2023-508859-39-00招募中3 期
A two-part randomized, double-blind, placebo-controlled multicenter dose ranging and confirmatory study to assess the safety and efficacy of VAY736 in autoimmune hepatitis patients with incomplete response to or intolerance of standard therapy (AMBER)
适应症
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 7
- 试验地点
- 3
- 主要终点
- Proportion of patients with normalization of ALT at Week 24
研究概览
简要总结
Part 1- To evaluate whether VAY736 is superior to placebo with respect to alanine aminotransferase (ALT) normalization at Week 24 in patients with AIH who are incomplete responders or intolerant to standard therapy. Part 2- To confirm the efficacy (biochemical and histological remission) and safety of the dose determined from Part 1 in this population.
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 是
入选标准
- •Written informed consent must be obtained before any assessment is performed.
- •Part 1: Male and female patients with Type 1 AIH 18 to 75 years of age;
- •AIH diagnosed according to International Autoimmune Hepatitis Group (IAIHG) original or simplified diagnostic criteria, including the presence of characteristic autoantibodies
- •Documented liver biopsy result consistent with autoimmune hepatitis and obtained at screening or within 6 months prior to Screening (if on stable immunosuppression doses since that biopsy) with Ishak modified HAI score of ≥5 on local reading. If the biopsy at Screening cannot be read locally due to inadequacy of specimen, the patient may be randomized if all other inclusion and exclusion criteria are met
- •Patients with either incomplete response to OR intolerance of standard therapy * (according to AASLD guidelines) defined as: - Incomplete responder: ALT ≥1.5x ULN during Screening, PLUS: o at least 6 months of first line standard therapy (per AALSD guidelines: corticosteroids ≥10mg/d OR budesonide ≥6 mg/d AND/OR azathioprine/6-mercaptopurine ≥50mg/d or appropriate weight-based dosing) * between diagnosis and screening - Intolerant- ALT ≥1.5x ULN during screening despite attempting monotherapy or combination regimen of standard first line therapy* and discontinuing due to standard therapy related adverse event(s) (AE). Note for inclusion the mean of three independent ALT measurements, usually taken within about four weeks prior to randomization, will be used. *Standard therapy is defined as sufficient dose and duration of immunosuppression, during both induction and maintenance phases, according to AASLD guidelines (Manns 2010a, see Appendix 3). Incomplete responders and intolerant (drug toxicity) subjects are also defined as in Manns 2010a, see Appendix
- •For incomplete responders non-compliance should be ruled out by use of i.v. corticosteroids according to EASL 2015 guidelines (Appendix 5).
- •Stable doses of either corticosteroids and/or azathioprine/6-mercaptopurine during the 4 week Screening period and during the entire treatment periods. However, the predniso(lo)ne dose should be not higher than 20 mg/d, oral budesonide not higher than 9 mg/d and azathioprine not higher than 2 mg/kg/d or 150 mg/day Subjects who have previously taken mycophenolate mofetil (MMF) or mycophenolic acid (MPA) are allowed into the study. If a patient is taking MMF or MPA at time of consent and meets all inclusion/exclusion criteria (except for biopsy and mean of 3 ALT values, which will be performed during Screening), they will enter into a Pre-Screening period during which MMF or MPA will be withdrawn or converted to azathioprine/6-mercaptopurine. Azathioprine conversion should follow local practice and monthly study visits will be performed during the Pre-Screening period.
排除标准
- •Use of other investigational drugs within 5 half-lives of Screening or within 30 days of Screening, whichever is longer, or longer if required by local regulations.
- •Patients with a historical diagnosis of NASH or NASH diagnosed on (entry) liver biopsy
- •Screening CBC laboratory values as follows: - Hemoglobin <10.0 g/dL - Total leukocyte count <3 x109/L - Platelets <75 x109/L - Neutrophil count <1.5 x109/L
- •Use of tacrolimus, cyclophosphamide, or any other small molecule immunosuppressive drug (with the exception of MMF/MPA) within 1 month prior to Screening (V1) OR use of monoclonal antibodies, thymoglobulin or soluble cytokine receptors within 6 months prior to Screening
- •Diagnosis of overlap syndrome with autoimmune hepatitis (e.g., AIH+PBC, AIH+PSC)
- •Drug related AIH at screening or a history of drug related AIH.
- •History of drug abuse or unhealthy alcohol use (i) within 12 months prior to randomization or evidence of such abuse indicated by laboratory assays during screening (ii) defined as historical/current intake of five or more drinks on the same occasion on each of 5 or more days in the past 30 days OR >20 g/d for females and >40 g/d for males (World Health Organization, WHO, criteria)
- •History of primary or secondary immunodeficiency, including a positive HIV (ELISA and Western blot) test result, according to local or central laboratory
- •Receipt of live/attenuated vaccine within a 4-week period before enrollment
- •History of hypersensitivity to any of the study drugs or its excipients (sucrose, L-Arginine hydrochloride, L-histidine, polysorbate 80, hydrochloric acid) or to drugs of similar chemical classes (e.g., IgG1 biologics).
- •Active viral, bacterial or other infections at the time of screening, or history of recurrent clinically significant infection or of recurrent bacterial infections with encapsulated organisms
- •History of major organ or hematopoietic stem cell/marrow transplant
- •Uncontrolled, co-existing serious disease, i.e., uncontrolled hypertension, heart failure, type I diabetes, thyroid disease within 3 months prior to dosing, or significant illness within 2 weeks prior to dosing
- •Any surgical, medical, psychiatric or additional physical condition that the Investigator feels may potentially jeopardize the patient in case of participation in this study
- •Donation or loss of 400 mL or more of blood within 3 months prior study entry, or longer if required by local regulations
- •History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
- •Subjects who have been committed to an institution by way of official or judicial order
- •Prior use of any B-cell depleting therapy (e.g., rituximab or other anti-CD20 mAb, anti- CD22 mAb or anti-CD52 mAb) - within 1 year prior to Screening - or as long as B-cell count <50 cells/μL
- •Required regular use of medications with known hepatotoxicity
- •Excl criteria no 5 was removed from the PA01
- •Serum albumin level <32 g/L or INR >1.2 except for patients on chronic anticoagulation where the INR should not be outside target therapeutic range
- •Direct bilirubin in serum >2-fold ULN
- •ALT ≥10x ULN
- •Decompensated cirrhosis (Child-Pugh score B or C); Child-Pugh Score A without history of decompensation and preserved synthetic function will be eligible.
结局指标
主要结局
Proportion of patients with normalization of ALT at Week 24
Proportion of patients with normalization of ALT at Week 24
次要结局
- Proportion of patients achieving ALT normalization at Week 24
研究者
Novartis Pharma Arzneimittel GmbH
Scientific
Novartis Pharma AG
研究点 (3)
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