A Randomized Controlled Study to Evaluate the Efficacy and Safety of Dupilumab in Combination With Short-term Low-dose Tofacitinib in Adult Patients With Moderate to Severe Atopic Dermatitis
Overview
- Phase
- Phase 4
- Intervention
- Dupilumab
- Conditions
- Atopic Dermatitis
- Sponsor
- Second Affiliated Hospital, School of Medicine, Zhejiang University
- Enrollment
- 220
- Primary Endpoint
- Percentage of participants with a ≥75% reduction from baseline in Eczema Area and Severity Index (EASI) score (EASI-75) at 16 weeks
- Status
- Not yet recruiting
- Last Updated
- last year
Overview
Brief Summary
Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by intense pruritus and sleep disturbances. The clinical manifestations of AD are varied, with the most basic features being dry skin, chronic eczema-like dermatitis, and intense pruritus. The prevalence in children and adults is about 30% and 10%, respectively. Most patients respond well to topical anti-inflammatory drugs, but approximately 10 percent of patients with moderate-to-severe AD require one or more systemic therapies to achieve good disease control. Although nonspecific immunosuppressive drugs (including glucocorticoids, cyclosporine A, methotrexate, azathioprine, or mycophenolate mofetil) are effective in alleviating or controlling these disorders to some extent, their overall efficacy in patients is limited and associated with significant side effects with long-term use.
The main hallmarks of systemic type II inflammation are eosinophilia and elevated serum immunoglobulin E (IgE) levels. Type II inflammatory response is not only associated with allergic reactions, but is also a driver of such diseases. The release of cytokines (interleukins 4, 5, and 13) in the response to type II inflammation can trigger a lymphocyte-mediated type II inflammatory response, inducing the onset and progression of allergic diseases. Reducing the inflammatory response by inhibiting the above-mentioned inflammatory factors is a potential therapeutic means for the treatment of allergic diseases represented by AD.
Investigational drug Dupilumab injection, an interleukin-4 receptor α (IL-4Rα) antagonist, is a human monoclonal antibody that binds IL-4Rα and inhibits IL-4 and IL-13 signaling. With a molecular weight of about 147 kDa, it inhibits the signaling of interleukin 4 and interleukin 13 and blocks its signaling pathway through the atopic binding of the interleukin 4Ra subunit shared with the interleukin 4 and interleukin 13 receptor complex, and blocks their signaling pathways, which can achieve continuous, efficient and safe improvement of skin lesions, itching and other symptoms and alleviate the condition.
Tofacitinib is a Janus kinase (JAK) inhibitor. JAK is an intracellular enzyme that conducts signals generated by cytokine or growth factor-receptor interactions on cell membranes, thereby affecting cell hematopoiesis and cellular immune function.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have the ability to understand the content of the research and voluntarily sign the ICF.
- •18 years old≤ age ≤ 60 years old (calculated from the date of signing the ICF), male or female.
- •The diagnosis of AD at screening meets the consensus criteria for dermatology in the United States (2014) (see Appendix), and the disease has been in condition for ≥ half a year before screening, and all of the following conditions are met at screening and randomization:
- •A. EASI score ≥ 12 points at screening and randomization; B. IGA score ≥ 3 points at screening and randomization (0-4 points IGA scale, 3 points are moderate, 4 points are severe); C. AD involvement of BSA ≥10% at screening and randomization; D. Weekly average of daily peak pruritus NRS score at randomization ≥ 4 points.
- •Subjects of childbearing potential and their partners agree to use effective contraceptive measures throughout the study period (from signing the ICF to 3 months after the last study drug administration) .
- •Able to communicate well with the investigator and comply with the follow-up requirements of the protocol.
Exclusion Criteria
- •Subjects with any of the following cannot be enrolled in this study:
- •Allergy to any ingredient in dupilumab or tofacitinib, or allergy or intolerance to other oral JAK inhibitors.
- •Use of any of the following medications or treatments:
- •Received treatment with other oral JAK inhibitors within 1 month prior to baseline, or lack of efficacy/intolerance to other oral JAK inhibitors in the past, including but not limited to baricitinib, upadatinib and abuxitinib;
- •Use of excessive pilumab within 6 weeks prior to baseline;
- •Within 3 months (or within 5 drug half-lives, whichever is longer) prior to baseline, use of other systemic biologics other than dupilumab that are known or likely to affect AD (such as IL-13 receptor antibody \[tracilumab\], IL-31Rα antibody \[nimolizumab\], etc.);
- •Within 4 weeks (or within 5 half-lives, whichever is longer) prior to baseline, have used any kind of systemic therapy for AD: immunosuppressants (such as cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, etc.), glucocorticoids, PDE-4 inhibitors, etc.;
- •Treatment with phototherapy (narrowband ultraviolet B \[NBUVB\], ultraviolet B \[UVB\], ultraviolet A1 \[UVA1\], psoralen + ultraviolet A \[PUVA\]), tanning bed, or any other luminescent device within 4 weeks prior to baseline;
- •Allergen-specific immunotherapy (desensitization therapy) within 6 months prior to baseline;
- •Vaccination with any live vaccine or live attenuated vaccine within 12 weeks prior to baseline; or anticipated need to receive a live or live attenuated vaccine during the study, including at least 12 weeks after the last dose of the investigational drug;
Arms & Interventions
dupilumab plus tofacitinib
this arm receives dupilumab injection and oral tofacitinib.
Intervention: Dupilumab
dupilumab plus tofacitinib
this arm receives dupilumab injection and oral tofacitinib.
Intervention: Tofacitinib
dupilumab mono
this arm receives dupilumab treatment only.
Intervention: Dupilumab
Outcomes
Primary Outcomes
Percentage of participants with a ≥75% reduction from baseline in Eczema Area and Severity Index (EASI) score (EASI-75) at 16 weeks
Time Frame: 16 weeks
Secondary Outcomes
- Percentage of participants with an IGA score of 0 or 1 at W12(12 weeks)
- Percentage of participants with a ≥4-point reduction from baseline in the weekly mean of the Daily Peak Pruritus NRS score at W16(16 weeks)
- Percentage of participants achieving EASI-75 at W12(12 weeks)
- Percentage of participants achieving EASI-90 at W16(16 weeks)
- Percentage of participants with an Investigator Global Scoring Method (IGA) score of 0 or 1 at W16(16 weeks)
- Percentage of participants achieving EASI-90 at W12(12 weeks)
- Percentage of participants with a ≥4-point reduction from baseline in the weekly mean of the Daily Peak Pruritus Numeric Assessment Scale (NRS) score at W12(12 weeks)
- Percentage of atopic dermatitis control tool (ADCT) score less than 7 at W12(12 weeks)
- Percentage of atopic dermatitis control tool (ADCT) score less than 7 at W16(16 weeks)