The RELIEF Clinical Trial

The RELIEF Clinical Trial
Study Site Initiation Visit

Introduction/Study Team Milestones and Timelines Key Protocol Highlights Study Design Overview Subject Recruitment and Retention Strategy Investigator , Sponsor and Monitor Responsibilities SAE Reporting Study Supplies, Procedures and Documents DataLabs – eCRF Completion IWR Regulatory Files/IRB/Contracts Tour of Facilities Wrap up and Discussion Agenda

Study Teams and Roles

PAREXEL – Main Point of Contact Cytori – Main Point of Contact
Study Team Contact PAREXEL – Main Point of Contact Alina BenitezGracco Site Contract Leader Tel: Anthony Bohnert Associate Medical Director Tel: Meghan Novy Project Leader Tel: Cynthia Brown Clinical Trial Specialist Tel: Clinical Operations Leader Laurie Spiess Tel: Clinical Site Managers DeLana Orr Tel: Cytori – Main Point of Contact Mike DeEmedio Technical Support Manager Tel: x5320 Chris Keefe Process Engineering Tel: x5435 John Fraser Chief Scientist Tel: x5262 Min Zhu Clinical Study Manager Tel: x5247

Study Milestones & Timelines
Task Timeline Final Approved Protocol April 1st Site Initiated 20 April 2018 First Patient In TBD Last Subject Out

The RELIEF Clinical Trial Protocol Review
John K. Fraser Ph.D. Chief Scientist Cytori Therapeutics Inc. CONFIDENTIAL

“Safety and Feasibility of Adipose Derived Regenerative Cells (ADRCs) in the Treatment of Deep Partial Thickness and Full Thickness Thermal Wounds” Preclinical studies show that intravenous administration of cells obtained from adipose tissue can increase the rate of healing of meshed skin grafts and the skin graft donor site The RELIEF Trial is designed to determine the safety and feasibility of this approach in patients with large (20%-50% TBSA) thermal burns

RELIEF Status Trial is approved by the FDA (IDE#17234)
Funded by the Biomedical Advanced Research and Development Authority Within the Office of the Assistant Secretary for Preparedness and Response; Department of Health and Human Services Sponsor: Cytori Therapeutics Inc. CRO: PAREXEL

What Are ADRCs? In 2001 a group of Investigators from the University of Pittsburgh and UCLA demonstrated the presence of adult stem cells within human adipose tissue These cells were isolated by culturing cells obtained following enzymatic digestion of adipose tissue and removal of mature adipocytes Enzyme Digestion Cell Culture Aspirated Adipose Tissue Stromal Vascular Fraction Adipose-Derived Stem Cells IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

Stromal Vascular Fraction
Stem cells comprise ~1-2% of SVF cells Also includes other cells with regenerative properties Anti-inflammatory Type 2 macrophages Regulatory T cells Endothelial progenitor cells IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

Path to This Point In 2012 Cytori was awarded a contract from BARDA (a group within Dept. of Health and Human Services) to develop ADRCs for the treatment of thermal burn injury From Cytori executed preclinical studies demonstrating safety and efficacy in large animal models of thermal burn injury Data indicate efficacy in meshed STSG and donor site healing On the basis of the safety and efficacy profile obtained in these activities and in prior trials executed by Cytori the FDA has approved and BARDA has funded the RELIEF trial IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

Preclinical Data: ADRCs and Burn
Large animal preclinical with ~20% TBSA burn injury Yorkshire swine model Two groups: intravenous autologous ADRCs or placebo Assessed healing of three wound types Full thickness burn treated with fascial excision and grafting with 3:1 meshed autologous STSG Partial thickness wound left untreated other than simple dressing STSG donor site STSG Donor Site Full Thickness Partial Thickness IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

Partial Thickness Wounds
% Epithelialization Barrier Function (Water Loss) p=0.03 ns p=0.02 Days post-Injury LR (n=7) iv ADRCs (n=8) IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

Grafted Wounds % Epithelialization Barrier Function (Water Loss)
ns p=0.21 p=0.01 p=0.01 p=0.05 p=0.04 p=0.02 Days post-STSG Days post-STSG LR (n=7) iv ADRCs (n=8) IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

Donor Site % Epithelialization Barrier Function (Water Loss)
ns p=0.07 p=0.04 p=0.02 ns Days post-donor site excision Days post-donor site excision LR (n=7) iv ADRCs (n=8) IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

Other Preclinical Data
Earlier epithelialization and reduced inflammation following intravenous injection in Gottingen miniswine with full thickness thermal burn wounds and sub-lethal radiation exposure Topical delivery of ADRCs associated with improved histology (rete ridges) following excisional partial thickness (2mm) cutaneous wounds in scar prone Red Duroc swine ADRCs isolated from adipose tissue present in fascial excision of human burn patients have yield, viability, composition, and function that are similar to those of healthy (non-burned) donors IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

Prior Clinical Experience with ADRCs
Subcutaneous injection into the fingers of the subset of patients with diffuse cutaneous systemic sclerosis (scleroderma) leads to improved hand function at 48 weeks Disability Hand Function Quality of Life p=0.010 p=0.069 p=0.044 p=0.034 p=0.021 Placebo ADRCs

Prior Intravascular Clinical Experience
APOLLO Randomized, placebo-controlled, double blind study of ADRCs delivered via intracoronary infusion in patients with ST-segment elevation myocardial infarction (STEMI) 14 patients were enrolled at two European clinical centers Two SAEs related to bleeding Protocol amended to exclude subjects with GPIIb/IIIa inhibitors; no subsequent issues No SAEs attributed to administration of ADRCs IB0010_B: Adipose derived Regenerative Cells for Thermal Wound

