was placed on the donor sites. Her death is attributed to
complications from her burn injury and was considered by the
Investigator unlikely to be related to the study device (CCS). Ortec's
Medical Director reviewed the adverse events and determined that they
were unrelated to the study device.

#### Other serious adverse events

[Patient 01-005]{.underline}

Patient 01-005, a 39-year-old male was hospitalized for several
corrective surgical procedures to repair extensive burn and scar
deformities. The events were considered mild in severity and began on
October 5 lasting through December 21, 1999. The procedures included
contracture releases, complex closure of a wound dehiscence, placement
of PICC catheter, K-wire fixation and subsequent removal of K-wires, and
grafting, removal of Steinmann pin from hand, and facial reconstruction.
His relevant medical history included a 32% TBSA thermal burn injury
resulting in severe burn scars and contractures as well as excision and
grafting on May 18,1999 at which time the Investigational device was
placed on the donor sites. These surgical procedures are considered by
both the Investigator and Ortec's Medical Director to be unrelated to
the investigational device, (CCS). Subsequently, he was readmitted to
the hospital to evaluate an ectropion of the right eye. The event which
began on March 31,2000 was considered moderate in severity. The patient
was taken to the OR for evaluation under anesthesia and possible attempt
at repair. The patient was discharged on April 3, 2000. This event was
considered by both the Investigator and Ortec's Medical Director
unlikely to be related to the study treatment. This hospital readmission
was considered by the Investigator to be unlikely related to the study
device (CCS). This hospital admission was reviewed by Ortec's Medical
Director and determined to be unrelated to the study device.

[Patient 01-007]{.underline}

Patient 01-007, a 7- year old female, was admitted to the hospital for
release of a contracture involving the left popliteal fossa and excision
of a chronic wound. The event which began on May 1,2000 was considered
mild in severity. Her relevant medical history included a 33% TBSA burn
injury as well as excision and grafting on May 1999, at which time the
investigational device was placed on the donor sites. This adverse event
was considered by both the Investigator and Ortec's Medical Director
unlikely to be related to the study device (CCS). The patient was
subsequently re admitted to the hospital for reconstructive surgery of
burn scars on bilateral thighs. The event, which began on September 7,
2000, was considered mild in severity. Her relevant medical history
included a 33% TBSA burn injury as well as excision and grafting in June
1999 at which time the investigational device was placed on the donor
sites. This event was considered by the Investigator unlikely to be
related to the study device. Ortec's Medical Director reviewed the
events and determined that they were unrelated to the investigational
device.

[Patient 01-009]{.underline}

Patient 01-009, a 35-year-old male, was re-admitted to the hospital with
a diagnosis of a contracture of the left axilla and median nerve
entrapment. The event, which began on June 20, 2000, was considered mild
in severity. His relevant medical history included a 65% TBSA burn
injury as well as excision and grafting in August 2000, at which time
the investigational device was placed on the donor sites. This adverse
event was considered by the Investigator as unlikely to be related to
the study device (CCS). This adverse event was reviewed by Ortec's
Medical Director and determined to be unrelated to the investigational
device.

[Patient 01-012]{.underline}

Patient 01-012 a 61-year old female experienced an adverse event that
consisted of the development of a new right occipital lobe infarction,
identified by CT scan. She was placed on one-half aspirin per day and
further evaluation was sought via a carotid doppler exam. The doppler
results were unremarkable; there was no evidence of atherosclerotic
disease, no hemodynamically significant stenosis, and no significant
surface irregularities. Her relevant history included a head injury with
loss of consciousness, respiratory arrest requiring intubation, a
previous right frontal region brain infarction and a 22 % TBSA burn
injury as well as excision and grafting on August 16, 1999 at which time
the investigational device was placed on the donor sites. This serious
adverse event was judged to be unrelated to the investigational device
(CCS) by both the Investigator and Ortec's Medical Director.

