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Supplementary materials

Supplementary Annex 1. Methodology

Determination of CS response variables using principal component analysis

Using patient-reported data collected during the 4 weeks prior to treatment (screening), the

analysis derived clinically meaningful response thresholds for the most relevant outcomes

related to patient functioning in those living with a neuroendocrine tumor (NET), a concept

referred to here as “carcinoid syndrome (CS) response.” The objectives of the analysis were

to compare the effect of lanreotide versus placebo on the incidence of CS response during

screening to week 12 of the double-blind phase and to explore the association between the

primary ELECT1 endpoint (use of subcutaneous [sc] octreotide rescue medication) and the

CS response measures.

Two types of patient-reported outcomes (PROs) were collected during the screening and

double-blind phases of the ELECT trial. An interactive voice response system (IVRS) was

used to collect symptoms of CS from screening through the 16 weeks of double-blind

treatment. Frequency (ie, daily events) and overall severity (0 = absent, 1 = mild, 2 =

moderate, 3 = severe) of diarrhea and flushing were obtained on a daily basis. Quality-of-life

(QoL) data were collected at baseline and at the end of week 12 using the 30-item European

Organisation for the Research and Treatment of Cancer (EORTC) Core Quality of Life

Questionnaire Version 3.0 (QLQ-C30, or “C30”) and the 21-item disease-specific QoL

questionnaire for gastrointestinal NETs (QLQ-GINET21, or “GINET21”).2 In addition, the

use of sc octreotide rescue medication (which was also collected through the IVRS) was

included as a proxy for a patient-reported variable because octreotide use may mask future

symptoms or, alternatively, may reflect the severity or frequency of existing symptoms.

Rescue medication use can thus be considered a “masked symptom.”

This multidimensional space of correlated variables was reduced to a smaller set of

independent variables, called principal components (PCs), by applying principal component

analysis (PCA) to the baseline (ie, pretreatment) values of 14 subscale scores of the C30

questionnaire and 8 subscale scores of the GINET21 questionnaire, the 4 symptom score

variables, and rescue medication use, a total of 27 variables. The C30 overall health/QoL

subscale was excluded because it is an overall summary measure. The GINET21 Sexual

Function subscale was excluded due to a high degree of missing values.

Inspection of the PC loadings indicated that PC1 primarily consisted of variables derived

from the QoL questionnaires (Supplementary Annex 1, Figure S1A), while the symptom

variables and the QoL subscales related to these symptoms (the C30 Diarrhea [DI] and

Endocrine Symptoms [ENS] subscales) exhibited weak loadings toward PC1. PC2 was

primarily loaded by the frequency and severity of diarrhea variables as well as the C30 DI

subscale (1B). Flushing frequency and severity were the strongest loading variables in PC3,

together with the GINET21 ENS subscale (1C).

C30 summary score

The MCID for the C30-SS score was derived using the standard error of measurement (SEM)

technique. The SEM technique is adequate for this response variable because it is assembled

as a linear combination of different response variables of the questionnaire for which a

reliability coefficient can be determined. The SEM is given by:

SEM=s √1−r

where s is the standard deviation of the C30-SS at baseline, which equals 13.328, and r is a

reliability coefficient, for which typically the Cronbach’s alpha is used (0.8202 in this case),

which leads to:

SEM=13.328√1−0.8202=5.6506

Diarrhea and flushing

Because BD was highly correlated (r=0.71; P<0.0001) with the DI in the C30, DI was used

as an anchor to establish the MCID for BD. Similarly, the ENS was highly correlated

(r=0.71; P<0.0001) with BF and hence used as anchor.

For both BD and BF, the MCID was established by maximizing the proportion of true

positives and true negatives vis-à-vis the respective anchor variables DI and ENS, which

resulted in MCIDs of 0.62 and 0.31 for BD and BF, respectively.

References

1. Vinik AI, Wolin EM, Liyanage N, Gomez-Panzani E, Fisher GA. Evaluation of

lanreotide depot/autogel efficacy and safety as a carcinoid syndrome treatment

(ELECT): a randomized, double-blind, placebo-controlled trial. Endocr Pract

2016;22(9):1068-1080.

2. Giesinger JM, Kieffer JM, Fayers PM, et al. Replication and validation of higher

order models demonstrated that a summary score for the EORTC QLQ-C30 is robust.

J Clin Epidemiol 2016;69:79-88.

3. U.S. Department of Health and Human Services Food and Drug Administration.

Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product

Development to Support Labeling Claims. December 2009.

http://www.fda.gov/downloads/Drugs/Guidances/UCM193282.pdf.

Supplementary Annex 1, Table S1. Correlations between the 3 main PCs and the baseline

symptom domains

Domain PC1 P-value PC2 P-value PC3 P-value

PC1 1.000 0.000 . . . .

PC2 0.000 1.000 1.000 0.000 . .