The RELIEF Clinical Trial Study Design
CONFIDENTIAL

Study Design Open label 15 subjects at up to 10 sites randomized (2:1)
Treatment + Usual Care Usual Care alone No change from care that the patient would receive outside the study Each subject can contribute up to three graft areas ~250cm2 each Meshed as per standard practice at site This is a change from the original protocol which had specified 2:1 or 3:1 mesh 7 day hold period Each of the 1st 5 subjects enrolled in active treatment (for the study as a whole) will be observed for adverse events over a 7 day period following treatment An independent Safety Monitoring Committee will review any adverse events reported for that subject over 7 day window and recommend whether the study should continue as-is or with modifications During the review period no other subject can be enrolled

Key Inclusion/Exclusion Criteria
Inclusion Criteria Key Exclusion Criteria Males or females age ≥ 18 to ≤ 65 BMI > 20 kg/m2 Burn TBSA 20% - 50% At least one deep partial thickness and/or full thickness thermal burn ≥ 250 cm2 on the arms, legs, back, abdomen or chest that is anticipated to be covered with an autologous meshed STSG Ability to safely undergo tissue harvest that is anticipated to yield ~150 mL of adipose tissue at a site that is free from infection Donor site availability for skin graft harvest Able to provide written informed consent signed by either the patient or their legally authorized representative Subjects with burns > 3rd degree Subjects with electrical or chemical burns Subjects with significant inhalation injuries necessitating intubation and mechanical ventilation or requiring > 50% FI02 on a continuous basis to maintain oxygenation (02 sat > 90%) In the opinion of treating physician, patient not expected to survive beyond 30 days Subjects with psychiatric conditions or chronic illicit drug or alcohol abuse that is anticipated to interfere with patient compliance with the protocol Participation in another clinical trial within 60 days of the screening visit Any concurrent disease or condition that, in the opinion of the investigator, would make the patient unsuitable for participation in the study, such as uncontrolled diabetes

Study Design: Time Points
One year follow-up with study visits at: At initial dressing changes Estimate day 5-7 after grafting and day after grafting Week 2, 3, 4, 8, 12, 26, and 52 after grafting

Initial Assessment On procedure day, the PI will record and label the location(s) of the area(s) treated with a meshed skin graft that will be designated as areas to be assessed in the RELIEF Trial. PI may designate up to three non-contiguous areas each comprising approximately 250cm2. Similarly, a representative control area will be identified and recorded on this map* The location of these areas will be recorded on a paper form “Burn Area Assessment Location Map” and in notes captured in the digital imaging system CLF1170_A: Burn Area Assessment Location Map *The control area is intended as a control for this patient’s skin pigmentation, elasticity, hardness, water loss, etc.. The Sponsor recognizes that for many patients it will not be possible to select an area that is properly representative of normal skin at the injured area. Investigators should use best judgment in this selecting a suitable area.

Later Assessments Epithelialization Early Wound Assessments
% epithelialized as assessed in real time by the PI % graft take as assessed in real time by the PI Digital imaging Complete Wound Closure (yes/no) Early Wound Assessments Wound pain VAS Transepithelial water loss Late Wound (Scar) Assessments Pruritis VAS Patient and Observer Scar Assessment Scale Vancouver Scar Scale Skin Elasticity (Elastimeter) Skin pigmentation (SkinColorCatch) Skin hardness (SkinFibrometer) Biomarkers related to burn injury From serum samples collected through week 12

Endpoints Primary Endpoint: Safety and Feasibility
Safety (will be monitored during the whole study duration of 52 weeks): incidence, type and seriousness of adverse events related to the IV administration of test substance as well as the low volume lipoharvest procedure. Feasibility (on procedure day): The feasibility of harvesting > 100mL of adipose tissue from the burn patients The feasibility of generated more than 20 million of ADRCs from the tissue amount for cell treatment Key Secondary Endpoint Percent epithelialization of the graft at day 7, day 10 and weeks 2, 3 and 4 post grafting Percent take of the graft at days 7 and 10 and weeks 2, 3 and 4 Percent of group with complete wound healing at weeks 2, 3, 4, 8 and 12 Exploratory Endpoints Transepithelial water loss at days 7 and 10 and weeks 2, 3 and 4 Wound pain VAS (visual analogue scale) at days 7 and 10 and weeks 2, 3 and 4 Pruritis VAS at weeks 3, 4, 8, 12, 26 and 52 Patient and Observer Scar Assessment Scale (v2.0) at weeks 3, 4, 8, 12, 26 and 52 Skin Elasticity measurement at weeks 12, 26 and 52 Vancouver Scar Scale at weeks 12, 26 and 52 Measurement of skin pigmentation (Skincolorcatch) and hardness (Fibrometer) at weeks 12, 26 and 52 Serum biomarkers related to burn injury at days 1, 7, and 10 and weeks 2, 3, 4, 8, and 12

-2 to +1 Proc Day 1st Chng1 D102 Wk 2 Wk 3 Wk 4 Wk 8 Wk 12 Wk 26 Wk 52
Informed consent X Medical History (including demographics) Physical examination Vital signs (BP, HR, Temp, RR) 3 Concomitant medications Laboratory Testing4 Inclusion and exclusion criteria (Preg. Test) Randomization Adverse events Digital photography of wounds Low Volume Lipoharvest ADRC dose prep, testing, and delivery % Epithelialization % Graft Take Biomarkers5 Transepithelial water loss Wound Pain VAS Pruritis VAS POSAS questionnaires Vancouver Scar Scale Skin elasticity Skin pigmentation Skin hardness Complete Wound Closure First dressing change Performed only if dressing change performed between days 8 and 12 Per Institutional procedures CBC with Platelets, INR, PTT, Electrolytes, alkaline phosphatise, AST, ALT, bilirubin, total protein, albumin, BUN and creatinine Biomarkers tested by central lab from serum prepared from 5ml blood draw

