Risk-Based Monitoring Approach to Ensure the Quality of Clinical Study Data and Enable Effective Monitoring.

BACKGROUND: Following the Guidance for Industry by FDA, the concept of risk-based approach has spread rapidly in recent years. It facilitates more effective, efficient, and high-quality clinical study execution. METHOD: We carried out a pilot study that adopted risk-based monitoring. In the preparatory stage, the risks of this study (protocol level and program level) were assessed and mitigated as much as possible. During the study, centralized monitoring were conducted in parallel with site (on-site/off-site) monitoring, and study risks were assessed based on the results of both monitoring in accordance with the risk management plan. RESULTS: We found that average on-site monitoring frequency decreased as the study progressed. After study completion, we conducted a Pharmaceutical and Medical Devices Agency inspection but found no significant nonconformance that would have affected the study results and patient safety. CONCLUSIONS: The results indicate that a risk-based approach, which is an innovative monitoring approach, contributes to the reliability of study results and promotes efficient monitoring.

[Pharmacological and clinical profile of linaclotide (Linzess®), a novel therapeutic agent for irritable bowel syndrome with constipation and chronic constipation].

Linaclotide (Linzess® tablets 0.25 mg) is a guanylate cyclase-C (GC-C) agonist with high selectivity and binding affinity to GC-C. In Japan, linaclotide was approved for 〝irritable bowel syndrome with constipation (IBS-C)〟 in December 2016 and 〝chronic constipation (CC) (excluding constipation due to organic disease)〟 in August 2018. Non-clinical studies demonstrated that linaclotide binding to GC-C increases intracellular cyclic guanosine monophosphate (cGMP), resulting in increased fluid secretion and gastrointestinal transit. In rats with colonic hyperalgesia, but not in normal rats, linaclotide suppressed the visceral nociceptive response, mediated by increased submucosal cGMP. In clinical studies in Japan, improvements were observed in the responder rates for global assessment of IBS symptom relief, complete spontaneous bowel movements in patients with IBS-C, and the frequency of spontaneous bowel movement in patients with CC, which were maintained during long-term treatment. Additionally, abdominal bloating, which has been associated with lower quality of life (QOL) and lower satisfaction with other approved therapies, and IBS QOL were improved throughout treatment with linaclotide. Diarrhea, a consequence of linaclotide's mechanism of action, was observed during the clinical studies, but was generally controllable by decreasing the linaclotide dose. No drug resistance was observed during the clinical studies, unlike some other approved agents. These results of non-clinical and clinical studies demonstrate that linaclotide can improve constipation, various abdominal symptoms, and QOL with a favorable safety profile in patients with IBS-C and CC.

High-dose linaclotide is effective and safe in patients with chronic constipation: A phase III randomized, double-blind, placebo-controlled study with a long-term open-label extension study in Japan.

BACKGROUND: A previous phase II dose-ranging study of linaclotide in a Japanese chronic constipation (CC) population showed that 0.5 mg was the most effective dose. This study aimed to verify the hypothesis that 0.5 mg of linaclotide is effective and safe in Japanese CC patients. METHODS: This was a Japanese phase III randomized, double-blind, placebo-controlled (part 1), and long-term, open-label extension (part 2) study of linaclotide. CC patients (n = 186) diagnosed using the Rome III criteria were randomly assigned to linaclotide 0.5 mg (n = 95) or placebo (n = 91) for a 4-week double-blind treatment period in part 1, followed by an additional 52 weeks of open-label treatment with linaclotide in part 2. The primary efficacy endpoint was the change from baseline in weekly spontaneous bowel movement (SBM) frequency at the first week. Secondary endpoints included responder rate for complete SBM (CSBM), changes in stool consistency, and severity of straining. KEY RESULTS: Part 1: Change in weekly mean SBM frequency in the first week of treatment with linaclotide (4.02) was significantly greater than that with placebo (1.48, P < 0.001). Linaclotide produced a higher CSBM responder rate (52.7%) compared to placebo (26.1%, P < 0.001). Part 2: Patients continued to show improved SBM frequency with linaclotide. Through parts 1 and 2, the most common drug-related adverse event was mild and occasionally moderate diarrhea. CONCLUSIONS AND INFERENCES: The results of this study indicate that a linaclotide dose of 0.5 mg/day is effective and safe in Japanese CC patients.

Influence of the requirement for abdominal pain in the diagnosis of irritable bowel syndrome with constipation (IBS-C) under the Rome IV criteria using data from a large Japanese population-based internet survey.