PC3 0.000 1.000 -0.000 1.000 1.000 0.000

QL -0.639 0.000 0.056 1.000 0.067 1.000

PF -0.658 0.000 0.066 1.000 0.102 1.000

RF -0.681 0.000 0.053 1.000 0.156 1.000

EF -0.700 0.000 0.142 1.000 -0.068 1.000

CF -0.595 0.000 0.250 1.000 -0.047 1.000

SF -0.641 0.000 0.212 1.000 0.068 1.000

FA 0.764 0.000 0.019 1.000 -0.133 1.000

NV 0.513 0.000 0.039 1.000 -0.260 1.000

PA 0.484 0.000 -0.176 1.000 -0.180 1.000

DY 0.480 0.000 -0.111 1.000 0.135 1.000

SL 0.621 0.000 0.054 1.000 0.069 1.000

AP 0.585 0.000 -0.009 1.000 -0.272 1.000

CO 0.078 1.000 -0.425 0.002 -0.041 1.000

DI 0.304 0.753 0.725 0.000 -0.322 0.352

FI 0.508 0.000 -0.160 1.000 0.101 1.000

ENS 0.514 0.000 0.230 1.000 0.656 0.000

GIS 0.642 0.000 0.025 1.000 -0.062 1.000

TRS 0.098 1.000 -0.229 1.000 0.258 1.000

SOF -0.671 0.000 0.180 1.000 0.016 1.000

DRW 0.520 0.000 -0.294 1.000 0.149 1.000

MBP 0.426 0.002 -0.074 1.000 -0.072 1.000

BIM 0.279 1.000 -0.045 1.000 -0.419 0.003

ICF -0.134 1.000 0.008 1.000 0.177 1.000

SEF -0.520 0.003 0.158 1.000 0.220 1.000

QLQ -0.943 0.000 0.047 1.000 0.164 1.000

FreqD 0.254 1.000 0.806 0.000 -0.181 1.000

SevD 0.208 1.000 0.838 0.000 -0.256 1.000

BDa 0.253 1.000 0.854 0.000 -0.211 1.000

FreqF 0.365 0.053 0.358 0.074 0.710 0.000

SevF 0.357 0.076 0.375 0.032 0.619 0.000

BFa 0.381 0.024 0.379 0.027 0.725 0.000

FreqO 0.114 1.000 -0.044 1.000 -0.311 0.566

aDiarrhea and flushing burden were obtained by averaging the average baseline frequency

and severity for each subject.

Abbreviations: AP, C30 appetite loss; BD, burden of diarrhea; BF, burden of flushing; BIM,

GINET21 body image C30, EORTC (European Organization for the Research and Treatment

of Cancer) core quality-of-life questionnaire QLQ-C30; CF, C30 cognitive functioning; EF,

C30 emotional functioning; CO, C30 constipation; DI, C30 diarrhea; DRW, GINET21

disease related worries; DY, C30 dyspnea; ENS, GINET21 endocrine symptoms; FA, C30

fatigue; FI, C30 financial difficulties; FreqD, diarrhea frequency; FreqF, flushing frequency;

FreqO, frequency of octreotide use; GINET21, EORTC quality-of-life questionnaire for

gastrointestinal neuroendocrine tumors (QLQ-GINET21); GIS, GINET21 GI symptoms;

MBP, GINET21 muscle/bone pain symptoms; ICF, GINET21 information/communication

function; NV, C30 nausea vomiting; PA, C30 pain, PC, principal component; PF, C30

physical functioning; QL, C30 global health/QoL; QLQ, C30 summary score; RF, C30 role

functioning; SEF, GINET21 sexual function; SevD, diarrhea severity; SevF, flushing

severity; SF, C30 social functioning; SOF, GINET21 social function; SL, C30 insomnia;

TRS, GINET21 treatment related symptoms.

.

Supplementary Annex 1, Figure S1. Variable loadings on (A) PC1, (B) PC2, and (3) PC3.

C30, EORTC (European Organisation for the Research and Treatment of Cancer) core

quality-of-life questionnaire QLQ-C30; GINET21, EORTC quality-of-life questionnaire for

gastrointestinal neuroendocrine tumors (QLQ-GINET21); PC1, principal component 1; PC2,

principal component 2; PC3, principal component

Supplementary Annex 1, Table S1. Correlations between the 3 main PCs and the baseline symptom domains

Domain PC1 P-value PC2 P-value PC3 P-valuePC1 1.000 0.000 . . . .PC2 0.000 1.000 1.000 0.000 . .PC3 0.000 1.000 -0.000 1.000 1.000 0.000QL -0.639 0.000 0.056 1.000 0.067 1.000PF -0.658 0.000 0.066 1.000 0.102 1.000RF -0.681 0.000 0.053 1.000 0.156 1.000EF -0.700 0.000 0.142 1.000 -0.068 1.000CF -0.595 0.000 0.250 1.000 -0.047 1.000SF -0.641 0.000 0.212 1.000 0.068 1.000FA 0.764 0.000 0.019 1.000 -0.133 1.000NV 0.513 0.000 0.039 1.000 -0.260 1.000PA 0.484 0.000 -0.176 1.000 -0.180 1.000DY 0.480 0.000 -0.111 1.000 0.135 1.000SL 0.621 0.000 0.054 1.000 0.069 1.000AP 0.585 0.000 -0.009 1.000 -0.272 1.000CO 0.078 1.000 -0.425 0.002 -0.041 1.000DI 0.304 0.753 0.725 0.000 -0.322 0.352FI 0.508 0.000 -0.160 1.000 0.101 1.000ENS 0.514 0.000 0.230 1.000 0.656 0.000GIS 0.642 0.000 0.025 1.000 -0.062 1.000TRS 0.098 1.000 -0.229 1.000 0.258 1.000SOF -0.671 0.000 0.180 1.000 0.016 1.000DRW 0.520 0.000 -0.294 1.000 0.149 1.000MBP 0.426 0.002 -0.074 1.000 -0.072 1.000BIM 0.279 1.000 -0.045 1.000 -0.419 0.003ICF -0.134 1.000 0.008 1.000 0.177 1.000SEF -0.520 0.003 0.158 1.000 0.220 1.000QLQ -0.943 0.000 0.047 1.000 0.164 1.000FreqD 0.254 1.000 0.806 0.000 -0.181 1.000SevD 0.208 1.000 0.838 0.000 -0.256 1.000BDa 0.253 1.000 0.854 0.000 -0.211 1.000FreqF 0.365 0.053 0.358 0.074 0.710 0.000SevF 0.357 0.076 0.375 0.032 0.619 0.000BFa 0.381 0.024 0.379 0.027 0.725 0.000FreqO 0.114 1.000 -0.044 1.000 -0.311 0.566

