|Year : 2017 | Volume
| Issue : 1 | Page : 6-12
Efficacy and safety of hepano tablet in liver disorder patients with abnormal liver function test: A randomized active controlled prospective clinical study
Satyendra Kumar1, Arun Gupta1, Meenakshi Revadekar2, Sagar More3, Abhay Kulkarni4, Sunil S Borkar5
1 Medical Affairs and Clinical Research Division, Dabur Research and Development Centre, Ghaziabad, Uttar Pradesh, India
2 Department of Kayachikitsa, R. A. Podar Medical College (Ayu), Mumbai, Maharashtra, India
3 Department of Kayachikitsa, MAM's Sumatibhai Shah Ayurved Mahavidyalaya and Sane Guruji Aarogya Kendra, Pune, Maharashtra, India
4 Ayurveda Research Center, Ayurved Seva Sangh, Nashik, Maharashtra, India
5 Department of Kaychikitsa, Shri Gurudeo Ayurved College, Gurukunj Ashram, Amravati, Maharashtra, India
|Date of Web Publication||18-Oct-2017|
Medical Affairs and Clinical Research Division, Dabur Research and Development Centre, Dabur India Limited, 22, Site IV, Sahibabad, Ghaziabad - 201 010, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Objective: Hepano Tablet is an Ayurvedic herbal formulation studied in pre-clinical models for safety and hepatoprotective efficacy. The current study was a randomized, active controlled, multicentre, prospective clinical study that aimed to evaluate hepatoprotective efficacy and safety of Hepano Tablets. Materials and Methods: Male and female liver diseases patients (18-65 years) with abnormal liver function tests were randomized to receive two tablets twice daily orally of either Hepano or a marketed comparator for 8 weeks with follow up at day 7, 14, 28 & 56 during treatment period and thereafter at day 84. Results were assessed from baseline to end of treatment basis changes in liver function tests and improvement in clinical symptoms of icterus in both the groups. Safety was assessed at all the visits basis changes in laboratory parameters and adverse event reporting for all cases who took at least one dose of the study drug. Results: Hepano Tablet and marketed comparator showed significant improvement in Liver functions - Serum Aspartate transaminase (AST), Alanine transaminase (ALT) and Total, Direct and Indirect Bilirubin Levels and a significant reduction in clinical symptoms of icterus that was comparable at all the visits. Conclusion: Hepano Tablets can significantly improve Liver Function Tests and clinical symptoms in liver disease patients and could be consumed safely.
Keywords: Ayurveda, hepatoprotective, herbal, liver disorders, liver function test, serum alanine transaminase, serum aspartate transaminase, total bilirubin
|How to cite this article:|
Kumar S, Gupta A, Revadekar M, More S, Kulkarni A, Borkar SS. Efficacy and safety of hepano tablet in liver disorder patients with abnormal liver function test: A randomized active controlled prospective clinical study. Drug Dev Ther 2017;8:6-12
|How to cite this URL:|
Kumar S, Gupta A, Revadekar M, More S, Kulkarni A, Borkar SS. Efficacy and safety of hepano tablet in liver disorder patients with abnormal liver function test: A randomized active controlled prospective clinical study. Drug Dev Ther [serial online] 2017 [cited 2018 Nov 15];8:6-12. Available from: http://www.ddtjournal.org/text.asp?2017/8/1/6/216929
| Introduction|| |
The liver is a vital organ that plays a major role in maintaining the various physiological processes in the body including metabolism, secretion, storage, and excretion. It is the site where waste products of metabolism are detoxified through processes such as amino acid deamination. The liver is also responsible for excretion of xenobiotics., Liver functions may be compromised in many conditions such as liver cell injury caused by chemicals such as a certain antibiotic, chemotherapeutic agents, and excessive alcohol consumption. As the primary site of Phase I and II enzyme activities, some drugs can be transformed into hepatotoxic drug metabolites due to the “ first pass effect” through the liver. Drug-induced hepatotoxicity associated with nonsteroidal anti-inflammatory drugs is one of the main causes of liver diseases and accounts for increasing number of hospital admissions. The liver may also be involved in infections by hepatotropic viruses like hepatitis A, B, C, and E viruses that replicate in the liver and for which the liver is the main target. In addition, the liver may be affected as part of a generalized host infection with viruses that primarily target other tissues; particularly the upper respiratory tract such as herpes viruses, cytomegalovirus, and in severe acute respiratory syndrome associated coronavirus. Acute liver failure is a syndrome characterized by a rapid decline in hepatic synthetic functions and a significant risk of mortality. Liver disease is often reflected by biochemical abnormalities of different hepatic systems or of liver function. Liver function tests (LFTs) reflect hepatocyte integrity or cholestasis apart from the state of liver functions. Injury to the liver, whether acute or chronic, eventually results in an increase in serum concentrations of aminotransferases aspartate transaminase (AST) and alanine transaminase (ALT). A change in serum albumin level or prothrombin time and international normalized ratio (PT/INR) may be associated with a decrease in liver functioning mass, although neither is specific for liver disease.
