search
Back to results

Comparison of Bovine Colostrum Versus Placebo in Treatment of Severe Alcoholic Hepatitis: A Randomized Double Blind Controlled Trial (BASH)

Primary Purpose

Alcoholic Hepatitis

Status
Active
Phase
Phase 3
Locations
India
Study Type
Interventional
Intervention
Bovine Colostrum
Placebo
Sponsored by
Dayanand Medical College and Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alcoholic Hepatitis focused on measuring Bovine Colostrum, Corticosteriods, Endotoxin, MELD, mDF

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Alcoholic hepatitis Jaundice < 3 months Bilirubin > 5 mg/dl PTI (INR) Increased: >1.4 Leucocytosis >> 11,000/micro L. AST< 300 IU/l ; AST/ALT >2
  2. Hepatic Encephalopathy
  3. Men and women age > 18 years and above
  4. DF>32
  5. MELD≥21
  6. Actively consuming alcohol within 6 weeks of entry into the study
  7. Patient with controlled upper GI bleed, resolved sepsis and acute kidney injury can be enrolled
  8. Voluntary informed consent

Exclusion Criteria

  1. Failure to obtain informed consent
  2. Jaundice more than 3 months
  3. AST>500 IU/L, ALT>300 IU/L
  4. Other concomitant causes of liver disease: viral hepatitis, autoimmune liver disease, metabolic liver disease, vascular liver disease
  5. HIV positive
  6. Cow milk allergy or severe lactose intolerance
  7. Active Gastrointestinal bleeding
  8. Acute kidney injury at time of randomization with Creatinine> 1.5 mg/dL
  9. Evidence of acute pancreatitis or biliary obstruction
  10. Subjects who are pregnant or lactating
  11. Significant systemic cardio-pulmonary illness (what if on ventilator for HE or respiratory failure) - These are terminally ill patients, hence be excluded
  12. Patients requiring the use of vasopressors or inotropic support in 12 hours prior to randomization
  13. Treatment for alcoholic hepatitis within 1 month of study entry with corticosteroids use>1 week.
  14. Any patient who has received any investigational drug or device within 30 days entering into the study.
  15. Patient who withdraw consent

Sites / Locations

  • Department of Gastroenterology, D.M.C. and Hospital
  • Ajay Duseja
  • Dharmesh Kapoor
  • Sandeep Nijhawan
  • Shalimar

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Bovine colostrum

Placebo

Arm Description

Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Pasteurized Bovine colostrum as a freeze dried powder (20 gm thrice a day) for 4 weeks. + Antibiotics + Diuretics +Terlipressin for HRS + acid suppression for prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed +drugs for HE if indicated

Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Placebo (Pasteurised Milk Powder) 20 gms thrice a day for 4 weeks + Antibiotics + Diuretics + drugs for HE + Terlipressin for HRS + acid suppression for prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed + if indicated.

Outcomes

Primary Outcome Measures

Survival
Survival at 3 month

Secondary Outcome Measures

Change in mDF levels
Change in mDF levels will be measured at baseline and after 30 days of treatment
Change in Endotoxin levels
Change in Endotoxin levels will be measured at baseline and after 4 weeks of treatment
Change in Cytokines levels
Change in Cytokines levels will be measured at baseline and after 30 days of treatment
Number of episodes of sepsis
Number of episodes of sepsis (bacteremia, Pneumonia, SBP, Cellulitis, UTI)
Survival
Survival at 1 month

Full Information

First Posted
June 8, 2015
Last Updated
September 27, 2023
Sponsor
Dayanand Medical College and Hospital
search

