Effect Size Statistics to Inform an Exploratory Analysis of…

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Research Article Volume 10 Issue 2 - June 2019 DOI: 10.19080/JOJCS.2019.10.555783

JOJ Case Stud Copyright © All rights are reserved by Seán Lacey

Effect Size Statistics to Inform an Exploratory Analysis of a Double-Blinded, Randomised, Placebo Controlled Pilot Clinical Study to Evaluate the Efficacy of Naticol ® , Specific Fish Collagen Peptides to Alleviate Symptoms of Osteoarthritis in the Knee Seán Lacey 1 *, Christelle Bonnet 2 , Kelly Seamans 3 and Andrea Doolan 3 1 Department of Mathematics, Cork Institute of Technology, Ireland 2 Weishardt International, France 3 Atlantia Food Clinical Trials, Cork, Ireland Submission: June 06, 2019; Published: June 17, 2019 *Corresponding author: Seán Lacey, Department of Mathematics, Cork Institute of Technology, Bishops town, Cork, T12 P928, Ireland Abstract Background: Potential effects of different doses of specific fish collagen peptides (Naticol ® ) on the signs of skin ageing were firstly assessed in double-blind, randomised and placebo controlled clinical studies. The studies showed benefits of fish collagen peptides (Naticol ® ) oonf sspkeinciffiircmfinshescso, lslkaignehnypderpattiidoensa(nNdawtircionlkle appearance. In addition to these benefits, some animal experiments have suggested that ingestion ® ) might also have beneficial effects on joint health such as osteoarthritis. Aim: This pilot clinical trial study was designed to assess the safety and tolerability of daily oral doses of specific fish collagen peptides (Naticol ® ) in healthy subjects with knee osteoarthritis. Methods: In a double-blinded, placebo controlled pilot clinical study, 30 adults (20 active; 10 placebo) consumed a 10g sachet of the investigational product (Naticol ® ; specific fish collagen peptides) and a comparator product (maltodextrin) daily in 20cl of cold liquid (Mf rcuMi ta sj ut ei cr eU, nmi vi el kr soi tri ecso (l dW Ot eMa )A C1 )5 s mc oi rneust; eQs ubael if toyr eo f bLrief ea k( Qf aOs tL, ) f uo sr i n8 g wt he ee kPsa. r Pt ioc ti pe na nt i ta Gl lpoabi anl rAesds ue sc st imo ne nwt (aSs Ft- e3s6t ve 2d quus ei ns tgi ot nh ne aWi r ee )s taenr dn POhnytsai rc iaol performance using the Short Physical Performance Battery (SPPB) at both baseline and after 8 weeks. Results: From effect size statistics (Cohen’s d), subjects in the active group experienced more of an improvement across the majority of mg r eoauspu er ex mp eerni et sn ct he da na ssumbaj el lc itms pi nr ot hv ee mp el ancte(bdo =g 0r o. 6u8p) oavgeari nt shte t h8 ewaecet ikvse ogfr tohuep s’ st ul adryg. eF irmo mp r tohvee mWeOnMt (AdC =P1h.y0s8i c) .a Wl Fhui nl ec tf oi ornt hs eu bW- sOc Mo rAe Ct hC eo mp lpa oc es ibt oe sncoo cr eh at hn eg ea ci nt i vsec ogrreo uf opr etxhpee pr ileanc ec ebdo ag rl aorugpe (i dm p= r0o.v0e0m) , ewn th (i lde =t h1e. 0a7c)t. i vI ne tgerromu sp onf ot thi ce eSdF -a3n6 ivm2 pSroocvi ea ml Feunnt c bt iyo ns mi n ag l al n( dd =P a- i0n. 3s 4u )b asnc od rme se, dt hi uemr e (wd a=s -d0i s. 5- i0m) pa rmo ov ue dn tos v, er er st ph ee c8t i vweel ye .kWs (hdi l =e f0o. 0r 7t haen SdF0- 3. 165v, 2r eEsmp eoct ti iovneal yl )W, we lhl -i Bl ee ti nh ge as un bd j eGcetns ei rna tl hHeeaacl tt hi vye Igs rs ouue ps si mu bp rs oc ov er eds i, nt hbeo tphl accaesbeos - (bda s=e-d0 .s1u8b)j eacntds -r0e .s0p9e,crteivsepleyc)t. iTvehleyr)e. Iwnatse rnmo sdoi fff et hr eenScPePi Bn ,aadcvt eivres eg reovuepn tesxbpeetrwi eenecne dg raonu pi ms p( pr o>ve0m. 0e5n) .t i n t h e C h a i r t e s t a n d To t a l s c o r e . ( d = 0 . 4 7 a n d d = - 0 . 3 3 , Conclusion: The results demonstrated that daily oral doses of specific fish collagen peptides (Naticol ® ) in healthy subjects with knee opsrotedouacrtthforritsisubhjaescttshwe ipthotaenbtoidayl twoeriegdhut cgerepaateinr,thimanpr7o0vkegqsuhaoluitlyd obfe lpifeerfaonrdmleodw. er body function. Further studies with a higher dosage of Keywords: Clinical study; Effect size; Fish collagen peptides; Naticol ® ; Osteoarthritis Abbreviations: AE: Adverse Event; ANOVA: Analysis of Variance; BMI: Body Mass Index; CH: Collagen Hydrolysates; GP: General Practitioner; OP hAy: sOi csat el oPaerrtfhorrimt i as ;nQc eO BL :aQt tuear yl i;t yWoOf ML iAf eC; :SWA Ee s: tSeerrni oOunstAa rdivoear ns ed EMvceMn ta; sStDe r: SUtna ni vdearrsdi t iDees vOi asttieoona;rSt hF-r3i t6i sv 2I n: dS ehxo r t Fo r m – 3 6 Ve r s i o n 2 ; S P P B : S h o r t

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JOJ Case Stud 10(2) JOJCS.MS.ID.555783 (2019)

