Introduction

Tradipitant is a novel NK-1 receptor antagonist studied in diabetic and idiopathic gastroparesis for short-term relief of nausea. This report presents the pooled analysis from 2 multicenter, randomized, double-blind, placebo-controlled studies (VP-VLY-686-3301 and VP-VLY-686-2301) assessing the efficacy of tradipitant in relieving symptoms of gastroparesis.

Aims & Methods

N=342 idiopathic and diabetic gastroparesis patients with delayed gastric emptying, moderate to severe nausea were included in the pooled ITT (Intent-to-Treat) population. Subjects were randomized to 85mg tradipitant twice a day (n=175) or placebo (n=167) and endpoints were assessed at Week 4. Nausea was assessed with the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptom improvement was evaluated with the Patient Global Impression of Change (PGI-C) and Overall Patient Benefit (OPB) scales. Sensitivity analyses were performed to control for confounders.

Results

In a pooled analysis of double-blind subjects in the ITT population of Study 1 and Study 2, tradipitant demonstrated a clinically meaningful and statistically significant improvement in average nausea at week 4 (-1.15 for tradipitant v. -0.85 for placebo, p=0.0138). Significant improvement was seen in the number of nausea free days (20.96% improvement for tradipitant v. 12.52% for placebo, p=0.0085). Tradipitant also showed improvement in other gastroparesis symptoms as measured by the GCSI total score (-0.99 for tradipitant v. -0.76 for placebo, p=0.0265). Responder rates for PGI-C were 79.3% on tradipitant versus 69% on placebo at week 4 (p value = 0.036). For the Overall Patient Benefit, more patients improved on tradipitant versus placebo with 85.3% v. 71.2% at week 4 (p= 0.002). Sensitivity analysis adjusting for drug compliance confirmed the PK population (tradipitant blood levels ≥ 140ng/mL) in the pooled data set (n=284). In the pooled PK Population, tradipitant significantly improved average nausea at week 4 with -1.38 for tradipitant v. -0.85 for placebo (p=0.0001).

Conclusion

Pooling the data provided an opportunity to analyze a much larger data set, increase statistical power, and confirm results and subpopulations from the two separate studies. In the pooled analysis, we observed a clinically meaningful and significant effect on change of nausea severity at week 4. Improvements were also seen across core gastroparesis symptoms and overall measures of gastroparesis.

Disclosure

Study was sponsored by Vanda Pharmaceuticals, Inc. Authors are employees of Vanda Pharmaceuticals, Inc.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is associated with increased technical difficulty and can potentially contribute to prolonged procedural duration and excess exposure to ionizing radiation.

Aims & Methods

The purpose of the present study was to present descriptive information about fluoroscopy during ERCP from a large reference center and to investigate possible determinants of the radiation dose or fluoroscopy duration during ERCP. We examined a prospectively collected single-center database of adult patients undergoing ERCP between 09/2021 and 12/2023 in a tertiary greek public hospital. Detailed information concerning patient, endoscopist and procedural parameters including ERCP indication, degree of difficulty of ERCP (defined using the Schutz score), types of interventions and fluoroscopy were recorded retrospectively. Non parametric statistical methods were used (Mann–Whitney U-test and Kruskal–Wallis test) for the analysis.

Results

In total, data of 1051 ERCPs were collected at first, while 1028 ERCPs with complete information for fluoroscopy duration and radiation dose were included (mean patient age 72.20 ±14.02years, 49.1% men) in the analysis. The mean procedure time was 34.22 ± 14.9 minutes, carried out by three different endoscopists (n₁=321, 31.4%, n₂=338, 33%, n₃= 363, 35.6%). The majority of ERCPs were performed for treatment of choledocholithiasis (64.5%) and were classified as of intermediate difficulty according to Schutz scoring system [Schutz score 2 (n=523, 53.4%)]. Fluoroscopy was used in 1010 ERCPs (98.2%) and the median fluoroscopy duration was 2.4 minutes (IQR=2.6 min) and the median radiation dose was 1031.6 μGym²(IQR=1237.5 μGym²). ERCPs performed with an indication of biliary tract neoplasm (e.g. cholangiocarcinoma, liver metastases) were associated with prolonged fluoroscopy duration [5.05min (IQR=6.35 min), p=0.008] and increased radiation dose [2372.75 μGym² (IQR=2462.68 μGym²), p=0.003] in comparison to the rest of the indications including choledocholithiasis, pancreatic neoplasm, obstructive jaundice and other indications.ERCP difficulty was also related with increased radiation; ERCPs with Schutz score ≥3 were associated with increased radiation dose and fluoroscopy duration compared with ERCP procedures evaluated as Schutz sore ≤2 [3.3min (IQR=3.9 min) vs. 2.1min (IQR=2.15 min), p<0.001 and 1280.8 μGym² (IQR=1836.8 μGym²) vs. 937.6 μGym² (IQR=820.25 μGym²),p<0.001 respectively]. There was no significant difference of the fluoroscopy duration (p=0.495) and radiation dose (p=0.950) among the three performing endoscopists.