[Patient 01-016]{.underline}

Patient 01-016, a 26-year-old male was admitted to the hospital for the
surgical treatment of a non-healing wound of the lower left extremity.
The event took place on January 3, 2000. He was treated surgically with
a commercially available biological dressing, Apligraf®. The patient did
well and was discharged on January 6, 2000. His relevant medical history
included a 50% TBSA burn injury as well as excision and grafting on
September 27, 1999 at which time the investigational device was used to
treat the donor sites. This adverse event was considered by the
Investigator and Ortec's Medical Director to be unrelated to the study
device (CCS).

[Patient 01-017]{.underline}

Patient 01-017, a 75-year-old male was admitted to the hospital for
release of a contracture of the right axilla. The event, which occurred
on March 30, 2000, was considered mild in severity. His relevant medical
history included a 20% TBSA burn injury as well as excision and grafting
in September 1999 at which time the investigational device was placed on
the donor sites. This adverse event was considered by the Investigator
and Ortec's Medical Director unlikely related to the study device (CCS).

[Patient 01-018]{.underline}

Patient 01-018, a 64-year old male, was hospitalized for swelling of his
left arm to rule out cellulitis or lymphedema. The event occurred on
November 30, 1999 and was considered moderate in severity. The patient
was diagnosed with lymphedema. The patient was treated and the problem
resolved. The patient's relevant history included an escharotomy of the
left medial forearm and a 22% TBSA burn injury as well as excision and
grafting at which time the investigational device was placed on the
donor sites. This serious adverse event was judged to be unrelated to
the investigational device (CCS) by both the Investigator and Ortec's
Medical Director.

[Patient 03-001]{.underline}

Patient 03-001, a 39-year-old male, was admitted to the hospital for
left elbow contracture release and heterotopic ossification excision.
The event, which occurred on April 11, 2000, was considered moderate in
severity. His relevant medical history included a 85% TBSA burn injury
as well as excision and grafting on July 21, 1999, at which time the
investigational device was placed on the donor sites. This adverse event
was considered by both the Investigator and Ortec's Medical Director
unlikely to be related to the study device (CCS). He had previously been
admitted to a facility for rehabilitation purposes on November 16, 1999,
due to the extensive size of the previous burn injury. The event was
considered moderate in severity and unrelated to the investigational
device (CCS). On June 18, 2000 he had another hospital admission for
moderately severe cellulitis of his left arm. That event was also
considered unlikely to be related to the investigational device.

[Patient 03-005]{.underline}

Patient 03-005, 40- year old male, was admitted to the hospital for
outpatient surgery for excision of a hypertrophic right hand and index
scar with a split thickness skin graft placement. The event which
occurred on May 24, 2000 was considered mild in severity. His relevant
medical history included a 30% TBSA burn injury as well as excision and
grafting on September 3, 1999 at which time the investigational device
was placed on the donor sites. This adverse event was considered by both
the Investigator and Ortec's Medical Director unlikely related to the
study device (CCS).

[Patient 03-006]{.underline}

Patient 03-006, a 38- year old male, was admitted to the hospital for
outpatient surgery to release a burn scar contracture of his left groin.
The event, which occurred on August 16, 2000, was considered mild in
severity. His relevant medical history included a 55 % TBSA burn injury
as well as excision and grafting on October 6, 1999 at which time the
investigational device was placed on the donor sites. This adverse event
was considered by both the Investigatorand Ortec's Medical Director
unlikely to be related to the study device (CCS).

[Patient 03-007]{.underline}

Patient 03-007, a 64-year-old male, was admitted to rehabilitation
facility due to the size of the previous burn injury. The event, which
occurred on February 18, 2000, was considered severe. The patient was
subsequently discharged on February 25, 2000 because of his improved
condition. However because of worsening dysphagia he experienced
aspiration pneumonia, which was considered severe. He also required
treatment for a urinary tract infection. He received medical treatment
and was discharged home and was then readmitted on March 30, 2000 to
undergo left thoracotomy with Heller myomotomy to relieve symptoms of
severe dysphagia. His relevant medical history included a 40% TBSA of
second and third degree burns, peptic ulcer disease (PUD), dysphagia, as
well as excision and grafting on January 19, 2000 at which time the
investigational device was placed on the donor sites. All of the adverse
events and hospital admissions were considered by the Investigator and
Ortec's Medical Director as unlikely to be related to the
investigational device (CCS).

