Antioxidant Supplements in the Reversal of Schistosomal Peri-portal Fibrosis

Study on the Role of Antioxidant Micronutrients on the Reversal of Schistosomal Peri-portal Fibrosis of the Liver.

Liver fibrosis is the most serious complication of schistosomiasis mansoni. However only limited proportion of subjects with infection develop this pathology and there is limited knowledge on risk factors for the differential morbidity patterns observed in endemic communities. Our preliminary cross-sectional study indicated that serum levels of antioxidants may be related with the development of fibrosis. The present project is a randomised double blinded placebo controlled prospective study investigating the role of food based antioxidant supplements on the outcome of anti-schistosomal chemotherapy with regards to the extent of fibrosis reversal.

Study Overview

• Status: Unknown
• Conditions: Oxidative Stress; Liver Fibrosis; Schistosomiasis; Periportal Fibrosis
• Intervention / Treatment: Dietary supplement: Praziquantel+antioxidant suppl; Dietary supplement: Praziquantel+antioxidant; Other: Praziquantel + placebo 2mths then antioxidant for 10 mths; Dietary supplement: Praziquantel therapy and placebo as supplement

Detailed Description

Schistosomiasis is the second leading parasitic disease worldwide, after malaria. Liver fibrosis is the most serious complication of schistosomiasis mansoni which can lead to reduced work capacity and early death in endemic countries. There is, however, limited knowledge on the development of liver fibrosis and the differential patterns morbidity observed in endemic communities. Our preliminary cross-sectional study in Ethiopia seems to indicate that serum levels of antioxidants may influence the development of fibrosis. The present project is a translational study combining basic antioxidant laboratory work with is a randomised double blinded placebo controlled prospective study in endemic areas in Ethiopia, investigating the role of food based antioxidant supplements on the outcome of anti-schistosomal chemotherapy with regards to the extent of fibrosis reversal. In addition, analysis of dietary intakes of antioxidants among communities with comparable levels of S. mansoni infection but with differing levels of schistosomal periportal fibrosis will be undertaken to compare serum levels of antioxidants and prevalence of liver fibrosis. Furthermore we plan to assess development of schistosomal peri-portal fibrosis in a cohort of students established 9 years back who had comparable levels of community prevalence of schistosomiasis but with differing access to fruits and vegetables. Research on this topic has a high priority globally which is in line with the millennium development goals. Knowledge in this field will also add to our understanding of fibrosis development in general and to the efficacy of clinical treatment of schistosomiasis in particular.

• Study Type: Interventional
• Enrollment (Anticipated): 414
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nega Berhe, MD, PHD; Phone Number: 00251-911-408340; Email: nega_berhe@yahoo.com
• Study Contact Backup: Name: Svein Gunnar Gundersen, MD, PHD; Phone Number: 0047 38074474; Email: svein.g.gundersen@sshf.no

Study Locations

• Ethiopia
  • Addis Ababa, Ethiopia, 1176
    • Recruiting
    • Aklilu Lemma Institute of Pathobiology, Addis Ababa University
    • Contact: Nega Berhe, Md PhD; Phone Number: 00251-911-408340; Email: nega_berhe@yahoo.com
    • Principal Investigator: Nega Berhe, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 60 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with schistosomal periportal fibrosis will be eligible for the study

Exclusion Criteria:

• Subjects with acute malaria, tuberculosis or other chronic diseases such as diabetes mellitus, cardiovascular disease or cancer will be excluded from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: praziquantel+antioxidant; Praziquantel therapy will be offered at the start, at six weeks and at 12 weeks from date of enrollment. Thereafter praziquantel therapy will be offered if subjects have demonstrable S. mansoni eggs on the subsequent six-monthly evaluations. In additions, antioxidant suppliment will be given daily for a period of one year	Dietary supplement: Praziquantel+antioxidant suppl; Praziquantel therapy will be offered at the start, at six weeks and at 12 weeks from date of enrollment. Thereafter praziquantel therapy will be offered if subjects have demonestrable S. mansoni eggs on the subsequent six-monthly evaluations. In addition subjects will receive antioxidant supplement on daily basis for a period of one year.; Dietary supplement: Praziquantel+antioxidant; Praziquantel treatment will be offered at time 0, six weeks and 12 weeks from the start. Antioxidant supplement will be offered on a daily basis for a period of one year; Other Names: Interventional
ACTIVE_COMPARATOR: Praziquantel +placebo 2mths then antioxidant for 10 months; Praziquantel therapy will be offered at the start, at six weeks and at 12 weeks from date of enrollment. Thereafter praziquantel therapy will be offered if subjects have demonstrable S. mansoni eggs on the subsequent six-monthly evaluations. In addition subjects will receive placebo as a supplement for two months which will be followed by antioxidant as a supplement for the rest of the year.	Other: Praziquantel + placebo 2mths then antioxidant for 10 mths; Praziquantel therapy will be offered at the start, at six weeks and at 12 weeks from date of enrollment. Thereafter praziquantel therapy will be offered if subjects have demonestrable S. mansoni eggs on the subsequent six-monthly evaluations. In addition subjects will receive placebo as a supplement for two months which will be followed by antioxidant as a supplement for the rest of the year.
NO_INTERVENTION: Praziquantel therapy with placebo supplement; Praziquantel therapy will be offered at the start, at six weeks and at 12 weeks from date of enrollment. Thereafter praziquantel therapy will be offered if subjects have demonstrable S. mansoni eggs on the subsequent six-monthly evaluations. In addition subjects will receive placebo as a supplement for a period of one year.	Dietary supplement: Praziquantel therapy and placebo as supplement; Praziquantel at day 0, 6-weeks and at 12 weeks from start of study. Thereafter praziquantel therapy will be offered if subjects have demonestrable s.mansoni eggs on six-monthly evaluation periods. Placebo will be given as a supplement for one year.; Other Names: Placebo; Praziquantel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of antioxidant supplement on fibrosis reversal following praziquantel therapy	Patients schistosomal periportal fibrosis will be treated with praziquantel at the start, at six weeks and at 3 months from the start of the study. Praziquantel therapy will then be offered if subjects have demonstrable S. mansoni eggs on six-monthly evaluation periods. In addition, one group will recieve supplemental antioxidant for one year, the second group will recieve supplement as a placebo for two months and then antioxidant suppliment for 10 months, the third group will receive placebo as a supplement for one year.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time required for the reversal of schistosomal periportal fibrosis	Subjects will be followed with six-monthly evaluations for a period of 4 years and praziquantel therapy will be offered if subjects have demonstrable S. mansoni eggs on the six-monthly evaluations. Over the four year period we plan to assess the time required for the reversal of the various stages of schistosomal periportal fibrosis.	4 years

