Devika Nair|Fredric O. Finkelstein
Pruritus as a Patient-Reported Primary Trial End Point in Hemodialysis: Evaluation and Implications
Vanderbilt University|Vanderbilt University Medical Center|Yale University
commentary fishbane jamal munera c wen w menzaghi f kalm1 trial investigators phase 3 trial difelikefalin hemodialysis patients pruritus n engl j med 20203823222232 commentary fishbane jamal munera c wen w menzaghi f kalm1 trial investigators phase 3 trial difelikefalin hemodialysis patients pruritus n engl j med 20203823222232 uremic pruritus widespread burdensome underreported inadequately treated individuals receiving maintenance hemodialysis hd prevalence estimates uremic pruritus population range 40 60 moderate severe pruritus associated clinical depression low sleep quality poor perceptions healthrelated quality life qol increased risk cardiovascular mortality1pisoni rl wikstrom b elder sj et alpruritus hemodialysis patients international results dialysis outcomes practice patterns study doppsnephrol dial transplant 2006 21 34953505crossref pubmed scopus 305 google scholar 2rayner hc larkina wang et alinternational comparisons prevalence awareness treatment pruritus people hemodialysisclin j soc nephrol 2017 12 20002007crossref pubmed scopus 54 google scholar 3mathur vs lindberg j germain et ala longitudinal study uremic pruritus hemodialysis patientsclin j soc nephrol 2010 5 14101419crossref pubmed scopus 128 google scholar 4weng ch hu cc yen th hsu cw huang wh uremic pruritus associated twoyear cardiovascular mortality longterm hemodialysis patientskidney blood press res 2018 43 10001009crossref pubmed scopus 9 google scholar mechanisms uremic pruritus remain poorly understood limiting ability develop safe effective therapies management strategies included ultraviolet b therapy antihistamines selectiveserotonin reuptake inhibitors increased solute removal better dialysis efficacy recently aminobutyric acid gaba analogues reported helpful5eusebioalpapara kmv castillo rl dofitas bl gabapentin uremic pruritus systematic review randomized controlled trialsint j dermatol 2020 59 412422crossref pubmed scopus 10 google scholar 6reszke r szepietowski jc endstage renal disease chronic itch managementdermatol clin 2018 36 277292abstract full text full text pdf pubmed scopus 16 google scholar 7gilchrest ba rowe jw brown rs steinman ti arndt ka ultraviolet phototherapy uremic pruritus longterm results possible mechanism actionann intern med 1979 91 1721crossref pubmed scopus 138 google scholar 8pakfetrat malekmakan l hashemi n tadayon sertraline reduce uremic pruritus hemodialysis patient double blind randomized clinical trial southern iranhemodial int 2018 22 103109crossref pubmed scopus 12 google scholar 9kouwenhoven ta van de kerkhof pcm kamsteeg use oral antidepressants patients chronic pruritus systematic reviewj acad dermatol 2017 77 10681073abstract full text full text pdf pubmed scopus 23 google scholar 10gobooliveira pigari vg ogata ms miot ha ponce abbade lp gabapentin versus dexchlorpheniramine treatment uremic pruritus randomized controlled trialeur j dermatol 2018 28 488495crossref pubmed scopus 9 google scholar 11hiroshige k kabashima n takasugi kuroiwa optimal dialysis improves uremic pruritusam j kidney dis 1995 25 413419abstract full text pdf pubmed scopus 98 google scholar limitations therapies generally agreed pruritus remains major problem individuals maintained hd evidence pointed potential role opioid pathway treatment uremic pruritus triggering interest pathway potential therapeutic target12andersen lw friedberg lokkegaard n naloxone treatment uremic pruritus case historyclin nephrol 1984 21 355356pubmed google scholar 13peer g kivity agami et alrandomized crossover trial naltrexone uremic prurituslancet 1996 348 15521554abstract full text full text pdf pubmed scopus 226 google scholar 14kumagai h ebata takamori k et alefficacy safety novel kappaagonist managing intractable pruritus hemodialysis patientsam j nephrol 2012 36 175183crossref pubmed scopus 85 google scholar fishbane et al recently published results phase 3 randomized doubleblind placebocontrolled trial across 56 sites aimed test efficacy difelikefalin peripherally restricted selective agonist opioid receptor reduction uremic pruritus 378 individuals receiving incenter hd15fishbane jamal munera c wen w menzaghi f kalm1 trial investigators phase 3 trial difelikefalin hemodialysis patients pruritusn engl j med 2020 382 222232crossref pubmed scopus 38 google scholar participants moderate severe pruritus randomly assigned receive either 05 gkg difelikefalin placebo dialysis session 12 weeks pruritus measured using 24hour worst itching intensity numerical rating scale winrs asks individuals choose ordinal scale 0 10 number accurately corresponds degree pruritus last day16naegeli flood e tucker j devlen j edsonheredia e worst itch numeric rating scale patients moderate severe plaque psoriasis psoriatic arthritisint j dermatol 2015 54 715722crossref pubmed scopus 32 google scholar primary outcome pruritus score end intervention least 3 points lower baseline secondary outcome investigators measured changes healthrelated qol assessed using 5d itch scale 5item measure