The first study to treat moderate-to-severe eczema in infants and children six months to five-years-old with a biologic drug rather than immune-suppressing medications shows the drug was highly effective in reducing the signs and symptoms of eczema.
More than half of the children had at least a 75% reduction in signs of eczema and itch and slept through the night for the first time instead of scratching, and parents saw children’s personalities change as they were able to lead a normal life, according to the results of the multi-site international phase III study.
The 16-week course of dupilumab, a medication that targets a key immune pathway in allergies, resulted in more than half the children having at least a 75% reduction in signs of eczema and highly significant reductions in itch with improved sleep.
This is the first large-scale, randomised, placebo-controlled trial of a monoclonal antibody in any skin disease, including eczema, in children as young as six months. The study included 31 sites in Europe and North America and was published in The Lancet.
“Pre-schoolers who are constantly scratching, awake multiple times a night with their parents, irritable and markedly curtailed in their ability to do what other children their ages can do improved to the extent that they sleep through the night, change their personalities and have a normal life – as babies and children should,” said lead study author Dr Amy Paller, chair of dermatology at Northwestern University Feinberg School of Medicine and an attending physician at Ann & Robert H Lurie Children’s Hospital of Chicago.
An estimated 19% or more of all children under six have eczema and 85% to 90% of people affected overall with eczema have the onset of disease during the first five years of life.
The children’s debilitating itch leads to sleep disturbance, poor neurocognitive development and, on average, a full night of sleep lost per week.
“This drug 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 so much more than just itchy skin. It is a devastating disease. The quality of life of severe eczema, not only for the child but also parents, is equivalent to many life-threatening diseases.”
As a result of this study, this medication is now available to infants and pre-schoolers as young as six-months-old. It has “an outstanding safety profile” and does not even require any laboratory tests before starting the medication, Paller said.
Although one-half to two-thirds of children with eczema have mild symptoms, which can be handled with steroid ointment and moisturisers, the other one-third or more have moderate-to-severe disease and require more aggressive management.
“Until now, all we have had to treat more severe eczema is immune-suppressing medications, such as oral steroids, which we try to avoid in children, because they are associated with so many side effects and thus are not a preferred treatment for a chronic skin disease,” Paller said. “The potential long-term impact on the development of the immune system in young children is also of concern with these immunosuppressants.”
During the past few years, a new medication has become available called dupilumab, the first “biologic” drug to treat eczema in a targeted manner, meaning a narrow attack on just what scientists have found is causing the manifestations of the disease in skin. This medication was found to be effective and safe in studies with adults, then adolescents, then other school-aged children.
“But the group in whom we worry the most about safety – those under five – had not been tested and were unable to get this medication,” Paller said.
The parent or a health care provider gives the child a monthly shot to administer the medication. ”The effect for most of these younger children is dramatic and at least as good as we’ve seen with the risky immunosuppressant medications,” Paller said.
Potential added benefit by treating associated allergies
This medication has also been shown to be effective for treating asthma, gastrointestinal manifestations of allergy and other allergy-mediated problems but is not yet approved for these indications in infants and young children.
In fact, 66% of children in this trial had developed their eczema during the first six months of life and, by the time of initiating the dupilumab, more than 80% had already developed at least one allergic disorder, such as asthma or food allergy.
“By treating more aggressively to calm the immune system activation in these young children with early, severe eczema, we may also reduce the risk of their developing a range of allergic problems, changing their life beyond improving eczema,” Paller said.
“These associated allergic issues most often begin after the eczema starts.”
Children were randomised to receive either a placebo injection or the dupilumab (weight-based dosing) every four weeks for 16 weeks. Only children who were not responding adequately to topical medications were allowed to enroll, and they had to be of a high severity, even with the topical medications.
As a result of the study, Paller said, scientists and physicians can start to better understand the relationships between eczema and a variety of allergic disorders and can consider the possibility of using this medication for other disorders that affect these very young children.
The trial was sponsored by Regeneron Pharmaceuticals, Inc. and Sanofi, who jointly developed dupilumab.
Study details
Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial.
Amy Paller, Eric Simpson, Elaine Siegfried, Michael Cork, Andreas Wollenberg, Peter Arkwright, Weily Soong, Mercedes Gonzalez, Lynda Schneider, Robert Sidbury, Benjamin Lockshin, Steven Meltzer, Zhixiao Wang, Leda Mannent, Nikhil Amin, Yiping Sun, Elizabeth Laws, Bolanle Akinlade, Myles Dillon, Matthew Kosloski, Mohamed Kamal, Ariane Dubost-Brama, Naimish Patel, David Weinreich, George Yancopoulos, John O’Malley, Ashish Bansal, Amber Pepper, Amy Paller, Benjamin Lockshin, David Cohen, David Pariser, Elaine Siegfried, Eric Simpson, Jeffrey Leflein, Jeffrey Weinberg, John Browning, Joyce Teng, Lara Wine Lee, Lawrence Sher, Lucia Diaz, Lynda Schneider, Mercedes Gonzalez, Ned Rupp, Peck Ong, Robert Cartwright, Robert Sidbury, Weily Soong, Andreas Pinter, Andreas Wollenberg, Christina Schnopp, Michael Cork, Peter Arkwright, Anna Korkosz, Dorota Bystrzanowska, Ewa Sygula, Jacek Zdybski, Kamila Padlewska.
Published in The Lancet on 17 September 2022.
Summary
Background
Current systemic treatments for children younger than six years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged six months to younger than six years with moderate-to-severe atopic dermatitis.
Methods
This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator’s Global Assessment [IGA] score 3–4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0–1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug.
Findings
Between June 30, 2020, and Feb 12, 2021, 197 patients were screened 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). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation.
Interpretation
Dupilumab significantly improved atopic dermatitis signs and symptoms versus 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.
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