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

Randomized, Open and Controlled Clinical Trial for Evaluation of Treatment With Multiple Infusions of Mononuclear Bone Marrow Cells in Patients With Chronic Liver Diseases

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.

Study Overview

• Status: Unknown
• Conditions: Hepatic Cirrhosis; Chronic Hepatitis
• Intervention / Treatment: Biological: Infusion of bone marrow mononuclear cells.

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 Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: André C Lyra, PhD; Phone Number: 557132816455; Email: aclyra@live.com

Study Locations

• Brazil
  • Bahia
    • Salvador, Bahia, Brazil, 41253-190
      • Recruiting
      • Hospital Sao Rafael
      • Contact: André C Lyra, PhD; Phone Number: 55713281-6455; Email: aclyra@live.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group
Active Comparator: Bone marrow mononuclear cell therapy	Biological: Infusion of bone marrow mononuclear cells.; Patients on this group will receive therapy with mononuclear cells. The cells will be diluted on saline and then injected on the hepatic artery through femoral artery puncture.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of Child-Pugh score	Functional class improvement of 2 points on Child-Pugh score.	12 months
Evaluation of MELD score	Functional class improvement of 2 points on MELD score.	12 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Hospital Sao Rafael
• Collaborators: Ministry of Health, Brazil; Ministry of Science and Technology, Brazil
• Investigators: Principal Investigator: André C Lyra, PhD, Hospital Sao Rafael; Study Chair: Eduardo L Braga, PhD, Hospital Sao Rafael; Study Chair: Lourianne N Cavalcante, PhD, Hospital Sao Rafael; Study Chair: Milena BP Soares, PhD, Hospital Sao Rafael; Principal Investigator: Ricardo R dos Santos, PhD, Hospital Sao Rafael

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): June 1, 2019

Study Registration Dates

• First Submitted: June 16, 2014
• First Submitted That Met QC Criteria: June 20, 2014
• First Posted (Estimate): June 24, 2014

Study Record Updates

• Last Update Posted (Actual): November 28, 2017
• Last Update Submitted That Met QC Criteria: November 27, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Chronic hepatitis; Hepatic cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Hepatitis; Hepatitis, Chronic; Liver Cirrhosis
• Other Study ID Numbers: PCL 03/13