Different Treatment Frequencies for Hepatic Fibrosis Due to Schistosomiasis

The overarching goals of this proposal are to conduct a double blind, randomizedcontrolled trial (RCT) (Phase III) among N=600 participants ages 15‐40 in Lake Albert,Uganda, that will examine varying frequencies of treatment with Praziquantel (standard 40mg/kg PO every 4 months or annually for three years) to identify approaches that bestreverse or halt fibrosis as captured by ultrasound annually.After excluding other causes of hepatic fibrosis, the trial will randomize/enroll N = 600participants for the RCT (N = 150 individuals in each age and sex strata (4 sub‐groups))who have compensated schistosomal liver fibrosis based on the WHO "Niamey" ultrasoundprotocol for S. mansoni.Using stratified randomization by subgroup treatment arms are as follows: 1. Annual treatment (standard) arm: Participants in the annual treatment study arm willreceive active study agent (PZQ at 40 mg/kg) at baseline and one, two, and threeyears post randomization and placebo at intervening 4 month visits (i.e. 4, 8, 16,20, 28, 32 months post baseline). 2. Every 4 months treatment (intervention) arm: Participants in this arm will receivepraziquantel at a dose of 40 mg/kg every 4 months for 3 years. (i.e. at 4, 8, 12,16, 20, 24, 28, 32 and 36 months post baseline).Randomization and blinding The trial statistician will generate randomization codes bystudy number in blocks for each age/sex group and share with the pharmacist. Because theplacebo and praziquantel tablets will be matched, allocation to a given study arm will beconcealed to participants and study staff, including ultra‐sonographers who are assessingstudy outcomes.The overall goals of this trial are to examine varying frequencies of treatment withPraziquantel (every 4 months or annually for three years) to identify approaches thatbest reverse or halt fibrosis as captured by ultrasound annually. Investigators will alsoidentify novel biomarkers using our multiplexed assay which captures over 40 analytesinvolved in fibro‐degradation and fibro‐proliferation, which best predict progression offibrosis.The primary objective for the trial will be to assess the impact of PZQ dosed annually vsevery 4 months over three years on grade of fibrosis as captured by the Niamey protocolfrom baseline to three years with ultrasound performed annually. The primary endpoint isimprovement in grade of fibrosis (any improvement) during this three‐year period offollow up. Grades by image pattern are below and improvement, stability or worsening isbased on changes in these categories from baseline.Secondary objectives are to: 1. assess the impact PZQ administered annually versus every 4 months over three yearson presence and of severity portal hypertension status (absent, dilated or severelydilated) based on portal vein quotient 2. assess the impact of PZQ administered annually versus every 4 months on grade ofhepatic fibrosis after one and two years. 3. assess the impact of PZQ administered annually versus every 4 months presence andseverity (absent, dilated, severely dilated) of portal hypertension after one andtwo years. 4. evaluate the impact of two different treatment frequencies with Praziquantel (40mg/kg) annually or every 4 months on key biomarkers of fibrosisThe primary outcome will be any improvement in grade of fibrosis (mild, moderate, severe)from baseline to study close out at three years dichotomized as Yes/No improvement toproduce a rate of improvement across study arms.Hepatic Fibrosis Grade: Investigators will employ the "Niamey" protocol, for theassessment of fibrosis in the context of S. mansoni. Hepatosplenic schistosomiasis (HSS)encompasses a characteristic type of portal fibrosis, also called Symmer's clay pipefibrosis or periportal fibrosis, and its resulting complications such as portalhypertension. The Niamey protocol has a detailed scoring system for fibrosis that isbased on both "image pattern" and degree of periportal fibrosis. For S. mansoni, fibrosisis characterized by grades (B‐ F) with grades C to F constituting mild to severe gradesof fibrosis.Since image pattern B is not specific to schistosomiasis, individuals with pattern B willnot be included. Fibrosis will be graded with respect to location (periphery (C) &central (D, E, F)). These scores culminate in a severity grading that maps to mild,moderate, and severe.Mild: Image Pattern C Moderate: Image Pattern D Severe: Image pattern E or FImprovement is defined as change from baseline status as follows: ‐ E or F to D (severe to moderate) ‐ E or F to C (severe to mild) ‐ E or F to A or B (severe to none/non specific) ‐ D to C (moderate to mild) ‐ D to A or B (moderate to none/non specific) ‐ C to A or B (mild to none/non specific) Stability is defined as no change fromoverall group (mild (C), moderate (D) or severe (E or F)) at defined follow uptimepoints.Progression is defined as change in baseline status as follows: ‐ C to D (mild to moderate) ‐ C to E or F (Mild to severe) ‐ D to E or F (Moderate to Severe)Clinical secondary outcomes include change in grade of portal hypertension from baseline.Portal Hypertension: We will separately assess whether there is evidence of significantportal hypertension by ultrasound as per the Niamey protocol. The presence of portalhypertension will be defined by the portal vein quotient (adjusted for height). Aquotient greater than 7.5 is indicative of portal hypertension. It's severity is assessedas absent, dilated or severely dilated (Normal: ≤ 7.5 mm/m, Dilated: 7.6 ‐ 10 mm/m,Severely dilated: > 10 mm/m)Secondary outcomes include: 1. Improvement in severity of portal hypertension after three years and 2. improvement or stability in grade of fibrosis (as described above) after one and twoyears 3. Improvement in severity of portal hypertension after one and two yearsInvestigators will also address the following exploratory objectives which do notrepresent clinical endpoints for the trial but rather identify key fibrosis biomarkersthat predict the presence of hepatic fibrosis and its progression from baseline. Thesesecondary/exploratory outcomes will use the aforementioned definition of change infibrosis grade from baseline.At baseline, investigators will cross‐sectionally evaluate fibrosis biomarkers with amultiplexed assay "FibroPlex" (e.g microRNAs, hyaluronic acid) with over 40 analytesusing Area Under the Curve Analyses to identify specific biomarkers and "cut offs" whichaccurately identify individuals with varying stages of liver fibrosis by ultrasound.Investigators will then longitudinally evaluate fibrosis biomarkers that identify risk ofprogression from mild‐moderate to higher grades of fibrosis as assessed by ultrasoundannually stratified by treatment allocation among the N=600 RCT participants. This willallow identification of individuals at greatest risk of fibrosis progression before overtsymptoms and while still reversible.