Keloid
Conditions
Keywords
Keloid, MicroRNAs, Wound healing
Brief summary
Remlarsen (MRG-201) is designed to mimic the activity of a molecule called miR-29 that decreases the expression of collagen and other proteins that are involved in scar formation. Remlarsen is being studied to determine if it can limit the formation of fibrous scar tissue in certain diseases. The objectives of this study are to investigate the safety and tolerability of remlarsen in subjects with a history of keloid scars, and to investigate the activity of remlarsen in prevention or reduction of keloid formation. Another objective is to study the pharmacokinetics of remlarsen (the movement of a drug into, through and out of the body). A group of 12-16 study volunteers will undergo two small skin biopsies in the upper back/shoulder region that will be closed with sutures. One biopsy site will be injected with up to 6 doses of remlarsen over a period of 2 weeks and the second site will be injected similarly with a placebo solution. Participants will be monitored for keloid formation at the two biopsy sites, for signs or symptoms of adverse effects on the body, and for the levels of remlarsen in the blood over time. A second 2-week cycle of treatment may be administered if there are signs that a keloid may be forming at one or both biopsy sites. Subjects will be followed for about 1 year following their final course of treatment to assess the long-term safety of remlarsen and the potential for later appearance of a keloid scar. Additional groups of subjects may be enrolled to test lower doses of remlarsen or an extended dosing schedule.
Interventions
DRUGRemlarsen
Intradermal injection at site of one excisional wound
DRUGPlacebo
Intradermal injection at site of second excisional wound
Sponsors
miRagen Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
The treatment administered to each of two wound sites will be randomized (left versus right), such that all subjects will receive both remlarsen and placebo in a double-blinded fashion.
Intervention model description
Up to 6 cohorts of 12-16 subjects each may be enrolled to study various dose levels and dosing regimens.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must provide written informed consent. * Females must not be pregnant, or lactating, and have negative pregnancy tests. * Study candidates should be likely to form keloids in the upper back/shoulder area after punch biopsy based on a history of a high frequency of keloid formation (≥ 10 keloids) or a history of large keloids (≥ 4 cm). * Subjects should not anticipate requiring systemic corticosteroids during the study. * Must have area in upper back/shoulder region free of keloids, acne, striae, or other skin pathologies or complications. * Female subjects of childbearing potential or male subjects engaged in sexual relations with a female of childbearing potential must be willing to use a highly effective method of contraception throughout their study participation and for at least 6 months after the last dose of study drug. Key
Exclusion criteria
* Clinically significant abnormalities in medical history or physical exam that, in the opinion of the Investigator, would make the subject unsuitable for inclusion in the study. * History of genetic disorders that predispose to keloids (e.g. Ehlers-Danlos syndrome, Ullrich congenital muscular dystrophy, etc.). * History of renal or liver dysfunction or evidence of renal or liver dysfunction at screening. * Evidence of clinically significant anemia, neutropenia, or thrombocytopenia at screening. * History of bleeding diathesis or coagulopathy. * Active or uncontrolled infection at screening or baseline. * Recent history of alcoholism, drug abuse or illicit drugs (within the last year), and agreement to refrain from using illicit drugs throughout the study. * Positive for bloodborne pathogen (HBV, HCV, HIV) at screening. * Prior malignancies within the past 3 years (allowing squamous cell and basal cell carcinomas that have been successfully treated). * Use of systemic steroids within 4 weeks of the Baseline visit or local use of steroids within 1 week of the Baseline visit. * Use of an investigational small molecule drug within 30 days of the baseline visit or use of an investigational oligonucleotide or biologic drug within 90 days of the baseline visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Confirmed Keloid Formation at Treated vs. Untreated Lesions at 24 Weeks | 24 weeks (± 7 days) from first dose | The percentage of subjects with confirmed keloid formation at treated versus untreated lesions at 24 weeks (± 7 days) after first dose, analyzed using the modified Vancouver Scar Scale which reports a cumulative score based on subscores for vascularity, pliability and height. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Confirmed Keloid Formation at Treated vs. Untreated Lesions at 52 Weeks | 52 weeks (± 7 days) from first dose | The percentage of subjects with confirmed keloid formation at treated versus untreated lesions at 52 weeks (± 7 days) after first dose, analyzed using the modified Vancouver Scar Scale which reports a cumulative score based on subscores for vascularity, pliability and height. |
| Time to Keloid Formation | First dose to 365 days | Time to first confirmed keloid formation |
| Volume of Keloid at 24 Weeks | 24 weeks from first dose | — |
| Volume of Keloid at 52 Weeks | 52 weeks from first dose | — |
| Percentage of Subjects With Improvement, Defined as no Confirmed Keloid Formation in the Treated Lesion vs. Confirmed Keloid Formation in the Untreated Lesion. | 24 weeks (± 7 days) from first dose | Percentage of subjects with improvement at 24 weeks (± 7 days), defined as no confirmed keloid formation in the treated lesion vs. confirmed keloid formation in the untreated lesion, based on assessment using the modified Vancouver Scar Scale which reports a cumulative score based on subscores for vascularity, pliability and height. |
| Peak Plasma Concentration (Cmax) of Remlarsen - Single Dose | First dose to 24 hours post-dose | Peak plasma concentration (Cmax) of remlarsen + active metabolites (total active drug) after first dose |
| Area Under the Plasma Concentration vs. Time Curve (AUC) of Remlarsen - Multi-dose | First dose to up to 13 days post-dose | Area under the curve (AUClast) for remlarsen + active metabolites (total active drug) after multiple doses |
| Peak Plasma Concentration (Cmax) of Remlarsen - Multi-dose | Dosing on Day 10 or Day 12 through 24 hours post-dose | Peak plasma concentration (Cmax) of remlarsen + active metabolites (total active drug) after multiple doses |
| Area Under the Plasma Concentration vs. Time Curve (AUC) of Remlarsen - Single Dose | First dose to 24 hours post-dose | Area under the curve (AUClast) for remlarsen + active metabolites (total active drug) after a single dose |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at four medical centers
Participants by arm
| Arm | Count |
|---|---|
| Remlarsen-Treated Excisional Skin Wound and Placebo-Treated Excisional Skin Wound Six doses remlarsen (5.3 mg) over a period of 2 weeks at the site of one excisional skin wound and six doses Placebo over the same period at the site of a second excisional skin wound. Each subject served as their own simultaneous control. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
Baseline characteristics
| Characteristic | Remlarsen-Treated Excisional Skin Wound and Placebo-Treated Excisional Skin Wound |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height of largest pre-existing keloid | 2.96 millimeters STANDARD_DEVIATION 3.96 |
| Length of largest pre-existing keloid | 89.9 millimeters STANDARD_DEVIATION 83.6 |
| Number of pre-existing keloids at screening | 10.7 millimeters STANDARD_DEVIATION 5.44 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 5 Participants |
| Volume of largest pre-existing keloid | 10,366 millimeters cubed |
| Width of largest pre-existing keloid | 26.0 millimeters STANDARD_DEVIATION 35 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 12 / 14 | 6 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
Percentage of Subjects With Confirmed Keloid Formation at Treated vs. Untreated Lesions at 24 Weeks
The percentage of subjects with confirmed keloid formation at treated versus untreated lesions at 24 weeks (± 7 days) after first dose, analyzed using the modified Vancouver Scar Scale which reports a cumulative score based on subscores for vascularity, pliability and height.
