Partners in the Study Enterprise: Sponsor, CRO & Large Site Networks SCOPE Conference February 23, 2016

Partners in the Study Enterprise Sponsor: Trevi Therapeutics, Inc. Vicki Duvall, RN, BSN Director, Global Site Management and Clinical Monitoring CRO with Investigative Site Network: Frenova Renal Research Brigid Flanagan, MS, RN, CCRC Senior Director, Clinical Development

Partners in the study enterprise Results: The studies were completed 6 months ahead of schedule Every site selected enrolled patients* Successful partnerships established for Phase III and/or future studies January 15, 2013 New Research from Tufts [CSDD] Characterizes Effectiveness and Variability of Patient Recruitment and Retention Practices While nine out of 10 clinical trials worldwide meet their patient enrollment goals, reaching those targets typically means that drug developers need to nearly double their original timelines, according to new research from the Tufts Center for the Study of Drug Development, benchmarking patient recruitment and retention practices. Tufts CSDD said its recent analysis, based on more than 150 clinical studies involving nearly 16,000 sites, will help clinical research professionals better plan and manage clinical trials. "Patient recruitment and retention are among the greatest challenges that the clinical research enterprise faces today, and they are a major cause of drug development delays," said Ken Getz…… * Tufts Center for the Study of Drug Development, January 15, 2013

Partners in the Study Enterprise Usual scenario: Sponsor selects CRO CRO identifies sites Site qualification visit occurs Site selection based on a number of criteria Sponsor input e.g. KOLs Prior history with CRO Investigator experience Potential enrollment Investigators typically respond to say they can enroll 8 to 10 patients.

Partners in the Study Enterprise This scenario: Sponsor identified more than one CRO Sponsor identified site networks Kick off meeting attended by representatives of all parties Input provided on Protocol design Feasibility questionnaire Lessons learned from prior studies in patient population PPD and River City (FQ only) DaVita and FMS: Large Dialysis Organizations (LDOs)

Partners in the Study Enterprise This scenario: Sponsor focused on one product to treat moderate to severe chronic itch Lead indication Uremic Pruritus: chronic itch in patients on kidney dialysis. No approved therapies in US or EU Uremic Pruritus: a chronic itching sensation in ESRD patients on dialysis, without evidence of any other active disease to explain the pruritus Estimated prevalence ~ 84% in dialysis patients* (frequently unreported) Brigid: Please note: The Mathur et al paper was based on a study using healthcare related quality of life instruments to measure daily itching or nearly daily by 84% of patients whose itching had gone on for > 1 year. Please also note that this study only looked at 103 people. In a larger scale study, the Dialysis Outcomes and Practice Patterns study (DOPPS), 42% dialysis patients experienced itch. I think you can say that UP is a complication of CKD but is hard to characterize. However it is measured, it is a problem for dx patients and thus needs to be addressed. *Mathur et al, A Longitudinal Study of Uremic Pruritus in Hemodialysis Patients, Clin J Am Soc Nephrol. 2010 Aug; 5(8): 1410–1419

Partners in the Study Enterprise Study Challenges: Many challenges for sites and sponsor throughout study Multiple protocol amendments Increased protocol deviations Extra regulatory workload Electrocardiograms Vendor added after the study started No standardized equipment Site experience varied/GCP issues

Partners in the Study Enterprise Study Challenges (continued): Labor intensive for study staff Patient visit compliance Numerous QoL Surveys Protocol deviations Problematic blister card design Non-compliant patient population Change in IP destruction policy midway through study Lack of experience in trials using oral IP at some sites GCP issues

Partners in the Study Enterprise Study Challenges (continued): EDC/Clinical Monitoring EDC not ready to go “live” at study start up Rapid enrollment resulted in backlog of data to be monitored Monitors changed more than once at some sites Quality issues identified at some sites CRO change midway through the study

Partners in the Study Enterprise Lessons learned included: CRAs need a strong clinical background Tools or questionnaires used must be designed with the end user in mind Schedule of Events should align with standard of care where possible Seek input from Investigators prior to finalizing the protocol and with subsequent amendments …and preferably have experience monitoring the CKD population

Partners in the Study Enterprise Lessons learned included (continued): Sick patient population with multiple AEs & SAEs Increased compliance issues with poly pharmaceutical study populations Labor intensive study design require more onsite time for monitoring EDC should ‘go live’ prior to starting enrollment Sponsor/CRO/Site Network should be prepared to dedicate resources for additional training at identified sites

Partners in the Study Enterprise Lessons Learned (cont): Important to choose and place all study vendors before study start-up. Sponsor to CRO match is crucial for trial success.

Partners in the Study Enterprise In Conclusion: Despite these challenges, the study met enrollment goals early, locked the database ahead of schedule, and achieved a statistically significant study result. Testimony to the hard work and dedication of the sites involved and the successful partnership between the Sponsor, CRO, and large site networks.