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アルストローム症候群患者におけるPBI-4050による治療：第2相、単施設、単群、非盲検試験の試験プロトコール
Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial.
PMID: 30477455 PMCID: PMC6258144. DOI: 10.1186/s12902-018-0315-6.
抄録
背景:
BACKGROUND: Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS.
方法:
本試験は、第2相、単施設、単群、非盲検試験。ALMS患者18名が登録され、PBI-4050を1日合計800mgの経口投与で初回24週間投与され、その後36週間または48週間継続して投与されます。安全性の標準的な評価には、有害事象、臨床検査値、バイタルサイン、身体検査、心電図が含まれます。有効性の評価には、脂肪組織生検、高インスリン血症-高グルコースクランプ、脂肪組織マイクロダイアリシス、肝臓一過性エラストグラフィ、肝臓と心臓の磁気共鳴画像、および臨床検査での血液検査が含まれます。
METHODS: This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests.
DISCUSSION:
本試験は ALMS 患者を対象とした PBI-4050 の初の臨床試験です。この疾患の希少性と複雑性を考慮し、被験者の曝露量を最大化し、本試験のエンドポイントを達成する可能性を高めるために、単施設、単群、非盲検のデザインが選択されました。この結果は、進行性の線維化と早期死亡率を伴う稀な異種疾患であるALMSにおけるPBI-4050の効果について、貴重な安全性と予備的なエビデンスを提供するものと考えられます。
DISCUSSION: This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality.
トライアル登録:
本試験は、ClinicalTrials.gov（Identifier; NCT02739217 , 2016年2月）および欧州連合薬物規制当局臨床試験（EudraCT番号2015-001625-16, 2015年9月）に登録されています。
TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217 , February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015-001625-16, Sept 2015).