31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) SUMMARY OF CHANGES 1- Qualisex questionnaire Background: This ancillary study to ECLAIR is set up to measure the impact of certolizumab pegol (CZP) treatment on sex life of patients suffering from RA, assessed by Qualisex questionnaires, as an additional quality of life parameter. Summary of modifications brought to the below-mentioned sections Section 1: Summary Qualisex questionnaire added Section 3.2 : Secondary objectives An additional secondary objective added: The impact of the treatment on quality of sexual life as measured by the Qualisex questionnaire (see Appendix 17.2) Section 4.1.2: Secondary variables An additional secondary variable added: Change from Baseline at 3, 6, 12, 18, 24 and 36 months in patient s quality of sexual life as measured by the Qualisex questionnaire Section 5.2.: Schedule of Study assessments An additional assessment added: Qualisex questionnaire (See Appendix 17.2) performed at each visit. Section 8.2. : From the patients Qualisex questionnaire added Section 8.3.2. : Site initiation Patients questionnaires, «including Qualisex (Ancillary study questionnaire- See Appendix 17.2)» Section 8.4.1.: Patients inclusion- Hospital rheumatologists and internal medicine specialists Give the patient HAQ-DI, SF-36 and Qualisex Baseline questionnaires. The questionnaires will be filled in by the patient alone in the physician's office. 3
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) Section 8.4.2.: Patients inclusion- Private rheumatologists and general practitioners «Patients questionnaires, including Qualisex (Ancillary study questionnaire)» Section 8.5. :Follow-up HAQ-DI, SF-36 and Qualisex follow-up questionnaires will be filled in by the patient in the physician's office and handed in to the physician who will send them in a pre-paid envelope provided by REGISTRAT-MAPI. Section 9.8.: Qualisex Questionnaire (see Appendix 17.2) added Qualisex questionnaire is a simple and valid tool investigating impact of RA on sexuality. A 10- question questionnaire was constructed, with assessement by numeric rating scale from 0 (no impact of RA) to 10 (full impact of RA). The questionnaire contains 2 general questions, 1 question on negative aspect of medication, 2 on self-perception, 2 on couple/relationship, 2 on RA related physical difficulties and 1 on performance. An answer modality not applicable allows this questionnaire to be distributed to all patients whatever the situation (single or with a partner). The validated of Qualisex questionnaire in French will be used in this study. The patient will be prompted to complete the questionnaire at the physician s office and handed in to the physician who will send it in a pre-paid envelope provided by REGISTRAT-MAPI.together with SF36 The questionnaire will be used in parallel to SF-36 at baseline and after 12 months and also in all follow-up visits, as an additional secondary objective in ÉCLAIR study. This evaluation will be conducted among a subgroup of patients after implementation of this amendment. Section 12.3.3.: Analyses of secondary variables Qualisex added The scores of the 8 dimensions (Physical functioning, Role-physical limitations, Bodily pain, General health, Vitality, Mental health, Role-emotional limitations, Social functioning) and 2 summary measures (Physical component summary score and Mental component summary score) of the SF-36 and Qualisex questionnaire will be described at each visit and changes from Baseline will be computed at each follow up visit. 4
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) Section 12.8.: Sample size calculation for the ancillary study added (see Appendix 17.2) Sample size calculation for the ancillary study: The primary objective of the ancillary study is to evaluate CZP impact on sexual life at 12 months compared to baseline assessed by Qualisex questionnaire using 10 questions scored from 0 (minimum impact on sexuality) to 10 (maximum impact ). An overall score is calculated by averaging the responses and therefore varies from 0 to 10. Secondary objective of the ancillary study is to evaluate this score during follow-up visits versus baseline. The number of subjects required is calculated to ensure a satisfactory level of accuracy to describe the response at 12 months. The data available in the literature are taken from the article "Elaboration and validation of a questionnaire (Qualisex) to assess the impact of rheumatoid arthritis on sexuality with patient involvement" Gossec