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

• ClinicalTrials.gov Identifier: NCT02171949
• Recruitment Status: Unknown
• First Posted: June 24, 2014
• Last Update Posted: November 28, 2017
• Sponsor: Hospital Sao Rafael
• Collaborators: Ministry of Science and Technology, Brazil; Ministry of Health, Brazil
• Information provided by (Responsible Party): Ricardo Ribeiro dos Santos, Hospital Sao Rafael

Tracking Information

• First Submitted Date: June 16, 2014
• First Posted Date: June 24, 2014
• Last Update Posted Date: November 28, 2017
• Actual Study Start Date: April 2015
• Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 20, 2014)

• Evaluation of Child-Pugh score [ Time Frame: 12 months ]
  Functional class improvement of 2 points on Child-Pugh score.
• Evaluation of MELD score [ Time Frame: 12 months ]
  Functional class improvement of 2 points on MELD score.

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02171949 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 20, 2014)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Chronic Hepatitis
• Hepatic Cirrhosis

Intervention

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.

Study Arms

• No Intervention: Control group
• Active Comparator: Bone marrow mononuclear cell therapy
  Intervention: Biological: Infusion of bone marrow mononuclear cells.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: June 20, 2014): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 2019
• Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil

Administrative Information

• NCT Number: NCT02171949
• Other Study ID Numbers: PCL 03/13
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Ricardo Ribeiro dos Santos, Hospital Sao Rafael
• Study Sponsor: Hospital Sao Rafael

Collaborators

• Ministry of Science and Technology, Brazil
• Ministry of Health, Brazil

Investigators

• Principal Investigator: André C Lyra, PhD; Hospital São Rafael
• Study Chair: Bruno SF Souza, MD, Msc; Hospital São Rafael
• Study Chair: Eduardo L Braga, PhD; Hospital São Rafael
• Study Chair: Lourianne N Cavalcante, PhD; Hospital São Rafael
• Study Chair: Milena BP Soares, PhD; Hospital São Rafael
• Principal Investigator: Ricardo R dos Santos, PhD; Hospital São Rafael
• Study Chair: Ticiana F Larocca, MD, Msc; Hospital São Rafael

• PRS Account: Hospital Sao Rafael
• Verification Date: November 2017