Randomization Randomization to ADRC and usual care will occur within 2 hours prior to the scheduled surgery for STSG Randomization will be done via an interactive web response system (IWRS). Subjects will be randomized in a 2:1 ratio to receive intravenous delivery of ADRCs prepared using the Celution System and usual care or to usual care alone A total of up to 15 subjects will be enrolled Each patient will contribute up to three qualified non-contiguous wound areas for the analysis

Patients Randomized to Treatment
Adipose-Derived Regenerative Cells (ADRCs) During burn surgery (escharectomy and grafting) a plastic surgeon will aspirate mL (target 150ml) of subcutaneous adipose from the patient ADRCs will be prepared from this tissue using an automated device in or nearby the OR ADRC preparation takes ~2-3hours (including testing for sterility and cell viability) 20 million ADRCs will be infused intravenously

Small Volume Liposuction
Performed manually Infusion of tumescent solution using syringe and infusion cannula 1 vol solution:1 vol adipose to be aspirated Lactated Ringers solution, 0.1% lidocaine, 2µg/mL epinephrine Manual aspiration of tissue using 50cc syringe and 4mm cannula Aspirate ~6-7 syringes with each syringe ~50% fluid and 50% tissue CLWI1043: RELIEF Fat Harvest Procedure CLF1123: Clinical Liposuction and Processing Worksheet

Safety Issues from Prior Experience
Bruising and pain at the site of liposuction Typical cosmetic liposuction >1L of tissue aspirated Target for RELIEF is 150mL Bleeding is minimal in subjects with adequate clotting function Study excludes subjects with abnormal aPTT

ADRCs and the Celution System
Cytori has developed a GMP-quality system that comprises a semi-automated device, pharmaceutical grade enzymes, and single-use consumables for the preparation of SVF cells in a clinically-relevant fashion When SVF cells are prepared in this system we refer to them as ADRCs In the USA Cytori is developing this system for two indications: thermal burn injury and hand dysfunction in patients with systemic sclerosis

Processing Tissue is injected into the consumable loaded onto the Celution device Tissue is washed to remove blood Celase reagent is added to digest the tissue and release ADRCs Celase reagent is washed away and Intravase reagent is added to reduce cell clumping ADRCs are retrieved from the Celution System, counted to prepare the dose, tested for sterility (stat gram stain) then infused intravenously through an in-line filter CLWI1040: RELIEF Device Operation and Dose Preparation

Process Small volume liposuction to collect ~150mL of adipose tissue
Tissue is processed in the Celution System ~2 hours ADRCs are counted, tested and prepared for iv infusion

Critical Steps from Prior Experience
ADRCs transportation after isolation Cell Injection Procedure (detail in procedure section) No infusion-related toxicity observed in intravascular administration

The RELIEF Clinical Trial Subject Recruitment and Retention
CONFIDENTIAL

Subject Recruitment Number of subjects with adequate diagnosis
How will subjects be identified? Are there any referral networks in place? Number of new subjects per month Planned recruitment numbers Top 3 challenges identified by investigator to enroll subjects in this study What can PAREXEL do to help? Competitive Enrolment

Subject Retention Every effort should be made to keep subjects in the study until the end of the follow up period (52 weeks) Patient retention is critical for the study to meet endpoints Subject outcomes for safety and efficacy are heavily dependent on a high percentage of completers in this study Site staff, with the support of their CRA, should engage subjects and parents to continue through out study

The RELIEF Clinical Trial Investigator, Sponsor and Monitor Responsibilities
CONFIDENTIAL

ICH-GCP / GCP Training requirements Key Principles of ICH/GCP
Compliance with ICH/GCP provides public assurance that the rights, safety, and well being of trial subjects are protected consistent with the principles of the Declaration of Helsinki Ethical principles of the Declaration of Helsinki Benefit of the individual (benefits justify risk) Protection of individuals prevail Adequate drug data to support clinical trial Clinical trials should be scientifically sound IRB/IEC approvable / favorable opinion Subject care is under a qualified physician Staff is qualified, educated, experienced & trained Obtain freely given informed consent Data accuracy Confidentiality of records Good manufacturing practice Quality systems implemented

ICH-GCP / GCP Training requirements ICH/GCP Compliance
As per ICH/GCP, Principal Investigator is responsible for overseeing all study related activities at the site. Investigator is also responsible for all site staff actions and must be involved in the work of the team. Investigator needs to ensure that the Protocol is adhered to at ALL TIMES and no deviation or violation is made from the procedures specified in the study protocol. PAREXEL Medical Monitor should be contacted in the event that a significant protocol deviation does occur. Any changes in the primary study staff should be communicated to PAREXEL immediately and appropriate training should be provided to the new staff. Investigator is required to report all Serious Adverse Events within 24 hours of their knowledge to PAREXEL.

Investigator Obligations and Responsibilities
Is medically qualified Has adequate resources (facilities, team, time) Approved by an Ethics committee Follows the trial protocol Reports serious adverse events within 24 hours Has full control over test article at the site - if not delegated to a pharmacist Follows the Informed Consent procedure Retains source data Delegation of responsibilities / Training of site staff (IRB) Informed Consent eCRF completion requirements Availability and Direct Access of Source documents Protocol adherence / non-compliance Reporting of Serious Adverse Events Investigator Site File / Regulatory documents Record retention

Investigator Obligations: Delegation of responsibilities / Training of site staff
The PI is overall responsible for the conduct of the study at the site. Tasks may be delegated to other members of the team when: The PI ensures the person is properly trained The delegation is documented on the ”Site signature and delegation log” The PI must inform the CRA immediately in case the PI role will be taken over by another investigator due to any reason. Training of site staff should always be documented. Inform your CRA when new staff is joining so he/she can assist with the training and/or the documentation of the training.