Conclusion

Increased difficulty of ERCP and the indication of biliary tract neoplasm were related to higher radiation dose and prolonged fluoroscopy duration. These factors could be utilized to predict ERCP procedures related to increased radiation exposure and may contribute to adoption of appropriate radiation reduction methods.

Introduction

To assess the exposure response of NK-1 receptor antagonist tradipitant in the reduction of gastroparesis symptoms in patients with idiopathic gastroparesis in the open label arm of phase 3 study (VP-VLY-686-3301).

The four etiologies of gastroparesis are diabetic, post-surgical, drug-induced, and idiopathic. The idiopathic etiology of gastroparesis is least common, presenting in about 11.3% of patients, which amounts to about 90,000 patients in the United States. Standards set by the FDA define a rare disease or condition as one that affects less than 200,000 people in the United States. This establishes idiopathic gastroparesis as a rare condition, as well as one with a high unmet need for treatment. Patients with gastroparesis have decreased quality of life associated with severe and chronic symptoms and no treatment is currently approved for idiopathic gastroparesis specifically. Tradipitant previously demonstrated efficacy in idiopathic gastroparesis in reducing gastroparesis symptoms in a phase 2 study (VP-VLY-686-2301).

Aims & Methods

The open label arm of Study 3301 enrolled n=531 idiopathic and diabetic gastroparesis patients with delayed gastric emptying, moderate to severe nausea, and at least 1 vomiting episode. Patients received 85 mg tradipitant twice a day for 12 weeks. Nausea was assessed daily using the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptoms were assessed every 2 weeks in clinic using the Gastroparesis Cardinal Symptom Index (GCSI).

An exposure response analysis was performed on a subgroup of patients to control for low drug exposure. We used a threshold of ≤140ng/ml tradipitant blood concentration at any visit to classify participants in the High (n=309) and Low (n=218) PK Populations. Results were further stratified to compare average nausea severity and gastroparesis symptoms at baseline nausea severity scores of ≥2 and ≥2.5 for Low (n=129 and n=89, respectively) and High (n=170 and n=110, respectively) PK subgroups.

Results

Patients in the High PK subgroup had statistically improved nausea severity at Week 12 compared to the Low PK subgroup (-1.19 vs. -0.78, respectively; p<0.0001), including at baseline nausea severity scores of ≥2 (-1.61 vs. -0.98, respectively; p<0.0001) and ≥2.5 (-1.77 vs. -1.03, respectively; p<0.0001). The High PK subgroup also had statistically significant improvement in nausea-free days at Week 12 compared to Low PK (+35.65% vs. +22.56%, respectively; p=0.0002), including at baseline nausea scores of ≥2 (+36.36% vs. 18.15%, respectively; p=0.0002) and ≥2.5 (+33.44% vs. 14.11%, respectively; p=0.0009).

Conclusion

A significant exposure response was seen in idiopathic gastroparesis patients receiving open label tradipitant for 12 weeks. Patients with higher blood levels of tradipitant significantly improved in average nausea severity and in endpoints measuring overall gastroparesis symptoms compared to subjects with low drug blood levels.

Disclosure

Study was sponsored by Vanda Pharmaceuticals, Inc. Authors are employees of Vanda Pharmaceuticals, Inc.

