Hepatitis, Autoimmune Clinical Trial
Official title:
DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL WITH CHLOROQUINE VERSUS PLACEBO FOR MAINTENANCE OF REMISSION OF AUTOIMMUNE HEPATITIS
Autoimmune hepatitis is an autoimmune chronic liver disease whose treatment includes the use of immunosuppressive drugs, particularly azathioprine, and corticosteroids. When properly treated, patients have a good survival. One of the major problems related to its treatment is the the high rate of relapses after stopping therapy that has lead to biochemical and histological remissions, close to 80%. Many authors recommend continuous treatment throughout life, resulting in the occurrence of many side effects. Chloroquine is a drug with anti-inflammatory properties already used in the treatment of other extrahepatic autoimmune liver diseases. There are some reports in the literature about its beneficial use in liver diseases such as chronic hepatitis B, and a pilot study in patients with autoimmune hepatitis, in which its use was associated with a 6.49 times lower risk of disease recurrence when compared with patients in whom treatment was discontinued after remission. Our purpose is to investigate, in a double-blind randomized trial with placebo, whether chloroquine prevents the recurrence of AIH in patients with histological remission after discontinuation of conventional treatment and to evaluate the occurrence of side effects.
Autoimmune hepatitis (AIH) is a chronic disease with a progressive destruction of hepatic
parenchyma, leading to cirrhosis and high mortality in the absence of specific treatment. It
has been demonstrated that the treatment with corticosteroids and azathioprine provides
clinical and laboratory improvement, reduction of histological inflammatory activity on
liver biopsy and an increased survival. The life expectancy of correctly treated patients
can approach that of age- and gender-matched controls. One of the features of AIH is the
high rate of recurrence after discontinuation of treatment in patients who achieved
histological remission. The chances of recurrence reach up to 50% at 6 months and 70% after
one year, and the rates of sustained remission, are limited to 10 to 15% in 5 years. Thus,
most patients require maintenance treatment to prevent recurrence.
Chloroquine is a drug of the group of 4-aminoquinolines, synthetic derivatives of quinine
and constituent of the bark of the Cinchona tree. Chloroquine accumulates in tissues in
considerable amounts. In animals, from 200 to 700 times the plasma concentration can be
found in liver, spleen, kidneys and lungs. As a weak base, it accumulates intracellularly,
particularly in lysosomes with a consequent increase in pH within these organelles, which
could contribute to its toxicity. Lysosomal lamellar bodies are observed in tissues affected
by chloroquine, such as retina and neuromuscular system. Chloroquine inhibits the absorption
and the binding of mitochondrial calcium, alters the membrane permeability and the transport
of enzymes to the lysosomes. Apparently there are other mechanisms to explain its
anti-inflammatory action; such as the interference with the release of TNF from mononuclear
phagocytes by inhibiting gene expression and the down-regulation of TNF receptors, by
delaying their transport to the cellular surface. Due to these mechanisms of action,
chloroquine has anti-inflammatory activities and therefore is used in diseases such as
rheumatoid arthritis and systemic lupus erythematosus. In liver diseases, chloroquine was
used in patients with hepatitis B with normalization of the levels of aminotransferases and
of the prothrombin time during treatment and relapse after drug discontinuation. Chloroquine
was also evaluated in patients with porphyria cutanea tarda and despite the clinical and
biochemical improvement, liver biopsies remained unchanged after one year of treatment.
A previous pilot study was performed in our institution, and published in 2005, with
chloroquine diphosphate for the maintenance treatment of AIH. In this study, 14 patients
with a biochemical and histological remission were treated with chloroquine diphosphate 250
mg/day for at least 12 months or until disease recurrence, and compared with 18 historical
controls, which was held in discontinuation of treatment after remission. The chance of
relapse was 6.49 times higher in the historical controls when compared with patients in the
group treated with chloroquine (72.2% versus 23.5%, p = 0.031). The use of chloroquine was
safe in patients with liver cirrhosis without decompensation, and there were no serious
adverse events within two years of use.
The most common adverse effects of chloroquine are mild and transient such as
gastrointestinal symptoms, headache, dizziness, blurry vision and fatigue. The more severe
reactions described are itching, cardiovascular manifestations, dyskinesias, eye injuries,
neuromuscular disorders and hearing loss. Among the most feared adverse effects of
chloroquine, are the eye injuries, usually associated with chronic treatment. They may
consist of changes in the retina, lens, cornea and optic nerve. Usually they remain stable
after drug withdrawal, if the drug is discontinued in early stages. However, the retinal
damage can increase when found in advanced stages, and may progress even years after
cessation of chloroquine. It is believed that the chloroquine retinopathy can be prevented
or recognized in an early reversible stage with judicious use, appropriate doses and regular
ophthalmologic follow-up. It is recommended that the daily dose does not exceed 250 mg of
chloroquine diphosphate or 400 mg of hydroxychloroquine, and ophthalmologic evaluations are
carried out every 4 to 6 months. Despite the adverse effects and toxic reactions described
above, there is a consensus in most studies with chloroquine that it is a well tolerated
drug, provided that the appropriate dosage guidelines and regular eye examinations are
followed. With these cautions in mind, its use rarely causes serious side or irreversible
effects.
The purpose of this study is to investigate whether chloroquine prevents the risk of
recurrence of AIH in patients in remission after discontinuation of conventional treatment,
in prospective, randomized, double-blind trial, and to evaluate the occurrence of side
effects from the use of chloroquine.