aDiarrhea and flushing burden were obtained by averaging the average baseline frequency and severity for each subject.

Abbreviations: AP, C30 appetite loss; BD, burden of diarrhea; BF, burden of flushing; BIM, GINET21 body image C30, EORTC (European Organization for the Research and Treatment of Cancer) core quality-of-life questionnaire QLQ-C30; CF, C30 cognitive functioning; EF, C30 emotional functioning; CO, C30 constipation; DI, C30 diarrhea; DRW, GINET21 disease related worries; DY, C30 dyspnea; ENS, GINET21 endocrine symptoms; FA, C30 fatigue; FI, C30 financial difficulties; FreqD, diarrhea frequency; FreqF, flushing frequency; FreqO, frequency of octreotide use; GINET21, EORTC quality-of-life questionnaire for gastrointestinal neuroendocrine tumors (QLQ-GINET21); GIS, GINET21 GI symptoms; MBP, GINET21 muscle/bone pain symptoms; ICF, GINET21 information/communication function; NV, C30 nausea vomiting; PA, C30 pain, PC, principal component; PF, C30 physical functioning; QL, C30 global health/QoL; QLQ, C30 summary score; RF, C30 role functioning; SEF, GINET21 sexual function; SevD, diarrhea severity; SevF, flushing severity; SF, C30 social functioning; SOF, GINET21 social function; SL, C30 insomnia; TRS, GINET21 treatment related symptoms

Supplementary Annex 2. List of Ethics Committees and/or Institutional Review Boards from the ELECT study

Country / Site

Central Ethics Committee Local Ethics Committee

Brazil1309

Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP

70058-900, Brazil

Comitê de Ética em Pesquisa em Seres Humanos da Irmandade da Santa Casa de Misericórdia de Porto AlegreRua Professor Annes

Dias, 295,Porto Alegre – RS, CEP90020-090 - Brazil Coordinator: Claudio Teloken

Brazil1304

Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo - Ala B - 4o andar- Sala 436B Brasilia - DF - CEP70058-900, Brazil

Comitê de Ética emPesquisa em Seres Humanos da Faculdade de Ciências da Saúde – UNB Campus Universitário Darcy Ribeiro – Faculdade de Ciências da Saúde, Brasília, DF, CEP70910-000 – Brazil

Brazil1302


Comitê de Ética emPesquisa em Seres Humanos do Hospital Vera CruzRua Timbiras 3156 – 9º andar – Sala 902, Barro Preto,Belo Horizonte-MG, CEP 30140-060 - Brazil

Brazil1306


70058-900, Brazil

Comitê de Ética emPesquisa em Seres Humanos do Hospital SOCORRua Tupis, 1540 – BarroPreto,Belo Horizonte, MG –CEP 30190-062 - Brazil

Brazil1301


70058-900, Brazil

Comitê de Etica emPesquisa em Seres Humanos do Fundação Antônio Prudente-Rua Prof.Antônio Prudente, 211- Liberdade-São paulo BrazilChairperson: RicardoRenzo Brentani

Brazil1307


Comitê de Ética emPesquisa em Seres Humanos do Hospital Erasto Gaertner/ Liga Paranaense de Combate ao CâncerRua Dr. Ovande doAmaral, 201 – Jardin dasAmericasCuritiba, PR – CEP81620-060 - BrazilBrazil

1308Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - EdificioAnexo - Ala B - 4o andar- Sala 436BBrasilia - DF - CEP70058-900, Brazil

Comitê de Ética emPesquisa em Seres Humanos do Hospital Moinhos de VentoRua Ramiro Barcelos,910,Porto Alegre – RS, CEP90035-001 -Brazil

Brazil1303


Comitê de Ética emPesquisa em Seres Humanos da Faculdade de Medicina de São José do Rio PretoAv. Brigadeiro Faria

Lima, 5416 –São José do Rio Preto, SP - CEP 15090-000 - Brasil –Coordinator: FernandoBatigalia

Brazil 1305

Comissão Nacionalde Ética em Pesquisa(CONEP) Esplanada dos Ministerios, Bloco "G" - EdificioAnexo - Ala B - 4o andar- Sala 436BBrasilia - DF - CEP70058-900, Brazil

Comitê de Ética emPesquisa em Seres Humanos do Hospital Lifecenter,Avenida do Contorno,4747 - 20.o andar –Funcionários,Belo Horizonte – MG –CEP 30110-090 – Brazil

