Clinical Trials in Pancreatitis: Opportunities and Challenges in the Design and Conduct of Patient-Focused Clinical Trials in Recurrent Acute and Chronic Pancreatitis: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

ABSTRACT: Recurrent acute pancreatitis and chronic pancreatitis represent high morbidity diseases, which are frequently associated with chronic abdominal pain, pancreatic insufficiencies, and reduced quality of life. Currently, there are no therapies to reverse or delay disease progression, and clinical trials are needed to investigate potential interventions that would address this important gap. This conference report provides details regarding information shared during a National Institute of Diabetes and Digestive and Kidney Diseases-sponsored workshop on Clinical Trials in Pancreatitis that sought to clearly delineate the current gaps and opportunities related to the design and conduct of patient-focused trials in recurrent acute pancreatitis and chronic pancreatitis. Key stakeholders including representatives from patient advocacy organizations, physician investigators (including clinical trialists), the US Food and Drug Administration, and the National Institutes of Health convened to discuss challenges and opportunities with particular emphasis on lessons learned from trials in participants with other painful conditions, as well as the value of incorporating the patient perspective throughout all stages of trials.

Ethical and regulatory oversight of clinical research: The role of the Institutional Review Board.

The history of clinical research is, unfortunately, filled with examples of research studies that took advantage of and harmed research participants, to fulfill the research goals of scientists. Over time, we have created a system of ethical codes, principles, and regulations that are designed to prevent these abuses and to ensure that the rights and welfare of research participants are protected and honored. This review article will provide a brief history of clinical research ethics and ethical codes, outlining how those codes developed into the current regulatory requirements for the ethical oversight of clinical research. Understanding the current human subject protection systems will allow researchers to use best practices for planning and conducting rigorous, scientifically valid and ethical clinical studies. Understanding the history, principles, and foundations of the development of this system will equip researchers to understand what resources are available to them and how to make the best decisions when confronted with unique ethical situations in the conduct of their research.

DRAVET ENGAGE. Parent caregivers of children with Dravet syndrome: Perspectives, needs, and opportunities for clinical research.

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy significantly impacting affected children and their families. A novel, one-time, adeno-associated virus (AAV)-mediated gene regulation therapy was designed to treat the underlying cause of DS, potentially improving the full spectrum of DS manifestations. To ensure the first-in-human clinical trial addresses meaningful outcomes for patients and families, we examined their perspectives, priorities, goals, and desired outcomes in the design phase through a mixed methods approach (quantitative and qualitative). We conducted a non-identifiable parent caregiver survey, shared through a patient advocacy organization (n = 36 parents; children age ≤6 years). Parents were also engaged via three group discussions (n = 10; children age 2-20 years) and optional follow-up in-depth individual interviews (n = 6). Qualitative data analysis followed an inductive interpretive process, and qualitative researchers conducted a thematic analysis with a narrative approach. Survey results revealed most children (94%) were diagnosed by age 1, with onset of seizures at mean age 6.2 months and other DS manifestations before 2 years. The most desired disease aspects to address with potential new disease-modifying therapies were severe seizures (ranked by 92% of caregivers) and communication issues (development, expressive, receptive; 72-83%). Qualitative results showed the need for trial outcomes that recognize the impact of DS on the whole family. Parents eventually hope for trials including children of all ages and were both excited about the potential positive impact of a one-time disease-modifying therapy and mindful of potential long-term implications. Participants reflected on the details and risks of a clinical trial design (e.g., sham procedures) and described the different factors that relate to their decision to participate in a trial. Their main aspirations were to stop neurodevelopmental stagnation, to reduce seizures, and to reduce the impact on their families' wellbeing. To our knowledge, this is the first study within a patient-oriented research framework that specifically explored parents' needs and perceptions regarding clinical trials of a potential disease-modifying therapy for children with a severe, developmental disease, such as DS.

Ethical Issues in Research Involving Participants With Opioid Use Disorder.

In the current epidemic of opioid use disorders, there is both a scientific and ethical imperative to develop effective medical and behavioral treatments for opioid addiction. Research in subject populations with active and ongoing drug addictions bring unique ethical considerations and challenges. Sponsors, researchers, and institutional review board (IRB) members should be familiar with these unique ethical and medical issues as they design, review, and conduct research planned for this population. Issues include those of informed consent and decision-making capacity of research participants, compensation for participation and concerns about undue inducement, forces that threaten the voluntary nature of research participation including the scarcity of available drug treatment programs, and ensuring that participants are aware of and understand risks that may continue after research participation such as increased risk of overdose after research-mandated drug abstinence. This manuscript discusses the current thinking on these issues.

Incorporating ethical principles into clinical research protocols: a tool for protocol writers and ethics committees.

