This Phase 1, First in Human study is designed to assess the safety and systemic exposure (pharmacokinetics (PK)) of single dose (Part A,B) and multiple dose (thrice daily) for 14 days (Part C) topical M528101 Liquid 0.3% in healthy volunteers (Part…
ID
Source
Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints are safety, tolerability and PK after IMP is administered
once a day in part A and B and three times a day for 14 days in Part C.
Secondary outcome
Pharmacodynamic endpoints
• Change from baseline in EASI total score in part C.
• Change from baseline in SCORAD total score and each component signs and
symptoms of AD in part C (erythema, induration/papulation, exudation,
excoriation, lichenification).
• Change from baseline in treatable BSA in part C.
• Change in NRS itch score (Peak pruritus NRS, average NRS) from Baseline to
Day 14 for Part C.
• Time course change in NRS itch score in Part B.
• Time course change in NRS itch score (Daytime 12 hr itch and nighttime 12 hr
itch) in Part C.
• Change of nighttime duration of scratching in Part C.
• Change in NRS sleeplessness in Part C.
Background summary
In many dermatological diseases, pruritus (or itch) is one of the impactful and
burdensome symptoms patients face every day. Although pruritus by itself is
seen as a benign symptom, pruritus can have adverse effects on the patients*
wellbeing and daily life. In addition, chronic itch is often accompanied by
several unpleasant sensations such as pain or a burning sensation. The
mechanisms that underlie pruritus are not well known and are compounded by the
subjective nature of itch.
In dermatological conditions, itch is mainly caused by inflammation or skin
damage. Changes in barrier function of the skin can lead to itch by endogenous
mediators or exogenous allergens that come into contact with the skin.
The primary sensory nerve fibers that innervate the skin are categorized into
three groups based on the degree of myelination, diameter, and conduction
velocity. The thick myelinated Aβ fibers transmit tactile sensation, whereas
the thinly myelinated Aδ and unmyelinated C-fibers are mainly involved in the
conduction of thermal and pain/itch sensation. Itch is transmitted
predominately by these unmyelinated, slow conducting C-fibers. These fibers
extend to the dermo-epidermal junction with free endings penetrating into the
epidermis where sensation is detected. The cell bodies for these fibers are in
the dorsal root ganglia (DRG), just outside the spinal cord. From here, both
sensations involve secondary transmission neurons that ascend via the
contralateral spinothalamic tract to the thalamus (Garibyan et al 2013).
Pruritogens interact with receptors or ion channels on the nerve fibers. The
receptors that are often involved are G-protein coupled receptors (GPCR). GPCRs
detect and respond to a diverse range of ligands or stimuli and are the target
of many drugs. GPCRs that are relevant to itch respond to histamine,
prostaglandins, neuropeptides, and proteases. When a pruritogen activates a
GPCR, this results in a rise of cytosolic calcium levels partly via
voltage-gated sodium channels (NaV) (Kühn et al 2020).
Upon membrane depolarization, voltage-gated sodium channels (NaV) are opened,
triggering the initiation and propagation of action potentials. For their
indispensable role in the generation and propagation of action potentials,
these NaV channels have been suggested as potential drug targets for blunting
sensory perceptions. Case studies revealed that gain-of-function mutations in
NaV channels can cause paroxysmal itch in affected patients (Devigili et al
2014, Faber et al 2012, Salvatierra et al 2018, Woods et al 2015).
M5281 is a dual inhibitor for voltage-gated sodium channel (NaV) 1.7 and
NaV1.8, which was initially developed by RaQualia Pharma Inc. M5281 is
currently being developed as a topical product for treatment of pruritus and
pain.
The current first-in-human study will evaluate the safety/tolerability,
pharmacokinetics and efficacy of M528101 in healthy volunteers and AD patients.
Study objective
This Phase 1, First in Human study is designed to assess the safety and
systemic exposure (pharmacokinetics (PK)) of single dose (Part A,B) and
multiple dose (thrice daily) for 14 days (Part C) topical M528101 Liquid 0.3%
in healthy volunteers (Part A) and subjects with mild to moderate atopic
dermatitis (AD) (Part B, C).
Primary objectives
• To evaluate safety and tolerability of M528101 after topical administration
• To evaluate systemic exposure of M528101 after topical administration and
establish PK profile if possible
Secondary objectives
• To evaluate efficacy of M528101 after topical administration
• To evaluate M5281 metabolites in blood and urine samples
Study design
Design
This is a single-center, randomized, vehicle-controlled, double-blind, Phase 1
study to assess the safety and PK of single dose (Part A,B) and multiple dose
(thrice daily) for 14 days (Part C) topical M528101 in healthy adults (Part A)
and patients with mild to moderate AD (Part B, C)
The study is divided into three parts: part A, B and C. In total nine (9)
healthy male volunteers and twenty-seven (27) male subjects with mild to
moderate AD will be enrolled. The subjects will have total treatable body
surface area (BSA) of 3% to 10%.
Part A will serve to evaluate safety and tolerability of a single dose 0.3%
M528101 or placebo in a cohort of healthy volunteers.
Part B will evaluate safety and tolerability of a single dose of 0.3% M528101
or placebo in a cohort of subjects with atopic dermatitis.
Part C will evaluate safety and tolerability of multiple doses 0.3%M528101or
placebo. In this part, the first 6 subjects will have a maximum treated BSA of
approximately 5%.
Intervention
0.3% M528101
Study burden and risks
The pharmacological and toxicological profile of M528101 observed in
pre-clinical studies suggest that administration to humans in a carefully
monitored study is acceptable. In addition, several non-selective sodium
channel blockers with systemic rout of administration have known
well-established safety profile.