To be included patients had to satisfy the following criteria simultaneously: a diagnosis of
probable / definite AIH (according to the criteria of the international AIH Group), normal
liver function and absence of clinical signs of decompensated liver disease ( ascites,
hepatic encephalopathy, gastrointestinal bleeding and hepatocellular carcinoma); biochemical
(aminotransferase levels within the normal value for at least 18 months) and histological
remission in liver biopsy (periportal inflammatory activity less than 2) in the presence of
immunosuppressive treatment; men or non-pregnant women and women with no intention to become
pregnant; willing to participate in the study. An explanation of this study will be made to
patients. For their enrollment, it is necessary that the patients are in accordance with the
proposed study, following the precepts of the Declaration of Helsinki. If patients refuse to
participate in the study, they will be treated following the traditional guidelines of our
service. We will exclude patients who stop the drug before six months for side effects,
patient's desire or loss of follow up. Treatment will be discontinued in case of pregnancy,
patient's desire, side-effects or relapse of AIH. Recurrence was defined as a sustained
increase in liver enzymes, greater than or equal to two times the upper normal value
(according to the criteria of the International Autoimmune Hepatitis Group).
The sample size was calculated by exact Fisher test to compare the treatment and placebo
groups considering the relapse percentage varying between 25% to 40% and 65% to 80%,
respectively. Thus, the sample size was obtained between from 30 to 128 patients for each
group considering the power of 80% and the statistical significance level of 5%. The
statistical analysis will present mean and standard error for quantitative variables and
percentages for qualitative variables as descriptive measures. The survival analysis will be
performed,through of simple Cox regression and multiple Cox regression with treatment as a
fixed covariate, to test the effect of treatment considering patients' characteristics on
the relapse risk from the beginning of treatment to the relapse in a period of 3 years. In a
second step, survival analysis will be repeated for patients that finished or stopped the
treatment for side effects to verify if the absence of relapse during treatment is due the
patients' characteristics. Furthermore, the proportions of side effects will be compared
between the groups by exact Fisher test. A p-value less than 5% will be considered of
statistical significance.
Patients will be randomized to receive placebo or chloroquine, under the name of drug A or
drug B. Information on the composition of the tablets is kept secret with the Pharmacy's
staff of Hospital das Clinicas, University of Sao Paulo School of Medicine. The treatment
regimen that led to the histological remission will be maintained for a month, in
association with drug A or B, at which time it will be withdrawal. Patients who were taking
ursodeoxycholic acid to achieve remission will remain in use of this drug during the study.
Drugs A or B will be maintained until disease recurrence (persistent changes of
aminotransferases greater than twice the normal value) or until three years if biochemical
tests are normal, or until the time that patient want to remain in the study. If there is
recurrence of the disease, the patient will be excluded from the study and will receive the
treatment they received previously. All patients will have visits every 30 days during the
first six months after using drug A or drug B in monotherapy, with routine blood tests
performed. After then, consultations will be every two months. All complaints will be
recorded and the number of tablets will be counted at each visit to assess adherence and to
account for failures in taking the medication. Every patient will be treated by the doctors
responsible for the study, laboratory tests will be performed in the Central Laboratory of
the hospital in which the protocol will be performed and will be available online for
consultation. In the case of side effects, the drug may be stopped at the request of the
patient or according to medical advice. All patients will undergo to initial ophthalmologic
evaluation followed by six-monthly evaluations. The drug will be withdrawal, if changes
suggestive of retinopathy are observed. After the end of treatment, patients will be
followed over the next five years due to the risk of late onset of retinopathy.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT02994537 -
Study of the Clinical Features of Autoimmune Hepatitis
|
||
Recruiting |
NCT04617561 -
Ursodeoxycholic Acid Combined With Low Dose Glucocorticoid in the Treatment of PBC With AIH Features II
|
Phase 4 | |
Recruiting |
NCT04376528 -
Mycophenolate Mofetil Versus Cyclosporin A in the Treatment of Primary Biliary Cholangitis-autoimmune Hepatitis Overlap Syndrome Due to Nonresponse to Standard Therapy
|
Phase 4 | |
Not yet recruiting |
NCT05473403 -
Validation of a Prognostic Score for Steroid Therapy Response in Acute Severe Autoimmune Hepatitis
|
N/A | |
Terminated |
NCT00286663 -
Autoimmune Hepatitis Study
|
Phase 1 | |
Withdrawn |
NCT03593460 -
Phase II AutoImmune Hepatitis
|
Phase 2 | |
Completed |
NCT03941184 -
Spontaneous Coronary Artery Dissection (SCAD) and Autoimmunity
|
||
Recruiting |
NCT03146884 -
Swiss Autoimmune Hepatitis Cohort Study
|
||
Recruiting |
NCT02997878 -
Selected Mesenchymal Stromal Cells to Reduce Inflammation in Patients With PSC and AIH
|
Phase 1/Phase 2 | |
Recruiting |
NCT02874586 -
Plasma Exchange Combination of Immunosuppressive Regimens for Auto-immune Hepatitis
|
N/A | |
Recruiting |
NCT02936596 -
Remission Induction of Primary Biliary Cholangitis-autoimmune Hepatitis Overlap Syndrome
|
N/A | |
Withdrawn |
NCT02878863 -
Paeoniflorin Combination of Hepatoprotective Drugs Versus Hepatoprotective Drugs Only for Auto-immune Hepatitis
|
Phase 3 |