appendix iv questions 24-32 hours
appendix ix protocol amendment version

| Note: Modified part is in Bold font                   | Protocol Version 5.0                                                                                                                                                                                                                                               | Protocol Version 6.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
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| Section Updated                                       | Original Text                                                                                                                                                                                                                                                      | Description of Change / New Text                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Trial title                                           | A Phase 3 Multicenter Trial Evaluating the  Efficacy and Safety of MitoGel™ on Ablation of  Upper Urinary Tract Urothelial Carcinoma                                                                                                                               | UGN-101 was added: A Phase 3 Multicenter Trial Evaluating the Efficacy and  Safety of MitoGel™ (UGN-101) on Ablation of Upper Urinary Tract Urothelial  Carcinoma                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| 13.3.1.                                               | General                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Instructions for  Instillation Visits                 | "GFR ≥30"; "In the event that one or more of the  above values are outside of the required limits,  and the PI is confident that the treatment can be  safely performed, he/she should contact UroGen  Trial manager to obtain approval to proceed to  treatment": | Deleted:  In case of use of an external lab, the external lab's quality assurance documentation,  normal ranges and CV of head lab must be collected by the site Deleted: "GFR ≥30"; "In the event that one or more of the above values are  outside of the required limits, and the PI is confident that the treatment can be  safely performed, he/she should contact UroGen Trial manager to obtain approval  to proceed to treatment";  Added " - For patients whose baseline GFR is ~30 mL/min/1.73m2, decreases  of up to 15% will be allowed - For patients with normal baseline creatinine, increases of up to 2x will be  allowed"; " o A repeated volumetric measurements may be performed  prior to each instillation, at the discretion of the treating investigator";  - For all other patients, changes in creatinine should not result in GFR less  than 30mL/min/1.73m2. |
| 13.3.1 General  Instructions for  Instillation Visits | If parameters do not conform to the detailed  above, treatment will be postponed until  recuperation for up to 4 weeks.                                                                                                                                            | Wording revised: If laboratory parameters do not conform to the detailed above,  treatment will be postponed until laboratory values improve, for up to 4 weeks.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 13.3.1 General  Instructions for  Instillation Visits | Added: Repeated volumetric measurements may be performed prior to each  instillation, at the discretion of the treating investigator.                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| 13.3.3. Instillation                                  | " For instillation, a 7–8 Fr ureter catheter                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Procedure                                             | supplied by UroGen shall be used."; "Prior to  every instillation, the investigator must review the  pyelocalyceal volume measurement done for that  patient, withdraw the exact volume required into  the syringe…"                                               | Added: " •For instillation, a 7–8 Fr ureter catheter supplied by UroGen shall be  used. in situations where it is technically challenging to pass the Urogen  provided 7Fr catheter, a 5Fr Ureteral Catheter with molded Luer-Lock port  may be used."; Prior to every instillation, the investigator must review the  pyelocalyceal volume measurement done for that patient. A repeated volumetric  measurements may be performed prior to each instillation, at the discretion  of the treating investigator. and The investigator must withdraw the exact  volume required into the syringe…"                                                                                                                                                                                                                                                                                        |  
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344 Document Version: 6.0  
| Effective Date: 18-Jun-2018                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
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| Protocol Version 5.0                                                                                                                                                                                                                        | Protocol Version 6.0                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Section Updated                                                                                                                                                                                                                             | Original Text                                                                                                                                                                                                                                                                                                                                                                                                                | Description of Change / New Text                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 13.3.5.                                                                                                                                                                                                                                     | Instillations #2–                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| #6 Visit Procedures (V2– V6)                                                                                                                                                                                                                | Updated: "CBC (complete blood count), renal and liver blood function and  coagulation - Should be performed in 1st week and 3rd week following the 6th  instillation. This blood test can be performed also in the patient's local clinic. The  CBC, renal and liver blood function and coagulation results should be recorded  in the CRF."                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| 13.4 LAB 1 (V7) & LAB                                                                                                                                                                                                                       | " One week and 3 weeks following the last of the                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| 2 (V8):                                                                                                                                                                                                                                     | weekly instillations, complete blood count tests  …" "CBC (complete blood count) - Should be  performed in 1st week and 3rd week following the  6th instillation. This blood test can be performed  also in the patient's local clinic. The CBC results  should be recorded in the CRF."                                                                                                                                     | Updated: " One week and 3 weeks following the last of the weekly instillations,  CBC (complete blood count), renal and liver blood function and coagulation  tests…"                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| 13.9.                                                                                                                                                                                                                                       | Treatment                                                                                                                                                                                                                                                                                                                                                                                                                    | Heading: "Treatment Discontinuation Visit"; " If                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Discontinuation                                                                                                                                                                                                                             | a patient discontinues during the treatment period  or at any time prior to the PDE Visit, an  unscheduled visit should be done (one month after  the last installation treatment) in which following  activities should be performed:  All assessments scheduled to be conducted during  the PDE visit (Section 13.4); If the patient appears to have CR, document if the  patient agrees to continue FU within the trial;" | Updated: " Treatment discontinuation prior to PDE If a patient discontinues during the treatment period or at any time prior to the  PDE Visit, an unscheduled visit should be done (one month after the last  installation treatment) in which the patient to complete PDE visit within 4+/-1  week of last instillation following activities should be performed: and perform  all All assessments scheduled to be conducted during theof the PDE visit (Section  13.4); If the patient appears to have CR at PDE, document if the patient agreespatient  should continue to continue FU within the trial receiving the maintenance  treatments should be considered as well;"; Sub-heading was added:  "Treatment Discontinuation during Maintenance" |
| 14. Schedule of Events 14.1. Part I - All Patients  - Up to PDE Visit                                                                                                                                                                       | CBC, liver and renal function, coagulation, wk 6                                                                                                                                                                                                                                                                                                                                                                             | Updated: "Only CBC X" (X stand for CBC, liver and renal function, coagulation)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| and wk 8 : "Only CBC"                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| 18. Statistical                                                                                                                                                                                                                             | Added: "A formal Statistical Analysis Plan (SAP) will be developed and                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| Methodology                                                                                                                                                                                                                                 | finalized prior to database lock. The SAP will supersede this statistical  analysis section."                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| 18.4.1.                                                                                                                                                                                                                                     | Safety Analysis                                                                                                                                                                                                                                                                                                                                                                                                              | "...Intent-to-Treat (ITT) Analysis Set                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Set                                                                                                                                                                                                                                         | The intent to treat (ITT) analysis set will consist  of all patients enrolled in the trial who have a  confirmed diagnosis of LG UTUC by local  pathology and have received at least one  instillation of MitoGel™.";                                                                                                                                                                                                        | Updated: " Intent-to-Treat (ITT) Analysis Set (=safety analysis set). The intent to treat (ITT) analysis set will consist of all patients enrolled in the trial  who have a confirmed diagnosis of LG UTUC by local pathology and have  received at least one instillation of MitoGel™"; Updated: " ITT subjects with no observed value on primary efficacy will be  imputed primary efficacy failures. Note that this only include patients who  dropped from the study for any reason before the PDE evaluation. At the  same time, sensitivity analyses will evaluate the robustness of results to different  assumptions of missingness. For the key secondary endpoint only observed data will be used.                                             |
| " ITT subjects with no observed value on primary  efficacy will be imputed primary efficacy failures.  At the same time, sensitivity analyses will  evaluate the robustness of results to different  Document State: Effective (Controlled) | Page 125 of 130                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |  
  
  
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344 Document Version: 6.0  
| Effective Date: 18-Jun-2018                                                                   |                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                       |
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| Protocol Version 5.0                                                                          | Protocol Version 6.0                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                       |
| Section Updated                                                                               | Original Text                                                                                                                                                                                                                                                                                                                                                               | Description of Change / New Text                                                                                                                                                                                                                                                                                      |
| assumptions of missingness. For the key secondary endpoint only observed  data will be used." | Treatment of missing values for the secondary endpoint detailed in Section  18.7.2."                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                       |
| 18.4.2.                                                                                       | Local Modified                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                       |
| Intent-to-Treat (mITT)  Analysis Set                                                          | Heading:" 18.4.2. Modified Intent-to-Treat  (mITT) Analysis Set";  " The modified intent to treat (mITT) analysis set  will be a subset of ITT subjects with confirmed  LG UTUC at Screening by central lab."                                                                                                                                                               | Added:" 18.4.2. Local Modified Intent-to-Treat (mITT) Analysis Set"; " The local modified intent to treat (local - mITT) analysis set will be a subset of  ITT subjects with confirmed LG UTUC at Screening by local lab and who  arrived to the PDE evaluation. by central lab."                                     |
| 18.4.3.                                                                                       | Central                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                       |
