Levodopa Carbidopa Intestinal Gel in Advanced Parkinson’s Disease: DUOGLOBE Final 3-Year Results

Jou nal o Pa kinson’s Disease 13 (2023) 769–783 DOI 10.3233/JPD-225105 IOS P ess 769 Clinical Resea ch Le odopa Ca bidopa In es inal Gel in Ad anced Pa kinson’s Disease: DUOGLOBE Final 3-Yea Resul s K. Ray Chaudhu ia,∗, No be Ko ´ acsb, F ancesco E. Pon ie ic,d, Jason Ald ede, Paul Bou geois , Thomas L. Da isg, Es he Cuboh, Ma ie a Anca-He schko i schi, Robe Iansekj, Mus a a S. Siddiquik, Mihaela Simul, La s Be gmannm, May a Ballinam, Pa ni Kuk ejam, Oma Ladhanim, Jia Jiamand Da id G. S andae n aPa kinson’s Founda ion In e na ional Cen e o Excellence, King’s College Hospi al, and King’s College Ins i u e o Psychia y, Biomedical Resea ch Cen e, Psychology & Neu oscience, London, Uni ed Kingdom bDepa men o Neu ology, Uni e si y o P´ecs, P´ecs, Hunga y cDepa men o Neu oscience, Men al Heal h and Senso y O gans, Sapienza Uni e si y o Rome, Rome, I aly dSan a Lucia Founda ion, IRCCS, Rome, I aly eSelki k Neu ology, Spokane, WA, USA Depa men o Neu ology AZ G oeninge, Ko ijk, Belgium gDepa men o Neu ology, Vande bil Uni e si y Medical Cen e , Nash ille, TN, USA hNeu ology Depa men , Hospi al Uni e si a io Bu gos, Bu gos, Spain iDepa men o Neu ology, Edi h Wol son Medical Cen e , Holon, Is ael jKings on Cen e, Monash Heal h, Melbou ne, Vic o ia, Aus alia kDepa men o Neu ology, Wake Fo es School o Medicine, Wins on Salem, NC, USA lDepa men o Neu ology, Vic o Babes Uni e si y o Medicine and Pha macy, Timisoa a, Romania mAbbVie Inc., No h Chicago, IL, USA nDepa men o Neu ology, Uni e si y o Alabama a Bi mingham, Bi mingham, AL, USA Accep ed 14 May 2023 P e-p ess 5 June 2023 Published 25 July 2023 Abs ac . Backg ound: Le odopa-ca bidopa in es inal gel (LCIG) imp o es mo o and non-mo o symp oms in pa ien s wi h ad anced Pa kinson’s disease (aPD). Objec i e: To p esen he inal 36-mon h e icacy and sa e y esul s om DUOGLOBE (DUOdopa/Duopa in Pa ien s wi h Ad anced Pa kinson’s Disease – a GLobal OBse a ional S udy E alua ing Long-Te m E ec i eness; NCT02611713). Me hods: DUOGLOBE was an in e na ional, p ospec i e, long- e m, eal-wo ld, obse a ional s udy o pa ien s wi h aPD ini ia ing LCIG in ou ine clinical ca e. The p ima y endpoin was change in pa ien - epo ed “O ” ime o Mon h 36. Sa e y was assessed by moni o ing se ious ad e se e en s (SAEs). ∗Co espondence o: D . K. Ray Chaudhu i, Depa men o Basic and Clinical Neu oscience, The Mau ice Wohl Clinical Neu oscience Ins i u e, King’s College London, 5 Cu combe Road, London SE5 9RT, UK. Tel.: +44 203 299 7154; E-mail: Ray[email p o ec ed].; ORCiD: 0000-0003-2815-0505. ISSN 1877-7171 © 2023 – The au ho s. Published by IOS P ess. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY 4.0). 770 K.R. Chaudhu i e al. / Final 3-yea Resul s om he DUOGLOBE S udy Resul s: Signi ican imp o emen s in “O ” ime we e main ained o e 3 yea s (mean [SD]: –3.3 hou s [3.7]; p< 0.001). The e we e signi ican imp o emen s o Mon h 36 in o al sco es o he Uni ied Dyskinesia Ra ing Scale (–5.9 [23.7]; p= 0.044), Non-Mo o Symp oms Scale (–14.3 [40.5]; p= 0.002), Pa kinson’s Disease Sleep Scale-2 (–5.8 [12.9]; p< 0.001), and Epwo h Sleepiness Scale (–1.8 [6.0]; p= 0.008). Heal h- ela ed quali y o li e and ca egi e bu den signi ican ly imp o ed h ough Mon hs 24 and 30, espec i ely (Mon h 24, 8-i em Pa kinson’s Disease