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A novel oral nutraceutical formula of omega-3 and omega-6 fatty acids with vitamins (PLP10) in relapsing remitting multiple sclerosis: a randomised, double-blind, placebo-controlled proof-of-concept clinical trial

Author(s): Pantzaris MC, Loukaides GN, Ntzani EE, Patrikios IS

Abstract

Objective:Toassesswhetherthreenovelinterventions,formulatedbasedonasystemsmedicinetherapeuticconcept,reduceddiseaseactivityinpatientswithrelapsing-remittingmultiplesclerosis(MS)whowereeithertreatedornotwithdisease-modifyingtreatment.

Design:A30-monthrandomised,double-blind,placebo-controlled,paralleldesign,phaseIIproof-of-conceptclinicalstudy.

Settings:CyprusInstituteofNeurologyandGenetics.

Participants:80participantswererandomisedintofourgroupsof20each.Atotalof41(51%)patientscompletedthe30-monthtrial.Theeligibilitycriteriawereanageof18-65;adiagnosisofrelapsing-remittingMSaccordingtotheMcDonaldcriteria;ascoreof0.0-5.5ontheExpandedDisabilityStatusScale(EDSS);MRIshowinglesionsconsistentwithMS;atleastonedocumentedclinicalrelapseandeitherreceivingornotadisease-modifyingtreatmentwithinthe24-monthperiodbeforeenrolmentinthestudy.Patientswereexcludedbecauseofarecent(<30days)relapse,priorimmunosuppressantormonoclonalantibodytherapy,pregnancyornursing,otherseverediseasecompromisingorganfunction,progressiveMS,historyofrecentdrugoralcoholabuse,useofanyadditionalfoodsupplements,vitaminsoranyformofpolyunsaturatedfattyacids,andahistoryofsevereallergicoranaphylacticreactionsorknownspecificnutritionalhypersensitivity.

Interventions:Thefirstintervention(A)wascomposedofΩ-3andΩ-6polyunsaturatedfattyacidsat1:1wt/wt.Specifically,theΩ-3fattyacidsweredocosahexaenoicacidandeicosapentaenoicacidat3:1wt/wt,andtheΩ-6fattyacidswerelinoleicacidandγ-linolenicacidat2:1wt/wt.Thisinterventionalsoincludedminorquantitiesofotherspecificpolyunsaturated,monounsaturatedandsaturatedfattyacidsaswellasvitaminAandvitaminE(α-tocopherol).Thesecondintervention(B,PLP10)wasacombinationofAandγ-tocopherol.Thethirdintervention(C)wasγ-tocopherolalone.Thefourthgroupof20participantsreceivedplacebo.Theinterventionswereadministeredperos(bymouth)oncedaily,30minbeforedinnerfor30months.

Mainoutcomemeasures:Theprimaryendpointwastheannualisedrelapserate(ARR)ofthethreeinterventionsversustheplaceboat2years.Thesecondaryendpointwasthetimetoconfirmeddisabilityprogressionat2years.

Results:Atotalof41(51%)patientscompletedthe30-monthtrial.Overall,fortheper-protocolanalysisofthe2-yearprimaryendpoint,eightrelapseswererecordedinthePLP10group(n=10;0.40ARR)versus25relapsesintheplacebogroup(n=12;1.04ARR),representinga64%adjustedrelativeratereductionforthePLP10group(RRR0.36,95%CI0.15to0.87,p=0.024).Inasubgroupanalysisthatexcludedpatientsonmonoclonalantibody(natalizumab)treatment,theobservedadjustedRRRbecamestronger(72%)overthe2years(RRR0.28,95%CI0.10to0.79,p=0.016).Theper-protocolanalysisforthesecondaryoutcomeat2years,thetimetodisabilityprogression,wassignificantlylongeronlyforPLP10.Thecumulativeprobabilityofdisabilityprogressionat2yearswas10%inthePLP10groupand58%intheplacebogroup(unadjustedlog-rankp=0.019).Inasubgroupanalysisthatexcludedpatientsonnatalizumab,thecumulativeprobabilityofprogressionwas10%forthe10patientsinthePLP10groupand70%forthe12patientsintheplacebogroup,representingarelative86%decreaseintheriskofthesustainedprogressionofdisabilityinthePLP10group(unadjustedlog-rankp=0.006;adjustedHR,0.11;95%CI0.01to0.97,p=0.047).Noadverseeventswerereported.InterventionsA(10patients)andC(9patients)showednosignificantefficacy.

Conclusions:Inthissmallproof-of-concept,randomised,double-blindclinicaltrial;thePLP10treatmentsignificantlyreducedtheARRandtheriskofsustaineddisabilityprogressionwithoutanyreportedseriousadverseevents.LargerstudiesareneededtofurtherassessthesafetyandefficacyofPLP10.

Trialregistration:InternationalStandardRandomisedControlledTrial,numberISRCTN87818535.

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