Although there has been remarkable progress in discovering treatment of chronic liver diseases over the past several decades, most of the therapies have not yielded satisfactory outcomes. At times, the available synthetic drugs to treat liver disorders may cause further damage to the liver. The cost of conventional drugs, adverse drug reactions, and their inefficacy has further limited their use. Herbal medicines have been used for healthcare since long as they are believed to have lesser or milder adverse effects and recently, an increasing number of herbal products, including medicinal herbs and phytochemicals, have been used for treating chronic liver diseases. Studies have indicated herbs can protect the liver by several mechanisms such as eliminating viruses, blocking fibrogenesis, inhibiting oxidative injury, and suppressing tumorigenesis.,
Hepano tablet (Mfd: Dabur India Limited) is a proprietary Ayurvedic herbal formulation that contains the goodness of herbs like Tinospora cordifolia (Thunb.) (Miers, Azadiracthta indica A. Juss Andrographis paniculata (Burm. f.) Wall. ex Nees), Terminalia chebula Retz., Emblica officinalis Gaertn. and Picrorrhiza kurrooa L. etc., that have traditionally been used in liver disorders., Preclinical studies on Hepano tablet have demonstrated hepatoprotective activity against paracetamol and D-galactosamine-induced liver toxicity through significant (P < 0.001, vs. toxicant) reduction in serum AST, ALT, and alkaline phosphatase (ALP) and bilirubin levels; as well as decreased lipid peroxidation. Moreover, there was a significant elevation (P < 0.001, vs. toxicant) in serum albumin and glutathione levels compared to toxicant groups. The rationale behind conducting the current clinical study was to establish the efficacy and safety of an Ayurvedic herbal hepatoprotective formulation “Hepano tablets” in patients of liver disorder with abnormal LFTs. Results were evaluated in comparison to a marketed herbomineral comparator with established safety and efficacy.
| Materials and Methods|| |
This study was a double-blind, randomized, active-controlled, multicenter, prospective clinical study conducted across four sites in Maharashtra, India, namely, R. A. Podar Medical College (Ayurvedic) and M.A. Podar Hospital Worli (site 01); Sumatibhai Shah Ayurved Hospital, Pune (site 02); Ayurved Seva Sangh Vibhag, Nashik (site 03); Shri Gurudeo Ayurved College and Hospital, Amravati (site 04) in subjects presenting with liver disorders and having abnormal LFTs. This study was performed in the period spanning March 2014 to August 2015.
The study was initiated after approval from the Institutional Ethics Committees of respective sites and all patients gave written informed consent. The trial was registered with Clinical Trial Registry of India with No. CTRI/2014/02/0044 on February 17, 2014. The trial protocol can be accessed at: http://ctri.nic.in/Clinicaltrials/advsearch.php.
Study products and blinding
Hepano tablet batch no.: AP/0008/1012/HPT-20; mfd: October 2012; expiry: September 2014 was used in the present study. The composition details of Hepano tablet are given in [Table 1].
Marketed Comparator Batch No. 37201823B and 37401221B, mfd: October 2012 and August 2014 with expiry in September 2015 and July 2017, respectively, were used in the current study. Each tablet of Marketed Comparator comprised ingredients such as Capparis spinosa Linn., Cichorium intybus Linn., Solanum nigrum Linn., Terminalia arjuna (Roxb.) Bedd., Cassia occidentalis Linn., Achillea millefolium Linn., Tamarix gallica Linn., and calcined ferric oxide along with other herbal ingredients.
Although the double-blind study design was followed, the study was not double-blind in a true sense, because size/shape/color of tablets in both the group was different. However, the primary packing of the two study drugs was kept absolutely similar (PET bottles) to keep both investigators as well as the subject blind of which drug they received.