Czech Rep.0301

Ethics Committee ofthe General University Hospital PragueNa bojisti1128 08 Prague 2Czech Republic Chairperson: Josef Sedevy

NA

Czech Rep.0302

Ethics Committee ofthe General University Hospital PragueNa bojisti1128 08 Prague 2Czech Republic Chairperson: Josef Sedevy

Eticka komise Fakultninemocnice Na BulovceBudinova 2, 180 81Praha 8Czech republic

India1109

NA Institutional EthicsCommittee Basavatarakam Indo American Cancer Hospital & Research InstituteRoad#14, Banjara Hills500034 Hederabad (AP) IndiaChairperson: Dr. S. S. Reddy

India1104

NA Institutional EthicsCommittee, Shatabdi Super Specialty Hospital Suojit city centre Opp.Mahamarg Bus StandMumbai Naka422005 Nasik India Chairperson: Dr.Neelima Chafekar

India1110

NA Ethics Committee,Bhagwan Mahaveer Cancer Hospital & Research CentreJawahar Lal Nehru Marg302017 JaipurIndia

India1101

NA The Ethics CommitteeJaslok Hospital & Research Centre15,Dr. G. Deshmukh Marg, Peddar Road Mumbai 400 026IndiaChairperson: A. A. Cazi

India1106

NA Institute of MedicalSciences, Banaras HinduUniversityDepartment of medicine Lanka-221005 Varanasi IndiaChairperson: Dr. J. K. Agrawal

India1108

NA Institutional EthicsCommittee, IGIMS, PatnaRegional Cancer Centre Indira Gandhi Institute of Medical Sciences Sheikhpura-800014Patna India Chairperson: Dr. S.N.P.Sinha

India1102

NA Ethics Committee-SirGanga Ram HospitalMargRajinder NagarNew Delhi 110060IndiaChairperson: Dr. S.D. Seth

India1111

NA Institutional EthicsCommitteeOffice of Research Cell Chhatrapati Shahuji Maharaj Medical University Uttar Pradesh226003 Lucknow (UP) IndiaChairperson: Dr. U. C. Chaturvedi

India1107

NA Institutional EthicsCommitteeCancer Hospital & Research institute Jan Vikas Nyas4740009 Gwalior (MP) India

India1103

NA Ethics Committee,Santokba Durlabji Memorial Hospital D-201Bhawani Singh MargNear Rambag Circle302015 Jaipur RajasthanIndiaChairperson: Dr. B.R Madan

India1105

NA Human EthicsCommittee,Tata Memorial CentreDr. E Borges Road, Parel400012 Mumbai, India Chairperson: Dr. Madhuri Gore

India1112

NA MAARG IndependentEthics CommitteeSree Nilayam, Plot No.38, P & T Colony, Trimulgherry, Secunderabad,Andhra Pradesh-500015, India.Chairperson: Dr. AnandA. M

India1113

NA Northern IndependentEthics Committee,84, Savitri Nagar, New Delhi, 110017, India,Chairperson: Dr. Prashant Gupta

India1114

NA Ethics Committee,SMS Medical College & Hospital,JLN Marg, Jaipur-302004Rajasthan, India Chairperson: Dr. V. N. Sharma

Latvia0401

Ethics Committeefor Clinical Research at Pauls Stradins Clinical University Hospital DevelopmentSocietyPilsonu 13LV 1002 RigaLatvia

NA

Poland050105020505

Ethics Committee.Medical University of BialystokUl. Jana Kilińskiego115-089 BiałystokPoland

NA

Russia0606

Ethics Committee atFederal Service on Surveillance in Healthcare and Socila DevelopmentPetrevskii Boulevard127051 MoscowRussia

Ethics Committee at Rossiyskiy Oncologicheskiy Nauchnyi Tsentr im. N.N.Blokhina RAMN24 Kashirskoe shosse115478 MoscowRussia

Russia0604


Independent EthicsCommittee of Negosudarstvennoe Uchrezhdenie Zdravookhraneniya "Tsentral'naya Clinicheskaya Bol'nitsa#1 OAO "RossiyskieZheleznyie Dorogi"84 Volokolamskoe shosse125367 MoscowRussia

Russia0603


Ethics Committee of fLeningradskii Oblastnoi Onkologicheskii Dispanser37 Liteyny pr.191104 Saint-PetersburgRussia

Russia0605


NA

Serbia1001

NA Etički Komitet Kliničkogcentra Srbije, KliničkiCentar Srbije ul. Pasterova 2Beograd 11000Serbia

Serbia1003

NA Klinički Centar NišEtički Odbor Blvd. Dr. Zorana Djindjica 4818000 NisSerbia

Serbia1002

NA Etički Komitet Institutaza onkologiju VojvodineInstitutski put 4Sremska Kamenica21204Serbia

South Africa1202

NA Pharma-Ethics123 Amcor RoadLyttletown Manor 0157Republic of South Africa

South Africa1204


South Africa1203


South Africa1205

NA Biomedical ResearchEthics Committee Westville campus Govan Mbeki Building Private bag X 540014000 DurbanKwaZulu-natal, SOUTH AFRICAChairperson: Prof. D. Wassenaar

