Trial of Naltrexone & Dextromethorphan for Gulf War

Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

TrialofNaltrexone& DextromethorphanforGulfWar Illness

WilliamJ.Meggs,MD,PhD BrodySchoolofMedicine EastCarolinaUniversity

Background

• GulfWarIllness

• Approximately250,000veteransofGulfWar

• Nodefinitivetreatment Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

ClinicalFeaturesofGWI • ChronicFatigue • ChronicPain – Headaches,diffusemuscleandjointpains • Neuropsychologicaldisabilities – Memory,cognition,concentration,sleep,libido, mood,irritability,inappropriateanger • Subgroupswithrespiratory,GI,rash

hypothesis

• inflammatorycycleinvolvingthebrain • maybeacommonmechanismofmany neurologicalconditions • whetherinitiatedbytoxicexposures, infection,ortrauma Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

PreͲclinicalStudies

• novelantiͲinflammatorydrugsmaybeof benefitinsymptomͲdefinedillnessesrelated toneuroͲinflammation • Dr.J.S.Hong’sworkattheNIEHS • MorphineͲrelatedanalogs,including naltrexone& dextromethorphan • antiͲinflammationandneuroͲprotective effects

NaltrexoneHCl

• Genericdrug • FDAApprovedIndications – Alcoholdependence – Opioiddependence • NonͲFDAApprovedIndications – Drugwithdrawal Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

NaltrexoneHCl AdverseEffects

• asymptomaticelevationsofhepatic transaminases(7%v3%placebo) • Clinicallysignificantliverdysfunctionhasbeen reportedinpatientstreatedwithnaltrexone hydrochlorideinclinicaltrialsandduring postmarketing surveillance – Ofteninassociationwithalcoholicliverdisease, viralhepatitis,useofotherhepatoxic drugs

NaltrexoneHCl Adverseeffects

• Dizziness13%v4% • Headache21%v18% • Insomnia13%v12% • Somnolence5%v1% Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

LowDoseNaltrexone:4.5mg/day

• PilottrialsofLDN • Crohn's disease(Smithetal.) • multiplesclerosis(Gironi etal.) • cancerͲrelatedpain(Valentineetal.) • Fibromyalgia(Youngeretal.) • Chroniclowbackpain(Ghai etal.)

Chroniclowbackpain Casereport Ghai etal.2014 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

Lowdosenaltrexoneforfibromyalgia

Figure1.Overall,selfͲ reported,daily fibromyalgiasymptoms (scale0–100,with100 beingmostsevere)asa functionofplaceboand lowͲdosenaltrexone administration.Sections are:baseline,placebo, drug,andwashout.A3Ͳ daysmoothinghas beenapplied.(A)Data fromallparticipants(N =10).(B)Data separatedbydrug responders(30%or greaterreductionof symptomsover placebo;solidline,N= 6)andnonresponders (brokenline,N=4). Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 LowDoseNaltrexoneforActive Crohn’s Disease • openͲlabeledpilotprospectivetrial • endoscopically confirmedactiveCrohn's disease(CDAI220–450) • 4.5mgnaltrexone/dayfor12weeks • inflammatoryboweldiseasequestionnaire (IBDQ)& shortͲform(SFͲ36)q4wk ontherapy &4wk aftercompletion

ActiveCrohn’s DiseaseResults

• 17subjects • meanCDAIscoreof356 • CDAIscoresdecreasedsignificantly(P =0.01) withLDN • remainedlowerthanbaseline4wk after completingtherapy • 89%response • 67%remission(P <0.001) • Improvementinqualityoflifesurveys • sleepdisturbancesin7subjects Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

MeanCrohn's diseaseactivityindex(CDAI)scoresSEMareshownatbaseline(wk 0),wk 4,8,and12afterinitiationofLDNtherapyand4wk afterdiscontinuationofLDN therapy(wk 16).****SignificantlydifferentfrombaselineatP <0.0001.