Ques ionnai e Summa y Index, –6.0 [22.5]; p= 0.006; Mon h 30, Modi ied Ca egi e S ain Index, –2.3 [7.6]; p= 0.026). Sa e y was consis en wi h he well-es ablished LCIG p o ile (SAEs: 54.9% o pa ien s; discon inua ions: 54.4%; discon inua ions due o an ad e se e en : 27.2%). O 106 s udy discon inua ions, 32 pa ien s (30.2%) con inued LCIG ou side he s udy. Conclusion: DUOGLOBE demons a es eal-wo ld, long- e m, educ ions in mo o and non-mo o symp oms in pa ien s wi h aPD ea ed wi h LCIG. Keywo ds: DUOGLOBE, Pa kinson’s disease, le odopa-ca bidopa in es inal gel, dyskinesia, eal-wo ld da a INTRODUCTION Le odopa is conside ed he “gold s anda d” o he ea men o Pa kinson’s disease (PD) [1]. Wi h disease p og ession, he bene i o o al le odopa diminishes as he he apeu ic window na ows due o he sho hal -li e o le odopa and p og essi e dene a ion o he s ia um and subsequen pos - synap ic plas ici y [2]. In addi ion, e a ic gas ic emp ying (a common symp om wi h ad ancing PD) leads o i egula gas oin es inal abso p ion o o al le odopa and uns able plasma le odopa concen a- ions, collec i ely esul ing in pulsa ile s imula ion [2, 3]. Thus, mo o and non-mo o symp oms become inc easingly di icul o manage wi h o al le odopa, which can cause pa ien s o expe ience p edic able and unp edic able luc ua ions be ween “On” pe i- ods wi h po en ially disabling dyskinesias and “O ” pe iods when he pa ien expe iences a e u n o hei pa kinsonian symp oms and may e en be “ ozen” and akine ic [2, 4, 5]. These symp oms p og es- si ely wo sen o e ime and g ea ly impac pa ien s’ unc ional capaci y and heal h- ela ed quali y o li e (HRQoL) [6, 7]. Le odopa ca bidopa in es inal gel (LCIG; also known as ca bidopa-le odopa en e al suspension [CLES]) is a s able gel suspension o le odopa- ca bidopa (20 mg/mL and 5 mg/mL, espec i ely) o con inuous day ime in usion in pa ien s wi h ad anced PD (aPD) [8, 9]. Con inuous in usion enables le odopa concen a ions o be kep a a con- s an le el wi hin he indi idual’s op imal he apeu ic window, making LCIG a meaning ul op ion o man- aging aPD [3, 10]. Resul s om con olled clinical ials ha e demons a ed bene icial e ec s o LCIG he apy on mo o symp oms, including educ ions in “O ” ime, inc eases in “On” ime wi hou ouble- some dyskinesia, and imp o emen s in HRQoL and ac i i ies o daily li ing [11–14]. No ably, esul s om a ecen andomized clinical ial demons a ed an imp o ed educ ion in dyskinesia as measu ed by he Uni ied Dyskinesia Ra ing Scale (UDysRS) ol- lowing ea men wi h LCIG s. op imized medical ea men [15]. LCIG has also demons a ed bene- icial e ec s on mo o and non-mo o symp oms in obse a ional s udies [16–21], and sys ema ic li e a- u e e iews and me a-analyses [22, 23]. DUOdopa/Duopa in Pa ien s wi h Ad anced Pa kinson’s Disease, a GLobal OBse a ional S udy E alua ing Long-Te m E ec i eness (DUOGLOBE), was he i s in e na ional, ully p ospec i e, long- e m, non-in e en ional, pos - ma ke ing, obse a ional s udy o pa ien s wi h aPD ea ed wi h LCIG in a ou ine clinical se - ing. One-yea in e im esul s indica ed signi ican imp o emen s in mo o symp oms (including “O ” ime and dyskinesia), non-mo o symp oms (includ- ing sleep), HRQoL, and ca egi e bu den, wi h sa e y e en s consis en wi h hose no ed in p e ious con olled clinical ials and obse a ional s udies [24]. This epo p esen s he inal 36-mon h esul s om he