Collaborators and Investigators

• Sponsor: Addis Ababa University
• Collaborators: University of Oslo; Ullevaal University Hospital; Sorlandet Hospital HF; University of Agder
• Investigators: Principal Investigator: Nega Berhe, MD, PhD, Aklilu Lemma Institute of Pathobiology, Addis Ababa University; Study Director: Svein G Gundersen, MD PhD, Sorlandet Hospital HF, Box 416, 4604 Kristiansand - Norway; Study Chair: Bjørn Myrvang, MD, PhD, Ullevål University Hospital, Department of Infectious Diseases, Centre for Imported and Tropical Diseases, 0407 Oslo; Principal Investigator: Rune Blomhoff, MSc, PhD, Institute for Basic Medical Sciences, Department of Nutrition, University of Oslo, P.O.box 1046, N-0316 Oslo, Norway

Publications and helpful links

General Publications

• Halliwell B. The antioxidant paradox. Lancet. 2000 Apr 1;355(9210):1179-80. doi: 10.1016/S0140-6736(00)02075-4. No abstract available.
• Berhe N, Halvorsen BL, Gundersen TE, Myrvang B, Gundersen SG, Blomhoff R. Reduced serum concentrations of retinol and alpha-tocopherol and high concentrations of hydroperoxides are associated with community levels of S. mansoni infection and schistosomal periportal fibrosis in Ethiopian school children. Am J Trop Med Hyg. 2007 May;76(5):943-9.
• El-Sokkary GH, Omar HM, Hassanein AF, Cuzzocrea S, Reiter RJ. Melatonin reduces oxidative damage and increases survival of mice infected with Schistosoma mansoni. Free Radic Biol Med. 2002 Feb 15;32(4):319-32. doi: 10.1016/s0891-5849(01)00753-5.
• Berhe N, Myrvang B, Gundersen SG. Reversibility of schistosomal periportal thickening/fibrosis after praziquantel therapy: a twenty-six month follow-up study in Ethiopia. Am J Trop Med Hyg. 2008 Feb;78(2):228-34.
• Karlsen A, Paur I, Bohn SK, Sakhi AK, Borge GI, Serafini M, Erlund I, Laake P, Tonstad S, Blomhoff R. Bilberry juice modulates plasma concentration of NF-kappaB related inflammatory markers in subjects at increased risk of CVD. Eur J Nutr. 2010 Sep;49(6):345-55. doi: 10.1007/s00394-010-0092-0. Epub 2010 Feb 2.
• Paur I, Austenaa LM, Blomhoff R. Extracts of dietary plants are efficient modulators of nuclear factor kappa B. Food Chem Toxicol. 2008 Apr;46(4):1288-97. doi: 10.1016/j.fct.2007.09.103. Epub 2007 Nov 5.
• Blomhoff R. Dietary antioxidants and cardiovascular disease. Curr Opin Lipidol. 2005 Feb;16(1):47-54. doi: 10.1097/00041433-200502000-00009.
• Eboumbou C, Steghens JP, Abdallahi OM, Mirghani A, Gallian P, van Kappel A, Qurashi A, Gharib B, De Reggi M. Circulating markers of oxidative stress and liver fibrosis in Sudanese subjects at risk of schistosomiasis and hepatitis. Acta Trop. 2005 May;94(2):99-106. doi: 10.1016/j.actatropica.2005.03.001. Epub 2005 Apr 7.

Helpful Links

• Financial support for the research project was obtained from Ulleval hospital, Centre for Imported and Tropical Diseases

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (ANTICIPATED): June 1, 2013
• Study Completion (ANTICIPATED): December 1, 2015

Study Registration Dates

• First Submitted: December 13, 2010
• First Submitted That Met QC Criteria: December 14, 2010
• First Posted (ESTIMATE): December 15, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): December 15, 2010
• Last Update Submitted That Met QC Criteria: December 14, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: antioxidant; Schistosomiasis; Schistosoma mansoni; periportal fibrosis; fibrosis reversal
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Liver Diseases; Vector Borne Diseases; Parasitic Diseases; Helminthiasis; Trematode Infections; Fibrosis; Liver Cirrhosis; Schistosomiasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Protective Agents; Antiparasitic Agents; Anthelmintics; Antioxidants; Praziquantel
• Other Study ID Numbers: 2010/794-1