1. Study Identification

Unique Protocol Identification Number
NCT02473341
Brief Title
Comparison of Bovine Colostrum Versus Placebo in Treatment of Severe Alcoholic Hepatitis: A Randomized Double Blind Controlled Trial
Acronym
BASH
Official Title
Comparison of Bovine Colostrum Versus Placebo in Treatment of Severe Alcoholic Hepatitis: A Randomized Double Blind Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 14, 2017 (Actual)
Primary Completion Date
August 16, 2023 (Actual)
Study Completion Date
November 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dayanand Medical College and Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Severe Alcoholic hepatitis, defined by modified Maddrey's Discriminant Function (DF) ≥32, is associated with significant morbidity and mortality.(1,2) Of the various treatment modalities evaluated for treatment of Severe Alcoholic hepatitis, corticosteroids have been the most extensively studied.(1) Five out of 13 randomized controlled trials, and four out of 5 meta-analysis have shown a survival benefit with corticosteroids, especially in patients with DF ≥32 and/ or encephalopathy.(1-4) However, the role of corticosteroids in Severe Alcoholic hepatitis still remains controversial.(5-6) Corticosteroid therapy is not considered the ideal option by most authors because their beneficial effect seems to be confined to a highly select minority group in which the inhibitory effect of corticosteroids on liver inflammation is not outweighed by side effects such as weakened defence against infections, anti-anabolic effects, and possible ulcer promoting effects.(6) Corticosteroids are usually contraindicated in those with DF > 54 or MELD >24 (7) .Also corticosteroids are contraindicated in those with renal failure, gastro-intestinal bleed, pancreatitis and active sepsis. Therefore, there have been constant efforts to evaluate new therapies for Severe Alcoholic hepatitis (SAH). In a recent trial, combination of glucocorticoids plus N-acetylcysteine was found to improve one month survival in patients with Severe Alcoholic hepatitis, compared with glucocorticoids alone. However, the 6 month survival similar in both the groups.(8) Human colostrum and bovine colostrum are rich in protein, immunoglobulin, lactoferrin and growth factors. Recent studies suggest that colostrum components, immunoglobulin and growth factor benefits physically active person as well as in the treatment of autoimmune disorders. It is used for the treatment of a wide variety of gastrointestinal conditions, including non-steroidal anti-inflammatory drug-induced gut injury, Helicobacter pylori infection, immune deficiency related diarrhea as well as infective diarrhea.(9,10,11) It has also been sucessfully used to significantly decrease the level of Endotoxemia - lower levels of Lipopolysaccharides. We plan to compare the efficacy of bovine colostrum versus Placebo (Pasteurized milk powder) alone in treatment of severe alcoholic hepatitis. Bovine Colostrum is rich in protein, immunoglobulin, lactoferrin and growth factors. Recent studies suggest that Colostrum components, immunoglobulin and growth factor benefits physically active person and in treatment of autoimmune disorders. It is used for the treatment of a wide variety of gastrointestinal conditions, including non-steroidal anti-inflammatory drug-induced gut injury, H pylori infection, immune deficiency related diarrhea as well as infective diarrhea.(9) The guidelines by American College of Gastroenterology (10) and other authors (11) have suggested that a combination of Corticosteroids and other drugs, which have different mechanisms of action, may be more beneficial for reducing mortality in severe alcoholic hepatitis. Hence, the investigators plan to compare the efficacy of combined therapy of Corticosteroids and Bovine colostrum versus Corticosteroids alone in treatment of severe alcoholic hepatitis.
Detailed Description
Diagnosis: The diagnosis of Alcoholic hepatitis is made by the following criteria (12) I. Chronic active alcohol abuse - >80 grams in males and > 60 grams in females for > 5 years for developing Alcoholic Cirrhosis (13) Alcohol use will be evaluated with the AUDIT score (EASL guidelines (14) II. Duration of jaundice < 3 months III. Serum Bilirubin >5 mg/dl IV. AST/ALT > 2:1 V. AST <300 IU/L VI. Prolonged PTI/INR VII. Neutrophilicleucocytosis VIII. Liver biopsy (Percutaneous or Transjugular). [Optional] Assessment of Severity Maddrey's Discriminant Function (15) Discriminant Function Index (DFI) was originally described by Maddrey and colleagues in a placebo controlled study to assess the benefit of corticosteroids in patients with AH. The original formula was 4.6 x prothrombin time (seconds) + serum Bilirubin (mg/dl). It was observed that patients with a DFI >93 and treated with placebo had a 28 day survival of 25%, whereas those with a DFI < 93 had a 100% survival. Subsequently this score was modified in 1986 and called Modified Discriminant Function (MDF). MDF = 4.6 x (Patient's PT - Control PT) + serum bilirubin (mg/dl). Untreated patients with MDF >32 had a survival of 68%. The American College of Gastroenterology9 recommends that patients with MDF > 32 and / or Encephalopathy should be treated. The prothrombin time varies greatly depending on the sensitivity of the thromboplastin reagent used for the test. This is the drawback of the MDF. MELD score (16) The model for end stage liver disease (MELD) score predicts survival in patients with cirrhosis and is used to prioritize patients for liver transplantation. MELD score = (0.957 x log serum creatinine + 0.378 x log serum bilirubin + 1.120 x log INR + 0.643) x 10. The advantage of MELD score is the use of INR in place of PT. The INR is comparable and uniform across laboratories worldwide. The American Association for Study of Liver Diseases recommends that a MELD score >20predicts SAH and should be the criterion for initiating treatment. Serial monitoring of MELD score with a change of 2 or more points over the first week on treatment has independently predicted mortality. GAHS score (17) Glasgow Alcoholic Hepatitis Score (GAHS) includes age, peripheral Total Leucocyte Count, serum Bilirubin (at days 1 and 6-9), blood urea nitrogen and PT. It is a better predictor of mortality at 28 days than MDF. GAHS score > 9 has an extremely poor prognosis unless treated with Corticosteroids. The drawback is lack of international validation. LILLE'S model (18) It is not traditionally used for predicting mortality of SAH. However, it helps to predict mortality at 7 days of SAH patients on Corticosteroids .If the score is more then 0.45 then Corticosteroids should be stopped. The diagnosis of Severe Alcoholic Hepatitis is made by the following criteria MDF>32, or MELD>20 Treatment Abstinence from alcohol This is the