DUOGLOBE s udy. METHODS S udy design and ea men DUOGLOBE was a global mul icen e , single- a m, non-in e en ional, pos -ma ke ing, obse a- ional s udy (NCT02611713) conduc ed in 55 si es ac oss 10 coun ies (Aus alia, Belgium, Hunga y, Is ael, I aly, Romania, Slo enia, Spain, Uni ed King- dom, and he Uni ed S a es) [24]. De ailed me hods o his s udy ha e been pub- lished [24]. In b ie , pa ien s en olled in his 36-mon h eal-wo ld s udy had aPD o whom hei physi- K.R. Chaudhu i e al. / Final 3-yea Resul s om he DUOGLOBE S udy 771 cians decided o s a LCIG ea men acco ding o he local p oduc label and speci ic eimbu semen c i e ia. LCIG dosage was indi idually op imized o clinical esponse and concomi an PD med- ica ions we e pe mi ed a he disc e ion o he ea ing physician. Na ional and/o local indepen- den e hics commi ees, ins i u ional e iew boa ds, and/o heal h au ho i ies in all coun ies app o ed he p o ocol, pa ien in o ma ion, and in o med consen equi emen s acco ding o he applicable na ional egula o y equi emen s. Pa ien s In addi ion o pa ien inclusion being based on local LCIG label and eimbu semen c i e ia, key eligibili y c i e ia included pa ien s ha ing no p io exposu e o LCIG; a Mini-Men al S a e Examina- ion sco e ≥24; no p io su ge y o PD including, bu no limi ed o, deep b ain s imula ion o cell ansplan a ion ( o non-US cen e s); and no cu - en subcu aneous apomo phine in usion (wi h ≥4 weeks equi ed be ween d ug discon inua ion and s udy inclusion). All pa ien s and ca egi e s p o ided in o med consen . Assessmen s Assessmen occu ed be o e s a ing LCIG (base- line) he apy; a Day 1 (s a o LCIG ea men ia pe cu aneous endoscopic gas os omy wi h jejunal ex ension o hose pa ien s who pa icipa ed in he p eceding nasojejunal es phase only); and a ou- inely scheduled isi s, which we e closes o Mon hs 3, 6, 12, 18, 24, 30, and 36 (±14 days each), o a he ime o p ema u e discon inua ion. The p ima y endpoin was he change in he num- be o hou s o “O ” ime as epo ed by he pa ien o he day be o e he clinical isi (baseline) com- pa ed wi h he same measu e a Mon h 36. Seconda y endpoin s included mean change om baseline o he end o he s udy in he Uni ied Pa kinson’s Dis- ease Ra ing Scale (UPDRS) Pa II (ac i i ies o daily li ing); Pa III (mo o examina ion pe o med in he “On” s a e); and he ollowing i ems in Pa IV: i em 33 (dyskinesia- ela ed disabili y), i em 34 (dyskinesia- ela ed pain), and i em 35 (ea ly mo n- ing dys onia). Seconda y endpoin s also included he UDysRS o al sco e (signs/symp oms o dyski- nesia) and subdomain sco es, Non-mo o Symp om Scale (NMSS) o al and subdomain sco es, Pa kin- son’s Disease Sleep Scale-2 (PDSS-2) o al sco e (sleep quali y), Epwo h Sleepiness Scale (ESS) o al sco e (day ime somnolence), 8-i em PD Ques- ionnai e (PDQ-8) summa y index (HRQoL), and ca egi e bu den (Modi ied Ca egi e S ain Index). Only se ious ad e se e en s (SAEs) and ad e se e en s (AEs) leading o p ema u e discon inua ion we e epo ed as pa o his obse a ional s udy om ini ia ion o LCIG ea men o 30 days a e he las s udy isi . S a is ical analysis Planned en ollmen was app oxima ely 200 pa ien s. I was assumed ha 60% o pa ien s would comple e he 36-mon h ollow-up pe iod and ha he mean (SD) dec ease om baseline o Mon h 36 in he numbe o hou s in “O ” ime would be 4 hou s. The e o e, he dis ance om he lowe limi o he 95% con idence