[Patient 03-009]{.underline}

Patient 03-009, a 40-year-old male, was admitted to a rehabilitation
hospital for aggressive physical therapy. The event, which occurred on
August 4, 2000, was considered moderate in severity. His relevant
medical history included a 65% TBSA burn injury as well as excision and
grafting on May 10, 2000 at which time the investigational device was
placed on the donor sites. This adverse event was considered by both the
investigator and Ortec's Medical Director as unlikely to be related to
the investigational device (CCS).

[Patient 04-001]{.underline}

Patient 04-001 a 23-month-old male experienced hypotension post
operatively and required dopamine treatment. A septic episode was
suspected. The patient's white blood cell count was 25.1, with a fever
of 37.0 Celsius. His relevant history included a 65% TBSA burn injury as
well as excision and grafting on June 25, 1999 at which time the
investigational device was placed on the donor sites. This adverse event
was judged by the Investigator to be unlikely related to the study
device (CCS). The adverse event was reviewed by Ortec's Medical Director
and determined to be unrelated to the study device.

[Patient 04-009]{.underline}

Patient 04-009, a 6 year old male, had amputation of the fingers due to
burn injury during initial hospitalization was re- admitted to the
hospital for excision of scalp wound, contracture releases of face and
left hand and nasal reconstruction, which were all considered moderate
in severity between February 4, 2000 to November 8, 2000. His relevant
medical history included a 26% TBSA burn injury as well as excision and
grafting on October 8, 1999 at which time the investigational device was
placed on the donor sites. The adverse events were considered by the
Investigator to be unlikely related to the study device (CCS). The
adverse events were reviewed by Ortec's Medical Director and determined
to be unrelated to the study device.

[Patient 04-014]{.underline}

Patient 04-014, a 14-year-old female was re- admitted to the hospital
for increased seizure activity. The event occurred on July 13, 2000 and
was considered mild in severity. The EEG did not capture any seizure
activity and the patient was discharged home two days later. Her
relevant history included a seizure disorder diagnosed in February 2000,
and a 20 % TBSA burn injury as well as excision and grafting on April
12, 2000 at which time the investigational device was placed on the
donor sites. This adverse event was judged by the Investigator to be
unlikely related to the study device (CCS). The adverse event was
reviewed by Ortec's Medical Director and determined to be unrelated to
the study device.

[Patient 05-001]{.underline}

Patient 05-001, a 29-year-old male, was re-admitted to the hospital for
intermittent surgeries for hypertrophic scarring. The re-admisssions
occurred during the period of December 6, 1999 through September 14,
2000 and were considered severe. His relevant medical history included a
37% TBSA burn injury as well as excision and grafting on July 16, 1999
at which time the investigational device was placed on the donor sites.
The readmissions were considered by the Investigator to be unlikely
related to the study device (CCS). The readmissions to the hospital were
reviewed by Ortec's Medical Director and determined to be unrelated to
the study device.

[Patient 05-002]{.underline}

Patient 05-002, a 59-year-old male, was re-admitted to the hospital for
release of left arm contracture and hypertrophic scarring with
corticosteriod injections. The events occurred on December 13, 1999 and
were considered moderate in severity. His relevant medical history
included a 25% TBSA burn injury as well as excision and grafting on July
28, 1999 at which time the investigational device was placed on the
donor sites. These adverse events were considered by the investigator to
be unlikely related to the study device (CCS). The adverse events were
reviewed by Ortec's Medical Director and determined to be unrelated to
the study device.

[Patient 08-001]{.underline}

Patient 08-001 was admitted to the hospital for repair of a right
rotator cuff as well as facial reconstruction of the right lower eyelid,
right cheek and reconstruction of the elbow. The events occurred during
the period of July 6, 1999 through July 8, 1999 and were considered mild
in severity. His past relevant history included epilepsy and a 20% TBSA
burn injury as well as excision and grafting on May 25, 1999 at which
time the investigational device was placed on the donor sites.

