Clinical trial designs of new medicinal products for treating schizophrenia: discussion of EMA's Guideline and a Better Long Term Trial Design

Background and Objectives: Schizophrenia is a severe chronic disease. Endpoint variables lack objectivity and the diagnostic criteria have evolved with time. In order to guide the development of new drugs, European Medicines Agency (EMA) issued a guideline on the clinical investigation of medicinal products for the treatment of schizophrenia. Methods: Authors reviewed and discussed the efficacy trial part of the Guideline. Results: The Guideline divides clinical efficacy trials into short-term trials and long-term trials. The short-term three-arm trial is recommended to replace the short-term two-arm active-controlled non-inferiority trial because the latter has sensitivity issues. The Guideline ultimately makes that three-arm trial a superiority trial. The Guideline discusses four types of long-term trial designs. The randomized withdrawal trial design has some disadvantages. Long-term two-arm active-controlled non-inferiority trial is not recommended due to the sensitivity issue. Extension of the short-term trial is only suitable for extension of the short-term two-arm active-controlled superiority trial. The Guideline suggests that a hybrid design of a randomized withdrawal trial incorporated into a long-term parallel trial might be optimal. However, such a design has some disadvantages and might be too complex to be carried out. Authors suggest instead a three-group long-term trial design, which could provide comparison between test drug and active comparator along with comparison between the test drug and placebo. This alternative could arguably be much easier to carry out compared with the hybrid design. Conclusions: The three-group long-term design merits further discussion and evaluation.

The impact of serum uric acid on the diagnostic of metabolic syndrome in apparently healthy Brazilian middle-aged men

Background: Hyperuricemia is related to Metabolic Syndrome (MetS) and cardiovascular diseases, but the use of serum uric acid (UA) to diagnose MetS is currently ignored in clinical practices. Objectives: To examine the impact of serum UA on the diagnostic of MetS and the relationship of serum UA with cardiometabolic risk factors in apparently healthy Brazilian middle-aged men residents in a city of Minas Gerais. Methods: In a cross-sectional analysis, 289 apparently healthy middle-aged men underwent anthropometric, clinical, sociodemographic and blood serum biochemical evaluation. By using receive operating curve the internal cutoff of serum UA was determined (5.25 mg/dL). Results: Subjects with two or more components of MetS exhibited higher serum UA as compared to those with one or none component. The inclusion of serum UA ≥ 5.25mg/dL as an additional component of MetS increased the occurrence of this syndrome by 13%. Subjects with UA ≥ 5.25mg/dL showed high prevalence for MetS and association with its components (central obesity, hypertriglyceridemia, dyslipidemia and hypertension) as well as atherogenic risk. Conclusions: Serum UA has an important impact on the diagnostic of MetS and is related to cardiometabolic risk factors in apparently healthy Brazilian middle-aged men. Its use in clinical practices could aggregate accuracy to diagnose MetS.

Characteristics of Clostridium difficile infection in patients with discordant diagnostic test results

Background: Clinical features of Clostridium difficile infection (CDI) cases diagnosed by detection of polymerase chain reaction (PCR), with negative toxin enzyme immunoassay results (EIA) have not been fully elucidated. The purpose of this study was to determine the magnitude of CDI patients who had negative EIA toxin determinations but positive PCR tests, and their differences in clinical presentation. Methods: We performed a retrospective study comparing the clinical features of CDI cases detected by EIA (toxins A + B) with cases detected by PCR (toxin negative, PCR positive) over a 16-month period. Only patients with an initial Clostridium difficile infection episode that fulfilled a standardized definition were included. Results: During the study period, 107 episodes of CDI were detected. Seventy-four patients (69%) had positive glutamate dehydrogenase (GDH) antigen and EIA determinations (EIA positive patients). Thirty-three patients (31%) had GDH positive, negative toxin EIA and positive PCR determination (PCR positive patients). PCR positive patients were younger, 57 (27) years (mean [SD]), than EIA positive patients, 71 (16) years, (p < 0.001). Fewer PCR positive patients were receiving proton pump inhibitors (21 patients, 64%) than EIA positive patients (61 patients, 82%, p = 0.034). The clinical presentation was similar in both groups. In the multivariate analysis, lower age was identified as the only independent variable associated with PCR positive patients. Conclusions: One third of Clostridium difficile infection patients present negative toxin EIA and PCR positive tests. Performing PCR determination after the negative EIA test is more relevant in younger patients.

Management of the clinical issue of constipation with abdominal complaints in adults: a national survey of Primary Care physicians and gastroenterologists

Irritable bowel syndrome and functional constipation represent a relevant and common health issue. However, real-world clinical practice includes patients with constipation who may or may not have other abdominal complaints (pain, bloating, abdominal discomfort) with variable frequency. The goal of the present study was to obtain information on the workload entailed by patients with constipation and associated abdominal complaints, predominant clinical behaviors, education needs, and potential daily practice aids both in Primary Care and gastroenterology settings. The clinical behavior of doctors is generally similar at both levels, despite differences in healthcare approach: use of empiric therapies and clinically guided diagnostic tests, with some differences in colonoscopy use (not always directly accessible from Primary Care). Regarding perceptions, general support and osmotic laxatives are most valued by PC doctors, whereas osmotic laxatives, combined laxatives, and linaclotide are most valued by GE specialists. Furthermore, over half of respondents considered differentiating both diagnoses as challenging. Finally, considerable education needs are self-acknowledged at both levels, as is a demand for guidelines and protocols to help in managing this issue in clinical practice. A strength of this study is its providing a joint photograph of the medical approach and the perceptions of constipation with abdominal discomfort from a medical standpoint. Weaknesses include self-declaration (no formal validation) and a response rate potentially biased by professional motivation.

Clinical Practice Guideline: irritable bowel syndrome with constipation and functional constipation in the adult

In this Clinical Practice Guideline we discuss the diagnostic and therapeutic approach of adult patients with constipation and abdominal complaints at the confluence of the irritable bowel syndrome spectrum and functional constipation. Both conditions are included among the functional bowel disorders, and have a significant personal, healthcare, and social impact, affecting the quality of life of the patients who suffer from them. The first one is the irritable bowel syndrome subtype, where constipation represents the predominant complaint, in association with recurrent abdominal pain, bloating, and abdominal distension. Constipation is characterized by difficulties with or low frequency of bowel movements, often accompanied by straining during defecation or a feeling of incomplete evacuation. Most cases have no underlying medical cause, and are therefore considered as a functional bowel disorder. There are many clinical and pathophysiological similarities between both disorders, and both respond similarly to commonly used drugs, their primary difference being the presence or absence of pain, albeit not in an "all or nothing" manner. Severity depends not only upon bowel symptom intensity but also upon other biopsychosocial factors (association of gastrointestinal and extraintestinal symptoms, grade of involvement, and perception and behavior variants). Functional bowel disorders are diagnosed using the Rome criteria. This Clinical Practice Guideline has been made consistent with the Rome IV criteria, which were published late in May 2016, and discuss alarm criteria, diagnostic tests, and referral criteria between Primary Care and gastroenterology settings. Furthermore, all the available treatment options (exercise, fluid ingestion, diet with soluble fiber-rich foods, fiber supplementation, other dietary components, osmotic or stimulating laxatives, probiotics, antibiotics, spasmolytics, peppermint essence, prucalopride, linaclotide, lubiprostone, biofeedback, antidepressants, psychological therapy, acupuncture, enemas, sacral root neurostimulation, surgery) are discussed, and practical recommendations are made regarding each of them.