in e al (CI) o he mean dec ease would be 0.72 hou s (i.e., he lowe limi o he 95% CI o he mean dec ease om baseline o Mon h 36 would be 3.28 hou s). Signi icance o all e i- cacy measu es was de e mined using a one-sample es compa ed wi h baseline e icacy assessmen s. Sa e y assessmen s we e pe o med wi h he sa e y popula ion, which included all pa ien s who had nasojejunal and/o pe cu aneous endoscopic gas os- omy wi h jejunal ex ension placemen , i espec i e o whe he pa ien s wi hd ew p ema u ely o no . E icacy assessmen s we e pe o med wi h he ull analysis popula ion, which included all pa ien s in he sa e y popula ion who had a leas one pos -baseline e ec i eness assessmen a e unde going pe cu a- neous endoscopic gas os omy wi h jejunal ex ension placemen . Da a sha ing Clinical ial da a can be eques ed by any quali ied esea che s who engage in igo ous, inde- penden scien i ic esea ch, and will be p o ided ollowing e iew and app o al o a esea ch p o- posal and s a is ical analysis plan and execu ion o a da a sha ing ag eemen . Da a eques s can be submi ed a any ime and he da a will be accessible o 12 mon hs, wi h possible ex en- sions conside ed. Fo mo e in o ma ion on he p ocess, o o submi a eques , isi he ollowing link: h ps://www.abb ieclinical ials.com/hcp/da a- sha ing/. 772 K.R. Chaudhu i e al. / Final 3-yea Resul s om he DUOGLOBE S udy RESULTS Pa ien s Pa ien demog aphics and baseline cha ac e is ics o he 195 pa ien s included in he analysis ha e been epo ed p e iously [24]. Mos pa ien s we e male (61.5%), mean (SD) age was 70.2 (8.2) yea s, and mean du a ion o PD was 11.2 (4.8) yea s (Table 1). Two pa ien s p e iously unde wen deep b ain s im- ula ion. Mean (SD) LCIG ea men du a ion was 923.5 (367.2) days, wi h a median daily du a ion o LCIG in usion o 16 hou s om Day 1 h ough Mon h 36. A each imepoin , be ween nine and 12 pa ien s we e ecei ing 24-hou LCIG he apy. O no e, mean (SD) daily dose o LCIG emained ai ly s able om Day 1 (1241.2 [501.6] mg/day) h ough Mon h 36 (1365.4 [499.1] mg/day) (Fig. 1A). Wi hin he i s 6 mon hs o LCIG use, he e we e dec eases in concomi an use o o al le odopa de i a i es; monoamine oxidase B inhibi o s; and, mos p ominen ly, ca echol-O- me hyl ans e ase inhibi o s ha emained s eady h oughou he nex 2.5 yea s (Fig. 1B). A Mon h 3, 18.1% o pa ien s we e ecei ing LCIG mono he apy and 13.3% we e ecei ing LCIG in combina ion wi h o al le odopa only (“le odopa mono he apy”); hese pe cen ages emained ela i ely s able h oughou he s udy (Mon h 36 : 15.5% and 17.9%, espec- i ely) (Fig. 1C). To al le odopa equi alen dose also emained s able h oughou he s udy, ega dless o whe he pa ien s we e ecei ing LCIG as a mono he - apy o in combina ion wi h o he PD medica ions (Fig. 1D). O 195 en olled pa ien s, 106 (54.4%) discon in- ued he s udy p ema u ely wi h AEs being he p ima y eason (pa ien s could ha e mul iple easons o dis- con inua ion) in 48 o hese pa ien s (Supplemen a y Figu es 1 and 2). Impo an ly, o he 106 pa ien s who discon inued he s udy, 32 (30.2%) con inued ea - men wi h LCIG ou side he s udy (Supplemen a y Figu e 2). Mo o complica ions Mean (SD) daily hou s spen in he “O ” s a e signi ican ly dec eased om baseline o Day 1 and emained dec eased h ough Mon h 36 (Mon h 36 [p ima y endpoin ]: –3.3 [3.7]; p< 0.001) (Fig. 2A). Changes om baseline a Mon h 36 we e s a is ically signi ican