Safety and Tolerability Study of MSC Exosome Ointment

Study Overview
=================
Brief Summary
-----------------
This phase 1 study aims to evaluate the safety and tolerability of the application of the MSC exosome ointment with repeated topical application on adult healthy subjects (TID from Day 1 to 20). The results of this study were to provide the first clinical information on the drug's safety and inform the selection of administration of exosome ointment to be evaluated in subsequent clinical studies. The endpoints included to assess the safety and tolerability of exosome ointment for topical application in healthy adult volunteers are: Frequency of treatment-emergent adverse events (TEAEs) The incidence rate of local skin responses (LSR, i.e., erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration, hyperpigmentation, hypopigmentation, and scarring) [Time Frame: Days 1 and 21] Changes from baseline in blood parameters (including hematology, chemistry, and other inflammation parameters such as C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) [Time Frame: Days 1 and 21]

Detailed Description
-----------------
This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines including the Declaration of Helsinki, Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, applicable International Conference on Harmonization (ICH), Good Clinical Practice (GCP) Guidelines, and other applicable laws and regulations. This was a Phase 1, single-center, open-label study. After signing an ICF, subjects underwent screening procedures on Day 1 prior to the first study product application to determine eligibility. Once eligible, all subjects (n=10) received topical treatment with the MSC exosome ointment immediately followed by Vesiderm liposome cream TID on the forearm with a gap of 4 hours between doses. The study consisted of the following periods: A Screening Period of 1 day (Day 1) A Treatment Period of 20 days (Day 1 to 20) An End of Study (EOS) Period of 1 day (Day 21 [+3 days]). Screening Period The subjects were screened for eligibility on Day 1 prior to the application of the study product. Subjects were asked to sign the ICF after having the study described to them. After obtaining written informed consent, subjects underwent the following screening procedures for participation in the study: Inclusion/exclusion criteria assessments Vital signs Medical history Demographic data review Standard hematology panel Renal panel Liver function test Inflammatory blood examinations Pregnancy test (if applicable) Concomitant medications Identification, visual assessment, and photography of application area A trained expert evaluator (an Investigator or designee) identified the area of study product application and performed visual assessments which were carried out using an adapted version of SCORing Atopic Dermatitis (SCORAD) scale and visual assessment score (VAS). A photograph of the area of application was also taken using a dedicated compact digital camera at the clinic where subject visits were done. Treatment Period After confirmation of the application site, the subjects applied exosome ointment along with Vesiderm liposome cream (TID per day). Each day (from Day 1 to 20), the study product was applied with a gap of 4 hours between each dose to a healthy area (one hand area) on the forearm using 1 fingertip unit (FTU). The Vesiderm liposome cream was meant to keep the application site moisturized. All through the treatment period, the subjects completed the Subject Diary to capture adverse events (AEs; skin-related and other), concomitant medications, and time of study product application. The site coordinator called the subjects every 3 days (Days 3, 6, 9, 12, 15, and 18) to follow up on the investigational product's (IP) compliance, and if subjects had any adverse events or had taken any concomitant medications during the period. Any AEs reported by the subject during the calls were to be referred to the investigator for appropriate review and follow-up. End of Study (EOS) Period The EOS period was on Day 21 (+3 days). The subjects visited the clinic on this day for the assessments such as vital signs, blood examinations (hematology, chemistry, and inflammatory blood examinations), photographs of the area of application, visual assessment of the area of application, AEs, and concomitant medications used. The assessments at this visit were also to be conducted in case of early termination or withdrawal of any subject.

Official Title
-----------------
A Phase 1, Open-label Study to Determine Safety and Tolerability of the Topical Application of Mesenchymal Stem/Stromal Cell (MSC) Exosome Ointment to Treat Psoriasis in Healthy Volunteers

