trial title a phase 3
13.3.1. general instructions for instillation

instillations - (± 3 day).  
**Prior to MitoGel**™ administration, except the first treatment, the treating investigator MUST review the last patient's safety lab results to determine if the instillation can be performed as planned. The review must be documented in the patient medical file prior to study treatment.  
Following are the threshold parameters for acceptable laboratory values prior to each treatment*, blood tests will be performed according to Appendix III. These tests must be done no longer than 3 days prior to the instillation and can be done also in the patient's local clinic** if not feasible to have them done within short time period in the hospital:
o Absolute neutrophil count ≥1,000/μL (≥1.0×109/L), o Platelets ≥80,000/μL (≥80×109/L)
o AST (SGOT)/ALT (SGPT) ≤5 × upper limit of normal (ULN)  
  
  
o ALP ≤2.5 institutional ULN
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 For all other patients, changes in creatinine should not result in GFR less than 30mL/min/1.73m2.  
* The results of these specific test must be reviewed prior to each treatment.  
Exception in Visit 1: Tests should be taken but results may be reviewed after the treatment.  
If laboratory parameters do not conform to the detailed above, treatment will be postponed until laboratory values improve, for up to 4 weeks.  
**In the event of urinary tract infection or another safety reason which causes the PI**
to postpone a treatment, the treatment will be postponed until the event is resolved and not over 4 weeks; In case treatment has been delayed beyond 4w due to ADR (adverse drug reaction) study treatment will be discontinued permanently however study follow-up will be continued.  
Volume of MitoGel™ **Admixture to be instilled** (see Screening [V0] for details) -
o The volume to be instilled will be based on estimation of the pyelocalyceal space conducted during the screening / prior to treatment initiation.  
o The volume of contrast agent required to fill the pyelocalyceal space (without causing distention) shall be measured.  
o To increase accuracy, an average of three (3) measurements should be carried out. In case the number contains decimal fraction, please round it as follows:
≥0.5 - round it up to the closest whole number.  
<0.5 - round it down to the closest whole number.  
o Repeated volumetric measurements may be performed prior to each instillation, at the discretion of the treating investigator.  
o The volume of MitoGel™ instilled will be 100% of the estimated pyelocalyceal volume or 15 mL (whichever is lower); all the measurement procedure and each of the three (3) measurement must be recorded in the patient's source document and in the CRF.  
**Sodium Bicarbonate:** The Patient will be given 1.3 g Sodium bicarbonate tablets AND  
  
  
written instructions/dosing diary to consume 1.3 g of Sodium Bicarbonate orally, the night before the instillation, the morning of instillation, and 30 minutes prior to the instillation procedure (total of 3.9 g); in case that patient is planned to be anesthetized, bicarbonate might not be taken 30 minutes prior to the treatment.  
**Diuretics**: It is preferred that diuretics not be taken the night before and prior to the instillation. If a patient is on diuretic medications, the PI should determine, based on his/her clinical judgment whether the medication can be skipped prior to the instillations as recommended above and should advise the patient on the diuretics use during the study;
**Pre-instillation drinking:** General guidelines for drinking instruction pre- and postinstillation are included below. The need for de-hydration will be decided by the physician based upon the clinical guidelines mentioned herein:
o To the extent that it is possible, drinking should be avoided in the 4-6 hours prior to the instillation.  
**Post instillation drinking should be limited**. A recommended drinking schedule follows:
o 0-2 hours post instillation: refrain from drinking any liquid; o 2-4 hours post instillation: 1 cup of water every 2 hours; o 4 hours post instillation: resume normal liquids consumption ; o Following instillation, the patient will be carefully monitored for urine output and clinical symptoms, which might indicate urinary obstruction. Special caution should be taken in single kidney patients. Pre and post-Instillation Patient's Instructions will be provided to the patient prior to the first instillation (Patient Guidance Letter).  
**Prophylactic antibiotics**: Aiming to minimize the risk for Urinary Tract Infections
(UTI), especially Acute Pyelonephritis, anti-microbial prophylaxis will be prescribed (e.g., Ciprofloxacin) according to the AUA Best Practice Policy Statement on Urologic Surgery Antimicrobial Prophylaxis (See Appendix VI);
**Prophylactic anti-allergic treatment –** Prophylactic anti-allergic treatment will be given per PI discretion. Recommended regimen–Anti-histaminic agents to be taken the day before instillation, on the day of instillation and 1-3 days post instillation.  
Diazepam (5-10 mg) (or any other relaxation pill) will be given before instillations according to the PI discretion to reduce the anxiety.  
**Local ointment for protection of skin -** Use of local ointment prior to instillation for  
  
  
reduction of local irritation around the genitalia;
**Special precautions should be taken with females; the woman shall be instructed to**
carefully wash the genitalia following each urination during the day of instillation followed by using local ointment on the genitalia.  
13.3.2. Treatments as Needed
**Management of dysuria -** Local and systemic analgesics administration; Management of other lower urinary tract symptoms (LUTS) such as Frequency/
urgency/incontinence - Use of anticholinergic agents if not contraindicated;
**Diazepam 5-10 mg (or any other relaxation pill)** as an optional therapy, to reduce anxiety before each instillation. To be given an hour before. The patient should be cautioned of driving on that day.
trial title a phase 3
13.3.3. instillation procedure

For the instillation procedure the site should first verify they have Protocol TC-UT-03-P
ancillaries, Injector device, and IFU manual.  
MitoGelTM Admixture must be instilled by study authorized person as documented in the delegation log and only after proper training was given regarding the instillation procedure.  
For instillation, a 7–8 Fr ureter catheter supplied by UroGen shall be used. In situations where it is technically challenging to pass the 7Fr catheter, a 5Fr Ureteral Catheter with molded Luer-Lock port may be used.  
Due to the viscose nature of the MitoGelTM Admixture the instillation must be done using the designated Injector device supplied by UroGen. Please refer to the UroGen's Injector Device Instructions for Use Manuel for detailed instillation instructions.  
Instillation volume of MitoGel™ Admixture/Administration Form: The pharmacy will dispense a 17-20 mL MitoGel™ Admixture for every instillation regardless of the individual volume required.  
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. The investigator must withdraw the exact volume required into the syringe, and document the required volume in the supplied Administration Form. The required volume information and syringe filling should be completed in the Administration Form, and confirmed by additional trial authorized personnel who should be present at that time. Both must sign the Administration Form before instillation begins. Once instillation is over, the investigator or designee who performed the instillation must complete the actual volume instilled and sign the Administration Form. The Administration Form must be filed in the study patient file.  
To obtain better dispersing of MitoGel™ Admixture in the pyelocalyceal system, the patient should be in Trendelenburg Position (if possible) lying down on the side that should be treated. In cases where Trendelenburg Position can't be obtained, the patient should lie down (if possible) on the side that should be treated.
trial title a phase 3
the following procedures should be

Prior to MitoGelTM administration, cystoscopy should be performed (SOC) to obtain screening of the urethra and the bladder for abnormal findings.  
**Pyelography**- Prior to every instillation pyelography with contrast agent shall be performed to demonstrate pyelocalyceal system for abnormal findings and to verify that the catheter tip, is located above the UPJ for proper instillation to the renal pelvis. The technique for an office-based approach for placement of ureteral catheter has been previously described (Nepple, 2009). If a single J catheter is being used, the insertion of the catheter can be done prior to the treatment visit under pyelography (see above).  
Placement of guidewire and ureteral catheter shall be performed under fluoroscopy. Advance guidewire through the cystoscope working channel via the ureter to the renal pelvis. nephrostomy tube:  
  
  
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344 Document Version: 6.0 Anchor the guidewire in the renal pelvis and remove the cystoscope. Advance the ureteral catheter over the guidewire to the preferable location in the renal pelvis and take photos to document the location of the catheter tip. Preferable location will be considered as the place where the flow from the catheter tip of the investigational product will enable best coverage of the renal pelvis and the calyces.  
MitoGel™ Admixture administration shall be according to individual dose/volume
(Installation instructions-to be provided in the study manual);
The same documentation is required also for patients administered through a In case of instillation via nephrostomy tube - the nephrostomy tube types allowed  
  
 are Silicon or Simplastic.  
Latex is not allowed, due to fear of rupture.  
At the end of the instillation the catheter must be washed with 2 cc of saline, to remove remaining MitoGel™ Admixture. Prior to patient leaving the clinic the site staff must verify that the patient urinates via the nephrostomy tube, by watching the urinary bag filling.  
13.3.4. Instillation \#1 Visit Procedures (V1):
The following procedures should be conducted prior to 1st instillation:
It is recommended to perform the first instillation in the OR under sedation. Patient reminder phone call shall be done a day before the treatment regarding antibiotic treatment, bicarbonate, antihistamine (if applicable) and limited drinking and diuretics; Confirmation of patient's eligibility; Confirmation that the safety labs results are available. Confirmation of limited drinking and/diuretics as per need; Safety assessment, see Section 13.3.6; On treatment day - Verification of consumption of oral dose of 1.3 g of sodium bicarbonate the night before the instillation, at the morning of and 30 minutes prior to the instillation procedure; Completion of bicarbonate compliance log. In case that patient is planned to be anesthetized, bicarbonate should not be taken 30 minutes prior to the treatment.  
Verification /administration of prophylactic anti-biotic treatment Verification of consumption of oral dose of prophylactic anti-allergic treatment (if applicable). The anti-histaminic agents should be consumed the day before instillation, on the day of instillation and 1 to 3 days following the instillation.  
Pre-Dose MMC PK blood draw (when applicable; See PK instructions, Appendix VII:
Collection and Handling of Plasma Samples for MMC Pharmacokinetics);
Evaluation and recording of AE and concomitant medications; Urology oriented physical exam & vital signs measurements (Appendix II & Appendix III);
Blood tests (**Appendix III**); In case patient preformed all required blood test according  
  
  
to **Appendix III** up to 3 days prior to the instillation- no need to repeat; Urinalysis/dipstick; Review of urine culture results from the Screening Visit; If urine dip-stick is positive for pregnancy, serum pregnancy test should be performed.  
In this case, the instillation should be postponed until the serum pregnancy test results are available. If pregnancy test is positive, patient should be discontinued from study.
trial title a phase 3
the following procedures should be

Recording of pain during the instillation procedure by the patient, by marking the score on the 0-10 scale VAS for pain*.  
Following the **first** instillation, the patient should remain in the clinic/hospital for at least 6 hours for general observation; the patient will not be discharged before the first free urination. The medical team should document the patient assessment timely before leaving the clinic.  
At the first treatment subset of patients (N=6) who gave informed consent, PK samples will be collected for MMC plasma level measurements; a notification will be sent to the study sites, when all the six specimens will be completed in order to stop offering the other patients this procedure. If from some reason, a sample from a patient will be destroyed, another patient will be picked to complete the quorum.  
o MMC plasma level measurements:
The samples will be collected at 0 (pre-dose) and 30 min, 1, 2, 3, 4, 5, and 6 hours post instillation. At each time point, 3 mL of blood will be collected to yield at least 1.5–2 mL of plasm after centrifugation. Altogether, a total of approximately 24 mL of blood will be collected for PK samples for each patient who signed an informed consent and contributed to this portion of the trial. The plasma samples will be analyzed by validated bioanalytical assay. For detailed information, please refer to Appendix VII: Collection and Handling of Plasma Samples for MMC Pharmacokinetics; Recording of AE post instillation; Documentation of concomitant medications;  
  
 Telephone contact 24–32 hours post treatment (section 13.3.7); Patient should be given or prescribed (not recommended) with 1.3 g Sodium bicarbonate tablets AND written instructions to consume 1.3 g of Sodium Bicarbonate the night before instillation, the morning of, and 30 min (total of 3.9 g) prior to the instillation; 24-30 hour questionnaire should be provided; A reminder phone call to the patient should be done the day before treatment.
trial title a phase 3
13.3.5. instillations #2-#6 visit procedures

The allowed visit window deviation is ±3 days.  
**A reminder phone call** to the patient should be done the day before the treatment regarding the following:
o Confirmation that the safety labs results are available.  
o Bicarbonate and antibiotic, antihistamine (if applicable) and limited drinking
/diuretics uptake;
trial title a phase 3
the following procedures should be

Verification of consumption of oral dose of 1.3 g of sodium bicarbonate the night before the instillation, at the morning of and 30 minutes prior to the instillation procedure; In case that patient is planned to be anesthetized, bicarbonate should not be taken 30 minutes prior to the treatment.  
Verification of consumption of oral dose of prophylactic anti-allergic treatment. Where used, the anti-histaminic agents should be consumed the day before instillation, on the day of instillation and the day after the instillation.  
Confirmation of limited drinking and/diuretics as per need, Safety assessment, see Section 13.3.6; Evaluation and recording of AEs and concomitant medications; Urology oriented physical exam & vital signs measurements; Blood tests according to **Appendix III**; in case patient preformed all required blood test according to **Appendix III** up to 3 days prior to the instillation - no need to repeat; Urinalysis/dipstick; Urine Culture (only when applicable); Urine test for pregnancy - when applicable;  
  
 Serum pregnancy tests may be performed only if urine test is positive for pregnancyresults must be available before the next instillation. In the case that a serum pregnancy test is conducted, the instillation should be postponed until the serum pregnancy test results are available. If pregnancy test is positive, patient should be removed from study.
trial title a phase 3
the following procedures should be

Prior to IP administration, cystoscopy should be performed (SOC) to obtain screening of the urethra and the bladder for abnormal findings.  
Cystoscopy for catheterization as described herein above followed by ureteral catheter placement under fluoroscopy in the preferable location in the renal pelvis; MitoGel™ Admixture administration according to individual dose/volume; Patients will be requested to record VAS for pain to describe the degree of pain they felt during the instillation procedure. The patients will complete the VAS immediately after the procedure (only at visits 1-6).
trial title a phase 3
the following procedures should be

Recording of AE post instillation; 24-32 hour questionnaire should be provided (only at visits 1-6); Telephone contact 24–32 hours post treatment (section 13.3.7) (only at visits 1-6);
CBC (complete blood count), renal and liver function tests - 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. Results should be recorded in the CRF.
trial title a phase 3
13.3.6. safety assessment prior and

In addition to general inquiry about patient's condition, prior to each instillation, the physician should query the patient specifically regarding pain, especially in the lower abdomen, flank, or urethra. The physician should also inquire whether the patient has experienced symptoms suggestive of obstruction, urinary tract infection, or allergic reaction to MMC. If symptoms of obstruction/UTI or allergy are backed up by physical/laboratory tests treatment will be postponed until symptom resolution.  
In cases of allergic response to MMC, antihistamines with/without cortisone treatment may be administered at the physician's discretion. Allergic response severity must be assessed according to CTCAE version 4.03 in Appendix VIII.  
Any unexpected AE related to MitoGel™ and qualified per National Cancer Institute (NCI)  
  
  
Common Terminology Criteria for Adverse Events (CTCAE) as grade 3 or 4 will be evaluated by the sponsor medical team and steering committee. In case of need, a DMC meeting will be gathered.  
The following information about the AE must be included in the CRF:
Reporting person details; Adverse event and relevant clinical findings; Time/date of onset; Time/date of recovery; Intensity/Severity (mild, moderate, severe, life threatening, lethal); Action taken on study drug; Other actions taken to treat the event; Toxicity Grade according to CTCAE 4.03 (Investigator to designate); Causality: relationship to study drug (Investigator to designate); Seriousness of the AE; The study period for AEs collection is defined as 30 days following the last administration of trial treatment unless the AE is unexpected and suspected to be related to the study treatment, in such case the AE should be reported regardless to the scope of reporting period.
trial title a phase 3
13.3.7. telephone contact 24-32 hours

After each instillation, the patient will be given a questionnaire and requested to capture his/her post-treatment experience: first urination time, and remnant of gel in the urine (Appendix IV). Twenty-four (24 to 32 hours post each instillation, the patient will be contacted (via telephone) and answers for the questionnaire will be collected, and the questionnaire will be returned at the next visit. At this point, any spontaneously reported adverse events will also be recorded. If necessary, a patient may be called for an unscheduled visit to follow up on any post-treatment adverse event that requires clinical evaluation or follow-up.
trial title a phase 3
13.4. lab 1 (v7) &

One week and 3 weeks following the last of the weekly instillations, CBC (complete blood count), renal and liver function tests will be done for safety control. A deviation window of ±
3d is allowed.  
  
