83 research outputs found
Dupilumab provides favourable longâterm safety and efficacy in children aged â„ 6 to < 12 years with uncontrolled, severe atopic dermatitis: results from an openâlabel phase IIa study and subsequent phase III openâlabel extension study
Background
Children aged â„ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16âweek, randomized, placeboâcontrolled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)â4/ILâ13 signalling, significantly improved signs and symptoms with acceptable safety; longerâterm safety and efficacy data are lacking.
Objectives
To report the pharmacokinetic profile and longâterm safety and efficacy of dupilumab in children (aged â„ 6 to < 12 years) with severe AD.
Methods
Children (aged â„ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, openâlabel, ascendingâdose, sequential cohort study and subsequent openâlabel extension (OLE) study. Patients received singleâdose dupilumab 2 or 4 mg kgâ1 followed by 8âweek pharmacokinetic sampling, then 2 or 4 mg kgâ1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentrationâtime profile and treatmentâemergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PPâNRS) score.
Results
Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, targetâmediated pharmacokinetics characterized dupilumab concentrations (week 24â48 mean serum concentrations: 2 mg kgâ1, 61â77 mg Lâ1; 4 mg kgâ1, 143â181 mg Lâ1). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kgâ1, 47%; 4 mg kgâ1, 56%) and AD exacerbation (29% and 13%, respectively). Singleâdose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PPâNRS improved by â37%/â33% and â17%/â20% at week 2 (phase IIa) and â92%/â84% and â70%/â58% at week 52 (OLE), respectively.
Conclusions
These safety and efficacy results support the use of dupilumab as a continuous longâterm treatment for children aged â„ 6 to < 12 years with severe AD
Infections in Dupilumab Clinical Trials in Atopic Dermatitis : A Comprehensive Pooled Analysis
Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649
Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.
BACKGROUND
Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits
signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important
drivers of atopic or allergic diseases such as atopic dermatitis.
METHODS
In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1
and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose
disease was inadequately controlled by topical treatment. Patients were randomly
assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg)
or placebo weekly or the same dose of dupilumab every other week alternating
with placebo. The primary outcome was the proportion of patients who had both
a score of 0 or 1 (clear or almost clear) on the Investigatorâs Global Assessment
and a reduction of 2 points or more in that score from baseline at week 16.
RESULTS
We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary
outcome occurred in 85 patients (38%) who received dupilumab every other week and
in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received
placebo (P<0.001 for both comparisons with placebo). The results were similar in
SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab
every other week and in 87 (36%) who received dupilumab weekly, as compared
with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition,
in the two trials, an improvement from baseline to week 16 of at least 75% on the
Eczema Area and Severity Index was reported in significantly more patients who received
each regimen of dupilumab than in patients who received placebo (P<0.001 for
all comparisons). Dupilumab was also associated with improvement in other clinical
end points, including reduction in pruritus and symptoms of anxiety or depression
and improvement in quality of life. Injection-site reactions and conjunctivitis were
more frequent in the dupilumab groups than in the placebo groups.
CONCLUSIONS
In two phase 3 trials of identical design involving patients with atopic dermatitis,
dupilumab improved the signs and symptoms of atopic dermatitis, including
pruritus, symptoms of anxiety and depression, and quality of life, as compared
with placebo. Trials of longer duration are needed to assess the long-term effectiveness
and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals;
SOLO 1 ClinicalTrials.gov number, NCT02277743; SOLO 2 ClinicalTrials
.gov number, NCT02277769.
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Dupilumab in adolescents with uncontrolled moderateâtoâsevere atopic dermatitis : results from a phase IIa openâlabel trial and subsequent phase III openâlabel extension
Background
Dupilumab (monoclonal antibody inhibiting ILâ4/ILâ13 signalling) is approved for use in adolescents aged â„ 12 years with inadequately controlled moderateâtoâsevere atopic dermatitis (AD). Dupilumab significantly improved AD signs/symptoms in a 16âweek, randomised, placeboâcontrolled phase III trial in adolescents (NCT03054428).
Objectives
To characterize the pharmacokinetics of dupilumab, and longâterm safety and efficacy in adolescents.