asks patients report ordinal scale duration severity distribution associated disability pruritus skindex10 61item scale asks patients report degree social isolation embarrassment fear anger result pruritus17elman hynan ls gabriel v mayo mj 5d itch scale new measure pruritusbr j dermatol 2010 162 587593crossref pubmed scopus 229 google scholar18chren mm lasek rj quinn lm mostow en zyzanski sj skindex qualityoflife measure patients skin disease reliability validity responsivenessj invest dermatol 1996 107 707713abstract full text pdf pubmed scopus 511 google scholar additional secondary outcomes investigators determined percentage patients reported decrease pruritus 4 points weekly mean winrs score measures safety 158 patients randomly assigned difelikefalin treatment 82 519 achieved primary outcome improvements pruritus reported early 1 week randomization results suggested effects may persist beyond 12week followup encouragingly participants received difelikefalin exhibited significant signs symptoms suggestive opioid withdrawal 2week observation period study discontinuation study fishbane et al number strengths selecting patientreported pruritus primary outcome investigation aligns increasingly prioritized need increase use patientreported outcomes pros primary clinical trial end points nephrology19nair wilson fp patientreported outcome measures adults kidney disease current measures ongoing initiatives future opportunities incorporation patientcentered kidney caream j kidney dis 2019 74 791802abstract full text full text pdf pubmed scopus 12 google scholar patients randomly assigned difelikefalin treatment also reported statistically significant improvements validated measures pruritusrelated qol trial took additional admirable steps toward alleviating significant symptom burden faced patients receiving maintenance hd improvements pruritus observed difelikefalin treatment even adjustments made concurrent use antipruritic medications sensitivity analyses treated individuals discontinued therapy nonresponders described articles supplementary information investigators used strict inclusion exclusion criteria including participants completed 7day runin test intervention fidelity excluding reported pruritus limited hands 503 participants screened 37 declined participate 189 randomly assigned difelikefalin treatment 8 withdrew consent study close signs symptoms opioid withdrawal rigorously monitored using pro short opioid withdrawal scale obsro observerreported outcome objective opioid withdrawal scale20handelsman l cochrake kj aronson mj ness r rubinstein kj kanof pd two new rating scales opiate withdrawalam j drug alcohol abuse 1987 13 293308crossref pubmed scopus 384 google scholar although analysis fishbane et al may provide hope patients experiencing persistent uremic pruritus certain aspects warrant discussion 165 patients randomly assigned placebo 51 309 also achieved statistically significant reduction pruritus participants study arms moderate severe pruritus intervention raising question contribution regression mean findings additionally exact methods change baseline winrs score 3 deemed significant remain unclear mean change 5d itch score approximately 51 intervention group 37 placebo group corresponding mean changes skindex10 score approximately 16 12 respectively patients may differing opinions constitutes clinicallymeaningful improvement symptom burden challenge interpreting many studies using measure healthrelated qol outcome serious adverse events including hyperkalemia pneumonia sepsis hypotension chronic obstructive pulmonary disease occurred 259 difelikefalin group 218 receiving placebo 2 deaths difelikefalin group 2 deaths placebo group due sepsis septic shock respectively participants randomly assigned difelikefalin treatment also experienced frequent gastrointestinal side effects diarrhea nausea reported 95 53 intervention group versus 37 32 placebo group respectively dizziness reported 69 intervention group versus 11 placebo group high response rate found placebo group need monitor additional adverse events stresses importance ongoing 52week openlabel phase study currently way21clinicaltrialsgovnational institutes healthhttpsclinicaltrialsgovct2shownct03422653date accessed january 10 2020google scholar also important consider treating patient maintained hd difelikefalin may improve symptoms pruritus patients overall qol may still compromised would investigators found broader measures healthrelated qol used outcomes lack consensus regarding measure uremic pruritus difficult compare efficacy difelikefalin therapies literature due variation instruments followup times used22razeghi e eskandari ganji mr meysamie ap togha khashayar p gabapentin uremic pruritus hemodialysis patientsren fail 2009 31 8590crossref pubmed scopus 72 google scholar opposed numerical scales used fishbane et al many studies evaluating efficacy intervention uremic pruritus use visual analogue scale10gobooliveira pigari vg ogata ms miot ha ponce abbade lp gabapentin versus dexchlorpheniramine treatment uremic pruritus randomized controlled trialeur j dermatol 2018 28 488495crossref pubmed scopus 9 google scholar scales participants asked specify severity