most important factor in predicting the outcome after surviving the acute alcoholic hepatitis (AH) episode. The incidence of recidivism after recovery from the first episode of AH varies from 10 - 70 %. Abstinence will be reinforced by giving patient oral/enteral Baclofen (GABA B receptor agonist) Nutrition Enteral nutrition is the preferred mode for supplemental nutrition. It is cheap, maintains gut mucosal integrity. This in turn decreases the risk of bacterial and endotoxin translocation resulting in less infections and endotoxemia. Pooled data from 5 RCT's of AH have demonstrated improved nutritional status compared to standard dietary intake, but without improving survival rates.19 The patient will be given 40k cal/kg diet along with 1.5gm/kg protiens, emphasizing breakfast and a night time snack with regular oral diet. Frequent interval feeding will be given to improved nitrogen balance. B complex multivitamins supplementation will be provided to all patients (EASL guidelines (14) Pharmacotherapy of Severe Alcoholic Hepatitis Corticosteroids Corticosteroids are the most extensively used treatment for Severe Alcoholic Hepatitis. 6/13 Randomized Controlled Trials and 4/6 meta-analysis have supported the use of Corticosteroids in Severe Alcoholic Hepatitis. The last meta-analysis of individual patient data from 5 high quality Randomized Controlled Trials using Corticosteroids forSevere Alcoholic Hepatitis concluded that Corticosteroids confers a 50% relative survival benefit at 1 month (85% versus 65% survival amongst those treated with Corticosteroids versus untreated patients). The number of patients needed to treatedis 5 to reduce one death. Oral Prednisolone 40mg daily or parenteral methylprednisolone (for patients unable to take orally) 32 mg intravenously daily for 4 weeks is the standard therapy. A Lille score of >0.45 after 7 days of treatment with Corticosteroids is an indication of non-response, increased susceptibility to infections and diminished survival (20). The Corticosteroids should be stopped if the Lilli score is >0.45. The most recent STOPAH trial was unable to show a significant improvement in mortality of SAH patients treated with Corticosteroids. There was a trend in favour of Corticosteroids. Pentoxifylline Pentoxifylline is a phosphodiesterase inhibitor. It is given orally in the dose of 400mg thrice a day for 28 days. In a pivotal study of 101 patients of SAH21, it was associated with survival benefit of 50%. In another study, it was found to be superior to Corticosteroids (22). In a recent study involving 50 patients at our center (23), we found that 20% vs 40% mortality in patients treated with Pentoxifylline versus controls, after 4 weeks of treatment. Acute kidney injury was the cause of death in 20% compared to 70% patients in Pentoxifylline group versus controls. Pentoxifylline induces recovery of renal & hepatic functions with a trend towards increased survival. However, a metanalysis of 5 Randomized Controlled Trials failed to show any benefit with Pentoxifylline24.In a large recent trial Corticosteriods plus Pentoxifyllinefor 4 weeks treatment with compared with prednisolone alone, did not result in improved 6-month survival.25 The major adverse effects include vomiting, diarrhea, abdominal pain, headache and skin rash. N-Acetylcyteine N-acetylcysteine could have value as an antioxidant in the treatment of acute alcoholic hepatitis,because the thiol group in N-acetylcysteine is able to reduce levels of free radicals. Administration of N-acetylcysteine might reconstitute the glutathione stocks of the hepatocytes. At present, N-acetylcysteine is used in the treatment of acetaminophen induced hepatitis. Intravenous acetylcysteine is most often used as an antidote for acetaminophen overdose due to its ability to increase levels of glutathione; however, it is also used to treat non-acetaminophen-induced acute liver failure (NAI-ALF) and severe alcoholic hepatitis and to prevent contrast-induced nephropathy (CIN). Although the i.v.and oral formulations of acetylcysteine have been evaluated for these indications, most studies have examined the i.v. form. I.V. acetylcysteine is used in the treatment of NAI-ALF to improve oxygenation to the liver. A trial to evaluate the efficacy of glucocorticoids plus N-acetylcysteine, as compared with glucocorticoids alone, in patients with severe acute alcoholic hepatitis.(26) reported improved one month survival in the combined treatment group. However the 6 month survival was not different in the two groups. Bovine colostrum Human colostrum is the first milk produced after birth and is particularly rich in immunoglobulin, antimicrobial peptides (lactoferrin and lacto peroxidase) and other bioactive molecule, including growth factors which are important for nutrition, growth and development of newborn infants and also for passive immunity. Bovine colostrum is produced by the cows during the first one day post parturition. This "early" milk has nutrient profile and immunological composition substantially different from 'mature' milk. It contains macronutrient like proteins, carbohydrate, oligosaccharides, fats and micronutrients like vitamins and minerals, also growth factors, anti-microbial compounds and immune regulating constituents either not present in mature milk or present substantially in lower concentration.(27,28) Bovine colostrum used in the treatment of HIV-positive patients with chronic diarrhea,(29) and rotavirus diarrhea in children.(30) Available evidence suggests a beneficial effect of supplementation of bovine colostrums in improving body composition, aspects of athletic performance, diarrhea in persons with immune-deficiency syndromes, NSAID-induced gastrointestinal ulcers, and aspects of the acute phase response that occurs secondary to surgery. Specific hyperimmune bovine colostrums, produced to have high neutralizing titer activity against Cryptosporidia, H. pylori, measles, rotavirus, and Shigella sp., appear to have clinical utility in conditions associated with these infectious organisms (31) Historically colostrum has been used for various illnesses in India as well as abroad for thousands of years. Ayurvedic physicians of India have used bovine colostrum for both medicinal and spiritual purposes since cows were first domesticated. By the late 18th century, Western medicine started to take an interest in colostrum and study it for its potential health benefits. As a consequence, it was prescribed for many conditions, including immune system enhancement. Interestingly, until the development of penicillin and other artificial antibiotics in the 20th century, colostrum was commonly used for fighting bacterial infections. In the early 20th century it was noted that antibody levels in the first milk produced after birth were much higher than levels found in the milk that was produced 72 hours later.There are now over 2000 published scientific articles that document the safety and efficacy of using colostrum. This seemingly perfect food has been shown to be non-species specific (32). In 2005, it was reported that is safe and effective in repair of tissues as well as for enhancing immunity.