L, Solano C, Paternotte S, Beauvais C, Gaudin P, von Krause G, Sordet C,.Perdriger A. - Clinical and experimental Rheumatology. Qualisex average score obtained among 53 patients was 3.3 (+ / -2.5). In the ancillary study, the inclusion of 300 to 400 patients will be sufficient to compute the average score for patients answering the questionnaire with an accuracy of + / - 0.4 around an average score of 3.3 and detect a significant change(around 24%) in the score from 12 months versus baseline(assumption of a change of 0.8 between baseline and one year). Considering a variation of the mean score of 2.5 (standard deviation), a bilateral significance level α of 5%, a significance level β of 10% (90% power), a CZP treatment maintenance level at 65% at one year and a drop-out rate at 20%, the calculation leads to a subgroup of 335 patients to be included. The calculation is performed with SAS 9.2 - (Proc Power - Onesamplemeans). Section 15.: Ancillary study references added HELLAND Y, et al.: Rheumatic diseases and sexuality : Disease impact and self management strategies. Arthritis Care Res (Hoboken). 2011 Jan 10. (Epub ahead of print) Pub Med PMID: 21225671. Gossec L, Solano C, Paternotte S, Beauvais C, Gaudin P, von Krause G, Sordet C,.Perdriger A. : Elaboration and validation of a questionnaire (Qualisex) to assess the impact of rheumatoid arthritis on sexuality with patient involvement. Clin Exp Rheumatol. 5
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) Section 17.2.: APPENDIX 2: Ancillary Study Protocol added EVALUATION OF CIMZIA (CERTOLIZUMAB PEGOL) TREATMENT ON SEXUAL LIFE OF PATIENT SUFFERING FROM RA ASSESSED BY QUALISEX QUESTIONNAIRE. Background: This ancillary study to ÉCLAIR is set up to measure the impact of certolizumab pegol (CZP) treatment on sex life of patients suffering from RA, assessed by Qualisex questionnaires, as an additional quality of life parameter. Little is known about the characteristics of RA difficulties in sex life compared to other inflammatory disorders (1-) as well as about treatment effect on this parameter. Qualisex questionnaire, a simple (10 questions) and valid tool investigating impact of RA on sexuality, has been developed by Professor Perdriger s team after a 10 year collaboration with sexologists, rheumatologists and patients. This new tool can be useful to assess this important, though neglected, aspect of quality of life as well as the efficacy of CZP treatment on it. The questionnaire will be used in parallel to SF-36 at baseline and after 12 months and also in all follow-up visits, as an additional secondary objective in ÉCLAIR study. This evaluation will be conducted among a subgroup of patients after implementation of this amendment. Number of subjects required in ÉCLAIR study: The main study is aiming at 750 enrolled patients. As of end of July, 520 patients still need to be enrolled. The remaining patients still to be enrolled are sufficient to answer the question of the ancillary study using "Qualisex"tool. Additionnally, the calculation of required number of patients for this ancillary study will be integrated in the amended study protocol (amendment n 2). ECLAIR primary objective: The main objective of ECLAIR is to describe the disease outcome at 12 months, in patients with moderate to severe active RA treated with CZP, assessed by the EULAR response criteria: responders (good or moderate response) and non- responders (no response), based on the DAS 28 (ESR) score. The sample size of the study was computed to ensure a satisfactory level of accuracy to describe the EULAR response at 12 months. A population of 323 patients is sufficient to estimate with a 95% confidence interval, a response of 60% to 80% with an acceptable precision of around 5%. To get 323 analyzable patients still under CZP at week 52, it was planned in the protocol to include 750 patients considering a lower treatment maintenance rate of 55% at 12 months and a drop-out rate at 20%. 6