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diagnosis. Forty eligible subjects were scheduled for an initial visit. The pilot study involved 2 visits over an 8-week period. At ot 7t h5e yi ne ai tri sa l ( vi ni sciltu, ssiuv be )j e; cHt sa dw edroec ui nmc leundt ee dd idf itahgenyo ws i se roe f: Ap rg iemd a3r 0y op sr ti oe ro at rot ht hr ei t ivsi s( iOt ;AH) aodf trhaed itoagrrgaept hki nc eeev imd eandceeaot f l eOaAs ti n1 2t hme ot inbtihos- foesmt eoorpahl yctoem apna dr t ma e nmt eoafs ut hr ea bt laer g jeoti nk tn esep wa ci et h, aa ts l edai sa tg n1 odseefdi n ibt ye sf et amnadl ae rsdu Xb -j er ac yt ss ; wHear de ea xKc leul dl gerde ei -f Ltahwe yr ewn ce er eg pr ar de ge n2a-n4t. , Pl aoct teant ti ni agl oa lrs ow iesxhcel du dt eodb ei fc ot hmeey :p rHeagdn avni st cdous ruipnpg l et hmee snttuadt iyo. nS ui bn j eacnt ys wj oei nr et it no c lt uh de i ni ng i ttihael tvai sr igte; t Hkande ec oonr cootmh ei tra nj ot i ni nt fwl aimt hmi na t6o rmy odnitshesa sper i oo rr os ut hpeprl ecmo ne nd ti tsi owni t ht hi na tt haef f pe cr et sv itohues j4o-iwn tese; kHs ;aHd atda ka edni s ae na ys e c/ai ll lcni ue sms that would preclude supplement ingestion and/or assessment oc of ms apf eotnyeannt sd ot fh tehset ut edsyt op br oj edcut ci vt e; Hs aa nd dl o/ sotr >h 5a d%aokf nt hoewi rn taoltlaelr bg yo dt oy weight in the last 3 months. The site, investigator, protocol, informed consent form and other pertinent documents for this study were approved by the CL ao nr kc aRset es re aHr cahl l ,E6t hLi ci tst lCeo mH amniot vt eeer oSft rt he ee tC, oCrokr kT.e Aa cl lh isnugb jHe oc tssp igt aa vl se, their written consent according to the Helsinki Declaration. Design and conduct of study Table 1: Naticol® values expressed in percentage of each amino acid reported to all amino acids and corresponding nutritional information. Glycine 20.9 Proline 12.6 Glutamic Acid 11.6 Hydroxyproline 10.5 Arginine 8.9 Alanine 8.3 Aspartic Acid 5.1 Lysine 3.5 Serine 3.5 Threonine 2.7 Leucine 2.6 Phenylalanine 2.3 Valine 2 Isoleucine 1.5 Hydroxylysine 1.5 Histidine 1.3 Methionine 0.8 Tyrosine 0.4 Cysteine + Cystine 0.03 Total 100

Introduction Osteoarthritis (OA) results from an imbalance of anabolism ab ni odl ocgai ct aabl oal insdm mi ne ct hh ae n jioc ianl t , e nwvhi ircohn mmeanyt . b eE xicnef sl us ievnec efdo rbc ey s t hi ne specific regions of the joint surfaces and alterations in tissue responses, leading to the development of osteoarthritis are aolvseor wexeaicgehrtboart eadj owi ni tthdai sbonrodremr a[ 1l -l o3a] .d i n g o f t h e k n e e j o i n t d u e t o Today, the total cost of osteoarthritis has been estimated to be between 1% and 2.5% of the total gross domestic product in western countries [4]. In Europe, over 100 million people have arthritis, and in the United States, the direct costs of arthritis wi n ec rr ee a$s5e1s ,. 1o sbtiel loi oa rnt hi nr i 2t i0s 0r 4e p[r5e]s. eAnst st haemnauj mo rbeecro on fo eml di ce br luyr pd ee on pol ne tl ihf ee wh ei tahl ti nh tchaer ep os yp sutleamt i os nasn. dF oi sr ian ss et ar ni ocue s, i tnh trhe ea tUtKo i tnh 2e 0q1u0a, l ti thye roef wf o er rpea4t i. e7 nmt si lol ivoenr d4 o5cyt eo ar rasp. pI tohi na st mb ee ennt spdr ue de itcot ekdn teheaot st thei os anrut hmrbi tei sr will increase to 6.7 million by 2051 [6]. This pilot study was designed to assess the tolerability and efficacy of oral doses of fish collagen peptides (Naticol ® , 10g/day) in volunteers with knee osteoarthritis. The collagen hydrolysates or peptides (Naticol ® ) which were the object of tchoil sl aegfef ni c a(cgye lsat tui dn y) ws ueirtea bpl reo df ourc t su sdee riinv e hd ufmr oamn ffios ho dh. y Pd rr eovl yi os euds clinical studies aimed at assessing the effects of oral intakes of fish collagen peptides, Naticol ® , on skin firmness and hydration, and the decrease of wrinkles were conducted using different dosages ([ 71 ]0 ag n/ dd aSyi;b5i lgl a/ de at ya;l .2[,85]g c/odna fyi)r m[ 7e, 8d ]p. Tr ehcel i rnei cs au ll tasnfdr ocml i nDi cuatlehi luemt aanl . tcroi lal al sg ei nn vpeespt itgi da et isntgh at th he a ve ef f ei nc dt si c aotf e do rtahle spuops ps ilbe iml i teyn tt ha taito dn i ewt ai rt hy ce ot ma l .p[o9u] nrde sp ocratne dmt oh da tu il na tpe i gs ks ian 9f-uwnecet iko on r. aFloi rn geexsatmi opnl eo,f Mc oal tl as ug edna he ny dh raonlcyesda tfeosr m( Ca tHi o) n i onfdcuoclel adg ei nn cf ri be raisl es di n ftihber odbelrams ti s di ne na spi tryo t ea innd- shpy edcriof li yc s ma t ae ns ni ne rj. oLi ni ttesr aa tsutrhee ya las roe i anbdsi coar tbeesd ,bde inset rf iitbsu ot ef dc tool l aj ogiennt t[i1s0s-u1e4s].and have analgesic and anti-inflammatory properties The aim of the study was to determine the effect of 8 weeks’ supplementation of Naticol ® , Fish collagen peptides on change iAns sWe sOsMmAe Cn t s(cSoFr-e3s6; vQ2u qa ul i et ys t oi of nLni faei r, eu)s ianngd tPh he yPs iacrat li cpi pe ra fnotr mG laonbcael using the Short Physical Performance Battery (SPPB), along with saudpveprosretienvgetnhtes.safety of the product by recording any reported Participants and Methods Participants Subjects underwent an initial phone screen and were asked questions regarding their age, general health and osteoarthritis