BACKGROUND: Rome III was revised to Rome IV in May 2016. One important change in the Rome IV criteria is that abdominal pain must be present for a diagnosis of irritable bowel syndrome (IBS). Under Rome III, in contrast, patients with abdominal discomfort only could be diagnosed with IBS, but these cases under Rome IV are now classified as unspecified functional bowel disorder (FBD). In a simple comparison of Rome III and Rome IV, it is unclear whether this difference reflects the influence of symptomatic frequency or the presence of abdominal pain. In particular, the influence of abdominal pain restriction on the diagnosis of IBS with predominant constipation (IBS-C) in the Rome IV criteria is largely unknown. METHODS: We reclassified subjects from a Japanese internet survey experiencing abdominal pain or discomfort at least one day each week as surrogate Rome III IBS-C subjects. Among them, we then reclassified subjects experiencing abdominal pain as surrogate Rome IV IBS-C subjects and subjects not experiencing abdominal pain as surrogate Rome IV FBD subjects. Symptoms were quantified and compared between the two groups. RESULTS: The surrogate Rome IV IBS-C subjects felt a significantly higher degree of anxiety in their daily lives (p < 0.001) compared with the surrogate Rome IV FBD subjects. The combined female and 20-49 years surrogate Rome IV IBS-C subjects felt a higher degree of anxiety in their daily lives (p < 0.05) than the respective Rome IV FBD subjects. CONCLUSIONS: These results suggest that female IBS-C patients aged 20-49 years with abdominal pain in Rome IV have more anxiety than those without abdominal pain in Rome III. Changes in the diagnostic criteria from Rome III to Rome IV will better identify candidates for the biopsychosocial approach. TRIAL REGISTRATION: Although this survey was an anonymous internet survey, we obtained informed consent for the study as an online response. The disclosure of this study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (approval number: 2015-1-405).

Impact of symptoms by gender and age in Japanese subjects with irritable bowel syndrome with constipation (IBS-C): a large population-based internet survey.

BACKGROUND: Irritable bowel syndrome with constipation (IBS-C) is a representative psychosomatic disorder. Several pathophysiological factors have been linked to IBS symptoms such as the modulation of gastrointestinal motility, visceral hypersensitivity, dysregulation of the gut-brain axis, genetic and environmental factors, sequelae of infection, and psychosocial disorders. It is likely that biopsychosocial aspects of IBS-C underlie its gender and age effects. However, the influence of each symptom of IBS-C by gender and age is not well understood. We hypothesized that the expression rate of each IBS-C symptom in females and in subjects aged 20-49 years was higher than that of subjects who were male and aged 50-79 years. METHODS: We conducted an internet survey of 30,000 adults from the general Japanese population. IBS-C subjects were asked to answer a questionnaire on the degree of anxiety, thoughts about bowel habits, and their dominant gastrointestinal symptoms together with exacerbation factors. The correlation between gender and age and IBS-C symptoms was analyzed. RESULTS: When analyzed by gender, the expression rate of abdominal discomfort, abdominal distention, and abdominal fullness was significantly higher in female than male IBS-C subjects (66.5% vs. 58.7%, p < 0.05; 54.7% vs. 43.6%, p < 0.01; 18.9% vs. 9.6%, p < 0.01, respectively). When analyzed by age, the expression rate of abdominal distention and abdominal pain was significantly higher among IBS-C subjects aged 20-49 years than those aged 50-79 years (55.7% vs. 46.8%, p < 0.05; 36.6% vs. 20.6%, p < 0.001, respectively). In contrast, there was no gender or age differences with regard to the most common and bothersome symptom (abdominal bloating) among IBS-C subjects. CONCLUSIONS: The expression rate of some IBS-C symptoms was higher among females and those aged 20-49 years than males and those aged 50-79 years, respectively. It is important to understand the impact of symptoms by gender and age to evaluate the pathology of IBS-C from a biopsychosocial perspective. TRIAL REGISTRATION: Although this survey was an anonymous internet survey, we obtained informed consent for the study as an online response. The disclosure of this study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (approval number: 2015-1-405).

Dose-finding study of linaclotide in Japanese patients with chronic constipation: A phase II randomized, double-blind, and placebo-controlled study.