Investigator Obligations: Informed Consent Requirements
Ensure the subjects are given sufficient time to consider their participation in the study Ensure the consent process is documented in the source notes: When was the subject informed about the study When was the study discussed When was the ICF provided to read If the study was discussed with the SC, when were questions answered by the investigator When was the ICF signed Was a copy of the signed ICF provided to the subject A written procedure for the consent process must be filed in the Investigator Site File

Investigator Obligations: e-CRF Completion Requirements
All data must be recorded in the eCRF Data should be entered within the specified time of the subject visit Queries should be answered within the specified days Investigator must sign the eCRF electronically when all data are entered and confirmation has been received that no more queries will be raised

Investigator Obligations: Availability and Direct Access of Source Documents
Source documents must be available for all datapoints per protocol. The location of each datapoint is described in the Source Document Agreement. This is a living document and must be updated should changes occur. During monitoring visits, the CRA will verify that all datapoints in the eCRF are present in the source data (SDV). The eCRF is not acceptable as a stand-alone source document. Documentation of eligibility is required for all subjects and must include: Statement noting subject meets criteria and is now entered in study Signed/dated by Investigator

Investigator obligations: Protocol Adherence / Non-compliance
The protocol must be followed at all times. If a deviation is discovered by any member of the site staff, the CRA should be immediately notified. All protocol non-compliance is tracked by the CRA Ensure patient safety is not jeopardized Develop a plan to ensure the non-compliance will not be repeated in the future The CRA will work with site staff to ensure preventive and corrective actions are implemented The EC/IRB should be notified according to local requirements

Investigator Obligations: Regulatory Documents and ISF
PAREXEL has provided the Investigator Site File (ISF) Organized as per PAREXEL Indexing structure If any part of the ISF is maintained separately throughout the study duration (e.g. lab manual, contract), a file note should explain its location All study related documents must be filed in the ISF provided by PAREXEL All significant communications received must be printed and filed in the ISF (e.g. Monitoring follow up letters, SUSARs, etc.) Ensure the ISF is kept up-to-date for the duration of the study

Investigator Obligations: Record Retention
Study records are to be retained for a period of 15 years after termination of the Study unless Cytori authorizes, in writing, earlier destruction Inform Cytori prior to destroying any records Cytori is to be immediately notified if: The archiving location is changed If the PI can no longer take responsibility for the archive If the PI is moving to another location and can no longer take responsibility for the archive, then this responsibility must be transferred to another person.

Investigator Obligations: Audits and Regulatory Inspections
Audits may be performed by Cytori or PAREXEL Audits are performed to ensure the quality of the trial Auditors are independent from the study team Site staff will be informed about any planned audit Regulatory inspection may be performed by the Regulatory Authorities or your local IRB/EC Regulatory inspections are performed to ensure applicable regulatory requirements, ICH-GCP, and study procedures are followed Regulatory inspections may occur without notice. In this case, site staff should immediately inform their CRA.

Sponsor Responsibilities
The sponsor is responsible for the quality assurance and quality control of the study and must ensure the study is conducted according to the protocol, ICH-GCP and applicable regulatory requirements. The sponsor must inform the sites about the investigational protocol and update the IB when new significant information becomes available. The sponsor is responsible for the ongoing safety evaluation of the product and must inform the sites of any safety events which could adversely affect the safety of the subjects.

CRA Responsibilities The CRA is responsible for the monitoring of the site to ensure: The rights and well-being of human subjects are protected The reported trial data are accurate, complete, and verifiable from the source documents The conduct of the study is in compliance with the currently approved protocol/amendment, with ICH-GCP, and with applicable regulatory requirements Facilitate communication between site and sponsor Ensure site staff is adequately trained to conduct the study Ensure site staff is provided with study specific information and relevant documentation (protocol, IB, instructions, guidelines) Verify the latest ICF is obtained from all subjects prior to start of any study activies Ensure eCRF is completed and source documents are adequate

Monitoring Expectations
Source documents: - made available for review for blinded CRA at each visit Access to Electronic Records: - should be printed and certified copies required if read only access can not be provided to PAREXEL CRA Timely completion of eCRFs (within 4 working days of subject visit) Lab Reports: - reviewed and signed by Investigator

Site Staff – Roles and Responsibilities
Principal Investigator Study Coordinator Regulatory Coordinator Other study personnel

The RELIEF Clinical Trial Safety and SAE/UADE Reporting
CONFIDENTIAL

Safety and SAE/UADE Reporting
Safety and Feasibility of Adipose Derived Regenerative Cells (ADRCs) in the Treatment of Deep Partial Thickness and Full Thickness Thermal Wounds (RELIEF) Safety reporting for this study includes both a Test Product and a Device Test Product  Adipose Derived Regenerative Cells (ADRCs) Device  Celution® System, Infusion and Macro-Syringe Filter

Safety and SAE Reporting
ADVERSE EVENT DEFINITION ICH-GCP 1.2 “An untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with the treatment.” ADVERSE ADVERSE A key point to emphasize is that the event does not have to be considered related to the study treatment.

ICH-GCP 1.50 SERIOUS ADVERSE EVENT (SAE) OR SERIOUS ADVERSE DRUG REACTION (SERIOUS ADR) An SAE is any AE (adverse event) occurring at any dose and regardless of causality that: results in death is life-threatening requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity other important medical events which may jeopardize the patient or require intervention to prevent one of the above listed events is a congenital anomaly/birth defect It is important to emphasize that a severe event is not automatically classified as a Serious Adverse Event. For example, you could have a severe headache but it must also satisfy one or more of the SAE criteria to be classified as serious (i.e. the headache would need to require hospitalization or be disabling or incapacitating etc. to be reported as an SAE). SAE Definitions may differ slightly between Client, between studies and between countries. (You may wish to discuss your own country-specific requirements). life-threatening. The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe. requires hospitalisation or prolongation of existing hospitalisation. In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfils any other serious criteria, the event is ’serious’.