How to cite this article: Seán Lacey, Christelle Bonnet, Kelly Seamans, Andrea Doolan. Effect Size Statistics to Inform an Exploratory Analysis of a Double-Blinded, Randomised, Placebo Controlled Pilot Clinical Study to Evaluate the Efficacy of Naticol ® , Specific Fish Collagen Peptides to Alleviate Symptoms of Osteoarthritis in the Knee . JOJ Case Stud. 2019; 10(2): 555783. DOI: 10.19080/JOJCS.2019.10.555783 0031

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tshtaetudsuroartmionedoicf atthieonsstuwdeyr. eArneycosyrdmepdt.oms and changes in health Statistical analysis Subjects were randomized by a computer-generated ss ct ahtei sdtui cl ea l taon aeliyt sheesr wt heer e a cc at irvrei e do r o uptl a cuesbi nog gSrPoSuSp sVe(r2s:i1o)n. A2 4l l f5o%r Wl e vi ne dl oowf ss .i gAn li lf i ct ea sntcse . wCeorhe e nt w’ s ods i dweads auns edd pteor fdoertme remd i na et tt hh ee setf rf eecntg: t0h ≤( s tda n< d0 a. 2r;dSi sme da l ml eefaf encdt :i f0f e. 2r e≤n cde <) o0f . s5t;aMt i setdi ci ua ml r eesfuf el tcst : 0N. 5o ≤s udm<m0a. r8i;z Le da r gbey e mf f eecatnds ≥o f0 . 8a b[s1o6l ]u. tCe a tneugmo rbi ec rasl . p Na ruammeertiecrasl wd ea rt ae wa veari el asbul me dmaat rai, zme de abny , ms teaanndsaor df sdt aenv di aatri od ns ,t amt ii sntiimc su(mi . e, .m, nauxmi mb ue mr o)f. The change in subject’s measurements (WOMAC scores; SF- 36v2; SPPB) between treatment groups from baseline to the end o( wf ti trhe at thme ea np tp rwoeprrei aat ne at leyszt eodf nu os irnmg aal i trye, pheoamt eodg emneeai tsyu roef sv aArNi aOnVcAe at rneda t smpehnetr-ircei tl ay t ecda rardi evde r os eu te vi ne int ti as l lwy )a.s Tc ho em po av reer da l la ci nr oc si ds egnrcoeu posf by Fisher’s exact test and the chi squared test. Measurements Analysis of WOMAC scores, SF-36v2 and SPPB were based on [w1o7r- s1e9 ]p, ar iens, psetci ft fi vn ee lsys. , Tahned h fi ug hn ec tri os cnoa rl elsi mo ni t at thi eo nWs O[ M2 0A] C. Ti nhde i cSaFt 6e 36 consists of eight scaled scores, which are the weighted smuomr es od fi stahbei l qi tuy e[s1t i8o]n. sI ni nr et lhaet ii or ns et cot itohne. STPhPeBl ot we set r, ht hi geh secr osrceo trhe es it nh de i cs at ut ed yb eatstseers sl oewd eera cbho dsyu bf uj encct t’ si o- rne p[ 2o 1r t]e. dT haed vcel irns iec aelv teenatm( Af Eo r) aAnc dt i ocna tteagkoerni z; eOdu ti tc oamc ceo;rSdei nr igo ut os IAndt ev ne rssi teyE; vReenl at t(i SoAn Es h) .i p t o s t u d y ; Results Exploratory analysis on the effect of 8 weeks’ supplementation of specific fish collagen peptides (Naticol ® ), on osteoarthritis measurements, for subjects that completed the study With the exception of gender, there was no difference in ss uu bb jj ee cc tt sf raocmr o es sa cthr etar tema temn et ngtr og ur opus pa ht abda st er el iantem, es en et dTiasbc loen 2t i.nOu ne de dt huee ptroo dnuacut s(epal a (caecbtoi v eg r ogur opu) ,p )s e ea nTda bal en 3a. l l He regni cc e ,r eraecstui lotns ot no mstueadsyu–rei.me.e, 9n:t1s9aPrleacreebpoo:rAtecdtivoen. subjects that completed the

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Typical Values per 100g 1593 kJ (381 kCal)

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of the target knee were included. The study occurred between M( l aasyt s9u, b2j0e 1c t7, l (afsi rt svti ssi ut )b. jBe ac ts ,e df i rosnt fvi ni sdi ti )n gasn fdr oDme cKeummbaerr e1t 2a ,l . 2[ 10 51 ]7, 3w0e rs eu br aj encdt so mw el yr ea sr sa ingdnoemd itsoe dt hi en tpol aocneeb oo f gt wr oou gp r, owuipt hs . 21 00 ss uu bb jj ee cc tt ss to the active group - i.e., receiving the investigational product (Naticol ® , fish collagen peptides). The investigational product (NATICOL ® , fish collagen peptides) was manufactured and rt oe l etahsee d Cuonodredri nt ha et orre/sIpnov ne ss ti bi gi al i tt oy ro f i Wn e bi sohxaersd t caonndt awi na isnpgr osvi indgel de dose sachets. A 10g sachet of the investigational products and tohnee cdoami l yp ai nr at at okre pi nr o2d0ucclt o(fmcaolltdo dl ieqxut irdi n()f rwu ietr ej u it coe ,b me icl ok nosru mc oel dd tea) 15 minutes before breakfast, for 8 weeks. The Naticol® reveals the presence of numerous amino acids including proline, hvayldureoxisyaplrsoolisnuem, gmlyacriinzeedainndTaabrglein1i.ne, see Table 1. Nutritional At baseline, subjects were provided with a box containing 8-weeks supply of the study product, along with an additional 4-day supply in case of loss. Subjects were instructed to one sachet each morning, with their breakfast, for the duration of the study. Subjects returned after 8 weeks. At each visit the vitals, anthropometric measurements, concomitant medication at hned f oa nl l yo wai dnvge rqsuee set vi oennnt sa i rwe es :r eWreesct oe rr dn e Od .n tSaur bi oj e ac tnsd cMo mc Mp al estteedr Up anri tviecri ps iat ni et sg lOo bs tael oaasrstehsrsi mt i se nItnsdheoxr tLfiokremr t 3S6c(aSl eF - 3( W6 vO2M) . AS uC b) j eacntds returned any unused study product and compliance was au snsdeesrswe de nat ntdh enSehwo rst t uP dh yy s ipcraol dPuecrtf oardmma innci es t Be raet dt e. r Sy u(bSjPe Pc tBs) at el ssot ad ti eet a ac hn dv i es xi te. rScui sbej ercot su twi neer ea innds t nr uo ct t ec do ntsou fmo lel omw etdhi ec iart isotna sn dt ahradt could interfere with the assessment of the study product for

