Double-blind Clinical Trial to Evaluate the Safety and Efficacy of Two Doses of Prolonged Release Pirfenidone, Compared Against Placebo Plus Conventional Therapy in Patients With Compensated Liver Cirrhosis.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 180
- 主要终点
- Clinical side effects
研究概览
简要总结
This will be a multicenter, double-blind clinical trial to evaluate the safety and efficacy of two doses of prolonged release pirfenidone, compared against placebo plus conventional therapy in patients with compensated liver cirrhosis. The study will be conducted in compliance with International Standard good clinical practices (GCPs) and the Declaration of Helsinki. The protocol is approved by a local Institutional Review Board and registered in clinical trials.gov.
详细描述
Liver cirrhosis represents a clear public health problem all over the world. In Mexico it ranks sixth as a cause of general mortality (third place in men and seventh in women) with 28,000 to 30,000 deaths per year, according to the latest National Institute of Statistics and Geography report. and the National Population Council.
Hepatic stellate cells are, to date, the main fibrogenic cells in the liver, thus becoming one of the most important therapeutic targets for treatment. Advances in the understanding of the molecular biology of the liver have allowed us to devise therapeutic strategies in order to avoid fibrosis and the consequent loss of liver function.
In 1994, a preliminary report was released publishing the antifibrotic properties of Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone, here and after PFD), a drug initially known for its analgesic and anti-inflammatory capabilities.
In 1995, its antifibrotic properties were described when administered in a hamster model with pulmonary fibrosis induced by bleomycin. Its mechanism of action was not completely well established at that time. It was known to be at the transcriptional level and was shown to modulate the deposition of extracellular matrix, the production of cytokines, growth factors and fibroblast proliferation. It is associated with the inhibition of the production and activity of tumor necrosis factor (TNF-α), transforming growth factor (TGF-ß), interferon-gamma and interleukin (IL) -6 and increases the production of anti-inflammatory cytokines such as IL-10.
The PFD molecule has shown promising effects both in vitro and in vivo in the prevention and treatment of idiopathic pulmonary fibrosis (IPF), in the prevention of capsular contracture after breast implants, renal interstitial fibrosis, in particular focal and segmental glomerulosclerosis or diabetic nephropathy and a wide range of conditions that share the phenomenon of abnormal scarring including hypertrophic and keloid scars, peritoneal adherences, neurofibromatosis and uterine fibromyomas. More recently it has also been evaluated in secondary and progressive variety multiple sclerosis, with promising results. In IPF, PFD has been positioned as the standard of care because it improves the outcomes, slowing down or blocking the decline of respiratory function and improving survival.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Placebo will be identical to medication.
Methods to assign treatment:
Before assigning numbers to subjects, the researcher must confirm that the inclusion criteria have been met, that none of the exclusion criteria apply, that written and signed informed consent has been obtained, that the evaluations of the scrutiny (of admission) and that the required laboratory results are available and meet the admission criteria. To do this, the centers will be assisted with a check list format that contains all the selection criteria.
The person responsible for the medication at the research site will contact the Randomization center, where the treatment will be assigned to the patient.
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Both genders over 18 years of age.
- •Patients with clinical, biochemical, radiological diagnostic confirmation as well as evidence of grade 4 fibrosis based on an invasive (liver biopsy) or non-invasive method (fibrotest and/or fibroscan).
- •With functional class A (score of 5 and 6) and B (score of 7 or 8) on the Child-Pugh scale.
- •Optionally, transjugular liver biopsy with measurement of the portal system flow pressure gradient, in at least 20% of the population.
- •Be controlled with medications that are consumed at stable doses for at least 30 days.
- •Have a BMI greater than 19.1 kg/m 2 and less than 34.9 kg/m 2
- •Have the required standardized and homogeneous diet for patients
- •Do not drink alcoholic beverages for at least one year prior to the start of the study.
- •Electrocardiogram normal or without clinical significance.
- •Laboratory tests that confirm your condition and functional class, with results that, in the opinion of the principal investigator, do not put the patient at risk:
- •Complete blood count, with hemoglobin values ≥ 12 g/dL, leukocytes ≥ 3,500 mL, platelets ≥ 50,000 mL
- •Blood chemistry (glucose, urea, creatinine, uric acid, cystatin C).
- •Complete liver function tests (total protein, globulin, albumin, ALT, AST, gamma-glutamyltransferase (GGT), alkaline phosphatase (AP), lactic dehydrogenase (LDH), Total Bilirubin, C-reactive Protein).
- •Fibrotest and/or FibroScan with a result of F
- •General urine examination.
- •Inclusion Criteria for patients with hepatitis C virus liver damage.
- •Having been previously treated with standardized antiviral management
- •More than 12 months have passed since the end of antiviral treatment.
- •Inclusion Criteria for patients with liver damage of autoimmune etiology.
