RITAZAREM. CRF Completion Guidelines

Transcription

1 RITAZAREM CRF Completion Trial Title: Protocol Number: An international, open label, randomised controlled trial comparing rituximab with azathioprine as maintenance therapy in relapsing ANCA-associated vasculitis V3 IRAS ID: EudraCT Number: Investigational Product: Chief Investigator: Trial Sponsor: Rituximab David Jayne / Peter Merkel Cambridge University Hospitals NHS Foundation Trust and University of Cambridge Fax/ all completed CRFs to the RITAZAREM Data Manager at the following address RITAZAREM Data Manager FAX: +44(0) RITAZAREM@medschl.cam.ac.uk CRF pages should be sent within 2 weeks of the end of a treatment cycle/trial visit. SAE forms have a more urgent timeline, detailed in section 4.9. Remember to retain each completed CRF for your site records. Remember that CRFs (and any other study-related documentation) sent to the Data Manager MUST NOT contain any patient-identifiable data. Version No 2.0 Page 1 of 21

2 Version Date Changes June July 2013 Renaming of Infections (non-sae) Form to Infections Form September 2013 PROMIS questionnaire used from Month 0 onwards, not from Screening July 2017 Updated and more detailed instructions ALL CRFs covered Cumulative doses of Rituximab and Methylpredniso(lo)ne always to be reported at M24 Treatment drugs for infections always to be added to the ConMeds Version No 2.0 Page 2 of 21

3 Contents 1 List of RITAZAREM Case Report Forms Abbreviations Case Report Form Overview General Principles for CRF Completion Header Boxes Footer Boxes Patient Data Completion of Dates Entering numbers Unavailable Data Amend Incorrect Data Sending CRFs to the Data Manager/Coordinator Enrolment Form Eligibility Review Form Baseline Medical History Form Clinical Laboratory Tests Concomitant Medications BVAS/WG Treatment Form CDA (Combined Damage Assessment Index) Questionnaires (EQ5D, PROMIS, SF-36) Follow Up Form Randomisation Form Relapse Form Withdrawal (from Protocolised Treatment) Forms Version No 2.0 Page 3 of 21

4 Death Form End of Trial Form PI Certify Form Infections Form (AEs) Serious Adverse Event (SAE) Reporting Form Pregnancy Form Adverse Event Form for Reporting a New Relevant Concomitant Medication. 18 Adverse Event Form for Reporting a New Relevant Laboratory Abnormality.. 18 Adverse Event Form for Reporting New Malignancies Appendix Appendix Appendix Version No 2.0 Page 4 of 21

5 1 List of RITAZAREM Case Report Forms Visit Screening, M0, M1.5, M3, M4, M8, M12, M16, M20, M24, M27, M30, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit Screening Screening Screening/Baseline (M0) Screening/Baseline (M0) M1.5, M3, M4, M8, M12, M16, M20, M24, M27, M30, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit Screening/Baseline (M0) M0, M1.5, M3, M4, M8, M12, M16, M20, M24, M27, M30, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit M0, M1.5, M3, M4, M8, M12, M16, M20, M24, M27, M30, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit Week 1-4 M4, M8, M12, M16, M20 M0, M4, M12, M24, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit M0, M4, M12, M24, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit M0, M4, M12, M24, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit M0, M1.5, M3, M4, M8, M12, M16, M20, M24, M27, M30, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit M0, M1.5, M3, M4, M8, M12, M16, M20, M24, M27, M30, M36, M42, M48, Relapse or Study Termination/Withdrawal Visit M4 CRF Name Check List Form Eligibility Review Form Enrolment Form Baseline Medical History Form Clinical Laboratory Tests Form Clinical Laboratory Tests Form Concomitant Medications Form Concomitant Medications Form BVAS/WG Form Treatment Form Rituximab CDA Form SF-36 (V1) Form EQ5D Form PROMIS Questionnaire Follow Up Form Randomisation Form Death Form End of Trial Form Infections Form AE Form for Reporting New Malignancies AE Form for Reporting a New Relevant Laboratory Abnormality AE Form for Reporting a New Relevant Concomitant Medication PI Certify Form Relapse Form Withdrawal from Protocolised Treatment Withdrawal Form Version No 2.0 Page 5 of 21