Patients included were male and female subjects aged between 18 and 65 years of age who were suffering from clinical icterus as manifested by one or more of the symptoms - dark colored urine, light-colored stools, pruritus, pruritic red hives, fatigue, fever, nausea, vomiting, anorexia, aversion to smoking, right upper abdominal discomfort, pain or feeling of pressure in abdomen, and abnormal LFT (serum total bilirubin [TBL] level ≥2 mg/dl, AST or ALT >2 times ULN of respective laboratories), subjects who could take oral medications, were willing to participate in the study and undertake all the study-related procedures and practice effective contraception method during the study period.
Subjects having the presence of clinically significant laboratory, electrocardiogram (ECG) or X-ray findings during screening, history of drug addiction, chronic alcoholics, immunologically compromised subjects, suspected hypersensitivity to contents of Hepano tablet or contents of Marketed Comparator, known case of hepatitis-B or hepatitis-C, obstructive jaundice (diagnosed clinically and biochemically), advanced liver disease (e.g., ascites, bleeding esophageal varices and hepatic encephalopathy, hepatic cancer), uncontrolled diabetes mellitus, hypertension, symptomatic congestive heart failure, unstable angina, history of myocardial infarction, subjects who had participated in any other clinical trial within 3 months before recruitment in this study, current or recent (≤2 weeks) use of herbal hepatoprotective drugs, pregnant or lactating females, subjects having any other medical condition that in the investigator's opinion would preclude patient participation were excluded.
A written informed consent was obtained from subjects on the screening visit (day-3), and they were evaluated for eligibility to participate as per inclusion and exclusion criteria. Subjects' demographic details, medical history, physical examination, vitals (blood pressure, pulse rate, respiratory rate, temperature), history of prior medication were recorded and laboratoryinvestigations - complete blood count [CBC] (red blood cell [RBC], white blood cell [WBC], hemoglobin, platelets), erythrocyte sedimentation rate (ESR), fasting blood sugar, LFT, renal function test (RFT) (serum creatinine), lipid profile (serum total cholesterol and triglycerides), X-ray chest, and ECG were done. Females of childbearing age underwent a urine pregnancy test to rule out pregnancy.
Interventions and dosage
Subjects confirming eligibility criteria were randomized 1:1 at day 0 (baseline) to receive two tablets orally B.D. of either Hepano tablet or marketed herbomineral comparator for 8 weeks by investigator/CRC.
Response evaluation and follow-up
The total duration of the study after randomization was 12 weeks including a treatment period of 8 weeks and further subject follow-up after 4 weeks after cessation of medication. Subjects were followed up during the treatment phase at day 7, 14, 28, 56, and thereafter at day 84. First subject enrollment at site 01 was on March 4, 2014 and date of last follow-up at site 04 was August 17, 2015.
Assessment of efficacy parameters
The efficacy of the study drug was assessed through improvement in the hepatic condition as measured by the biochemical and clinical improvement. The biochemical improvement was assessed through changes in LFT (serum AST, ALT, and bilirubin levels) at day 0, 7, 14, 28 and 56. Clinical improvement was assessed though improvement in signs/symptoms of icterus-fatigue, loss of appetite, nausea, vomiting, and itching using a predefined 4-point scale – the subjective clinical improvement assessment scale where, 0 represented none/absence of sign/symptom, 1 = mild, 2 = moderate, 3 = severe sign/symptom. The subjects were monitored for the clinical symptoms of liver dysfunctions such as chills, headache, malaise, anorexia, nausea, vomiting, diarrhea, upper abdominal pain, tender liver, enlarged spleen, dark urine, and yellow tint to the sclera.
Assessment of safety parameters
Safety was assessed using clinical review of all safety parameters, including laboratory investigations-hematology, biochemistry, ECG and urine analysis, adverse event (AE) reporting as applicable, and monitoring of vitals (pulse rate, respiratory rate, body temperature, and blood pressure). Safety assessment was done for all cases who took at least one dose of the study drug at all the visits.
The primary population for this study was per-protocol population. With almost fifty subjects in each group, the sample size was sufficient for analysis of change in LFTs. The primary efficacy endpoint was analyzed using two proportion test. The 95% confidence interval was constructed for the proportion, all other secondary outcomes were analyzed by applying appropriate statistical methods like proportion test, t-test, etc., The value of P < 0.05 was considered statistically significant. Data are expressed as a mean ± standard error.
| Results|| |
A total of 147 subjects were screened for eligibility. There were 15 screen failures and 132 subjects were enrolled. Enrolled subjects were randomized equally (66 each) into either of the study groups. In Hepano tablet group, 50 subjects (43 male and 7 female) completed the total study duration, and 16 patients dropped out for reasons not related to study or study products. In Marketed Comparator group, a total 51 subjects (39 male and 12 female) completed the total study duration, and 15 subjects dropped out for reasons not related to study or study products. There was no significant difference between the average ages of subjects in the study groups [Figure 1].