(33) The use of bovine colostrum as dietary supplement has increased substantially over the past decades. Bovine colostrum is harvested within first few hours of calving from dairy animals. The herds of cows are kept under close supervision in good state of hygiene without exposure to antibodies, pesticides and anthelmintics. The colostrum collected within 24 hours contains maximum substances but less in amounts, colostrum collected later will be more in quantity but contain less immunoglobins.(33) Colostrum contains the growth factors that help build lean muscle, including insulin-like growth factors (IGF-I & IGF-II) and growth hormone (GH). IGF-I, which is found naturally in colostrum, is the only natural hormone capable of promoting muscle growth by itself. The IGFs in humans and cows are identical, but bovine colostrum actually contains a greater concentration of IGF-I than human colostrum. This fact makes bovine colostrum attractive to bodybuilders, athletes and others seeking to gain muscle mass. According to a study conducted in Finland, IGF-1 induces protein synthesis, which leads to an increase in lean muscle mass without a corresponding rise in adipose (fat) tissue. The growth factors in colostrum "shift fuel utilization from carbohydrate to fat. It mean that body will burn more fat, including fat made from the carbohydrate and protein that are consumed, producing fuel more efficiently.(34) Bovine has hormone factor like gastrin which plays a role as a trophic factor for mucosal growth with in stomach. GLP-2 has shown a general trophic response with in the gut. Peptide growth factors in colostrum can influence the maintenance of mucosal mass and integrity. EGF stimulates cell proliferation and also influences crypt fission.(25) Human colostrum has higher concentration of growth factors as compared to bovine colostrum. The tables and figure below indicate how HC and BC differ in their nutrient content, immunological factors and growth factors (9,35,36) While BC are considered a rich source of IgG, growth factors, and lactoferrin, currently no specific standards exist that define BC dietary supplements with respect to actual constituents or amounts of constituents. The following constituents are generally present in bovine colostrums: macronutrients; vitamins; minerals; Ig (IgG, IgM, and IgA - including the secretory form); cytokines including interleukin-1beta (IL-1β), interleukin- 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ); growth factors including insulin-like growth factor (IGF) I and II, transforming growth factor-beta (TGF-β), and epidermal growth factor; lactoperoxidase; and lactoferrin. Depending on the health of the cows, feeding practices followed, collection period, and the processing/concentration practices utilized by specific manufacturers, the actual range and quantities of specific macro- and micronutrients, Ig, cytokines, growth factors, and other compounds might vary considerably.(37,38,39) BC contain relatively high amounts of Ig. Typically, Ig in general, and IgG specifically, constitutes the largest contribution to protein content in BC, with lactalbumin and casein contributing lesser amounts. Mean percentages of fat, protein, and lactose in colostrum were 6.7, 14.9, and 2.5, respectively.40 Other reports have estimated Ig concentrations from bovine mammary secretions with ranges for IgG1 (52-87 g/L), IgG2 (1.6-2.1 g/L), IgM(3.7-6.1 g/L), and IgA (3.2-6.2 g/L).41,42 As a rule, the Ig contribution will decline substantially in any BC collected more than 24 hours post-parturition and the amount of lactalbumin and casein will increase proportionately. Detailed research plan (Materials and Methods) Study design and setting This will be Double blind Randomized Placebo controlled Trial. We are planning a study of 2 independent groups in the ratio of 1:1. The correct dose appears to be 60 grams and the number of patients required to be randomized should be more than 40 patients (10,11). We plan to enroll 250 patients. We will use an uncorrected chi-squared statistic to evaluate this null hypothesis. The study will be conducted on patients of Severe Alcoholic Hepatitis admitted in Principal Investigator: Sandeep S Sidhu, Dayanand Medical College and Hospital, Ludhiana, Punjab, India . Principal Investigator: Omesh Goyal, Dayanand Medical College and Hospital, Ludhiana, Punjab, India Principal Investigator: Shalimar, All India Institute of Medical Sciences, New Delhi Principal Investigator: Ajay Duseja, PGI Hospital, Chandigarh, India Principal Investigator: Sandeep Nijhawan, SMS Hospital, Jaipur, India Principal Investigator: Dharmesh Kapoor, Global Hospital, Hyderabad, India Informed consent shall be taken from the patient/nearest relative of the patient for enrollment in the trial. Assignment Consecutive patients diagnosed to have Severe Alcoholic Hepatitis will be randomized into two groups (group A and B). The randomization will be performed using a computer generated random sequence with permuted blocks of varying size stratified for each centre. Masking Each center will have serially numbered identical vials containing bovine colostrum or pasteurized bovine milk arranged by a personnel who are not involved in the study according to the random sequence. The drug and the placebo will be identical in color, taste, appearance to ensure masking. All study personnel will be blinded to the treatment assignment (Bovine colostrum and placebo) for the duration of the study. The study drug will be administered by an oral route. The randomization code will be revealed only after the completion of recruitment, data collection and data analysis has been carried out. Randomization implementation Enrolment of patients, assessing eligibility and obtaining informed consent will be carried out by Principal Investigator (S.S. Sidhu) and other Centers Principal Investigator. Study Intervention The patients will be randomized to either Experimental arm: Bovine colostrum Enteral nutrition: Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Pasteurized Bovine colostrum as a freeze dried powder (20 gm thrice a day) for 4 weeks. + Antibiotics + Diuretics +Terlipressin for HRS + acid suppression for prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed +drugs for HE if indicated Placebo Comparator: Placebo Enteral nutrition: Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Placebo (Pasteurised Milk Powder) 20 gms thrice a day for 4 weeks + Antibiotics + Diuretics + drugs for HE + Terlipressin for HRS + acid suppression for prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed + if indicated. Study Methods Enrolment of patients, assessing eligibility and obtaining informed consent will be carried out by P.I. of each center Study Intervention Treatment for SAH: Enteral nutrition: Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Pasteurized Bovine colostrum (20gm thrice a day) for 4 weeks in one arm or Placebo (Pasteurize milk) 20gms thrice a day for4 weeks . Laboratory tests Liver biopsy: Transjugular liver biopsies will be obtained before start of therapy diagnosis of Alcoholic hepatitis [if possible] Biochemical tests Hemogram, blood glucose, liver function tests, prothrombin time, serum electrolytes, blood urea and serum creatinine will be done at baseline, and at and 7th day,14 days, 21 days , 28 days and then bimonthly for two monthsor earlier if indicated. Microbiologic tests: A diagnostic paracentesis will be done in all patients with ascites, at baseline, to diagnose Spontaneous Bacterial Peritonitis. A repeat cell count (Total and differential) shall be done on day 5 in patients diagnosed to have Spontaneous Bacterial Peritonitis. Blood culture, urine culture, cultures of aspirates from endotracheal tubes in ventilated patients for aerobic and anaerobic bacteria, and fungi shall be done on at admission. A chest radiograph shall also be done. Endotoxin level estimation, alpha TNF,IL6& IL8 will be done at baseline and at end of treatment. Tests for etiologic evaluation: Etiology of cirrhosis will be taken as alcohol if there is a history of significant alcohol intake (20 gm/day for females, and 80 gm/day for males for 10 years or more). Each patient will be tested for Hepatitis B surface antigen (HBsAg) and Anti-hepatitis C (HCV) antibody using a third generation commercial ELISA. Wherever indicated, autoimmune hepatitis will be diagnosed using antinuclear antibody, anti-smooth muscle antibody and anti-LKM; and hemochromatosis using serum iron, TIBC, ferritin and transferrin saturation. Each patient shall have an abdominal ultrasonography. Upper gastrointestinal endoscopy would be done, if indicated. Ascitic Fluid analysis:Ascitic Fluid analysis will be done on 1st day and 5th day of treatment. Outcome measures and endpoints Primary outcome measure Survival at 3 month Secondary outcome measure Survival at 1 months Change in mDF levels/ MELD will be measured at baseline and after 4 weeks of treatment Change in Endotoxin levels will be measured at baseline and after 4 weeks of treatment Change in Cytokines levels will be measured at baseline and after 4 weeks of treatment Number of episodes of sepsis (bacteremia, Pneumonia, SBP, Cellulitis, UTI) Study Endpoints Liver related death Liver Transplantation Death due to other causes Complication of Disease (GI Bleed, Renal failure, Sepsis) Monitoring for Adverse Events: Any adverse event will be recorded specifying the time of onset, the duration, the severity and the relationship to the test medication. Tolerability Tolerability of the study drug will be assessed by comparison of full blood cell count, liver function tests and renal function tests at baseline and at end of treatment. Follow-up All patients will be followed up to 3 months or until death. The status alive or dead will be assessed by telephoning a family member or by contacting the death registry at patients at birth place or place of residence. Statistical Analysis: Comparisons will be made with the Wilcoxon or t test for continuous variables according to the normality of distribution, and the χ2 test or Fisher exact test for qualitative variables. All results of continuous variables were expressed as means and 95% confidence intervals (CIs) for continuous variables and as the frequencies, percentages, and 95% CIs for categorical variables. The primary results will be presented for all analyses as unadjusted. The cumulative incidence of death will be estimated by the Kaplan-Meier method in each treatment group. The statistical significance of hazard ratio (HR) for treatment allocation will be tested using the Cox proportional hazards regression model. The potential heterogeneity in the treatment effect according to different study centers will tested by adding an interaction center × treatment in the Cox proportional hazards regression model. Potential risk factors will be first tested by the Cox proportional hazards regression model in univariate analysis. Prognostic variables with a significance at a level of less than 0.10 in univariate analyses will be included in a multivariable Cox proportional hazards regression model after removing variables showing a high degree of co - linearity. Factors included in a composite score will not be included in multivariable analysis to avoid bias related to the effect of co - linearity. All statistical analyses were performed in the intention- to-treat population as well as per-protocol population. We are planning a study of 2 independent groups in the ratio of 1:1. Prior data indicates that when 40 patients undergoing gastrointestinal surgery were randomized and given 56 g daily of Bovine Colostrum for 3 days preoperatively) or placebo and the course of the plasma endotoxin levels and the endotoxin neutralization capacity (ENC) were measured daily up to the 10th postoperative day10. The results showed that the LPS-levels in the LC1-group, expressed as AUC, were significantly lower than those in the control group (p < 0.05). The difference between the two groups was apparent on the day of the operation and the day after. The fall in endotoxin neutralizing capacity (ENC) was significantly lower in the patients treated with the BCC and the return to initial values was faster than in the control group (p < 0.006). In the second randomized study, 40 gms of Bovine Colostrum were given perioperatively to 60 open heart surgery patients without any decrease in LPS levels or fall in the ENC.(11) The correct dose appears to be 60 grams and the number of patients required to be randomized should be more than 40 patients (10,11). Sample Size:The Survival rate of patients in standard medical treatment arm was 22% (Am J Gastroenterol 2014; 109:1417-1423). There is no contemporary Randomized controlled trial on the such type of patient (mDf >60, MELD >30). We consider a 20% increase in survival rate to clinically meaningful and sufficient to change practice. To detect a 20% increase in survival (from 22% to 42 %) in 3 month, The sample size based on survival at a fixed time point (22% vs 42% at 3 months), we require 79 per group + 10% drop outs. The total sample size required for the study is 174.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholic Hepatitis
Keywords
Bovine Colostrum, Corticosteriods, Endotoxin, MELD, mDF

