| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe atopic dermatitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate to severe eczema |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003639 |
| E.1.2 | Term | Atopic dermatitis |
| E.1.2 | System Organ Class | 100000004858 |
|
| 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 |
| To characterize the efficacy of ISB 830 monotherapy in adults with moderate-to-severe AD (AD) compared to placebo as measured by percentage change from baseline in EASI score at Week 16. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate safety, tolerability, pharmacokinetics (PK), and immunogenicity of ISB 830 in adults with moderate-to-severe AD.
To measure the effect of ISB 830 on disease activity in adult subjects with moderate-to-severe AD, as measured by validated tools (such as IGA, EASI response, SCORing Atopic Dermatitis [SCORAD]. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provided written informed consent and any locally required authorization prior to any protocol-related procedures, including screening evaluations.
2. Willing and able to comply with all aspects of the protocol.
3. Male or female ≥18 years at the time of screening.
4. Physician diagnosis of AD for > 1 year; diagnosis of AD as defined by the American Academy of Dermatology Consensus Criteria (Eichenfeld et al, 2014).
5. AD involvement of ≥10% Body surface area (BSA) at screening and baseline.
6. EASI score of ≥12 at screening or ≥16 at baseline.
7. IGA score of ≥3 at screening and baseline (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe).
8. Baseline NRS score for maximum itch intensity ≥3 over the previous 24 hours.
9. Documented/reported recent history (within 6 months before the screening visit) of inadequate response to treatment with topical medications (topical corticosteroids or crisaborole or topical calcineurin inhibitors) or for whom topical treatments are otherwise medically inadvisable (eg, because of important side effects or safety risks as defined in the protocol). Documents may include medical records, physician to healthcare provider communication (with date and time of communication and physician signature), or, pharmacy records (with clearly listed dates of dispensation). A course of marketed systemic immunosuppressants (eg, prednisone, cyclosporine, methrotrexate) for AD in the 6 months prior to screening assumes failure of topicals and is acceptable in place of topical failure.
10. Have applied a stable dose of topical emollient (moisturizer) twice-daily for at least 7 consecutive days immediately before the baseline visit (with the exception of prohibited moisturizers containing additives listed in Exclusion Criteria #5).
11. Must agree to the following requirements during the study:
a. If female and of childbearing potential, she must have a negative serum pregnancy test result within 7 days prior to first dosing and a negative urine pregnancy test predose on Day 1. She must be willing to use a highly effective form of contraception (ICH E8 Guideline, 1997; (ICH M3 [R2] Guidance, 2009; (FDA M3 [R2] Guidance, 2010) for the duration of the study and for at least 3 months after the last dose of study medication. Methods like periodic abstinence, post ovulation procedures and withdrawal are not considered adequate. Each woman will be considered to have childbearing potential unless she has been surgically sterilized by hysterectomy or bilateral tubal ligation/salpingectomy or has been post-menopausal for at least 2 years. For postmenopausal women only, follicle stimulating hormone (FSH) testing will be performed at screening to confirm non-childbearing potential (FSH ≥40 IU/L).
b. If male with a partner of childbearing potential, he must be willing to use condoms in combination with a second effective method of contraception during the study. Each man will be considered as potent unless surgically sterilized (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate). Male subjects must continue to use contraception for 180 days following administration of the study drug.
c. Male subjects should agree not to donate sperm during the study and for 180 days following administration of the study drug.
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|
| E.4 | Principal exclusion criteria |
1. Prior treatment with ISB 830.
2. Employee of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals.
3. Concurrent enrollment in another investigational clinical study.
4. Treatment with any of the following before baseline:
a. Investigational biological agent within 8 weeks of baseline or 5 half-lives, whichever is longer.
b. Investigational drugs eg, phosphodiesterase type 4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, within 4 weeks of baseline.
c. Phototherapy for AD within 4 weeks of baseline.
d. Marketed drugs, including systemic corticosteroids, immunosuppressive/immunomodulatory drugs including but not limited to cyclosporine, mycophenolate-mofetil, interferon-gamma (IFN-γ), PDE4 inhibitors, JAK inhibitors, azathioprine or methotrexate within 4 weeks of baseline.
e. Topical medications, including corticosteroids, tacrolimus, and/or pimecrolimus, and crisaborole within 1 week of baseline.
f.Regular use (>2 visits/week) of a tanning booth/parlor within 4 weeks of baseline.
g. Biologics, depending on the type of biologic such as cell-depleting agents including but not limited to rituximab: within 6 months of baseline, or until lymphocyte and CD19+ lymphocyte count returns to normal, whichever is longer.
h. Biologics including infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, anakinra, dupilumab: within 12 weeks of baseline, or 5 half-lives, whichever is longer.
i.Other biologics: within 5 half-lives (if known).
5. Initiation of treatment of AD with prescription moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products during the screening period (subjects may continue using stable doses of such moisturizers if initiated before the screening visit).