Both Hepano group and Marketed Comparator group showed a significant reduction in mean AST levels from baseline at all follow-up visits. Mean serum AST levels reduced by 44.10, 56.98, 61.25 and 66.76% at day 7, 14, 28, and 56 in Hepano group when compared to its baseline value, whereas in the Marketed Comparator group, this reduction was 31.28, 45.29, 46.11, and 53.27%, respectively [Figure 2]. Between the groups, analysis showed no significant difference at any follow-up visits after initiation of the treatment.
A significant reduction in ALT levels was observed in both the groups at all follow-up visits when compared to its baseline value. There was a reduction of 44.43, 59.81, 64.66, and 72.88% at day 7, 14, 28, and 56 in Hepano group when compared to its baseline value, whereas in the Marketed Comparator group this reduction was 46.21, 55.93, 58.62, and 65.19%, respectively [Figure 3]. There was, however, no significant difference between the effects of the two groups at any follow-up visits.
TBL levels showed a significant reduction in both the groups at all the follow-up visits day 7 onward till the end of the treatment at day 56. The reduction in Hepano group was found to be 36.94, 51.27, 59.23 and 67.19% as compared to 29.56, 44.34, 52.17, and 53.04% at day 7, 14, 28, and 56, respectively. There was, however, no significant difference between the effects of two groups at all the follow-up visits [Figure 4].
Direct and indirect bilirubin levels
Direct bilirubin and indirect bilirubin showed a significant reduction in both the groups on all the follow-up visits starting from day 7 onward till the end of the treatment, i.e., day 56. There was, however, no significant difference between the two groups at all the follow-up visits [Figure 5] and [Figure 6].
Other liver function tests
All the other LFTs such as serum ALP, total proteins, albumin, AG ratio, and PT/INR were found to be within normal limits at the baseline and at all the follow-up visits in both the study groups. There was also no significant difference between the two groups at all the follow-up visits.
Symptoms of icterus
A significant reduction in the symptoms of icterus in both the groups was observed day 7 onwards and continued further to day 14, 28, 56, and 84. Almost complete recovery in the symptoms of icterus was observed in the Hepano group (97.05%) as compared to Marketed Comparator group (86.40%). However, there was no significant difference between the effects of two groups at all the follow-up visits.
Symptoms - fatigue
There was a significant reduction in fatigue in both the groups which started from the day 7 onwards at all follow-up visits in both the groups. On analyzing between groups, there was no significant difference between the two groups at all the follow-up visits. At the end of the study, there was the almost complete recovery of the symptom (96.22%) in the Hepano group as compared to Marketed Comparator group where the percentage reduction was 80.73%.
Symptom - loss of appetite
There was a significant decrease in the symptom - loss of appetite from the baseline visit to the follow-up visits in both the groups. The reduction started day 7 onward and continued at all follow-up visits. There was, however, no significant difference between the two groups at all the follow-up visits. At study completion, there was complete recovery (100%) of the symptom in the Hepano group and almost complete recovery in the Marketed Comparator group (94.31%).
Symptom - nausea
A significant reduction in nausea was observed from the day 7 onward and continued further to day 14, 28, 56, and day 84 in both the groups. Between groups, analyses showed that there was no significant difference at all the follow-up visits. It was observed that at the end of the study there was no incidence of nausea in the Hepano group from day 56 onward and almost complete recovery in the Marketed Comparator group as well (91.66% at day 56 and 95% at day 84).
Symptom - vomiting
There was a significant reduction in vomiting in both the groups' day 7 onward and continued at all the follow-up visits. On analyzing between groups, there was no significant difference between the effects of the two groups at all the follow-up visits. It is observed that there was no incidence of vomiting in Hepano Group from day 56 onward; however, in Marketed Comparator group, no incidence of vomiting was seen day 14 onward.
Symptom - itching
There was a significant reduction in itching in both the groups from day 7 onward and continued further throughout the study. On analyzing between groups, there was no significant difference at all the follow-up visits; however, there was complete recovery (100%) from the symptom in Hepano group day 56 onward and almost complete recovery (95.65%) in the Marketed Comparator group.