in all age g oups (Fig. 2B). Table 1 Baseline demog aphics and clinical cha ac e is ics Cha ac e is ic To al N= 195 Sex, n(%) Male 120 (61.5) Female 75 (38.5) Age (y); mean ±SD 70.2 ±8.2 <65 y, n(%) 44 (22.6) 65–75 y, n(%) 95 (48.7) >75 y, n(%) 56 (28.7) BMI; mean ±SD BMI, kg/m225.9 ±4.1a PD du a ion, y: mean ±SD 11.2 ±4.8 <10 y, n(%) 94 (48.5) ≥10 y, n(%) 100 (51.5) Time o LCIG ini ia ion, y; mean ±SD om: PD symp oms 12.2 ±5.0 S a o mo o luc ua ions 5.6 ±4.7 MMSE o al sco eb; mean ±SD 27.7 ±2.2 Hoehn and Yah s age; n(%) Du ing “On” 1 4 (2.1) 1.5 0 2 33 (17.6) 2.5 21 (11.2) 3 80 (42.6) 4 43 (22.9) 5 7 (3.7) Missing 7 Du ing “O ” 10 1.5 2 (1.1) 2 6 (3.2) 2.5 15 (8.1) 3 59 (31.7) 4 82 (44.1) 5 22 (11.8) Missing 9 Daily “O ” ime (h); mean ±SD 6.0 ±3.4 UPDRS Pa II (ADL); mean ±SD 14.8 ±7.8 UPDRS Pa III (mo o unc ion); mean ±SD 27.6 ±13.2 UDysRS o al sco e; mean ±SD 33.7 ±21.1 NMSS o al sco e; mean ±SD 88.2 ±51.1 PDSS-2 o al sco e (sleep quali y); mean ±SD 26.6 ±11.7 ESS o al sco e (day ime sleepiness); mean ±SD 9.8 ±5.3 PDQ-8 summa y index (HRQoL); mean ±SD 45.1 ±18.1 MCSI o al sco e (ca egi e bu den); mean ±SD 10.9 ±6.4 an=182. bPa ien MMSE o al sco e a baseline mus be ≥24 o inclusion. ADL, ac i i ies o daily li ing; BMI, body mass index; ESS, Epwo h Sleepiness Scale; HRQoL, heal h- ela ed quali y o li e; LCIG, le odopa-ca bidopa in es inal gel; MCSI, Modi ied Ca egi e S ain Index; MMSE, Mini-Men al S a e Examina ion; NMSS, Non-Mo o Symp oms Scale; PD, Pa kin- son’s disease; PDSS-2, Pa kinson’s Disease Sleep Scale-2; PDQ-8, 8-i em Pa kinson’s Disease Ques ionnai e; SD, s anda d de ia- ion; UDysRS, Uni ied Dyskinesia Ra ing Scale, UPDRS, Uni ied Pa kinson’s Disease Ra ing Scale. Fo UDysRS o al sco es, signi ican educ ions om baseline we e obse ed a all ime poin s h ough Mon h 36 (Mon h 36 mean [SD]: –5.9 [23.7]; p= 0.044) (Fig. 2C). Explo a o y analysis K.R. Chaudhu i e al. / Final 3-yea Resul s om he DUOGLOBE S udy 773 Fig. 1. S abili y o he apy o e ime. (A) LCIG dose, (B) an i-PD comedica ions, (C) mono he apy s. combina ion he apy, and (D) o al le odopa equi alen dose. aOnly pa ien s who pa icipa ed in he p eceding nasojejunal es phase we e assessed a D1. BL, baseline; COMT, ca echol-O-me hyl ans e ase; D, day; LCIG, le odopa-ca bidopa in es inal gel; LED, le odopa equi alen dose; M, mon h; MAO-B, monoamine oxidase-B; PD, Pa kinson’s disease; SD, s anda d de ia ion. was conduc ed o e alua e he e ec o LCIG on UDysRS a Mon h 36 based on age; he e was no signi ican di e ence a any o he ages e alua ed (Fig. 2D). The composi e his o ical sco e was sig- ni ican ly educed om baseline h ough Mon h 36 (Mon h 36 p= 0.012). The subdomain o “On” dyski- nesia (Pa I) was signi ican ly educed om baseline un il Mon h 24 (Mon h 24 p= 0.001), wi h “O ” dys- onia (Pa II) signi ican ly educed h ough Mon h 36 (Mon h 36 p< 0.001); bo h hese imp o emen s exceeded he le el o clinical ele ance [25]. Signi - ican educ ions om baseline du ing he s udy we e seen o o he componen s o he UDysRS, includ- ing he objec i e sco e h ough Mon h 18 (Mon h 18 p= 0.045), he impai men subdomain (Pa III) h ough Mon h 6 (Mon h 6 p< 0.001), and he disabil- i y subdomain (Pa IV) h ough Mon h 24 (Mon h 24 p= 0.033) (Supplemen a y Figu e 3). Addi ional suppo o he educ ion o he p esence and symp- oms o dyskinesia and dys onia h ough Mon h 36 was seen in he UPDRS