  
These tests may be done in lab which is external to the hospital. 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.
trial title a phase 3
13.5. primary disease evaluation visit

Following completion of the instillation treatment series, a 5-week ± 1 week healing period prior to evaluation of treatment response and, if needed, performance of ureteroscopic resection of remaining UTUC lesions. At the PDE visit, the following activities will be performed:
Review and recording of AEs and concomitant medication; Full physical examination and vital signs measurements (**Appendix I and Appendix II**); Blood tests and urinalysis (**Appendix III**);
Urine culture (only when applicable);
Pregnancy tests (for women with childbearing potential; **Appendix III**); Upper tract urine cytology (**Appendix III**) - The upper tract urine must be collected using a catheter (wash), **before** any biopsy or topical treatment was done.  
UUT lesions status, i.e., number of lesions, lesion size, location and morphology of remaining lesions (if any) will be assessed visually during the URS and documented in the patient's file. Document the lesions in the UUT Lesion Documentation Form; Biopsy or brush biopsy for histopathology for all remaining tumors if technically feasible; Evaluation of response (Section 14) Re-Evaluation of UTUC Treatment - Has UTUC treatment plan changed compared to prior entering the trial? N / Y, and planned treatment.
trial title a phase 3
13.5.1. complete response (cr) patients

For patients who demonstrate Complete Response (CR) evaluated by visual inspection via URS upper tract urine cytology will be performed to confirm no residual disease (See Section 9.2.1)
Patient demonstrating CR at PDE will undergo a maintenance MitoGel™ treatment (refer to section 11.3.5).
trial title a phase 3
13.5.2. non-cr patients

For patients who did not demonstrate CR, to the extent that it is possible, all remaining lesions will be biopsied. The patients shall undergo any additional surgical or other treatment the PI decides deem necessary to treat the patient. The tumor location, size and grade, as well as the surgical procedure or treatment provided to treat the remaining disease will be documented; If no lesion was detected via URS, but the UUT urine cytology from the upper tract is equivocal positive, patient will be re-evaluated by urine cytology prior to the next scheduled maintenance treatment (~3 weeks after the original cytology test at the PDE)
and prior to the instillation on that day. If the urine cytology is negative, the patient will be considered as a CR. If repeated cytology results are positive or equivocal, patient will be considered as not having CR (i.e., CR = "failure"; see Section 9.2.1)
trial title a phase 3
13.6. cr patients maintenance instillations

A maintenance treatment will start immediately after the local lab confirms that patient's cytology is negative for cancer, and no longer than 3 weeks post PDE, unless there is a medical condition which requires postponing the treatment. In these cases, the first maintenance instillation should be delayed until recovery.  
Maintenance Regimen - MitoGel™ Admixture will be given once monthly (±1 week)
until one month prior to last FU visit within the study (i.e., until Month 11 post PDE).  
Safety assessment - During maintenance treatment at each instillation the patients will have performed in the hospital local lab, safety lab tests, physical examination and vital signs per protocol (see **Appendix I - Appendix II**). For patients who drop out of the study safety will be assessed according to the SOC.
trial title a phase 3
13.7. follow-up visits (v12 v15

Follow up visits for patients who demonstrate CR will be performed 3, 6, 9, and 12 months following the PDE:
Allowed visit window deviation for each of the FU visits is ±2 wks. The following activities will be performed:
Review of unresolved AEs and recording of newly AEs (See Section 19 for management of AEs)
Physical examination & vital signs, and laboratory tests required the investigator think  
  
  
are required for the follow up on any unresolved AEs, should be conducted at the discretion of the investigator or according to the Standard of Care (SOC)
CTU (only in FU 12 months (V21)
Blood tests and urinalysis (**Appendix III**)
Pregnancy tests (for women with childbearing potential only)
Upper tract washing urine cytology at every Follow-up Visit (**Appendix III**). The upper tract urine must be collected using catheter (wash), **before** any biopsy or topical treatment was done Review of concomitant medications During FU period, patients will be followed-up for twelve months (12) or until disease recurrent or progression; however, during this period the following activities should be done:
When done, histopathology results will be recorded in the patient's FU records, The presence of UUT lesions and status will be visually assessed during URS.  
Recurrence, progression (defined as increase in grade or stage), or durable CR (defined as NDD) will be determined for each patient Recurrence is to be confirmed by histopathology. To rule out recurrence biopsy of all visible lesions must be negative for urothelial carcinoma.  
Recurrence for the analysis purpose will only count the direct recurrence of the original treated area, meaning the upper urinary tract above the UGJ. Disease appearance/recurrence in other locations will be documented in the CRF, but will not be considered in this trial as a tumor recurrence.  
In case of disease progression in the UT during the follow-up period, the patient will be considered as a durable CR until the time of the progression findings. In case of recurrence or progression assessed during the FU period, the patient will be considered as having completed the trial and will not be summoned for further follow-up visits.
trial title a phase 3
13.8. unscheduled visit

An unscheduled visit may be performed at any time during the trial if the investigator decides that the clinical state of the patient does not permit instillation of the IP, for assessment of safety, at the Patient's request, or as deemed necessary by the investigator. The date, reason, and procedures done in unscheduled visit will be recorded in the patient's file and the CRF.
trial title a phase 3
13.9. treatment discontinuation

Treatment Discontinuation Prior To Pde  
If a patient discontinues during the treatment period or at any time prior to the PDE Visit, the patient to complete PDE visit within 4+/-1 week of last instillation and perform all assessments of the PDE visit (Section 13.4);
If the patient appears to have CR at PDE, patient should continue FU within the trial receiving the maintenance treatments should be considered as well; If patient agrees for FU within the trial or agrees to continue to share information regarding his/her disease status, information collected during the FU care of the patient should be recorded in the CRF.
trial title a phase 3
treatment discontinuation during maintenance

If patient discontinues during the maintenance period or at any time after PDE visit, an unscheduled visit should be done (one month after the last installation treatment), in which following activities should be performed:
Full physical examination and vital signs measurements Blood tests and urinalysis Pregnancy tests (for women with childbearing potential) Review and recording of AEs and concomitant medication If patient agrees to continue to share information regarding his/her disease status, information collected during the FU care of the patient should be recorded in the CRF.
trial title a phase 3
14. schedule of events

14.1.**Part I - All Patients - Up to PDE Visit**  
| Treatment period                                   | Primary Disease  Evaluation   |        |        |       |       |       |       |       |       |     |
|----------------------------------------------------|-------------------------------|--------|--------|-------|-------|-------|-------|-------|-------|-----|
| Wk 0                                               | Wk 1                          | Wk 2   | Wk 3   |       |       |       |       |       |       |     |
| (±3 d)                                             | Wk 4                          | Wk 5   | Wk 6   | Wk 8  |       |       |       |       |       |     |
| (±3 d)                                             | (±3 d)                        |        |        |       |       |       |       |       |       |     |
| Study Week†                                        | Wk                            | Wk 10  |        |       |       |       |       |       |       |     |
| (±3 d)                                             | (±3 d)                        | (±3 d) | (±3 d) |       |       |       |       |       |       |     |
| (-)4-(-)1                                          | (±1 w)                        |        |        |       |       |       |       |       |       |     |
| Visit Number                                       | V0                            | V1     | V2     | V3    | V4    | V5    | V6    | V7    | V8    | V9  |
| Visit Name                                         | Screening‡                    | Tx #1  | Tx #2  | Tx #3 | Tx #4 | Tx #5 | Tx #6 | Lab 1 | Lab 2 | PDE |
| Informed consent                                   | X                             |        |        |       |       |       |       |       |       |     |
| Demographics                                       | X                             |        |        |       |       |       |       |       |       |     |
| General and Urothelial  Carcinoma Medical History, | X                             |        |        |       |       |       |       |       |       |     |
| Smoking Concomitant Medications  Review            | X                             | X      | X      | X     | X     | X     | X     | X     |       |     |
| Eligibility criteria                               | X                             | X§     |        |       |       |       |       |       |       |     |
| Full Physical Examination                          | X                             | X      |        |       |       |       |       |       |       |     |
| Urology oriented Physical  Examination             | X                             | X      | X      | X     | X     | X     | X     | X     |       |     |
| Vital signs♠                                       | X                             | X      | X      | X     | X     | X     | X     | X     |       |     |  
† Time windows for study visits: V2-V6 ±3 day; V9 ±1 week ‡ Screening activities may be performed on separate days as long as they are completed within the screening period, before treatment starts.  
§ Investigator and sponsor confirmation of eligibility prior to instillation. Entry into the trial will be based on the local pathologist diagnosis. ♠ Vital signs: Body temperature, blood pressure, heart rate, height and weight (screening)
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                 |                             |        |        |        |       |       |       |       |       |     |
|---------------------------------------------|-----------------------------|--------|--------|--------|-------|-------|-------|-------|-------|-----|
| Treatment period                            | Primary Disease  Evaluation |        |        |        |       |       |       |       |       |     |
| Wk 0                                        | Wk 1                        | Wk 2   | Wk 3   |        |       |       |       |       |       |     |
| (±3 d)                                      | Wk 4                        | Wk 5   | Wk 6   | Wk 8   |       |       |       |       |       |     |
| (±3 d)                                      | (±3 d)                      |        |        |        |       |       |       |       |       |     |
| Study Week†                                 | Wk                          | Wk 10  |        |        |       |       |       |       |       |     |
| (±3 d)                                      | (±3 d)                      | (±3 d) | (±3 d) | (±1 w) |       |       |       |       |       |     |
| (-)4-(-)1                                   |                             |        |        |        |       |       |       |       |       |     |
| Visit Number                                | V0                          | V1     | V2     | V3     | V4    | V5    | V6    | V7    | V8    | V9  |
| Visit Name                                  | Screening‡                  | Tx #1  | Tx #2  | Tx #3  | Tx #4 | Tx #5 | Tx #6 | Lab 1 | Lab 2 | PDE |
| coagulation **                              | X                           | X     | X     | X     | X    | X    | X    | X     |       |     |
| CBC, liver and renal function,              | coagulation  not required   | X      |        |        |       |       |       |       |       |     |
| coagulation                                 | X                           |        |        |        |       |       |       |       |       |     |
| not required                                |                             |        |        |        |       |       |       |       |       |     |
| Urinalysis/dipstick                         | X                           | X      | X      | X      | X     | X     | X     | X     |       |     |
| Urine culture                               | X                           | X††    | X††    | X††    | X††   | X††   | X††   | X††   |       |     |
| CTU or MRI                                  | X‡‡                         |        |        |        |       |       |       |       |       |     |
| Biopsy for histopathology                   | X§§                         | X***   |        |        |       |       |       |       |       |     |
| Upper Urinary Tract Urine  cytology-washing | X§§                         | X      |        |        |       |       |       |       |       |     |
| Pregnancy serum test †††                    | X                           | X‡‡‡   | X‡‡‡   | X‡‡‡   | X‡‡‡  | X‡‡‡  | X‡‡‡  | X‡‡‡  |       |     |
| Pregnancy urine test †††                    | X                           | X      | X      | X      | X     | X     | X     |       |       |     |  
  
** If done one week prior to screening, acceptable. Treatment period- To be performed before the instillation, see Appendix III
In case patient preformed all required blood test according to Appendix III up to 3 days prior to the instillation- no need to repeat;
†† To be performed when UTI is suspected according to urinalysis results.  
‡‡ CTU to be repeated if done more than 3 months prior to first treatment. In the event that CTU is not applicable from any reason, an MRI should be performed instead
§§ Histopathology and cytology evidence of LG UTUC performed ≤2 months prior to V0 (or 3 months prior to the first instillation) is acceptable provided that the slides can be sent for central pathology evaluation. All Histopathology evaluations performed locally will be reviewed centrally.  
*** Biopsy will be taken at PDE and any follow up visit when lesions are detected and recurrence is suspected. ††† Only for women of childbearing potential
‡‡‡ Only for women of childbearing potential and a positive pregnancy urine test 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                                                 |                             |        |        |        |       |       |       |       |       |     |
|-----------------------------------------------------------------------------|-----------------------------|--------|--------|--------|-------|-------|-------|-------|-------|-----|
| Treatment period                                                            | Primary Disease  Evaluation |        |        |        |       |       |       |       |       |     |
| Wk 0                                                                        | Wk 1                        | Wk 2   | Wk 3   |        |       |       |       |       |       |     |
| (±3 d)                                                                      | Wk 4                        | Wk 5   | Wk 6   | Wk 8   |       |       |       |       |       |     |
| (±3 d)                                                                      | (±3 d)                      |        |        |        |       |       |       |       |       |     |
| Study Week†                                                                 | Wk                          | Wk 10  |        |        |       |       |       |       |       |     |
| (±3 d)                                                                      | (±3 d)                      | (±3 d) | (±3 d) | (±1 w) |       |       |       |       |       |     |
| (-)4-(-)1                                                                   |                             |        |        |        |       |       |       |       |       |     |
| Visit Number                                                                | V0                          | V1     | V2     | V3     | V4    | V5    | V6    | V7    | V8    | V9  |
| Visit Name                                                                  | Screening‡                  | Tx #1  | Tx #2  | Tx #3  | Tx #4 | Tx #5 | Tx #6 | Lab 1 | Lab 2 | PDE |
| Ureteroscopy (URS)+C arm                                                    | X§§§                        | X      |        |        |       |       |       |       |       |     |
| Recording/ Photographing of  UUT lesions number, size,                      | X                           | X      |        |        |       |       |       |       |       |     |
| appearance and location  Volumetric estimation  (retrograde pyelography and | X                           |        |        |        |       |       |       |       |       |     |
| fluoroscopy) 3 repetitions Provide prescription for  sodium bicarbonate,  Prophylaxis antibiotic, antihistaminic and  diazepam(optional) and written  instructions                                                                             | X                           |        |        |        |       |       |       |       |       |     |
| Patient card, letter to GP,  Guidance letter to patient                     | X                           |        |        |        |       |       |       |       |       |     |
| Fluoroscopy                                                                 | X                           | X      | X      | X      | X     | X     |       |       |       |     |
| Cystoscopy for catheterization                                              | X                           | X      | X      | X      | X     | X     |       |       |       |     |
| MitoGel™ Admixture  administration                                          | X                           | X      | X      | X      | X     | X     |       |       |       |     |  
  
