In this study we describe in detail the characteristics of sphincter of Oddi motor function in a large group of healthy subjects. Studies were obtained in 50 healthy volunteers. The findings showed a sphincter of Oddi segment that had a basal pressure of 14.8 +/- 6.3 mm Hg (X +/- SD). Phasic contractions were superimposed on the basal pressure. They had an amplitude of 119.7 +/- 32 mm Hg, a duration of 4.7 +/- 1 sec, and a frequency of 5.7 +/- 1.2 contractions/min. In 40 subjects the propagation sequence of phasic contractions could be evaluated and were simultaneous in 53%, antegrade in 35%, and retrograde in 11% of the waves. In 20 subjects, pressure measurements done at the common bile duct sphincter waves. In 20 subjects, pressure measurements done at the common bile duct sphincter were similar to those obtained at the pancreatic duct sphincter. In 10 subjects, pressure values obtained at the common bile duct sphincter within a week were similar. Our study should help to establish standards for normal manometric values of the sphincter of Oddi and emphasizes the importance of having a healthy volunteer group from which to obtain the normal values of sphincter of Oddi motor function.
GED-0301 is an antisense oligodeoxynucleotide with a sequence complementary to the Smad7 mRNA transcript. Smad7 is a negative regulator of transforming growth factor-β, which is increased in the intestinal mucosa of patients with active Crohn's disease (CD). We randomly assigned 63 CD patients to 4-, 8-, or 12-week treatment groups receiving oral GED-0301 (160 mg/day). The primary objective was to determine GED-0301's effect on endoscopic CD measures; secondary objectives included effects on clinical activity. Endoscopic improvement was observed in 37% of participants with evaluable endoscopy results at week 12. At week 12, 32% (4 weeks), 35% (8 weeks), and 48% (12 weeks) of patients receiving GED-0301 were in remission (CD activity index score <150); corresponding reductions from baseline in mean CD activity index scores were -124, -112, and -133 points. No new safety signals were observed. These findings support a GED-0301 benefit in active CD. ClinicalTrials.gov no: NCT02367183.
Introduction:
The objective was to assess the efficacy and safety of GED-0301, an antisense oligodeoxynucleotide to Smad7, in active Crohn's disease (CD).
METHODS:
This phase 3, blinded study randomized patients (1:1:1:1) to placebo or 1 of 3 once-daily oral GED-0301 regimens: 160 mg for 12 weeks followed by 40 mg continuously or alternating placebo with 40 or 160 mg every 4 weeks through week 52.
RESULTS:
In all, 701 patients were randomized and received study medication before premature study termination; 78.6% (551/701) completed week 12, and 5.8% (41/701) completed week 52. The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo. More placebo vs GED-0301 patients achieved endoscopic response (>50% decrease from baseline Simple Score for CD) at week 12 (18.1% vs 10.1%). Additional endoscopic endpoints were similar between groups at weeks 12 and 52. More placebo vs GED-0301 patients had clinical response (≥100-point decrease in the CD Activity Index score) at week 12 (44.4% vs 33.3%); at week 52, clinical response rates were similar. Adverse events were predominantly gastrointestinal and related to active CD, consistent with lack of clinical and endoscopic response to treatment. Two deaths occurred (GED-0301 total group) due to small intestinal obstruction and pneumonia; neither was suspected by the investigator to be treatment-related.
DISCUSSION:
GED-0301 did not demonstrate efficacy vs placebo in active CD.
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