scale, including dyskinesia- ela ed disabili y (mean [SD], –0.4 [1.3]; p= 0.016), dyskinesia- ela ed pain (–0.4 [1.0]; p< 0.001), and ea ly mo ning dys onia (–0.2 [0.6]; p< 0.001) (Sup- plemen a y Figu e 4). UPDRS Pa II and III sco es, a e ini ial imp o e- men s (signi ican o UPDRS III un il Mon h 3), demons a ed signi ican wo sening om baseline o Mon h 36 in he o e all g oup (Supplemen a y Fig- u e 4). Pa ien s aged ≥65 yea s showed signi ican wo sening in UPDRS Pa II and III sco es a Mon h 36, while pa ien s aged younge han 65 yea s had nominal, bu no s a is ically signi ican , imp o e- men s in UPDRS Pa III sco es h oughou he s udy (Supplemen a y Figu e 4). A summa y o baseline and change- om-baseline alues o pa ien s wi h Mon h 36 da a can be ound in Table 2. 774 K.R. Chaudhu i e al. / Final 3-yea Resul s om he DUOGLOBE S udy Fig. 2. Change om baseline o Mon h 36 in (A) pa ien epo ed “O ” ime, (B) “O ” ime by age subg oups, (C) dyskinesia as measu ed by UDysRS o al sco e, and (D) UDysRS o al sco e by age subg oups. Signi icance le el o change om baseline was de e mined using he one-sample es . *p<0.05; **p<0.01; ***p<0.001. aOnly pa ien s who pa icipa ed in he p eceding nasojejunal es phase we e assessed a D1. bAs epo ed in Hause e al [26]. BL, baseline; D, day; LCIG, le odopa-ca bidopa in es inal gel; M, mon h; MCID, minimal clinically impo an di e ence; SD, s anda d de ia ion; UDysRS, Uni ied Dyskinesia Ra ing Scale. Table 2 Change om baseline o mon h 36 in mo o and non-mo o endpoin s among pa ien s wi h 36-mon h da a Endpoin s nBaseline Change om baseline Daily “O ” ime (h) 80 5.8 (3.1) –3.3 (3.7)*** UDysRS o al sco e 67 35.2 (21.4) –5.9 (23.7)* UPDRS Pa II (ADL) 85 13.4 (8.5) 4.3 (8.3)***a UPDRS Pa III (mo o unc ion) 83 24.9 (13.6) 5.8 (13.9)***a NMSS o al sco e 79 83.7 (46.5) –14.3 (40.5)** PDSS-2 o al sco e (sleep quali y) 85 27.7 (12.3) –5.8 (12.9)*** ESS o al sco e (day ime sleepiness) 84 9.6 (5.3) –1.8 (6.0)** PDQ-8 summa y index (HRQoL) 84 45.2 (18.6) –2.5 (19.6) MCSI o al sco e (ca egi e bu den) 52 12.3 (6.8) –1.3 (7.8) Table includes pa ien s wi h Mon h 36 da a only. All da a a e p esen ed as mean ±SD. aRe lec s wo sening om baseline. *p<0.05; **p<0.01; ***p<0.001. ADL, ac i i ies o daily li ing; ESS, Epwo h Sleepiness Scale; HRQoL, heal h- ela ed quali y o li e; MCSI, Modi ied Ca egi e S ain Index; NMSS, Non-Mo o Symp oms Scale; PDSS-2, Pa kinson’s Disease Sleep Scale-2; PDQ-8, 8-i em Pa kinson’s Disease Ques ionnai e; SD, s anda d de ia ion; UDysRS, Uni ied Dyskinesia Ra ing Scale, UPDRS, Uni ied Pa kinson’s Disease Ra ing Scale. K.R. Chaudhu i e al. / Final 3-yea Resul s om he DUOGLOBE S udy 775 Fig. 3. Change om baseline in (A) NMSS o al sco e and (B) NMSS o al sco e by age subg oups. Signi icance le el o change om baseline was de e mined using he one-sample es . *p<0.05; **p<0.01; ***p<0.001. aOnly pa ien s who pa icipa ed in he p eceding nasojejunal es phase we e assessed a D1. bAs epo ed in Ma inez-Ma in e al [31]. BL, baseline; D, day; M, mon h; MCID, minimal clinically impo an di e ence; NMSS, Non-Mo o Symp om Scale; SD, s anda d de ia ion. Non-mo o symp oms NMSS o al sco es demons a ed signi ican and sus ained imp o emen om baseline a Mon h 36 (mean [SD], –14.3 [40.5]; p= 0.002) and all ime poin s (Fig. 3A,B). In addi ion, h ee o nine NMSS subdomains we e signi ican ly imp o ed h ough Mon h 36: sleep/ a igue (mean [SD], –3.7 [12.3]; p= 0.007), gas oin es inal ac (–2.5 [6.1]; p< 0.001), and miscellaneous (–3.9 [10.3]; p< 0.001) (Supplemen a y Figu e 5). O no e, he las s a is ically signi ican imp o emen was mea- su ed a Mon h 12 o one domain (ca dio ascula , including alls), and Mon h 24 o h ee domains (mood/cogni ion, a en ion/memo y, and sexual unc- ion) (Supplemen a y Figu e 5). In addi ion o imp o emen in he NMSS sleep/ a igue subdomain, s able and signi ican imp o emen in sleep quali y (Fig. 4A,B) and day- ime sleepiness (Fig. 4C) was seen wi h LCIG. Signi ican imp o emen om baseline a Mon h 36 was obse ed o PDSS-2 o al sco es (mean [SD], –5.8 [12.9]; p< 0.001) and ESS o al sco es (mean [SD], –1.8 [6.0]; p= 0.008). Signi ican imp o emen was seen om Day 1 (PDSS-2) and Mon h 3 (ESS) onwa d. Pa ien HRQoL and ca egi e bu den Pa ien HRQoL and ca egi e bu den imp o ed om baseline, wi h signi ican and consis en imp o emen in PDQ-8 h ough Mon h 24 (mean [SD]: –6.0 [22.5]; p= 0.006) (Fig. 5A,B) and Modi- ied Ca egi e S ain Index h ough Mon h 30 (–2.3 [7.6]; p= 0.026) (Fig. 5C,D). Bo h scales con inued o show nume ical, bu no s a is ically signi ican , imp o emen s a Mon h 36. Sa e y A o al o 107 (54.9%) pa ien s expe ienced SAEs (Table 3), wi h 31 SAEs conside ed as ha ing a easonable possibili y o being ela ed o LCIG ea - men . The mos common SAEs we e all (n= 8), (wo sening o ) PD (n= 8), and u ina y ac in ec- ion (n= 7) (Table 3). One pa ien expe ienced an SAE o polyneu opa hy, and one expe ienced an SAE o ch onic in lamma o y demyelina ing poly adicu- loneu opa hy; bo h SAEs we e adjudica ed by he in es iga o as ha ing no easonable possibili y o ela ionship o s udy d ug. A o al o 53 (27.2%) pa ien s discon inued he s udy owing o an SAE. Howe e , his includes 34/195 (17.4%) a al AEs, wi h all epo ed as ha ing no easonable possi- bili y o ela ionship o s udy ea men wi h he excep ion o one pa ien wi h an in es inal obs uc- ion and a medical his o y o di e iculi is ha was adjudica ed as possibly ela ed o ea men (Supplemen a y Table 1). Mos a al AEs we e ela ed o complica ions o aPD, ca dio ascula dis- ease, and complica ions om non- ea men - ela ed in ec ions. A o al o six pa ien s (3.1%) discon inued he s udy due o COVID- ela ed in ec ions, es ic ions, o ea s o in ec ion. These discon inua ions included wo pa ien s (1.0%) who had an SAE o COVID- 776 K.R. Chaudhu i e al. / Final 3-yea Resul s om he DUOGLOBE S udy Fig. 4. Change om baseline in (A) PDSS-2 o al sco e, (B) PDSS-2 o al sco e by age subg oups, and (C) ESS o al sco e. Signi icance le el o change om baseline was de e mined using he one-sample es . *p<0.05; **p<0.01; ***p<0.001. aOnly pa ien s who pa icipa ed in he p eceding nasojejunal es phase we e assessed a D1. bAs epo ed in Ho a h e al [32]. BL, baseline; D, day; ESS, Epwo h Sleepiness Scale; M, mon h; MCID, minimal clinically impo an di e ence; PDSS-2, Pa kinson’s Disease Sleep Scale-2; SD, s anda d de ia ion. 19 and/o COVID- ela ed pneumonia, bo h o which esul ed in dea h. In gene al, body weigh and body mass index (BMI) emained ela i ely s able h oughou he s udy. A baseline, mean body weigh was 73.2 kg and mean BMI was 25.7 kg/m2; a Mon h 36, mean weigh and BMI we e 71.2 kg and 24.9 kg/m2, espec- i ely, wi h bo h dec easing h oughou he s udy (Supplemen a y Figu e 6A). Mean (SD) dec ease om baseline