He was subsequently readmitted to the hospital at two separate intervals
for primary stage facial reconstruction related to burn injuries. The
first admission occurred on September 13^th^, 1999 and was considered
mild in severity. The patient was discharged on September 14^th^, 1999.
The second admission occurred on October 4^th^, 1999 for facial
reconstruction related to burn injuries and was considered mild in
severity. The patient was subsequently discharged on October 8, 1999.

Another readmission to the hospital was required on October 27, 1999 for
evacuation of a hematoma involving the neck and cervicofacial flap which
had developed three weeks after undergoing facial reconstruction. The
hematoma occurred in the operative region. The event was considered
moderate in severity. The patient was subsequently discharged. All of
the adverse events experienced by this patient were judged to be
unlikely related to the investigational device (CCS) by the
Investigator. The adverse events were reviewed by Ortec's Medical
Director and determined to be unrelated to the study device.

[Patient 15-001]{.underline}

Patient 15-001, a 33-year-old male, was re-admitted to the hospital to
undergo repair of a right ectropion with a full thickness skin graft to
the right lower eyelid. The event, which occurred on March 2, 2000, was
considered severe. His relevant medical history included a 35% TBSA burn
injury as well as excision and grafting on November 24, 1999 at which
time the investigational device was placed on the donor sites. The
adverse event was considered by the Investigator to be unlikely related
to the study device (CCS). The adverse event was reviewed by Ortec's
Medical Director and determined to be unrelated to the study device.

[Patient 15-005]{.underline}

Patient 15-005, a 35-year-old female was re-admitted to the hospital for
a local wound infection. The event occurred on March 8, 2000 and was
considered moderate in severity. Her relevant medical history included a
28% TBSA burn injury as well as excision and grafting on February 11,
2000 at which time the investigational device was placed on the donor
sites. The adverse event occurred during a follow-up visit and was
considered by the Investigator to be unlikely related to the study
device (CCS). The adverse event was reviewed by Ortec's Medical Director
and determined to unrelated to the study device.

[Patient 15-010]{.underline}

Patient 15-010, a 32-year-old male, was re-admitted to the hospital for
right hand contractures resulting in limited range of motion and
decreased sensation. The event occurred on June 28, 2000 and was
considered severe. His relevant medical history included a 15% TBSA burn
injury as well as excision and grafting on March 26, 2000 at which time
the investigational device was placed on the donor sites. This adverse
event was considered by the Investigator to be unlikely related to the
study device (CCS). The adverse event was reviewed by Ortec's Medical
Director and determined to be unrelated to the study device.

### Analysis and Discussion of Deaths, Other Serious Adverse Events and Other Significant Adverse Events.

In this study of patients with burn injuries, the incidence of adverse
events was 78%. This is not unexpected considering the morbidity and
mortality that can be associated with burns. There were three deaths
among the study subjects. All of the deaths occurred in subjects who
were elderly or who had burn injuries involving \>40% TBSA. The causes
of death were sepsis, septic shock with multiple organ failure and
respiratory failure that were complications of the burn injury. None of
the deaths were related to the investigational device, CCS. Twenty-eight
percent of the study population experienced serious adverse events,
which were most likely consequences of underlying disease states. None
of the serious adverse events were attributed to the use of CCS.

The majority of the adverse events experienced by the study participants
were of mild to moderate severity and all were judged to be unrelated to
CCS. Only one adverse event, pruritus at the Biobrane site, was judged
to be likely related to the study. The most frequent adverse events
(i.e., 5.0%) were constipation (19.5%), insomnia (14.6%), anemia
(13.4%), vomiting (11.0%), fever (9.8%), nausea (9.8%), pharyngitis
(9.8%), pruritus (9.8%), agitation (7.3%), hyperglycemia (6.1%),
hypernatremia (6.1%), thrombocythemia (6.1%), anxiety (6.1%),
atelectasis (6.1%), relaxation of scar (6.1%), and vaginal hemorrhage in
females (5.3%). All adverse events occurring at a frequency of 5.0% were
mild to moderate in severity.