  
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                                                                        |                             |        |        |        |       |       |       |        |       |     |
|----------------------------------------------------------------------------------------------------|-----------------------------|--------|--------|--------|-------|-------|-------|--------|-------|-----|
| Treatment period                                                                                   | Primary Disease  Evaluation |        |        |        |       |       |       |        |       |     |
| Wk 0                                                                                               | Wk 1                        | Wk 2   | Wk 3   |        |       |       |       |        |       |     |
| (±3 d)                                                                                             | Wk 4                        | Wk 5   | Wk 6   | Wk 8   |       |       |       |        |       |     |
| (±3 d)                                                                                             | (±3 d)                      |        |        |        |       |       |       |        |       |     |
| Study Week†                                                                                        | Wk                          | Wk 10  |        |        |       |       |       |        |       |     |
| (±3 d)                                                                                             | (±3 d)                      | (±3 d) | (±3 d) | (±1 w) |       |       |       |        |       |     |
| (-)4-(-)1                                                                                          |                             |        |        |        |       |       |       |        |       |     |
| Visit Number                                                                                       | V0                          | V1     | V2     | V3     | V4    | V5    | V6    | V7     | V8    | V9  |
| Visit Name                                                                                         | Screening‡                  | Tx #1  | Tx #2  | Tx #3  | Tx #4 | Tx #5 | Tx #6 | Lab 1  | Lab 2 | PDE |
| VAS for pain evaluation                                                                            | X                           | X      | X      | X      | X     | X     |       |        |       |     |
| 6 hours observation post  treatment                                                                | X                           |        |        |        |       |       |       |        |       |     |
| 1.3 gr  3 of sodium  bicarbonate (|The night before,  morning of and 30 min. prior to  treatment) | X                           | X      | X      | X      | X     | X     |       |        |       |     |
| MMC level (plasma) ****                                                                            | X ††††                      |        |        |        |       |       |       |        |       |     |
| Phone reminder day prior to  instillation: Bicarbonate, liquid                                     | X                           | X      | X      | X      | X     | X     |       |        |       |     |
| limitation, diuretics,  Supply questionnaire for 24-32  h Post treatment telephone                 | X                           | X      | X      | X      | X     | X     |       |        |       |     |
| contact‡‡‡‡ 24-32 h Post treatment                                                                 | X                           | X      | X      | X      | X     | X     |       |        |       |     |
| telephone contact ‡‡‡‡ Adverse Events                                                              | X                           | X      | X      | X      | X     | X     | X     | X §§§§ |       |     |  
  
**** In 6 treated patients
†††† Prior to instillation, 30min., 1, 2, 3, 4, 5, and 6 hours post instillation ‡‡‡‡ For patients treated in retrograde fashion only
§§§§ Review of unresolved AEs and recording of newly emerging AEs considered to be related to participation in the study (See Section 19)  
| Maintenance Treatment (±1 w)                     |                 |           |          |        |        |        |        |        |        |        |        |               |
|--------------------------------------------------|-----------------|-----------|----------|--------|--------|--------|--------|--------|--------|--------|--------|---------------|
| up to 3  Weeks  post  PDE                        | FU1             | FU2       | FU 3     | FU 4   |        |        |        |        |        |        |        |               |
| +3mo                                             | +6mo  Post  PDE | +9mo      | +12mo    |        |        |        |        |        |        |        |        |               |
| Study Month*****                                 | Post  PDE       | Post  PDE | Post PDE |        |        |        |        |        |        |        |        |               |
| (±2 w)                                           | (±2 w)          | (±2 w)    | (±2 w)   |        |        |        |        |        |        |        |        |               |
| Visit Number                                     | V10             | V11       | V12      | V13    | V14    | V15    | V16    | V17    | V18    | V19    | V20    | V21 FU4 Trial |
| Completion                                       |                 |           |          |        |        |        |        |        |        |        |        |               |
| Visit Name                                       | Maint.          | Maint.    | Maint.   | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. |               |
| #1                                               | #2              | #3        | #4       | #5     | #6     | #7     | #8     | #9     | #10    | #11    |        |               |
| Urology oriented Physical Examination            | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      | X             |
| Vital signs                                      | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      | X             |
| CBC, liver and renal function,  coagulation††††† | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      | X             |
| Urinalysis/dipstick                              | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      | X             |
| Urine culture‡‡‡‡‡                               | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      | X             |
| CTU Scan                                         | X§§§§§          |           |          |        |        |        |        |        |        |        |        |               |
| Biopsy for histopathology******                  | X               | X         | X        | X      |        |        |        |        |        |        |        |               |  
Part II –Maintenance & Follow Up - Complete Response Patients  
  
***** Time windows for study visits V10, V12, V15, V18, V21 ±2 weeks.  
††††† CBC, liver and renal function, coagulation tests to be performed before the instillation, see Appendix III ‡‡‡‡‡ To be performed when UTI is suspected according to urinalysis results
§§§§§ At the 12 M FU Visit, CT scan should be obtained for all patients who continue to demonstrate CR
****** Biopsy will be taken at PDE and any follow up visit when lesions are detected and recurrence is suspected.  
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ -
US, IL
Document Number: CLP-0002344 Document Version: 6.0  
| Maintenance Treatment (±1 w)                                         |                 |           |          |        |        |        |        |        |        |        |        |               |
|----------------------------------------------------------------------|-----------------|-----------|----------|--------|--------|--------|--------|--------|--------|--------|--------|---------------|
| up to 3  Weeks  post  PDE                                            | FU1             | FU2       | FU 3     | FU 4   |        |        |        |        |        |        |        |               |
| +3mo                                                                 | +6mo  Post  PDE | +9mo      | +12mo    |        |        |        |        |        |        |        |        |               |
| Study Month*****                                                     | Post  PDE       | Post  PDE | Post PDE |        |        |        |        |        |        |        |        |               |
| (±2 w)                                                               |                 |           |          |        |        |        |        |        |        |        |        |               |
| (±2 w)                                                               | (±2 w)          | (±2 w)    |          |        |        |        |        |        |        |        |        |               |
| Visit Number                                                         | V10             | V11       | V12      | V13    | V14    | V15    | V16    | V17    | V18    | V19    | V20    | V21 FU4 Trial |
| Completion                                                           |                 |           |          |        |        |        |        |        |        |        |        |               |
| Visit Name                                                           | Maint.          | Maint.    | Maint.   | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. |               |
| #1                                                                   | #2              | #3        | #4       | #5     | #6     | #7     | #8     | #9     | #10    | #11    |        |               |
| Upper Urinary Tract Urine cytologywashing                                                                      | X               | X         | X        | X      |        |        |        |        |        |        |        |               |
| Pregnancy urine test ††††††                                          | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      | X             |
| Pregnancy serum test ‡‡‡‡‡‡                                          | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      | X             |
| Ureteroscopy (URS)                                                   | X               | X         | X        | X      |        |        |        |        |        |        |        |               |
| Recording/Photographing of UUT  lesions number, size, appearance and | X               | X         | X        | X      |        |        |        |        |        |        |        |               |
| location Fluoroscopy                                                 | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      |               |
| Cystoscopy for catheterization                                       | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      |               |
| MitoGel™ Admixture instillation                                      | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      |               |
| 1.3 g  3 of sodium bicarbonate                                      | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      |               |  
  
†††††† Only for women of childbearing potential
‡‡‡‡‡‡ Only for women of childbearing potential and a positive pregnancy urine test A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ -
US, IL
Document Number: CLP-0002344 Document Version: 6.0  
| Maintenance Treatment (±1 w)                                                          |                 |           |          |        |        |        |        |        |        |        |        |               |
|---------------------------------------------------------------------------------------|-----------------|-----------|----------|--------|--------|--------|--------|--------|--------|--------|--------|---------------|
| up to 3  Weeks  post  PDE                                                             | FU1             | FU2       | FU 3     | FU 4   |        |        |        |        |        |        |        |               |
| +3mo                                                                                  | +6mo  Post  PDE | +9mo      | +12mo    |        |        |        |        |        |        |        |        |               |
| Study Month*****                                                                      | Post  PDE       | Post  PDE | Post PDE |        |        |        |        |        |        |        |        |               |
| (±2 w)                                                                                |                 |           |          |        |        |        |        |        |        |        |        |               |
| (±2 w)                                                                                | (±2 w)          | (±2 w)    |          |        |        |        |        |        |        |        |        |               |
| Visit Number                                                                          | V10             | V11       | V12      | V13    | V14    | V15    | V16    | V17    | V18    | V19    | V20    | V21 FU4 Trial |
| Completion                                                                            |                 |           |          |        |        |        |        |        |        |        |        |               |
| Visit Name                                                                            | Maint.          | Maint.    | Maint.   | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. | Maint. |               |
| #1                                                                                    | #2              | #3        | #4       | #5     | #6     | #7     | #8     | #9     | #10    | #11    |        |               |
| Phone reminder day prior to  instillation: Bicarbonate, liquid  limitation, diuretics | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      |               |
| Review of Disease Outcome and  Complete Response Durability                           | X               | X         | X        | X      |        |        |        |        |        |        |        |               |
| Adverse Events /Concomitant Med.                                                      | X               | X         | X        | X      | X      | X      | X      | X      | X      | X      | X      | X             |
trial title a phase 3
15. evaluation of response

Patient response will be evaluated according to the following criteria:
Complete Response (CR): A patient will be considered to have had CR if there is no detectable disease (NDD). To determine NDD, the following conditions should be fulfilled (see also Figure 1 in Section 9.2.1) 1. If visual assessment (URS) indicates no remaining tumors the upper tract urine cytology must be negative; 2. If tumors are visible during URS, all remaining and accessible tumors should be biopsied.  
If the biopsied tumors are not viable upon histopathological evaluation and the cytology is negative, the patient should be considered to have had CR;
3. In a case where the preferable treatment is RNU and its pathological evaluation indicates that no viable tumor(s) remained in the affected kidney (e.g., non-viable lesion), the patient will be considered CR retroactively.  
No Complete Response (NCR): A patient will be considered to have had NCR if there is a residual disease. NCR should be determined only after pathology result was received from the pathology local lab.  
| Visual Assessment via   | Biopsy (central lab)   | Cytology (central lab)   | CR Yes/No     |
|-------------------------|------------------------|--------------------------|---------------|
| Video-URS               |                        |                          |               |
| Negative                | NA                     | Negative                 | Yes (Success) |
| Negative                | NA                     | Equivocal positive       | No*           |
| Negative                | NA                     | positive                 | No (Failure)  |
| Positive                | Positive               | Negative                 | No (Failure)  |
| Positive                | Negative               | Negative                 | Yes (Success) |  
Table 2 Response: Classification in possible scenarios (Assessed at PDE Visit)
* Unless at next maintenance the upper tract urine cytology is negative
trial title a phase 3
15.1. tumor measurements and classification

At Baseline, during the diagnostic ureteroscopy, the size of all measurable tumors for each patient will be estimated and recorded. Each measurable lesion will be identified with a unique identifier number, and the morphology and location will be recorded on a diagram of the upper urinary tract provided in the chart and CRF. Tumors size will be recorded in one dimension (the longest diameter; mm). Measurable tumors are defined as those for which a reasonable visual  
 estimation can be obtained visually and photographically. At PDE, the size of all measurable tumors identified at baseline, if still present, should be recorded, using the same identifier tumors number and location as recorded at baseline. PR is every change in the tumor size or number which is not CR or NR.
trial title a phase 3
15.2. assessment of uc tumor

Diagnosis of UC at the PDE visit with an increase in stage or grade compared to baseline will be tracked; however, as is explained below, it likely does not represent true progression for the following reasons:
1. Following RNU, a high rate (> 33%) of change in grade and stage of UC compared with the initial diagnostic biopsy has been reported [Smith, 2011). This is likely due to the poor specimens usually obtained during initial diagnostic URS. Therefore, if a patient diagnosed at Baseline with LG non-invasive UC and at the PDE with HG, or the tumor is found to be more invasive (stage increase); this more likely represents under grading/ under staging at the time of first diagnosis rather than true tumor progression; 2. The overall risk of progression for patients with LG papillary UC is about 5%. A 12-week interval, during which the patient is exposed to MMC treatment, is not generally considered long enough for progression to occur in patients with non-invasive urothelial carcinoma; Upstaging/upgrading detected at the PDE visit will be recorded and the overall incidence will be compared with that reported in the literature. The progression of the initial disease during the FU period after the patient already achieved CR will be documented in the CRF.
trial title a phase 3
15.3. assessment of uc tumor

Follow up will be conducted for patient who were defined as CR at PDE, or for patients for whom the investigator was uncertain of the final diagnosis and chose to continue to the next FU visit for re-assessment.  
Starting with the FU 1 visit (3 months post PDE visit), information regarding disease status based on Ureteroscopy, Upper tract washing urine cytology, and Biopsy, if needed, as well as intervention should be recorded. For a patient to be defined as having recurrence complete documentation should be obtained and the following criteria should be met:
Visual confirmation of tumor presence; AND Positive biopsy for UC where it is technically feasible.  
  
 Only recurrence in the treated area will be counted for the analysis as treatment failures. A new lesion within the renal pelvis be considered recurrent disease (meaning a disease recurrent in the UPJ and up). The appearance of urothelial carcinoma during the follow-up period in another area in the urinary system (the other kidney, ureter, bladder, and urethra) will be documented but will not be considered as a recurrence for the trial primary analysis.  
In a patient which during the trial period has a UC recurrence in the bladder and is required to undergo a TURBT, the surgery can be done during the FU period, and as long as his treatment doesn't require intravesical instillations the patient can stay in the FU with the maintenance treatment for his UTUC disease.  
If the recurrent bladder cancer in the FU period requires full course of intravesical treatment, it is the PI discretion whether to keep the patient in the FU period without the MitoGel maintenance treatment for the UT during the 6 weeks of the bladder instillations.  
If the recurrence is in the other kidney, and the patient requires immediate intervention, the FU
period may be terminated for this patient and the durability will be calculated based on the existing data (depending also on the planned kidney surgery).
trial title a phase 3
15.4. pathological evaluation

Biopsies and upper tract washing urine cytology specimens obtained at baseline should be evaluated by the local institutional pathologist. Patient's enrollment to the trial will be based on the local pathologists' diagnosis.  
A central pathology service will be used for this trial. Biopsy and urine cytology slides obtained either at Screening/Baseline, PDE and every FU visit, will be read by the central pathologist. The diagnosis based on local reading will be considered the final one for the purpose of primary efficacy evaluation. Note: Further details on the process will be provided in the Administrative Binder of the trial procedures.  
16. Trial Flow-Chart Per Patient
trial title a phase 3
17. patients withdrawal from treatment

A patient's preterm withdrawal from the treatment or from the trial can take place at any stage prior to trial completion, and in any case, in which emerging adverse events are of such a nature that the risk/benefit ratio is unacceptable to the individual patient.
trial title a phase 3
17.1. criteria for patient withdrawal

The single most important reason for premature discontinuation should be marked on the End of Treatment Form, under one of the following categories:
Adverse Event/Serious Adverse Event Mandatory criterion for discontinuation per protocol Patient wishes to withdraw his/her consent for participation in the trial; Patient's non-compliance with treatment or protocol requirements; Patient lost to FU; Pregnancy.  
17.1.1. Discontinuation from MitoGel Treatment is mandated in the following event:
a. Grade 4 neutropenia lasting >5 days b. Febrile neutropenia c. Grade 4 thrombocytopenia d. Grade 3 thrombocytopenia with hemorrhage e. Dose delay of >4 weeks due to an adverse reaction f. Grade 3-4 non-infective cystitis g. Grade 3-4 hematuria h. Any grade of urinary system perforation i. Any Grade 4 non-hematologic toxicity EXCEPT:
I. Grade 4 vomiting/diarrhea lasting <72 hours in the absence of maximal medical therapy II. Grade 4 laboratory abnormalities that can be readily corrected and do not result in hospitalization Note: No dose modifications or delays are allowed in patients who do not tolerate MitoGel
trial title a phase 3
17.1.2. fu of patients that

For a patient who completes at least one instillation but withdraws from the treatment prior to the 6th instillation, the patient should be invited for an unscheduled visit in which all assessments scheduled for the PDE visit should be conducted. If the patient is classified as CR., the patient will be asked to continue providing follow up data during FU visits, which are similar to the ones conducted under the standard of care. Regardless, the site should explain to the patient the importance of continuing FU for disease management.  
PDE will be performed 5 weeks (±1w) after last treatment, and all other FU procedures (safety and recurrence) will continue according to protocol. The patient's follow-up data will be collected in the trial database, upon completion of the trial (or an early withdrawal from the trial). In case of tumor recurrence, the patient's participation in the trial will be terminated.  
If a patient withdraws from the interventional portion of a trial and does not consent to continue FU or provide clinical outcome information, the investigator must not access for purposes related to the trial the patient's medical record or other confidential records requiring the patient's consent. However, an investigator may review trial data related to the patient collected prior to the patient's withdrawal from the trial for the purpose of clinical management of the patient, and may consult public records, such as those establishing survival status.
trial title a phase 3
17.1.3. patients withdrawal from the