- •a. Be under immunosuppressive treatment (steroid plus azathioprine) at a stable dose for at least 6 months at the beginning of the study.
- •Inclusion Criteria for patients with liver damage due to alcohol.
- •With alcohol inactivity for at least one year before the start of the study.
排除标准
- •Pregnancy and breastfeeding.
- •History of known allergy or hypersensitivity to PFD.
- •Have liver cirrhosis with functional reserve B (score of 9) or functional reserve C (score of 10 or more) on the Child-Pugh scale. 11 (See annexes).
- •History of Upper Gastrointestinal Bleeding, Ascites, Hepatic Encephalopathy or any other complication due to previous Portal Hypertension.
- •Body Mass Index less than 19 kg/m 2 or greater than 35 kg/m 2
- •Hemoglobin values less than 12 g/dL.
- •Have participated in another clinical study in the 60 days prior to the start of this one.
- •Hospitalization within 30 days prior to the start of medication administration.
- •Concomitant systemic infection other than hepatitis C virus (HCV), including Respiratory Tract Infections , Urinary Tract Infections, human immunodeficiency virus (HIV), cellulitis, etc.
- •Current use (less than 1 month) of colchicine, ursodeoxycholic acid, silimarin, or s-adenosine methionine, or cytotoxic agent, cytokine modulator or receptor antagonist, daily sildenafil or fluvoxamine, theophylline or other methylxanthines, or alternative medicine.
- •Have clinical data of pulmonary fibrosis, heart, respiratory or kidney failure (serum creatinine > 1.5 mg/dL).
- •Other medications that, in the opinion of the principal investigator, may interfere with the study.
- •Any other clinical condition that causes fibrosis other than liver fibrosis or a condition that, in the opinion of the principal investigator, could compromise the safety and well-being of the patient or put the conduct of the study at risk, such as hepatocellular carcinoma.
- •Elimination criteria
- •Any patient who presents a clinical finding compatible with decompensated cirrhosis (bleeding of variceal origin, clinical ascites, evident hepatic encephalopathy, hepatocellular carcinoma) or an adverse event or condition that, in the opinion of the principal investigator, warrants suspension of the patient's participation will be suspended from the study, but their data will be considered in the "intention to treat" analysis, when applicable.
- •In the event that a serious adverse event occurs that, in the opinion of the principal investigator, warrants suspension of the patient's participation. In these cases, clinical and biochemical data will be considered in the intention-to-treat analysis, when applicable.
研究组 & 干预措施
Prolonged release pirfenidone (PR-PFD), 1200 mg group
Subjects will receive one tablet during breakfast and 2 tablets during dinner.
干预措施: Pirfenidone 1200 mg (Drug)
PR-PFD, 1800 mg group
Subjects will receive one tablet during breakfast and 2 tablets during dinner.
干预措施: Pirfenidone 1800 mg (Drug)
Placebo group
Subjects will receive one tablet during breakfast and 2 tablets during dinner.
干预措施: Placebo (Drug)
结局指标
主要结局
Clinical side effects
时间窗: 6, 12, 18 and 24 months
Clinical side effects will be evaluated according to World Health Organization guidelines. The following definitions will be used to grade the severity of adverse events: Mild: Awareness of sign, symptom or event, but easily tolerated. Moderate: Discomfort sufficient to cause interference with usual activity and may require intervention. Serious: Disabling without ability to do usual activities, or significantly affects clinical status and requires intervention. Puts Life at Risk: Immediate risk of death (Sponsor must be notified within 24 hours). The Investigators must also evaluate the relationship of any adverse event with the use of the study drug, based on the available information, according to the following guidelines: 0 = Unrelated 1. = Possibly related 2. = Probably related
Change in liver fibrosis
时间窗: 6, 12, 18 and 24 months
Fibrosis change based on Hepatic Elastography. Variation of fibrosis score by at least 30% in kilo Pascals (kPa) according to accurate hepatic elastography measurements. Fibrosis change based on Fibrotest. Change of fibrosis score by at least 10% in Fibrotest units.
次要结局
- Improvement in Child Pugh score(6, 12, 18 and 24 months)
- Improvement in MELD score(6, 12, 18 and 24 months)
- Improvement in bilirrubin and albumin(6, 12, 18 and 24 months)
- Improvement in prothrombin time(6, 12, 18 and 24 months)
- Improvement in liver enzymes(6, 12, 18 and 24 months)
- Improvement in EuroQol Visual analog scales(6, 12, 18 and 24 months)
- Improvement in EuroQol five dimensions Scale(6, 12, 18 and 24 months)
- Improvement in modified fatigue impact scale (MFIS)(6, 12, 18 and 24 months)
研究者
Jorge L Poo
PROMHEPA administrator and Co-Investigator
Grupo Mexicano para el Estudios de las Enfermedades Hepaticas