A novel Protocol Ethics Tool Kit ('Ethics Tool Kit') has been developed by a multi-stakeholder group of the Multi-Regional Clinical Trials Center of Brigham and Women's Hospital and Harvard. The purpose of the Ethics Tool Kit is to facilitate effective recognition, consideration and deliberation of critical ethical issues in clinical trial protocols. The Ethics Tool Kit may be used by investigators and sponsors to develop a dedicated Ethics Section within a protocol to improve the consistency and transparency between clinical trial protocols and research ethics committee reviews. It may also streamline ethics review and may facilitate and expedite the review process by anticipating the concerns of ethics committee reviewers. Specific attention was given to issues arising in multinational settings. With the use of this Tool Kit, researchers have the opportunity to address critical research ethics issues proactively, potentially speeding the time and easing the process to final protocol approval.

Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study.

BACKGROUND & AIMS: Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward. METHODS: In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation. RESULTS: Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%). CONCLUSIONS: Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.

Assessing Awareness and Implementation of a Recommendation for Surgical Innovation Committees: A Survey of Academic Institutions.

OBJECTIVE: In 2008, a Position Statement of the Society of University Surgeons (SUS) recommended the creation of institutional surgical innovation committees (SICs) to ensure appropriate oversight of surgical innovations. The purpose of this study was to determine the level of awareness of the position statement, and how innovations are handled in academic departments of surgery. METHODS: An electronic survey was designed to determine the level of awareness of the SUS recommendations among members of the Society of Surgical Chairs; the existence and characteristics of SICs; and alternative means of oversight of surgical innovations. RESULTS: The survey was distributed to 150 persons, and 65 (43%) surveys were returned; 84% reported their institution promoted innovative surgery as a strength, but 55% were unaware of the SUS recommendations; 23% reported that their institution has an SIC, and 20% said their institution has discussed or plans an SIC. Existing SICs have a median of 7 members; 57% reviewed 3 or fewer procedures in the prior year; and only 7% reviewed 10 or more. The majority of respondents reported alternative mechanisms of oversight, including morbidity/mortality conferences (88%), peer review (77%), and outcomes registries (51%). CONCLUSIONS: A minority of Surgery Department Chairs is aware of the SUS Position Statement. Although most reported surgical innovation was an institutional strength, only 23% had an SIC and most rely on other mechanisms of oversight. It is unclear whether academic surgical departments are committed to providing education and awareness of the appropriate development and implementation of surgical innovations.

The effect of CYP3A inhibitors and inducers on the pharmacokinetics of telaprevir in healthy volunteers.

AIM: To evaluate the effects of ketoconazole, rifampicin and efavirenz on the pharmacokinetics of telaprevir in healthy volunteers. METHOD: Results from three clinical studies are described. (1) Volunteers received a single 750 mg dose telaprevir with and without a single 400 mg dose ketoconazole. (2) Volunteers received (a) 1250 mg telaprevir followed by three 750 mg doses given every 8 h and (b) four 1250 mg telaprevir doses given every 8 h, with a single 400 mg dose ketoconazole given with the fourth dose of telaprevir. (3) Volunteers received either a single 750 mg dose telaprevir with or without 600 mg once daily rifampicin, or 750 mg every 8 h telaprevir with and without 600 mg once daily efavirenz. RESULTS: A single 400 mg dose of ketoconazole increased single dose telaprevir exposure: the geometric least-squares mean ratio (GLSMR, with 90% confidence limits) was 1.24 (1.10, 1.41) for C(max) and 1.62 (1.45, 1.81) for AUC(0,∞). However, after multiple doses of telaprevir, there was no discernible effect of ketoconazole on telaprevir exposure. Co-administration of rifampicin at steady-state markedly reduced single dose telaprevir exposure with GLSMRs of 0.14 (0.11, 0.18) for C(max) and 0.08 (0.07, 0.11) for AUC(0,∞), whereas efavirenz had a smaller effect on telaprevir exposure when both drugs were co-administered at steady-state, with GLSMRs of 0.91 (0.81, 1.02) for C(max) , 0.53 (0.44, 0.65) for C(min), and 0.74 (0.65, 0.84) for AUC(0,8 h). CONCLUSION: CYP3A inducers, rifampicin and efavirenz, can reduce telaprevir exposure to varying degrees based on their potency. The effect of ketoconazole as an inhibitor of telaprevir metabolism is more pronounced after a single dose of telaprevir than after repeated administration.

The potential influence of Internet-based social networking on the conduct of clinical research studies.

The rapid growth of internet usage has led to an explosion of social networking sites for discussion of health issues. This provides a forum for subjects to communicate with one another during the course of the studies. Previous studies have raised concerns about the quality of health information on social networking sites, although none have evaluated content related to ongoing clinical trials. We reviewed material posted in virtual communities by self-identified clinical trial participants. We identified material posted in online health forums that could introduce bias into clinical research studies; we believe that this issue warrants further study and discussion. Physicians and others who conduct clinical trials should be aware of this issue. Study investigators and research teams should also talk to their study subjects about where and how they are obtaining information in order to prevent behaviors and correct misinformation that could put a subject's safety or the study objectives at risk. Given the rapid increase in Internet use for health care, a broader evaluation of both the benefits and potential risks of social networking among research participants during the course of a clinical trial appears warranted.

Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study.

Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted.

Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders.

UNLABELLED: Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. CONCLUSION: The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.