6 2 Abbreviations Abbreviation AE BLMH BSA BVAS/WG CCTU CDA ClinLabs ConMeds CRF EQ5D FDA FEV1 FVC GC GCP ICH IV M MedDRA NA NAD ND NK PGA PI PROMIS Rel/WD SAE SUSAR UK Adverse Event Baseline Medical History Form Body Surface Area Full Term Birmingham Vasculitis Activity Score for Wegener s Granulomatosis Cambridge Clinical Trials Unit Combined Damage Assessment Index Clinical Laboratory Tests Form Concomitant Medications Form Case Report Form EuroQol 5D Quality of life Questionnaire Food and Drug Administration Forced Expiratory Volume in 1 second Forced Vital Capacity Glucocorticoid Good Clinical Practice International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Intravenous Month Medical Dictionary for Regulatory Activities Not Applicable No Abnormalities Detected Not Done Not Known Physicians Global Assessment Principal Investigator Patient Reported Outcomes Measurement Information System Relapse or Study Termination/Withdrawal Visit Serious Adverse Event Suspected Unexpected Serious Adverse Reaction Unknown Version No 2.0 Page 6 of 21

7 3 Case Report Form Overview CRF NAME Screening M0 M1.5 M3 M4 M8 M12 M16 M20 M24 M27 M30 M36 M42 M48 Rel/WD Check List BLMH Eligibility Review Enrolment Clinical Labs BVAS/WG CDA EQ5D SF-36 PROMIS Questionnaire ConMeds Randomisation Treatment (x4) Follow-Up Infections AE New ConMeds AE New Malignancy AE Lab Abnormality Withdrawal from Protocolised Treatment Withdrawal End of Trial Death Relapse PI Certify Key Done at this visit Version No 2.0 Page 7 of 21

8 4.1 General Principles for CRF Completion 4 General Completion Always refer to the study protocol before completing forms. Ensure that the correct version (most to-date version is V3) of the CRF form is used. A comprehensive list can be found on the RITAZAREM trial website at: Data reported on the CRF must be extracted from, and be consistent with, documented source data (usually the patients medical notes). All data recorded on the study forms will be verifiable in the source documents maintained by the clinical sites according to FDA and ICH Good Clinical Practice (GCP) guidelines. Questionnaires (SF-36, EQ5D, PROMIS) are completed by the study participant. Local language versions are available on the RITAZAREM website. Some CRF pages, for example the ConMeds Form and the Infections Form, may require more than one page to be completed but the number of pages is unknown before CRF completion. In this case, digit boxes are provided in the notation, which should be completed to indicate how many pages were populated All CRF pages must be clear, legible and completed using a black pen o Important as 1 and 7 can be misrepresented if the writing is not clear 1 or I and 7 or 7 Avoid abbreviations and acronyms, unless they are standard medical abbreviations known to be acceptable Do not write outside the designated boxes (excluded are results with more digits after the decimal point, e.g. for IgG, IgM and IgA on ClinLabs/p.2, than available boxes on the CRF) Where selection boxes indicate a selection of Y or N or numerical options (i.e. 1, 2, 3), only ONE entry should be recorded per box (excluded are results with more digits after the decimal point, e.g. for IgG, IgM and IgA on ClinLabs/p.2, than available boxes on the CRF) Tick/Check the box to indicate the units used for weight, height, lab results, etc. Some questions will require a code to be entered according to a key provided (e.g. on the ConMeds Form). Ensure that you read the key for each section and follow any further instructions provided. CRFs must only be completed by authorised personnel who have received trial-specific training and are competent in CRF completion. They should also have completed and signed the site s RITAZAREM Delegation of Responsibilities Log The CRFs must be completed, dated and signed by an Investigator or designee as soon as the requested information is available and the ORIGINAL CRF pages returned promptly to the trial file Once a CRF is completed, ensure a copy is placed in the patient s trial file. This may be a photocopy or the original if the CRFs are faxed/scanned and ed to the Data Manager or the Coordinator (in case of SAEs). The investigator site should always retain a copy of each completed form If a patient fails to attend an appointment or if for some other reason a scheduled assessment is missed, a File Note with an explanation as to the reasons should be provided to the Coordinator/Data Manager Version No 2.0 Page 8 of 21