ThepercentofpatientsrespondingwithadeclineinCDAIscoreofatleast70points(A),and thepercentofpatientsachievingremissionbyaCDAIscoreof150orless(B),toLDNtherapy areshownatwk 4,8,and12and4wk afterdiscontinuationofLDNtherapy(wk 16). Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

Meaninflammatoryboweldiseasequestionnaire(IBDQ)scoresSEMareshownatbaseline (wk 0),wk 4,8,and12afterinitiationofLDNtherapy,and4wk afterdiscontinuationof treatment(wk 16).Significantlydifferentfrombaselineat**P <0.01,***P <0.001,and ****P <0.0001.

MeanSFͲ36healthsurveyscoresSEMare shownatbaseline(wk 0),wks 4,8,12of LDNtherapy,and4wk afterdiscontinuation oftreatment(wk 16)foreachofthe parametersmeasuredbytheSFͲ36health survey.Significantlydifferentfrombaseline valuesincludedthefollowing:*P <0.05,**P <0.01,***P <0.001,****P <0.0001. Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 Conclusions LDNforactiveCrohn’s Disease

• LDNtherapyappearseffectiveandsafein subjectswithactiveCrohn's disease.

• Furtherstudiesareneededtoexploretheuse ofthiscompound.

dextromethorphan

• Generic,availableoverthecounter • Coughsuppressantsimilartocodeine • Complexmechanismsofaction • Abusedbyoverdose– similartophencyclidine • Hepaticmetabolism – Variablebyphenotype – Quininemayinhibitrapidmetabolism Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

dextromethorphan

• animalstudies • NeuroͲprotective – antiͲconvulsion,antiͲParkinson’s,protectivein ischemia,antiͲpseudobulbar (crying/laughing), • Neurotoxic – neuropathologic mechanismsathighdose

ShinEͲJetal.JPharmacol Sci 116,137– 148(2011)

dextromethorphan

• Sideeffects – mild – drowsiness,fatigue,dystonia,&dizziness • Serotoninsyndrome – PrimarilyfromdruginteractionswithantiͲdepressants – twocasereportsofserotoninsyndromeassociatedwith concurrentparoxetineanddextromethorphantherapy (Skop etal,1994a;Skop etal,1995). – CoͲadministrationofdextromethorphan&monoamine oxidaseinhibitorsiscontraindicated (deathsreportedfrom serotoninsyndrome,Rivers&Horner,1970q;Sovner & Wolfe,1988i ) Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

dextromethorphan

• Toxicity – Seenattoxicbutnottherapeuticdoses – euphoria,floating/flyingsensation,hallucinations (auditoryandvisual),increasedselfͲawareness, increasedperception,increasedsenseofself, increasedsociability,modificationofsounds,and synesthesia(associationofsoundswithcolor) – inebriation

Methods Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

Materials

• naltrexoneHCl 4.5mgobtainedbyresearch pharmacistfromcompoundingpharmacy • dextromethrophan 60mgBID(sustained release) – TSHBiopharm CorporationLtd. – 3FͲ1,No.3Ͳ1,Yuanqu St.,Nangang Dist.,Taipei, Taiwan(R.O.C.)

IRBApproval

• ECUIRB – Tough – 2months • DODIRB – Tougher – 2years • CDMRPStatementofWork – Allowatleast6monthsforIRBapproval Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

ReasonsforDelaysinIRBApproval

• Slowturnaround • INDApplications • Modificationofcasedefinition – CoͲmorbiditiesdevelopedoverthe20yearsthat excludedmanyveteransusingtheinitialKansascase definition • Modificationofprotocol – Exclusionsduetodruginteractions – Manyveteranscouldtakenaltrexoneor dextromethorphanbutnotboth

FDAINDApplications

• RequiredbybothIRBsforofflabeluseof approvedmedications • naltrexone – RequirementforINDwaivedbyFDA • dextromethorphan – NoapprovedSustainedReleaseproductonUS market – INDrequired – analyticaldataonproductrequired. Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

