Breakthrough Clinical Results
Enterra Medical has launched the NAVIGATE study to evaluate the safety and effectiveness of Gastric Electrical Stimulation (GES) for treating chronic nausea in patients with normal gastric emptying. The FDA-approved IDE study, also granted Breakthrough Device designation, aims to expand the use of GES beyond patients with gastroparesis. The multi-center, randomized, double-blind, placebo-controlled trial will enroll at least 148 subjects across the US, Europe, and the UK. This represents a significant advancement for patients with chronic nausea who haven't found relief from existing treatments.
Key Highlights
- Initiation of NAVIGATE study to evaluate GES for chronic nausea with normal gastric emptying.
- FDA IDE approval and Breakthrough Device designation received.
- Multi-center, randomized, double-blind, placebo-controlled study design.
- Potential to expand GES therapy to a broader patient population.
Incidence and Prevalence
Global Epidemiology of Chronic Nausea
Prevalence in General Population
The prevalence of clinically significant chronic nausea in the general population has been found to be 1.6% (1.4-1.8%) according to a telephone survey of 5000 representative subjects. Interestingly, about 90% of chronic nausea was not accompanied with vomiting.
In this study, clinically significant nausea was identified by lowered quality of life if the frequency was more than one day per week. The research confirmed that health-related quality of life (HRQoL) is significantly lower in people with nausea occurring at this frequency in the general population.
Chronic Unexplained Nausea
After exclusion of organic causes through meticulous medical examination, the prevalence of chronic unexplained nausea was determined to be 0.6% (95% CI 0.4-0.8%). Patients with chronic unexplained nausea were more likely to report functional dyspepsia and irritable bowel syndrome.
Organic Causes and Associated Conditions
Organic diseases associated with chronic nausea were identified as reflux esophagitis, duodenal ulcer, and hyperthyroidism.
Nausea in Specific Conditions
Several studies report nausea prevalence in specific conditions: - In gastroparesis patients, 96% experienced nausea and nausea was severe or very severe in 41% of cases - In cancer patients undergoing chemotherapy, the prevalence of nausea had a very broad range (e.g., nausea: 9-74%) - In patients with new daily persistent headache (NDPH), nausea occurred in 21.1% of the patients - In COVID-19 survivors, the global prevalence of prolonged nausea was 3.23% (95% CI: 0.54%-16.53%) among 527 COVID-19 survivors - In the context of chemotherapy/radiotherapy-induced nausea and vomiting (CINV/RINV), 60% of patients reported nausea alone
Mechanism of Action
Mechanisms of Action in Trials for Unapproved Chronic Nausea Drugs
Based on the available information, several mechanisms of action have been investigated in trials for drugs that have not been approved for chronic nausea:
Endocannabinoid System
The endocannabinoid system, particularly 2-arachidonoylglycerol (2-AG), has been investigated for its role in suppressing nausea. Research has shown that:
- Bilateral intra-VIC (visceral insular cortex) infusions of 2-AG (1 μg, but not 0.5 μg) dose-dependently suppressed conditioned gaping, a rat model of nausea
- 2-AG reduced conditioned gaping despite pretreatment with the selective cannabinoid receptor type 1 (CB1) antagonist, AM-251
- Concomitant pretreatment with the cyclooxygenase inhibitor, indomethacin (0.5 μg), blocked the suppressive effects of intra-VIC 2-AG
- Exogenous N-arachidonoylethanolamide (AEA) was tested but found to be without effect on nausea
- The synthetic cannabinoid HU210 has also been investigated for its ability to interfere with nausea-induced conditioned gaping
Serotonin Pathway
The conventional anti-emetic ondansetron has been shown to interfere with the establishment of conditioned gaping when administered locally in the visceral insular cortex.
Histamine Signaling
Histamine receptors and signaling have been identified as potential targets, with antagonists showing inhibitory effects in some models.
These mechanisms represent areas of investigation in the development of treatments for nausea, including chronic nausea, though specific information about their prevalence in clinical trials for unapproved drugs specifically targeting chronic nausea is not fully detailed.
Drug used in other indications
Gastric Electrical Stimulation (GES) Applications Beyond Chronic Nausea
Indications Under Investigation
Gastric Electrical Stimulation is being trialed for several indications beyond chronic nausea:
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Gastroparesis - This is the primary indication mentioned in multiple studies, with GES showing:
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Significant effects on nausea and vomiting in patients with severe, drug-refractory diabetic gastroparesis and postsurgical gastroparesis
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Response in a proportion of patients with severe idiopathic gastroparesis
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Improvement in combined symptoms score (P = .04), nausea (P = .039), and vomiting (P = .0016) in pediatric patients
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Idiopathic nausea and vomiting - A proportion of patients with this condition also respond to GES therapy
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Adolescents with intractable nausea - GES has been successfully applied to this population
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Obesity management - GES devices have been investigated for this indication
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Refractory gastroesophageal reflux disease - GES has been investigated for this condition
Intervention Models and Protocols
Several intervention models are being utilized in GES trials:
Fully Implantable Device
- Used for long-term treatment
- Described as a "promising treatment" for severe cases
- Follow-up ranging from 8 to 42 months in pediatric studies
Two-Stage Approach
- Temporary followed by permanent GES device
- Used in pediatric studies where all 9 patients underwent temporary GES followed by permanent device implantation
- Allows assessment of response before permanent implantation
Acute GES
- Used in experimental settings
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Various stimulation parameters tested:
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Pulse duration: 0.3, 1, 5, and 10 ms
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Current amplitude: 0.5, 1, and 2 mA
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Pulse frequency: 8, 15, 30, and 60 Hz
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Different electrode placements: antrum, body, and fundus
Single vs. Two-Lead Approaches
- Studies compared single lead versus two lead approaches
- Two-lead recordings appear "to be superior to single point recordings, while awaiting practical high-resolution recordings"
- Using two leads provides "greater insight of gastric electrical wave propagation"
Stimulation Parameters and Protocols
- High frequency GES is noted as the most commonly encountered form of GES in clinical practice
- One study mentioned that "All patients utilized a standardized energy algorithm with the majority of patients receiving medium energy at 12 months"
- Some studies measured electrophysiological parameters including frequency and amplitude during GES
Assessment Methods and Outcomes
Assessment methods in these trials include: - Likert scale for gastroparesis symptoms - Measurement of gastric emptying time - Electrogastrogram values - Quality of life assessments
In terms of outcomes: - For single lead patients with initial low mucosal frequency, there was an increase from 3.10 to 4.93 (P = 0.0155) - High frequency group decreased from 5.89 to 5.12 (P = 0.135) - For two leads, "the mucosal frequency decreased at the proximal electrode (P = 0.402), and increased at the distal electrode (P = 0.514)" - Mucosal electrogram amplitude values changed with "mean decrease of 0.34 mV (P = 0.241)" at proximal electrode and "mean increase of 0.05 mV (P = 0.65)" at distal electrode - In adolescents, 7 of 9 patients reported sustained improvement in symptoms and improved quality of life with no adverse effects
The evidence supporting GES is described as "limited and heterogeneous in quality," with studies suggesting that high-quality, large clinical trials are needed to establish efficacy and identify appropriate patient populations.