How to cite this article: Seán Lacey, Christelle Bonnet, Kelly Seamans, Andrea Doolan. Effect Size Statistics to Inform an Exploratory Analysis of a Double-Blinded, Randomised, Placebo Controlled Pilot Clinical Study to Evaluate the Efficacy of Naticol ® , Specific Fish Collagen Peptides to Alleviate Symptoms of Osteoarthritis in the Knee . JOJ Case Stud. 2019; 10(2): 555783. DOI: 10.19080/JOJCS.2019.10.555783 0032 Table 2: Count of subject demographics, along mean ± SD [Min, Max] of vital signs, anthropometric measurements at baseline. Placebo Active p-value n 10 20 Male:Female 0:10 2:18 <0.001* Age (years) 62.3± 6.31 [51, 73] 60.4± 6.98 [39, 72] 0.463

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Temperature (°C) Systolic BP (mmHg) Distolic BP (mmHg) Pulse (bpm) Weight (kg) Height (m) BMI (kg/m²)

36.3± 0.47 [35.5, 37.0] 121.0 ± 16.02 [93, 148] 73.9± 10.11 [63, 88] 68.3± 13.01 [44, 86] 1.6 ± 0.03 [1.6, 1.7] 26.9 ± 4.26 [21.9, 34.3]

36.4± 0.29 [36.0, 37.0] 125.1 ± 16.65 [91, 148] 78.9± 10.32 [61, 95] 65.4± 6.92 [53, 79] 1.6 ± 0.10 [1.5, 1.8] 28.4± 4.93 [20.0, 37.2]

0.24 0.53 0.218 0.522 0.224 0.296 0.44

69.8± 10.71 [54.7, 85.5] 75.5± 12.50 [51.1, 100.0]

*Binomial-test conducted (Active group only). Table 3: Classification of reported adverse events.

Relationship to Study

Action Taken

Group Subject ID

Description

Visit

Intensity

Outcome

SAE

Active 076-002 Subject got nausea and feltill after consuming the product Baseline Moderate Probable d Ti srceoant tmi neunet d Recovered No 076-007 Clinically significant blood pressure Baseline Moderate Unrelated Referred to GP Resolved; Recovering No 076-013 Nausea, diarrhoea Week 08 Moderate Unlikely None Recovered No 076-014 Head-cold Week 08 Mild Unrelated None Recovered No 076-029 Chest infection Week 08 Moderate Unlikely None Recovered No Placebo 076-009 s lbi pr upies de da ns idd fee al lnadt thhoi mg he , Week 08 Moderate Unrelated None Resolved; Recovering No 076-020 Allergic reaction to the product. rash on skin red and blistered Baseline Moderate Probable d Ti srceoant tmi neunet d Resolving; Not recovered No 076-030 Mild Head-cold & Dry Cough Week 08 Mild Unlikely None Resolved; Recovering No 076-033 Bruised ribs, chin, nose and wrist after a fall. Week 08 Moderate Unrelated None Resolved; Recovering No p-value 1.000* 1.000* 0.894** 0.638** 0.051** N/E * Fisher’s exact test; ** Chi-squared test. baseline to 8 weeks, with a larger difference, in magnitude op fl atcheeb oe f fgercot uspi z ae c sr toastsi s tt hi ces , mf oauj on rdi t iyn ot hf emaecat si vuer egmr oeunpt s .t hDa un e t ht oe tchoemepxapr li onrga teof rf eyc nt astiuz rees oafr et hae sr teul idayb laen adptphreo as cmha ltlos ai nmf oprl em s itzhee, statistical power of future studies, [22]. Table 4: Effect of 8 weeks’ supplementation of Naticol®, on osteoarthritis related measurements, for subjects that completed the study. Placebo (n = 9) Active (n = 19) p-value Baseline* Week 08 Baseline* Week 08 WOMAC Pain sub-scores 6.9 ± 3.55 4.8 ± 5.04 7.1 ± 3.05 4.3 ± 2.98 0.583 WOMAC Physical Function sub-scores 25.8 ± 10.72 18.4± 15.15 28.6± 10.34 19.3± 10.30 0.606 WOMAC Composite score during the study 36.3± 15.53 25.8± 21.06 38.9± 13.55 26.6± 13.61 0.726 SF-36v2 Role Limitations due to Physical Problems 56.3± 23.59 70.1± 22.273 58.9± 16.05 71.1± 20.75 0.867 SF-36v2 Role Limitations due to Emotional Problems 69.4± 22.44 80.6± 17.18 73.7± 21.91 78.3± 21.72 0.548 SF-36v2 Emotional Well-Being score 70.2± 10.97 69.3± 23.75 69.9± 11.11 71.4± 12.09 0.564 SF-36v2 Social Functioning scores 76.4± 26.84 76.4± 23.75 68.4± 26.80 77.6± 23.78 0.392 SF-36v2 Pain score 56.7± 23.08 56.7± 31.62 51.6± 16.33 61.4± 22.57 0.272 SF-36v2 General Health score 72.2± 22.65 70± 18.03 70.8± 16.44 71.8± 14.83 0.541 SPPB Balance Score 4.0 ± 0.00 4.0 ± 0.00 4.0 ± 0.00 4.0 ± 0.00 SPPB Chair Test Score 1.9 ± 1.17 2.2 ± 1.20 2.1 ± 1.09 2.5 ± 1.01 0.769 SPPB Total score 10± 1.20 10.1± 1.25 10.1± 1.09 10.4± 1.18 0.639 *No difference between groups at baseline. Upon investigation it was apparent that subjects in the active go rf omu epaesxupr ee rmi eennct es dt hma on r seuobf j ea cnt si mi np rt oh ve epml aecnet baoc rgor sosu tph oe vme ra jtohrei t 8y wo f e tehkes od fi ftfheer es nt uc de sy , os ebes eTravbel de 4w, Te ra eb l ceo5m&p Fa irgeudr eu s1i. nTgh ee fmf eac gt nsiitzued –e i.e., the standardized mean difference in measurements from