3ArmProtocol:11months

Randomized,DoubleͲBlindedtrial

3monthcourseofDextromethorphen,Naltrexone,orPlacebo

Onemonthwashout

3monthcourseofDextromethorphen,Naltrexone,orPlacebo

Onemonthwashout

3monthcourseofDextromethorphen,Naltrexone,orPlacebo

NaltrexoneOnlyProtocol:7Months VeteransTakingAntiͲdepressantsbutnoOpioids

Randomized,DoubleͲBlindedtrial

3monthcourseofNaltrexoneorPlacebo

Onemonthwashout

3monthcourseofNaltrexoneorPlacebo Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 DextromethorphanOnlyProtocol Chronicopioidtherapybutnoantidepressants

Randomized,DoubleͲBlindedtrial

3monthcourseofDextromethorphen orPlacebo

Onemonthwashout

3monthcourseofDextromethorphen orPlacebo

Recruitment(NC,SC,VA)

• Pressreleases • Veteransgroups • VAclinics&hospitals • Website • Postings • Mailings Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

ScreeningInstrument Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

ClinicalEvaluations

• History&PhysicalExamination • VisualAnalogueScale – Symptomsscores • SFͲ36 • ClinicalGlobalImpressionScale • Connor’sContinuousPerformance Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

LaboratoryEvaluations

• Routine – Completebloodcount,comprehensivemetabolic profile,UA • Research – CͲreactiveprotein(CRP) – Nervegrowthfactor • ElizaAssay, • EMDMillipore (http://www.emdmillipore.com/US/en). Billerica, Massachusetts. – Lincoplex humancytokine/chemokinepanel • ILͲ1ɴ,ILͲ6,ILͲ8,ILͲ10,IFNͲɶ,TNFͲɲ,

PreliminaryResults Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

Demographics

• Meanage:53.35years(41Ͳ75) • 38men;3women • 31Caucasian;7AfricanͲAmerican,1 Hispanic • Meanyearsinservice8.24(1Ͳ36) Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

BranchofService

Branch Numberofparticipants Army 33 MarineCorp 14 Navy 3

MedicationUse

• varietyofpsychotropic,seizure,analgesic,and antiͲinflammatorymedicationsusedtotreat symptomsofGWI • Meannumberofmedicationstotreatsymptoms was1.9,andrangedfrom0to11 • Visualanaloguescoreswerenotsignificantly differentforthosetakingmorethan2 medicationsrelativeto2orlessexceptfor greaterfatigueanddifficultywithsleepinthose taking2ormoremedications Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

MedicationUse

• Symptomsscoresforfatiguewere86.2+36.6cm (3+medications)versus58.2+33.8cm(0,1,or2 medications)p=0.003 • scoresfordifficultywithsleepwere86.9+21.8 versus66.7+29.7,p=0.02 • Thosetakingoneormoremedicationsrelativeto thosetakingnomedicationsweremorelikelyto reportnasalcongestion(p=0.02),sinus congestion/pain(p=0.001),andweightgain (p=0.04).

PhysicalExaminations

• Muscle&jointtenderness • Overweight • Abnormalupperrespiratoryexaminationsin 100% – Congestion,hypertrophicturbinates,injection, discoloration(blotchypaletoyellow) • Decreasedvibratorysensein6% Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

BodyMassIndex

HighestBMIwas39

CGIScores,Q#1,dextromethorphan

Dextro-Placebo Dextro-Placebo Dextro. Dextro. 5 0 -.1 4 -.2 3 -.3 -.4 2 -.5 -.6 1 -.7 0 -.8 Baseline Post-TX Change from Baseline

Unpaired Means Comparison for Change from Baseline Grouping Variable: Treatment Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Dextro-Placebo, Dextro. .188 30 .635 .5304 -.416 .791