South Africa1201

NA Research EthicsCommitteeRoom E52-24 Groote Schuur hospital old Main BuildingObservatory7925 Cape Town South Africa Chairperson: Prof. M. Blockman

Turkey0801080208030804

Ethics Committeefor Clinical Research Ankara University- Faculty of Medicine, Office of the Dean Morfoloji Binası,06100 Sıhhiye- Ankara/Turkey Chairperson: Prof. Dr. Mehmet MELLİ

NA

Ukraine070107020703070407060708070907100711

Ministry of Healthof Ukraine CentralEthics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: OlgaVasylivna Silantieva

NA

Ukraine070707120713

Ministry of Healthof Ukraine CentralEthics Committee5, NarodnogoOpolchennia str.03680 Kyiv Ukraine Chairperson: OlgaVasylivna Silantieva

NA

USA0216*

NA NA

USA0217*

NA Providence Health andServicesInstitutional ReviewBoard5251 NE Glisen Street Building A, 3rd Floor Portland, OR 97213

USA0218*

NA Louisiana StateUniversity Health Science Center – New Orleans IRB433 Bolivar Street, 2ndFloorNew Orleans, LA 70112

USA0219

NA UCLA Office ofProtection of ResearchSubjects11000 Kinross Ave, Suite102, Box 951694Los Angeles, CA 90095

USA0220

NA University ofPennsylvaniaOffice of RegulatoryAffairs3624 Market StreetSuite 301 SPhiladelphia, PA 19104-6006

USA0223

NA Institutional ReviewBoard and Research Development Committee VAGLAHS, WLA11301 Wilshire Blvd. Building 114 Room 329Los Angeles, CA 90073

USA0224

NA OHSU InstitutionalReview Board3181 S.W. Same JacksonPark Rd.Mailcode: L-106-R1Portland, OR 97239

USA0225

NA Chesapeake ResearchReview Inc.7063 Columbia GatewayDrive, Suite 110Columbia, MD 21046

USA0226

NA Cedars Sinai MedicalCenter8700 Beverly Blvd.Los Angeles, CA 90068

USA0229

NA Stanford UniversityResearch and Compliance Administrative Panel on Human Subject in Medical Research Administrative Panels Office1215 Welch Road, Modular AStanford, CA 94305-5401

USA0230*

NA Western InstitutionalReview Board (WIRB)3535 Seventh AvenueSWOlympia, WA 98508

USA0231

NA Penn State College ofMedicinePenn State Milton S. Hershey Medical Center Human Subjects Protection Office600 Centerview Drive, PO Box 855Hershey, PA 17033-0855

USA0232*

NA IRBUniversity of MississippiMedical Center2500 North State StreetJackson, MS 39216-4505

USA0234*

NA NA

USA0235*

NA MCW/FH InstitutionalReview Board8701 Watertown PlankRoadMilwaukee, WI 53226

USA0236

NA Western InstitutionalReview Board (WIRB)3535 Seventh AvenueSWOlympia, WA 98508

USA0237

NA University of MichiganMedical School Institutional Review Board (IRBMED)2800 Plymouth RoadBuilding 200, Room2086Ann Arbor, MI 48109-2800

Brazil1309

Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil

Comitê deÉtica em Pesquisa em Seres Humanos da Irmandade da Santa Casa deMisericórdia de Porto AlegreRua Professor Annes Dias,

295,Porto Alegre– RS, CEP90020-090 - Brazil

Brazil1304

ComissãoNacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous

Comitê deÉtica em Pesquisa em Seres Humanos da Faculdadede Ciências da Saúde – UNBCampusUniversitário Darcy Ribeiro – Faculdadede Ciências da Saúde, Brasília, DF, CEP 70910-000 - Brazil Coordinator: Natan Monsores de Sa

Brazil1302

Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle

Comitê deÉtica em Pesquisa em Seres Humanos do Hospital Vera Cruz RuaTimbiras3156 – 9ºandar – Sala902, BarroPreto, Belo Horizonte- MG, CEP30140-060 - Brazil Coordinator: Carlos Ernesto Ferreira StarlingBrazil

1306Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous

Comitê deÉtica em Pesquisa em Seres Humanos do Hospital SOCORRua Tupis,1540 – BarroPreto, Belo Horizonte, MG – CEP30190-062 - Brazil Coordinator: Luiz Ricardo de Ataide Castro

Brazil1301

Comissão Nacional de Ética em Pesquisa (CONEP) Esplanada dos Ministerios, Bloco "G" - Edificio Anexo- Ala B - 4o andar- Sala436B – Brasilia- DF - CEP70058-900, Brazil Coordinator: Gyselle Saddi Tannous

Comitê deEtica em Pesquisa em Seres Humanos do Fundação Antônio Prudente- Rua Prof. Antônio Prudente,211- Liberdade- São paulo Brazil Chairperson: RicardoRenzoBrentani

Brazil1307


Comitê deÉtica em Pesquisa em Seres Humanos do Hospital Erasto Gaertner/ Liga Paranaense de Combate ao Câncer Rua Dr. Ovande do Amaral, 201– Jardin das Americas Curitiba, PR– CEP81620-060 - Brazil

Brazil1308


Comitê deÉtica em Pesquisa em Seres Humanos do Hospital Moinhos de VentoRua RamiroBarcelos,910,Porto Alegre– RS, CEP90035-001 - Brazil