Both donor site treatments were well tolerated. There were no serious
adverse events associated with the donor sites. Of the adverse events
reported for the donor sites, all were mild to moderate in severity.
There were 12 adverse events associated with the CCS donor site and 13
associated with the Biobrane-L donor site.

## Clinical Laboratory Evaluation

Not applicable

## Vital Signs, Physical Findings and Other Observations Related to Safety

[Vital Signs]{.underline}

There were no clinically significant changes in mean body temperature or
blood pressure (systolic and diastolic) throughout the 24 weeks of
follow up. Pretreatment tachycardia was present (mean pulse rate 110).
By the Day 28 visit, the mean pulse rate was 98. Summaries of body
temperature, systolic blood pressure, diastolic blood pressure, pulse
and weight are displayed in Section 14.3 Tables S17, S18, S19, S20, and
S21, respectively.

[Nutritional Evaluation]{.underline}

By day 28 of the study follow-up period, approximately 33% of patients
were meeting or exceeding their required daily caloric intake, however,
25% of the study population had caloric intake values that indicated
ongoing catabolism. There was not enough data to assess the caloric
status of the rest of the study population. Patient listing of
nutritional assessments by visit are contained in Section 16.10, Listing
28 and summarized in Section 14.3, Table S22.

[Assay for Collagen Type I IgG Autoantibodies]{.underline}

Table 12.5.1 displays screening and week 24 results of testing for
collagen Type I IgG autoantibodies. A listing of individual patient
results may be found in Section 16.10, Listing 37.

Table 12.5.1: Summary of Collagen Type I IgG Autoantibodies

+-----------------+-----------------+-----------------+-----------------+
|                 | **Screening**   | **Week 24**     | **Difference**  |
|                 |                 |                 |                 |
|                 |                 |                 | **Week 24 -     |
|                 |                 |                 | Screening**     |
+-----------------+-----------------+-----------------+-----------------+
| N               | 79              | 54              | 53              |
+-----------------+-----------------+-----------------+-----------------+
| Mean (SD)       | 8.3 (22.07)     | 10.5 (18.70)    | 1.5 (18.9)      |
+-----------------+-----------------+-----------------+-----------------+
| Median          | 5               | 5               | 0               |
+-----------------+-----------------+-----------------+-----------------+
| Min, Max        | \<5, \>200      | \<5, 111        | -89, 73         |
+-----------------+-----------------+-----------------+-----------------+
| *Source:        |                 |                 |                 |
| Section 14,     |                 |                 |                 |
| Table S2*       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

The mean rise in collagen Type 1 autoantibodies over the 24 weeks after
surgery was 1.5 (SD 18.9) with a median difference of zero. A total of
19 patients had elevated IgG at some point during the 24-week post
surgical period. Of these 19 patients, nine demonstrated elevated levels
at screening, indicating the elevated titer post surgery was probably
not due to product. Three of the 19 patients had transient elevations
that were totally or partially back to normal by week 24. An additional
three patients who began with an elevated titer demonstrated lower
levels upon subsequent testing. Leaving four patients with significantly
increased anti Collagen I IgG titers that may have been attributed to
the use of CCS. However, no patient with an elevated titer at any time
was found to have clinical evidence of graft rejection, and, in fact,
the healing times in these patients were identical to those for the
entire patient group. Given the high incidence of abnormal titers at
time zero, a the similar incidence of rising and falling titers over
time, and the lack of clinical signs and symptoms of graft rejection in
any patient with elevated titers, a clinically meaningful association
between the use of CCS and the inducement of anti-collagen I antibody
cannot be concluded.

## Safety Conclusions

Both donor site treatments were well tolerated. Of the donor site
adverse events reported, all were mild to moderate in severity. There
were no serious adverse events associated with the donor sites.

# DISCUSSION AND OVERALL CONCLUSIONS

Harvesting split thickness skin grafts creates more open surface area
(donor sites) for the already challenged burn patient thereby increasing
their susceptibility to infections and metabolic complications.
Optimizing the management of donor site wounds can produce substantial
benefits by accelerating and preventing delays in wound healing,
decreasing the incidence of local infection, reducing pain and
discomfort at the donor site, improving cosmetic outcomes and reducing,
or eliminating entirely, the costs that would be incurred for treatment
of donor site wound complications.

