Who can participate
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Part 1: Male and female patients with Type 1 AIH 18 to 75 years of age; Part 2: Male and female patients with any type of AIH 16 to 75 years of age.
3. AIH diagnosed according to International Autoimmune Hepatitis Group (IAIHG) original or simplified diagnostic criteria (Alvarez 1999 or Hennes 2008), including the presence of characteristic autoantibodies.
4. 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 (Ishak 1995) 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.
5. Patients with either incomplete response to OR intolerance of standard therapy (according to AALSD guidelines, Manns 2010a, Appendix 3) defined as: Incomplete responder: ALT ≥1.5x ULN during screening, PLUS: at least 6 months of first line standard therapy (i.e. per Manns 2010a, Appendix 3: 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 AE. Note for inclusion the mean of three independent ALT central laboratory measurements, usually taken within about four weeks prior to randomization, will be used.
6. 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 not be 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/d
Subjects who have previously taken mycophenolate mofetil (MMF) or mycophenolic acid (MPA) are allowed into the study. If a patient is taking MMF/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which will be performed during Screening), they will enter into a Pre-Screening period during which MMF or MPA will be withdrawn or converted to azathioprine/6-mercaptopurine.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.
*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 4. For incomplete responders non-compliance should be ruled out by use of i.v. corticosteroids according to EASL 2015 guidelines (Appendix
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients/subjects. For laboratory exclusions (chemistry, hematology, viral serology and pregnancy) below it is intended that local laboratory values should be used, however central laboratory screening values may be used, provided the approach is consistent at each site.
1. 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.
2. 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).
3. Prior use of any B-cell depleting therapy (e.g., rituximab or other anti-CD20 mAb, antiCD22 mAb or anti-CD52 mAb) within 1 year prior to Screening or as long as B-cell count <50 cells/µL
4. Required regular use of medications with known hepatotoxicity (see Table 5-3)
6. Serum albumin level <32 g/L or INR >1.2
7. Direct bilirubin in serum >2-fold ULN
8. ALT ≥10x ULN
9. Decompensated cirrhosis (Child-Pugh score B or C); Child-Pugh Score A without history of decompensation and preserved synthetic function will be eligible.
10. Patients with a historical diagnosis of NASH or NASH diagnosed on (entry) liver biopsy
11. 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
12. 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
13. Diagnosis of overlap syndrome with autoimmune hepatitis (e.g., AIH+PBC, AIH+PSC)
14. Drug related AIH at screening or a history of drug related AIH.
15. 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)
16. History of primary or secondary immunodeficiency, including a positive HIV (ELISA and Western blot) test result, according to local or central laboratory
17. Positive hepatitis B surface antigen (HBsAg), anti-HB core antigen (anti-HBc) or anti-HB surface antigen (anti-HBs) or positive hepatitis C test result (Patients positive for anti-HBs
after Hep B vaccination but negative for HBsAg and anti-HBc are eligible), this viral testing can be done by the local or central laboratory
18. Evidence of active tuberculosis (TB) infection (after anti-TB treatment, patients with history of or latent TB may become eligible if treated and followed according to national guidelines)
19. Receipt of live/attenuated vaccine within a 2 month period before enrollment
20. 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
21. History of major organ or hematopoietic stem cell/marrow transplant
22. 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
23. Any surgical, medical, psychiatric or additional physical condition that the Investigator feels may potentially jeopardize the patient in case of participation in this study
24. Donation or loss of 400 mL or more of blood within 3 months prior study entry, or longer if required by local regulations
25. 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.
26. Subjects who have been committed to an institution by way of official or judicial order
27. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
28. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception from screening and for 4 months after stopping of investigational medication. Highly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment
Male sterilization (at least 6 months prior to screening and confirmed as successful). For female patients in the study, the vasectomized male partner should be the sole partner for that patient
Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential. In case local regulations deviate from the contraception methods listed above, local regulations apply and will be described in the ICF.