ICH-GCP 1.60 UNEXPECTED ADVERSE DRUG REACTION An Unexpected Adverse Drug Reaction (ADR) is an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) All serious, unexpected ADRs (SUSARs) require expedited reporting to the Regulatory Authorities (ICH-GCP) It is important to understand what classifies an ADR as unexpected as these events. If serious, require expedited reporting to the regulatory authorities within 7 days for fatal/life-threatening events and 15 days for other serious unexpected ADRs

Protocol Specific Definitions Drug for this study is defined as Adipose Derived Regenerative Cells (ADRC’s). Medical and scientific judgment should be exercised in deciding whether a case is serious and whether expedited reporting is appropriate. Pain and ecchymosis/hemorrhage around the fat harvest site are expected and should not be recorded as an adverse event unless meeting one or more of the following criteria: (a) serious adverse event (SAE), (b) greater severity than expected according to Investigator clinical judgment, or (c) hemorrhage requiring evacuation. It is important to understand what classifies an ADR as unexpected as these events. If serious, require expedited reporting to the regulatory authorities within 7 days for fatal/life-threatening events and 15 days for other serious unexpected ADRs

UADE Definition per protocol
UNANTICIPATED ADVERSE DEVICE EFFECT Protocol Specific Definitions Unanticipated adverse device effect (UADE) is defined as any serious adverse effect on the health and safety or any life-threatening problem or death caused by, or associated with the Celution® system device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application or any other unanticipated serious problem with the Celution® system device that relates to the rights, safety or welfare of subjects. UADEs would be considered related to one of the following: Celution ® Device Infusion SYSTEM Macro-Syringe Filter It is important to understand what classifies an ADR as unexpected as these events. If serious, require expedited reporting to the regulatory authorities within 7 days for fatal/life-threatening events and 15 days for other serious unexpected ADRs

PROTOCOL SPECIFIC PROCEDURES FOR AE/SAE REPORTING
Adverse events will be assessed according to the NIH Common Terminology Criteria for Adverse Events (CTCAE) v4.0 for scale grading adverse events. Grade 1 Mild Grade 2 Moderate Grade 3 Severe Grade 4 life-threatening Grade 5 death All AEs (including SAEs and UADEs) will be recorded by the investigator or designee on the appropriate electronic case report form (eCRF).

PROTOCOL SPECIFIC PROCEDURES FOR AE/SAE/UADE REPORTING
The investigator shall submit to the sponsor and to the reviewing IRB a report of any UADE occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect. In addition, the Investigator or designee will report any serious adverse events occurring during this study to the PAREXEL Safety Services via faxed or ed SAE/UADE form as soon as possible, but no later than 24 hours after the Investigator first identifies the adverse event. The Investigator will take appropriate measures to ensure the subject’s well-being and document these measures on the appropriate eCRF.

Timeframe and process for reporting of SAEs/UADES
SAEs/UADEs must be reported VIA SAE/UADE FORM COMPLETION to the PAREXEL Safety Services team within 24 hours of the site’s first awareness of the event Complete the Cytori SAE/UADE report form; attach any available relevant source documents (with patient confidential information fully redacted, and patient’s study ID written on each page of source documents submitted) Obtain PI/Sub I assessments and signature Submit via or by fax to Include a coversheet whether submitting via fax or If you need assistance, call the SAE “hot-line”: (during Eastern US business hours, Monday – Friday, 8:30 AM until 5:00 PM) submission should be multi-page pdf If PI or Sub-I not available to sign, obtain verbal assessment and note on the report; if possible obtain assessments via and include the with the submission. Submit the signed copy as soon as possible thereafter All versions of the submitted reports will require an investigator signature

Follow-up SAE reports and query process
PAREXEL Safety Services team will issue queries for any missing, discrepant, or additional information needed to complete the case. SAE/UADE queries will be sent by fax or and unanswered queries will be re-issued every two weeks. Follow-up information should be submitted on an SAE/UADE Report form, signed by the PI or Sub-I. If requested source documents cannot be obtained, please indicate this on the SAE/UADE Report form. With each follow-up report, the investigator should re-assess causality, severity, and if applicable, any additional serious criterion. It is helpful if the site attaches a copy of the query letter to the follow-up report so everyone is aware of the queries being addressed

AE/SAE/UADE Reporting – selecting an event term
When reporting AEs/SAEs/UADEs, general terms such as pain, edema, etc. should be associated with the anatomic location (e.g., abdominal, ankle, etc.) Whenever possible, report the clinical diagnosis and NOT the signs/symptoms of the condition, for example: If the subject has the flu, report the AE/UADE of "influenza", and NOT separate AE terms of "cough", "fever", "diffuse muscle pain“ If the subject has gastroenteritis, report AE/UADE of "gastroenteritis" and NOT separate AE terms of "diarrhea", "nausea", and "vomiting” The event term should be supported in the source records (such as the final discharge diagnosis for hospitalized patient, post-operative diagnosis was an event treated by surgery)

Pregnancy REPORTING Although not considered an adverse experience, it is the responsibility of investigators or their designees to report any pregnancy involving the spouse/partner of a study subject (spontaneously reported to them) which occurs during the study or within 30 days of completing the study (through week 52) All pregnancies are followed until completion/termination of the pregnancy If the pregnancy continues to term, the outcome (health of the infant) must also be reported

AE/SAE/UADE Reporting FORM

The RELIEF Clinical Trial Study Supplies, Procedures and Documents
CONFIDENTIAL

Supplies and Equipment
Provided by the sites IV Infusion Catheter (cell delivery) Epinepherine/Lidocaine Urine pregnancy tests Dry Ice -80 C freezer (serum samples for biomarkers) -20 C freezer (Celase) 2-8 C refrigerator (Intravase) Any supplies related to usual burn care Provided by Cytori Celution® System Reagents (Celase & Intravase) Sin Elasticity Measurement Skin Pigmentation (Skincolorcatch) Fibrometer TEWL Vapor meter Laptop (for data capture) Aranz Silhouette Camera 530/IS Tissue Harvest Instrument Set Nucleocounter Device (+ printer) Rapid Fluid Warmer Nutating Mixer