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
174 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bovine colostrum
Arm Type
Experimental
Arm Description
Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Pasteurized Bovine colostrum as a freeze dried powder (20 gm thrice a day) for 4 weeks. + Antibiotics + Diuretics +Terlipressin for HRS + acid suppression for prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed +drugs for HE if indicated
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Placebo (Pasteurised Milk Powder) 20 gms thrice a day for 4 weeks + Antibiotics + Diuretics + drugs for HE + Terlipressin for HRS + acid suppression for prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed + if indicated.
Intervention Type
Drug
Intervention Name(s)
Bovine Colostrum
Intervention Description
Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Pasteurized Bovine colostrum as a freeze dried powder (20 gm thrice a day) for 4 weeks. + Antibiotics + Diuretics +Terlipressin for HRS + acid suppression for prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed +drugs for HE if indicated
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins daily. Placebo (Pasteurised Milk Powder) 20 gms thrice a day for 4 weeks + Antibiotics + Diuretics + drugs for HE + Terlipressin for HRS + acid suppression for prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed + if indicated.
Primary Outcome Measure Information:
Title
Survival
Description
Survival at 3 month
Time Frame
3 month
Secondary Outcome Measure Information:
Title
Change in mDF levels
Description
Change in mDF levels will be measured at baseline and after 30 days of treatment
Time Frame
one month
Title
Change in Endotoxin levels
Description
Change in Endotoxin levels will be measured at baseline and after 4 weeks of treatment
Time Frame
one month
Title
Change in Cytokines levels
Description
Change in Cytokines levels will be measured at baseline and after 30 days of treatment
Time Frame
one month
Title
Number of episodes of sepsis
Description
Number of episodes of sepsis (bacteremia, Pneumonia, SBP, Cellulitis, UTI)
Time Frame
1 month
Title
Survival
Description
Survival at 1 month
Time Frame
1 month

