2024
A Seamless Phase 2A‐Phase 2B Multi‐Center Trial to Test the Benefits of Benfotiamine on the Progression of Alzheimer’s Disease‐Benfoteam: Design and Methods
Luchsinger J, Feldman H, Messer K, Edland S, Leger G, Jacobs D, Salmon D, Revta C, Lupo J, Durant J, Gibson G. A Seamless Phase 2A‐Phase 2B Multi‐Center Trial to Test the Benefits of Benfotiamine on the Progression of Alzheimer’s Disease‐Benfoteam: Design and Methods. Alzheimer's & Dementia 2024, 20: e091963. PMCID: PMC11714007, DOI: 10.1002/alz.091963.Peer-Reviewed Original ResearchPhase 2bDosing decisionsPerson-months of exposureLonger-term safetyWeeks of treatmentCo-primary endpointsClinically significant benefitBiomarker test resultsMulti-center trialTolerated doseDouble-blindEvaluate safetySmall molecule treatmentBlood levelsActive treatmentPhase 2aThiamine deficiencyPerson-monthsDoseCohen's d effect sizesPharmacological effectsTherapeutic directionsBenfotiamineGlucose metabolismMg/dayVaroglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease
Feldman H, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner R, Lopez O, Smith A, Durant J, Lupo J, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs D, Salmon D, Léger G, DeMarco M, Weber F. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease. Advances In Alzheimer's Disease 2024 DOI: 10.3233/aiad240007.Peer-Reviewed Original ResearchGlutaminyl cyclasePost-translationallyAlzheimer's diseasePhase 2bEarly phase clinical trialsAmyloid-bCytokine monocyte chemoattractant protein-1Monocyte chemoattractant protein-1Highest tolerated doseLonger-term safetyPhase clinical trialsWeeks of treatmentFirst-in-classTarget of therapyUnique dual mechanismChemoattractant protein-1Interim futility analysisClinical efficacyDisease cascadeProtein 1Electroencephalogram changesOptimal doseClinical trialsAnalysis of cognitive functionHigh dosesA Phase 2B, Open-Label Multicenter Study of Tebapivat (AG-946), a Potent Pyruvate Kinase Activator, in Patients with Anemia Due to Lower-Risk Myelodysplastic Syndromes
Zeidan A, Sekeres M, Al-Samkari H, Carraway H, DeZern A, Mittelman M, Little M, Beynon V, Dai X, Sommakia S, Despotovic J, Patel P, Dibacco M, Fattizzo B, Stein E, Sallman D, Kulasekararaj A, Platzbecker U, Fenaux P. A Phase 2B, Open-Label Multicenter Study of Tebapivat (AG-946), a Potent Pyruvate Kinase Activator, in Patients with Anemia Due to Lower-Risk Myelodysplastic Syndromes. Blood 2024, 144: 6708-6708. DOI: 10.1182/blood-2024-203073.Peer-Reviewed Original ResearchLower-risk MDSErythropoiesis-stimulating agentsLower-risk myelodysplastic syndromesRed blood cell unitsMyelodysplastic syndromeProportion of patientsDose levelsRed blood cellsIPSS-RTransfusion burdenOpen-labelFirst doseRevised International Prognostic Scoring SystemHistory of acute myeloid leukemiaMDS mouse modelsMedian duration of responsePhase 2bInternational Prognostic Scoring SystemOpen-label multicenter studyAssociated with increased morbidityBone marrow neoplasmsHigh transfusion burdenIPSS-R scoreLow transfusion burdenDose level 1Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease
Feldman H, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner R, Lopez O, Smith A, Durant J, Lupo J, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs D, Salmon D, Léger G, DeMarco M, Weber F, Group F. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease. Journal Of Alzheimer’s Disease 2024, 101: s79-s93. PMID: 39422941, PMCID: PMC11494639, DOI: 10.3233/jad-231126.Peer-Reviewed Original ResearchConceptsGlutaminyl cyclasePost-translationallyAlzheimer's diseasePhase 2bEarly phase clinical trialsAmyloid-bCytokine monocyte chemoattractant protein-1Monocyte chemoattractant protein-1Highest tolerated doseLonger-term safetyPhase clinical trialsWeeks of treatmentFirst-in-classTarget of therapyUnique dual mechanismChemoattractant protein-1Interim futility analysisClinical efficacyDisease cascadeProtein 1Electroencephalogram changesOptimal doseClinical trialsAnalysis of cognitive functionHigh dosesProtocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer’s disease (BenfoTeam)
Feldman H, Luchsinger J, Léger G, Taylor C, Jacobs D, Salmon D, Edland S, Messer K, Revta C, Flowers S, Jones K, Koulman A, Yarasheski K, Verghese P, Venkatesh V, Zetterberg H, Durant J, Lupo J, Gibson G, Group F. Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer’s disease (BenfoTeam). PLOS ONE 2024, 19: e0302998. PMID: 38809849, PMCID: PMC11135745, DOI: 10.1371/journal.pone.0302998.Peer-Reviewed Original ResearchConceptsPhase 2bPhase 2aRandomized double-blind placebo-controlled trialDouble-blind placebo-controlled trialCo-primary efficacy endpointsTolerability eventsBest-tolerated dosePlacebo-controlled trialWell-tolerated dosesAlzheimer's diseaseLonger-term safetyEfficacy of drug deliveryWeeks of treatmentTargeted therapeutic approachesErythrocyte transketolase activityGroups of participantsDouble-blindPlacebo armEfficacy endpointSecondary endpointsOral treatmentPharmacokinetic measurementsClinical trialsTherapeutic approachesBlood markersOlezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk
Bergmark B, Marston N, Prohaska T, Alexander V, Zimerman A, Moura F, Murphy S, Goodrich E, Zhang S, Gaudet D, Karwatowska-Prokopczuk E, Tsimikas S, Giugliano R, Sabatine M. Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk. New England Journal Of Medicine 2024, 390: 1770-1780. PMID: 38587249, DOI: 10.1056/nejmoa2402309.Peer-Reviewed Original ResearchConceptsNon-HDL cholesterolElevated cardiovascular riskLevels of triglyceridesTriglyceride levelsCardiovascular riskModerate hypertriglyceridemiaApolipoprotein BAdverse eventsNon-high-density lipoprotein (HDL) cholesterolLow-density lipoprotein (LDL) cholesterolBaseline to 6 monthsMedian triglyceride levelsRisk of adverse eventsLDL cholesterol levelsHigh cardiovascular riskTriglyceride-rich lipoproteinsApolipoprotein C-IIISevere hypertriglyceridemiaMedian ageTriglyceride loweringPlatelet abnormalitiesNo significant changesPlaceboPhase 2bPrimary outcome
2023
Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS)
Warren R, French L, Blauvelt A, Langley R, Egeberg A, Mrowietz U, Hunter H, Gooderham M, Soerensen P, Andres P, Sommer M, Carlsson A, Kjøller K, Strober B. Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS). Journal Of The American Academy Of Dermatology 2023, 90: 494-503. PMID: 37951245, DOI: 10.1016/j.jaad.2023.11.005.Peer-Reviewed Original ResearchSevere psoriasisWeek 16PDE4 inhibitionPhase 2b trialSevere plaque psoriasisDose-ranging studyModified-release formulationTolerability effectsPlaque psoriasisBaseline characteristicsEfficacy endpointPrimary endpointPsoriasis AreaSafety findingsSafety profileStudy populationPhase 2bPotential treatmentPsoriasisDisease proportionsGreater efficacyPlaceboPercentage changeSmall sample sizeSeverity Index
2021
Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial.
Faustino EVS, Raffini LJ, Hanson SJ, Cholette JM, Pinto MG, Li S, Kandil SB, Nellis ME, Shabanova V, Silva CT, Tala JA, McPartland T, Spinella PC. Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial. Critical Care Medicine 2021, 49: e369-e380. PMID: 33566465, PMCID: PMC7979442, DOI: 10.1097/ccm.0000000000004848.Peer-Reviewed Original ResearchConceptsCentral venous catheter-associated deep venous thrombosisCatheter-associated deep venous thrombosisCentral venous cathetersEfficacy of prophylaxisDeep venous thrombosisAge-dependent heterogeneityAnti-Xa levelsVenous cathetersVenous thrombosisFactor VIII activityThrombin generationPlatelet countClinical trialsIll childrenPhase 2bVIII activityLow factor VIII activityCatheter-associated thrombosisInternational units/mLMinimum platelet countOlder childrenCritically Ill ChildrenEndogenous thrombin potentialHigher platelet countsPost Hoc Analysis
2020
Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial.
Faustino EVS, Shabanova V, Raffini LJ, Kandil SB, Li S, Pinto MG, Cholette JM, Hanson SJ, Nellis ME, Silva CT, Chima R, Sharathkumar A, Thomas KA, McPartland T, Tala JA, Spinella PC. Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial. Critical Care Medicine 2020, 49: e235-e246. PMID: 33372745, PMCID: PMC7902342, DOI: 10.1097/ccm.0000000000004784.Peer-Reviewed Original ResearchConceptsCentral venous catheter-associated deep venous thrombosisCatheter-associated deep venous thrombosisDeep venous thrombosisUsual care armCentral venous cathetersVenous thrombosisClinical trialsEnoxaparin armCare armVenous cathetersEarly prophylaxisIll childrenThrombin generationPhase 2bCatheter-associated thrombosisInternational units/mLAnti-Xa levelsCritically Ill ChildrenRandomized clinical trialsEndogenous thrombin potentialRelevant bleedingUsual careTrial armsRisk ratioThrombin potential
2015
Assessment of the Efficacy and Safety of BMS-820836 in Patients With Treatment-Resistant Major Depression
Bhagwagar Z, Torbeyns A, Hennicken D, Zheng M, Dunlop BW, Mathew SJ, Khan A, Weisler R, Nelson C, Shelton R, Thase ME, Lane R. Assessment of the Efficacy and Safety of BMS-820836 in Patients With Treatment-Resistant Major Depression. Journal Of Clinical Psychopharmacology 2015, 35: 454-459. PMID: 25961781, DOI: 10.1097/jcp.0000000000000335.Peer-Reviewed Original ResearchConceptsBMS-820836MADRS total scoreTreatment-resistant depressionMean changeAntidepressant treatmentTotal scoreMontgomery-Åsberg Depression Rating Scale (MADRS) total scoreTreatment-resistant major depressionEnd pointStandard antidepressant treatmentPrimary end pointDouble-blind studyScale total scoreAdequate trialAntidepressant therapyAdverse eventsFlexible doseContinuation groupInadequate responseMajor depressionInadequate respondersPhase 2bPatientsPhase treatmentWeeks
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