9 Completed CRFs should be returned to the Data Manager in Cambridge within 2 weeks of the patient visit. Any changes made to the CRF pages must be sent to the Data Manager within 2 weeks, see section 4.9 Sending CRFs to the Data Manager The timely completion, legibility and accuracy of the CRFs remain the responsibility of the Investigator or designee. 4.2 Header Boxes The following data must be completed in the header of every completed CRF: - Patient Initials: If 2 initials, use a dash in the middle digit box (e.g. A - B B ) - Patient Date of Birth: Enter using the DD/MMM/YYYY format (e.g. 13 AUG 2013) - Subject ID number: Each subject will receive a unique XXX-XXXX trial number upon enrolment consisting of a Site ID (e.g. N01, provided by the CCTU) and the Patient Study ID (e.g. 012) => N Ensure that the header information is consistent on every completed CRF page 4.3 Footer Boxes The following data must be completed in the footer of every completed CRF: - Signature: Signature of person completing the form - Date: Enter using the DD/MMM/YYYY format (e.g. 13 AUG 2013) 4.4 Patient Data CRFs (and any other study-related documentation) sent to the Trial Coordinator and/or the Data Manager MUST NOT contain any patient-identifiable information Please use ONLY the Patient s Initials, Date of Birth and Subject ID number when communicating with the RITAZAREM team 4.5 Completion of Dates All dates are to be completed in the sequence day/month/year (DD/MMM/YYYY) with the month written using LETTERS not numbers If the day or month is unknown complete the boxes with NK or UK 4.6 Entering numbers Enter a digit in each box provided, if three boxes are provided but only two are required please enter a preceding 0 e.g Always complete each box, also if the number is an integer e.g mg 4.7 Unavailable Data All applicable questions must be answered and every field on each CRF page (unless indicated otherwise) filled in Where data are not available please do not leave the answer blank as this will create unnecessary data queries Please include one of the following abbreviations instead: - NK = Not known - NA = Not applicable Version No 2.0 Page 9 of 21

10 - ND = Not done - UK = Unknown 4.8 Amend Incorrect Data Typing correction fluid should NOT be used To amend incorrect data on a CRF page: o Score through the error with a single line o Write the correct data nearby o Initial and date each correction (to be done by authorised personnel listed on the site delegation log) o Ensure a copy of the amended CRF is retained at site along with the copy of the original which was sent 4.9 Sending CRFs to the Data Manager/Coordinator Please /fax the CRFs to: Kerstin Wolf Tel: +44(0) FAX: +44(0) RITAZAREM@medschl.cam.ac.uk Fully completed SAE/PREGNANCY forms should be sent to the trial coordinator by /fax within 24 hours of becoming aware of the event Kim Mynard Tel: +44(0) (x.59350) SAE FAX: +44(0) RITAZAREM@medschl.cam.ac.uk Other CRF pages should be sent in a timely manner, ideally within two weeks of the end of a treatment/period/visit Version No 2.0 Page 10 of 21