6. Planned or anticipated use of any prohibited medications and procedures during study treatment as defined in the study protocol.
7. Subjects who are immunocompromised (congenital or acquired), or who have had a recent (within 3 months prior to baseline) or current serious systemic infection (including infectious mononucleosis-like illness or herpes zoster).
8. Treatment with a live (attenuated) vaccine within 12 weeks before the baseline visit.
9. Subjects who have evidence of active or latent tuberculosis (TB) as documented in their medical history or test positive at screening. For indeterminate cases, an informed decision will be made between the Principal Investigator and Medical Monitor.
10. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline visit, or superficial skin infections within 1 week before the baseline visit. NOTE: subjects may be rescreened after infection resolves.
11. Presence of skin comorbidities that may interfere with study assessments, in the opinion of the Investigator, including subjects with psoriasis.
12. Poorly controlled asthma as assessed by the Asthma Control Questionnaire [ACQ] based on International ERS/ATS guidelines.
13. Any condition at baseline which is part of the criteria for discontinuation of study drug as defined in the study protocol.
14. Subjects who are known to be seropositive for human immunodeficiency virus (HIV) or who test positive at screening.
15. History of a positive result for Hepatitis B surface antigen (HBsAg), antibody to Hepatitis B core antigen (anti-HBcAg), or antibody to Hepatitis C virus (anti-HCV) or presence of and of these findings at screening.
16. History of alcohol or drug abuse within 2 years of the screening visit.
17. Subjects with a history of non-malignant lymphoproliferative disorders, or a history of malignancy within 5 years before baseline (except completely treated in situ cervical carcinoma or non-metastatic squamous or basal cell carcinoma of the skin).
18. In the opinion of the Investigator, subjects with any other medical or psychological condition as well as laboratory values, which are significantly different from normal reference ranges and/or judged to be clinically significant; and/or any condition that would interfere with evaluation of the study drug or interpretation of subject safety or study results, including conditions that are inadequately understood at the time of screening.
19. Subjects with a history of substance abuse or dependence that in the opinion of the Investigator, is considered to interfere with the subject’s participation in the study.
20. Planned or anticipated major surgical procedure during the subject’s participation in this study.
21. Women who are pregnant or breast feeding.
22. Known hypersensitivity to monoclonal antibodies or any of the
excipients of the drug product.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage change from baseline in EASI score from baseline at Week 16. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Proportion of subjects with EASI-75 (≥75% improvement from baseline) at Week 16.
• Proportion of subjects with both IGA 0 or 1 (on a 5-point scale) and an IGA reduction from baseline >2 points at Week 16.
• Proportion of subjects with improvement (reduction) of pruritus
Numerical Rating Scale (pruritus Numerical Rating Scale (NRS) ≥4 from
baseline to Week 16.
• Proportion of subjects who achieve an EASI 50 (≥50% improvement from baseline) response from baseline through Week 16.
• Change in SCORAD from baseline through Week 16 .
• Change in the Dermatology Life Quality Index (DLQI) from baseline through Week 16.
• Change in Global Individual Signs Score (GISS) (erythema, infiltration/population, excoriations, lichenification) from baseline through Week 16.
• Change in Hospital Anxiety Depression Scale (HADS) from baseline through Week 16.
• Change in Patient Oriented Eczema Measure (POEM) from baseline through Week 16.
• Absolute and percent change in Patient Global Assessment of Disease from baseline through Week 16.
• Absolute and percent change in Patient Global Assessment of Treatment from baseline through Week 16.
• Assessment of sick leave and/or missed school days through Week 16.
Safety Endpoints:
• Incidence of TEAEs from baseline through Week 16 and Week 54.
• Incidence of skin infection TEAEs requiring systemic treatment from baseline through Week 16 and Week 54.
• Incidence of conjunctivitis TEAEs requiring systemic treatment from baseline through Week 16 and Week 54.
Incidence of treatment-emergent SAEs from baseline through Week 16 and Week 54.
• Incidence of TEAEs leading to treatment discontinuation from baseline through Week 16 and Week 54.
• Overall number of TEAEs and SAEs through Week 16 and Week 54.
• Vital signs, clinical laboratory values, and ECG results monitored from baseline through Week 16 and Week 54.
• Formation of ADA to GBR 830 to evaluate immunogenicity.
Pharmacokinetics Endpoints:
• Cmax, tmax, AUC0-tau, AUC from time 0 to the last measurable concentration (AUC0-t), and other related parameters will be estimated using data from the rich PK group. from the blinded treatment phase. Ctrough values will be estimated using data from both rich and sparse PK groups from the blinded treatment phase.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 1, Week 16 (Day 113)
Safety: Day 1, Week 16 (Day 113) and Week 54 (Day 379) |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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 | 6 |
| 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 | 22 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 |
| Bulgaria |
| Canada |
| Czech Republic |
| Germany |
| Hungary |
| Latvia |
| Lithuania |
| Poland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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