The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis

Ichthyosis Clinical Trial

— ASCEND  

Official title:

The ASCEND Study: A Phase III, Multicenter, Double Blinded Vehicle Controlled Study of TMB-001 With a Parallel Optional Maximal Use Arm- in Treatment of RXLI or ARCI Ichthyosis in Subjects Aged >6

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05295732
• Other study ID #: TMB01-301
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 21, 2022
• Est. completion date: November 2024

Study information

• Verified date: March 2024
• Source: Timber Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, double-blind and vehicle-controlled Phase III study to evaluate the safety and efficacy of topical TMB-001 0.05% ointment for the treatment of CI in subjects with either the RXLI or ARCI subtypes.

In addition, a subset of preselected centers will recruit subjects in parallel with either the RXLI or ARCI subtypes for enrollment into an Optional Maximal Use arm for evaluation of the systemic exposure and safety of topical TMB-001 0.05% ointment for the treatment of CI.

The Phase III Study is designed in three periods:

• Period 1 - Induction (3 weeks): At the beginning of the 3-week Induction Period, eligible subjects will be randomized (2:1 ratio) to either TMB-001 0.05% once-a-day (QD) or Vehicle QD treatment, with use of mandatory standardized bland emollient (Cetaphil™) provided by the Sponsor.

• Period 2 - Treatment (9 weeks): The dosing frequency in the 9-week treatment period will be increased in each treatment group to TMB-001 0.05% BID or Vehicle BID. Mandatory bland emollient will be discontinued.

• Period 3 - Maintenance (12 weeks): At Week 12, eligible subjects in the TMB-001 treatment group will be randomized (1:1 ratio) to an open-label treatment with TMB-001 0.05% BID or TMB-001 0.05% QD. To be eligible, subjects must have achieved a ≥1-point reduction in IGA score from Baseline. Subjects with less than a 1-point reduction in IGA score from Baseline will be discontinued from the study.

Vehicle-treated subjects who achieved <1-point reduction in IGA score from Baseline are eligible to cross over to the TMB-001 0.05% BID treatment group. Subjects with a ≥1-point reduction in IGA score from Baseline will be discontinued from the study.

Subjects at the end of the study or subjects discontinued from the study at any time will be followed-up for additional 2 weeks for AEs.

Description:

This is a multicenter, randomized, double-blind, vehicle-controlled Phase III study to evaluate the efficacy and safety of TMB-001 0.05% topical ointment in the treatment of CI. Subjects will be selected according to predefined entry criteria. The study treatment duration is 24 weeks and expected to be sufficient to show a treatment effect.

Isotretinoin is an approved active pharmacological ingredient with a long history of safe use in humans. However, isotretinoin is a known teratogen with an extremely high risk for severe birth defects if pregnancy occur while taking oral isotretinoin in any amount, even for a short period of time. Therefore oral, systemic isotretinoin requires an iPLEDGE program (iPLEDGE 2012), which is a risk management distribution program mandated by the FDA. To minimize pregnancy risks, WOCBP will only be enrolled if they agree to use highly effective methods of contraception consistently and correctly as described in Table 17 and undergo regular pregnancy testing .

To minimize bias, subjects will be blinded and randomly assigned to treatment with TMB-001 0.05% or Vehicle, additionally subjects who had previously been treated with TMB 001 will be excluded from this study but can be enrolled in the optional Maximal Use arm (in a subset of preselected centers). The use of a vehicle control group is consistent with FDA's standard for generating valid scientific evidence to definitively support safety and efficacy. The vehicle group accounts for the effects of treatment that do not depend on the test treatment. The study is designed to mitigate safety risks by using an initial 2:1 randomization (active treatment to vehicle), along with frequent clinic visits over the 12-week treatment period. The subsequent 1:1 randomization of eligible TMB-001 0.05% treated subjects to two dosing regimen (QD or BID) allows for assessment of the optimal TMB-001 0.05% maintenance therapy as well as provides additional safety data for 12 weeks. The cross-over of eligible subjects from the vehicle control group will also provide additional safety data.

Overall, the study design is considered to be scientifically robust and clinically relevant for evaluating TMB-001 0.05% treatment for the safe and effective treatment of CI.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 209
• Est. completion date: November 2024
• Est. primary completion date: September 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

Inclusion Criteria:

1. Subject is male or female, 6 years of age and older at Visit 2 (Baseline).

2. Subject has provided written informed consent/assent. A subject under 18 years of age must provide written informed assent and be accompanied by the parent or legal guardian at the time of consent/assent signing. The parent or legal guardian must provide informed consent for the subject. If a subject becomes 18 years of age during the study, the subject must provide written informed consent at that time to continue study participation.