11 5 Completion Note: are only provided for questions on the Case Report Form (CRF) where guidance will be of benefit to support completion. Therefore, not all questions on the CRFs are covered by these guidelines. Contact the Coordinator or Data Manager if you require clarification on any questions. Enrolment Form Enter the patient s height, weight, predniso(lo)ne regimen, ANCA and relapse type Log into the Enrolment/Randomisation System at and enter the required information The system will calculate and output the Body Surface Area (BSA) and the induction dose of Rituximab (mg/infusion), and provide the target randomisation date. The Study ID of the patient will also be generated at this stage. Enter these data on the Enrolment Form Eligibility Review Form For a patient to be eligible, all inclusion criteria questions must be answered Yes and all exclusion criteria questions must be answered No. Answer ALL questions on the form The Evaluation Date cannot be a more recent date than the Date of Consent Baseline Medical History Form The completion of the CRF is required at screening, once the patient has given informed consent and has been deemed eligible for the study Clinical Laboratory Tests Ensure all questions are completed ClinLabs results are permitted to be within ± 2 weeks of the evaluation date. Results with more digits after the decimal point than available boxes on the CRF, e.g. for IgG, IgM and IgA on ClinLabs/page 2, can be entered outside but close to the available box A single Lymphocyte marker can be reported. Date Test Done applies to either one reported CD19 result or to both. Version No 2.0 Page 11 of 21

12 Concomitant Medications The ConMeds Form is not a running log! A new form must be completed at each assessment point even if there are no changes to the medications Use the available key for Category and Frequency for reporting Only record prescribed medications; it is not necessary to list vitamins or other dietary supplements If more than one page is needed at a visit, complete multiple pages and document the page number: The question New since last trial visit? refers to new medications not new dosages of ongoing medications Study drugs such as Rituximab, IV Methylprednisolone, Methotrexate and Mycophenolate Mofetil don t have to be reported on the ConMeds Form. If reported, ensure the details (dose, unit, frequency) match the reporting on the Follow Up form. Exception: Rituximab, if administered off protocol, has to be reported on the ConMeds Form! Ensure medications administered to treat Infections (Adverse Events) are added to the ConMeds Form. BVAS/WG There is a separate BVAS/WG form for each assessment point; please ensure you use the correct form for the assessment. BVAS/WG is designed to capture clinical features that are directly due to active disease. In addition, the instrument separates the features that represent new or worse disease activity from those that represent persistent activity. When scoring BVAS/WG, it is important not to confuse activity with damage. Damage, defined as the presence of non-healing scars, is a concept distinct from current disease activity Only tick the Persistent box if the abnormality is persistent disease activity since the last assessment and not worse within the previous 28 days Only tick the New/Worse box if the abnormality since the last assessment is newly present or worse within the previous 28 days If required, minor items can be raised to the status of a major item by adding an asterisk (*) to the item. Please sign and date the amendment Version No 2.0 Page 12 of 21

13 Items reported as persistent for more than 6 months should be reported on the CDA CRF (see below) If both Hematuria (item 8.a.) and *RBC casts (item 8.b.), Renal section, are present, score only the RBC casts (the major item). Ensure section 11. Total Number of Items (page 2) is completed and the sum for each group matches the items ticked/checked on the form If no items for a category were reported, complete the respective total(s) as 0 Detailed information on BVAS/WG completion can be found as part of the BVAS/WG Training Package. Treatment Form Complete this form for all patients randomised to the Rituximab treatment at the following points in the trial: Weeks 1-4 (Induction Phase) M4 (Maintenance Phase) M8 (Maintenance Phase) M12 (Maintenance Phase) M16 (Maintenance Phase) M20 (Maintenance Phase) Complete a new form each time an infusion is given Rituximab treatment off protocol and/or outside the induction and maintenance phases should be documented on the ConMeds Form Circle the appropriate treatment week/month If, for any reason, an infusion was not given or could not be completed, the treatment form should still be completed indicating the reason for it. CDA (Combined Damage Assessment Index) Damage items should NOT in general disappear.0 Once reported (e.g. at the M0 visit), the item has to be reported on all following CDAs independent of the damage still existing (e.g. high blood pressure) Ensure all questions are completed. If a damage is reported in a section (e.g. in the Cardiac section), ensure a Yes/No response is given for ALL items in this section If a damage is reported in the Pulmonary section (page 2), ensure FVC, FEV1, and Right Ventricular Systolic Pressure is either reported or an indication of N/A or not measured is given. Version No 2.0 Page 13 of 21