How to cite this article: Seán Lacey, Christelle Bonnet, Kelly Seamans, Andrea Doolan. Effect Size Statistics to Inform an Exploratory Analysis of a Double-Blinded, Randomised, Placebo Controlled Pilot Clinical Study to Evaluate the Efficacy of Naticol ® , Specific Fish Collagen Peptides to Alleviate Symptoms of Osteoarthritis in the Knee . JOJ Case Stud. 2019; 10(2): 555783. DOI: 10.19080/JOJCS.2019.10.555783 0033

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Figure 1: Effect size calculations on osteoarthritis related measurements from Baseline – Week 8 for (a) WOMAC scores; (b) SF-36v2; (c) SPPB. Table 5: Cohen’s d, within groups effect size calculations on osteoarthritis related measurements from baseline to Week 08. Measurements Placebo Active WOMAC Pain sub-scores 0.81 0.88 WOMAC Physical Function sub-scores 0.68 1.08 WOMAC Composite score during the study 0.82 1.07 SF-36v2 Role Limitations due to Physical Problems -0.51 -0.51 SF-36v2 Role Limitations due to Emotional Problems -0.44 -0.17 SF-36v2 0.07 -0.18 SF-36v2 0 -0.34 SF-36v2 0 -0.5 SF-36v2 0.15 -0.09 SPPB Balance Score 0 0 SPPB Chair Test Score -0.25 -0.47 SPPB Total score -0.1 -0.33

WOMAC Noting a higher score on the WOMAC indicates worse pain, ss ti zi fef n( eBsass, eal ni nde f –u nWc teieokn a8l) l ri me pi rt ae tsieonntss [a2n0 i]m. Hperno cvee ,ma epnot siint i vWe OeMf f eAcCt oP va ei nr ts hu eb -8s cwo er ee k, sb. oFt rho gmr oTuapbsl ee 5x p&e rFi ei gnucreed 1a( al )a, r wg ei t ihmt ph reo Wv eOmMe An tC, dt h =e p0 l. 8a c1e, b0o. 8 g8r, orue ps peexcpt ievrei el yn c[ 1e 6d ] a. Fsomr aWl l Oi mMpArCo vPehmy se inc ta l( dF u=n0c t. 6i o8n) af ogra it nh set Wt hOe Ma Ac tCi vCe ogmr opuops ’ist el asrcgoer ei mt hper opvl ae cme ebnot g(rdo u= p1 e. 0x8p)e. rFi ei nnaclel yd, ae v me ne dl ai ur gme r i mi mpprroovveemmeennt t ((dd == 10 .. 08 72 )) . aTghaei nWs tO tMh Ae Ca cs tt ii vf fen egsrso us upbs score is not presented Table 5 and Figure 1(a).

SF-36v2 Noting the lower the score the more disability [18]. Hence, ad i snaebgi laittiyv e( a ne f ifme cpt r os vi zeem e( Bn at )s eolvi ne er t h– e W8 ewe ek e k8s). Irne pt errems esnot sf Rl eosl es Limitations due to Physical Problems score, Role Limitations due to Emotional Problems score active group experienced medium improvements, see Table 5. Physical functioning, energy and vr ei tgaal ri tdy Ss oc oc irael s Faurne cnt ioot npi rnegs ea nn tde dP ai ni n Tsacbol ree5s , atnhde rFei gwu ar se n1 o( bc) h. Wa ni gt he inno st iccoerde af onr i tmh pe rpolvaecme beon tg rboyu ap s( dm =a l l0 .(0d0 =) , -w0h. 3i l4e) tahneda cmt ievdei ug mr o u( pd =a n-d0 . 5G0e)naemr aol uHn et ,arl tehsyp eIcstsi vueelsy. tFhi ne a pl l yl a, cf oe br oE-mb aostei odn as lu Wb j ee cl lt-sB edi ni sg-

How to cite this article: Seán Lacey, Christelle Bonnet, Kelly Seamans, Andrea Doolan. Effect Size Statistics to Inform an Exploratory Analysis of a Double-Blinded, Randomised, Placebo Controlled Pilot Clinical Study to Evaluate the Efficacy of Naticol ® , Specific Fish Collagen Peptides to Alleviate Symptoms of Osteoarthritis in the Knee . JOJ Case Stud. 2019; 10(2): 555783. DOI: 10.19080/JOJCS.2019.10.555783 0034

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iwmhpi lreo vt he ed souvbej re ctths ei n8 t hwee ae cktsi v(edg =r o 0u .p0 7i mapnrdo v0e.d1 5i n, rbeostphe cc at isveesl y( )d, = -0.18) and 0.09, respectively). SPPB Noting higher scores indicate better lower body function [21]. Hence, a negative effect size (Baseline – Week 8) represents an improvement in lower body function over the 8 weeks. Both gTroot aulp ss c oerxep. eWr i ehni lcee dt h ea np l ai mc epbroo vgermo uepn te xi pn e rtiheen cCehdaai r s mt eas ltl aa nn dd nwehgi ll ieg ti bh lee a ci mt i vper ogvr eomu pe ne txsp e(rdi e =n c e- 0d. 2a 5s ma na ldl i m- 0p. 1r 0o ,v erme sepnetcitni vbe ol yt )h, tneosttspr(des=en-0te.4d7inanTdabdl=e 5-0a.3n3d, Freigsupreect1iv(ce)ly. ). Gait score results are Adverse events Fisher’s exact test found there was a statistically insignificant association between the number of adverse events reported per vt hi seirt ea nwd at sr e aat mset na tt i sgtrioc ua lpl y( p i =n s1i g. 0n0i 0f i )c,asnete Taas bs ol ec i3a.t Fi ounr t hbeertmwoe reen, tt ra ekae tnmaenndt gOruotuc po ma ne do tf haen: Iandtveenrssi et ye, vReenl at t(i po n=s h1 i. p0 0t o0 , s0t u. 8d9y4; , A0c. t6i 3o n8 and 0.051, respectively). Discussion This double-blinded, placebo-controlled pilot clinical study ds pe emc oi fni cs tf ri sa ht e cs ot lhl ae gpeont epnetpi at il df oe sr , oNnac tei cdoal i®l y, ot or aal ldl eovs ieast eo fs Ny ma t pi ct oo lm®s, oi nf onsat teuoraer, t ha rni dt i s eifnf e tcht e ski znee ec. aTl chuel asttiuodnys dsehsoi gwn twh aa st esxupbljoercat tso ri ny tt hh ee amc taijvoer i gt yr o ou fp me xepaes rui reenmc eedn tms ot rhea no f saunb j iemc tpsr oi nv e mt heen tp laaccreobsos gt hr oo suep oofv eprr et vhieo u8 s wpereekc sl i no ifc tahl ea ns tdu dc yl i. nTi chael s es t ur edsi ue sl t st oc oarsrsoebs os rtaht ee pp oh tyesni ct ai al lmeof bf ei lcittsy aosf acsos lel as sgeedn bhyytdhreo lWy seastteesr noOn n tj oa irni ot Mp ac iMn a satnedr Universities (WOMAC) scoring system. Clinical studies suggest that the ingestion of 10g collagen hydrolysates daily reduces pain in patients with osteoarthritis of the knee or hip while blood concentration of hydroxyproline is increased. Clinical use was associated with minimal adverse eufnfepcletsa,samnat itnalsyteg[a2s3t]r.ointestinal, characterized by fullness or In a prospective, randomized, double-blind, placebo- ckonne ter ool lsetde o as trut hdryi t iisn, oe rl da el r li yn t awkoe moefn c wo liltahg e mn i lpde- pt ot i dme so dfeorra t ae da nu dr a tiimo np roofv6e mp ho ynst ihcsa ls hmo wo beidl i ttyo saisg nai fsisceasnstel yd rbe yd utchee j oWi net spt eari nn Oc l ni nt ai crai ol sMt uc dMya sctoe nr f Ui rnmi veedr stiht iaets c(oWl lOa gMeAn C p) espc toi rdiensg as ryes t eamh. i Tg hh liys efficient nutraceutical to improve joint health in patients with osteoarthritis which can help to maintain an active lifestyle throughout ageing [24].