A patient will be withdrawn from the trial for any of the following reasons:
Lost to follow-up; Withdrawal of consent; Sponsor terminates the study; Death.  
If a patient is lost to follow-up, any reasonable effort must be made by the trial site personnel to contact the patient and determine the reason for discontinuation/withdrawal. Attempts to contact the patient must be documented in the patient's file (at least 3 documented attempts). If a FU visit was performed, relevant measures taken must be documented in the source document and entered into the CRF.  
When a patient withdraws before completing the trial, the reason for withdrawal is to be documented in the source document and entered into the CRF.  
In case of death at any trial time point throughout the trial FU period, the cause of death will be  
  
  
reported to the Ethics Committee.
trial title a phase 3
17.2. definition of trial completion

A patient will be considered to have completed the trial in the following cases:
Patient was defined as PR or NR to treatment at PDE visit; For patients with CR at PDE, FU will continue until one of the following occurs:
o Recurrence of tumor has occurred, o Patient has completed 12 months FU visit.
trial title a phase 3
17.3. replacement of individual patients

Patients who discontinued treatment will not be replaced. Ineligible (screen-failures) patients, or patients who did not receive any study medication will be replaced. Screen failed patient can be re-screen if he meets the criteria later on the study period. Screen Failures Minimal Required Data The minimal required CRF forms for screen failure patients are:
Demographics Inclusion Criteria Exclusion Criteria Patient Eligibility by site investigator Patient Eligibility by sponsor.
trial title a phase 3
18. statistical methodology

At least 74 evaluable patients meeting all inclusion and exclusion criteria with a confirmed diagnosis of LG UTUC will participate in this trial to provide 88.5% power to demonstrate efficacy (See Section 18.2). Assuming a lost to follow-up rate of about 10%, approximately 83 subjects will participate in this trial. While no formal, interim analysis for stopping the trial for success is planned, the trial's DMC will have continuous access to safety and efficacy data. This is meant to:
a. Enable carrying out the following FDA suggestion: "The agency clarified that the sponsor does not have to wait until all patients have completed this additional follow up before submitting the application. The sponsor can submit an application once they believe they have demonstrated safety and efficacy of this product." (PIND Nov, 2015 meeting minutes, p. 7).  
b. Avoid operational bias by providing the access to cumulative ongoing trial data to an  
  
  
independent body only.  
The DMC will have the authority to decide whether the data is sufficiently indicative of safety and efficacy for submission to FDA even before the complete sample has been recruited and/or followed up. At the same time, even if UroGen provides interim data to FDA at DMC's recommendation, the study will continue to enroll subjects as per study plan while discussions with the FDA are taking place.  
It should be noted that MitoGel is intended for treating the *entire* upper urinary tract, not only a single marker lesion. Thus, subjects with multiple lesions will be included in the study and treatment will be considered successful only if all lesions disappear. This study will test one primary and one key secondary efficacy endpoints. The former relates to CR at PDE visit while the latter assesses durability of CR at 12 months (for those demonstrating CR at PDE). To control Alpha for Type I Error, hypotheses will be tested hierarchically—primary first and key secondary, second—and only a significant result on the first test will enable conducting the second hypothesis test. Consequently, Alpha will be 0.05 two sided for both tests. A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to database lock. The SAP will supersede this statistical analysis section.
trial title a phase 3
18.1. significance level

The overall significance level for testing primary efficacy is 0.05, two sided. Since there is no formal interim analysis (DMC's independent review of the data is described in Section 18), and Alpha is controlled for multiple testing hierarchically, Alpha for statistical testing will be 0.05, two sided. Non-confirmatory analyses will not control for multiple testing so that Alpha for significance in each will remain 0.05, two-sided.
trial title a phase 3
18.2. sample size rationale

Sample size determination was performed under the following assumptions:
The primary efficacy endpoint of the trial is the Complete Response (CR) rate at the PDE Visit; It is expected that the true CR rate following treatment with MitoGel™ is 30% or more; The principal analysis of the primary endpoint will aim to rule out a threshold rate of 15% using a two-tailed exact test for binomial proportion at two-sided Alpha = 0.05; i.e., 15% CR is the study's performance goal (PG).  
Under these assumptions, a sample of 74 evaluable patients will provide a power of 88.5% to  
  
  
demonstrate that the observed CR rate is superior to the PG of 15%. Assuming a lost to follow-up rate of about 10%, at total of about 83 subjects will participate in this trial.  
It should be noted that this trial is not powered for the key secondary endpoint.
trial title a phase 3
18.3. futility analysis

A futility analysis is planned for this trial after 20 evaluable subjects have provided primary efficacy data at the PDE visit or after as applicable24. Since this interim analysis will be for futility only (i.e., it will not provide the option of stopping for success). Alpha remains unaffected and need not be adjusted for multiplicity.  
Futility will be declared if the conditional power for success at the end of the trial given results at N = 20 is below 25% (i.e., less than 1 CR case out of 20). It should be noted that the choice of futility analysis after 20 subjects was made based on: a) Company's wanting to analyze the data as early as possible, so as not to conduct a larger trial that is futile and b) Error of Type II, Beta, at N = 20 and the above rule for futility is 0.0; i.e. this futility analysis does not reduce overall study power. Results of the futility analysis will be presented in closed session to the DMC, which will make the final determination of trial continuation based on the statistical and clinical considerations.
trial title a phase 3
18.4. analysis sets 18.4.1. safety

The safety analysis set will consist of all patients who enrolled in the trial and received at least 1 instillation of MitoGel™ Admixture. This analysis set, which will include all data captured in data base for these patients, will serve as the primary analysis set for safety assessment. Intent-to-Treat (ITT) Analysis Set (=safety analysis set).  
This analysis set, which will include all data captured in the database for these patients, will serve as the primary analysis set for the primary efficacy analyses and inference.
trial title a phase 3
treatment of missing values in

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.  
Treatment of missing values for the secondary endpoint detailed in Section18.7.2.
trial title a phase 3
18.4.2. local modified intent-to-treat (mitt)

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. Missing values: Only observed values will be used in local - mITT; i.e. missing data will not be imputed.
trial title a phase 3
18.4.3. central modified intent-to-treat (mitt)

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.
trial title a phase 3
18.4.4. per protocol (pp) analysis

The Per Protocol (PP) analysis set is a subset of the Local mITT Analysis Set and will consist of all enrolled patients who received at least 4 MitoGel™ Admixture instillations and have observed data on the primary efficacy endpoint. Patients who are identified as HG at the PDE visit will be excluded from the PP1 population. This analysis set will include all data captured in database for this subpopulation.
trial title a phase 3
18.4.5. per protocol (pp) analysis

The Per Protocol (PP) analysis set is a subset of the Local mITT Analysis Set and will consist of all enrolled patients who received a total of 6 MitoGel™ Admixture instillations, who do not have major protocol violation, and have observed data on the primary efficacy endpoint. Patients who are identified as HG at the PDE visit will be excluded from the PP2 population. This analysis set will include all data captured in database for this subpopulation.  
18.4.6. Complete Responders at the PDE Visit (PDECR) Analysis Set  
  
  
The PDECR analysis set is a subset of the ITT Analysis Set who had a Complete Response (CR)
at the PDE Visit.
trial title a phase 3
18.5. patient disposition

Subject disposition will be tabulated; the number of enrolled, exposed, prematurely terminated and completed subjects will be summarized separately according to treatment and by visit (where relevant). A list of dropouts will be prepared including reason for discontinuation, and time of discontinuation.
trial title a phase 3
18.6. demographic and baseline characteristics

Demographics and baseline data as well as disease prognostic factors, medical history, and prior medications will be summarized using the safety analysis set by descriptive statistics. For continuous variables, descriptive statistics (number [n], mean, standard deviation (SD), standard error, median, minimum, and maximum) will be provided. For categorical variables, patient counts and percentages will be provided. Categories for missing data will be presented separately if necessary.
trial title a phase 3
18.7. efficacy analyses 18.7.1. primary

The principal analysis of the primary endpoint will test the Complete Response (CR) rate defined as percent of patients with CR at the PDE Visit or necessary follow-up (See Section 9.2.1) using the ITT Analysis Set. Patients who did not demonstrate confirmed CR at PDE visit or necessary follow-up will be considered for the purpose of this analysis as treatment failures.  
The primary efficacy analysis will test the following hypotheses.  
H0: CRrate ≤15%
H1: CRrate >15%
Testing will be done by using an exact binomial two-sided hypothesis testing, with two-sided Alpha = 0.05. (Note that this is in fact identical to the one-sided testing with Alpha=0.025). In addition, exact binomial 95% confidence interval about the observed CRrate will be provided.  
It should be noted that FDA has made allowance for data assessed qualitatively by the DMC
being submitted for the Agency's evaluation (see Section 18) that, in FDA's opinion, may be sufficient for demonstrating safety and efficacy of the product.
trial title a phase 3
18.7.2. sensitivity analysis for the

The following analyses will be done to examine the robustness of the study's primary conclusion to inclusion criteria and differing patterns of missingness. 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
In addition, two alternative imputation methodologies will be examined in the ITT population.
trial title a phase 3
1. tipping point

In this analysis missing values on CR will be progressively imputed "failure" until such point when the CR rate is no longer significant; i.e. the 95% confidence interval about CR rate is no longer wholly above 15%. The point at which results are no longer significant will be defined as the "tipping point." (Recall that missing subjects in ITT are imputed "failure" for the primary analysis, which is essentially a worst case analysis.)
2. Multiple Imputation The missing response status will be imputed using the multiple imputation procedure (PROC MI in SAS®). Ten (10) imputed datasets will be created. The imputation model will use the following covariates: Sex, Age, number of papillary lesions at screening, the largest diameter at Screening, Tumor Burden and total number of episodes.
trial title a phase 3
18.7.3. key secondary efficacy analysis

The study's key secondary endpoint is durable response at 12-month follow-up in the CR
analysis set, which will test the following hypotheses:
H0: CR12-months ≤ 40%
H1: CR12-months > 40%
The key secondary endpoint will be tested by constructing a two-sided, 95%, Exact Binomial confidence interval about the rate of subjects in the CR analysis set continuing to show CR at 12 months. We will declare success on this endpoint if the lower bound of the confidence interval is above 40%.  
The key secondary endpoint will be tested on 12-month data, where missing data due to: - Discontinuation due to AEs related or probably related to investigational therapy = "failure" - Discontinuation or lost-to-follow-up for any other reason will not be imputed Since Alpha for multiple testing is controlled using the hierarchical method, there is no need to  
  
  
adjust Alpha for the key secondary endpoint.  
Observed rate of CR at 12 months was selected because of its clinical meaningfulness. At the same time, the continuous durability of CR will also be analyzed by Kaplan Maier analysis. Durability will be defined from the time of the PDE visit where first CR is confirmed until the first visit where a patient do not meet the definition of CR. Patients who discontinued the study for any reason will be censored at their last assessment in which they had maintained a complete response.  
18.7.4. Sensitivity Analysis for the Dichotomous Key Secondary Endpoint 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 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.
trial title a phase 3
18.7.5. secondary efficacy analyses

Secondary efficacy analyses will be conducted using all but the safety analysis sets. Durable CR at 3, 6 and 9 months will be analyzed using the CR analysis set, so that the denominator for CR rate consists only of those subjects demonstrating CR at PDE.  
Durable CR at 3, 6 and 9 months will be analyzed by constructing a two-sided, 95%, exact binomial confidence interval about CR rate. Subjects whose data are missing at 3, 6 and 9 months due to AEs definitely or probably related to treatment will be imputed failures. Subjects whose status of CR is missing at some FU visit, but the CR is confirmed at any further FU visit will be imputed CR (Success) backward. Data missing for other reasons will be excluded from the analysis.  
For patients with PR at PDE visit, originally planned and actually received UTUC treatment will be compared.
trial title a phase 3
18.8. evaluation of safety

Safety analyses will be descriptive and narrative in nature, with SAE's and AE's coded using MedDRA Version 19.0 or higher and tabulated by body system, preferred term, severity and relation to study drug and procedure. Descriptive statistics will be provided over time as appropriate.
trial title a phase 3
18.8.1. adverse events

Adverse events will be recorded from the time a patient has signed the Informed Consent.  
Adverse Events (AEs) reported by the investigators will be coded according to the MedDRA dictionary.  
The following will be incorporated into the analysis of adverse events:
All analyses to be provided will include coded AEs; Adverse events analyses will include only Treatment Emergent Adverse Events (TEAEs),
namely, those events which started on the day of first trial IP administration or afterwards. Listings of both TEAEs and non-TEAES will be provided; The incidence (no. of patients) and frequency (no. of events) of TEAEs will be provided when broken down by System Organ Class (SOC) and by Preferred Term (PT) according to MedDRA dictionary; Breakdowns of TEAEs by all AEs attributes will also be provided; Breakdowns of TEAEs by age, sex and volume of instillation will also be provided; The derived dictionary used in the analyses displaying the MedDRA System Organ Class
(SOC), the Preferred Term (PT), and the AE Verbatim Term as specified by the Investigator, will be provided; The incidence (no. of patients) and frequency (no. of events) of serious TEAEs will be provided when broken down by System Organ Class (SOC) and by Preferred Term (PT) according to MedDRA dictionary as well as by SAEs attributes and by age, sex, and volume of instillation. SAEs will also be listed.
trial title a phase 3
18.8.2. safety laboratory tests

Analyses of safety laboratory data will be performed in the following manner: Graphical presentation given in mean values + 2 standard errors of the mean of laboratory tests results by scheduled visits will be provided as well; Quantitative laboratory measurements will be categorized with reference to the normal  
  
  
ranges as Low, Normal, or High. Shift analysis of the categorical change from baseline to each scheduled visit and to the last observed assessment will also be performed; A list of parameters and related cut-off values defining the potentially clinically significant
(PCS) abnormal values will be outlined by the Sponsor prior to initiation of the first trial instillation. Measurements used in the analysis are those taken following first trial instillation. The incidence tables of PCS lab values as well as the individual patient listing will be provided using the denominator which is the number of patients with at least one post-baseline administration of trial medication. Individual patients' listings of PCS measurements will also be presented.
trial title a phase 3
18.8.3. vital signs

Analyses of vital signs (blood pressure, pulse, temperature, and respiration rate) will be performed in the following manner:
Descriptive statistics of vital signs before first trial instillation and during trial as well as the changes from baseline by scheduled visit will be displayed; The incidence (no. of patients) of potentially clinically significant (PCS) abnormal values will be summarized in a frequency table using the criteria defined by the Sponsor before first trial instillation. Please note that the denominator to be used for calculating percentages is the number of patients with at least one post-baseline evaluation. The incidence tables as well as the individual patient listing of vital signs of PCS will be reported.
trial title a phase 3
18.8.4. physical examination

Any clinically relevant changes occurring from screening until the last trial visit will be recorded in the Adverse Event Sections of the CRF.
trial title a phase 3
18.8.5. tolerability assessments

Tolerability analysis will be based on the number and percent of patients who failed to reach the PDE visit due to related adverse events (probably, definitely) and overall discontinuation rate. The time to withdrawal due to adverse events and overall discontinuation rate, starting from first trial instillation censored by the date of the PDE visit, will be presented using Kaplan-Meier curves.  
A similar analysis approach will be repeated for the FU1 and FU4 visits.
trial title a phase 3
18.8.6. use of concomitant medications

