| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Primary Objective
To ascertain the efficacy of TMB-001 0.05% topical ointment as a treatment for CI compared with Vehicle during a 12-week treatment.
|
|
| E.2.2 | Secondary objectives of the trial |
• Key Secondary Efficacy Objectives
1. To ascertain the efficacy of TMB-001 0.05% topical ointment at Week 12 using the VIIS-50 scaling score.
2. To ascertain the efficacy of TMB-001 0.05% topical ointment at Week 12 using the IGA-scaling and fissuring scores.
3. To evaluate the effect of TMB-001 0.05% topical ointment on subject Ichthyosis Quality of Life Questionnaire (IQoL-32) at Week 12.
• Other Secondary Efficacy Objective
4. To ascertain the efficacy of TMB-001 0.05% topical ointment at Week 12 using different levels of VIIS-scaling and IGA-scaling and fissuring scores.
5. To determine optimal maintenance therapy with TMB-001 0.05% topical ointment using the IGA-scaling and fissuring scores.
6. To determine optimal maintenance therapy with TMB-001 0.05% topical ointment using VIIS-scaling scores.
• Patient-reported Outcome Measures
• Safety Objective |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional Maximal Use Arm
Adult and pediatric subjects, at a subset of preselected centers, will be enrolled in an open-label Optional Maximal Use arm to evaluate the systemic exposure and safety of topical TMB-001 0.05% ointment for the treatment of CI under maximal use conditions.
Initially, adult CI subjects (≥17 years; n=16) and pediatric subjects (12-16 years; n=7-9) will be dosed for 14 days with TMB-001 0.05% BID. Following an interim pharmacokinetic (PK) analysis and based on the exposure data for subjects aged ≥12 years, pediatric subjects aged 6 to 11 years (n=7-9) will begin dosing with TMB-001 0.05% BID for 14 days. Following the 14-day PK assessment period, subjects will receive TMB-001 0.05% BID treatment for 10 weeks to provide additional safety and limited efficacy data.
• Primary Objective
To determine systemic exposure of isotretinoin and metabolites after single or multiple applications of TMB-001 0.05% ointment in subjects with RXLI or ARCI.
• Exploratory Objective
To compare systemic exposure of isotretinoin and metabolites after single or multiple applications of TMB-001 0.05% ointment cross-trial for PK parameters obtained for oral isotretinoin (single dose 80 mg) in healthy volunteers.
• Safety Objective
To assess local safety and tolerability of TMB-001 0.05% ointment in adult and pediatric subjects for up to 12 weeks. |
|
| E.3 | Principal inclusion criteria |
Subjects must fulfill all of the following inclusion criteria to be eligible for participation:
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. Women of childbearing potential (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 [β-hCG]/mL). Methods of acceptable contraception are further defined in Appendix 4. 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 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 (Appendix 5).
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 body surface area (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.
• 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 Visual Index for Ichthyosis Severity (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. |
|
| E.4 | Principal exclusion criteria |
A subject is ineligible to enter the study if he/she meets 1 or more of the following 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 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 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).
11 of 90
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Comparison of proportions of subjects with ≥2-point changes from Baseline in IGA-scaling and fissuring scores in the Treatment Area at Week 12 between TMB-001 0.05% and vehicle-treated subjects. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Comparison of proportion of subjects who achieve 50% reduction from Baseline in VIIS-scaling scores at Week 12 in all areas with Baseline VIIS score ≥3 between TMB-001 0.05% and vehicle-treated subjects.
2a. Comparison of proportion of subjects with IGA-scaling and fissuring scores of clear or almost clear at Week 12 between TMB-001 0.05% and vehicle-treated subjects.
2b. Assessment of IGA-scaling severity sub-scores from Baseline to Week 12 between TMB-001 0.05% and vehicle-treated subjects.
3. Comparison of proportion of absolute changes from Baseline in IQoL-32 at Week 12 between TMB-001 0.05% and vehicle-treated adult subjects.