Conditions
-----------------
Psoriasis

Intervention / Treatment
-----------------
* Drug: Exosome ointment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed ICF prior to entering the study or undergoing any study procedures. Male or female, >21 years of age at the time of signing the informed consent. Subject who had been fully vaccinated for COVID-19 and was not under quarantine or Stay Home Notice or on medical leave. Subject who was willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Subject was able to read and write in the English language. For women who were not postmenopausal (> 12 months of non-therapy induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): had a negative pregnancy test at screening remained abstinent or used contraceptive methods during the treatment period and continued for at least 30 days (one menstrual cycle) after the last treatment dose. Exclusion Criteria: Subject had any serious skin condition that was not well controlled. Subject was currently using topical treatments. Pregnant or breast-feeding women. Subject had received phototherapy, oral corticosteroids, oral retinoid, oral immunosuppressive / immune modulative drugs, cytostatic / cytotoxic drugs, cyclosporine, or methotrexate within 30 days prior to the first application of the study product. Subject was currently using any medications including biologics or undergoing treatment known to affect skin conditions. Subject had any other clinically significant laboratory abnormalities, co-morbidities or psychiatric conditions that would place the subject at increased risk or confound the objectives of the study. Subject had used any investigational drugs or biologics and/or participated in any clinical trial within the last 60 days before the day of the first dose of the study drug or was taking part in a non-medication study that would interfere with study compliance or outcome assessments.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single-center, single-arm, open-label study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exosome Ointment<br>The subjects will apply exosome ointment along with Vesiderm liposome cream (TID per day, 20 days). Each day (from Day 1 to 20), the study product will be applied with a gap of 4 hours between three doses to a healthy area (one hand area) on the forearm using 1 fingertip unit (FTU). The Vesiderm liposome cream is meant to keep the application site moisturized. | Drug: Exosome ointment<br>* 100 µg MSC exosomes/g ointment<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-emergent adverse events (TEAEs) | All through the treatment period, the subjects completed the Subject Diary to capture the frequency of TEAEs. | Day 1 - 20 | 
| Change from baseline in the systolic blood pressure after 20 days of treatment | Systolic blood pressure (mmhg) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the diastolic blood pressure after 20 days of treatment | Diastolic blood pressure (mmhg) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the heart rate after 20 days of treatment | Heart rate (beats/min) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the respiratory rate after 20 days of treatment | Respiratory rate (breaths/min) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the body temperature after 20 days of treatment | Body temperature (°C) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the basophils after 20 days of treatment | Basophils (X 10^9 /L) were assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the eosinophils after 20 days of treatment | Eosinophils (X 10^9 /L) were assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the hemoglobin after 20 days of treatment | Hemoglobin (g/dL) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the lymphocytes after 20 days of treatment | Lymphocytes (X 10^9 /L) were assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the monocytes after 20 days of treatment | Monocytes (X 10^9 /L) were assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the red blood cell after 20 days of treatment | Red blood cell (X 10^12/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the white blood cell after 20 days of treatment | White Blood Cell (X 10^9 /L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the bicarbonate after 20 days of treatment | Bicarbonate (mmol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the blood urea nitrogen after 20 days of treatment | Blood urea nitrogen (mg/dL) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the calcium after 20 days of treatment | Calcium (mmol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the chloride after 20 days of treatment | Chloride (mmol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the creatinine after 20 days of treatment | Creatinine (umol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the glucose after 20 days of treatment | Glucose (mmol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the potassium after 20 days of treatment | Potassium (mmol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the sodium after 20 days of treatment | Sodium (mmol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the alanine transaminase after 20 days of treatment | Alanine transaminase (U/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the albumin after 20 days of treatment | Albumin (g/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the alkaline phosphatase after 20 days of treatment | Alkaline phosphatase (U/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the aspartate aminotransferase after 20 days of treatment | Aspartate aminotransferase (U/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the direct bilirubin after 20 days of treatment | Direct bilirubin (umol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the total bilirubin after 20 days of treatment | Total bilirubin (umol/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the c-reactive protein after 20 days of treatment | C-reactive protein (mg/L) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Change from baseline in the erythrocyte sedimentation rate after 20 days of treatment | Erythrocyte sedimentation rate (mm/hr) was assessed on Day 1 (pre-treatment) and Day 21 (+3 days) | Day 1 - 21+3 | 
| Assessment of the dryness of the area of application | Visual assessments of the dryness of the area of application was carried out using an adapted version of SCORAD scale on Day 1 (pre-treatment) and Day 21 (+3 days). SCORAD scale assessment (range: 0-3) 0= none, 1= mild, 2= moderate, 3= severe | Day 1 - 21+3 | 
| Assessment of the oozing/crusting of the area of application | Visual assessments of the oozing/crusting of the area of application was carried out using an adapted version of SCORAD scale on Day 1 (pre-treatment) and Day 21 (+3 days). SCORAD scale assessment (range: 0-3) 0= none, 1= mild, 2= moderate, 3= severe | Day 1 - 21+3 | 
| Assessment of the redness of the area of application | Visual assessments of the rednessof the area of application was carried out using an adapted version of SCORAD scale on Day 1 (pre-treatment) and Day 21 (+3 days). SCORAD scale assessment (range: 0-3) 0= none, 1= mild, 2= moderate, 3= severe | Day 1 - 21+3 | 
| Assessment of the scratch marks of the area of application | Visual assessments of the scratch marks the area of application were carried out using an adapted version of SCORAD scale on Day 1 (pre-treatment) and Day 21 (+3 days). SCORAD scale assessment (range: 0-3) 0= none, 1= mild, 2= moderate, 3= severe | Day 1 - 21+3 | 
| Assessment of the skin thickening of the area of application | Visual assessments of the skin thickening the area of application was carried out using an adapted version of SCORAD scale on Day 1 (pre-treatment) and Day 21 (+3 days). SCORAD scale assessment (range: 0-3) 0= none, 1= mild, 2= moderate, 3= severe | Day 1 - 21+3 | 
| Assessment of the swelling of the area of application | Visual assessments of the swelling of the area of application was carried out using an adapted version of SCORAD scale on Day 1 (pre-treatment) and Day 21 (+3 days). | Day 1 - 21+3 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mesenchymal stem/stromal cell, Exosome, Exosome ointment, Topical application, Safety and Tolerability, Extracellular vesicle