Brazil1303


Comitê deÉtica em Pesquisa em Seres Humanos da Faculdadede Medicina de São José do Rio PretoAv. Brigadeiro

Faria Lima,5416 –São José do Rio Preto, SP - CEP15090-000 - Brasil –

Brazil1305


Comitê deÉtica em Pesquisa em Seres Humanos do Hospital Lifecenter, Avenida do Contorno,4747 - 20.o andar – Funcion- ários,Belo Horizonte – MG – CEP30110-090 - Brazil Secretary:Pa triciaCaixeta DosSantos

CzechRep.0301

EthicsCommittee of the General University Hospital Prague Na bojisti1128 08 Prague2Czech Republic Chairperson: Josef Sedevy

NA

CzechRep.0302


Eticka komise Fakultni nemocnice Na Bulovce Budinova 2,180 81 Praha8Czech republic

India1109


InstitutionalEthics Committee Basavatarak am Indo American Cancer Hospital & Research Institute Road#14, Banjara Hills500034Hederabad(AP) India Chairperson: Dr. S. S. Reddy

India1104

NA InstitutionalEthics Committee, Shatabdi Super Specialty Hospital Suojit city centre Opp.Maham arg Bus Stand Mumbai Naka422005Nasik India Chairperson: Dr. Neelima Chafekar

India1110

NA EthicsCommittee, Bhagwan Mahaveer Cancer Hospital & Research Centre Jawahar Lal Nehru Marg302017JaipurIndia

India1101

NA The EthicsCommittee Jaslok Hospital & Research Centre15,Dr. G. Deshmukh Marg,Peddar RoadMumbai 400026India Chairperson: A. A. Cazi

India1106

NA Institute ofMedical Sciences, Banaras Hindu University Department of medicine Lanka-221005Varanasi India Chairperson: Dr. J. K. Agrawal

India1108

NA Institutional Ethics Committee, IGIMS, Patna Regional Cancer Centre Indira Gandhi Institute of Medical SciencesSheikhpura-800014Patna India Chairperson: Dr. S.N.P. Sinha

India1102

NA EthicsCommittee- Sir Ganga Ram Hospital Marg Rajinder NagarNew Delhi110060India Chairperson: Dr. S.D.Seth

India1111

NA InstitutionalEthics Committee Office of Research Cell Chhatrapati Shahuji Maharaj Medical University Uttar Pradesh226003Lucknow(UP) India, Chairperson: Dr. U. C. Chaturvedi

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Supplementary Annex 3. Minimal clinically important differences (MCID) derivation

for the carcinoid syndrome (CS) response measures

Background: common methods for MCID determination

Patient-reported outcomes (PROs) are frequently incorporated in clinical trials comparing

treatments for chronic diseases. PROs include measures of quality of life, symptoms,

functioning, and other outcomes and provide the patient’s perspective on the effects of

disease and treatment.1

One of the challenges with using PROs is determining if statistically significant differences

also represent a clinically important difference. Therefore, translating observed changes in a

PRO score into clinically meaningful terms is important in the interpretation of study results.

Information on the interpretation of changes (or differences) in PRO scores is based on the

minimal clinically important difference (MCID). The MCID was first defined as the smallest

difference in score in the domain of interest, which patients perceive as beneficial, and which

would mandate a change in the patient’s management.2

To establish an a priori responder definition (ie, the individual patient PRO score change over

a predetermined time period that should be interpreted as a treatment benefit), two general

approaches are used:

1. Anchor-based approaches compare the change in a PRO score to some other measure

of change, considered an objective external criterion or anchor.3 Two requirements for

the anchor apply: it must be interpretable and be at least moderately correlated with

the target PRO instrument.4 Clinically accepted endpoints, patient-rated global

improvement, change in other PRO measures, or some combination of clinical and

patient-based outcomes can be used for defining a meaningful change in a PRO

measure.1,5 It should, however, be noted that few studies have relied on an objective

external criterion. Due to the lack of such satisfying objective assessment, PRO scores

may be compared to another anchor or subjective assessment (eg, a global assessment

rating) in which the patient rates his/her health status as, for example, “better,”

“unchanged,” or “worse.”3 An anchor should have a nontrivial association with

change in the PRO measure, and a minimum correlation threshold of 0.30 is

recommended to define an acceptable association between an anchor and a PRO

change score.5

2. Distribution-based approaches compare the change in PRO score to some measure of

variability, such as the standard error of measurement (SEM), the standard deviation

(SD), the effect size, or the minimum detectable change.3,6 In essence, these methods

convey a notion that a meaningful change can be estimated based on the distribution

of observed scores in a relevant sample.1

Each of these broad approaches can be further subdivided, and currently there is no

consensus on the best strategy to determine a clinically meaningful difference.

As an alternative to anchor-based or distribution-based methods, the entire distribution of

responses for treatment and control group can be presented through cumulative distribution of

response curves. Cumulative distribution displays show a continuous plot of the percent

change from baseline on the X-axis and the percent of patients experiencing that change on

the Y-axis. With this approach, a variety of responder definitions can be identified along the

cumulative distribution of response curve,6 and the impact of alternative responder criteria on

treatment effect can be estimated.