• Other Secondary Efficacy Endpoints
4a. Comparison of proportion of subjects who achieve 25% reduction from Baseline in VIIS-scaling scores at Week 12 in all areas with Baseline VIIS score ≥3 between TMB-001 0.05% and vehicle-treated subjects.
4b. Assessment of IGA-fissuring severity sub-scores from Baseline to Week 12 between TMB-001 0.05% and vehicle-treated subjects.
5. Comparison of absolute changes from Baseline in IGA-scaling and fissuring scores at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing.
6a. Comparison of proportion of TMB-001 0.05% BID randomized subjects who experience 25% worsening in VIIS-scaling scores from Week 12 to Week 24 in all areas with Baseline VIIS score ≥3 when compared to TMB-001 0.05% QD randomized subjects.
6b. Comparison of proportion of subjects who achieve 50% reduction from Baseline in VIIS-scaling scores at Week 24 in all areas with Baseline VIIS score ≥3 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing.
6c. Comparison of proportion of subjects who achieve 25% reduction from Baseline in VIIS-scaling scores at Week 24 in all areas with Baseline VIIS score ≥3 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing.
• Patient-reported Outcome Endpoints
7a. Comparison of absolute changes from Baseline in Itch-QoL scores at Week 12 in subjects with Baseline Itch-Numeric Rating Scale (I-NRS) of ≥7 between TMB-001 0.05% and vehicle-treated subjects.
7b. Comparison of proportion of absolute changes from Baseline in Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index (CDLQI) at Week 12 between TMB-001 0.05% and vehicle-treated subjects in adult subjects with Baseline scores ≥11 and pediatric subjects with Baseline scores of >13.
7c. Comparison of proportion of subjects with reduction from Baseline in DLQI or CDLQI ≥4 points at Week 12 between TMB-001 0.05% and vehicle-treated subjects in adult subjects with Baseline scores ≥11 and pediatric subjects with Baseline scores of >13.
7d. Comparison of changes from Baseline in Itch-QoL scores (in subjects with Baseline I-NRS ≥7) at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing.
7e. Changes from Baseline in DLQI or CDLQI at Week 24 in adult subjects with Baseline scores ≥11 and pediatric subjects with baseline scores of >13.
7f. Comparison of changes from Baseline in DLQI or CDLQI at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing in adult subjects with Baseline scores ≥11 and pediatric subjects with Baseline scores of >13.
7g. Changes from Baseline in IQoL-32 at Week 24 in adult subjects.
7h. Comparison of changes from Baseline in IQoL-32 at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing in adult subjects.
• Safety Endpoints
8a. Comparison of proportion of subjects experiencing local skin reactions (LSRs) through Week 12 between TMB-001 0.05% and vehicle-treated subjects.
8b. Comparison of proportion of subjects experiencing treatment-emergent adverse events (TEAEs) through Week 12 between TMB-001 0.05% and vehicle-treated subjects.
8c. Comparison of proportion of subjects experiencing LSRs through Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing.
8d. Comparison of proportion of subjects experiencing TEAEs through Week 24.
9. Comparison of proportion of subjects experiencing allergic contact dermatitis through Week 12 between TMB-001 0.05% and vehicle-treated subjects.
Optional Maximal Use Arm
• Primary Endpoint
Assessment of individual concentrations of isotretinoin, tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin and change from Baseline.
•Exploratory Endpoint
Assessment of individual concentrations of metabolites (isotretinoin, tretinoin and 4-oxo-isotretinoin, 4-oxo-tretinion) and change from Baseline in contemporaneously treated subjects with oral and topical isotretinoin.
• Safety Endpoint
Local safety and tolerability based on dermal irritation scale, physical exam and monitoring of adverse events. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline, Wek 12, Week 24, |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United States |
| Austria |
| France |
| Spain |
| Germany |
| Italy |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
Print
