Clinical trial protocol

OrphanetDatabase.Clinicaltrial2006-212:PROFIDYStrialInclusionCriteria:•StudyI:patientswithfibrousdysplasiaofbone,withbonepainintensityabove3onavisualanalogicalscalefrom0to10.•StudyII:patientswithfibrousdysplasiaofbone,withatleastoneosteolyticlesionandnocurrentbonepain.ExclusionCriteria:•patients8yearsold(noadequateexperienceintheuseofBPbeforethisage)•patientswithotherdiseasesortakingothertreatmentslikelytoaffectbonemetabolism•patientswithmalignantdiseasesorconditionslikelytoreducetheirlifeexpectancytolessthanthreeyears•patientswithahistoryofsignificantuppergastrointestinaldisorders(e.g.oesophagitisandgastroduodenalulcer),whichcaninterferewithcompliance•kidneyfailure(creatininclearance25ml/mn)•severeliverdiseasethatwouldaffectalkalinephosphataselevels,suchashepatitis,primarybiliarysclerosis,andcirrhosis•historyofiritisoruveitis•untreatedricketsorosteomalacia•allergytoBP•prioruseofbisphosphonates,fluoride•pregnancyandlactation•laboratoryabnormalitiesthatmaybeconsideredasclinicallysignificantbytrialphysiciansStartofthestudyDecember2006Scheduledduration6yearsExpectednumberofpatients150OrphanetDatabase.Clinicaltrial2006-212®(risedronate,35mgtablets)NationalmulticenterstudyOrphanetDatabase.Clinicaltrial2006-212(PROFIDYSTrial)1.THENEEDFORTHETRIAL1.1RationaleFibrousdysplasiaofbone(FD),ararecongenitalbonediseasecharacterizedbyreplacementofnormalbonebyafibroustissue1,accountsforabout2.5%ofbonedisordersand7%ofbenignbone«tumorsorpseudo-tumors».Butitsactualprevalenceisunknown.ManypatientsareasymptomaticsothetrueprevalenceofFDisdifficulttoestimate.Thisdiseaseischaracterizedbyafocalproliferationoffibroustissueinbonemarrowspacesandleadstoosteolyticlesions.Thedysplasticbonematrixbecomesirregularlymineralizedandsomefociundergoametaplasticossificationprocess,leadingtotheformationofconvolutedso-called«chinese-character-like»wovenboneislets.FDaffectsmainlyadolescentsandyoungadults,butdoesnotdisappearamongaffectedindividuals.Itmayaffectonlyonebone(monostoticFD)orseveralbones(polyostoticFD).Whensymptomatic,FDisresponsibleforbonepain,ofvariableintensity.Bonedeformitiesexhibitdifferentpatterns,accordingtotheaffectedbone:coxavaraorcrook-likedeformity,genuvalgumorvarum,curvatureofanarmorforearm,calvarialoroccipitalbump,leontiasisossea…Theinvolvementofbonesadjacenttoneurologicalstructures(orbitalbones,skull,cervicalspine)canresultinneurologicsymptomsorcomplications,themostcommonbeingopticnervecompression.Insomepatients,bonelesionsareassociatedwithareasofbrownhyperpigmentationoftheskin(café-au-laitspots),variousendocrine(hyperthyroidism,adrenalhyperplasia,pituitarytumors…)ormetabolic(hypophosphatemicrickets)disorders,andoccasionallynonendocrineabnormalities.ThetriadpolyostoticFD,earlypubertyandcafe-au-laitspotsstampstheMcCuneAlbrightsyndrome2(MAS).Radiologicalfeaturesarediverse3.Typicallesionsappearasegg-shapedosteolyticareas,expandingfromthemedullatothecortex,thinningthesurroundingcorticeswhichcanalsobecomesclerotic.Thetextureofthelesionisoftenheterogeneous,mainlyradiolucentbutatsomeplaceswithasuggestive«groundglass»appearance.Thereisnoperiostealreactionorsofttissueinvolvement.SkullinvolvementisoftenreminiscentofPaget’sdisease,sothediagnosiscanbedifficult.Othermisleadingradiologicalaspectscanjustifyabonebiopsytoconfirmthediagnosis.RecentadvancesintheunderstandingofpathophysiologyofFDandMASincludethediscoveryofsomaticmutationsoftheGssubunitgene4,5,withsubsequentconstitutiveproductionofcAMPinvarioustissues,includingbonecells.Themutatedgenecoexistsasamosaicwiththenormalgene,whichseemstobecompulsoryfortheviabilityofthe«mutatedcells»,anddeterminestheexpression/severityofthediseaseinvarioustissues.Bonelesionsincludepoorlydifferentiatedosteoblasts,withanincreasedproliferationrate6,7.Theyproduceanabnormal,poorlyandirregularlymineralizedmatrix,andsecretecytokines,whichlocallystimulatethedifferentiationandactivityofosteoclasts,thusallowingtheexpansionofthelesioninthemedullaryspacesandtheerosionoftheendostealsideoftheadjacentcortices.AnanimalmodelwasrecentlyestablishedinimmunodeficientmicetransplantedwithskeletalprogenitorcellsexpressingmosaicsofnormalandmutatedGs8.RenalphosphatewastinghasbeendemonstratedinmostpatientswithpolyostoticFD,sometimeswithdecreasedserumphosphate,andmayberesponsibleformineralizationdefectsinsomepatients9.Itislikelytoincreasetheriskoffracture10.Similarly,secondaryhyperparathyroidism–inrelationtothecommonvitaminDdeficiency–mayimpairbonelesions11.ConventionaltherapeuticapproachesofFDaremainlysymptomatic(painreliefmedications)andorthopedic(preventionandmanagementoffractures).Isolatedcasereportsoftheuseofoldantiosteoclasticdrugs(calcitonin,mithramycine,etidronate,tiludronate)areratherdisappointing