MCID determination in current analysis

In this analysis, the symptom-based response variables, diarrhea burden (BD) and flushing

burden (BF), each represent a composite endpoint defined as the average of frequency and

severity of symptoms. Distribution-based methods to establish a threshold MCID value for a

bi-dimensional response variable are currently lacking. Hence, an anchor-based approach was

explored to determine a meaningful change for this composite endpoint.

In carcinoid syndrome (CS) there is no established objective external criterion to distinguish

responders from non-responders on PRO patient-centered endpoints, nor did the ELECT trial

collect data on a patient- or clinical-rated global assessment of health status. To identify

alternative anchor candidates, we first explored the associations between the targeted concept

of the PRO instrument (BD and BF) and the concept measured by the anchors (the QLQ

subscale scores of diarrhea [DI] and endocrine symptoms [ENS], respectively).6 This was

accomplished by investigating the correlation structure between BD and BF symptom scores

and QLQ subscale scores. Supplemental Table 1 shows the associations between symptom-

based scores and anchor candidates (only those variables with correlations >0.3 are shown).

Baseline BD was highly correlated with DI, as was baseline BF with ENS.

Supplementary Annex 3, Table S1 Correlationsa between baseline symptom-based scores and baseline QLQ subscale scores of the EORTC QLQ questionnaires.

Domain QLQ QL FreqD SevD BD1 DI FreqF SevF BF1 ENS FreqOQLQ 1.000

P 0.000QL 0.604 1.000P 0.000 0.000

FreqD -0.193 -0.197 1.000P 1.000 1.000 0.000

SevD -0.164 -0.140 0.778 1.000P 1.000 1.000 0.000 0.000

BD -0.194 -0.190 0.984 0.878 1.000P 1.000 1.000 0.000 0.000 0.000DI -0.309 -0.129 0.651 0.753 0.710 1.000P 0.051 1.000 0.000 0.000 0.000 0.000

FreqF -0.182 -0.134 0.270 0.129 0.243 0.037 1.000P 1.000 1.000 0.193 1.000 0.494 1.000 0.000

SevF -0.208 -0.146 0.170 0.232 0.196 0.148 0.729 1.000P 1.000 1.000 1.000 0.688 1.000 1.000 0.000 0.000

BF -0.197 -0.143 0.261 0.157 0.244 0.063 0.989 0.822 1.000P 1.000 1.000 0.262 1.000 0.471 1.000 0.000 0.000 0.000

ENS -0.337 -0.249 0.132 0.073 0.122 0.102 0.677 0.666 0.707 1.000P 0.017 0.440 1.000 1.000 1.000 1.000 0.000 0.000 0.000 0.000

FreqO -0.110 -0.119 0.043 0.058 0.049 0.019 -0.148 0.073 -0.108 -0.018 1.000P 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.000

aOnly correlations greater than 0.3 are shown.Burden of Diarrhea, (BD), is defined as the average of the diarrhea severity (SevD) and frequency (FreqD), i.e., BD=(SevD+FreqD)/2 while burden of flushing (BF), is defined as the average of the flushing severity (SevF) and frequency (FreqF), i.e., BF=(SevF+FreqF)/2).

Abbreviations: EORTC, European Organization for the Research and Treatment of Cancer; DI, diarrhea subscale of the EORTC core quality of life questionnaire QLQ-C30; ENS, Endocrine subscale of the EORTC quality of life questionnaire for gastrointestinal neuroendocrine tumors (QLQ-GINET21); FreqD, mean diarrhea frequency; SevD, mean diarrhea severity; BD, mean diarrhea burden; FreqF, mean flushing frequency; SevF, mean flushing severity; BF, mean flushing burden; r, Pearson’s correlation coefficient; N, number of case pairs in the correlation analysis.

The associations between changes of the different response variables from baseline to week

12 were further explored. Supplemental Table 2 shows that changes in BD and BF were

highly correlated with changes in DI and ENS, respectively. Therefore, DI and ENS were

retained as anchors to determine the MCID threshold for the BD and BF, respectively.

Supplementary Annex 3, Table S2 Correlationsa between change from baseline to week 12 of symptom-based scores and the changes from baseline to week 12 in the diarrhea and endocrine symptoms subscale scores of the EORTC QLQ questionnaires.

Domain dQLQb dQL dFreqD dSevD dBD dDI dFreqF dSevF dBF dENS dFreqOdQLQ 1.000 . . . . . . . . . .P 0.000 . . . . . . . . . .

dQL 0.222 1.000 . . . . . . . . .P 1.000 0.000 . . . . . . . . .

dFreqD -0.138 -0.211 1.000 . . . . . . . .P 1.000 1.000 0.000 . . . . . . . .

dSevD -0.208 -0.225 0.800 1.000 . . . . . . .P 1.000 1.000 0.000 0.000 . . . . . . .

dBD -0.166 -0.224 0.981 0.902 1.000 . . . . . .P 1.000 1.000 0.000 0.000 0.000 . . . . . .dDI -0.442 -0.210 0.519 0.636 0.578 1.000 . . . . .P 0.002 1.000 0.000 0.000 0.000 0.000 . . . . .

dFreqF -0.087 -0.027 0.222 0.175 0.217 0.074 1.000 . . . .P 1.000 1.000 1.000 1.000 1.000 1.000 0.000 . . . .

