Alain Matthey
Geneva College
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Featured researches published by Alain Matthey.
The New England Journal of Medicine | 2016
Angela Huttner; Patricia Njuguna; Christine Dahlke; Sabine Yerly; V. Kraehling; Rahel Kasonta; Marcus Altfeld; Floriane Auderset; Nadine Biedenkopf; S. Borregaard; R. Burrow; Christophe Combescure; Jules Alexandre Desmeules; Markus Eickmann; Axel Finckh; Jay W. Hooper; A. Jambrecina; Kabwende Al; Gürkan Kaya; Domtila Kimani; Bertrand Lell; Barbara Lemaître; Marguerite Massinga-Loembe; Alain Matthey; A. Nolting; Caroline Ogwang; Michael Ramharter; Jonas Schmidt-Chanasit; Stefan Schmiedel; Peter Silvera
BACKGROUND The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).
Lancet Infectious Diseases | 2015
Angela Huttner; Julie-Anne Dayer; Sabine Yerly; Christophe Combescure; Floriane Auderset; Jules Alexandre Desmeules; Markus Eickmann; Axel Finckh; Ana Rita Goncalves; Jay W. Hooper; Gürkan Kaya; Verena Krähling; Steve A. Kwilas; Barbara Lemaître; Alain Matthey; Peter Silvera; Stephan Becker; Patricia Fast; Vasee S. Moorthy; Marie Paule Kieny; L Kaiser; Claire-Anne Siegrist
BACKGROUND Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×10(7) pfu (n=35) or 5 × 10(7) pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold. METHODS The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18-65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 × 10(5) pfu or placebo, whereas deployable participants received single-injection 3 × 10(5) pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 10(7) or 5 × 10(7) pfu, 56 participants were given a lower dose (3 × 10(5) pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov, number NCT02287480. FINDINGS Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 × 10(5) pfu) or placebo in a double-blind fashion, whereas 13 deployable participants received 3 × 10(5) pfu open-label. Altogether, in the low-dose group, 51 participants received rVSV-ZEBOV and five received placebo. No serious adverse events occurred. At 3 × 10(5) pfu, early-onset reactogenicity remained frequent (45 [88%] of 51 compared with 50 [98%] of 51 high dose and two [15%] of 13 placebo recipients), but mild. Objective fever was present in one (2%) of 51 low-dose versus 13 (25%) of 51 high-dose vaccinees receiving at least 1 ×10(7) pfu (p<0·0001). Subjective fever (p<0·0001), myalgia (p=0·036), and chills (p=0·026) were significantly reduced and their time of onset delayed, reflecting significantly lower viraemia (p<0·0001) and blood monocyte-activation patterns (p=0·0233). Although seropositivity rates remained similarly high (48 [94%] of 51), day-28 EBOV-glycoprotein-binding and neutralising antibody titres were lower in low-dose versus high-dose vaccinees (geometric mean titres 344·5 [95% CI 229·7-516·4] vs 1064·2 [757·6-1495·1]; p<0·0001; and 35·1 [24·7-50·7] vs 127·0 [86·0-187·6]; p<0·0001, respectively). Furthermore, oligoarthritis again occurred on day 10 (median; IQR 9-14) in 13 (25%) of 51 low-dose vaccinees, with maculopapular, vesicular dermatitis, or both in seven (54%) of 13; arthritis was associated with increasing age in low-dose but not high-dose vaccinees. Two vaccinees presented with purpura of the lower legs; histological findings indicated cutaneous vasculitis. The presence of rVSV in synovial fluid and skin lesions confirmed causality. INTERPRETATION Reducing the dose of rVSV-ZEBOV improved its early tolerability but lowered antibody responses and did not prevent vaccine-induced arthritis, dermatitis, or vasculitis. Like its efficacy, the safety of rVSV-ZEBOV requires further definition in the target populations of Africa. FUNDING Wellcome Trust through WHO.
Multiple Sclerosis Journal | 2015
Tobias Derfuss; François Curtin; Claudia Guebelin; Claire Bridel; Maria Rasenack; Alain Matthey; Renaud Du Pasquier; Myriam Schluep; Jules Alexandre Desmeules; Alois B. Lang; Hervé Perron; Raphaël Faucard; Hervé Porchet; Hans-Peter Hartung; Ludwig Kappos; Patrice H. Lalive
Background: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. Objective: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. Methods: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. Results: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27–37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. Conclusion: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.
Journal of Neuroimmunology | 2015
Tobias Derfuss; François Curtin; Claudia Guebelin; Claire Bridel; Maria Rasenack; Alain Matthey; Renaud Du Pasquier; Myriam Schluep; Jules Alexandre Desmeules; Alois B. Lang; Hervé Perron; Raphaël Faucard; Hervé Porchet; Hans-Peter Hartung; Ludwig Kappos; Patrice H. Lalive
GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12months of a trial testing GNbAC1 in 10 MS patients at 2 and 6mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments. During the extended study, no safety issues occurred in the 8 remaining patients. No anti-GNbAC1 antibodies were detected. GNbAC1 appears well tolerated.
