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Efficacy and safety trial of AJG555 in patients with chronic constipation (Phase 3 study)

Phase 3 study of AJG555 in patients with chronic constipation

156

The breakdown of the enrolled patients was 76 patients in the placebo group and 80 patients in the AJG555 group. The female ratio was 80.3% (61/76 patients) in the placebo group and 88.8% (71/80 patients) in the AJG555 group. The mean age was 42.0 [12.8] years old (mean [SD], hereafter the same) in the placebo group and 44.3 [11.6] years old in the AJG555 group. The BMI was 21.77 [2.97] and 21.64 [2.94] kg/m2 in the placebo and AJG555 groups, respectively.

Among the 204 patients who gave Informed Consent, six were discontinued prior to the eligibility assessment for provisional enrollment. Six patients were considered ineligible at the eligibility assessment for provisional enrollment. Accordingly, 192 patients were provisionally enrolled. Among those provisionally enrolled, three were discontinued prior to the eligibility assessment for formal enrollment. At the eligibility assessment for formal enrollment, 33 patients were considered ineligible. Therefore, in total, 156 patients were formally enrolled (randomized). The breakdown of the enrolled patients was 76 patients in the placebo group and 80 patients in the AJG555 group. The study drug treatment was initiated at the Confirmatory phase. After the study drug treatment initiation, three patients of the placebo group discontinued the study drug treatment at the Confirmatory phase. Seventy-three patients of the placebo group and 80 patients of the AJG555 group, or a total of 153 patients, completed the study drug treatment at the Confirmatory phase. The reasons for discontinuation of three patients from the placebo group were the following: Adverse events (2 patients) and patient's reason (1 patient). Adverse events included vertigo positional and contusion. After completion of the Confirmatory phase, no patient was discontinued prior to the study drug treatment at the Extension phase and 153 patients initiated AJG555 treatment in the Extension phase. By the end of the Extension phase, 25 patients discontinued the AJG555 treatment and 128 patients completed 52 weeks of treatment at the Extension phase. The reasons for discontinuation at the Extension phase were as follows: Patient's reason (10 patients), adverse events (8 patients), others (4 patients), lack of treatment efficacy (2 patient), and lost to follow-up (1 patient). Adverse events included infectious colitis, breast cancer, insomnia, abdominal discomfort, constipation, nausea, eczema, and erythema.

A common adverse event in the AJG555 group was Nasopharyngitis and common adverse events in which a causal relationship with the study drug could not be ruled out were Gastrointestinal disorders such as Abdominal pain and Diarrhea. There was no fatal case observed. Non-fatal, serious adverse events were Infectious colitis, Breast cancer, Retinal detachment and Macular hole each in one patient. However, the causal relationship with the study drug was ruled out. During the entire study period, 8 patients experienced adverse events in AJG555 group who resulted in treatment discontinuation. Although the outcome of Insomnia was not recovered, all the others were recovered or improved. Finally, there were no clinically significant changes in clinical laboratory values and vital signs during the Confirmatory phase and the Extension phase.

Efficacy analysis was conducted in FAS and included 156 patients in the Confirmatory phase (placebo group, 76 patients; AJG555 group, 80 patients). The primary endpoint or the changes in the number of SBMs at Week 2 of the Confirmatory phase versus Week 2 of the Screening period (FAS) was 1.64 [2.00] times in the placebo group and 4.25 [2.93] times in the AJG555 group. For the primary analysis, FAS was used as Analysis Set and an ANOVA was conducted with the number of SBMs at Week 2 of the Screening period as a covariate. The changes in the number of SBMs at Week 2 of the Confirmatory phase versus Week 2 of the Screening period in the AJG555 group were significantly larger than those in the placebo group and the superiority was demonstrated (p < 0.0001).

For the secondary endpoints, AJG555 demonstrated apparent improvements versus placebo, and its efficacy in patients with chronic constipation was demonstrated. Moreover, the number of SBMs, the number of CSBMs, and the total number of bowel movements were increased from Week 1 of the Extension phase and were stable until Week 52. The ratio of responders in the number of SBMs and number of CSBMs was stable from Week 1 to Week 52 of the Extension phase. Stool hardness based on the Bristol stool form scale also showed an improvement from the Extension phase and remained stable until Week 52. The ratio of subjects who used rescue medication(s) decreased from Extension phase Week 1 and was stable until Week 52.

Treatment with AJG555 was initiated at 2 sachets once a day in patients with chronic constipation for both the 2-wk Confirmatory phase and 52-wk Extension phase. Based on their bowel condition, the dose was adjusted in accordance with the Dose Adjustment Criteria. As a result, the superiority of AJG555 versus the placebo was demonstrated. Moreover, the efficacy of AJG555 lasted for the entire 52-wk Extension phase. the tolerability of AJG555 in patients with chronic constipation was considered acceptable.

April. 22, 2019

https://link.springer.com/article/10.1007/s00535-019-01581-x

No

EA Pharma Co., Ltd.

contact_ea@eapharma.co.jp

EA Pharma Co., Ltd.

contact_ea@eapharma.co.jp

completed

Feb. 18, 2016

Interventional

Placebo controlled, randomized, double blind, Multicenter, parallel group design + Open labeled, Multicenter

treatment purpose

3

<Main inclusion criteria>
Patients with chronic constipation

<Main exclusion criteria>
Patients with known or suspected organic constipation
Patients with known or suspected symptomatic constipation or drug-induced constipation

Both

Chronic constipation

investigational material(s)
Generic name etc : AJG555 (MOVICOL)
INN of investigational material : Macrogol 4000
Therapeutic category code : 235 Purgatives and clysters
Dosage and Administration for Investigational material : Oral

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Oral

efficacy
confirmatory
Frequency of Spontaneous Bowel Movement
Change from baseline

efficacy
Complete Spontaneous Bowel Movement
SBM and CSBM Responder Rate
Number of Dates to the First SBM
Use of Rescue Medication
Stool Consistency Measured by Bristol Stool Form Scale

Feb. 09, 2016