Fat Harvest Procedure CLWI1043: RELIEF Fat Harvest Procedure
A specific set of requirements has been established for the collection of fat that can then be used for the successful preparation of ADRCs using the Celution® technology. Syringe-based fat harvest is required A total volume of mL of adipose tissue must be harvested Symmetric fat removal is required, keeping the overall area of aspiration as small as possible The abdominal region is the preferred site for fat harvest, however multiple sites should be evaluated and prepared and non-abdomen regions (e.g., inner thigh) used if abdomen not available Make an approximately 0.5 cm stab skin incision Infiltrate tumescent solution using a 14 gauge, up to 30 cm, blunt LAMIS™ infiltrator for tumescent fluid administration ; tumescent fluid should be infiltrated at a ratio of approximately 1:1 to 3:1 of tumescent solution to fat to be harvested The tumescent fluid formula to be used is: 500 mL of Lactated Ringers solution 20-50 mL of 1% Lidocaine 1 mg of epinephrine CLWI1043: RELIEF Fat Harvest Procedure CLF1123: Clinical Liposuction and Processing Worksheet

Fat Harvest Procedure Continued…
To sufficiently induce vasoconstriction/hemostasis during the tissue harvest procedure a minimum of 100 mL of tumescent fluid must be used. Estimated volume should generally be limited to 500 mL Approximately 10 minutes after the tumescent fluid injection, the adipose tissue is harvested through the same incision, using an up to 32 cm long, 3-5 mm inner diameter Toomey cannula with a Mercedes standard tip attached to a sterile 60 mL Toomey syringe After the first syringe is filled (complete filling is not required) it is detached from the cannula, capped with a sterile cap and set aside; additional syringes are filled until the desired amount of fat is harvested (6-7 syringes with each syringe ~50% fluid and 50% tissue) Fat harvest will be limited to areas where donor tissue availability Vital signs are monitored during tissue harvest procedure Close surgical incision as per the surgeon’s standard procedure. Apply pressure bandage immediately upon conclusion of tissue harvest CLWI1043: RELIEF Fat Harvest Procedure CLF1123: Clinical Liposuction and Processing Worksheet

Fat Harvest Stopping Rules
The physician performing the fat harvest procedure should continuously monitor the patient for signs of significant bleeding from the puncture site(s) and overall hemodynamic stability. The tissue harvest procedure should be terminated if any of the following occur: Drop in systolic blood pressure < 90 mm/Hg requiring pressor support. Profuse or uncontrollable bleeding from the puncture site(s) Rapid expansion of subcutaneous space at the fat cell tissue harvest site(s) related to bleeding into the subcutaneous space Hemoperitoneum or pneumopertineum Hemothorax or pneumothorax Evidence of perforation of a vascular structure that requires ligature or surgical control Evidence of perforation into abdominal cavity, peritoneum or gastrointestinal organ Should any of the above occur, the fat harvest procedure should be terminated and the patient treated according to standard of care. DO NOT PROCEED WITH ADRCs

Procedure Day Activities (Post-Lipo)
Cell Isolation – Celution System Technician (Certificate of Training) Investigators (general overview) Dose Preparation - NucleoCounter Randomization Unblinded Designee (Certificate of Training) Cell injection

The Celution® System Low volume lipoharvest will only be performed on subjects randomized to ADRCs in order to obtain mL lipoaspirate, which will then be transferred to the Celution® System for processing to isolate and concentrate ADRCs for same-day administration. All treatment will be delivered in a total volume of 10 mL which will be delivered by slow intravenous administration. 5 Steps of Celution Processing 1. Celution Device Set Up 2. Add Tissue to the Device 3. Tissue Digestion (Celase®) 4. ADRC concentration 4b. Dissociation of Cell Clumps (Intravase®) 5. ADRC Pellet Wash ADRC Removal, Cell Counting, Dose Preparation and Microbiological Sample Preparation

Celution® System Output
The product is a suspension of cells in a diluent. The cellular components of the suspension are made up of nucleated and non-nucleated cells. The non-nucleated cells are red blood cells (RBC) that comprise > 95% of the total cell suspension. The nucleated cells make up approximately 0.1 – 5% of the total cell suspension. Cell Type Phenotype Relative Identity of Nucleated Cell Population Non-nucleated Cells Red Blood cells Endothelial Cells CD45-, CD31+, CD34+ > 2% Stromal Cells CD34+, CD31-, CD45- > 5 % Leukocytes CD45+, CD31-, CD34- > 5% Mural Cells CD45-, CD34-, CD 31- ,CD146+

Cell Isolation / Dose Prep / Sterility
Performed by technician(s) Gram Stain result must be negative, then the Dose syringe will be provided to appropriate designee for injection If the Gram Stain result is positive, then the ADRCs will not be infused into the patient. The subject will continue to be monitored for the duration of the study. 10 mL dose in 10 mL syringe: ADRCs: not to exceed 20 million cells (20 x 106 cells)

RELIEF Cell Injection Procedure
Please reference CLWI1045_A The study treatment will be assigned according to a randomization code generated by the Interactive Web Response System (IWRS), as follows: Treatment: 20 x 106 cells (10 patients) Control: Standard of care (5 patients) Sterile transfer of dose onto sterile field Sterile technique should be maintained throughout the procedure. The intravenous infusion of ADRCs will be administered via peripheral vein. IV catheter – no smaller than 20 gauge 10 mL dose containing 20 x 106 ADRCs The syringe will be attached to the sterile macro syringe filter and the dose will be infused through the catheter over 60 seconds. Catheter flush – 5 mL lactated Ringer’s solution CLWI1045_A: RELIEF Cell Injection Procedure