Pain | 2015
Marie Besson; Alain Matthey; Youssef Daali; Antoine Poncet; Pascal Henri Vuilleumier; Michele Curatolo; Hanns Ulrich Zeilhofer; Jules Alexandre Desmeules
Abstract Positive allosteric modulators of GABAA receptors (GAMs) acting at specific subtypes of GABAA receptors effectively restore compromised spinal pain control in rodents. Studies addressing a similar antihyperalgesic effect in humans are sparse and are hampered by sedative effects of nonselective GAMs available for use in humans. We present results from a randomized controlled double-blind crossover study in 25 healthy volunteers, which addressed potential antihyperalgesic actions of clobazam (CBZ) and clonazepam (CLN) at mildly sedating equianticonvulsive doses. Clobazam was chosen because of its relatively low sedative properties and CLN because of its use in neuropathic pain. Tolterodine (TLT) was used as an active placebo. The primary outcome parameter was a change in the area of cutaneous UVB irradiation–induced secondary hyperalgesia (ASH), which was monitored for 8 hours after drug application. Sedative effects were assessed in parallel to antihyperalgesia. Compared with TLT, recovery from hyperalgesia was significantly faster in the CBZ and CLN groups (P = 0.009). At the time point of maximum effect, the rate of recovery from hyperalgesia was accelerated by CBZ and CLN, relative to placebo by 15.7% (95% confidence interval [CI] 0.8-30.5), P = 0.040, and 28.6% (95% CI 4.5-52.6), P = 0.022, respectively. Active compounds induced stronger sedation than placebo, but these differences disappeared 8 hours after drug application. We demonstrate here that GAMs effectively reduce central sensitization in healthy volunteers. These results provide proof-of-principle evidence supporting efficacy of GAMs as antihyperalgesic agents in humans and should stimulate further research on compounds with improved subtype specificity.
Clinical Pharmacology & Therapeutics | 2018
Flavia Storelli; Alain Matthey; Sébastien Lenglet; Aurélien Thomas; Jules Alexandre Desmeules; Youssef Daali
We investigated whether CYP2D6 extensive metabolizers carrying a nonfunctional allele are at higher risk of phenoconversion to poor metabolizers in the presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully‐functional alleles and 17 heterozygous carriers of one fully‐functional and one nonfunctional allele participated in this trial. Dextromethorphan 5 mg and tramadol 10 mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60 mg (session 2) and paroxetine 20 mg (session 3). A higher rate of phenoconversion to intermediate metabolizers with duloxetine (71% vs. 25%, P = 0.009) and to poor metabolizers with paroxetine (94% vs. 56%, P = 0.011) was observed in heterozygous than homozygous extensive metabolizers. The magnitude of drug–drug interaction between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 vs. 8.5, P < 0.028). Our study suggests that genetic extensive metabolizers may not represent a homogenous population and that available genetic data should be considered when addressing drug–drug interactions in clinical practice.
Pharmacogenomics | 2013
Liliane Gschwind; Victoria Rollason Gumprecht; Françoise Boehlen; Michela Rebsamen; Christophe Combescure; Michèle Fernande Grunenwald; Alain Matthey; Pascal Bonnabry; Pierre Dayer; Jules Alexandre Desmeules
AIM The objective of this study was to investigate the impact of CYP2C9 polymorphisms and drug-drug interactions on the risk of overanticoagulation in patients treated with acenocoumarol, a vitamin K antagonist. MATERIALS & METHODS A prospective observational study was performed on patients starting acenocoumarol (n = 115). CYP2C9 genotypes were assessed. Data on International Normalized Ratio, comedications and doses of acenocoumarol were collected during the first 35 days of therapy. Overanticoagulation was defined as the occurrence of at least one International Normalized Ratio ≥4. RESULTS The presence of a CYP2C9 inhibitor or a CYP2C9 polymorphisms statistically increased the risk of overanticoagulation (hazard ratio [HR]: 2.8, p < 0.001 and HR: 1.7, p = 0.04, respectively). The presence of CYP2C9 polymorphisms almost tripled the risk of overanticoagulation (HR: 2.91, p = 0.01) in the presence of a clinically significant drug-drug interaction. CONCLUSION These findings support the fact that CYP2C9 genotyping could be useful to identify patients requiring closer monitoring, especially when a drug-drug interaction is expected.
