RESUMO
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.
Assuntos
Constipação Intestinal/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Agonistas da Guanilil Ciclase C/uso terapêutico , Peptídeos/uso terapêutico , Adulto , Idoso , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Constipação Intestinal/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/uso terapêutico , Adulto , Idoso , Constipação Intestinal/etiologia , Método Duplo-Cego , Feminino , Agonistas da Guanilil Ciclase C/uso terapêutico , Humanos , Síndrome do Intestino Irritável/complicações , Japão , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tempo , Resultado do Tratamento , Adulto JovemRESUMO
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.