o Mon h 36 was –3.1 (8.0) kg o weigh and –1.2 (2.8) kg/m2 o BMI. A las isi , 8.2% o pa ien s demons a ed an inc ease in base- line weigh ≥7%, while 22.1% demons a ed ≥7% dec ease. Mos pa ien s emained wi hin he same BMI ca ego y a he end o he s udy ha hey we e in a baseline (Supplemen a y Figu e 6B). Looking a sa e y indings ac oss age, pa ien s in he 65- o 75-yea age g oup expe ienced highe a es o SAEs han did hose in he younge han 65-yea age g oup and olde han 75-yea age g oups (whose a es we e simila o each o he ), wi h a es o se e e AEs lowes in he younge han 65-yea age g oup and simila in he 65 o 75 yea and olde han 75- yea age g oups (Table 3). Ra es o se e e AEs we e lowes in pa ien s aged younge han 65 yea s and we e simila in pa ien s aged 65 o 75 yea s and olde han 75 yea s. DISCUSSION We epo he inal esul s o DUOGLOBE, a 3- yea , ully p ospec i e s udy designed o e alua e LCIG use in ou ine clinical p ac ice in a la ge eal- wo ld popula ion wi h aPD. T ea men wi h LCIG demons a ed “O ” ime imp o emen s ha we e main ained o e 3 yea s and emained abo e he min- K.R. Chaudhu i e al. / Final 3-yea Resul s om he DUOGLOBE S udy 777 Fig. 5. Change om baseline in (A) PDQ-8 summa y index, (B) PDQ-8 summa y index by age subg oups, (C) MCSI o al sco e, and (D) MCSI o al sco e by age subg oups. Signi icance le el o change om baseline was de e mined using he one-sample es . *p<0.05; **p<0.01; ***p<0.001. aOnly pa ien s who pa icipa ed in he p eceding nasojejunal es phase we e assessed a D1. bAs epo ed in Ho a h e al [36]. BL, baseline; D, day; MCID, minimal clinically impo an di e ence; MCSI, Modi ied Ca egi e S ain Index; PDQ-8, 8-i em Pa kinson’s Disease Ques ionnai e; SD, s anda d de ia ion. imal clinically impo an di e ence (MCID) o 1 hou in his popula ion, despi e he p og essi e na u e o PD [26]. The bene icial e ec s o LCIG use we e also e lec ed in imp o emen s in UDysRS sco es and subsco es. Imp o emen s in “On” dyskinesia (Pa I) we e abo e he MCID o –2.1 h ough Mon h 24 and imp o emen s in “O ” dys onia (Pa II) we e abo e he MCID o –1.8 h ough Mon h 36 [25]. Reduc ions in UDysRS sco es a e pa icula ly no e- wo hy, as his scale (which includes bo h pa ien subjec i e and clinician objec i e dyskinesia a ings) has demons a ed a high sensi i i y o de ec ing ea men - ela ed changes [27]. The cu en indings o signi ican dec eases in “O ” ime coupled wi h signi ican imp o emen s in “On” dyskinesia wi h LCIG ea men a e consis en wi h hose epo ed in p e ious s udies [15, 28, 29]. Pa allel imp o emen s in “O ” ime and “On” ime wi h dyskinesia a e pos- sible wi h LCIG, likely due o con inuous deli e y o s able plasma le odopa le els ha can emain in he he apeu ic window [10, 15, 28]. Non-mo o symp oms o PD a e o en un ecog- nized and un ea ed [30]. Signi ican imp o emen s we e obse ed in he NMSS o al sco es, which emained abo e he 13.9-poin MCID h oughou he 3 yea s [31]. Imp o emen s in sleep and day- ime sleepiness (as measu ed by he PDSS-2 and ESS, espec i ely) we e also obse ed h oughou he s udy, wi h PDSS-2 changes exceeding he –3.4 poin MCID h eshold a all imepoin s [32]. These indings a e pa icula ly ele an , as non-mo o symp oms and sleep dis u bances ha e been di ec ly linked o de e- io a ion o HRQoL [33–35]. This s udy suppo s his ela ionship, wi h bo h non-mo o symp oms and HRQoL imp o ing a e LCIG ea men . Signi i-