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Alcoholic hepatitis Jaundice < 3 months Bilirubin > 5 mg/dl PTI (INR) Increased: >1.4 Leucocytosis >> 11,000/micro L. AST< 300 IU/l ; AST/ALT >2 Hepatic Encephalopathy Men and women age > 18 years and above DF>32 MELD≥21 Actively consuming alcohol within 6 weeks of entry into the study Patient with controlled upper GI bleed, resolved sepsis and acute kidney injury can be enrolled Voluntary informed consent Exclusion Criteria Failure to obtain informed consent Jaundice more than 3 months AST>500 IU/L, ALT>300 IU/L Other concomitant causes of liver disease: viral hepatitis, autoimmune liver disease, metabolic liver disease, vascular liver disease HIV positive Cow milk allergy or severe lactose intolerance Active Gastrointestinal bleeding Acute kidney injury at time of randomization with Creatinine> 1.5 mg/dL Evidence of acute pancreatitis or biliary obstruction Subjects who are pregnant or lactating Significant systemic cardio-pulmonary illness (what if on ventilator for HE or respiratory failure) - These are terminally ill patients, hence be excluded Patients requiring the use of vasopressors or inotropic support in 12 hours prior to randomization Treatment for alcoholic hepatitis within 1 month of study entry with corticosteroids use>1 week. Any patient who has received any investigational drug or device within 30 days entering into the study. Patient who withdraw consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sandeep Singh Sidhu, DM
Organizational Affiliation
Dayanand Medical College and Hospital, Ludhiana, Punjab, India
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ajay Duseja, DM
Organizational Affiliation
PGI Hospital, Chandigarh, India
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Shalimar S, DM
Organizational Affiliation
All India Institute of Medical Sciences, New Delhi
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dharmesh Kapoor
Organizational Affiliation
Gleneagles Global Hospital, Hyderabad
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sandeep Nijhawan
Organizational Affiliation
SMS Hospital, Jaipur, India
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Gastroenterology, D.M.C. and Hospital
City
Ludhiana
State/Province
Punjab
ZIP/Postal Code
141001
Country
India
Facility Name
Ajay Duseja
City
Chandigarh
Country
India
Facility Name
Dharmesh Kapoor
City
Hyderabad
Country
India
Facility Name
Sandeep Nijhawan
City
Jaipur
Country
India
Facility Name
Shalimar
City
New Delhi
Country
India