The WHO drug dictionary will be used to classify medications verbatim for Concomitant Medication and Pre-Trial Medications.  
Analysis of concomitant drug use will be performed in the following manner: Pre-Instillation Concomitant Medications Use: Analyses will include coded medications that were initiated prior to first instillation, regardless if stopped after trial first instillation. An incidence table including patient counts (no. of patients) and percentages broken down by Medication Class and Preferred Term will be provided; Concomitant Medications Use (Post-First Trial Instillation): Analyses will include only coded medications that were consumed following the first trial instillation, regardless if drug initiation date was before or after first trial instillation. An incidence table including patient counts (no. of patients) and percentages broken down by Medication Class and Preferred Term will be generated; Prohibited Medications: systemic chemotherapy, intravesical chemotherapy (full course) and BCG, which is part of the exclusion criteria.
trial title a phase 3
18.8.7. mmc levels (pharmacokinetics) profiling

Pharmacokinetic (PK) profile during the 6 hours following the first administration of MitoGel™
will be based on PK sampling at 0, 0.5, 1, 2, 3, 4, 5, and 6 hours post instillation. PK will be performed with just 6 patients who provide informed consent for PK testing. Concentration data as well as PK parameters (e.g., AUC) will be provided using descriptive statistics. Plasma samples for evaluation of PK properties of MMC following instillation with MitoGel™ Admixture will be collected and archived. These samples are to be used to characterize the plasma concentration of MMC during the 6 hours post instillation, which is the estimated duration of the dwell-time of MitoGel™ Admixture. The PK parameters obtained, specifically the Cmax, will be compared to the threshold of MMC plasma concentration (400 ng/mL) known to be associated with myelosuppression, as well as to the known PK profile of MMC obtained with different routes/methods of administration (e.g., intravesical instillation with WFI).  
Additionally, this data, combined with data emerging from other trials/compassionate use program may be used in population pharmacokinetic model development and analysis.
trial title a phase 3
19. management of adverse events

19.1. Definitions 19.1.1. Adverse Events  
Adverse Event (AE): Any untoward medical occurrence in a patient or in a clinical trial patient administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory, physical exam, or vital signs finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product ("Note for Guidance on Good Clinical Practice" CPMP/ICH/135/95). Any patient who reports an adverse event shall be examined by a doctor as soon as possible, making whatever is necessary for the safety and well-being of the patient. All anomalies shall be monitored through to the patient's recovery or clinical stabilization. The investigator shall evaluate all AEs in terms of severity and their relationship with the product being tested, indicating the test results and the measures to be taken.  
Adverse Drug Reaction (ADR)/ **Adverse Procedure Reaction:** Any noxious and unintended responses to a medicinal product/procedure, related to any dose administered. The phrase responses to a medicinal product/procedure, means that a causal relationship between a medicinal product/procedure, and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out ("Note for Guidance on Good Clinical Practice" CPMP/ICH/135/95). The definition also covers the medication errors and uses outside what is foreseen by the trial protocol, include misuse and abuse of the product.
trial title a phase 3
19.1.2. serious adverse events

A "**serious adverse event (SAE**) is any untoward medical occurrence or effect that at any dose:
Results in death; Is life-threatening; Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; or Is a congenital anomaly/birth defect.  
These characteristics/consequences have to be considered at the time of the event; some medical events may jeopardize the patient or may require an intervention to prevent one of above characteristics/consequences. Such events (hereinafter referred to as an "important **medical**
events") should also be considered as "serious" in accordance with the definition ("Note for  
  
  
Guidance on Good Clinical Practice" CPMP/ICH/135/95).  
A **"non-serious adverse event** is an AE which does not meet the above criteria.  
19.1.3. Suspected Unexpected Serious Adverse Reaction/Unexpected Adverse Drug Reaction (SUSAR /UADR):
trial title a phase 3
uadr

An "Unexpected Adverse Drug Reaction" (UADR) is any noxious and unintended response that is related to the administration of an investigational product that has not been reported as expected in this protocol or the Investigator's Brochure, either from previous clinical studies or the non-clinical studies.
trial title a phase 3
susar/suadr

A "Suspected Unexpected Serious Adverse Reaction" is any UADR that at any dose also meet the criteria of SAE above.
trial title a phase 3
19.1.4. causality

The investigator will determine the association between adverse event and treatment/procedure based on the following definitions:
trial title a phase 3
definitely related

A clinical event, including laboratory test abnormalities, which follows the administration of a medicinal product, over a reasonable time period, but which cannot be explained by a concomitant illness or by other medicinal products. The reaction must have already been observed for the suspected medicinal product. The reaction must improve with "de-challenge" and reappear with "rechallenge".
trial title a phase 3
probably related

A clinical event, including laboratory test abnormalities, which follows the administration of a medicinal product, over a reasonable time period, but which cannot be explained by a concomitant illness or by other medicinal products and the "de-challenge" response of which is clinically acceptable. "Re-challenge" data are not necessary.
trial title a phase 3
possibly related

A clinical event, including laboratory test abnormalities, which follows the administration of a medicinal product, over a reasonable time period, but which could also be explained by a concomitant illness or by other medicinal products. Information on suspension of the medicinal product may be missing or uncertain.
trial title a phase 3
not related

A clinical event, including laboratory test abnormalities, where the duration of which, after administration of a medicinal product, makes the causal relationship improbable and where other medicinal products or pre-existing conditions offer plausible explanations.
trial title a phase 3
19.1.5. ae intensity

The intensity of AE is to be graded by the investigator according to CTCAE 4.03 criteria, as outlined below:
0 No AE (or within normal limits);
1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only, intervention not indicated.  
2 Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery)
indicated; limiting age-appropriate instrumental activities of daily living (ADL);
3 Severe or **medically significant** but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL;
4 Life-threatening consequences; urgent intervention indicated (SAE);
5 Death related to AE (SAE).
trial title a phase 3
19.2. reporting procedures

19.2.1. Instructions for Trial Personnel Regarding Patient Adverse Events Reporting.  
Each patient must be given a patient card containing details of the contact person at the site he/she should contact in case any unusual or serious signs or symptoms develop after treatment. Where required, patients will be examined at the center and will be clinically monitored until they recover.
trial title a phase 3
19.2.2. events requiring immediate (24

Expedited reporting to the sponsor is required in the following conditions:
1. Any SAE & Follow up SAE report, if required;  
  
 2. Death of study patient; 3. Pregnancy and outcome of the pregnancy; The investigator must inform the relevant clinical research associate (CRA, Monitor) by phone about the above mentioned events AND notify via email the sponsor within 24 hours of becoming aware of the event. Sponsor contact: Email with copies to Initial SAE/Death/Pregnancy must be recorded in the electronic Case Report Form (eCRF)
within 24 hours of becoming aware of the event.  
In case event requires immediate reporting but the EDC system (eCRF) is not functioning, the site should use the relevant paper forms and email them to .  
The investigator should report the event to the local/central IRB/national EC, according to local requirements.  
Information regarding a pregnancy occurrence in a study subject and the outcome of the pregnancy will be collected. Pregnancy in a study subject is not considered an adverse event. However, the medical outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is considered a serious adverse event and must be reported to the sponsor. In the event of pregnancy occurring in the partner of an enrolled subject, written informed consent for release of medical information from the partner must be obtained prior to the collection of any pregnancyspecific information and the pregnancy will be followed to outcome.
trial title a phase 3
19.2.3. special reporting situations

Sponsor medicinal product that may require expedited reporting and/or safety evaluation include, but are not limited to:
1. Overdose of Investigational Product; 2. Suspected abuse/misuse of Investigational Product; 3. Inadvertent or accidental exposure to Investigational Product; 4. Medication error involving Investigational Product (with or without Patient/patient exposure to the sponsor medicinal product, e.g., name confusion).
trial title a phase 3
19.2.4. events of special interest

1. Allergic reaction to MMC severity grade 3 or 4 on the CTCAE Scale V 4.03 (Appendix VIII:
CTACAE 4.03 Severity Grades, and Allergic Reaction Grades);
2. Urosepsis; 3. Ureteral events, including stenosis, as well as symptoms suspicious of ureteral perforation/rupture - (prolonged localized abdominal or flank pain, abdominal tenderness/acute abdomen);
4. Any unexpected adverse drug reaction with severity grade of 3 or 4 on the CTCAE Scale V
4.03 (Appendix VIII: CTACAE 4.03 Severity Grades, and Allergic Reaction GradesAppendix VIII);
relevant section of the eCRF.  
  
  
A Ph-3 Multicenter Trial Evaluating the Efficacy and Safety of MitoGel™ - US, IL
Document Number: CLP-0002344 Document Version: 6.0 5. Any level of urinary flow interruptions unrelated to enlarged prostate, e.g., Hesitancy ,
Interrupted urine stream, difficulty to urinate and urinary retention; 6. Onset of renal insufficiency or deterioration of renal function which occurred following treatment initiation; 7. Onset of hepatic insufficiency or deterioration of liver function which occurred following treatment initiation; 8. Any indication of bone marrow suppression:
Anemia: Acute decrease of HB of 2gr% and over or anemia severity grade 2 and over; Neutropenia: New onset of Neutropenia grade 3 and over according to CTEAE version 4.0; Leukopenia: Acute onset of leukopenia grade 3 and over according to CTEAE version 4.0; Thrombocytopenia: Acute decrease of thrombocyte count to below 50,000/µL;
And any change in myeloid cellularity which in the opinion of the local PI indicates of possible health risk to the patient.  
Any of these Events of Special Interest that also meet criteria of Serious Adverse Event should be reported as such.
trial title a phase 3
19.2.5. management of anomalies in

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
trial title a phase 3
19.2.6. progression of underlying malignancy

Progression of underlying malignancy should not be reported as an adverse event if it is clearly consistent with the suspected progression of the underlying cancer, or other criteria as determined by protocol. Hospitalization due solely to the progression of underlying malignancy should NOT be reported as a serious adverse event. Clinical symptoms of progression may be reported as adverse events if the symptom cannot be determined as exclusively due to the progression of the underlying malignancy, or does not fit the expected pattern of progression for the disease under trial.
trial title a phase 3
19.2.7. concomitant illnesses and pre-existing

Ongoing medical conditions and past cancer history other than urothelial carcinoma, and significant medical history up to 5 years back from screening must be collected and recorded in the eCRF.  
Concomitant illnesses (including signs/symptoms of a pre-existing pathological condition) that are present during or before the administration of a product under trial and which are manifested with the same severity, frequency, or duration after administration of the medicinal product under trial must be recorded in the relevant section of the eCRF. However, cases which show an increase in the severity or duration of the concomitant illness or pre-existing condition must be reported as AEs.
trial title a phase 3
19.2.8. adverse events reporting period

The investigator is required to collect AEs beginning with informed consent signature.  
This information is to be entered into the eCRF.  
All serious adverse events, and All AEs which are suspected to be related to the study treatment and/or procedures occurring during the trial period should be reported throughout a subject's participation in the trial.  
Adverse events will be collected up to 30 days post last 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).
trial title a phase 3
progression of urothelial carcinoma disease

Death due to any cause occurring during the trial period including follow up period will be reported.  
Pregnancy should be reported at any time during the trial and during 6 months following last instillation (if site became aware of the pregnancy).  
The investigator should instruct each patient to report any subsequent event(s) that the patient,  
  
  
  
or the patient's personal physician, believes might reasonably be related to participation in this trial. The investigator should notify the trial sponsor of any death or any IP related adverse event.
trial title a phase 3
19.2.9. management of adverse events

All unresolved adverse events should be followed by the investigator until the events are resolved, the patient is lost to follow-up, or the adverse event is otherwise explained.
trial title a phase 3
unresolved ip/procedure related adverse event

All IP-related AEs shall be monitored until resolution and/or diagnosis or otherwise explained.  
Where a related adverse event is not resolved upon conclusion of the trial, the investigator will evaluate the need to continue follow-up. All medicinal products taken during the trial to treat AEs or previous diagnoses must be recorded in the eCRF.
trial title a phase 3
unresolved serious adverse events

SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation of the subject's participation in the study, must be followed until any of the following occurs:
1. The event resolves; 2. The event stabilizes; 3. The event returns to baseline, if a baseline value/status is available; 4. It becomes unlikely that any additional information can be obtained (subject or health care practitioner refusal to provide additional information, lost to follow-up after demonstration of due diligence with follow-up efforts).
trial title a phase 3
19.3. data monitoring committee (dmc)

An independent Data Monitoring Committee (DMC) will be appointed by the Sponsor The DMC will be responsible for safeguarding the interests of the patients by assessing the safety of the intervention during the trial, and for reviewing the overall conduct of the clinical trial.  
In addition, the DMC will have the responsibility to assess the efficacy data of the interim futility analysis and decide if stopping rules are met (see interim futility analysis in section 18). The DMC will have access to the individual treatment - and will be able to merge these with the collected trial data while the trial is ongoing.  
Any unexpected AE related to MitoGel™ and qualified per National Cancer Institute (NCI)  
  
  
Common Terminology Criteria for Adverse Events (CTCAE; Appendix VIII: CTACAE 4.03 Severity Grades, and Allergic Reaction Grades) as grade 3 or 4 will be evaluated by the sponsor medical team and steering committee. In case of need, a DMC meeting will be gathered.  
The DMC charter is prepared to detail precise roles and responsibilities, meetings timelines and procedures and criteria for considering study discontinuation.
trial title a phase 3
20. concomitant medications

The site should collect information and record in the eCRF all ongoing therapies, all past cancer therapies (including procedures), and other significant therapies taken within one month prior to screening.  
Concomitant medications given to treat an adverse event must be recorded in the eCRF. Concomitant medications must be recorded in the relevant section of the clinical data sheet and the CRF. Refer to inclusion/exclusion criteria regarding excluded concomitant medication such as systemic chemotherapy, intravesical chemotherapy, and immunotherapy for cancer treatment including but not limited to BCG.
trial title a phase 3
21. ethical considerations and confidentiality

The trial will be performed in accordance with Food and Drug Administration (FDA) Good Clinical Practice (GCP) Regulations (Code of Federal Regulations [CFR] 21 parts 50, 56, and 312) and International Conference on Harmonization (ICH) GCP Guidelines (E6) and clinical safety data management (E2A).
trial title a phase 3
21.1. informed consent

A properly executed, written informed consent form (ICF), in compliance with 21 CFR Part 50, must be obtained from each patient prior to enrollment and initiating screening evaluations required by this protocol. A copy of the ICF planned for use will be reviewed by the sponsor (or designee) for acceptability and must be submitted by the Investigator, together with the protocol, to the appropriate IRB/EC for review and approval prior to the start of the trial. Consent forms must be in a language fully comprehensible to the prospective patient. The Investigator must provide the sponsor (or designee) with a copy of the IRB/EC letter approving the protocol and the ICF(s) before the trial drug supplies will be shipped and the trial can be initiated.  
The written consent form must be revised if new information becomes available during the trial  
  
that may be relevant to the Patient. Any revision(s) must be submitted to the appropriate IRB/EC for review and approval in advance of use. It is the responsibility of the investigators or of any individuals appointed by them to obtain the informed consent of all patients, having given them sufficient information regarding the objectives, methods, expected benefits and foreseeable risks of the trial. The investigators or such appointed workers must also inform participants that they shall not undergo any damages whatsoever should they choose not to take part in or to withdraw from the trial.
trial title a phase 3
21.2. ethics committee and competent