Paying scrupulous attention to the care of the donor site wounds can
also produce an extremely important clinical advantage in patients who
have experienced massive surface area burns. Massive surface area
injuries limit availability of viable donor sites. In an attempt to
maximize the use of the patients' limited uninjured skin, fascial
excision and meshing of donor skin to create a wide expansion are
management strategies that a burn surgeon might employ. These
procedures, however, render the patient susceptible to wound
contractures and hypertrophic scar formation leaving them burdened with
severe long-term functional and cosmetic sequelae that impede their
resumption of activities of daily living. An alternative option involves
reharvesting of previously used donor sites (i.e., "recropping").
However, there is a waiting period during which maturation of donor site
has to occur so as to yield a viable conventional split thickness skin
graft which functions effectively in facilitating wound closure.
Optimizing donor site wound management can promote accelerated healing
and lead to the earlier availability of new skin that can be recropped.

This study was a prospective, controlled, randomized, multicenter study
designed to examine the safety and efficacy of CCS in facilitating
timely wound closure of split thickness skin donor sites in burn
patients, compared to a standard care dressing, Biobrane-L. The study
had a matched-pairs design and enrolled patients who required
conventional split thickness skin autografting for the management of
burn injuries.

Results obtained from this study clearly demonstrate the superiority of
CCS over Biobrane-L in time to complete wound closure, percentage of
donor sites healed by day 32, rate of wound closure, time to readiness
for re-cropping, and scarring severity. Furthermore, a clinically
meaningful difference was noted, in favor of CCS, for rate of infection,
donor site breakdown, and pain.

The primary efficacy outcome variable (i.e., time to complete wound
closure) was measured by three separate methods, photography,
planimetry, and investigator assessments. All assessment methods
provided clinically meaningful and statistically significant results
(p\<0.05) demonstrating the superiority of CCS over a conventional
treatment for skin graft donor sites. By photographic assessment,
complete wound closure with CCS occurred 7 days earlier than with
Biobrane-L. By planimetry, complete wound closure with CCS occurred 5
days earlier. Investigator assessment indicated that complete wound
closure with CCS occurred 4 days earlier than with Biobrane-L.
Additionally, the statistically significantly (p\<0.05) shorter time to
complete wound closure with CCS was consistent across the ITT and Per
Protocol populations and persisted regardless of age, race, gender, size
of donor site, or percentage of total body surface area burned.

The percentage of CCS donor sites completely healed by day 32 was also
statistically significantly higher than that of Biobrane-L with all
three assessment methods. By photographic assessment, 24% more CCS donor
sites were healed than Biobrane-L (p=\<0.0000). By planimetry, CCS
healed sites were 12% higher (p=0.0039); and by investigator assessment,
CCS healed sites were nearly 10% higher (p=0.0047).

The accelerated time to 100% wound closure with CCS versus Biobrane-L is
clearly reflected in the daily rate of wound closure. Planimetry data
from this study indicate that during the first 16 days of treatment, CCS
treated sites healed at a mean rate of 6.3 cm^2^/day while Biobrane-L
treated sites healed at a mean rate of 3.8 cm^2^/day, demonstrating a
statistically significant difference that translates into a CCS healing
rate that is nearly 70% faster than Biobrane-L during the first 16 days
of therapy. The rates of wound closure for both CCS and Biobrane-L
appear to decrease after the 16^th^ day, however, the mean rate of wound
closure for CCS during this time period remained greater than that of
Biobrane-L by 16% (i.e., approximately 4.0 cm^2^/day and 3.5 cm^2^/day,
respectively).

Wound measurement and determination of wound healing are matters of
significant controversy in published reports. Most published studies are
single site studies and the assessment of 100% wound closure varies as
well. In some studies 95% or 98% wound closure is considered as
completely healed; in some studies complete reepithelialization is
considered as complete healing; and in other studies the patients are
only followed until day 14 and the percentage of wound closure is
recorded at that time. Most studies also rely on only one evaluation
method, usually the investigator's visual assessment.