We can also indicate a double-blind, placebo-controlled, rpaonr dk o smkiizne d( P Ct rPi )a l a nwdi t hb o vc ionl el a gbeonn eh y( Bd Cr oPl)y ssaot ue sr c ei ss ocl aa trerdi e df roo umt tpoe pst ti du ed yt o t choe n terfof el ct thi ve epnreosgs r eosfs i oo nr a ol lfy o ss tuepopalretmh rei nt itse di n cpoaltl iaegnetns diagnosed with knee osteoarthritis. Improvement in treatment with reduction in WOMAC and quality of life (QOL) scores from baseline to 13 weeks were recorded. Indeed, all the score levels of WOMAC and QOL decreased significantly (p<0.01) in the study group compared to placebo group after week 13. Safety and tolerability were also good [15]. Additionally, research in mice has demonstrated that after oral administration of radiolabeled gelatin hydrolysate, the radioactivity was specifically found in cartilage indicating an accumulation of these peptides within the connective tissue [25]. The study demonstrated the intestinal absorption and cr oa rl et i l oa fg ec oa lcl ca ug me nu lha yt idorno loyfs ac toel sl a gi ne nr eppe apitri doef. Tdha umsa, gt eh de pc oa rt et inl at igael cc oo ul l ladg eb ne ahsysdorcoi laytseadt ewsi. t Ah trhe ec eanc tc ua mn i uml aa tl i sotnu od fy ohr aa sl l ya lasdoms ui ngi gs et es rt ee dd that oral ingestion of collagen hydrolysates 9 might have beneficial effects on joint health such as osteoarthritis (OA) as ca os sl loacgieant e hdy dwr iotlhy s ao tset es oma ri gt hh rt i triecd uc caer tti hl aeg em odrepsht roul oc tgiioc na l icnh aknng ee es joints, [26]. This mechanism about absorption, distribution and collagen pc lei np itci da lel ya rcec cuomr du el adt ioonn j ioni nctapr at iilna gaen dmpa hy yesxi cpal la imn otbhiel i tbye. nHeofwi t se vwe re, af onrt i b- iennf leafmi t sm. aI nt odreye dp, r ot hpee rl ti it ee sr a mt uar ye rael spoo rbt se tahna t a idndt irtai o- anrat li c uwl aa yr ao ds tme oi nairstthr raittiios n d eomf ocnosltlraagteend ai n s itghnei f i ckannete l oocfa l s iunbf jl ea cmt sm awt iiot nh decrease (increase in T regs, IL-10 and decrease in IL-1β) and a mitigation in the symptoms inherent to the pathology [13]. Similarly, oral administration of collagen hydrolysates in mice with post-traumatic osteoarthritis inhibited synovial inflammation and induced cartilage regeneration [12]. Moreover, in this pilot clinical trial study, we may indicate tt hh ae ts ftruodmy , t5h (e5258. 6 (%9 :)1o9f Pt hl aecpe lbaoc:e Ab oc t gi vreo)u spuabnj edc 1t s4 t (h7a3t . 7c o%m) pol fe tt eh de active group had a body weight greater than 70kg at baseline. From Table 2, the maximum weight of subjects (that completed the study) at baseline was 85.5kg and 100.0kg for the placebo and active groups, respectively. In Shigemura et al. [27], the daily ingested dose of collagen hydrolysates is linked to the bi nogdeys twe de i dg ho ts .eT/ hk ge sbeoaduyt hwoeri sg he tx aa mn di nf eo do dt h- dee rrei vl ae tdi ohnysdhriopx by ep trwo lei en ne loef vt ehles ci no l hl augme na np eppl at isdme sa. Ht oe ensctei ,mh ae tael tthhye veof lfue nc tt ieveer sb ei nngeef si ct ieadl 3d 0o .s8e, 1T 5h 3e . a8vaenr da g3e8p4l.a6smmga pceornkc ge nbtor da tyi owne oi gf hhtyodfr cooxlyl apgr eo nl i nhey dc or onltyasi anti ensg. peptides was dose-dependent, reaching maximum levels of 6.43,

How to cite this article: Seán Lacey, Christelle Bonnet, Kelly Seamans, Andrea Doolan. Effect Size Statistics to Inform an Exploratory Analysis of a Double-Blinded, Randomised, Placebo Controlled Pilot Clinical Study to Evaluate the Efficacy of Naticol ® , Specific Fish Collagen Peptides to Alleviate Symptoms of Osteoarthritis in the Knee . JOJ Case Stud. 2019; 10(2): 555783. DOI: 10.19080/JOJCS.2019.10.555783 0035