Assessment of safety
Assessment of incidence of adverse events
AEs were reported in 38 subjects. Of these, 20 subjects were in Hepano Group and 18 in the Marketed Comparator. A total of 42 AE were recorded in the study, 21 in each group. The common AE reported were related to the respiratory and gastrointestinal system such as fever, cough, and pain in the abdomen, loose motions, etc., However, none of the AE was assessed to be related to the study drugs.
Assessment of laboratory parameters
All the vital parameters were within the normal limits at all the follow-up visits in both the groups and there was no statistically significant difference.
All the laboratory parameters such as CBC (RBC, WBC, hemoglobin, platelets, ESR, fasting blood sugar; LFT, RFT (serum creatinine), lipid profile (serum total cholesterol and triglycerides), X-ray chest and ECG were within normal limits at both initial and final visits and did not show any significant difference between the groups.
| Discussion|| |
Approximately 80% of the world's population has employed traditional medicine for health care, which is based predominantly on plant materials and at least one-quarter of patients with liver disease use botanicals. Although botanicals have been used successfully for the treatment of hepatic disorders, the spectrum of current medically utilized herbal hepatoprotectives remains small, and their effectiveness has been a matter of continuous discussion. The prevalence of liver disorders has been increasing steadily, but the treatment outcomes are still considered poor. Clinical studies conducted on natural plant products have been promising and may also suggest herbal medicines becoming a major contributor to the treatment of liver disorders., A handful of herbal drugs, both single and compound preparations available in the market have been studied in this context, and the results have been encouraging., However, well-performed clinical trials on their therapeutic value in the treatment of certain liver diseases are rare and remain uncharted. In line with the same, the current clinical study was attempted to evaluate the hepatoprotective effects of an herbal hepatoprotective formulation - Hepano tablet. Preclinical studies on Hepano tablet have demonstrated hepatoprotective activity against paracetamol and D-galactosamine-induced liver toxicity. Safety of Hepano tablet has been established in animal studies.
Laboratory liver tests are broadly defined as tests useful in the evaluation and treatment of patients with hepatic dysfunction. Results of the current study exhibited Hepano tablet produced significant improvement in both the laboratory parameters and clinical symptoms of liver diseases from the 7th day of administration and till the end of study period. The majority of the subjects showed recovery in both symptoms of icterus as well as laboratory values of LFTs. Moreover, no relapse in symptoms, as well as change in the laboratory parameters after another four weeks, follow-up period after cessation of the study medication was observed suggesting potential hepatoprotective effects.
Hepano tablet comprises ingredients such as P. niruri, T. cordifolia, A. indica A. paniculata, T. chebula, E. officinalis, and P. kurroa which are traditionally known for hepatoprotective efficacy as mentioned in classical texts of Ayurveda as well as modern published literature. Conventionally, T. cordifolia and A. paniculata are known to promote digestion and are useful in disorders of liver like jaundice/hyperbilirubinemia. Ethanolic, aqueous, and PET extract of all the parts of T. cordifolia have shown the significant hepatoprotective effect by a reduction in serum ALT, AST, ALP, and TBL in animal models. Hepatoprotective activity of A. paniculata against liver toxicants has also been reported.,E. officinalis and T. chebula are traditionally known to promote digestion, are useful in jaundice and possess hepatoprotective and antioxidant properties., Hepatoprotective activity of Terminalia bellerica and A. indica are also reported.,P. kurroa is traditionally known to be beneficial in liver disorders. Its efficacy in hepatic disorders is supported by clinical trials on viral hepatitis and hepatoprotection in animal models.,,P. niruri also has established hepatoprotective activity. All these properties of ingredients of Hepano may have contributed to its hepatoprotective effects in liver disorders.
| Conclusion|| |
Hepano tablet showed significant improvement in laboratory parameters for abnormal liver functions and symptoms of liver disease and was found to be safe in the given dosage. The results were found to be comparable to that of marketed herbomineral comparator. It is concluded from the present study that Hepano tablet is the safe and effective product for liver disorder patients with abnormal LFT.
Financial support and sponsorship
The study samples and financial support for the study were provided by Dabur India Limited, Sahibabad (Ghaziabad), Uttar Pradesh, India.
Conflicts of interest
Satyendra Kumar and Arun Gupta are employed with Dabur India limited that manufactures/markets the study product Hepano tablets.
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