Metoclopramide Nasal Spray in Women with Symptomatic Diabetic Gastroparesis: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

BACKGROUND & AIMS: Metoclopramide nasal spray (MNS) was developed as an alternative to oral metoclopramide. Prior phase 2 studies demonstrated efficacy in reducing symptoms in women, but not men with diabetic gastroparesis. The aim of this phase 3 study was to further determine the safety and efficacy of MNS compared with placebo in reducing symptoms of diabetic gastroparesis in women. METHODS: This US multicenter, randomized, double-blind, parallel group study enrolled women aged 18-75 years with diabetic gastroparesis and delayed gastric emptying. Subjects were randomized 1:1 to receive placebo or MNS 10 mg. The primary efficacy end point was change in mean daily Gastroparesis Symptom Assessment total score from baseline to Week 4. The Gastroparesis Symptom Assessment daily diary is a validated patient-reported outcome instrument that averages scores of nausea, early satiety, prolonged fullness, bloating, and upper abdominal pain on a 5-point ordinal scale. RESULTS: Two hundred and five subjects were randomized to receive placebo (n = 103) or MNS (n = 102). Overall, the MNS group did not experience a significant reduction in symptoms compared with the placebo group from baseline to Week 4 (P = .881). However, subjects with moderate-to-severe symptoms at baseline had a significant treatment effect from Weeks 1 to 3 (P < .05) and experienced a significant reduction in nausea and upper abdominal pain for all 4 weeks versus placebo (P < .05). Treatment-emergent adverse events were primarily mild to moderate with headache and abdominal pain reported most frequently. CONCLUSIONS: Although the primary end point was not met using all enrolled patients, treatment with MNS provided significant relief for women with moderate-to-severe diabetic gastroparesis symptoms. MNS was well tolerated and demonstrated a similar safety profile to placebo. (ClinicalTrials.gov identifier: NCT02025725.).

Metoclopramide Nasal Spray Reduces Symptoms of Gastroparesis in Women, but not Men, With Diabetes: Results of a Phase 2B Randomized Study.

BACKGROUND & AIMS: Metoclopramide nasal spray, unlike oral tablets, is absorbed even when patients have delayed gastric emptying or nausea and vomiting. We performed a randomized phase 2b study to evaluate the efficacy and safety of 10-mg and 14-mg metoclopramide nasal spray vs placebo in patients with diabetes and gastroparesis. METHODS: We performed a multicenter, double-blind study of 285 subjects (71% female) with type 1 or type 2 diabetes and a previous diagnosis of gastroparesis. Subjects were assigned randomly to groups given metoclopramide nasal spray (10 or 14 mg) or placebo 30 minutes before meals and bedtime for 28 days. The primary end point was the change in total symptom score from baseline to week 4, based on symptom items (nausea, bloating, early satiety, and upper abdominal pain) reported in daily diaries. We performed a prespecified subgroup analysis of male vs female subjects. RESULTS: Subjects given metoclopramide nasal spray had an overall reduction in symptom scores, although there was no statistically significant difference in reduction between the metoclopramide groups and the placebo group. Gastroparesis symptom scores were reduced significantly in female subjects given either dose of metoclopramide compared with placebo (mean reduction from 10-mg dose, 1.2 ± 1.18; P = .0247; mean reduction from 14-mg dose, 1.3 ± 0.94; P = .0215). In men, symptom scores decreased more in the placebo group than the metoclopramide groups. The most common treatment-emergent adverse effects were dysgeusia, headache, and fatigue. CONCLUSIONS: Metoclopramide nasal spray reduces symptoms of gastroparesis in women, but not in men, with diabetes. Patient sex therefore might be considered in the selection of treatment for diabetic gastroparesis. ClinicalTrials.gov no: NCT00845858.

The current status of orphan drug development in Europe and the US.

Orphan drug legislation has been introduced in a number of countries in order to stimulate the development of treatments for rare diseases by introducing commercial incentives for companies wishing to undertake that development. In order to navigate the maze of regulatory regulations and procedures so that companies can make proper use of the orphan drug incentives, specialist knowledge is required. This article will review the current status of orphan drug development in the EU and the US, explain the incentives and procedures, and touch on the role of patient organisations in the process.

Previstage GCC colorectal cancer staging test: a new molecular test to identify lymph node metastases and provide more accurate information about the stage of patients with colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of death for both men and women in North America. The staging of the CRC at the time of diagnosis is the single most important prognostic factor in determining recurrence and survival. Until 2008, accurate evaluation of CRC stages I and II was based on examination of regional lymph nodes (LNs) under a microscope to identify cancer cells. This method can detect one cancer cell in 200 normal cells, but analyzes only a fraction of the available tissue from the LN (less than 0.1%). Up to 30% of patients assessed by traditional histopathology methods as having stage II disease (negative LNs) experience a recurrence of their cancer. Previstage GCC Colorectal Cancer Staging Test, a new molecular diagnostic test, is able to identify patients at high risk of recurrence by examining their LNs for guanylyl cyclase C (GCC). GCC is a marker found in cells lining the lumen of the gastrointestinal tract. The expression of GCC is conserved in CRC and metastatic disease. Using an ultrasensitive quantitative reverse transcription (RT)-PCR, the test interrogates a patient's LN tissues to identify GCC levels consistent with metastatic (stage III) disease. The technology employed in Previstage GCC is nearly 100,000 times more sensitive than microscopic staging methods. This molecular diagnostic test allows a more thorough examination of LNs and has an analytic sensitivity of 92% and a specificity of 98%. Such a test can be used to overcome the limitations of staging by traditional histopathology alone.

Ethical issues, safety, and data integrity in clinical trials.

Published in 1974, the Belmont Report established the ethical principles for conducting clinical research in the United States. The essential concepts are respect for the research participant, beneficence for society at large, and justice (equal access to participation and equal treatment) toward subjects in a research study. These principles are applied through the use of informed consent, risk/benefit assessment, and the impartial selection of study subjects. Strict adherence to these criteria often results in conflicts of interest, which the investigator must anticipate and manage. Investigators must also be thoroughly acquainted with the principles of Good Clinical Practice and regulatory requirements. Recent implementation of the Privacy Rule now requires the investigator to protect not only the safety but the privacy of the research subject. While the regulatory obligations can appear onerous, strict compliance results in clinical research that is safe, scientifically sound, and ethical.