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23 08 .41. 76 ma ng dd3o2s e. 8s4 onfmcool l/l ma glefno l hl oywd ri no gl y isnagt ee ,s trieosnp eo cf t3i v0e. 8l y, . 1I5n3g .e8s tai nn dg over 153.8mg of collagen hydrolysate significantly increased the average concentrations of the free and peptide forms of hl i ymdirt owx yaps rnool itnree a icnh e dp l wa simt ha i. n gTehset i o hnyodfr oa xs ymp ruoclhi naes 3a8b4s o. 6rmp tgi oonf collagen hydrolysate per kg body weight. These finding suggest that ingestion of less than 30.8mg of collagen hydrolysate per body weight is not effective for health benefits. They also show that the dose is calculated taking account of body weight. Hence, doses may vary from one subject to another due to the variations of body weight. In this way, in order to maintain a ss iumb ji el acrt sd wo sheopreerc ke igv be do daydwa iel yi gdh ot sbee ot wf 1e 0e ng oa lf l sspuebcjief icct sf i, st hh ec o1l0l a0gkegn- peptides (Naticol ® ) should have received more than 10g/day compared to the ones who received 10g/day for a body weight eb qo ud iyv awl ee ni gthttow7a0skng o. Ht ee qr eu, i vt ha lee nd to sbee towf eceonl l aa gl lesnu hb yj edcrtos l ydsuaet et so pt he er huge body weight variations. However, all subjects received the minimum df oors eb eonf ecfoi tlsl a. gTehni shdy od sr eo l oy sf actoelsl argeepno rhtyeddr ob lyy sSahtiegse mi n ug reas teetd abl .y[ 2t h7e] st ou bdj ee cmt so nwsittrha tae vseirgyn hi fiigc ha nbt obdeynwe feiitgshat nwda sl anr eg ve er r bt heenleefsi st se ni no ut hg he active group. Conclusion This pilot clinical trial study, which consisted in a once daily treatment for 8 consecutive weeks, indicates that oral supplement specific fish collagen peptides have some interesting effects on knee osteoarthritis symptoms. The results demonstrated that daily oral doses of specific fish collagen peptides (Naticol ® ) in hr eedaul tchey psauibnj, e icmt sp wr oivt he qk un ae lei t yo s ot ef olai fret harni tdi s l ohwa se rt hbeo dpyo tfeunnt ci at il otno. Fmuorrteh earn ds t ua dhi ei gsh we ri tdho as ang ee xot ef npsrioodnu oc tf fdour rsaut ibojne cttos w1 2i twh eae kbso doyr weight greater than 70kg should be performed to confirm these preliminary results. Acknowledgments The study was funded by Weishardt International Group (France) which provided the fish collagen peptides (Naticol ® ) assessed in this study. References 1. B47u(c2k)w: a1l-t3e2r.JA, Martin J (1995) Degenerative joint disease. Clin Symp 2. Cr aodoipo eg rr aCp h(i2c 0k0n0e)e Ro si st ke ofaarctthorrist i sf o. Ar rtthher i ti inscRi dheenucme 4a n3 d( 5 )p: r9o9g 5r e- 1s s0i 0o 0n . o f 3. Zo shtoeuo aZrYt ,h rLiitui s YrKi s, kC:h ea n dHo sLe, Lrieus pFo(n2s0e1 4m)e Bt ao- da ny aml yas si ss. iOn db ee xs i tayn d( Ski lnveeer 4. S M p p e a r r r s i c n p h g e ) c L t 2 M i 2 v , e ( B 1 . B a 0 c a ) h : i l 2 m li 1 e e 8 r i e e 0 s r - 2 C C 1 l J i 8 n ( 5 1 R . 9 h9e7u)mEactoonlo1m1(ic4s):o8f 1o7s-t8eo3a4r. thritis: a global