Group Info for Change from Baseline Grouping Variable: Treatment Count Mean Variance Std. Dev. Std. Err Dextro-Placebo 16 -.250 .333 .577 .144 Dex tro. 16 -.438 1.063 1.031 .258 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014 CGIQ#1,naltrexonevplacebo

Naltrexone Naltrexone Naltrexone-Placebo Naltrexone-Placebo 6 0 -.05 5 -.1 4 -.15 -.2 3 -.25 2 -.3 -.35 1 -.4 0 -.45 Baseline Post-TX Change from Baseline

Unpaired Means Comparison for Change from Baseline Grouping Variable: Treatment Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Naltrexone, Naltrexone-Placebo .123 40 .549 .5858 -.329 .574

Group Info for Change from Baseline Grouping Variable: Treatment Count Mean Variance Std. Dev. Std. Err Naltrex one 20 -.150 .661 .813 .182 Naltrexone-Placebo 22 -.273 .398 .631 .135

LaboratoryValues Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

NGF,pg/mL

0 Baseline Dextromethorphan Placebo

Interferonalpha IFN:13.1± 22.7(0.14Ͳ126.8)

30 30 103

103 117 25 141 25 117 164 141 20 214 20 164 232 214 15 258 15 232 278 258 10 4 278 10 90 4 5 93 90 5 0 93

0 -5 Baseline Dextromethorphan Placebo-Dex Baseline Naltrexone Placebo-Nal Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

Interleukin10

7 12

6 10 103 117 5 103 8 141 117 164 4 141 6 214 214 232 3 4 4 258 90 278 2 93 2 4 90 1 0 93

0 -2 Baseline Dextromethorphan Placebo-Dex Baseline Naltrexone Placebo-Nal

Interleukin1beta

3 4

2.5 3.5 103 103 3 117 117 2 141 141 2.5 164 164 1.5 2 214 214 232 278 1.5 1 278 4 1 4 90 .5 90 93 .5 93 0 0 -.5 -.5 Baseline Dextromethorphan Placebo-Dex Baseline Naltrexone Placebo-Nal Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

Interleukin6

14 14

12 12 103 103 10 117 10 117 141 141 8 164 8 164 214 214 6 278 6 4 4 90 4 90 4 93 93 2 2

0 0 Baseline Dextromethorphan Placebo-Dex Baseline Naltrexone Placebo-Nal

Interleukin8

55 100 50 90 103 45 80 117 103 141 40 117 70 164 141 35 60 214 164 232 30 214 50 258 4 25 40 278 90 20 30 4 93 15 20 90 93 10 10 5 0 Baseline Dextromethorphan Placebo-Dex Baseline Naltrexone Placebo-Nal Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

TNFͲalpha

16 13

12 103 14 11 117 103 141 12 117 10 164 141 9 214 10 214 232 4 8 258 278 8 90 7 93 4 6 90 6 93 5 4 4 Baseline Dextromethorphan Placebo-Dex Baseline Naltrexone Placebo-Nal

CͲreactiveprotein MeanCRPlevels: Baseline:3.96 Dex:1.59 DexͲPlacebo:2.4 Nal:2.8 NalͲPlacebo:2.66

Thedifference betweenbaseline anddex approaches significance p=0.07. Poweranalysis showsthat26 peoplewouldbe neededtoreach 0.05with80% power(currently N=13). Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

SymptomScores

VASscoresforHA.Significantlydecreasedwithbothnaltrexone,dex, andtheirrespectiveplacebos

60 60 50 50

40 40 30 30

20 20 10 10 0 Baseline Naltrexone Nal-Plac 0 Baseline Dex Dex-Plac

Paired Means Comparison Paired Means Comparison Hypothesized Difference = 0 Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Naltrexone 15.893 27 3.159 .0039 5.571 26.215 Baseline, Dex 27.200 14 4.707 .0003 14.806 39.594 Baseline, Nal-Plac 25.786 27 5.183 <.0001 15.577 35.994 Baseline, Dex-Plac 20.867 14 2.402 .0308 2.232 39.501 Naltrexone, Nal-Plac 9.556 26 1.652 .1106 -2.337 21.448 Dex , Dex -Plac .357 13 .063 .9510 -11.949 12.663 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

