Highlights
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Summary
Background
Current systemic treatments for children younger than 6 years with moderate to severe atopic dermatitis that are not controlled with topical therapies may have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. The objective was to evaluate the efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children 6 months to less than 6 years of age with dermatitis. moderate to severe atopic.
Methods
This phase 3, randomized, double-blind, placebo-controlled, parallel-group trial was conducted at 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were between 6 months and less than 6 years of age, with moderate to severe atopic dermatitis (Investigator Global Assessment [IGA] score of 3 to 4) diagnosed according to American Academy consensus criteria. of Dermatology, and an inadequate response to topical corticosteroid treatments.
Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (body weight ≥5 kg to <15 kg: 200 mg; body weight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-grade topical corticosteroids. potency (hydrocortisone cream 1% acetate) for 16 weeks. Randomization was stratified by age, initial body weight, and region. Patient assignment was performed through a central interactive web response system and treatment assignment was masked.
The primary endpoint at week 16 was the proportion of patients with an IGA score of 0 to 1 (clear or nearly clear skin). The key secondary endpoint (co-primary endpoint for EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in the severity index and eczema area (EASI-75).
Primary analyzes were performed on the full analysis set (i.e., all randomly assigned patients), and safety analyzes were performed on all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434.
Results
Between June 30, 2020 and February 12, 2021, 197 patients were assessed for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids.
At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0–1 (23 [28%] vs three [4%], difference 24% [95% CI 13–34]; p<0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p<0·0001).
The overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and the placebo group (58 [74%] of 78 patients).
The incidence of conjunctivitis was higher in the dupilumab group (four [5%]) than in the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation.
Interpretation
Dupilumab significantly improved signs and symptoms of atopic dermatitis compared to placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults.
Comments
The first study to treat moderate to severe eczema in infants and children ages 6 months to 5 years with a biologic drug (monoclonal antibody) instead of immunosuppressive medications shows that the drug was very effective in reducing signs and symptoms of eczema. moderate to severe, report researchers participating in a new international multi-site Phase III study led by Northwestern Medicine.
A 16-week course of dupilumab, a drug that targets a key immune pathway in allergies, resulted in more than half of the children having at least a 75% reduction in signs of eczema and very significant reductions in itching with improved sleep.
This is the first large-scale, randomized, placebo-controlled trial of a monoclonal antibody in any skin disease, including eczema, in children up to 6 months. The study, which included 31 sites in Europe and North America, was published in The Lancet .
“Preschool-age children who scratch constantly, wake up several times a night with their parents, are irritable, and have a markedly limited ability to do what other children their age can do and improve as they sleep all the time.” at night, they change their personality and behave normally. life, as babies and children should,” said the study’s lead author, Dr. Amy Paller, chair of dermatology at Northwestern University Feinberg School of Medicine and attending physician at Ann & Robert H. Children’s Hospital. Chicago Lurie.
Eczema, also known as atopic dermatitis, is a chronic inflammatory skin disorder characterized by red, dry, often oozing and itchy skin that can profoundly affect the lives of affected patients and their families.
It is estimated that 19% or more of all children under 6 years of age have eczema and between 85 and 90% of people generally affected with eczema have the onset of the disease during the first five years of life.
Debilitating itch in children causes sleep disorders, poor neurocognitive development, and, on average, one full night of lost sleep per week.
“The ability to take this medication will significantly improve the quality of life for infants and young children who suffer tremendously with this disease,” Paller said. “Atopic dermatitis or eczema is much more than an itchy skin. It is a devastating disease. The quality of life of severe eczema, not only for the child but also for the parents, is equivalent to many life-threatening diseases.”
As a result of this study, this medication is now available for infants and preschool children starting at 6 months of age. It has “an outstanding safety profile” and does not even require laboratory testing before starting the drug, Paller said.
Although half to two-thirds of young children with eczema have mild symptoms, which can be treated with steroid ointments and moisturizers, the other third or more have moderate to severe disease and require more aggressive treatment.
“So far, all we have had to treat more severe eczema are immunosuppressive medications, such as oral steroids, which we try to avoid in children, because they are associated with many side effects and are therefore not a preferred treatment. for a chronic skin disease,” Paller said. “The potential long-term impact on immune system development in young children is also a concern with these immunosuppressants.”
Over the past few years, a new medication called dupilumab has become available, which is the first "biologic" drug to specifically treat eczema, meaning a limited attack on what scientists have discovered is causing the manifestations of the disease. skin disease. . This medication was found to be effective and safe in studies with adults, then adolescents, and then other school-age children.
“But the group where we are most concerned about safety, those under 5 years old, had not been tested and could not get this medication,” Paller said.
The parent or a healthcare provider gives the child a monthly injection to administer the medication. “The effect for most of these younger children is dramatic and at least as good as what we have seen with risky immunosuppressive drugs,” Paller said.
Potential additional benefit when treating associated allergies
This medication has also been shown to be effective in treating asthma, gastrointestinal manifestations of allergy, and other problems caused by allergies, but is not yet approved for these indications in infants and young children.
In fact, 66% of the children in this trial had developed their eczema during the first six months of life, and by the time dupilumab was started, more than 80% had already developed at least one allergic disorder, such as asthma or allergy food. .
"By treating more aggressively to calm immune system activation in these young children with early, severe eczema, we can also reduce the risk of them developing a variety of allergic problems, changing their lives beyond improving their eczema," he said. Paller. “These associated allergic problems usually begin after eczema begins.”
Children were randomized to receive an injection of placebo or dupilumab (weight-based dosing) every four weeks for 16 weeks. Only children who did not respond adequately to topical medications could enroll and had to be high acuity, even on topical medications.
As a result of the study, Paller said, scientists and doctors may begin to better understand the relationships between eczema and a variety of allergic disorders and may consider using this medication for other disorders that affect these very young children.
The trial was sponsored by Regeneron Pharmaceuticals, Inc. and Sanofi, who co-developed dupilumab.