3. Females must be postmenopausal (defined as amenorrhea greater than 12 consecutive months in women 50 years of age and older), surgically sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), or use 2 acceptable forms of birth control. WOCBP must have a negative serum pregnancy test at screening and negative urine pregnancy test (UPT) at Visit 2 (Baseline) (UPTs must have a minimum sensitivity to detect 25 mIU beta human chorionic gonadotropin [ß hCG]/mL). Female subjects who become sexually active or begin to have relations with a partner during the study must agree to use 2 forms of birth control for 30 days prior to having relations and to continue such forms of birth control for the duration of the study.

4. Subject has clinical diagnosis of CI and has a genetic confirmation of either ARCI (including but not exclusively transglutaminase 1-deficient, ALOX-12B) or RXLI (e.g., deletion of steroid sulfatase gene) subtypes of CI. Other genetically confirmed ARCI-LI mutations can potentially be enrolled as long as the phenotype is consistent with ARCI and the other inclusion criteria are met, as determined by the Investigator

5. The amount of CI affected skin in the Treatment Area at Baseline will be between a minimum of 10% and maximum of 90% of the total BSA (1% BSA is approximately equal to the surface area of the subject's palm and fingers, with the fingers extended yet grouped together, creating a flat oval-like surface area).

• For the Optional Maximal Use arm: The amount of CI affected skin in the Treatment Area at Baseline will be between a minimum of 75% and maximum of 90% of the total BSA.

6. Documented history of moderate to severe disease at Screening. Subject's designated VIIS Assessment Areas at Baseline (not applicable for Optional Maximal Use arm) MUST:

• Include any of the 4 VIIS Assessment Areas that have some CI disease involving:

(a) the upper back from the posterior axillary fold to the other encompassing the T1-T10, (b) the upper arm (excluding elbows), left or right, (c) the shin/lower leg (the portion below the proximal aspect of the kneecap), left or right, and (d) dorsal foot (left or right); AND

• At least 2 of the 4 VIIS Assessment Areas MUST have a scaling score of 3 or more.

7. Subject's IGA score in the Treatment Area at Baseline must be 3 or more.

8. Subject and parent/guardian (if applicable) are willing and able to apply the study treatment(s) as directed, comply with study instructions, and commit to all follow-up visits for the duration of the study.

9. Subject, in the Investigator's opinion, is in good general health and free of any disease state or physical condition that might impair evaluation of the Treatment Areas or exposes the subject to an unacceptable risk by study participation.

Exclusion Criteria:

1. Subject is pregnant, lactating, or is planning to become pregnant during the study.

2. Subject has inflammatory skin diseases that confound the interpretation of results (e.g., atopic dermatitis) unrelated to ichthyosis.

3. Subject has genetic abnormality consistent with non-lamellar type or syndromic ichthyoses (including but not exclusively KRT1, KRT10, KRT2, GJB3, GJB4, CDSN)

4. Subject has previously failed on topical/oral retinoid therapy for treatment of CI, defined as documented intolerance and or lack of clinical efficacy as determined by the subject.

5. Subject, in the Treatment Areas, has used: (a) any topical prescription or over-the-counter (OTC) therapies (except emollients, keratolytics, and topical steroids - see below), that are intended for, or that in the opinion of the Investigator, may improve CI within 2 weeks of Visit 2 (Baseline), or (b) keratolytics or topical corticosteroids within 5 days prior to Visit 2 (Baseline).

6. Subject, in the Treatment Areas, has used TMB-001 in the past or oral isotretinoin in the past 12 months (not applicable for Optional Maximal Use arm).

7. Subject has used any topical products in the Treatment Areas, including bland emollients, on Visit 2 (Baseline).

8. Subject has used ultraviolet (UV) treatment within 4 weeks prior to Visit 2 (Baseline).

9. Subject has undergone systemic therapies using vitamin A supplements or St. John's Wort within 4 weeks prior to Visit 2 (Baseline). Note: Use of a multivitamin including vitamin A is not exclusionary provided it is taken as directed on the packaging.

10. Subject is immunosuppressed (e.g., human immunodeficiency virus, systemic malignancy, graft host disease) or receives systemic immunotherapy.

11. Subject is currently taking concomitant immunosuppressive drugs, including systemic corticosteroids, within 2 weeks of Visit 2 (Baseline).

12. Subject has untreated secondary infections; however, subject may become eligible after successful treatment of his/her infection(s) at the Investigator's discretion.