Digital Photography CLWI1055 Operation of SilhouetteStar Camera
Digital photographs of the target wounds must be taken shortly after application of the STSG. Images of wounds will be taken by using the Silhouette Star System in accordance with the detailed work instruction provided in the Study Manual. Digital photographs will be taken at a fixed distance of approximately cm from the wound. A reference image to identify the location of the target wound(s) with reference to anatomical landmarks should also be captured at the time of grafting. Images will be captured from directly above the wound (approximately perpendicular to the center of the wound surface) and at an oblique angle (approximately parallel to the center of the wound surface) to show scar height above adjacent skin. CLWI1055 Operation of SilhouetteStar Camera

Accountability Investigator & Site Coordinator shall ensure:
Correct use of device & supplies (Product device/consumables/enzymes) Detailed records maintained Product received from Cytori Product used in the treatment of trial subjects Instructions for storage of Product are adhered to Storage conditions of IP are documented Enzyme vials are not destroyed until authorized by CRA

Accountability Accountability Logs: Celution 800/IV Enzyme* Intravase
Celase, -15˚C to -25˚C Intravase, 2˚C to 8 ˚C Intravase Consumable Sets Procedure Day Kit Liposuction Kits ADRC PreparationKits Dose Delivery Kits Lactated Ringer’s Nucleocassette Supplies * Temperature Logs Temperature recording devices will be provided for refrigerator and freezer if needed

Return and Destruction
At the end of the study, the Celution device and other equipment will be shipped back to Cytori and recorded in the Accountability Logs All accountable supplies, reagents, and enzymes will be recorded in the accountability logs as used, unused, or destroyed.

The RELIEF Clinical Trial DataLabs - EDC
CONFIDENTIAL

System Requirements DataLabs v 5.5.2 will be utilized
DataLabs EDC now supports the following browsers (depend on OS): Internet Explorer 8, 9, 10, and 11 Firefox 3.6, 10, and 30 Safari 5, 6, and 7 Screen Resolution DataLabs EDC is designed for screen resolutions of 1024 x 768 or greater. If your screen resolution is less than this, some DataLabs EDC pages may not fit on your screen, and may not display correctly. Adobe Acrobat Support DataLabs EDC supports Adobe Acrobat Reader version 9.0 and above. You can download the Adobe Acrobat Reader for free from Adobe's website at

System Requirements (continued)
Change the Browser Settings For DataLabs EDC to work optimally, adjust your browser's settings.

System Access – user requests
CRA to please provide PAREXEL Data Management with user information for each site. Please send an requesting access to: Please include the following information for each user: First Name Last Name Address User Role Required (Monitor, Coordinator or Investigator) Site Name

DataLabs role based elearning
All users are required to take role-specific training as well as a generic DataLabs overview Upon completion of the assigned modules, users will receive a certificate to document completion of training

E-learning course times
Clinical Monitor_v5.3 (40-50 minutes) Clinical Team Sponsor_v5.3 (30-40 minutes) Investigator_v5.3 (20-30 minutes) Study Coordinator_v5.3 (20-30 minutes) Note: Sub Investigators should perform the Investigator training to enable them to sign subject CRFs (if delegated).

dATAlabs eCRF Training (eLearning) & SYSTEM Access
PXL DM release eCRF eLearning Training Letter ( with all eLearning registration instructions) Training Courses available for each role in the study Study Team need to complete eCRF eLearning Training before Access can be granted Once eLearning is completed, individual receive an automated from Perceptive titled “Perceptive MyTrials Access” Create a user account using the convention <firstname>.<lastname> (Note: this only needs to be once for ALL studies) Activate your key from Perceptive

E-LEARNING registration letter

System Access DataLabs users will be sent an access key via . Please follow the instructions in the in order to activate your access key. If the user does not have My Trials login credentials, from previous studies, then they will need to register by clicking “Join Perceptive My Trials”. The link to the My Trials registration is provided in the access key . Once account is created, user will be directed back to MyTrials login page so that they can enter their username and password

Register Account

System access Once logged in, user will be taken to the MyTrials home page. On the left hand side of the screen the user will see an access request box. User will need to click in the confirmation box and press submit.

Logging into DataLabs Forget your username? Email / Call Customer Care
Copy and Forget your password? MyTrials –click reset password link on URL DataLabs –click “forgot your password” link on URL Note: An address and security question must be set up to reset your own password

User preferences Set Up User Preferences (preferred)
Add address: need for reset password Date & Time: specify the date & time format

First screen after login

User prior activity details
Navigation to EDC User prior activity details

Patient view for site 5001-zurich

Crfs for patient vwp

Study specific ecrfs

CLP0010 (RELIEF) (PXL 236363) – Visits & Forms
eCRFs within Folder Screening Demographics Inclusion/Exclusion Criteria Physical Examination Total Burn Surface Area Body Measurements Vital Signs Hematology Chemistry Pregnancy Test Biomarkers Procedure Day 1 Digital Photography Low Volume Lipoharvest ADRC dose prep and delivery Bac T test result Flow Cytometry Day 6 Physical Examination Vital Signs Hematology Chemistry Biomarkers Digital Photography Epithelialization Wound Pain VAS Day 10 Week 2 Transepithelial Water Loss Wound Closure