5. AUrKt.hritis Care (2006) The impact of arthritis (statistics). Arthritis Care, 6. AArrtthhrriittiiss RReesseeaarcrchhUKU.K (2013) Osteoarthritis in general practise. 7. D( 2u0t 1e i6l )LS, pQeucei iflilce -nRaot uu rs as le lbCi o, aMc at iuvbe etrytpYe, E1s cdoalillaegJe, nB rpuenpot i- dBeosn on reat l Ci ,net ta ka el . reverse skin aging signs in mature women. Journal of Aging Research & Clinical Practice 5(2). 8. So af rt ah eS ,BMe naer ft ii cni aGl , ESf af ercaths Bo f, HR ay jdar oAl By s, eGde nC oo vl leasgee nL a( s2 0a 1N5u) t Ar anc eOuvtei cravli eown SNkuitnraPcreoupteicratilessJ:oSucrineanlti8f:ic2B9-a4c2k.ground and Clinical Studies. The Open 9. Mp eapt tsiuddea oNn, Kc oo yl laamg eanY,f iHb or isl as kaanYd ( g2l0y0c o6 s) aEmf fiencot sg loyfc ai nngse si nt i ot nh eo fdceorlml aigse. nJ Nutr Sci Vitaminol (Tokyo) 52(3): 211-215. 10. BE frfueyc èt roef cOo, l lZaeggeenl sh yBd, r Lo el yosnaot er i i nL ,a rRtai cbuelna dr ap aVi .n J: aan6s -sme no nAt ,h erta na dl . o(m2 0i z1e2d), d 12 ou 4 b -1 le 3 - 0 b . lind, placebo controlled study. Complement Ther Med 20(3): 11. C( 2l a0r0k0K) L2, 4S-eWb ea es tki asnt ue ldl yi Wo ,nF tl he ce hus seen ho af rc oKlRl a, gAeunk eh rymd raonl yn sDa tFe, Ma se zaa dFi, eet ta ar yl . sOuppinpl2e4m(e5n):t1in48a5th-1le4t9e6s.with activity-related joint pain. Curr Med Res 12. DO raar l QhAy ,d rMo al yyzneadr dt yRpDe , 1L icuo lZl a, gSecnh oi nt td uEcMe ,s Ccahtohnedl irnoer eSg, e ente raalt. i o( n2 0a1n6d) iOnsht ieboiat sr tshyrni toivs iCa la irnt ifllaagmem2 a4t(iSounpipn 1m) u: Sr i5n3e2p- So5s 3t t3r a. u m a t i c o s t e o a r t h r i t i s . 13. FOur dr ua zz a BwHa -, Ceatr ba al . l l(e2d0a1 2J , ) LPi oml ya mGe, r iLzleodr e- tnytpee LI, cNoul lña eg ze-nÁ ldvoa wr enz r eCg, uRl autiezs- isnyfml apmt omma at itoi cn kannede i mo spt reoovaerst h rciltiins i c af ol l l oo wu ticnogm easr t hi nr o spc aotpi ei cn t sl a vwa gi teh: aScireanntdifoicmWizoerdld, Joduorunballe2-b0l1in2d: ,34a2n8d54p.lacebo-controlled clinical trial. 1 4 . Hi nahri tboi gt sA z, Cy mo zoi jsnasne ni nMd ,udcee dV r ii nj Gf l ,aGmamr sastei no nJ . ( 2E0x1p3 )B Ci ool l l Ma geedn h( My daryowl yosoadt e) 238(7): 798-802. 15. K( 2u0m1 a5r) SA, dS ou ug bi hl ea -rba l iFn, dS, upzlua kc ei bKo, - Icnoonut er oNl l e, dV ,e rnaknadt eo smwi as er adt, hcilri nu ikcuaml satruad yS oAngrtihce95e(ff4e)c:t7iv0e2n-e7s0s7o. f collagen peptide on osteoarthritis. J Sci Food 16. Cohen J. Statistical Power Analysis for the Behaviorial Sciences Routledge ISBN 1-134-74270. 17. MM cc CMoansnt eerl l USn, iKv oe rl os pi tai ecsk OPs, tDe aovairst hArMi t i s( 2I 0n 0d 1e x) T( Wh eO WM Ae sCt)e: ran rOe nv iteawr i oo fa ni tds utility and measurement properties. Arthritis Rheum 45(5): 453-461. 18. Joef nt kh ien Ss oF n- 3 C6 , vSet re swi oa nr t 2- Bi rno twh ne US , nPi teet de rKs ei nng Sd, oPma .i cJ eE Cp i(d1e9m9 i9o)l AC os sme sms umnei nt yt Health 53(1): 46-50. 19. GV aólmi dei tzy J Fa, nCdu rrcei loi a Cb Li l ,i tAy l voafr at dh oe BS ,h Zo ur tn zPuhnyesgi cuai l MPVe, r fGour rma lanni cke J B( 2a t0t1e 3r y) (SPPB) Colomb Med (Cali) 44(3): 165-171. 20. AUmnievreircsaitnieCsoOllsetgeeoaorfthRrhiteisumInadteoxlo(gWy.OWMeAsCt)e.rn Ontario and McMaster 21. G( 1u9r 9a 4l n)i Ak sJ hMo, r St ipmh oy ns isciac lkp Ee rMf o, rFme rarnuccecbi aLt,t eGrlyy na sns eRsJs, i Bn ge rl ko mw ea rn e Lx tFr, eemt iat yl . fmu on rc tt ai ol int y: Aa ns sdonc ui artsi oi nng wh oi tmh es ea ldf -mr ei spsoi or tne. dJ oduirsna abli loi tf yG ae nr odn pt or leodgiyc t4i o9n( 2o) f: M85-M94. 22. SEunloliuvgahn. GJ MGr,aFdeiMnnedRE(d2u0c124)(3U)s:i2n7g9E-f2fe8c2t.Size-or Why the P Value Is Not

How to cite this article: Seán Lacey, Christelle Bonnet, Kelly Seamans, Andrea Doolan. Effect Size Statistics to Inform an Exploratory Analysis of a Double-Blinded, Randomised, Placebo Controlled Pilot Clinical Study to Evaluate the Efficacy of Naticol ® , Specific Fish Collagen Peptides to Alleviate Symptoms of Osteoarthritis in the Knee . JOJ Case Stud. 2019; 10(2): 555783. DOI: 10.19080/JOJCS.2019.10.555783 0036

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23. Md ios esaksoew. Si tezmRiWn A(r2t0h0r0i t)i sRRohl ee uomf c3o0l l(a2g)e:n8 7h-y9d9r.o lys a t e i n b o n e a n d j o i n t 24. Jiang JX, YU S, Huang QR, Zhang XL, Zhang CQ, et al. (2014) Collagen peptides improve knee osteoarthritis in elderly women A 6-month rInadnudsotmryizHedi T, ecdhouVbolle2-5b(li2n)d. , placebo-controlled study. Agro Food 25. Oesser S, Adam M, Babel W, Seifert J (1999) Oral administration of 14C labelled gelatin hydrolysate leads to an accumulation of radioactivity in cartilage of mice (C57/BL). J Nutrient Metabolism 129(10): 1891- 1895.

26. O’Hara H, Ilda H, Ito K, Takeuchi Y, Nomura Y (2010) Effect of Pro-Hyp, auscinolglagen hydrolysate derived peptide, on hyaluronic acid synthesis in vitro cultured synovium cells and oral ingestion of collagen hydrolysate in a guinea pig model of osteoarthritis. Biosci Biotechnol Biochem 74: 2096-2099. 27. Si nh itgheeml ue rvae l sY. ,o Kf uf rbeoemaunrda pDe, pSt ai dt oe Yf o r(m2 0s 1o4f) hDyodsreo‐xdyeppreonl idneen it nc hh au nmgaens plasma after collagen hydrolysate ingestion. Food Chem 159: 328-332. Your next submission with Juniper Publishers will reach you the below assets • Quality Editorial service •• SRwe pi frti nP tese ar vRaei lvai be wi l i t y • E-prints Service • • Manuscript Podcast for convenient understanding Global attainment for your research • Manuscript accessibility in different formats ( Pdf, E-pub, Full Text, Audio) • Unceasing customer service Track the below URL for one-step submission https://juniperpublishers.com/online-submission.php

This work is licensed under Creative Commons Attribution 4.0 License DOI: 10.19080/JOJCS.2019.10.555783

How to cite this article: Seán Lacey, Christelle Bonnet, Kelly Seamans, Andrea Doolan. Effect Size Statistics to Inform an Exploratory Analysis of a Double-Blinded, Randomised, Placebo Controlled Pilot Clinical Study to Evaluate the Efficacy of Naticol ® , Specific Fish Collagen Peptides to Alleviate Symptoms of Osteoarthritis in the Knee . JOJ Case Stud. 2019; 10(2): 555783. DOI: 10.19080/JOJCS.2019.10.555783 0037

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