Among the three methods used in this study (i.e., investigator's
clinical assessment, planimetry and photography), photography is the
most objective method, however it is less accurate and sensitive than
planimetry and the investigator's clinical assessment. The objectivity
of the photographic method is based on blinded expert reviewers who are
totally unconnected to the study. This method, however, is not as
accurate or sensitive as planimetry or the investigator's clinical
assessment due to confounding factors such as the possibility of
inconsistent lighting, limitation to viewing the wound in one direction,
and the inability to touch the wound. Additionally, there is no
interactivity with the patient when using photography. Planimetry
depends upon the clinician's judgment of the wound edges, and uses
computerized tools to calculate wound area. Because the clinician is
able to view the wound from multiple directions, to touch the wound and
to question the patient about pain in different sites, the resulting
wound tracing is inherently more accurate than using photography.
However, when the wound is completely resurfaced with thin epithelium,
photography might not indicate 100% healing, only physical examination
can determine if the reepithelialization is truly complete. Detecting
continued wound drainage on physical examination, for example, suggests
the presence of microscopic skin defects not demonstrable on photography
or planimetry. These considerations notwithstanding, the present study
demonstrates similar results when assessed by all three methods.

A number of factors have been associated with time to complete wound
healing. Wound healing can be delayed in patients with extensive burns,
advanced age, or deeper wounds. In one study comparing hydrophilic
polyurethane to petrolatum gauze, where the mean donor site surface
areas were 89.2 cm^2^ and 77.6 cm^2^ respectively, and the mean age of
patients was 62.8 years, the number of days to complete
reepithelialization was 20.6 days for hydrophilic polyurethane and 19.3
days for petrolatum gauze.^12^ In a younger patient population utilizing
Biobrane as the dressing, healing times have been as short as 9.7 days
in a pediatric population with a mean age of 7.9 years^13^ compared to a
mean of 19 days in another study where the mean age of patients
receiving the Biobrane treatment was 51 years.^14^

In the present study, the patient population was acutely catabolic, as
evidenced by a baseline daily caloric intake of 2384 calories and mean
albumin of 2.0 grams/dL. The mean age for the patients in this study was
31.7 years and the mean donor site surface area was 94.4 cm^2^ for CCS
treated wounds and 94.3 cm^2^ for donor site wounds treated with
Biobrane-L.

Patients with a larger percentage of total body surface area burned also
heal more slowly. Zapata-Sirvent et al.^15^ reported a mean healing time
of 9.8 days for Biobrane in a population of 31 patients with a mean TBSA
burn injury of 11.5%. In a second study by Hansbrough,^9^ where the mean
TBSA burn injury was higher (26%), the mean time to Biobrane removal was
13.3 days.

In the current study, no patients were enrolled with burns under 10% of
TBSA. The mean percentage of TBSA burned was 29.5% and the mean healing
time for Biobrane-L ranged from 18 to 22 days, depending on the
assessment methodology (i.e. photography, planimetry or investigator
evaluation). The extended healing time for Biobrane-L compared to
healing times previously reported in the literature is a function of the
increased mean percentage of TBSA burned, and other factors, in this
population of seriously ill patients.

A subset analysis of percent TBSA burned in the current study
population, confirmed that prolongation of healing time is directly
correlated with more extensive TBSA burn injuries. When TBSA burned was
10-20%, mean healing times (±SD) by planimetric analysis were 11.8±3.0
and 13.6±4.2 days for CCS and Biobrane-L, respectively. When TBSA burned
was between 21 and 40%, the mean healing times were extended to 14.1±6.9
days for CCS and 20.6±8.9 days for Biobrane-L. In the group with the
most extensive TBSA burn injuries (i.e., greater than 40%), the mean
healing times were 15.4±4.5 days for CCS and 23.5±7.1 days for
Biobrane-L.