| Modified Intent-to-Treat  (mITT) Analysis Set                                                 | Section was added:" The central modified intent to treat (Central - mITT)  analysis set will be a subset of ITT subjects with confirmed LG UTUC at  Screening by central lab and who arrived to the PDE evaluation and  received the central lab diagnostic.  Missing values: Only observed values will be used in central - mITT; i.e.  missing data will not be imputed." |                                                                                                                                                                                                                                                                                                                       |
| 18.4.4.                                                                                       | Per Protocol                                                                                                                                                                                                                                                                                                                                                                | "18.4.3 Per Protocol (PP) Analysis Set 1";                                                                                                                                                                                                                                                                            |
| (PP) Analysis Set 1                                                                           | " The Per Protocol (PP) analysis set is a subset of  the mITT Analysis Set…"                                                                                                                                                                                                                                                                                                | Updated: "18.4.34 Per Protocol (PP) Analysis Set 1"; " The Per Protocol (PP) analysis set is a subset of the Local mITT Analysis  Set…"                                                                                                                                                                               |
| 18.4.5.                                                                                       | Per Protocol                                                                                                                                                                                                                                                                                                                                                                | "18.4.4 Per Protocol (PP) Analysis Set 2";                                                                                                                                                                                                                                                                            |
| (PP) Analysis Set 1                                                                           | " The Per Protocol (PP) analysis set is a subset of  the mITT Analysis Set…"                                                                                                                                                                                                                                                                                                | Updated: "18.4.45 Per Protocol (PP) Analysis Set 2"; " The Per Protocol (PP) analysis set is a subset of the Local mITT Analysis  Set…"                                                                                                                                                                               |
| 18.4.6.                                                                                       | Complete                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                       |
| Responders at the PDE  Visit (PDECR) Analysis  Set                                            | "18.4.5. Complete Responders at the PDE Visit                                                                                                                                                                                                                                                                                                                               | "18.4.56 Complete Responders at the PDE Visit (PDECR) Analysis Set"                                                                                                                                                                                                                                                   |
| (PDECR) Analysis Set"                                                                         |                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                       |
| 18.7.2.                                                                                       | Sensitivity                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                       |
| Analysis for the  Principal Analysis of the  Primary Endpoint                                 | Updated: " The primary analysis described in the previous section will be  repeated using o Local diagnosis in Local-mITT, PP1, PP2 populations o Central diagnosis in Central-mITT o Only observed data from ITT (i.e., excluding missing data imputed  "failure") o mITT population  o PP1 population o PP2 population"                                                   |                                                                                                                                                                                                                                                                                                                       |
| 18.7.4.                                                                                       | Sensitivity                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                       |
| Analysis for the  Dichotomous Key  Secondary Endpoint                                         | " The primary analysis described in the previous  section will be repeated using o Only observed data from ITT (i.e.,  excluding missing data imputed "failure") o mITT population  o PP1 population PP2 population"                                                                                                                                                        | Section was added: " For dichotomous key secondary analysis, patients who  did not arrive the last FU visit and have no prior recurrence, are treated as  Failures (which is the "worst case" imputation scenario). Sensitivity analysis  will be done to examine the results if alternative imputation scenarios are |
| Document State: Effective (Controlled)                                                        | Page 126 of 130                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                       |  
  
  
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344 Document Version: 6.0 Effective Date: 18-Jun-2018  
| Effective Date: 18-Jun-2018                                                  |                                                                                  |                                                                |                                                                    |                                         |
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| Protocol Version 5.0                                                         | Protocol Version 6.0                                                             |                                                                |                                                                    |                                         |
| Section Updated                                                              | Original Text                                                                    | Description of Change / New Text                               |                                                                    |                                         |
| used. Specifically, the tipping point imputation will be applied.            |                                                                                  |                                                                |                                                                    |                                         |