Neuropharmacology | 2016
William T. Ralvenius; Mario A. Acuña; Dietmar Benke; Alain Matthey; Youssef Daali; Uwe Rudolph; Jules Alexandre Desmeules; Hanns Ulrich Zeilhofer; Marie Besson
Data from genetically modified mice suggest that benzodiazepine (BDZ)-site agonists with improved selectivity for α2-subtype GABAA receptors (α2GABAAR) are potentially useful for the treatment of neuropathic pain. Subtype-selective compounds available for preclinical tests in rodents support this concept but have not been approved for human use, hindering proof-of-concept studies in patients. We recently proposed that N-desmethyl clobazam (NDMC), the main metabolite of the licensed BDZ clobazam (CBZ), is responsible for most of the antihyperalgesia observed in mice after CBZ administration. In order to assess a potentially favorable pharmacological profile of NDMC, we analyzed differences in the GABAAR subtype specificity of CBZ, NDMC and diazepam (DZP) in recombinant receptors. DZP and CBZ potentiated sedating α1GABAARs and antihyperalgesic α2GABAARs with similar efficacies, whereas NDMC preferred α2GABAARs over α1GABAARs across a wide concentration range. In vivo, DZP and NDMC reduced neuropathic pain at doses between 3 and 30 mg/kg. At these doses, DZP had strong locomotor sedating effects while NDMC caused no or only weak sedation. Sedative effects of NDMC became apparent when the action of NDMC was restricted to α1GABAARs. However, when GABAAR point-mutated mice were studied that allow the analysis of antihyperalgesia and sedation in isolation, we found that, compared to DZP, NDMC had a significantly improved therapeutic window, consistent with its more favorable α2/α1 in vitro activity ratio. Given that NDMC should share the safety profile of its parent compound CBZ, it should be well-suited for proof-of-concept studies in human volunteers or patients.
Pharmacogenomics | 2015
Liliane Gschwind; Victoria Rollason; Françoise Boehlen; Michela Rebsamen; Christophe Combescure; Alain Matthey; Pascal Bonnabry; Pierre Dayer; Jules Alexandre Desmeules
BACKGROUND Acenocoumarol is a vitamin K antagonist used in some European countries. As warfarin, this drug is characterized by a narrow therapeutic index and a large interindividual variability. AIM The objective of this study was to assess the involvement of ABCB1 polymorphisms on acenocoumarol treatment. MATERIALS & METHODS An observational cohort study was conducted to assess whether there is an association between the presence of the allelic variants of the ABCB1 gene coding for P-glycoprotein and acenocoumarol stabilization and daily doses during the first 35 days of treatment. RESULTS One hundred and fifteen patients met the inclusion criteria. The results of the clinical study showed that carriers of ABCB1 c.3435TT were more rapidly stabilized than wild-type patients (HR: 2.97, 95% CI: 1.23-7.18; p = 0.02). The same tendency was observed for the ABCB1 c.2677GT and 2677TT genotypes compared with ABCB1 c.2677GG. The ABCB1 c.2677TT genotype was also associated with a significant increase in doses of acenocoumarol (p = 0.03), the same tendency was observed with the ABCB1 c.3435TT genotype compared with the wild-type patients. CONCLUSION These data suggest that ABCB1 polymorphisms could be involved in the response to acenocoumarol treatment.
Clinical Therapeutics | 2013
Victoria Rollason; Liliane Gschwind; F. Boehlen; Michela Rebsamen; Christophe Combescure; M. Grünenwald; Alain Matthey; Pascal Bonnabry; Pierre Dayer; Jules Alexandre Desmeules
OC035—Self-empOweriNg paTieNTS—a prOmiSiNg example iN Oral aNTiCOagulaTiON S.V. Vormfelde; M. Abu Abed; T.D. Hua; S. Schneider; T. Friede; and J.-F. Chenot Clinical Pharmacology; General Practice; Medical Statistics, University Medicine Göttingen, Göttingen; and General Practice, University Medicine Greifswald, Greifswald, Germany Introduction: Self-empowering patients on oral anticoagulation may improve their safety and the outcome of this therapy. The aim of this study was to evaluate the effect of an individual, video-assisted, 1-hour education on patient knowledge and on anticoagulation stability as an intermediate end point. Patients (or Materials) and Methods: In a cluster-randomized trial in 22 general practices, we investigated 369 patients who were on oral anticoagulation with phenprocoumon. In 11 practices, trained practice nurses educated the patients individually based on a 20-minute video, a leaflet, and a concluding questionnaire. The education lasted three quarters of an hour to an hour. Patients in the 11 control practices were handed over the leaflet and otherwise treated as usual. Patient knowledge was evaluated by questionnaires before and 6 months after the education; anticoagulation stability was evaluated by the international normalized ratio (INR) in the 6-month periods before and after the intervention. Results: Six months after the intervention, the educated patients had better safety-relevant knowledge and their anticoagulation tended to be more stable than before the education. Knowledge and INR stability did not change in the controls. In particular, 68% of the patients knew that acetaminophen (paracetamol) is the safest over-the-counter analgesic for the combination with phenprocoumon compared with 22% before (P < 0.001). Basic diet rules were known to 71% of the patients compared with 30% before (P < 0.001). Painful swelling realized 60% as a signal symptom compared with 26% before (P < 0.001). Suddenly disturbed speech was a signal symptom to 80% compared with 49% of these patients before the education (P < 0.001). How to proceed after a forgotten intake knew 57% compared with 14% before the education (P < 0.001). The INR was outside the intended range for 29% of the time during the 6 months after the education in the intervention group compared with 36% of the time in the control patients (P = 0.09). Conclusion: Self-empowering patients with this 1-hour education significantly improved patient knowledge over 6 months and tended to improve the intermediate end point INR stability. This education could be easily implemented in routine practice. In addition, this education provides a promising example to self-empower patients in further therapies. Disclosure of Interest: None declared.