Clinical trial NCT05523011
Conditions: Psoriasis
Keywords: Mesenchymal stem/stromal cell Exosome Exosome ointment Topical application Safety and Tolerability Extracellular vesicle
Sponsor: Paracrine Therapeutics Dermatology Pte. Ltd.
Start date: 2022-03-08; Completion date: 2022-04-05
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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.
Interventions: intervention 1: Exosome ointment
Intervention descriptions: intervention 1: 100 µg MSC exosomes/g ointment

Protocol documents:
Prot_SAP_000.pdf: 
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 
The trial was conducted under a clinical trial authorization (Authorisation No.: CTA2200019) approved by the Health 
Sciences Authority (HSA) Singapore. The clinical protocol and informed consent form (ICF) were approved by the National 
Healthcare Group Domain Specific Review Board (NHG DSRB reference number: 2021/00905). 
 
 
ClinicalTrials.gov Identifier: 
NCT05523011 
Document Date: June 23rd 2023  


Introduction 
Globally, 125 million people have psoriasis, estimating 2 to 3% of the total population[1]. Generally, 
first-line therapy for the treatment of mild to moderate psoriasis includes a topical regimen 
containing vitamin D analogues and glucocorticoids, and phototherapy. Whereas, for the treatment 
of moderate to severe psoriasis, systemic therapy is required, including small-molecule therapies 
and biologics [2-4]. However, the long-term use of systemic treatment is associated with some toxic 
adverse events (AEs) like nephrotoxicity, hepatotoxicity, hyperkalemia, hypomagnesemia, 
hypertension, tremors, malignancies, and loss of drug response [5-9]. A new treatment option is 
needed. 
Mesenchymal stem cells (MSCs) exosome ointment, PTD 2021P, is being developed as a potential 
and promising treatment for the management of psoriasis. MSCs are one of the extensively 
employed cells in clinical trials with established safety profiles in humans and are approved for 
treating extremely inflexible inflammatory diseases [10, 11]. MSC exosomes are highly known for 
their potent immunomodulatory properties and have the potential to mitigate inflammation by 
promoting the secretion of anti-inflammatory cytokines, stimulating Treg polarization, and 
preventing complement activation [12-14].  
We previously showed that topical application of MSC exosome not only reduced C5b-9 but also IL-
17, and IL-23 in the IMQ-induced psoriasis mouse model [10]. As psoriatic and IMQ-treated stratum 
corneum is rich in activated complements and complement-activated neutrophils, and neutrophils 
are now implicated as the major source of IL-17 in psoriasis [15], it was postulated that topically 
applied MSC exosome inhibits C5b-9 formation in psoriatic and IMQ-treated stratum corneum, and 
this, in turn, reduces IL-17 secretion by neutrophils. When topically applied TID, the MSC exosome 
ointment, on mouse skin for 20 days at 10x higher than the clinical dose, the MSC exosome ointment 
elicited minimal systemic and local adverse effects (unpublished).  
Before the conduct of this study, PTD 2021P has not been administered to humans thus far. 
Therefore, this phase 1 study was the first 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] 
 


Materials and Methods 
Study Design 
The trial was conducted under a clinical trial authorization (Authorisation No.: CTA2200019) 
approved by the Health Sciences Authority (HSA) Singapore. The clinical protocol and informed 
consent form (ICF) were approved by the National Healthcare Group Domain Specific Review Board 
(NHG DSRB reference number: 2021/00905). 
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 
Screening 
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). The study product was applied daily (Day 1 to 20) with a gap 
of 4 hours between each dose to an area of healthy skin  (one palm size) on the forearm using 1 
fingertip unit (FTU). The Vesiderm liposome cream was applied in the same area immediately after.  
All through the treatment period, the subjects completed the daily Subject Diary to capture adverse 
events (AEs; skin-related and other), concomitant medications, and time of study product 
application. 
Follow-up calls were made every 3 days (Days 3, 6, 9, 12, 15, and 18) to check on compliance to the 
investigational product’s (IP), and if subjects had any adverse events or 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), photograph 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. 
 
Study Participants 
Subjects were eligible to be included in the study only if they met all the following criteria: 
1. Signed ICF prior to entering the study or undergoing any study procedures. 
2. Male or female, >21 years of age at the time of signing the informed consent. 
3. Subject who had been fully vaccinated for COVID-19 and was not under quarantine or Stay 
Home Notice or on a medical leave.  
4. Subject who was willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures. 
5. Subject was able to read and write in the English language.  
6. For women who were not postmenopausal (> 12 months of non-therapy induced 
amenorrhea) or surgically sterile (absence of ovaries and/or uterus):  
a. had a negative pregnancy test at screening 
b. 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. 
Subjects were to be excluded from the study if there was evidence of any of the following at 
screening or check-in, as appropriate: 
1. Subject had any serious skin condition that was not well controlled. 
2. Subject was currently using topical treatments. 


3. Pregnant or breast-feeding women. 
4. 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. 
5. Subject was currently using any medications including biologics or undergoing treatment 
known to affect skin conditions. 
6. 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. 
7. 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. 
 
Dosage 
MSC exosome ointment (70 µg MSC exosomes/g ointment) was the study intervention to be 
administered. It was administered as a topical intervention of one FTU per one hand area on the 
forearm (average hand area was 160-200 cm2), thrice a day for 20 days. 
 
Safety Assessment 
Safety assessment included vital signs, clinical safety laboratory tests, inflammatory blood 
examinations, assessment of area of application and incidence and severity of AEs. 
Vital signs 
Vital signs including blood pressure (both systolic and diastolic), heart rate, respiratory rate, and 
body temperature were assessed on Day 1 (pre-treatment) and Day 21 (+3 days) 
Clinical safety laboratory tests 
Clinical safety laboratory tests including hematology panel, renal panel, and liver function test were 
assessed on Day 1 (pre-treatment) and Day 21 (+3 days) 
Inflammatory blood examinations 
Inflammatory blood examinations including CRP and ESR were performed on Day 1 (pre-treatment) 
and Day 21 (+3 days). 
Assessment of area of application 
The area of application was assessed by a dermatologist for parameters adapted from the SCORAD 
scale as shown in the next paragraph. The patient graded the subjective symptoms including itch and 
sleeplessness using an SCORAD scale.  
This scale assessed the following: 
• 
Intensity of reaction: The identified area of application was assessed for the intensity of 
signs including redness, swelling, oozing/crusting, scratch marks, skin thickening, and dryness and 
graded as none (0), mild (1), moderate (2) or severe (3). 


• 
Subjective symptoms: The identified area of application was assessed for the subjective 
symptoms including itch and sleeplessness and graded from 0 (no itch or no sleeplessness) to 10 
(worst imaginable itch or sleeplessness). 
Adverse events  
All through the treatment period, the subjects completed the Subject Diary to capture the frequency 
of TEAEs. 
 
Statistical Analysis 
The analysis was conducted on all subject data at the time the study ended. Data collected in this 
study were presented using summary tables and subject data listings. Continuous variables were 
summarized using descriptive statistics, including the number of subjects (n), mean, median, 
standard deviation (SD), and minimum and maximum values. Categorical variables were summarized 
as frequencies and percentages. No formal statistical assessment, in terms of sample size, was 
conducted. A sample size of 10 subjects was considered a feasible sample size to provide sufficient 
safety data for a topical formulation study. 
 
 
 
 


References 
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https://www.psoriasis.org/psoriasis-statistics/  
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