Time frame: 24 weeks (± 7 days) from first dose
Population: All subjects for whom an assessment of keloid formation using the modified Vancouver Scar Scale was performed at 24 weeks (± 7 days). Subjects who did not have keloid assessments within this time window were not included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Percentage of Subjects With Confirmed Keloid Formation at Treated vs. Untreated Lesions at 24 Weeks | 92.9 percentage of participants |
| Placebo-Treated Excisional Skin Wound | Percentage of Subjects With Confirmed Keloid Formation at Treated vs. Untreated Lesions at 24 Weeks | 85.7 percentage of participants |
Other Pre-specified
Area Under the Plasma Concentration vs. Time Curve (AUC) of Remlarsen - Multi-dose
Area under the curve (AUClast) for remlarsen + active metabolites (total active drug) after multiple doses
Time frame: First dose to up to 13 days post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Area Under the Plasma Concentration vs. Time Curve (AUC) of Remlarsen - Multi-dose | 1200 ng*hr/mL | Standard Deviation 383 |
Other Pre-specified
Area Under the Plasma Concentration vs. Time Curve (AUC) of Remlarsen - Single Dose
Area under the curve (AUClast) for remlarsen + active metabolites (total active drug) after a single dose
Time frame: First dose to 24 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Area Under the Plasma Concentration vs. Time Curve (AUC) of Remlarsen - Single Dose | 461 ng*hr/mL | Standard Deviation 359 |
Other Pre-specified
Peak Plasma Concentration (Cmax) of Remlarsen - Multi-dose
Peak plasma concentration (Cmax) of remlarsen + active metabolites (total active drug) after multiple doses
Time frame: Dosing on Day 10 or Day 12 through 24 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Peak Plasma Concentration (Cmax) of Remlarsen - Multi-dose | 75.5 ng/mL | Standard Deviation 23.7 |
Other Pre-specified
Peak Plasma Concentration (Cmax) of Remlarsen - Single Dose
Peak plasma concentration (Cmax) of remlarsen + active metabolites (total active drug) after first dose
Time frame: First dose to 24 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Peak Plasma Concentration (Cmax) of Remlarsen - Single Dose | 29.3 ng/mL | Standard Deviation 20.6 |
Other Pre-specified
Percentage of Subjects With Confirmed Keloid Formation at Treated vs. Untreated Lesions at 52 Weeks
The percentage of subjects with confirmed keloid formation at treated versus untreated lesions at 52 weeks (± 7 days) after first dose, analyzed using the modified Vancouver Scar Scale which reports a cumulative score based on subscores for vascularity, pliability and height.
Time frame: 52 weeks (± 7 days) from first dose
Population: All subjects for whom an assessment of keloid formation using the modified Vancouver Scar Scale was performed at 52 weeks (± 7 days). Subjects who did not have keloid assessments within this time window were not included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Percentage of Subjects With Confirmed Keloid Formation at Treated vs. Untreated Lesions at 52 Weeks | 100 percentage of participants |
| Placebo-Treated Excisional Skin Wound | Percentage of Subjects With Confirmed Keloid Formation at Treated vs. Untreated Lesions at 52 Weeks | 66.7 percentage of participants |
Other Pre-specified
Percentage of Subjects With Improvement, Defined as no Confirmed Keloid Formation in the Treated Lesion vs. Confirmed Keloid Formation in the Untreated Lesion.
Percentage of subjects with improvement at 24 weeks (± 7 days), defined as no confirmed keloid formation in the treated lesion vs. confirmed keloid formation in the untreated lesion, based on assessment using the modified Vancouver Scar Scale which reports a cumulative score based on subscores for vascularity, pliability and height.
Time frame: 24 weeks (± 7 days) from first dose
Population: Subjects for whom an analysis of improvement, defined as no confirmed keloid formation in the treated lesion vs. confirmed keloid formation in the untreated lesion based on assessment using the modified Vancouver Scar Scale, was performed at 24 weeks (± 7 days). Subjects who did not have an analysis of improvement, as defined, were not included in this outcome measure.
Other Pre-specified
Time to Keloid Formation
Time to first confirmed keloid formation
Time frame: First dose to 365 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Time to Keloid Formation | 58 days |
| Placebo-Treated Excisional Skin Wound | Time to Keloid Formation | 55 days |
Other Pre-specified
Volume of Keloid at 24 Weeks
Time frame: 24 weeks from first dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Volume of Keloid at 24 Weeks | 65 millimeters cubed | Standard Deviation 58 |
| Placebo-Treated Excisional Skin Wound | Volume of Keloid at 24 Weeks | 79 millimeters cubed | Standard Deviation 55 |
Other Pre-specified
Volume of Keloid at 52 Weeks
Time frame: 52 weeks from first dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Remlarsen-Treated Excisional Skin Wound | Volume of Keloid at 52 Weeks | 194 millimeters cubed | Standard Deviation 142 |
| Placebo-Treated Excisional Skin Wound | Volume of Keloid at 52 Weeks | 156 millimeters cubed | Standard Deviation 176 |