| In this analysis we begin by imputing all missing subjects (early            |                                                                                  |                                                                |                                                                    |                                         |
| terminations) "Success" (or CR). Then, at each step, number of imputed       |                                                                                  |                                                                |                                                                    |                                         |
| "Successes" will reduce by one and number of imputed "Failures" will         |                                                                                  |                                                                |                                                                    |                                         |
| increase by 1, until the case where all missing values are imputed "Failure" |                                                                                  |                                                                |                                                                    |                                         |
| (which is equivalent to the primary analysis). For each imputation scenario, |                                                                                  |                                                                |                                                                    |                                         |
| exact binomial hypothesis testing p-value will be reported.                  |                                                                                  |                                                                |                                                                    |                                         |
| In addition, to the described above, analysis where only observed data is    |                                                                                  |                                                                |                                                                    |                                         |
| used will be done."                                                          |                                                                                  |                                                                |                                                                    |                                         |
| 18.7.5. Secondary                                                            | "18.7.4.  Secondary Efficacy Analyses"                                           | Updated: "18.7.45.Secondary Efficacy Analyses"                 |                                                                    |                                         |
| Efficacy Analyses                                                            |                                                                                  |                                                                |                                                                    |                                         |
| 19.1.4. Causality                                                            | Non-classified/Non-Classifiable                                                  | Paragraph was deleted:" ► Non classified/Non Classifiable      |                                                                    |                                         |
| A clinical event for which there is insufficient                             | A clinical event for which there is insufficient information at the time of its  |                                                                |                                                                    |                                         |
| information at the time of its discovery and for                             | discovery and for which additional data is required to perform an adequate       |                                                                |                                                                    |                                         |
| which additional data is required to perform an                              | evaluation. A clinical event for which the information received is inadequate    |                                                                |                                                                    |                                         |
| adequate evaluation.  A clinical event for which                             | and/or contradictory and is unable to provide for a reasonable ascertainment."   |                                                                |                                                                    |                                         |
| the information received is inadequate and/or                                |                                                                                  |                                                                |                                                                    |                                         |
| contradictory and is unable to provide for a                                 |                                                                                  |                                                                |                                                                    |                                         |
| reasonable ascertainment."                                                   |                                                                                  |                                                                |                                                                    |                                         |
| 19.2.2. Events                                                               | " ...3.                                                                          | Pregnancy and outcome of the                                   | Updated:" ...3.                                                    | Pregnancy and outcome of the pregnancy; |
| Requiring Immediate (24                                                      | pregnancy;                                                                       | Special reporting situation event / Event of clinical Interest |                                                                    |                                         |
| hours) Reporting                                                             | Special reporting situation event / Event                                        | 4                                                              | Any of the event which requires treatment discontinuation (section |                                         |
| 4.                                                                           |                                                                                  |                                                                |                                                                    |                                         |
| of clinical Interest                                                         | 17.1.1)                                                                          |                                                                |                                                                    |                                         |
| Any of the event which requires                                              | The investigator must inform the site relevant clinical research associate (CRA, |                                                                |                                                                    |                                         |
| 5.                                                                           |                                                                                  |                                                                |                                                                    |                                         |
| treatment discontinuation (section 17.1.1)                                   | Monitor) by phone about the above mentioned events AND notify via email both     |                                                                |                                                                    |                                         |