The sponsor shall provide the designated EC and the Competent Authorities with the trial protocol and any other related documents issued to the patient (Patient Information and ICF). Approval must be obtained from both the EC and the Competent Authorities before undertaking any procedures related to the trial and must be documented through an official communication to the investigator. In the event that changes need to be made to the trial protocol during the course of the trial, the sponsor shall submit to the designated EC a request for amendment to the protocol, which must be approved following the procedures set forth in the regulations established by that EC.  
The sponsor, according the law in force, will be responsible to report to the all the National Competent Authorities, where the investigation has commenced, any SAE related to the study drug, and any Investigational Product Failure that might lead to an SAE or new findings/updates in relation to those already reported. For the duration of the clinical trial, the trial sponsor shall submit to all the National Competent Authorities and to the relevant Ethics Committee(s) a list of serious adverse reactions observed over the course of the reporting period, and a report on the safety of the individuals involved in the clinical trial. This will be done once a year or sooner if required by local regulations.  
Sponsor reporting to the EC and National Competent authorities should be done as follows:
trial title a phase 3
21.2.1. fatal or life-threatening unexpected

Regulatory agencies should be notified (e.g., by telephone, facsimile transmission, or in writing)
as soon as possible but no later than 7 calendar days after first knowledge by the sponsor that a case qualifies, followed by as complete a report as possible within 8 additional calendar days. This report must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar medicinal products.
trial title a phase 3
21.2.2. all other serious unexpected

Serious, unexpected reactions (ADRs) that are not fatal or life threatening must be filed as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting.
trial title a phase 3
21.2.3. minimum criteria for reporting

Information for final description and evaluation of a case report may not be available within the required periods for reporting outlined above. Nevertheless, for regulatory purposes, initial reports should be submitted within the prescribed time as long as the following minimum criteria are met:
1. An identifiable patient; 2. A suspect medicinal product; 3. An identifiable reporting source; 4. And an event or outcome that can be identified as serious and unexpected, and for which, in clinical investigation cases, there is a reasonable suspected causal relationship.  
Follow-up information should be actively sought and submitted as it becomes available.
trial title a phase 3
22. quality control and quality

At a minimum, source documentation must be available for the following to confirm data collected in the CRF: Patient identification, eligibility, and trial identification; trial discussion and date of informed consent; dates of visits; results of safety and efficacy parameters as required by the protocol; record of all AEs and follow-up of AEs; concomitant medication; drug receipt/dispensing/return records; trial IP administration information; and date of trial completion and reason for early discontinuation of trial IP or withdrawal from the trial, if applicable.  
In addition, the author of an entry in the source documents should be identifiable. At a minimum, the type and level of detail of source data available for a trial Patient should be consistent with that commonly recorded at the site as a basis for standard medical care. Specific details required as source data for the trial will be reviewed with the investigator before the trial and will be described in the monitoring guidelines (or other equivalent document).
trial title a phase 3
22.2. record retention

In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all source documents that support the data collected from each patient, as well as all trial documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical Trial, and all trial documents as specified by the applicable regulatory requirement(s). The investigator/institution will take measures to prevent accidental or premature destruction of these documents.  
Essential documents must be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents will be retained for a longer period if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained.  
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping the trial records, custody must be transferred to a person who will accept the responsibility. The sponsor must be notified in writing of the name and address of the new custodian. Under no circumstance shall the investigator relocate or dispose of any trial documents before having obtained written approval from the sponsor.  
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any documentation relating to this trial, the investigator must permit access to such reports.
trial title a phase 3
22.3. clinical monitoring

The sponsor will perform on-site monitoring visits as frequently as necessary, depending of recruitment frequency at each site. The monitor will record dates of the visits in a trial site visit log that will be kept at the site. Remote monitoring of patient screening data will be performed on all subjects, to assure eligibility. The first post-initiation visit will be made as soon as possible (approximately two weeks) after enrollment has begun. At these visits, the monitor will compare the data entered into the CRF with the hospital or clinic records (source documents). The nature and location of all source documents will be identified to ensure that all sources of original data required to complete the CRF are known to the sponsor and investigational staff and are accessible for verification by the sponsor site contact. If electronic records are maintained at the investigational site, the method of verification must be discussed with the investigational staff.  
Direct access to source documentation (medical records) must be allowed for verifying that the  
  
  
data recorded in the CRF are consistent with the original source data. Findings from this review of CRFs and source documents will be discussed with the investigational staff. The sponsor expects that, during monitoring visits, the relevant investigational staff will be available, the source documentation will be accessible, and a suitable environment will be provided for review of trialrelated documents. The monitor will meet with the investigator on a regular basis during the trial to provide feedback on the trial conduct. A separate clinical monitoring plan was put in place.
trial title a phase 3
22.4. protocol deviations

A protocol deviation is a departure from the study protocol and/or study related documents.  
The departure may be either on the part of the subject, the investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by the site and implemented promptly.  
All-important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient managements or patient assessment should be addressed in study source documents and reported to the sponsor. Protocol deviations must be submitted to the local or central IRB per their guidelines. The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  
Protocol Deviations are not allowed. If a subject's eligibility is in question, please contact the sponsor.
trial title a phase 3
22.5. audit and inspection

Representatives of the sponsor's clinical quality assurance department may visit the site at any time during or after completion of the trial to conduct an audit of the trial in compliance with regulatory guidelines and company policy. These audits will require access to all trial records, including source documents, for inspection and comparison with the CRFs. Patient privacy must, however, be respected. The investigator and staff are responsible for being present and available for consultation during routinely scheduled site audit visits conducted by the sponsor or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part of a national GCP compliance program or to review the results of this trial in support of a regulatory submission. The investigator should immediately notify the sponsor if they have been contacted by a regulatory agency concerning an upcoming inspection.
trial title a phase 3
23. trial systems

23.1. Data Collection And Management Responsibilities  
The web based electronic data capturing (EDC) system (named ) used for data collection in provided by .  
Clinical data (including AEs, concomitant medications, and expected adverse reactions data)
and clinical laboratory data will be entered into , a 21 CFR Part 11 compliant data capturing system.  
The data system includes password protection and internal quality verification checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source documents.
trial title a phase 3
passwords are personal and not

Data management services will be provided by . Data management plan will be in place.  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported according to ICH E6. The site PI will login to the EDC and sign the patients' electronic Case Report Forms (eCRFs) after the database lock has achieved, thus confirming its content.  
Data reported in the eCRF derived from source documents should be consistent with the source documents or the discrepancies should be explained and captured in a progress note and maintained in the participant's official electronic study record.
trial title a phase 3
23.2. procedures & timelines for

1. Patient registration in the system: Once patient signs informed consent, the site should register the patient in the system by completing the "Registration" eCRF form. The next sequential screening number available at the site should be recorded, starting at 001. The format of the screening number is 2 digits of the site number which is auto populated, followed by 'S', and 3 digits entered manually. Example: 05 S 001 (Site 05 patient screening number 001).  
2. Patient enrollment number is given automatically by the system.  
In order to obtain enrollment number the following forms in the 'Screening' visit must be completed first: Screening 'Visit date', Target Treatment Area Lesion Mapping' form, 'Target Treatment Area Lesion Mapping Information' form, 'Patient Eligibility by Investigator" AND  
  
 the 'Patient Eligibility by Sponsor" forms.  
3. To enroll a patient "Enrolment" tab should be selected from menu, data completed and submitted. The enrollment number will appear automatically. The format of the enrollment number is 2 digits of the site number, followed by 'E', and 3 digits which represent the running number of enrolled patients across all sites. Example: **05 E 010**
(site 05, patient enrollment number 010).  
4. The minimum data required in the eCRF for patients considered screen failures are:
Registration - Informed consent Demographics Inclusion Criteria Exclusion Criteria Patient Eligibility by site investigator Patient Eligibility by sponsor - This page will trigger the removal OR opening of the other forms in the screening visits and all other visits forms 5. The site investigator is responsible that the data from trial patients' visits will be recorded in eCRF no longer than 5 working days following the visit. Timelines may shorten during database clean-up and database lock period.  
6. Adverse event related queries must be resolved within 5 working days as well. 7. Initial report on subject's death, SAEs, SUSARs, and events of clinical interest must be reported in the eCRF within 24 hours. Paper SAE /AE forms will be supplied to the site for completion in case of technical problem with the eCRF, not to delay the required immediate reporting.  
8. Queries relevant to subject's death, SAEs, SUSARs, and events of clinical interest must be resolved within 24 hours.  
9. In case of delay in data recording/query resolution, the sites will receive email reminders reminding that data is to be completed.  
10. An Interim Analysis is planned when 20 patients have performed PDE visit, for which all data must be clean and up to date at the time of analysis.  
CRF data entry guidelines will be provided to all sites.
trial title a phase 3
23.3. acknowledgment of mitogel™️ kit

MitoGelTM Kit inventory will be managed via web-based system. MitoGelTM
Kits shipments will be shipped to the authorized site pharmacist. The pharmacist will receive a unique user name and password and should login to the system in order to confirm the receipt of shipments. In case shipment was sent to the site but was not confirmed in the system, the specific kits belonging to this shipment would not appear in the site inventory and the MitoGelTM Kit belonging to this shipment will not be dispensed. Therefore, the pharmacist should confirm shipments in the system as soon as they are received.
trial title a phase 3
23.4. system for images upload

The authorized site personnel will receive an email invitation with link to the website and will be requested to create account to the site. Personal username and password are required to access the website. The sites are required to upload URS/CTU/MRI/Pyelography images performed during the following visits:
Screening PDE visit Follow up visits 1-4 Any unscheduled visit in which imaging was performed to determine eligibility, primary endpoint and secondary endpoint.  
The system is validated and in compliance with FDA requirements and has a feature enabling the removal of patient identifiers while uploading the images to the portal.
trial title a phase 3
24. trial completion/termination 24.1. trial

The trial is considered completed with the last visit for the last Patient participating in the trial.  
The final data from the investigational site will be sent to the sponsor (or designee) after completion of the final Patient visit at that site, in the period specified in the Clinical Trial Agreement.
trial title a phase 3
24.2. trial termination

The sponsor reserves the right to close the investigational site or terminate the trial at any time for any reason at the sole discretion of the sponsor. Investigational sites will be closed upon trial completion. An investigational site is considered closed when all required documents and trial supplies have been collected and a site closure visit has been performed.  
The investigator may initiate site closure at any time, provided there is reasonable cause and  
  
  
sufficient notice is given in advance of the intended termination.  
Reasons for the early closure of an investigational site by the sponsor or investigator may include but are not limited to:
1. Failure of the investigator to comply with the protocol, the requirements of the IRB or local health authorities, the sponsor's procedures, or GCP guidelines; 2. Inadequate recruitment of patients by the investigator; 3. Discontinuation of further drug development.
trial title a phase 3
25. changes in the conduct

Neither the investigator nor the sponsor will modify this protocol without a formal amendment by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the investigator. Protocol amendments must not be implemented without prior IRB approval, or when the relevant competent authority has raised any grounds for non-acceptance, except when necessary to eliminate immediate hazards to the Patients, in which case the amendment must be promptly submitted to the IRB and relevant competent authority. Documentation of amendment approval by the investigator and IRB must be provided to the sponsor or its designee. When the change(s) involves only logistic or administrative aspects of the trial, the IRB (and IEC where required) only needs to be notified.  
During the course of the trial, in situations where a departure from the protocol is unavoidable, the investigator or other physician in attendance will contact the appropriate sponsor representative
(see Contact Information page(s) provided separately). Except in emergency situations, this contact should be made before implementing any departure from the protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the situation and agree on an appropriate course of action. The data recorded in the CRF and source documents will reflect any departure from the protocol, and the source documents will describe this departure and the circumstances requiring it.
trial title a phase 3
26. study leadership

Steering committee and data monitoring committee (DMC) have been assigned for this trial.  
DMC charter was put in place.  
The Steering Committee will govern the conduct of the study. In case need arises, Ad hoc DMC
meetings will be initiated by the steering committee.  
Every effort will be made to reach a consensus within the DMC and with the principal  
  
  
coordinating investigator. In case of disagreement on recommended modifications, the Steering Committee will make the final decision.
trial title a phase 3
27. administrative and regulatory details

The sponsor will register and/or disclose the existence of and the results of clinical studies as required by law.
trial title a phase 3
27.3. conflict of interest policy

The independence of this study from any actual or perceived influence is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed.  
Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the trial. The study leadership has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
trial title a phase 3
27.4. final report and publication

Publication of the trial results in scientific literature is encouraged and the investigator shall be entitled, consistent with academic standards, to publish the results of the trial patient to the stipulations set forth in research contract. The sponsor reserves the right to review any paper written utilizing data generated from the trial prior to such paper's presentation or submission for publication purposes. At least 90 (ninety) days prior to submitting or presenting a manuscript or other materials relating to the trial to a publisher, reviewer, or any third party, the investigator shall provide the sponsor a copy of all such manuscripts and materials, and allow the sponsor ninety (90) days to review and comment. The investigator will give due consideration to the sponsor's comments and should get prior in written consent from the sponsor to the content of any such publication. The investigator further agrees to delay the publication for an additional 120 days, at the request of the sponsor, where the sponsor considers such delay necessary for the protection of its intellectual property rights.  
a) If the trial is a part of a multi-center trial and the sponsor wishes to publicize a joint  
  
  
publication, which includes results of all sites, then the investigator shall not publicize the trial results before the first joint publication, unless such publication is not published within 12 months from the completion of the trial at the trial center.  
b) The sponsor can use, directly or indirectly, the name of the trial center and/or the investigator and/or any of the trial staff, in the sponsor's commercial publications.  
c) The sponsor undertakes that should it publicize the results of the trial, it shall publish the results in full and avoid quoting matters out of context.
trial title a phase 3
27.5. finance and insurance 27.5.1.

