Basimglurant for Trigeminal Neuralgia
Recruiting in Palo Alto (17 mi)
+29 other locations
Age: 18+
Sex: Male
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: Noema Pharma AG
Must not be taking: Opioids, Antipsychotics
Disqualifiers: Major psychiatric, Substance abuse, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing a medication called basimglurant to see if it can help reduce severe facial pain in adults with Trigeminal Neuralgia. The medication works by blocking a specific receptor in the nervous system to lower pain signals. Researchers will measure changes in pain using patient diaries and feedback.
Will I have to stop taking my current medications?
Yes, you will need to stop taking your current TN pain medication to participate in this trial. However, you can use opioids for pain control as long as it does not exceed 2 days per week.
Is basimglurant safe for human use?
Basimglurant has been tested in humans for conditions like Fragile X syndrome and major depressive disorder. It was generally well-tolerated, but some patients experienced psychiatric side effects like hallucinations or psychosis. Overall, it has shown a favorable safety profile in clinical trials, but further studies are needed to fully understand its safety in different populations.
12345How is the drug Basimglurant different from other drugs for trigeminal neuralgia?
Basimglurant is unique because it is being explored as a novel treatment option for trigeminal neuralgia, whereas traditional treatments primarily include anticonvulsant drugs like carbamazepine and oxcarbazepine. Unlike these standard treatments, Basimglurant may offer a different mechanism of action, potentially providing an alternative for patients who do not respond well to existing medications.
678910Eligibility Criteria
Adults aged 18-75 with a confirmed diagnosis of primary trigeminal neuralgia, experiencing significant pain despite current treatments. Participants must be fluent in the study language and capable of giving informed consent. Women must be non-pregnant, non-lactating, and using contraception if of childbearing potential.Inclusion Criteria
I have been diagnosed with trigeminal neuralgia by a neurologist.
I experience severe pain episodes daily for at least 2 months.
I experience severe pain episodes daily for at least 2 months.
+10 more
Exclusion Criteria
I have had stomach or small intestine surgery, or a condition that affects how my body absorbs nutrients.
I have not taken antipsychotic medications in the last 6 months.
I haven't had a heart attack, stroke, or major heart surgery in the last 6 months.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Run-in
Participants receive Basimglurant once daily starting at 1.5mg for 8 weeks to evaluate its effect on pain associated with TN
8 weeks
Double-blind Treatment
Participants receive double-blind treatment with Basimglurant or placebo to assess maintenance of effect on pain
12 weeks
Open-label Extension
Participants are offered open-label treatment with Basimglurant to evaluate long-term safety and efficacy
52 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing the effectiveness and safety of basimglurant (1.5mg - 3.5mg) for adults with trigeminal neuralgia compared to a placebo. The goal is to see if this medication can reduce the intense facial pain associated with TN.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Arm A: Basimglurant/NOE-101Experimental Treatment1 Intervention
* Period 1 (Run-in: Baseline1 to Week 8): Basimglurant once daily dosing starting dose 1.5mg
* Period 2 (Double blind: Weeks 9 to 20): Participants will receive double-blind treatment with Basimglurant once daily.
* Open-label Extension (OLE): On completion of Period 2, participants will be offered open label treatment with Basimglurant in an open label extension for up to 52 weeks.
Group II: Arm B: PlaceboPlacebo Group1 Intervention
- Period 2 (Double blind: Week 9 to Week 20): Participant randomized to placebo will receive the corresponding number of matching placebo capsules.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Altea Research - ClinEdge - PPDS (Site #: 1006)Las Vegas, NV
University of Pittsburgh Medical Center (Site #: 1003)Pittsburgh, PA
Kaizen Brain Center (Site #: 1001)La Jolla, CA
University of South Florida (Site #: 1002)Tampa, FL
More Trial Locations
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Who Is Running the Clinical Trial?
Noema Pharma AGLead Sponsor
References
Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results. [2018]Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications.
