Clinical trial NCT02171949: Clinical Trial for Evaluation of Treatment With Multiple Infusions of Mononuclear Bone Marrow Cells in Patients With Chronic Liver Diseases
Official title: Randomized, Open and Controlled Clinical Trial for Evaluation of Treatment With Multiple Infusions of Mononuclear Bone Marrow Cells in Patients With Chronic Liver Diseases
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Chronic Hepatitis
Hepatic Cirrhosis
Keywords: Chronic hepatitis
Hepatic cirrhosis
Lead sponsor: Hospital Sao Rafael
Sponsor class: OTHER
Collaborators: name: Ministry of Science and Technology, Brazil
name: Ministry of Health, Brazil
First posted: 2014-06-24
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Evaluation of Child-Pugh score
timeFrame: 12 months
measure: Evaluation of MELD score
timeFrame: 12 months
Secondary outcomes:
measure: Degree of muscle strength
timeFrame: 12 months
measure: Hepatic fibrosis
timeFrame: 12 months
measure: Quality of life
timeFrame: 12 months
measure: Evaluation of functional capacity
timeFrame: 12 months
measure: Evaluation of serum bilirubin levels
timeFrame: 12 months
measure: Evaluation of serum albumin levels
timeFrame: 12 months
measure: Evaluation of prothrombin time
timeFrame: 12 months
measure: Evaluation of serum levels of cytokines
timeFrame: 12 months
measure: Evaluation of fibrosis markers levels
timeFrame: 12 months
Other outcomes:
Locations:
city: Salvador
country: Brazil
facility: Hospital São Rafael
state: Bahia
Study officials:
affiliation: Hospital São Rafael
name: André C Lyra, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital São Rafael
name: Bruno SF Souza, MD, Msc
role: STUDY_CHAIR
affiliation: Hospital São Rafael
name: Eduardo L Braga, PhD
role: STUDY_CHAIR
affiliation: Hospital São Rafael
name: Lourianne N Cavalcante, PhD
role: STUDY_CHAIR
affiliation: Hospital São Rafael
name: Milena BP Soares, PhD
role: STUDY_CHAIR
affiliation: Hospital São Rafael
name: Ricardo R dos Santos, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital São Rafael
name: Ticiana F Larocca, MD, Msc
role: STUDY_CHAIR
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