Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease

Griese, Matthias; Kappler, Matthias; Stehling, Florian; Schulze, Johannes; Baden, Winfried; Koerner-Rettberg, Cordula; Carlens, Julia; Prenzel, Freerk; Naehrlich, Lutz; Thalmeier, Andreas; Sebah, Daniela; Kronfeld, Kai; Rock, Hans; Ruckes, Christian; Olivier, Margarete; Zielen, Stefan; Bagheri-Potthof, Azadeh; Thomé, Ulrich; Gebhardt, Julia; Mehl, Anna; Lau, Susanne Gabriele; Philipp, Utz; Kopp, Matthias; Stichtenoth, Guido; Sommerburg, Olaf; Stahl, Mirjam; Kitz, Richard J.; Rietschel, Christoph; Stock, Philippe; Ahrens, Frank; Hebestreit, Helge; Segerer, Florian; Brinkmann, Folke; Anne, Schlegtendal; Eismann, Claudia; Neuner, Dörthe; Witt, Sabine; Hengst, Meike; Feilcke, Maria; Babl, Juergen; Stauffer, Gabriele; Nickolay, Tanja; Gorbulev, Stanislav; Anthony, Gisela; Stöhr, Linda; Vieweg, Laura; Strenge-Hesse, Anke; Wetzke, Martin; Seidl, Elias; Schwerk, Nicolaus

doi:10.1186/s13023-022-02399-2

Cited by 33 publications

(18 citation statements)

References 22 publications

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“…Conducting clinical trials in children with fibrosing ILD is challenging due to factors including its rarity and a lack of consensus on how to measure the progression of pulmonary fibrosis in children [ 1 ]. Other than the InPedILD trial, the only randomised placebo-controlled trial of an intervention in children with fibrosing ILD to have published results is a trial of hydroxychloroquine conducted in Germany, which differed substantially from the InPedILD trial in its design [ 31 ]. The InPedILD trial is the first international placebo-controlled trial to have been conducted in children with ILD and as such represents a landmark in the field.…”

Section: Discussionmentioning

confidence: 99%

Nintedanib in children and adolescents with fibrosing interstitial lung diseases

et al. 2022

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Childhood interstitial lung disease comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. Patients aged 6–17 years with fibrosing ILD on HRCT and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary endpoints were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. Twenty-six patients received nintedanib and 13 placebo. The geometric mean (gCV%) AUCτ,ss for nintedanib was 175 µg×h·L−1 (85.1) in patients aged 6–11 years and 160 µg×h·L−1 (82.7) in patients aged 12–17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean (se) changes in FVC % predicted at week 24 were 0.3 (1.3) in the nintedanib group and −0.9 (1.8) in the placebo group. In conclusion, in children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

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Section: Discussionmentioning

confidence: 99%

Nintedanib in children and adolescents with fibrosing interstitial lung diseases

et al. 2022

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“…Meanwhile, supporting treatment including oxygen therapy and nutritional supplementation are started [16,17,25]. The final diagnosis is often awaited to start more specific medications such as corticosteroids, azithromycin, hydroxychloroquine or anti-fibrosing therapies [103][104][105][106][107][108][109][110][111][112]. In chILD related to connective tissue diseases or autoinflammatory syndromes, immunosuppressive drugs such as mycophenolate mofetil, azathioprine, rituximab or Janus kinase inhibitors may be discussed [96,97,[113][114][115][116].…”

Section: Lung Biopsymentioning

confidence: 99%

Diagnostic workup of childhood interstitial lung disease

Nathan

Griese²,

Michel³

et al. 2023

Eur Respir Rev

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Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of “undefined chILD” is stressed.

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“…Therefore patients should be regularly screened, especially after the age of 40 years [ 74 , 76 , 99 ] and family members genetically tested for the presence of SFTPA1/SFTPA2 mutations. No effective treatment exists for surfactant-related genetic disease and there is no consensus on it; studies report treatment with azithromycin or hydroxychloroquine, while others opt for the immunosuppressants azathioprine, methylprednisolone, and cyclophosphamide with no curative or long-term stabilizing effects [ 111 , 112 ]. Gene-based therapies as well as functional rescue therapies of misfolding ABCA3 mutations by molecular correctors are promising for the future [ 113 , 114 ].…”

Section: Clinical Implications Of Carriership Of Srg ...mentioning

confidence: 99%

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

et al. 2022

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Background: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. Aim: The aim of the present study is to overview the clinical significance of genetics in IPF. Perspective: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a “a sporadic entity of the elderly, limited to the lungs” and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and “faces” in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. Conclusion: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing.

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Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease

Cited by 33 publications

References 22 publications

Nintedanib in children and adolescents with fibrosing interstitial lung diseases

Nintedanib in children and adolescents with fibrosing interstitial lung diseases

Diagnostic workup of childhood interstitial lung disease

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

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