13. Subject is currently enrolled in an investigational drug or device study or has used an investigational drug or investigational device treatment within 30 days or five half-lives prior to Visit 2 (Baseline).

14. Subject has lesions suspicious for skin cancer (if skin cancer is not ruled out by biopsy) or untreated skin cancers within the Treatment Areas.

15. Subject has a physical condition or other dermatologic disorder that, in the Investigator's opinion, might impair evaluation of CI, or that exposes the subject to unacceptable risk by study participation.

16. Subjects with ALT or AST >2 x Upper Limit of Normal (ULN) and/or creatinine >1.5 x ULN.

17. Subject is unable to communicate or cooperate with the Investigator due to language problems, impaired cerebral function, or physical limitations.

18. Subject has a history of drug or alcohol abuse within the past 6 months, or if suspected to be noncompliant or is unlikely to comply with the requirements of the study protocol (e.g., due to alcoholism, drug dependency, mental incapacity) in the opinion of the Investigator.

19. Subject has a history of sensitivity to any of the ingredients in the study treatments.

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Related Conditions & MeSH terms

• Ichthyosis
• Ichthyosis, Lamellar

Intervention

Drug:
• TMB-001
Topical TMB-001 0.05% QD/BID
• Matching Vehicle
Topical Vehicle

Locations

Country	Name	City	State
Canada	Stollery children's hospital	Edmonton	Alberta
Canada	Dr. Chih-ho Hong Medical Inc.	Surrey	British Columbia
Canada	Sickkids Hospital, Toronto, Canada	Toronto	Ontario
Canada	Wiseman Dermatology Research Inc.	Winnipeg	Manitoba
France	Hôpital Femme Mère Enfant	Bron
France	CHU de Nantes Hotel Dieu	Nantes
France	Hopital Necker APHP	Paris
France	Hopital Larrey CHU Toulouse	Toulouse
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Katholisches Kinderkrankenhaus Wilhelmstift GmbH	Hamburg
Germany	Münster University Hospital	Münster
Italy	U.O. di Dermatologia e Venereologia Universitaria	Bari
Italy	Ambulatorio Malattie Rare IRCCS Sant'Orsola	Bologna
Italy	Ambulatorio di Malattie Rare Dermatologiche e Immunopatologia Cutanea	Firenze
Italy	U.O.C. di Dermatologia Dipartimento Pediatrico Universitario Ospedaliero	Roma
United States	The Indiana Clinical Trials Center (Optima Research)	Boardman	Ohio
United States	About Skin Dermatology	Centennial	Colorado
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University - Feinberg School of Medicine - Dermatology Department	Chicago	Illinois
United States	Austin Institute for Clinical Research	Houston	Texas
United States	Dawes Fretzin Clinical Research Group, LLC	Indianapolis	Indiana
United States	University of Miami, Dermatology Clinical Trial Unit	Miami	Florida
United States	Yale Dermatology	Middlebury	Connecticut
United States	North Sound Dermatology	Mill Creek	Washington
United States	Steven Kempers	New Brighton	Minnesota
United States	Pariser Dermatology Specialists	Norfolk	Virginia
United States	Stanford Children's Health	Palo Alto	California
United States	Austin Institute for Clinical Research, Inc.	Pflugerville	Texas
United States	Children's Hospital of Philadelphia (CHOP)	Philadelphia	Pennsylvania
United States	Medical Dermatology Specialists (US Derm Partners)	Phoenix	Arizona
United States	The Indiana Clinical Trials Center (Optima Research)	Plainfield	Indiana
United States	University of Mississippi Medical Center (UMMC) - Face and Skin Center	Ridgeland	Mississippi
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Timber Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Investigator global assessment (IGA) score	Comparison of proportions of subjects with =2-point changes from Baseline in Investigator Global Assessment (IGA)-scaling and fissuring scores in the Treatment Area at Week 12 between TMB-001 0.05% and vehicle-treated subjects on a 0-4 scale where 0 is clear and 4 is severe.	12 weeks
Secondary	Change in Visual Index of Ichthyosis Severity score	Comparison of proportion of subjects who achieve 50% reduction from Baseline in Visual Index of Ichthyosis Severity (VIIS)-scaling scores at Week 12 in all areas with Baseline VIIS score =3 between TMB-001 0.05% and vehicle-treated subjects on a 0-4 scale where 0 is clear and 4 is severe.	12 weeks
Secondary	To investigate the proportion of subjects experiencing local skin reactions with topically applied TMB-001 0.05% ointment.	Comparison of proportion of subjects experiencing LSRs through Week 12 between TMB-001 0.05% and vehicle-treated subjects.	12 weeks