14 Questionnaires (EQ5D, PROMIS, SF-36) Complete the header information before releasing the documents to the patient (If possible) Review the completed form to ensure all questions have been answered Follow Up Form Ensure a Yes/No response to the question regarding a deviation from the GC protocol is provided. Is the patient withdrawn from protocol, always tick No (and no specification is required). A deviation can no longer occur. Always report cumulative doses of Rituximab (1.b.) and IV Methylprednisolone (1.c.) at M24 independent of the Yes/No response for these items Ensure the following CRFs are provided in case of a Yes response: o 3.a. - Death Form o 3.b. - Relapse Form o 3.c. Infections Form o 3.d. - SAE Form o 3.e. - New Malignancy Form Randomisation Form The form should be completed at M4 ± 2 weeks from the Target Randomisation Date calculated with the Tenalea Enrolment/Randomisation System Enter the current Predniso(lo)ne dose and the BVAS/WG score. Log into the randomisation system at and enter the required information The system will provide the treatment assignment. Tick the relevant box on the CRF Relapse Form The date of relapse for the purpose of this study is the date that symptoms necessitated a treatment change, which may differ from the evaluation date. A relapse can occur between study visits. Version No 2.0 Page 14 of 21

15 In addition to the Relapse Form, the following CRFs should be completed at the time of relapse: o Follow Up o ConMeds o ClinLabs o BVAS/WG o CDA o EQ5D o SF-36 o PROMIS If the relapse occurred between visits, use the Relapse/Withdrawal Visit CRFs available in section Other Forms on the RITAZAREM website: If the relapse occurred at the time of a scheduled visit, use the visit CRFs for this particular visit and (if necessary) supplement missing CRFs (e.g. CDA, EQ5D and SF-36) with the relevant CRFs from the Relapse/Withdrawal Visit package If none of the CRFs could be completed at the time of relapse, provide a File Note with an explanation. For single, missing CRFs, simply record Not done on the Check List Withdrawal (from Protocolised Treatment) Forms The Withdrawal Form is to be completed when the patient has completely withdrawn from the study (e.g. because of death or withdrawal of consent) and no further data will be submitted after this event. The Withdrawal from Protocolised Treatment Form is to be completed when protocolised treatment is withdrawn (e.g. in case of a major or second minor relapse). The patient will continue to be followed up for safety purposes until the end of the trial. In addition to the Withdrawal (from Protocolised Treatment) Form, the following CRFs should be completed at the time of withdrawal from study or withdrawal from treatment: o Follow Up o ConMeds o ClinLabs o BVAS/WG o CDA o EQ5D o SF-36 o PROMIS If the withdrawal occurred between regular visits, use the Relapse/Withdrawal Visit CRFs available in section Other Forms on the RITAZAREM website: If the withdrawal occurred at the time of a scheduled visit, use the visit CRFs for this particular visit and (if necessary) supplement missing CRFs (e.g. CDA, EQ5D and SF-36) with the relevant CRFs from the Relapse/Withdrawal Visit package If none of the CRFs could be completed at the time of withdrawal, provide a File Note with an explanation. For single, missing CRFs, simply record Not done on the Check List Only record/tick one reason for withdrawal (e.g. on the Withdrawal from Protocolised Treatment Form) Version No 2.0 Page 15 of 21

