Possible Role of Chloroquine to Induce a Complete Remission in the Treatment of Autoimmune Hepatitis: a Randomized Trial

• ClinicalTrials.gov Identifier: NCT02463331
• Recruitment Status: Completed
• First Posted: June 4, 2015
• Results First Posted: December 30, 2016
• Last Update Posted: February 15, 2017
• Sponsor: University of Sao Paulo General Hospital
• Information provided by (Responsible Party): Lydia Teófilo de Moraes Falcão, University of Sao Paulo General Hospital

Study Description

Brief Summary:

The gold-standard treatment of Autoimmune hepatitis (AIH), with prednisone alone or in conjunction with azathioprine can reach resolution of the disease in 70-80% of the cases in US. However, in Brazil the response to these treatments seems to be worse, approximately 35% in five years. Because of the side effects of the gold-standard treatment and the need for an alternative option for the no responsive patients, news drugs must be evaluated for this proposal. Chloroquine diphosphate is an antimalarial drug that has been used for the treatment of rheumatological diseases for at the least five decades. Chloroquine was used as a single drug for up to two years for the maintenance of AIH remission in an open study. There was a 6.49 greater chance of relapse in the historical controls when compared with patients treated with chloroquine (72.2% x 23.5%; p = 0.031). The aim of this study was to investigate whether chloroquine in conjunction with prednisone can be used as an alternative treatment of AIH in a randomized study, and to evaluate its side effects.

Condition or disease	Intervention/treatment	Phase
Autoimmune Hepatitis	Drug: Chloroquine diphosphate; Drug: prednisone; Drug: azathioprine	Phase 4

Detailed Description:

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.

Because of the side effects of the gold-standard treatment and the need for an alternative option for the no responsive patients, news drugs must be evaluated for this proposal.

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 aim of this study was to investigate whether chloroquine in conjunction with prednisone can be used as an alternative treatment of AIH in a randomized study, and to evaluate its side effects.

To be included patients had to satisfy the following criteria simultaneously: a diagnosis of probable / definite AIH and the indication of treatment (according to the International AIH Group), normal liver function and absence of clinical signs of decompensated liver disease (ascites, hepatic encephalopathy, gastrointestinal bleeding and hepatocellular carcinoma). 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. Treatment will be discontinued in case of pregnancy, patient's desire, side-effects or relapse of AIH.

Patients were randomized to receive azathioprine and prednisone or chloroquine and prednisone. The alternative treatment, with chloroquine, was maintained unless it caused major side-effects, no biochemical response or treatment failure. In this case, azathioprine was introduced in association with prednisone. All patients had visits every 30 days during the first six months with routine blood tests performed. After then, consultations were every two months. All complaints were recorded. Every patient were treated by the doctors responsible for the study, laboratory tests were performed in the Central Laboratory of the hospital. All patients underwent to initial ophthalmologic evaluation followed by six-monthly evaluations. The drug was withdrawal, if changes suggestive of retinopathy were observed.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 57 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Possible Role of Chloroquine in Conjunction to Prednisone to Induce a Complete Remission in the Treatment of Autoimmune Hepatitis: a Randomized Trial
• Study Start Date: May 2003
• Actual Primary Completion Date: June 2015
• Actual Study Completion Date: July 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: chloroquine plus prednisone; Chloroquine diphosphate 250mg/day associated to prednisone in variable doses	Drug: Chloroquine diphosphate; One pill of chloroquine diphosphate per day until the end of the study; Other Name: Chloroquine; Drug: prednisone; Prednisone 5-15 mg/day until the end of the study
Experimental: azathioprine plus prednisone; azathioprine in variable doses (50-150mg/day) associated to prednisone in variable doses	Drug: prednisone; Prednisone 5-15 mg/day until the end of the study; Drug: azathioprine; azathioprine 1-2mg/Kg/day until the end of the study

Outcome Measures

Primary Outcome Measures :

1. Biochemical Response to Therapy [ Time Frame: six months ]
   The biochemical response is defined when there is normalization of hepatic enzymes, mainly AST and ALT.

Secondary Outcome Measures :

1. Histopathological Response to Therapy [ Time Frame: liver biopsy was was performed to evaluate histopathological response after 18 months of biochemical response ]
   Histopathological response is achieved when there is minimal or no inflammation in hepatic tissue, as assessed by liver biopsy.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of autoimmune hepatitis according to Autoimmune Hepatitis International Group with indication for treatment
• No evidence of decompensated liver cirrhosis
• Non-pregnant women and women with no intention to become pregnant
• Willing to participate in the study

Exclusion Criteria:

• Discrete biochemical changes and histological inflammatory activity absent / minimal (periportal / peri-septal: 0/1 +) or decompensated cirrhosis
• Cases of loss of follow up

Contacts and Locations

Sponsors and Collaborators

University of Sao Paulo General Hospital

Investigators

• Principal Investigator: Eduardo LR Cançado; University of Sao Paulo General Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

T de Moraes Falcão L, Terrabuio DRB, Diniz MA, da Silva Evangelista A, Souza FG, R Cancado EL. Efficacy and safety of chloroquine plus prednisone for the treatment of autoimmune hepatitis in a randomized trial. JGH Open. 2019 Sep 10;4(3):371-377. doi: 10.1002/jgh3.12258. eCollection 2020 Jun.

• Responsible Party: Lydia Teófilo de Moraes Falcão, Association of Chloroquine and Prednisone as an Alternative Treatment for Autoimmune Hepatitis: a Randomized Trial, University of Sao Paulo General Hospital
• ClinicalTrials.gov Identifier: NCT02463331
• Other Study ID Numbers: 0571/04
• First Posted: June 4, 2015
• Results First Posted: December 30, 2016
• Last Update Posted: February 15, 2017
• Last Verified: December 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Lydia Teófilo de Moraes Falcão, University of Sao Paulo General Hospital:

autoimmune hepatitis; chloroquine; treatment

Additional relevant MeSH terms:

Hepatitis A; Hepatitis; Hepatitis, Autoimmune; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Hepatitis, Chronic; Autoimmune Diseases; Immune System Diseases; Chloroquine; Chloroquine diphosphate; Prednisone; Azathioprine; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Amebicides; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Antimalarials