pruritus choosing position continuous line 2 end points visual analogue scale easier interpret individuals cognitive deficits may important consider given accelerated cognitive decline faced individuals receiving hd23arons amm krabbe pfm van der wilt gj olde rikkert mgm adang emm visual analogue scales scale calibration patients dementia proxiesqual life res 2013 22 979986crossref pubmed scopus 5 google scholar24drew da weiner de tighiouart h et alcognitive decline risk factors prevalent hemodialysis patientsam j kidney dis 2017 69 780787abstract full text full text pdf pubmed scopus 41 google scholar though winrs asks patients recall symptoms pruritus 24hour period thus may adequately capture perceptions pruritus peak severity night scale originally developed psoriasis may capture certain burdensome aspects pruritus specific kidney disease exacerbation heat coexistence overlap chronic pain25combs sa teixeira jp germain mj pruritus kidney diseasesemin nephrol 2015 35 383391abstract full text full text pdf pubmed scopus 62 google scholar 26sukul n speyer e tu e pruritus patientreported outcomes nondialysis ckdclin j soc nephrol 2019 14 673681crossref pubmed scopus 36 google scholar 27manenti l tansinda p vaglio uraemic pruritus clinical characteristics pathophysiology treatmentdrugs 2009 69 251263crossref pubmed scopus 62 google scholar study important expands nephrologists ability offer treatment options pruritus thus help reduce symptoms burden hd patients potential benefits difelikefalin treatment need considered nociceptive neuropathic pain frequently reported patients kidney disease occur sequelae underlying conditions peripheral vascular disease calcific uremic arteriolopathy diabetic neuropathy phantom limb pain28davison sn pain hemodialysis patients prevalence cause severity managementam j kidney dis 2003 42 12391247abstract full text full text pdf pubmed scopus 269 google scholar optimal use centrally acting opioid analgesics treat pain group limited pharmacokinetics agents potential abuse sedation respiratory depression associations mortality29davison sn clinical pharmacology considerations pain management patients advanced kidney failureclin j soc nephrol 2019 14 917931crossref pubmed scopus 37 google scholar 30ishida jh mcculloch ce steinman grimes ba johansen kl opioid analgesics adverse outcomes among hemodialysis patientsclin j soc nephrol 2018 13 746753crossref pubmed scopus 35 google scholar 31novick tk surapaneni shin ji et alassociations opioid prescriptions death hospitalization across spectrum estimated gfrclin j soc nephrol 2019 14 15811589crossref pubmed scopus 12 google scholar due difelikefalins peripheral selectivity lacks central side effects opioid receptor agonists peripherally acting opioid receptor agonists emerging attractive option treat pain due decreased potential abuse central side effects also result effects inflammatory pain animal models difelikefalin found reduce cytokine release sepsis decrease scratching behavior induced pruritogens improve visceral inflammatory neuropathic pain multicenter doublerandomized doubleblind placebocontrolled trial intravenous difelikefalin reported analgesic efficacy safety used elective laparoscopic hysterectomy exploratory trial using oral formulation difelikefalin effectively treated osteoarthritic pain resulting minimal use rescue pain medication adverse side effects32albertvartanian boyd mr hall al et alwill peripherally restricted kappaopioid receptor agonists pkoras relieve pain less opioid adverse effects abuse potentialj clin pharm ther 2016 41 371382crossref pubmed scopus 39 google scholar 33gardell lr spencer rh chalmers dt menzaghi f preclinical profile cr845 novel longacting peripheral kappa opioid receptor agonist cara therapeuticshttpircaratherapeuticscomstaticfiles396df363803147f6b903eca1df1df26fdate accessed january 10 2020google scholar 34clinicaltrialsgovnational institutes healthhttpsclinicaltrialsgovct2shownct02944448date accessed january 10 2020google scholar 35cara therapeutics announces positive topline results phase 2a trial oral cr845 chronic pain patients osteoarthritis knee hiphttpircaratherapeuticscomnewsreleasesnewsreleasedetailscaratherapeuticsannouncespositivetoplineresultsphase2areleaseid946233date accessed january 10 2020google scholar however difelikefalin peripherally acting opioid agents considered use treat pain patients kidney disease evidence needed regarding drugs pharmacokinetics tolerability patient population efficacy difelikefalin individuals receiving peritoneal dialysis chronic kidney disease requiring kidney replacement therapy remains unknown intravenous use presents obvious challenges patient perceptions pruritus change timing dialysis session difelikefalin dialyzable factors must continue taken consideration future studies36mistik utas ferahbas epidemiology study patients uremic pruritusj eur acad dermatol venereol 2006 20 672678crossref pubmed scopus 71 google scholar 37simonsen e komenda p lerner b et altreatment uremic pruritus systematic reviewam j kidney dis 2017 70 638655abstract full text full text pdf pubmed scopus 72 google scholar 38jaiswal uzans hayden j kiberd ba tennankore kk targeting opioid pathway uremic pruritus