Time to readiness for recropping was also used as a measure of efficacy.
CCS treated sites were ready for recropping 7 days earlier (median
value) than Biobrane-L treated donor sites. Mean time to readiness for
recropping was 15.9 days for CCS treated sites and 20.8 days for
Biobrane-L treated sites, (p=0.0002). The accelerated healing of the CCS
sites relative to the Biobrane-L sites is clinically significant in that
the CCS donor sites were able to provide a source of viable skin for
autografting earlier than the Biobrane-L treated sites. The ability to
recrop donor sites expediently hastens permanent coverage of injured
body surface areas thus potentially reducing morbidity and mortality.
Since complete coverage of the burns must be achieved prior to hospital
discharge, this would be expected to translate into earlier hospital
discharge. Hospital discharge and economic data were not measured in
this study. However, considering that much of the care of a seriously
burned patient is conducted in the intensive care unit, reducing this
stay by even a few days would translate into many thousands of dollars
saved.

Although a large portion of the study population experienced adverse
events, most of the adverse events were related to the underlying burn
injury and all adverse events were judged to be unrelated to CCS. Since
patients with burn injuries are very susceptible to infections and
metabolic and dermatologic complications related to their injuries, the
occurrence of a large number of adverse events, some of which were
serious, was not unanticipated. Three patients died during the study
however, none of the deaths were considered related to the study
treatment. The most frequent adverse events were constipation, insomnia,
anemia, nausea and vomiting.

It is noteworthy that there were no serious adverse events that were
associated with the donor sites. All of the donor site adverse events
were mild to moderate in severity and included pain, infection,
application site reaction, surgical site reaction, bullous eruption and
pruritus. There were 12 events associated with the CCS site and 13
events associated with the Biobrane-L site. The frequency and severity
of pain, infection, application site reaction and surgical site reaction
were exactly the same, 5%, 1%, 1%, and 1% respectively, for the CCS and
Biobrane sites. Mild to moderate pruritus was reported for 6% of the
Biobrane-L sites and 5% of CCS sites. The incidence of mild bullous
eruption was 1% at the Biobrane-L sites and 0% at the CCS sites.
Pustular rash was observed at 1% of CCS sites and 0% at Biobrane-L
sites.

Both the Hamilton Scar Score and the Vancouver Scar Score values were
significantly better (lower) for the CCS treated sites at Week 12 and
Week 24. Clinically meaningful differences in signs of infection and
breakdown were observed between CCS and Biobrane sites, in favor of CCS.
Additionally, the average mean pain intensity during the first 16 days
after surgery was approximately 25% more at the Biobrane sites. CCS
treated sites were significantly less painful on Days 9, 11, and 12 than
Biobrane-L sites.

For the study population as a whole, there were no clinically
significant changes in vital signs throughout the 24 weeks of follow-up.
Pretreatment mean pulse rate was 110 beats per minute that gradually
decreased and was below 100 beats per minute by the Day 28 study visit.

The CCS treated donor sites had a significantly raster rate of healing
by each of the three assessments (photography, planimetry and
investigator evaluation) employed. The faster healing of CCS treated
sites resulted in earlier times to readiness for recropping for these
sites relative to Biobrane-L treated sites and a significantly larger
proportion of CCS sites achieved complete wound closure by day 32. Both
donor site treatments were well tolerated with similar frequencies of
mild to moderate donor site associated adverse events, however scar
outcome was significantly better, as measured by both the Vancouver Scar
Score and the Hamilton Scar Score, for CCS sites at weeks 12 and 24.

The results demonstrate that CCS was more effective in facilitating
timely wound closure of split thickness skin donor sites in burn
patients compared to Biobrane-L. Healing time for CCS treated donor
sites was statistically significantly shorter than for the Biobrane-L
product. This acceleration of wound healing is clinically important in
enabling earlier recropping, alleviating donor site pain, reducing
infection rates, and improving post-operative patient mobilization.
These factors are also expected to result in earlier patient discharge
when CCS is used.

In conclusion, treatment of donor site wounds with CCS is
well-tolerated, promotes more rapid healing and has reduced scarring
when compared to conventional therapy with Biobrane L®.

#   {#section .unnumbered}