BACKGROUND: Based on the previous phase II/III studies of irritable bowel syndrome with constipation (IBS-C) in Japan that demonstrated the efficacy and safety of linaclotide 0.5 mg/d, we evaluated linaclotide at doses of 0.5 mg/d and lower in the treatment of Japanese patients with chronic constipation (CC). METHODS: This was a phase II randomized, double-blind, placebo-controlled, dose-finding study of linaclotide for Japanese patients with CC (n = 382, 64 men, 318 women, age 20-75). After a baseline period of two weeks, patients were randomized to receive placebo (n = 80), or 0.0625 mg (n = 82), 0.125 mg (n = 71), 0.25 mg (n = 73) or 0.5 mg (n = 76) of linaclotide during a two-week treatment period. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency during the first week. Secondary endpoints included complete SBM (CSBM) responder rates and IBS-QOL. Safety and adverse events were also evaluated. KEY RESULTS: The change in SBM frequency during the first week (mean) was 3.89, 3.11, 3.87, and 3.85 for 0.0625 mg, 0.125 mg, 0.25 mg, and 0.5 mg for linaclotide, significantly higher than for placebo (1.91, P < 0.05). The CSBM responder, which is an important parameter, showed the greatest improvement at the 0.5 mg during the 2 week. The most frequent adverse event in the linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES: Our results suggest that 0.0625, 0.125, 0.25, and 0.5 mg/d are effective doses of linaclotide for treating CC in Japanese patients. ClinicalTrials.gov: NCT02425722, supported by Astellas Pharma, Inc.

A randomized controlled and long-term linaclotide study of irritable bowel syndrome with constipation patients in Japan.

BACKGROUND: Clinical testing was required to verify the effect of linaclotide 0.5 mg/d in patients with irritable bowel syndrome with constipation (IBS-C) in Japan. METHODS: This was a randomized, double-blind, placebo-controlled (Part 1) and long-term, open-label extension (Part 2) study of linaclotide at 60 hospitals and clinics in Japan. Patients with IBS-C diagnosed using Rome III criteria (n = 500) were randomly assigned to linaclotide 0.5 mg (n = 249) or placebo (n = 251) for a 12-week treatment period followed by open-label treatment with linaclotide (n = 324) for an additional 40 weeks. The primary endpoints were the responder rate of global improvement of IBS symptoms and complete spontaneous bowel movement (CSBM) during 12 weeks. The secondary endpoints included responder rates of SBM and abdominal pain/discomfort relief. KEY RESULTS: Part 1: The responder rates for global improvement and for CSBM frequency were significantly higher for linaclotide compared to placebo (P < 0.001). Secondary endpoints including responder rates for SBM and abdominal pain/discomfort relief in the linaclotide group were also significantly greater than those in the placebo group. Part 2: Patients switched from placebo to linaclotide showed similar responder rates for global improvement and CSBM frequency to those in patients who continued to receive linaclotide, supporting sustained efficacy. Diarrhea was seen in 14.5% of patients; all cases were mild or moderate. CONCLUSIONS AND INFERENCES: This study suggests that a linaclotide dose of 0.5 mg is effective and safe for IBS-C patients in Japan.

Abdominal bloating is the most bothersome symptom in irritable bowel syndrome with constipation (IBS-C): a large population-based Internet survey in Japan.

BACKGROUND: Abdominal bloating is a common symptom in patients with irritable bowel syndrome with constipation (IBS-C). However, it is not included among the required items in the Rome III diagnostic criteria for IBS. Little is known about an impact of abdominal bloating seen in patients with IBS-C. Using a large population-based sample, the aim of the present study was to investigate what is the most bothersome symptom in subjects with IBS-C. METHODS: An Internet survey of 30,000 adults drawn from the general public throughout Japan was conducted to identify subtypes of IBS using the Rome III diagnostic questionnaire. Consecutively, the screened subjects with IBS-C and the same number of age- and sex-matched non-IBS subjects who were randomly selected as controls were asked to answer a questionnaire on the degree of anxiety they experienced in their daily lives, thoughts about bowel habit, and their dominant gastrointestinal symptoms together with exacerbation factors (for IBS-C only). RESULTS: The screening survey showed that the prevalence of overall IBS was 16.5 % (female 17.4 %, male 15.5 %) and that 2.8 % met the criteria for IBS-C, 4.5 % for IBS with diarrhea (IBS-D) and 8.2 % for mixed IBS (IBS-M). Seven hundred and fifty-nine of 835 (90.9 %) subjects with IBS-C and 746 of 830 (89.9 %) control subjects completed the consecutive questionnaire. IBS-C subjects felt a higher degree of anxiety in their daily lives (p < 0.01) and considered bowel habit to be an indicator of health (p < 0.01) to a greater extent than control subjects. In IBS-C, the degree of anxiety was significantly associated with abdominal discomfort (p < 0.01), pain (p < 0.01) and bloating (p = 0.02), but not with the frequency of bowel habit (p > 0.1). Abdominal bloating was the most bothersome symptom (27.5 %), which was more likely to occur after a meal (52.2 %), at work/school (29.2 %) and during times of stress (26.8 %). Only 4.5 % of IBS-C subjects reported abdominal pain as the 'most bothersome' symptom. CONCLUSIONS: A large population-based Internet survey suggests that abdominal bloating has a great impact on the daily lives of subjects diagnosed with IBS-C. Not only bowel movement/abdominal pain but also abdominal bloating should be evaluated in patients with IBS-C.