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) 520 patients are still likely to be included in the ÉCLAIR study. Sample size calculation for the ancillary study: The primary objective of the ancillary study is to evaluate CZP impact on sexual life at 12 months compared to baseline assessed by Qualisex questionnaire using 10 questions scored from 0 (minimum impact on sexuality) to 10 (maximum impact ). An overall score is calculated by averaging the responses and therefore varies from 0 to 10. Secondary objective of the ancillary study is to evaluate this score during follow-up visits versus baseline. The number of subjects required is calculated to ensure a satisfactory level of accuracy to describe the response at 12 months. The data available in the literature are taken from the article "Elaboration and validation of a questionnaire (Qualisex) to assess the impact of rheumatoid arthritis on sexuality with patient involvement" Gossec L, Solano C, Paternotte S, Beauvais C, Gaudin P, von Krause G, Sordet C,.Perdriger A. - Clinical and experimental Rheumatology. Qualisex average score obtained among 53 patients was 3.3 (+ / -2.5). In the ancillary study, the inclusion of 300 to 400 patients will be sufficient to compute the average score for patients answering the questionnaire with an accuracy of + / - 0.4 around an average score of 3.3 and detect a significant change(around 24%) in the score from 12 months versus baseline(assumption of a change of 0.8 between baseline and one year). Considering a variation of the mean score of 2.5 (standard deviation), a bilateral significance level α of 5%, a significance level β of 10% (90% power), a CZP treatment maintenance level at 65% at one year and a drop-out rate at 20%, the calculation leads to a subgroup of 335 patients to be included. The calculation is performed with SAS 9.2 - (Proc Power - Onesamplemeans). Since this number of patients is lower than the one remaining to be included in the ÉCLAIR study, it is thus possible to perform this ancillary study. 7
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) References: 1- HELLAND Y, et al.: Rheumatic diseases and sexuality : Disease impact and self management strategies. Arthritis Care Res (Hoboken). 2011 Jan 10. (Epub ahead of print) Pub Med PMID: 21225671. 2- Gossec L, Solano C, Paternotte S, Beauvais C, Gaudin P, von Krause G, Sordet C,.Perdriger A. : Elaboration and validation of a questionnaire (Qualisex) to assess the impact of rheumatoid arthritis on sexuality with patient involvement. Clin Exp Rheumatol. Qualisex questionnaire added 8
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) Qualisex questionnaire- English (1/2) 9
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) Qualisex questionnaire- English (2/2) 10
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) Qualisex questionnaire- French (1/2) 11
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) Qualisex questionnaire- French (2/2) 12
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) 2- Contact Information Modification n 1 from: Clinical Project Manager Name: Address: Ghislaine Lizon (REGISTRAT-MAPI) 27, rue de la Villette 69003 LYON, France Phone: +33 4 72 13 65 76 Fax: +33 4 78 53 67 61 To: Clinical Project Manager Name: Virginie Duroyon (REGISTRAT-MAPI) Address: 27, rue de la Villette 69003 LYON, France Phone: +33 1 53 02 07 75 Modification n 2 from: Clinical Trial Biostatistician Name: BOUSSETTA Sami (REGISTRAT-MAPI) Address: 27, rue de la Villette 69003 LYON, France Phone: + 33 4 72 13 55 83 Fax: +33 4 78 53 67 61 13
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) To: Clinical Trial Biostatistician Name: VIDAL Chrystelle (REGISTRAT-MAPI) Address: 27, rue de la Villette 69003 LYON, France Phone: + 33 4 72 13 69 54 Fax: + 33 4 72 13 66 61 3- Study timelines - Section 1- Summary Modification from: Study timelines First Patient first visit (FPFV) December 2011 Last Patient first visit (LPFV) December Last Patient last visit (LPLV) December 2015 Interim analysis Report (IAR) March 2015 Final statistical report (FSR) March 2016 To: Study timelines First Patient first visit (FPFV) December 2011 Last Patient first visit (LPFV) December Last Patient last visit (LPLV) December 2015 First Interim analysis Report (FIAR) March 2013 Second Interim analysis Report (SIAR) March 2014 Final statistical report (FSR) March 2016 14
31 July Addition of an ancillary study: Evaluation of Cimzia (Certolizumab pegol) Planned Interim analysis- Section 12.6. Modification from: Two interim analyses will be performed for all patients included: - The first interim analysis after 1-year follow-up (i.e., 12-month visit) - The second interim analysis after 2-year follow-up (i.e., 24-month visit) To: Two interim analyses will be performed for all patients included: - The first interim analysis after 1-year follow-up (i.e., 12-month visit) - The second interim analysis after 2-year follow-up (i.e., 24-month visit) - In addition, a descriptive analysis will be performed for all enrolled patients at the end of the inclusion period 15