A double-tracer technique to characterize absorption, distribution, metabolism and excretion (ADME) of [14C]-basimglurant and absolute bioavailability after oral administration and concomitant intravenous microdose administration of [13C6]-labeled basimglurant in humans. [2017]1. The emerging technique of employing intravenous microdose administration of an isotope tracer concomitantly with an [14C]-labeled oral dose was used to characterize the disposition and absolute bioavailability of a novel metabotropic glutamate 5 (mGlu5) receptor antagonist under clinical development for major depressive disorder (MDD). 2. Six healthy volunteers received a single 1 mg [12C/14C]-basimglurant (2.22 MBq) oral dose and a concomitant i.v. tracer dose of 100 μg of [13C6]-basimglurant. Concentrations of [12C]-basimglurant and the stable isotope [13C6]-basimglurant were determined in plasma by a specific LC/MS-MS method. Total [14C] radioactivity was determined in whole blood, plasma, urine and feces by liquid scintillation counting. Metabolic profiling was conducted in plasma, urine, blood cell pellet and feces samples. 3. The mean absolute bioavailability after oral administration (F) of basimglurant was ∼67% (range 45.7-77.7%). The major route of [14C]-radioactivity excretion, primarily in form of metabolites, was in urine (mean recovery 73.4%), with the remainder excreted in feces (mean recovery 26.5%). The median tmax for [12C]-basimglurant after the oral administration was 0.71 h (range 0.58-1.00) and the mean terminal half-life was 77.2 ± 38.5 h. Terminal half-life for the [14C]-basimglurant was 178 h indicating presence of metabolites with a longer terminal half-life. Five metabolites were identified with M1-Glucuronide as major and the others in trace amounts. There was minimal binding of drug to RBCs. IV pharmacokinetics was characterized with a mean ± SD CL of 11.8 ± 7.4 mL/h and a Vss of 677 ± 229 L. 4. The double-tracer technique used in this study allowed to simultaneously characterize the absolute bioavailability and disposition characteristics of the new oral molecular entity in a single study.
Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression. [2015]Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.
Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents. [2019]Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions. Adolescent (n = 119, aged 12-19 years) and adult (n = 148, aged 18-45 years) participants received up to 100 mg bid mavoglurant for up to 34 months. Both extension studies were terminated prematurely due to lack of proven efficacy in the core studies. Mavoglurant was well tolerated with no new safety signal. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Gradual and consistent behavioral improvements as measured by the ABC-CFX scale were observed, which were numerically superior to those seen in the placebo arm of the core studies. These two extension studies confirm the long-term safety of mavoglurant in FXS, but further investigations are required to determine whether and under which conditions the significant preclinical results obtained with mGluR5 inhibition can translate to humans.
Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases. [2015]Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.
The α6 subunit-containing GABAA receptor: A novel drug target for inhibition of trigeminal activation. [2021]Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABAA receptors (α6GABAARs) are expressed in trigeminal ganglia (TG), the hub of the trigeminal vascular system (TGVS) that is involved in the pathogenesis of migraine. Here we reveal an unprecedented role of α6GABAARs in ameliorating TGVS activation using several pharmacological approaches in an animal model mimicking pathological changes in migraine. TGVS activation was induced by intra-cisternal (i.c.) instillation of capsaicin in Wistar rats. Centrally, i.c. capsaicin activated the trigeminal cervical complex (TCC) measured by the increased number of c-Fos-immunoreactive (c-Fos-ir) TCC neurons. Peripherally, it elevated calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG and depleted CGRP-ir in the dura mater. Pharmacological approaches included a recently identified α6GABAAR-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABAAR-active PAMs (Ro15-4513 and loreclezole), an α6GABAAR-inactive benzodiazepine (diazepam), an α6GABAAR-selective antagonist (furosemide), and a clinically effective antimigraine agent (topiramate). We examined effects of these compounds on both central and peripheral TGVS responses induced by i.c. capsaicin. Compound 6 (3-10 mg/kg, i.p.) significantly attenuated the TCC neuronal activation and TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin. All these effects of Compound 6 were mimicked by topiramate, Ro15-4513 and loreclezole, but not by diazepam. The brain-impermeable furosemide antagonized the peripheral, but not central, effects of Compound 6. These results suggest that the α6GABAAR in TG is a novel drug target for TGVS activation and that α6GABAAR-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine.