12. IPD Sharing Statement

Citations:
PubMed Identifier
16026887
Citation
Mathurin P. Corticosteroids for alcoholic hepatitis--what's next? J Hepatol. 2005 Sep;43(3):526-33. doi: 10.1016/j.jhep.2005.06.003. No abstract available.
Results Reference
result
PubMed Identifier
19553649
Citation
Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009 Jun 25;360(26):2758-69. doi: 10.1056/NEJMra0805786. No abstract available.
Results Reference
result
PubMed Identifier
10782906
Citation
Taieb J, Mathurin P, Elbim C, Cluzel P, Arce-Vicioso M, Bernard B, Opolon P, Gougerot-Pocidalo MA, Poynard T, Chollet-Martin S. Blood neutrophil functions and cytokine release in severe alcoholic hepatitis: effect of corticosteroids. J Hepatol. 2000 Apr;32(4):579-86. doi: 10.1016/s0168-8278(00)80219-6.
Results Reference
result
PubMed Identifier
2358784
Citation
Han J, Thompson P, Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med. 1990 Jul 1;172(1):391-4. doi: 10.1084/jem.172.1.391.
Results Reference
result
PubMed Identifier
2142869
Citation
Imperiale TF, McCullough AJ. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials. Ann Intern Med. 1990 Aug 15;113(4):299-307. doi: 10.7326/0003-4819-113-4-299.
Results Reference
result
PubMed Identifier
1828447
Citation
Daures JP, Peray P, Bories P, Blanc P, Yousfi A, Michel H, Gremy F. [Corticoid therapy in the treatment of acute alcoholic hepatitis. Results of a meta-analysis]. Gastroenterol Clin Biol. 1991;15(3):223-8. French.
Results Reference
result
PubMed Identifier
22388710
Citation
Sidhu SS, Goyal O, Singla P, Gupta D, Sood A, Chhina RS, Soni RK. Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival in severe alcoholic hepatitis (COPE trial). Dig Dis Sci. 2012 Jun;57(6):1664-71. doi: 10.1007/s10620-012-2097-4. Epub 2012 Mar 3.
Results Reference
result
PubMed Identifier
14653766
Citation
Kelly GS. Bovine colostrums: a review of clinical uses. Altern Med Rev. 2003 Nov;8(4):378-94. Erratum In: Altern Med Rev. 2004 Mar;9(1):69.
Results Reference
result
PubMed Identifier
9820369
Citation
McCullough AJ, O'Connor JF. Alcoholic liver disease: proposed recommendations for the American College of Gastroenterology. Am J Gastroenterol. 1998 Nov;93(11):2022-36. doi: 10.1111/j.1572-0241.1998.00587.x.
Results Reference
result
PubMed Identifier
18164508
Citation
Louvet A, Diaz E, Dharancy S, Coevoet H, Texier F, Thevenot T, Deltenre P, Canva V, Plane C, Mathurin P. Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids. J Hepatol. 2008 Mar;48(3):465-70. doi: 10.1016/j.jhep.2007.10.010. Epub 2007 Nov 26.
Results Reference
result
PubMed Identifier
15349802
Citation
Levitsky J, Mailliard ME. Diagnosis and therapy of alcoholic liver disease. Semin Liver Dis. 2004 Aug;24(3):233-47. doi: 10.1055/s-2004-832937.
Results Reference
result
PubMed Identifier
22633836
Citation
European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012 Aug;57(2):399-420. doi: 10.1016/j.jhep.2012.04.004. Epub 2012 May 26. No abstract available.
Results Reference
result
PubMed Identifier
352788
Citation
Maddrey WC, Boitnott JK, Bedine MS, Weber FL Jr, Mezey E, White RI Jr. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology. 1978 Aug;75(2):193-9.
Results Reference
result
PubMed Identifier
11172350
Citation
Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, D'Amico G, Dickson ER, Kim WR. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001 Feb;33(2):464-70. doi: 10.1053/jhep.2001.22172.
Results Reference
result
PubMed Identifier
16009691
Citation
Forrest EH, Evans CD, Stewart S, Phillips M, Oo YH, McAvoy NC, Fisher NC, Singhal S, Brind A, Haydon G, O'Grady J, Day CP, Hayes PC, Murray LS, Morris AJ. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut. 2005 Aug;54(8):1174-9. doi: 10.1136/gut.2004.050781.
Results Reference
result
PubMed Identifier
18721242
Citation
Dominguez M, Rincon D, Abraldes JG, Miquel R, Colmenero J, Bellot P, Garcia-Pagan JC, Fernandez R, Moreno M, Banares R, Arroyo V, Caballeria J, Gines P, Bataller R. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol. 2008 Nov;103(11):2747-56. doi: 10.1111/j.1572-0241.2008.02104.x. Epub 2008 Aug 21.
Results Reference
result
PubMed Identifier
23101983
Citation
Singal AK, Charlton MR. Nutrition in alcoholic liver disease. Clin Liver Dis. 2012 Nov;16(4):805-26. doi: 10.1016/j.cld.2012.08.009.
Results Reference
result
PubMed Identifier
11113085
Citation
Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000 Dec;119(6):1637-48. doi: 10.1053/gast.2000.20189.
Results Reference
result
PubMed Identifier
19340904
Citation
De BK, Gangopadhyay S, Dutta D, Baksi SD, Pani A, Ghosh P. Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. World J Gastroenterol. 2009 Apr 7;15(13):1613-9. doi: 10.3748/wjg.15.1613.
Results Reference
result
PubMed Identifier
23029716
Citation
Sidhu SS, Goyal O, Singla M, Bhatia KL, Chhina RS, Sood A. Pentoxifylline in severe alcoholic hepatitis: a prospective, randomised trial. J Assoc Physicians India. 2012 May;60:20-2.
Results Reference
result
PubMed Identifier
4026598
Citation
Zaichenko AA. [Pubertal growth spurt in the thickness of the bones of the human cranium]. Arkh Anat Gistol Embriol. 1985 May;88(5):81-2. Russian.
Results Reference
result
PubMed Identifier
19821406
Citation
Whitfield K, Rambaldi A, Wetterslev J, Gluud C. Pentoxifylline for alcoholic hepatitis. Cochrane Database Syst Rev. 2009 Oct 7;2009(4):CD007339. doi: 10.1002/14651858.CD007339.pub2.
Results Reference
result
PubMed Identifier
11242449
Citation
Gopal PK, Gill HS. Oligosaccharides and glycoconjugates in bovine milk and colostrum. Br J Nutr. 2000 Nov;84 Suppl 1:S69-74. doi: 10.1017/s0007114500002270.
Results Reference
result
PubMed Identifier
2313232
Citation
Stephan W, Dichtelmuller H, Lissner R. Antibodies from colostrum in oral immunotherapy. J Clin Chem Clin Biochem. 1990 Jan;28(1):19-23.
Results Reference
result
PubMed Identifier
4100470
Citation
Mach JP, Pahud JJ. Secretory IgA, a major immunoglobulin in most bovine external secretions. J Immunol. 1971 Feb;106(2):552-63. No abstract available.
Results Reference
result

Learn more about this trial

Comparison of Bovine Colostrum Versus Placebo in Treatment of Severe Alcoholic Hepatitis: A Randomized Double Blind Controlled Trial

We'll reach out to this number within 24 hrs