dSevF -0.238 -0.189 0.297 0.344 0.326 0.290 0.555 1.000 . . .P 1.000 1.000 0.261 0.053 0.101 0.458 0.000 0.000 . . .

dBF -0.137 -0.076 0.265 0.240 0.269 0.142 0.972 0.736 1.000 . .P 1.000 1.000 0.658 1.000 0.587 1.000 0.000 0.000 0.000 . .

dENS -0.300 -0.162 0.385 0.316 0.379 0.258 0.358 0.463 0.421 1.000 .P 0.418 1.000 0.022 0.226 0.027 1.000 0.057 0.001 0.005 0.000 .

dFreqO -0.154 0.138 0.256 0.263 0.270 0.069 0.057 0.115 0.079 0.078 1.000P 1.000 1.000 0.855 0.700 0.579 1.000 1.000 1.000 1.000 1.000 0.000

aOnly correlations greater than 0.3 are shown.bThe “d” prefix denotes that the variable represents a change from baseline to week 12.

Abbreviations: EORTC, European Organization for the Research and Treatment of Cancer; DI, diarrhea subscale of the EORTC core quality of life questionnaire QLQ-C30; ENS, Endocrine subscale of the EORTC quality of life questionnaire for gastrointestinal neuroendocrine tumors (QLQ-GINET21); FreqD, diarrhea frequency; SevD, diarrhea severity; BD, diarrhea burden; FreqF, flushing frequency; SevF, flushing severity; BF, flushing burden; r, Pearson’s correlation coefficient; N, number of cases in the analysis.

Next, the relevant change in the anchor variables was determined. It is widely accepted that a

change of half a standard deviation in a response variable represents a meaningful change.7

The standard deviations for DI and ENS were 31.0 and 23.6, respectively.

The single-question DI subscale “Have you had diarrhea” varies between zero (“Not at all”)

to 100 (“Very much”), where a one-step change corresponds to a value of 33.3, which is

larger than a full standard deviation and, hence, appropriate as a meaningful change. The 3-

item ENS subscale varies from 0 (“No endocrine symptoms”) to 100 (“Very much”) in steps

of 11.1, which is very close to half a standard deviation. Consequently, patients were

classified as experiencing an improvement (responder) if they experienced a change in DI or

ENS of at least one step from screening to week 12.

Finally, receiver operating characteristics (ROC) curves were used to establish a threshold

MCID level. This is a frequently used approach that aims to select an MCID that allows for

the most accurate discrimination between responders and non-responders (ie, a score that

maximizes the correct classification of patients).1,3,4,8

In this context, the PRO instrument at issue (BD or BF) is considered the diagnostic test, and

the anchor (DI or ENS) functions as the gold standard. The anchor distinguishes subjects who

are importantly improved from those who are not changed or have gotten worse. The

instrument’s sensitivity is the proportion of importantly improved subjects according to the

anchor, who are correctly identified by the PRO instrument as importantly improved. Its

specificity is the proportion of “not changed/worse” subjects according to the anchor, who are

correctly identified as “not changed/worse” by the PRO instrument. The conventional ROC

cut-off point is the value for which the sum of proportions of false-positive and false-negative

classifications ([1-sensitivity] + [1-specificity]) is smallest.

It should be noted that a desirable MCID sensitivity or specificity level has yet to be

determined.3 If they are justified, alternative cut-off points are acceptable.8 In our analysis,

the optimal cut-off point was selected to minimize the number of misclassifications. The use

of the conventional sensitivity/specificity‒based ROC cut-off led to a BF MCID value of

0.05, which we felt to be lacking face validity. Analysis of the underlying data showed this

was due to a large number of patients who had no change in BF, as shown by the horizontal

line in the middle of the X axis on the ROC curve. Hence, the MCID threshold that

maximized the number of accurate classifications for BD was established at 0.62 with a

sensitivity of 62.5% and specificity of 88.0%. The area under the ROC curve was acceptable

at 80.6%.3 Similarly for BF, compared to the ENS anchor, sensitivity was 68.8% and

specificity was 87.8%, with an area under the ROC curve of 79.7%.

Supplementary Annex 3, Figure S1. ROC curves for changes in BD (Figure 1A) and BF

(Figure 1B) vs their respective anchors.

BD, diarrhea burden; BF, flushing burden; ROC, receiver operating characteristics.

As mentioned, anchor-based methods use a clinically accepted criterion or an appropriate

patient-based rating of change in health status for defining a meaningful change in a PRO

measure.5 The ELECT trial did not collect a clinician- or patient-reported assessment of

change at the end of the trial that could be used as an anchor to establish a clinically

meaningful change (responder) on the QoL-C30 summary score (SS). The two-item QL

(Global health status) domain of the QLQ-C30 could be considered as a potential anchor. The

correlation between baseline values of the QLQ-C30 SS was found to be acceptable (0.60);

however, the correlation between change from baseline to week 12 in the QL and SS was

inadequate (0.22). This finding was in line with previous reports that found that the two-item

Global QL scale of the QLQ-C30 was not sensitive enough to detect group differences.9 In

the absence of a suitable anchor for the QLQ-C30, a distribution-based approach was

followed, using the standard error of measurement (SEM) as outlined above.6

REFERENCES

1. Revicki DA, Cella D, Hays RD, Sloan JA, Lenderking WR, Aaronson NK.

Responsiveness and minimal important differences for patient reported outcomes.

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