VASscoresforsleepingproblems.Significantlydecreasedwith bothnaltrexone,dex,andtheirrespectiveplacebos 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Baseline Naltrexone Nal-Plac Baseline Dex Dex-Plac

Paired Means Comparison Hypothesized Difference = 0 Paired Means Comparison Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Naltrexone 25.741 26 4.730 <.0001 14.555 36.926 Baseline, Dex 23.625 15 4.155 .0008 11.505 35.745 Baseline, Nal-Plac 30.444 26 4.771 <.0001 17.328 43.561 Baseline, Dex-Plac 16.563 15 2.345 .0332 1.510 31.615 Dex , Dex -Plac -10.667 14 -1.509 .1534 -25.823 4.490 Naltrexone, Nal-Plac 2.385 25 .632 .5332 -5.387 10.157

VASscoresforconcentrationproblems.Noeffectof naltrexoneoritsplacebo.Significantlydecreasedwithdex, butnotitsplacebo!POSITIVEFINDING! 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Baseline Naltrexone Nal-Plac Baseline Dex Dex-Plac Paired Means Comparison Hypothesized Difference = 0 Paired Means Comparison Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Naltrexone 7.296 26 1.749 .0921 -1.279 15.872 Baseline, Dex 18.313 15 2.766 .0144 4.201 32.424 Baseline, Nal-Plac 6.556 26 1.131 .2684 -5.359 18.470 Baseline, Dex-Plac 9.000 15 1.520 .1493 -3.622 21.622 Naltrexone, Nal-Plac -.962 25 -.193 .8488 -11.242 9.319 Dex, Dex -Plac -8.333 14 -2.271 .0394 -16.203 -.464 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

VASscoresformemoryproblems.Effectofnaltrexone placeboandwithDex alone(butnotitsplacebo). POSITIVEFINDING! 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Baseline Dex Dex-Plac Baseline Naltrexone Nal-Plac

Paired Means Comparison Hypothesized Difference = 0 Paired Means Comparison Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Naltrexone 9.370 26 1.856 .0749 -1.010 19.751 Baseline, Dex 13.750 15 2.102 .0528 -.190 27.690 Baseline, Nal-Plac 11.852 26 2.565 .0164 2.355 21.349 Baseline, Dex-Plac 10.688 15 1.896 .0775 -1.330 22.705 Naltrexone, Nal-Plac 2.577 25 .583 .5649 -6.522 11.676 Dex, Dex-Plac -5.400 14 -1.253 .2307 -14.642 3.842

VASscoresforfatigue.Significanteffectwithnaltrexoneand itsplacebo.AlsowithDex alone(butnotitsplacebo). POSITIVEFINDING! 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Baseline Naltrexone Nal-Plac Baseline Dex Dex-Plac

Paired Means Comparison Paired Means Comparison Hypothesized Difference = 0 Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Naltrexone 13.407 26 2.378 .0251 1.817 24.998 Baseline, Dex 20.625 15 2.875 .0116 5.333 35.917 Baseline, Nal-Plac 13.815 26 2.788 .0098 3.628 24.001 Baseline, Dex-Plac 10.500 15 1.241 .2338 -7.539 28.539 Naltrexone, Nal-Plac .500 25 .082 .9353 -12.050 13.050 Dex , Dex-Plac -6.667 14 -.953 .3569 -21.674 8.341 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

VASscoresforjointpain.Nothingforeitherdrug

70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Baseline Naltrexone Nal-Plac Baseline Dex Dex-Plac