systematic review metaanalysiscan j kidney health dis 2016 32054358116675345crossref scopus 16 google scholar importantly patientlevel benefits targeting uremic pruritus alone opposed constellation pros include symptoms must carefully evaluated resuts ongoing study aimed evaluate metabolite profiling pharmacokinetics intravenous defelikefalin hd well multicenter randomized doubleblind placebocontrolled trial evaluating safety efficacy oral difelikefalin pruritus intensity patients chronic kidney disease eagerly awaited39clinicaltrialsgovnational institutes healthhttpsclinicaltrialsgovct2shownct03947970date accessed january 10 2020google scholar 40clinicaltrialsgovnational institutes healthhttpsclinicaltrialsgovct2shownct03617536date accessed january 10 2020google scholar work fishbane et al implications nephrologists move beyond introducing novel therapies symptom burden nephrology process rethinking design clinical trials protocol offers valuable insight care rigor required incorporate pro primary trial end point guidelines aim standardize procedures developed standard protocol items recommendations interventional trialspro spiritpro extension recommendations inform standardized incorporation pros nephrology research table 141calvert kyte merciecabebber r guidelines inclusion patientreported outcomes clinical trial protocols spiritpro extensionjama 2018 319 482494crossref scopus 225 google scholar 42fydrich dowdall chambless dl reliability validity beck anxiety inventoryj anxiety disord 1992 6 5561crossref scopus 434 google scholar 43nasreddine zs phillips na bedirian v et althe montreal cognitive assessment moca brief screening tool mild cognitive impairmentj geriatr soc 2005 53 695699crossref pubmed scopus 9441 google scholar 44sandjecklin k coyle efficiently assessing patient health literacy bhls instrumentclin nurs res 2014 23 581500crossref pubmed scopus 20 google scholar pros continue rigorously incorporated clinical trials researchers able generate additional evidence support protargeted interventions nephrology community truly move needle alleviating symptom burden faced individuals living advanced kidney diseasetable 1best practices incorporating patientreported outcome clinical trial protocolrecommendation spiritpro41calvert kyte merciecabebber r guidelines inclusion patientreported outcomes clinical trial protocols spiritpro extensionjama 2018 319 482494crossref scopus 225 google scholarexample hypothetic nephrology trialassignment specific individuals investigative team write prorelated content protocolcollaboration psychometrician nephrologist experience using pros research studiesjustification need use procurrently biomarkers exist reliably measure patients experiences anxietyinclusion details regarding psychmometric properties promthe beck anxiety inventory bai internally consistent cronbachs alpha 094 reliable period 11 days r 06742fydrich dowdall chambless dl reliability validity beck anxiety inventoryj anxiety disord 1992 6 5561crossref scopus 434 google scholarp 57state promspecific analysis metric hypothesis used evaluate intervention successwe hypothesize intervention result 4point decrease bai 12 weeks among patients receiving incenter hemodialysisif prom previously adapted special populations specify measurespecific exclusion criteriaparticipants nonenglishspeaking moderate cognitive dysfunction measured montreal cognitive assessment low subjective health literacy measured brief health literacy screen excluded43nasreddine zs phillips na bedirian v et althe montreal cognitive assessment moca brief screening tool mild cognitive impairmentj geriatr soc 2005 53 695699crossref pubmed scopus 9441 google scholarp 69644sandjecklin k coyle efficiently assessing patient health literacy bhls instrumentclin nurs res 2014 23 581500crossref pubmed scopus 20 google scholarspecify time window prom collection rationale approachparticipants anxiety scores collected prior dialysis session evidence shows anxiety amplified prior impending health threat change routinespecify method mode prom collectionparticipants anxiety scores collected via portable electronic devices prior start hemodialysis session trained research assistantsspecify justify ifwhy pro reported patient proxyas intervention aims measure patient experiences anxiety relation patients hemodialysis session pro collected directly patientdescribe prom data inform patients care plancases participants score within range moderatetosevere anxiety discussed monthly multidisciplinary meeting consisting participants nephrologist social worker potential addition participants caregiver applicableabbreviations pro patientreported outcome prom patientreported outcome measure spiritpro standard protocol items recommendations interventional trialspatientreported outcome open table new tab abbreviations pro patientreported outcome prom patientreported outcome measure spiritpro standard protocol items recommendations interventional trialspatientreported outcome devika nair md msci fredric finkelstein md none authors declare relevant financial interests received december 26 2019 response invitation journal direct editorial input associate editor deputy editor accepted revised form january 22 2020