| The investigator must inform the site clinical                               | site CRA and he sponsor within 24 hours of becoming aware of the event. after    |                                                                |                                                                    |                                         |
| research associate (CRA, Monitor) by phone                                   | its  occurrence first came to his knowledge. Sponsor contact: Email              |                                                                |                                                                    |                                         |
| about the above mentioned events AND notify via                              | with copies to                                                                   |                                                                |                                                                    |                                         |
| email both site CRA and sponsor within 24 hours                              | Initial SAE/Death/Pregnancy/Special or clinical interest events report must be   |                                                                |                                                                    |                                         |
| Initial SAE/Death/Pregnancy/Special or clinical                              | recorded in the electronic Case Report Form (eCRF) within 24 hours of first      |                                                                |                                                                    |                                         |
| interest events report must be recorded in the                               | knowledgebecoming aware of the event.                                            |                                                                |                                                                    |                                         |
| electronic Case Report Form (eCRF) within 24                                 | In case event requires immediate reporting but the EDC system (eCRF) is not      |                                                                |                                                                    |                                         |
| hours of first knowledge of the event.                                       | functioning, the site should use the relevant paper forms and fax email them to  |                                                                |                                                                    |                                         |
| In case event requires immediate reporting but                               | to the sponsor within 24 hours of site being made aware of                       |                                                                |                                                                    |                                         |
| the EDC system (eCRF) is not functioning, the                                | the serious adverse event.                                                       |                                                                |                                                                    |                                         |
| site should use the relevant paper forms and fax                             | Fax no. for events reporting:                                                    | Attn.:                                                         |                                                                    |                                         |
| to the sponsor within 24 hours of site being made                            | QPPV."                                                                           |                                                                |                                                                    |                                         |  
  
  
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ - US, IL  
Document Number: CLP-0002344 Document Version: 6.0  
| Effective Date: 18-Jun-2018                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                  |                                                                                   |
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| Protocol Version 5.0                                               | Protocol Version 6.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                  |                                                                                   |
| Section Updated                                                    | Original Text                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Description of Change / New Text                                                                                                                                                                                                                                 |                                                                                   |
| aware of the serious adverse event.  Fax no. for events reporting: | ,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                  |                                                                                   |
| Attn.:                                                             | , QPPV.'                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                  |                                                                                   |
| 19.2.3.                                                            | Special                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | " 19.2.3. Special Reporting Situations /Events of                                                                                                                                                                                                                |                                                                                   |
| Reporting Situations                                               | Clinical Interest"; " Safety events of interest on a  sponsor medicinal product…"                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Updated: " 19.2.3. Special Reporting Situations /Events of Clinical Interest ";  "Safety events of interest onSponsor a sponsor medicinal product…"                                                                                                              |                                                                                   |
| 19.2.4.                                                            | Events of                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | " 19.2.4. In addition, the following adverse events                                                                                                                                                                                                              | Updated:" 19.2.4. In addition, the following adverse events are defined as        |
| special interest                                                   | are defined as "events of special interest":"                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | "eEvents of special interest":";  Added to bullet #8:"Any of these Events of Special Interest that also meet  criteria of Serious Adverse Event should be reported as such. These events  will be evaluated and reviewed by the Sponsor pharmacovigilance team." |                                                                                   |
| 19.2.4 Events of special                                           | 19.2.4 bullet 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                  |                                                                                   |
| interest                                                           | "Symptoms suspicious of ureteral perforation/rupture -  (prolonged localized abdominal or flank pain, abdominal  tenderness/acute abdomen);"                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Revised 19.2.4 - bullet 3 Ureteral events, including stenosis, as well as symptoms suspicious of ureteral  perforation/rupture - (prolonged localized abdominal or flank pain, abdominal  tenderness/acute abdomen);                                             |                                                                                   |