Paired Means Comparison Paired Means Comparison Hypothesized Difference = 0 Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Naltrexone 2.148 26 .277 .7837 -13.773 18.070 Baseline, Dex -.375 15 -.040 .9686 -20.342 19.592 Baseline, Nal-Plac 5.778 26 .699 .4907 -11.208 22.764 Baseline, Dex-Plac -1.063 15 -.101 .9210 -23.520 21.395 Naltrex one, Nal-Plac 1.923 25 .370 .7148 -8.794 12.641 Dex, Dex-Plac 1.600 14 .215 .8329 -14.361 17.561

VASscoresformuscleaches.Nothingwithnaltrexoneorits placebo.EffectwithDex alone(butnotitsplacebo).POSITIVE FINDING!

70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Baseline Naltrexone Nal-Plac Baseline Dex Dex-Plac Paired Means Comparison Paired Means Comparison Hypothe s iz e d Diffe r e nce = 0 Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Dex 11.938 15 2.332 .0340 1.028 22.847 Baseline, Naltrexone 6.630 26 1.148 .2615 -5.244 18.503 Baseline, Nal-Plac 10.481 26 1.749 .0921 -1.838 22.801 Baseline, Dex-Plac 11.563 15 1.699 .1100 -2.946 26.071 Naltrexone, Nal-Plac 5.654 25 1.051 .3032 -5.424 16.731 Dex , Dex -Plac 1.000 14 .171 .8667 -11.550 13.550 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

VASscoresforinappropriateanger.Effectwithnaltrexoneand itsplacebo.NothingwithDex oritsplacebo 60 60 50 50

40 40 30 30 20 20 10 10 0 0 Baseline Dex Dex-Plac Baseline Naltrexone Nal-Plac

Paired Means Comparison Paired Means Comparison Hypothesized Difference = 0 Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Naltrexone 14.889 26 2.326 .0281 1.730 28.048 Baseline, Dex 15.063 15 1.913 .0750 -1.719 31.844 Baseline, Nal-Plac 18.815 26 2.546 .0172 3.626 34.003 Baseline, Dex-Plac 12.938 15 1.774 .0964 -2.610 28.485 Naltrexone, Nal-Plac 4.154 25 .601 .5533 -10.081 18.389 Dex, Dex-Plac -.400 14 -.099 .9226 -9.075 8.275

CGIscoressignificantlyincreasedoverbaselinewith naltrexoneoritsplacebo.CGIscoressignificantlyincreased overbaselinewithDex anditsplacebo..BUT DexͲplacebo scoresaresignificantlylowerthanDex alonescores.

7 14 6 12 5 10 4 8 3 6 2 4 1 2 0 0 Baseline Baseline Mean Nal Mean Dex Mean Nal-Plac Mean Paired Means Comparison Paired Means Comparison Mean Dex-Plac Hypothe s iz e d Diffe r e nce = 0 Hypothesized Difference = 0 Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Mean Diff. DF t-Value P-Value 95% Low er 95% Upper Baseline, Mean Nal -1.432 26 -3.901 .0006 -2.187 -.677 Baseline, Mean Dex -6.479 15 -7.450 <.0001 -8.333 -4.625 Baseline, Mean Nal-Plac -1.148 26 -3.217 .0035 -1.882 -.415 Baseline, Mean Dex-Plac -1.833 15 -4.466 .0005 -2.708 -.958 Mean Dex, Mean Dex-Plac 4.844 14 4.526 .0005 2.549 7.140 Mean Nal, Mean Nal-Plac .333 25 .731 .4715 -.606 1.272 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

Armyinfantry responder GWage21,in

Symptoms returned2days afterstopped medication Globalclinical impression: severelyillto mildlyill Oncelexa for depression, discontinued oxycodoneand hydrocodoneto participate Norashattimeof visit Exposures:2scudattacks,alarmswentoff,PB,oilwellfiresforonemonth,fumesfrom highwayof death,vaccinations,