The trial is financed by the sponsor as detailed in the financial agreement between the sponsor and the investigator/institution.
trial title a phase 3
27.5.2. insurance

The trial will be covered in accordance to local requirements. Insurance coverage will be provided by the sponsor. In case of any damage or inquiry occurring to a patient in association with the investigational product or the participation in this trial the sponsor will contract the insurance company which covers the liability of the sponsor, the investigator and other persons involved in the trial in compliance with the laws in the country where the trial takes place.
trial title a phase 3
28. bibliography

Aboumarzouk OM, Somani B, Ahmad S, Nabi G, Townell N, Kata SG. Mitomycin C instillation following ureterorenoscopic laser ablation of upper urinary tract carcinoma. Urol Ann. 2013 Jul;5(3):184-9. doi: 10.4103/0974-7796.115746. Accord Healthcare Inc. Mitomycin for Injection (ANDA 064144) Label. 2011 . Au JL, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001; 93(8):597-604. Au JL, Jang SH, Wientjes MG. Clinical aspects of drug delivery to tumors. J Control Release. 2002 Jan 17;78(1-3):81-95. Audenet F, Traxer O, Bensalah K, Rouprêt M. Upper urinary tract instillations in the treatment of urothelial carcinomas: a review of technical constraints and outcomes. World J Urol. 2013a Feb;31(1):45-52. doi: 10.1007/s00345-012-0949-3. Audenet F, Yates DR, Cussenot O, Rouprêt M. he role of chemotherapy in the treatment of urothelial cell carcinoma of the upper urinary tract (UUT-UUC). Urol Oncol. 2013b May;31(4):407-13. doi: 10.1016/j.urolonc.2010.07.016. Barlogie B, Drewinko B. Lethal and cytokinetic effects of mitomycin C on cultured human colon cancer cells. Cancer Res. 1980 Jun;40(6):1973-80.  
Bristol Laboratories DoB-MC. Mutamycin (Mitomycin for Injection, USP) Approved Label NDA
050450. 1985 . Bristol-Meyers Squibb Company. Mutamycin-mitomycin for injection approved label ANDA 062336. 2004 . Browne RF, Meehan CP, Colville J, Power R, Torreggiani WC. Transitional cell carcinoma of the upper urinary tract: spectrum of imaging findings. Radiographics. 2005 Nov-Dec;25(6):1609-27. Colin P, Rouprêt M, Ghoneim TP, Traxer O, Zerbib M, Xylinas E. Conservative management of upper tract urothelial carcinoma in France: a 2004-2011 national practice report. Eur Urol. 2013 Feb;63(2):405-6. doi: 10.1016/j.eururo.2012.10.020. Cutress ML, Stewart GD, Zakikhani P, Phipps S, Thomas BG, Tolley DA. Ureteroscopic and  
  
 percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int. 2012 Sep;110(5):614-28. doi: 10.1111/j.1464-410X.2012.11068.x. De Bruijn EA, Sleeboom HP, van Helsdingen PJ, van Oosterom AT, Tjaden UR, Maes RA. Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times. Int J Cancer. 1992 May 28;51(3):359-64. Deb AA, Wilson SS, Rove KO, Kumar B, Koul S, Lim DD, Meacham RB, Koul HK. Potentiation of mitomycin C tumoricidal activity for transitional cell carcinoma by histone deacetylase inhibitors in vitro. J Urol. 2011 Dec;186(6):2426-33. doi: 10.1016/j.juro.2011.07.107.  
Eastham JA, Huffman JL. Technique of mitomycin C instillation in the treatment of upper urinary tract urothelial tumors. J Urol. 1993 Aug;150(2 Pt 1):324-5. Elliott DS, Blute ML, Patterson DE, Bergstralh EJ, Segura JW. Long-term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma. Urology. 1996 Jun;47(6): 819– 25. European Commission. European Commission Guide to Good Manufacturing Practice, Revision to Annex 1. 2003. Grasso M, Fishman AI, Cohen J, Alexander B. Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15-year comprehensive review of 160 consecutive patients. BJU Int. 2012 Dec;110(11):1618-26. doi: 10.1111/j.1464-410X.2012.11066.x. Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC, Carroll PR. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy--part I: definition, detection, prevalence, and etiology. Urology. 2001 Apr;57(4):599-603. Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees. Food and Drug Administration. March 2006. Retrieved 2015-03-24. Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998 Oct;52(4):594-601. Hellenthal NJ, Shariat SF, Margulis V, Karakiewicz PI, Roscigno M, Bolenz C, Remzi M, Weizer A, Zigeuner R, Bensalah K, Ng CK, Raman JD, Kikuchi E, Montorsi F, Oya M, Wood CG, Fernandez M. Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper  
  
 Tract Urothelial Carcinoma Collaboration. J Urol. 2009 Sep;182(3):900-6. doi: 10.1016/j.juro. Hurwitz M, Spiess PE, Garcia JA, Pisters LL. Urothelial and Kidney Cancers. Cancer Management. 2011 Mar 25. Jarrard DF, Potretzke AM, Downs T. Urothelial Tumors of the Renal Pelvis and Ureters: Treatment and Management. Medscape, Retrieved 2015-03-26.  
Kalaitzis C, Zisimopoulos A, Giannakopoulos S, Touloupidis S. Ureteroscopic laser treatment of upper urinary tract urothelial cell carcinomas: can a tumour free status be achieved? Adv Urol. 2013;2013:429585. doi: 10.1155/2013/429585. Kapoor A, Allard CB, Black P, Kassouf W, Morash C, Rendon R. Canadian guidelines for postoperative surveillance of upper urinary tract urothelial carcinoma. Can Urol Assoc J. 2013 Sep- Oct;7(9-10):306-11. doi: 10.5489/cuaj.1578. Keeley FX Jr, Bagley DH. Adjuvant mitomycin C following endoscopic treatment of upper tract transitional cell carcinoma. J Urol. 1997 Dec;158(6):2074-7. Kim TS, Oh JH, Rhew HY. The efficacy of adjuvant chemotherapy for locally advanced upper tract urothelial cell carcinoma. J Cancer. 2013 Oct 5;4(8):686-90. doi: 10.7150/jca.7326. Krambeck AE, Thompson RH, Lohse CM, Patterson DE, Elliott DS, Blute ML. Imperative indications for conservative management of upper tract transitional cell carcinoma. J Urol. 2007 Sep;178(3 Pt 1):792-6; discussion 796-7.  
Lughezzani G, Sun M, Perrotte P, Shariat SF, Jeldres C, Budäus L, Latour M, Widmer H, Duclos A, Bénard F, McCormack M, Montorsi F, Karakiewicz PI. Gender-related differences in patients with stage I and III upper tract urothelial carcinoma: results from the Surveillance, Epidemiology, and End Results database. Urology. 2010 Feb;75(2):321-7. doi: 10.1016/j.urology.2009.09.048. Martínez-Piñeiro JA, García Matres MJ, Martínez-Piñeiro L. Endourological treatment of upper tract urothelial carcinomas: analysis of a series of 59 tumors. J Urol. 1996 Aug;156(2 Pt 1):377-85. Matin SF, Margulis V, Kamat A, Wood CG, Grossman HB, Brown GA, Dinney CP, Millikan R, Siefker-Radtke AO. Incidence of Downstaging and Complete Remission After Neoadjuvant Chemotherapy for High-Risk Upper Tract Transitional Cell Carcinoma. Cancer. 2010 Jul 1;116(13):3127-34. doi: 10.1002/cncr.25050.?Medical Enterprises Group. Synergo SB-TS 101.1  
  
 Device: Patient Information Guide. 2008 . Messer JC, Terrell JD, Herman MP, Ng CK, Scherr DS, Scoll B, Boorjian SA, Uzzo RG, Wille M, Eggener SE, Lucas SM, Lotan Y, Shariat SF, Raman JD. Multi-institutional validation of the ability of preoperative hydronephrosis to predict advanced pathologic tumor stage in upper-tract urothelial carcinoma. Urol Oncol. 2013 Aug;31(6):904-8. doi: 10.1016/j.urolonc.2011.07.011. Mohamed A, Elkoushy PD. Andonian VS. percutaneous instillation of chemolytic, chemotherapeutic, and antifungal agents.Smith's Textbook of Endourology, edited by Glenn Preminger, Gopal Badlani, Louis Kavoussi John Wiley & Sons, Nov 29, 2011 - Chapter 26: 290303 Martinez-Pineiro JA, Garcia Matres MJ, Martinez-Pineiro L. Endourological Treatment of Upper Tract Urothelial Carcinomas: Analysis of a Series of 59 Tumors. J Urol. 1996 Aug;156(2): 377–85.  
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0, NCI, NIH, DHHS. May 29, 2009. NIH publication \# 09-7473. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Bladder Cancer. Version 1.2014. 2013 . Nepple KG, Joudi FN, O'Donnell MA. Review of topical treatment of upper tract urothelial carcinoma. Adv Urol. 2009:472831. doi: 10.1155/2009/472831.  
Nozue M, Todoroki T, Fukao K. 5-fu dose-dependency in mtx/s-fu sequential therapy assessed by invitro assay using gastric-cancer cell-lines. Oncol Rep. 1995 Sep;2(5):737-40. O'Malley R, Kaag M, O'Malley P, Godoy G, Chen ML, Smaldone MC, Hrebinko RL, Vora KC, Bochner BH, Dalbagni G, Stifelman MD, Taneja SM, Huang WC, et al. Do changes in renal function following nephroureterectomy impact the use of perioperative chemotherapy? J Urol. 2009;181(4)(Suppl):136. doi: 10.1016/S0022-5347(09)60393-1 O'Brien T, Ray E, Singh R, Coker B, Beard R; British Association of Urological Surgeons Section of Oncology. Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). Eur Urol. 2011 Oct;60(4):703-10. doi: 10.1016/j.eururo.2011.05.064. O'Donoghue JP, Crew JP. Adjuvant topical treatment of upper urinary tract urothelial tumours. BJU  
  
 Int. 2004 Sep;94(4):483-5. Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982 Ozawa S, Sugiyama Y, Mitsuhashi Y, Kobayashi T, Inaba M. Cell killing action of cell cycle phasenon-specific antitumor agents is dependent on concentration--time product. Cancer Chemother Pharmacol 1988; 21(3):185-190 Pak RW, Moskowitz EJ, Bagley DH. What is the cost of maintaining a kidney in upper-tract transitional-cell carcinoma? An objective analysis of cost and survival. J Endourol. 2009 Mar;23(3):341-6. doi: 10.1089/end.2008.0251. Park BH, Jeon SS. Endoscopic management of upper urinary tract urothelial carcinoma. Korean J Urol. 2013 Jul;54(7):426-32. doi: 10.4111/kju.2013.54.7.426. Perry RR, Greaves BR, Rasberry U, Barranco SC. Effect of treatment duration and glutathione depletion on mitomycin C cytotoxicity in vitro. Cancer Res. 1992 Sep 1;52(17):4608-12. Porten S, Siefker-Radtke AO, Xiao L, Margulis V, Kamat AM, Wood CG, Jonasch E, Dinney CP, Matin SF. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma. Cancer. 2014 Jun 15;120(12):1794-9. doi: 10.1002/cncr.28655.  
Ristau BT, Tomaszewski JJ, Ost MC. Upper tract urothelial carcinoma: current treatment and outcomes. Urology. 2012 Apr;79(4):749-56. Rouprêt M, Babjuk M, Compérat E, Zigeuner R, Sylvester R, Burger M, Cowan N, Böhle A, Van Rhijn BW, Kaasinen E, Palou J, Shariat SF; European Association of Urology. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol. 2013 Jun;63(6):1059-71. doi: 10.1016/j.eururo.2013.03.032. Rouprêt M, Colin P, Yates DR. A new proposal to risk stratify urothelial carcinomas of the upper urinary tract (UTUCs) in a predefinitive treatment setting: low-risk versus high-risk UTUCs. Eur Urol. 2014 Aug;66(2):181-3. doi: 10.1016/j.eururo.2013.12.007. Rouprêt M, Hupertan V, Sanderson KM, Harmon JD, Cathelineau X, Barret E, Vallancien G, Rozet  
  
 F. Oncologic control after open or laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: a single center experience. Urology. 2007 Apr;69(4):656-61. Rouprêt M, Zigeuner R, Palou J, Boehle A, Kaasinen E, Sylvester R, Babjuk M, Oosterlinck W. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol. 2011 Apr;59(4):584-94. doi: 10.1016/j.eururo.2010.12.042. Sadeghi HM, Seitz B, Hayashi S, LaBree L, McDonnell PJ. In vitro effects of mitomycin-C on human keratocytes. J Refract Surg. 1998 Sep-Oct;14(5):534-40. Sakamoto N1, Naito S, Kumazawa J, Ariyoshi A, Osada Y, Omoto T, Fujisawa Y, Morita I, Yamashita H; Kyushu University Urological Oncology Group. Prophylactic intravesical instillation of mitomycin C and cytosine arabinoside for prevention of recurrent bladder tumors following surgery for upper urinary tract tumors: a prospective randomized study. Int J Urol. 2001 May;8(5):212-6. Schmittgen TD, Wientjes MG, Badalament RA, Au JL. Pharmacodynamics of mitomycin C in cultured human bladder tumors. Cancer Res. 1991 Aug 1;51(15):3849-56. Scolieri MJ, Paik ML, Brown SL, Resnick MI. Limitations of computed tomography in the preoperative staging of upper tract urothelial carcinoma. Urology. 2000 Dec 20;56(6):930-4. Singh P, Kumar R. Endourology for Upper Tract Lesions. JIMSA. 2011 Jul-Sep:24(3): 127-130.  
Slee PH, de Bruijn EA, Leeflang P, Kuppen PJ, van den Berg L, van Oosterom AT. Variations in exposure to mitomycin C in an in vitro colony-forming assay. Br J Cancer. 1986 Dec;54(6):951-5. Smith AK, Stephenson AJ, Lane BR, Larson BT, Thomas AA, Gong MC, Jones JS, Campbell SC, Hansel DE. Inadequacy of biopsy for diagnosis of upper tract urothelial carcinoma: implications for conservative management. Urology. 2011 Jul;78(1):82-6. doi: 10.1016/j.urology.2011.02.038. Sverrisson EF, Kim T, Espiritu PN, Sexton WJ, Pow-Sang JM, Dhillon J, Spiess PE. The merits of cytology in the workup for upper tract urothelial carcinoma - a contemporary review of a perplexing issue. Int Braz J Urol. 2014 Jul-Aug;40(4):493-8. doi: doi: 10.1590/S1677-5538.IBJU.2014.04.07. Tavora F, Fajardo DA, Lee TK, Lotan T, Miller JS, Miyamoto H, Epstein JI. Small endoscopic biopsies of the ureter and renal pelvis: pathologic pitfalls. Am J Surg Pathol. 2009 Oct;33(10):15406. doi: 10.1097/PAS.0b013e3181aec42a. TheraCoat Report No. TAS-4M-P-A-133 Revision 3, Mitomycin C Concentrations in Urothelial  
  
 Tissue Following Intravesical Instillation of TC-3 + Mitomycin C in . 3-17-2014a . Volanis D, DashGupta R, Patel A. Endoscopic Nephron-sparing Management of Superficial LG UTUC. Eur Urol Rev . 2012; 7(1) 10-14 . Walker MC, Masters JR, Parris CN, Hepburn PJ, English PJ. Intravesical chemotherapy: in vitro studies on the relationship between dose and cytotoxicity. Urol Res. 1986;14(3):137-40.  
Wang AJ, Goldsmith ZG, Neisius A, Astroza GM, Oredein-McCoy O, Iqbal MW, Simmons WN,
Madden JF, Preminger GM, Inman BA, Lipkin ME, Ferrandino MN. Increasing dwell time of mitomycin C in the upper tract with a reverse thermosensitive polymer. J Endourol. 2013 Mar;27(3):288-93. doi: 10.1089/end.2012.0211. WHO Classification: Eble JN, Sauter G, Epstein JI and Sesterhenn IA: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary and Male Genital Organs. Lyon: IARCPress 2004. Yoshimura K, Utsunomiya N, Ichioka K, Matsui Y, Terai A, Arai Y. Impact of superficial bladder cancer and transurethral resection on general health-related quality of life: an SF-36 survey. Urology. 2005 Feb;65(2):290-4. Wewers ME, Lowe NK. A Critical Review of Visual Analogue Scales in the Measurement of Clinical Phenomena Research in Nursing & Health, 1990, 13, 227-236.
trial title a phase 3
appendix i clinical evaluation

General Physical Examination (V0, V9)  
General Appearance Cardiovascular system Respiratory HEENT (head, eyes, ears, nose & throat) and neck Abdomen Extremities Neurologic Skin Other *specify*: ____________________________
Urology Oriented Examination (V0-V6) Urethral meatus Perineal skin and mucous membranes Scrotum and Testes (for male patients) Lymphadenopathy Palmar erythema Rectal Examination - Prostate (for male patients; Screening visit only)
trial title a phase 3
appendix ii vital signs

Blood Pressure Heart Rate Body Temperature Weight (only at screening) Height (only at screening)
trial title a phase 3
appendix iii required lab tests