There are no anticipated benefits for subjects participating in the part A of
the study, other than the benefit of medical evaluation at screening and
throughout the study. For participants (AD patients) in part B and C, there
might be relief of itch if M528101 is efficacious. Additionally, the eczema of
subjects will be monitored closely.
The study design has been used previously in first-in-man studies and is
accepted by
scientists and regulatory authorities. All initial study drug administrations
will be done in the clinic under medical supervision. The subjects
participating in part A or B (FIH in healthy volunteers and in AD patients)
receiving study drug for the first time will remain in the clinic for at least
24 hours after study drug administration. Thus, the subjects can be closely
monitored for any adverse event during the different treatments. In addition,
after part A, B and during part C, a blinded safety analysis will be performed.
The responsible person of Maruho Clinical Development Department (and sponsor*s
medical monitor) and the principal investigator or designee will decide in
mutual agreement on the proceeding to part B or Part C or continue of Part C.
Therefore, providing the protocol is adhered to, careful observation and
medical management will minimize any associated risk in this study.
Nakatsu, Kita-ku 1-5-22
Osaka 531-0071
JP
Nakatsu, Kita-ku 1-5-22
Osaka 531-0071
JP
Listed location countries
Age
Inclusion criteria
Part A
Subjects who meet all of the following criteria are eligible to participate in
this study:
1. Healthy male subjects, 18 to 45 years of age, inclusive. Healthy status is
defined by absence of evidence of any active or chronic disease following a
detailed medical and surgical history, a complete physical examination
including vital signs, 12-lead ECG, hematology, blood chemistry, blood serology
and urinalysis;
3. Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum
weight of 50 kg;
3. Subjects must use effective contraception for the duration of the study;
4. Able and willing to give written informed consent and to comply with the
study restrictions;
5. Subject has a negative result of COVID-19 test at Day -1.
Part B and C
1. Male subjects with mild to moderate AD (IGA 2 or 3) 18 to 65 years of age,
inclusive; Healthy status is defined by absence of evidence of any active or
chronic disease except for atopic dermatitis following a detailed medical and
surgical history, a complete physical examination including vital signs,
12-lead ECG, hematology, blood chemistry, blood serology and urinalysis;
2. Diagnosed with AD according to the Hanifin & Rajka criteria;
3. Body mass index (BMI )>=18 kg/m2, with a minimum of 50 kg;
4. Subjects must use effective contraception for the duration of the study;
5. Suitable target lesions defined as eczema lesions of 3- 10% BSA (excluding
the head, face and genitals)
In part C, the first 6 subjects have eczema lesions with 3 to 5% BSA and 3
subjects have 8 to 10% BSA;
6. Subject has a negative result of COVID-19 test at Day -1;
7. Average Pruritus (AP) NRS *3 at Screening and AP NRS*5 at Day1. The AP NRS
score for each visits will be determined by a single AP NRS assessment
(ranging from 0 to 10) of the past 24-hours.
Inclusion Criteria Part C only
8. Average of daily AP NRS*5 at Day 1 The average of daily AP NRS score will be
determined based on the average of Daily AP NRS scores (score ranging from 0 to
10) of the past three days.
Exclusion criteria
Exclusion Criteria part A
1. Any disease associated with immune system impairment, including auto-immune
diseases, allergies, HIV and transplantation patients;
2. History of pathological scar formation (keloid, hypertrophic scar);
3. Excessive sun exposure or a tanning booth within 21 days prior to Day 1;
4. Participation in an investigational drug or device study within 3 months
prior to screening or more than 4 times a year;
5. Loss or donation of blood over 500 mL within three months prior to
screening. Or the donation of plasma within 14 days prior to screening;
6. Current smoker and/or regular user, of other nicotine-containing products
(e.g., patches). Regular users are defined as someone who smokes more than 10
cigarettes per day;
7. History of or current drug or substance abuse considered significant by the
PI (or medically qualified designee), including a positive urine drug screen;
8. Subject has a body temperature of >38.0 °C at screening and/or Day 1;
9. Have known history of atopy;
10. No prescription medications and OTC medications will be permitted within 21
days prior to study drug administrations, or less than 5 half-lives (whichever
is longer, and during the course of the study;
11. Have any current and / or recurrent pathologically, clinically significant
skin condition at the treatment area (i.e. atopic dermatitis).
Exclusion Criteria part B and C
1. Any disease associated with immune system impairment, including auto-immune
diseases, allergies, HIV and transplantation patients;
2. History of pathological scar formation (keloid, hypertrophic scar);
3. Excessive sun exposure or a tanning booth within 21 days prior to Day 1;
4. Participation in an investigational drug or device study within 3 months
prior to screening or more than 4 times a year;
5. Loss or donation of blood over 500 mL within three months prior to
screening. Or the donation of plasma within 14 days prior to screening;
6. Current smoker and/or regular user of other nicotine-containing products
(e.g., patches). Regular users are defined as someone who smokes more than 10
cigarettes per day;
7. History of or current drug or substance abuse considered significant by the
PI (or medically qualified designee), including a positive urine drug screen;
8. Subject has a body temperature of >38.0 °C at screening and/or Day 1;
9. Any topical anti-AD drugs on the lesional sites within 7 days prior to Day
1, for all other systemic anti-AD drugs a washout period of 4 weeks or 5
half-lives (whichever is longer) is required, or planned to use during the
course of the study;
10. Requirement of immunosuppressive or immunomodulatory medication within 28
days or 5 half-lives (whichever is longer) prior to Day 1 or planned to use
during the course of the study;
11. Use of antihistamines within 14 days prior to start of the study (Day 1).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005223-36-NL |
| CCMO | NL76048.056.20 |