16 X X Death Form Complete this form at the following point in the trial: Patient death End of Trial Form The form has to be completed for ALL patients Patients who have completed 24 months of follow up (= on study for 48 months) or when the last patient reaches 12 month of follow up (= on study for 36 months) tick Common close out date reached Patients who have been withdrawn from study for reasons such as death or withdrawal of consent) tick Other reason and specify: PI Certify Form This form must be completed and signed by the Principal Investigator once all CRFs for the patient have been completed and all data queries are resolved at patient trial completion or patient trial discontinuation. Infections Form (AEs) For the purpose of this trial, an infection is any episode requiring antimicrobial, antiviral or antifungal medication. Accordingly, infections that have not been treated with these medications of the above categories don t have to be reported to the Data Management as AEs. Version No 2.0 Page 16 of 21

17 A new Infections Form must be completed for every infection, even if concurrent with another infection If more than one page is needed at a study evaluation, please complete multiple pages. If an infection is on-going, please leave the date of resolution blank and use Outcome code 3 When new information on an infection is available (or if the infection resolves), submit a new form containing the new information, ticking the box to indicate this is further information on a previously-reported event. Do not update an original, previously submitted CRF page Ensure the information on treatment medications include dose, unit and frequency or indicate if not available/unknown Add treatment medications to the relevant ConMeds Form Provide Yes/No (not N/A ) responses to ALL items regarding Any change to trial meds? and specify the changes if answered Yes If the infection meets any of the definitions of an SAE, i.e. results in death, is life-threatening, requires hospitalisation or prolongs hospitalisation, results in persistent disability or incapacity, or consists of a congenital anomaly or birth defect, then an SAE form must be completed in addition to the Infections Form. Please note: SAEs must be reported within 24 hours of becoming aware of the event. Serious Adverse Event (SAE) Reporting Form Refer to the cover sheet of the SAE Form for definitions, reporting timelines and where to send SAE forms (see also 4.9 above). The trial details of study title, R&D number and EudraCT number will all be pre-populated on the form. Complete the Patient s Initials, Date of Birth and Subject ID Indicate if this is an initial of follow up report Complete your centre number (Site ID first 3 digits of the Subject ID) as well as the remaining details The form should be sent to the trial coordinator within 24 hours of becoming aware of the pregnancy by fax/ as fully completed as possible. See section 4.9. Pregnancy Form The trial details of study title, R&D number and EudraCT number will all be pre-populated on the form. Complete the Date of Birth and Subject ID Indicate if this is an initial or follow up report Version No 2.0 Page 17 of 21

18 Complete your centre number (Site ID first 3 digits of the Subject ID) as well as the remaining details The form should be sent to the trial coordinator within 24 hours of becoming aware of the pregnancy by fax/ . Adverse Event Form for Reporting a New Relevant Concomitant Medication This form will be generated by the CCTU and sent to sites for completion when any anticoagulant, IVIg or any antibiotic, antiviral or antifungal agent has been recorded as new since last trial visit (see Appendix 1) on the ConMeds Form. The header information including a pre-set AE number (AENo) will be provided The event will be followed up until a date of discontinuation is obtained Adverse Event Form for Reporting a New Relevant Laboratory Abnormality This form will be generated by the CCTU and sent to sites for completion to document a relevant laboratory abnormality that has been submitted on the ClinLabs Form (see Appendix 2). The header information including a pre-set AE number (AENo) will be provided The criteria for relevant abnormalities are: Haemoglobin < 100g/L Platelet cell count < 75 x10 9 /L White cell count < 3.0 x10 9 /L Creatinine > 30% rise from baseline AND > 120µml/L ALT or AST > 3times upper limit of normal A separate form will be generated for each laboratory abnormality, even if two occur simultaneously and will be followed up until a date of resolution is obtained Adverse Event Form for Reporting New Malignancies This form (see Appendix 3) is available on the RITAZAREM website ( nancyform.pdf) and has to be submitted when a new malignancy has been detected and is reported on page 2 of the Follow Up Form. Version No 2.0 Page 18 of 21

19 Appendix 1 Version No 2.0 Page 19 of 21

20 Appendix 2 Version No 2.0 Page 20 of 21

21 Appendix 3 Version No 2.0 Page 21 of 21