Pharmacotherapy of trigeminal neuralgia. [2019]The efficacy of the anticonvulsant drug carbamazepine in the management of trigeminal neuralgia is evidenced in several controlled trials, and the numbers needed to treat to obtain one patient with at least 50% pain relief (NNT) is 1.7. Single small trials have shown that baclofen alone provides pain relief (NNT = 1.4) and that lamotrigine has an additional effect in patients with insufficient relief using carbamazepine or phenytoin (NNT = 2.1). Uncontrolled observations and clinical practice indicate that phenytoin, clonazepam, sodium valproate, gabapentin, and lidocaine will also relieve trigeminal neuralgia. In case of lacking effect of a single drug, combination of two or more drugs may be used, but with the exception of the lamotrigine-carbamazepine combination, this is not evidence-based medicine. Acute exacerbation has successfully been treated with intravenous loading with phenytoin or lidocaine, but again these procedures have not been tested in controlled trials. In conclusion, carbamazepine is the mainstay of pharmacotherapy of trigeminal neuralgia, and secondary drug choices are baclofen, lamotrigine, oxcarbazepine, phenytoin, gabapentin, and sodium valproate. Controlled trials testing the effect of some of these drugs, new drugs, and drug combinations are needed.
Clinical Effectiveness of Mirogabalin Besylate for Trigeminal Neuropathy after Skull Base Surgery: Illustrative Cases. [2023]Postoperative trigeminal neuropathy may be seen after surgery for middle and posterior cranial fossa lesions. Although neuropathic pain is a cause of reduced quality of life, global consensus on postoperative pain management is lacking. Mirogabalin besylate is a selective ligand for the α2δ subunit of voltage-gated calcium channels. Although mirogabalin has been used for patients with postherpetic neuralgia and painful diabetic peripheral neuropathy, few reports have assessed the effect on postsurgical neuropathy. In this report, we describe a clinical effectiveness of mirogabalin for trigeminal neuropathy after skull base surgery.
Trigeminal Neuralgia. [2020]The initial treatment for trigeminal neuralgia is medical. Carbamazepine is the drug of choice. If the patient proves to be intolerant of carbamazepine, a number of second-line drugs are available, though data on their relative efficacy are nonexistent. Phenytoin, baclofen, clonazepam, and sodium valproate are all worthy of consideration. Oxcarbazepine may be as effective as carbamazepine, but its availability is limited. Newer agents being tried in this condition include lamotrigine and gabapentin. Their comparative value has not been established. For patients resistant to or intolerant of drug therapy, interventional or surgical procedures are necessary. For younger, fit patients, particularly with involvement of the first division or all three divisions of the nerve, microvascular decompression is recommended. For older patients, for those not shown to have microvascular cross-compression, and for those not willing to undergo craniectomy, radiofrequency thermal rhizotomy is probably the next treatment of choice. Dogmatic recommendations are not appropriate in the absence of truly comparable data. Other techniques to be considered, if thermal rhizotomy is unsuccessful, include glycerol rhizotomy, balloon compression, partial sensory trigeminal rhizotomy, and peripheral neurectomy. The choice is given in no particular order. Patients offered such treatments require data on the track record of the relevant institution in performing that procedure. Stereotactic radiosurgery is still being evaluated for this condition. Because the associated morbidity is very low, it may become the treatment of choice for the elderly frail patient if longer-term follow-up establishes its continuing benefit.
Assessment of efficacy and safety of eslicarbazepine acetate for the treatment of trigeminal neuralgia. [2019]Antiepileptic drugs are the first-line treatment for trigeminal neuralgia (TN). Carbamazepine and oxcarbazepine are the most studied with well-known efficacy. Eslicarbazepine acetate is a third-generation antiepileptic drug that has not previously been evaluated for the treatment of TN. We aim to assess the efficacy, tolerability and safety of eslicarbazepine for TN.