CLP0010 (RELIEF) (PXL 236363) – Visits & Forms
eCRFs within Folder Week 3 And Week 4 Physical Examination Vital Signs Biomarkers Digital Photography Epithelialization Wound Pain VAS Transepithelial Water Loss Wound Closure Pruritis VAS POSAS Observer Scale POSAS Patient Scale Week 12 Vancouver Scar Scale Skin Elasticity Skin Pigmentation Skin Hardness Week 26 And Week 52 Physical Examination Vital Signs Digital Photography Pruritis VAS POSAS Observer Scale POSAS Patient Scale Vancouver Scar Scale Skin Elasticity Skin Pigmentation Skin Hardness End of Study Study Completion Common Forms Informed Consent Medical History Prior and Concomitant Medication Adverse Events Serious Adverse Events / Unanticipated Adverse Device Event

ecrf Data entry (points to remember)
Please always follow eCRF Completion Guidelines Good Practice for Data Entry is to complete transcription within 48-72hours of the actual visit or assessment completion in the clinic Always ensure that the “Entry Complete” check box at the bottom left corner of each eCRF is ticked before pressing “Save and Close”

ecrf Data entry (ecrf Log Forms)
Log Forms record study information throughout the entire study. These forms are not specific to a single visit, but can be updated as needed. To enter information into a Log Form, Click on the link to the eCRF, then click “Check Out” Click “Add a New Row” Once data entry is complete, you can: Click “Save Row” to save entered data and remain in edit view Click “Save and Close Row” to save entered data and exit edit view Click “Cancel Row” to dismiss new data and exit edit view

ecrf Data entry (Opening a CRF)
Initial view of visit dates will be collapsed. To open a visit, select the “+” next to the visit name. To open an eCRF, click on the eCRF name.

ecrf Data entry (check out CRF)
Click “Check Out” in order to enter data into the eCRF.

ecrf Data entry (data entry in log rows)
When entering data into an eCRF, some fields will accept multiple rows of data entry. To add a row, click “Add New Row”. All fields related to the row will open for data entry.

ecrf Data entry (Recording Burn Sites)
During this study, multiple eCRFs will be used to record information regarding 3 wound sites, and in some eCRFs, 1 designated normal skin site. When capturing the wound sites in each eCRF ensure that the wounds are recorded in the same order. During data entry, select: Area (Wound Site 1, 2, or 3, and Designated Normal Skin) Location of the wound site Confirmation that the Area and Location are the same During visit “Procedure Day 1”, select “Not Applicable” for the confirmation field, as this is the first time the Wound Area and Location will be entered. During subsequent visits, use the confirmation field to confirm that the Wound Area and Location fields are the same as previously entered.

ecrf help Three types of help is available to ensure smooth usage of eCRFs: eCRF eLearning Training to provide you specific support with regards to your role in the study eCRF Completion Guidelines to provide specific support with respect to eCRFs protocol specific eCRFs for this study Online help available by pressing the “Question Mark” sign on the top right hand corner of each page For out of hours technical support contact Perceptive Customer Care

DATALABS INBOX Mail: Send messages to other users
Jobs: For study designers Work Queue: Check for items that need actions Signature Requests Checked Out CRFs that need to be saved

Contacts AND HELP

DATALABS SYSTEM HELP Help regarding system navigation, basic skills, user preferences, icon guides and more, can be located by clicking on the help key in the top right hand corner of the DataLabs screen. A pop up box will open where links can be found to general help or help per user role.

HELP For DataLabs system issues (difficulty logging in, performance issues etc.), please contact the Perceptive Customer Help Desk using the contact information mentioned in the slides. Sites will be requested to contact their Clinical Monitor with study specific questions. Please note that the Perceptive Customer Helpdesk cannot assist with protocol specific questions. Make use of the comprehensive eCRF Completion Guidelines

CONTACTS HELPDESK The Perceptive Help Desk provides support for user login, password or technical issues and can be contacted by ( ) or by telephone at the below given numbers: An up to date list of numbers can also be found at PROJECT LEADERSHIP PAREXEL EPD Project Leader: Meghan Novy DATA MANAGEMENT PAREXEL Data Operations Lead: Mike Koutz, PAREXEL Clinical Data Analyst: Neldri Rabe,

The RELIEF Clinical Trial IWR System
CONFIDENTIAL

Introduction IRT Services provided by ClinPhone RTSM
IRT system is patient centric for patient functions Only those options relevant at the time will be shown All functionality available via the web (IWR) Access to functions and reports controlled Users can only perform functions they have access to

Accessing the ivr/iwr system

Web Log in Using MYTRIALS
Website: Enter User Name and Password Click ‘LOG ON’ Find your study link and click on the protocol number Click on ‘ClinPhone IWRS’ Successful Login shows Study Management Please ensure you have completed self-registration and study activation in MyTrials.

Forgotten Log In Website: www.mytrials.com Click ‘Forgot password’
Enter User Name and You will be asked to provide secret questions will be sent with a new password Log in to the system with the new password. After 5 failed login attempts, you will have to wait for 30 minutes before trying to login again.

Logging Out Log out of both the study & your account
Critical when using shared computers

Web Navigation Enables creation of new patients
Shows a list of all patients for the users site(s) ‘Create a new Patient’ will start patient screening Clicking on existing patient will show list of available options

Study Management Shows a list of all non-patient related functions
Functions shown are user access dependent

Reports Shows a list of all reports user has access to
Reports can be viewed real time Reports can be refreshed and ed Reports can be downloaded as PDF or CSV files

Available Help Administration can be used to change details about the user Login must be unique in the system Full Name changes must go through the Helpdesk User Guide is a link to the study specific user guide Contains helpful information for all functions, and information on how to contact the helpdesk

Help Desk Available 24/7 Local language support is available via phone
Helpdesk can be ed for Data Changes Non-Urgent Queries Helpdesk can be called for Urgent Queries Urgent Data Changes Helpdesk Phone Numbers are toll free in most countries The specific number(s) to call are sent in the study specific user guide and quick reference guide

Demo Demonstration of IRT

The RELIEF Clinical Trial Regulatory File/IRB/Contracts
CONFIDENTIAL

Investigator Site File (ISF)
PAREXEL will send the ISF to each site Protocol with Signature Page Investigator Brochure with Receipt Study Logs Complete Source Data Agreement and Computerized Data Checklist (if applicable)

Site Regulatory Package
Investigator Statement PSP PI CV (including ML information or stand alone ML) PI FDF IRB approval Approved ICFs/HIPAA IRB membership list or GCP statement

IRB and Contracts Central or Local IRB Review/Approval timelines
Any other approval committees Contracts will be managed by PAREXEL Key site staff involved Contract Budget

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