120

100

Pre 60 Post

0 headache joint muscle diarrhea rash memory sleep concent fatigue dizzy vertigo irritab anger depress Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

confounders

• Acuteillnesses – Smallbowelobstruction,pneumonia,acute sinusitis, • Changesintherapy – Steroidinjections,changesinpsychotropicdrugs, coursesofantibiotics,corticosteroids • Changesindietandlifestyle

ConfoundedbyChangesinLifestyle Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

PartI FoodChoices

PartII Recipes

PARTIII IdentifyingPersonalProblem Foods

PartIV Beyondwhatweeat–wherewe live&work,cleanair,healthy lifestyles,goodmindstates, supplements,thechemical environment,whatmedicinecan do

#237confounderofdietaryelimination eliminatedsugar,caffeine,gluten,dairy lost20poundsin10days

symptom Visit #5 Visit #6 Visit#7 Headache 5.9 2.2 3.8 Nasal congestion 6.7 1.8 3.5 Jointaches 6.8 3.9 3.3 Muscleaches 7.2 4.3 3.5 Abdominal pain 6.4 0.5 0.3 Memoryproblems 7.5 5.2 3.9 Sleepingproblems 7.5 4.9 1.4 confusion 4.3 1.7 0.3 Concentration 6.1 3.7 2.2 fatigue 6.4 3.6 2.3 Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

Responsetodietaryelimination+

Eliminationdiet+dex/placebo 8

0 Visit#5 Visit#6 Visit#7 headache congestion jointaches muscleaches abdominalpain memory sleep confusion concentration fatigue

Limitations

• Nopharmacokineticdata – Geneticdifferencesinmetabolism – Onedoseforall,independentofweight&other factors • NonormalcontrolsforNGFandHuman cytokine/chemokinepanels • Snapshotlimitation • Concurrenttreatments – “Igotmykneesinjected.” Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

PreliminaryConclusions

• Atthedosesused,therewereresponders& nonͲresponders • Nostatisticalbenefitwhenaveragedoverall participants • NGF&cytokinepaneldatashowedno consistentpatternofvariability • Empiricalpharmacologytreatments demonstratednobenefitrelativetothose usingnomedications

LessonsLearned (orwhatwouldbedonedifferently) • AllowadequatetimesforIRB&FDAapprovals – Don’tusefundsbeforeapproval • Adjustdosesusingpharmacokineticdata • WeeklyVASratherthanpreͲ andpostͲ symptomsscores • RecordVASafterdiscontinuationof medication Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

acknowledgements

• CDMRPforfunding • Dr.JohnHongatNIEHSforproposingthe study&advice • Mr.JimBinns forsuggestingthatIundertake thestudy • Dr.Kori BrewerͲͲscientist • AllisonMainhart—clinicalresearchspecialist

References

• Skop BP,FinkelsteinJA,Mareth TR,etal:The serotoninsyndromeassociatedwithparoxetine, anoverͲtheͲcountercoldremedy,andvascular disease.AmJEmerg Med1994c;12:642Ͳ644. • RiversN&HornerB:Possiblelethalreaction betweenNardil anddextromethorphan(letter). CanMedAssoc J1970k;103:85. • SmithJP,StockH,Bigaman S,etരal.LowͲdose naltrexonetherapyimprovesactiveCrohn's disease.AmJGastroenterol 2007;102:820–828. Appendix A RAC-GWVI Meeting Minutes Presentation 5 - William Meggs September 22-23, 2014

References

• Ghai Betal.OffͲLabel,LowͲDoseNaltrexonefor RefractoryChronicLowBackPain.PainMedicine 2014;15:883Ͳ884. • Gironi M,MartinelliͲBoneschi F,Sacerdote P,etരal. ApilottrialoflowͲdosenaltrexoneinprimary progressivemultiplesclerosis.Mult Scler 2008;14:1076–1083. • ValentineAD,MeyersCA,Talpaz M.Treatmentof neurotoxicsideeffectsofinterferonalpha with naltrexone.CancerInvest 1995;13:561–566