Introduction

Tradipitant is a novel NK1R antagonist studied in diabetic and idiopathic gastroparesis. This report presents the analysis from the open-label arm of a multicenter, randomized, double-blind, placebo-controlled study (VP-VLY-686-3301) assessing the efficacy of tradipitant in relieving symptoms of gastroparesis.

Aims & Methods

N=531 idiopathic and diabetic gastroparesis patients with delayed gastric emptying received open label 85mg tradipitant BID for 12 Weeks. Nausea was assessed using the 5-point Gastroparesis Core Symptom Daily Diary. An exposure response analysis was performed to control for low drug exposure. We used a threshold of ≤140ng/ml tradipitant blood concentration at any visit to classify participants in the High (n=309) and Low (n=218) PK Populations.

Results

Patients improved the average nausea score significantly from baseline after 12 weeks tradipitant (improvement of -1.01 vs 2.14 at baseline, p<0.0001). A significant improvement was also seen in the percent of nausea free days (an addition of 51.76% of days for tradipitant vs. 19.62% at baseline, p<0.0001).

Patients in the High PK group significantly improved average nausea score compared to the Low PK group at Week 12 (improvement of -1.19 vs -0.78, p<0.0001). A significant improvement was also seen in the percent of nausea free days (an addition of 35.6% of days for High PK versus 22.6% for Low PK, p=0.0002).

Conclusion

Tradipitant demonstrated statistically significant improvement from baseline in average nausea severity and percentage of nausea-free days in this 12 week open label study in both idiopathic and diabetic gastroparesis subjects. Additionally, a strong exposure response in nausea improvement was observed when comparing subjects with high drug exposure vs low drug exposure.

Disclosure

Study was sponsored by Vanda Pharmaceuticals. Inc. Authors are employees of Vanda Pharmaceuticals, Inc.

Introduction

This report presents the results of a multicenter, randomized, double-blind, placebo-controlled phase 3 study (VP-VLY-686-3301) assessing the efficacy of tradipitant in relieving symptoms of gastroparesis. Tradipitant, a novel NK-1 receptor antagonist, previously demonstrated efficacy in diabetic and idiopathic gastroparesis in reducing gastroparesis symptoms in a phase 2 study (VP-VLY-686-2301).

Aims & Methods

N=201 idiopathic and diabetic gastroparesis patients with delayed gastric emptying, moderate to severe nausea, and at least 1 vomiting episode were included in the ITT (Intent-to-Treat) population. Subjects were randomized to receive 85 mg tradipitant twice a day (n=102) or placebo (n=99) for 12 weeks. Nausea was assessed daily using the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptom improvement was evaluated using the Patient Global Impression of Change (PGI-C) and the Overall Patient Benefit (OPB) scales. Sensitivity analyses were also performed to control for confounders that may have masked the true treatment effect size.

Results

At the primary endpoint of change in nausea from baseline as measured by the GCSDD at week 12, both tradipitant and placebo showed significant and similar reductions from baseline at 1.55 and 1.49 respectively. Comparison between treatment arms did not reach statistical significance in this measure. However, in the PGI-C scale, more tradipitant treated patients demonstrated response as compared to placebo both at week 2 (74% v. 58%, p=0.019) and at week 12 (78% v. 66%, p=0.065). Similarly, in the OPB scale, more tradipitant treated patients demonstrated response as compared to placebo both at week 2 (81% v. 62%, p=0.0003) and week 12 (86% v. 71%, p=0.011).
Sensitivity analysis adjusting for rescue medication use further confirmed the ITT findings in both the PGI-C and OPB analysis at both week 2 and week 12.

Conclusion

Significant but similar improvements from baseline for tradipitant and placebo may have masked the true treatment effect size at the primary endpoint of the study of change in nausea severity as measured by daily diary at week 12 leading to no statistically significant difference between treatments. Despite this large placebo effect, tradipitant was shown to be significantly better than placebo in global measures of patient improvement including the Patient Global Impression of Change (PGI-C) and the Overall Patient Benefit (OPB) scales.

Disclosure

Study was sponsored by Vanda Pharmaceuticals, Inc. Authors are employees of Vanda Pharmaceuticals, Inc.