Clinical Trial for Evaluation of Treatment With Multiple Infusions of Mononuclear Bone Marrow Cells in Patients With Chronic Liver Diseases

Phase 2

• Conditions: Hepatic Cirrhosis; Chronic Hepatitis
• Interventions: Biological: Infusion of bone marrow mononuclear cells.

• Registration Number: NCT02171949
• Lead Sponsor: Hospital Sao Rafael

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of multiple infusions of mononuclear bone marrow cells in patients with chronic liver diseases.

Detailed Description

This is a safety/efficacy phase II, open, randomized, controlled clinical trial, with two arms. The study population will consist of 30 patients with chronic decompensated liver disease (Child-Pugh B or C). The candidates included in the study will be asked to voluntarily participate and sign the written consent.

The patients will be allocated randomly into 2 groups: in group A, the patients will undergo the intervention; and in group B, the patients will be the controls. Patients of both groups will receive clinical follow-up. They will be maintained on drug therapy commonly used in patients with cirrhosis, which may include: spironolactone, furosemide, lactulose, metronidazole, neomycin, analogs of nucleoside / nucleotide in patients with hepatitis B, and vitamin complexes.

All patients included in Group A will undergo cell therapy according to the technique described as follows: on day 1 (D-1), patients will be hospitalized to undergo the bone marrow puncture through the iliac crest. 150 to 200 ml of bone marrow aspirate will be collected. The procedure will be done under local anesthesia and sedation. The fraction of mononuclear cells will be isolated from the aspirated marrow by the SEPAX (System of cell processing) - Biosafe, Switzerland.

The enriched fraction of collected mononuclear cells will be resuspended in saline. The obtained cell populations will be analyzed by flow cytometry for its characterization, and then diluted in 20 ml saline. The cells will be injected 3 times throughout the study, on days 1 (D-1), 30 (D-30) and 60 (D-60).

Patients will undergo a series of clinical and laboratory evaluations and will also be submitted to the following procedures:

* Cell blood count

* Biochemical analysis (measurement of electrolytes - sodium and potassium)

* Renal function tests (urea and creatinine)

* Liver profile tests (total proteins and fractions, bilirubin, prothrombin time, transaminases, alkaline phosphatase, gamma-GT)

* Metabolic profile (glucose, total cholesterol and fractions, triglycerides)

* Thyroid profile tests

* Serology required for blood transfusion and bone marrow transplant in Brazil

* Alpha-fetoprotein

* Beta-HCG (human chorionic gonadotropin), for women

* Handgrip dynamometer

* Treadmill test

* Six-minute walk test

* Abdomen doppler ultrasound

* Magnetic resonance imaging of the upper abdomen with elastography

* Measurement of serum factors

* Shear wave elastography

Also, the patients will respond to questions from the SF (Short Form) -36 questionnaire (for assessment of quality of life).

Clinical follow-up will be kept for patients who suspend their participation in the study for any adverse event and / or laboratory abnormality, or for the patient's own desire, following insurance protocols. In addition to the clinical and surgical follow-up, specific medical care will be offered to patients who experience adverse events, until stabilization of the patient, even if the target date for completion of the study has been exceeded.

Study Timeline

• Study First Submitted: 2014-06-16
• Study First Submitted QC: 2014-06-20
• Study First Posted: 2014-06-24
• Study Start: 2015-04
• Status Verified: 2017-11
• Last Update Submitted: 2017-11-27
• Last Update Posted: 2017-11-28
• Primary Completion: 2018-12
• Study Completion: 2019-06

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Diagnosis of liver cirrhosis of different etiologies, confirmed by clinical examination, laboratory tests, imaging studies and / or biopsy that shows process of evolution to cirrhosis or established cirrhosis (equivalent to Metavir score F3/F4);
• Non-participation on the waiting list for liver transplantation or, in case of participation, allocation after the fifth position in the list, for subjects with blood group A or O, and after the third position for subjects with other blood groups;
• Absence of clinical, laboratory and radiological evidence of hepatocellular carcinoma;
• Absence of pregnancy potential or negative pregnancy test for female patients, or impossibility to use a contraception method during the study;
• Permission for doing the puncture of iliac crest after evaluation of pre-anesthetic visit.

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Exclusion Criteria

• Impossibility to obtain vascular access for percutaneous procedure;
• Sepsis;
• Hepatic encephalopathy detected at the screening tests;
• Budd-Chiari syndrome;
• Severe coagulopathy with INR > 2,4 or platelet count < 30.000;
• Presence of malignancies (excluding non-melanoma skin cancer);
• Decompensated heart failure;
• Primary hematologic diseases;
• Renal failure with creatinin > 2,5mg/dl;
• Coinfection with HIV;
• Pregnancy;
• Dependence of organic medium such as circulatory or ventilatory;
• Any other comorbidity with an impact on the survival in 2 years;
• Participation in other clinical trial.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Bone marrow mononuclear cell therapy	Infusion of bone marrow mononuclear cells.	-

Primary Outcome Measures

Name	Time	Method
Evaluation of Child-Pugh score	12 months	Functional class improvement of 2 points on Child-Pugh score.
Evaluation of MELD score	12 months	Functional class improvement of 2 points on MELD score.

Secondary Outcome Measures

Name	Time	Method
Evaluation of functional capacity	12 months	Improvement in the functional capacity, assessed by six-minute walk test.
Degree of muscle strength	12 months	Improvement in the degree of muscle strength assessed using handgrip dynamometer.
Hepatic fibrosis	12 months	Decrease of hepatic fibrosis detected by elastography shear waves.
Evaluation of fibrosis markers levels	12 months	Decrease in the serum levels of fibrosis markers.
Quality of life	12 months	Improvement on the SF-36 questionnaire score, which evaluates quality of life.
Evaluation of prothrombin time	12 months	Improvement in prothrombin time.
Evaluation of serum levels of cytokines	12 months	Decrease in the serum levels of cytokines.
Evaluation of serum bilirubin levels	12 months	Improvement in the serum bilirubin levels.
Evaluation of serum albumin levels	12 months	Improvement in the serum albumin levels.

Trial Locations

Locations (1)

Hospital São Rafael; 🇧🇷 Salvador, Bahia, Brazil