Methods
This was a global, multicentre, phase IIa, openâlabel, ascendingâdose, sequential cohort study with a phase III openâlabel extension (OLE) in adolescents with moderateâtoâsevere AD. In the phase IIa study, patients received one dupilumab dose (2 mg kgâ1 or 4 mg kgâ1) and 8 weeks of pharmacokinetic sampling. Thereafter, patients received the same dose weekly for 4 weeks, with 8âweek safety followâup. Patients then enrolled in the OLE, continuing 2 mg kgâ1 or 4 mg kgâ1 dupilumab weekly. Primary end points were dupilumab concentrationâtime profile and incidence of treatmentâemergent adverse events (TEAEs). Secondary outcomes included Eczema Area and Severity Index (EASI).
Results
Forty adolescents received dupilumab in the phase IIa study; 36 enrolled in the OLE. Dupilumab showed nonlinear, targetâmediated pharmacokinetics. Mean ± SD trough dupilumab concentrations in serum at week 48 (OLE) were 74 ± 19 mg Lâ1 and 161 ± 60 mg Lâ1 for 2 mg kgâ1 and 4 mg kgâ1, respectively. Dupilumab was well tolerated over 52 weeks; the most common TEAEs were nasopharyngitis (week 52: 41% [2 mg kgâ1], 47% [4 mg kgâ1]) and AD exacerbation (29%, 42%). After one dupilumab dose in the phase IIa study, EASI improved from baseline to week 2 [mean ± SD reduction â34% ± 20% (2 mg kgâ1) and â51% ± 29% (4 mg kgâ1)]. With continuing treatment, EASI scores improved further [week 52: â85% ± 12% (2 mg kgâ1) and â84% ± 20% (4 mg kgâ1)].
Conclusions
In adolescents with moderateâtoâsevere AD, dupilumab's pharmacokinetic profile was similar to that in adults. These 52âweek safety and efficacy data support longâterm use of dupilumab in this patient population
Conjunctivitis in dupilumab clinical trials
Background Dupilumab blocks the shared receptor component for interleukin (IL)-4
and IL-13. It is approved in the U.S.A. for patients aged â„ 12 years with moderate-tosevere atopic dermatitis (AD) uncontrolled by topical prescription medicines or who
cannot use topical medicines, for patients in Japan whose AD is uncontrolled with
existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged â„ 12 years for maintenance treatment
of moderate-to-severe asthma uncontrolled with their current medicines. AD trials
have reported increased incidence of conjunctivitis for dupilumab vs. placebo.
Objectives To characterize further the occurrence and risk factors of conjunctivitis
in dupilumab clinical trials.
Methods We evaluated randomized placebo-controlled trials of dupilumab in AD
(n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps
(CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47).
Results In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was
mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and
antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators.
In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both
dupilumab and placebo than in AD trials; dupilumab did not increase the incidence
compared with placebo. In the EoE trial, no patients had conjunctivitis.
Conclusions Conjunctivitis was more frequent with dupilumab treatment in most
AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the
incidence of conjunctivitis was associated with AD severity and prior history of
conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated
patients require further study
Edible forage production, chemical composition, rumen degradation and gas production characteristics of Calliandra calothyrsus (Messin) provenances in the humid tropics of West Africa
Two experiments evaluated variations in feed value among Calliandra calothyrsus provenances. In Experiment 1, edible forage production of four provenances were evaluated at Ibadan, southwestern Nigeria over a 2-year period in three seasons: main-wet (April-August), minor-wet (September-November) and dry (December-March). Forage samples from the main-wet and dry seasons were incubated for 6, 12, 48, 72 and 96 h in rumen-fistulated steers to estimate in sacco dry matter (DM) and nitrogen (N) degradation characteristics. In vitro gas production was estimated over 3, 6, 12, 24, 48, 72 and 96 h of incubation. In Experiment 2, DM degradation characteristics of 14 provenances of C. calothyrsus planted on an acid soil in Yaounde, Cameroon, were evaluated. Data were subjected to cluster analysis for grouping, and the 14 provenances were placed into four distinct cluster groups. Based on the potential extent of DM and, N degradation and gas production characteristics in Experiment 1, the four provenances of C. calothyrsus were classified into three forage quality groups: high (ILCA 16310), medium (ILCA 14891, ILCA 15166) and low (NFTA 896). In Experiment 2, using the extent of DM degradation as a forage quality index, C. calothyrsus provenances in cluster 3 and 4 (namely: 51/92, 11/91. 13/91, 45/92, 10/91, 15/91, 18/91, 134/91, 12/91, 62/92), were relatively higher in quality than their counterparts in clusters 1 and 2. The results suggested the existence of intra-species variation among the provenances, and confirmed earlier observations that forage quality of C. calothyrsus could be improved through provenance evaluation
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