| 19.2.5- Management of  Anomalies in Laboratory  Parameters         | The investigator must review the patient's lab results and  evaluate the clinical meaning of all anomalous laboratory  values based on the definition of standard values used by  leading laboratories and CTCAE. Each clinically  significant anomaly must be fully reported. "Clinically  Significant" means any anomaly which, according to the  investigator, represents a significant clinical problem, which  requires medical attention or which otherwise falls under the  definition of "Serious" adverse event. When clinically  advised, additional tests or evaluations should be carried out  to determine the significance or etiology of an anomalous  result or to monitor the course of an adverse event. Any  persistent anomalous value must be monitored at the  investigator's discretion. Clinically significant anomalous  results must be recorded in the relevant section of the eCRF. | Revised: 'The investigator must review the patient's lab results and evaluate all  anomalous laboratory values as clinically significant or not. Clinically significant  results must be recorded as adverse events in the relevant section of the eCRF".        |                                                                                   |
| 19.2.7.                                                            | Concomitant                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                  |                                                                                   |
| Illnesses and Pre-existing  Conditions                             | Added:"Ongoing medical conditions and past cancer history other than  urothelilal carcinoma, and significant medical history up to 5 years back  from screening must be collected and recorded in the eCRF."                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                  |                                                                                   |
| 19.2.8.                                                            | Adverse Events                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | " The investigator is required to report all nonserious adverse events/ occurring starting with                                                                                                                                                                                                                                                                  | Re-edited and updated: " - The investigator is required to report collect all non |
| Reporting Period                                                   | serious adverse events/ occurringAEs starting beginning with informed consent                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                  |                                                                                   |  
  
  
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344 Document Version: 6.0  
| Protocol Version 5.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Protocol Version 6.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                         |
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| Section Updated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Original Text                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Description of Change / New Text                                        |
| informed consent signing and up to 30 days post  last instillation visit to the sponsor. This  information is to be entered into the eCRF. - In case of complete response patients  continuing with maintenance treatments - Adverse  events will be collected up to 30 days post last  maintenance instillation and will be documented  in the eCRF. - In case of non-complete response  patients - All adverse events should be recorded  up to the PDE Visit (5 weeks after the last  instillation).  - All serious adverse events, all AEs which  are suspected to be related to the study treatment  and/or procedures occurring during the trial  period should be reported at all times." | signing signature. and up to 30 days post last instillation visit to the sponsor.  This information is to be entered into the eCRF.  - All serious adverse events, aand All AEs which are suspected to be  related to the study treatment and/or procedures occurring during the trial  period should be reported at all times. - In case of complete response patients continuing with maintenance  treatments Adverse events will be collected up to 30 days post last maintenance  instillation or until resolution, and will be documented in the eCRF. - In case of non-complete response patients - All adverse events should be  recorded up to the PDE Visit or until resolution (5 weeks after the last  instillation).  All serious adverse events, all AEs which are suspected to be related to  the study treatment and/or procedures occurring during the trial period should be  reported at all times. - In case of complete response patients continuing with maintenance  treatments Adverse events will be collected up to 30 days post last maintenance  instillation and will be documented in the eCRF. - In case of non complete response patients All adverse events should be  recorded up to the PDE Visit (5 weeks after the last instillation).  - All serious adverse events, all AEs which are suspected to be related to  the study treatment and/or procedures occurring during the trial period should be  reported at all times." |                                                                         |
| 20.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Concomitant                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Added:" Concomitant medications given to treat a reported adverse event |
| Medications                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | must be recorded in the eCRF."                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                         |
| Appendix III: Required                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | " Hematology Tests *                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                         |
| Lab Tests                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Complete blood count, including red                                     |
| blood cell indices and white blood cell differential Note: On visits where only CBC is required, it  may be performed at the community but less  recommendable. - Platelet count"                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Deleted:" " Hematology Tests *  - Complete blood count, including red blood cell indices and white blood  cell differential Note: On visits where only CBC is required, it may be performed at the  community but less recommendable. - Platelet count""                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                         |  
  
| Action Name                 | User Name                                                      | Title                     | Signature Date   |
|-----------------------------|----------------------------------------------------------------|---------------------------|------------------|
| Review                      | Director of Clinical Operations                                | 29-May-2018 18:27 (GMT+2) |                  |
| Review                      | VP QA                                                          | 29-May-2018 18:49 (GMT+2) |                  |
| Send for Approval           | VP QA                                                          | 29-May-2018 19:00 (GMT+2) |                  |
| Send for Approval           | VP QA                                                          | 14-Jun-2018 15:31 (GMT+2) |                  |
| Send for Approval           | VP QA                                                          | 14-Jun-2018 17:13 (GMT+2) |                  |
| Send for Approval           | VP QA                                                          | 18-Jun-2018 13:40 (GMT+2) |                  |
| Approve                     | VP Regulation                                                  | 18-Jun-2018 14:52 (GMT+2) |                  |
| Approve                     | Chief Scientific and Medical affairs 18-Jun-2018 15:23 (GMT+2) |                           |                  |
| Approve                     | SVP Clinical                                                   | 18-Jun-2018 19:48 (GMT+2) |                  |
| Approve                     | VP QA                                                          | 18-Jun-2018 20:43 (GMT+2) |                  |
| QA Approve Without Training | VP QA                                                          | 18-Jun-2018 20:43 (GMT+2) |                  |