The samples' handling, packaging, and shipping details will be given in the site and central lab manual.  
| Liver Function Tests *                                                                                                                            | Renal Function Tests                                                                      |                  |                       |
|---------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------|------------------|-----------------------|
|                                                                                                                                                  | SGOT/AST                                                                                  |                  |                       |
|                                                                                                                                                  | SGPT/ALT                                                                                  |                  |                       |
|                                                                                                                                                  | GGT                                                                                       |                  |                       |
|                                                                                                                                                  | Alkaline phosphatase                                                                      |                  |                       |
|                                                                                                                                                  | Total Bilirubin                                                                           |                  |                       |
|                                                                                                                                                  | Direct Bilirubin                                                                          |                  |                       |
|                                                                                                                                                  | Albumin                                                                                   |                  |                       |
|                                                                                                                                                  | Total Protein                                                                             |                 | Creatinine            |
|                                                                                                                                                  | BUN or Urea Nitrogen                                                                      |                  |                       |
|                                                                                                                                                  | Uric acid                                                                                 |                  |                       |
|                                                                                                                                                  | Sodium                                                                                    |                  |                       |
|                                                                                                                                                  | Potassium                                                                                 |                  |                       |
|                                                                                                                                                  | Phosphorus                                                                                |                  |                       |
|                                                                                                                                                  | Calcium                                                                                   |                  |                       |
| Hematology Tests *                                                                                                                                | Coagulation Tests                                                                         |                  |                       |
|                                                                                                                                                  | Complete blood count, including red blood cell  indices and white blood cell differential |                  |                       |
|                                                                                                                                                  | Platelet count                                                                            |                 | Prothrombin Time (PT) |
|                                                                                                                                                  | INR                                                                                       |                  |                       |
| Pregnancy Test **                                                                                                                                 | Urinalysis                                                                                |                  |                       |
|                                                                                                                                                  | Serum                                                                                     |                  |                       |
|                                                                                                                                                  | Urine dip stick for pregnancy                                                             |                  |                       |
| Urine Culture (at screening), on all other visits  only if urinalysis if suspicious for UTI Urine Cytology***  Upper Tract washing Urine Cytology |                                                                                          | Specific gravity |                       |
|                                                                                                                                                  | pH                                                                                        |                  |                       |
|                                                                                                                                                  | Glucose                                                                                   |                  |                       |
|                                                                                                                                                  | Urogilinogen                                                                              |                  |                       |
|                                                                                                                                                  | Bilirubin                                                                                 |                  |                       |
|                                                                                                                                                  | Blood                                                                                     |                  |                       |
|                                                                                                                                                  | Protein                                                                                   |                  |                       |
|                                                                                                                                                  | Nitrites Leukocyte Esterase                                                               |                  |                       |
|                                                                                                                                                  | Microscopic examination                                                                   |                  |                       |
|                                                                                                                                                  | Bacteriuria (if required)                                                                 |                  |                       |
|                                                                                                                                                  | WBC                                                                                       |                  |                       |
| Histology***  MMC Levels (6 Patients)**** Serum * The amount of blood required for hematology and biochemistry tests per visit is 15–20 cc.       |                                                                                           |                  |                       |  
* The amount of blood required for hematology and biochemistry tests per visit is 15–20 cc. ** The amount of blood required for pregnancy tests per visit is 5 cc.  
Women of non-childbearing potential are defined as:
a. At least 12 months since the last menstrual bleeding, or b. Without uterus and/or both ovaries, or c. Has been surgically sterile for at least 6 months prior to trial drug administration.  
*** Biopsy slides and urine cytology samples/slides will be sent to the central lab for central reading-a manual will be provided in separate to the pathology lab.  
**** The amount of blood required for each MMC PK level measurement time point is 5 cc; approximate total of 24 cc for PK visit. PK samples will be kept in -70 freezer in a lightblocking box until shipped to central lab for analysis. Refer to **Appendix VII.**
appendix iv questions 24-32 hours
appendix iii required lab tests

TC-UT-03-P Trial UroGen Pharma Instillations no.  1-6 Telephone Contact 24-32 Hours after Instillation Site no. _
Patient Enrollment no. _  
  
*Relevant only to patients who receive treatment via retrograde catheterization 1. Date of phone contact Date 2. Time of phone contact:
3. How long after the treatment did you have your first urination?  
□□ Hours 4. How long after the treatment was the urine clear (no purple color) for the first time?  
□□□ Hours Call made by (Name) Study role: (Nurse/study coordinator/investigator)
TC-UT-03-P Version 1 dated 13/Aug/16 -Telephone Contact Questions
appendix iv questions 24-32 hours
appendix v karnofsky & ecog

| Performance Scales: Karnofsky & ECOG Scores Karnofsky Status Karnofsky  ECOG   | ECOG Status                                                                                                                          |    |                                                                                                                                                                |
|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|----|----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                                                                          | Grade                                                                                                                                |    |                                                                                                                                                                |
| Normal, no complaints                                                          | 100                                                                                                                                  | 0  | Fully active, able to carry on all  pre-disease performance without  restriction                                                                               |
| Able to carry on normal activities.                                            | 90                                                                                                                                   | 1  | Restricted in physically                                                                                                                                       |
| Minor signs or symptoms of disease                                             | strenuous activity but  ambulatory and able to carry out  work of a light or sedentary  nature, e.g., light house work,  office work |    |                                                                                                                                                                |
| Normal activity with effort                                                    | 80                                                                                                                                   | 1  | Restricted in physically  strenuous activity but  ambulatory and able to carry out  work of a light or sedentary  nature, e.g., light house work,  office work |
| Care for self. Unable to carry on                                              | 70                                                                                                                                   | 2  | Ambulatory and capable of all                                                                                                                                  |
| normal activity or to do active work                                           | self-care but unable to carry out  any work activities. Up and  about more than 50% of waking  hours                                 |    |                                                                                                                                                                |
| Requires occasional assistance, but                                            | 60                                                                                                                                   | 2  | Ambulatory and capable of all                                                                                                                                  |
| able to care for most of his needs                                             | self-care but unable to carry out  any work activities. Up and  about more than 50% of waking  hours                                 |    |                                                                                                                                                                |
| Requires considerable assistance                                               | 50                                                                                                                                   | 3  | Capable of only limited selfcare, confined to bed or chair                                                                                                                                                                |
| and frequent medical care                                                      | more than 50% of waking hours                                                                                                        |    |                                                                                                                                                                |
| Disabled. Requires special care and                                            | 40                                                                                                                                   | 3  | Capable of only limited selfcare, confined to bed or chair                                                                                                                                                                |
| assistance                                                                     | more than 50% of waking hours                                                                                                        |    |                                                                                                                                                                |
| Severely disabled. Hospitalization                                             | 30                                                                                                                                   | 4  | Completely disabled. Cannot                                                                                                                                    |
| indicated though death no imminent                                             | carry on any self-care. Totally  confined to bed or chair                                                                            |    |                                                                                                                                                                |
| Very sick. Hospitalization  necessary. Active supportive  treatment necessary  | 20                                                                                                                                   | 4  | Completely disabled. Cannot  carry on any self-care. Totally  confined to bed or chair                                                                         |
| Moribund                                                                       | 10                                                                                                                                   | 4  | Completely disabled. Cannot  carry on any self-care. Totally  confined to bed or chair                                                                         |
| Dead                                                                           | 0                                                                                                                                    | 5  | Dead                                                                                                                                                           |
| Document State: Effective (Controlled)                                         | Page 120 of 130                                                                                                                      |    |                                                                                                                                                                |
appendix iv questions 24-32 hours
appendix vi recommended antimicrobial prophylaxis

Taken from "Best Practice Statement on urologic surgery antimicrobial prophylaxis"  
| Table 3a. Recommended antimicrobial prophylaxis for urologic procedures                                        |                                                                               |                               |                                |                               |             |
|----------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------|-------------------------------|--------------------------------|-------------------------------|-------------|
| Procedure                                                                                                      | Organisms Prophylaxis Antimicrobial(s) of Choice Alternative Antimicrobial(s) | Duration of                   |                                |                               |             |
| Indicated                                                                                                      | Therapy*                                                                      |                               |                                |                               |             |
| Lower Tract Instrumentation                                                                                    |                                                                               |                               |                                |                               |             |
| GU tracti                                                                                                      |                                                                               |                               |                                |                               |             |
| Removal of extent                                                                                              | TMP-SMXI                                                                      | Aminoglycoside (AztreonamY)   | 24 hours I                     |                               |             |
| unnary catheter                                                                                                | factors $ ,$                                                                  | Ampicillin¶                   |                                |                               |             |
| 1st/2nd gen. Cephalosporing                                                                                    |                                                                               |                               |                                |                               |             |
| Amoxacillin/Clavulanate][                                                                                      |                                                                               |                               |                                |                               |             |
| GU tract                                                                                                       | If nsk factors                                                                | £24 hours                     |                                |                               |             |
| Cystography, urodynamic                                                                                        | TMP-SMX                                                                       | Aminoglycoside (Aztreonamy) + |                                |                               |             |
| Ampicillin                                                                                                     |                                                                               |                               |                                |                               |             |
| study, or simple                                                                                               |                                                                               |                               |                                |                               |             |
| cystourethroscopy                                                                                              | 1st/2nd gen. Cephalosporing                                                   |                               |                                |                               |             |
| Amoxacillin/Clavulanate                                                                                        |                                                                               |                               |                                |                               |             |
| Cystourethroscopy with                                                                                         | GU tract                                                                      | AI                            | Fluoroquinolone
TMP-SMX                                | Aminoglycoside (Aztreonamy) + | 24 hours    |
| millillillill                                                                                                  | Ampicillin                                                                    |                               |                                |                               |             |
| 1st/2nd gen. Cephalosporin                                                                                     |                                                                               |                               |                                |                               |             |
| Amoxacillin/Clavulanate                                                                                        |                                                                               |                               |                                |                               |             |
| Prostate brachytherapy on                                                                                      | Incertain                                                                     | 1st gen. Cephalosporing       | <24 hours                      |                               |             |
| Clindamycin®                                                                                                   |                                                                               |                               |                                |                               |             |
| rotherapy                                                                                                      | AI                                                                            |                               |                                |                               |             |
| Transrectal prostate biopsy                                                                                    | Intestinett                                                                   | Fluoroquinolo                 | TMP-SMX                        | ~24 houn                      |             |
| 1st/2nd/3rd gen. Cephalosponne                                                                                 | Aminoglycoside (Aztreonamic)                                                  |                               |                                |                               |             |
| Upper Tract Instrument                                                                                         | GU tract                                                                      |                               |                                |                               |             |
| hock-wave lithotripsy                                                                                          | If risk factors                                                               | Fluoroquinoion                | Aminoglycoside (AztreonamV)    | <24 hours                     |             |
| TMP-SMX                                                                                                        | Ampicillin                                                                    |                               |                                |                               |             |
| 1st/2nd gen. Cephalosporin                                                                                     |                                                                               |                               |                                |                               |             |
| Amoxacillin/Clavulanate                                                                                        |                                                                               |                               |                                |                               |             |
| ercutaneous renal surgery                                                                                      | GU tract and                                                                  | Al                            | 1st/2nd gen. Cephalosporin     | Ampicillin/Sulbactam          | 24 hours    |
| Aminoglycoside (Aztreonamic) +                                                                                 | Fluoroquinolone                                                               |                               |                                |                               |             |
| sking                                                                                                          | Metronidazole or Clindamycin                                                  |                               |                                |                               |             |
| GU Tract                                                                                                       | Aminoglycoside (AztreonamY)                                                   | <24 hours                     |                                |                               |             |
| Ureteroscopy                                                                                                   | All                                                                           | Fluoroquinolone               |                                |                               |             |
| TMP-SMX                                                                                                        | Ampicillin                                                                    |                               |                                |                               |             |
| 1st/2nd gen. Cephalosporin                                                                                     |                                                                               |                               |                                |                               |             |
| Amoxacillin/Clavulanate                                                                                        |                                                                               |                               |                                |                               |             |
| Sopen or Laparoscopic Surgery                                                                                  |                                                                               |                               |                                |                               |             |
| GU tract, skin                                                                                                 | [All                                                                          | 1st/2nd gen. Cephalosporin    | Ampicillin/Sulbactam           | <24 hours                     |             |
| Vaginal surgery (includes                                                                                      | and Grp B                                                                     |                               |                                |                               |             |
| arethral sling procedures)                                                                                     | Aminoglycoside (Aztreonam) +                                                  | Fluoroquinolone               |                                |                               |             |
| srep                                                                                                           | Metronidazole or Clindamycin                                                  |                               |                                |                               |             |
| Without entering urinary                                                                                       | Skin                                                                          | If risk factors               | 1st gen. Cephalosporing        | Clindamycin                   | Single dose |
| tract                                                                                                          |                                                                               |                               |                                |                               |             |
| Involving entry into                                                                                           | GU tract and                                                                  | All                           | 1st/2nd gen. Cephalosporin     | Ampicillin/Sulbactam          | <24 hours   |
| unary tract.                                                                                                   | Aminoglycoside (Aztreonamic) +                                                | Fluoroguinolone               |                                |                               |             |
| string                                                                                                         | Metronidazole or Clindamycin                                                  |                               |                                |                               |             |
| Involving intestine §§                                                                                         | GU tract, skin                                                                | All                           | 131 gen. Cephalosponn          | Ampicillin/Sulbactam          | <24 hours   |
| Aminoglycoside (Aztreoname)                                                                                    |                                                                               |                               |                                |                               |             |
| and intestine                                                                                                  | Ticarcillin/Clavalanate                                                       |                               |                                |                               |             |
| Metronidazole or Clindamycin                                                                                   | Pipercillin/Tazobactam                                                        |                               |                                |                               |             |
| Fluoroquinolone                                                                                                |                                                                               |                               |                                |                               |             |
| Involving implanted                                                                                            | GU tract and                                                                  | AI                            | Aminoglycoside (Aztreonamic) + | Ampicillin/Sulbactam          | < 24 hours  |
| prosthesis                                                                                                     | 1st/2nd gen. Cephalosporin or                                                 | Ticarcillin/Clavulanate       |                                |                               |             |
| skin                                                                                                           | Pipercillin/Tazobactam                                                        |                               |                                |                               |             |
| Vancomycin                                                                                                     |                                                                               |                               |                                |                               |             |
| Order of agents in each column is not indicative of preference.  The absence of an agent does not preclude its |                                                                               |                               |                                |                               |             |
| appropriate use depending on specific situations.                                                              |                                                                               |                               |                                |                               |             |
| Kev                                                                                                            |                                                                               |                               |                                |                               |             |  
* Additional antimicrobial therapy may be recommended at the time of removal of an externalized urinary catheter.  
↑ GU tract: Common unnary tract organisms are E. coli, Proteus sp., Klebsielia sp., Enterococcus
$ See Table 1 "Patient-related factors affecting host response to surgical infections."
§ If urine culture shows no growth prior to the procedure, antimicrobial prophylaxis is not necessary.  
I Or full course of culture-directed antimicrobials for documented infection (which is treatment, not prophylaxis).  
Aztreonam can be substituted for aminoglycosides in patients with renal insufficiency.  
I Includes transurethral resection of bladder tumor and prostate, and any biopsy, resection, fulguration, foreign body removal, urethral dilation or urethrotomy, or ureteral instrumentation including catheterization or stent placement/removal.  
*Clindamycin, or aminoglycoside + metronidazole or clindamycin, are general alternatives to penicillins and cephalosporins in patients with penicillin allergy, even when not specifically listed.  
1 Intestine: Common intestinal organisms are E. coli, Klebsiella sp., Enterobacter, Serratia sp. Serratia sp., Proteus sp., Enterococcus , and Anaerobes
‡‡ Skin: Common skin organisms are S. aureus , coagulase negative Staph. sp., Group A Strep. sp.  
$ For sugery involving the colon, bowel preparation with oral neomycin plus either erythromycin base or metronidazole can be added to or substituted for systemic agents. Key: gen, generation; GU, genitourinary; TMP-SMX, trimethoprim-sulfamethoxazole Copyright © 2007 American Urological Association Education and Research, Inc.®
28 Updated September 2008 Revised 9/20/2012Copyright
appendix iv questions 24-32 hours
appendix vii collection and handling

Pharmacokinetics  
Plasma MMC levels will be analyzed at . Address: Instructions for plasma collection and handling are as follows: CAUTION! HANDLING OF THE SAMPLES SHOULD BE DONE WITH CAUTION ACCORDING TO THE INSTITUTE GUIDELINES FOR HANDLING CYTOTOXIC SAMPLES
1. Time points of plasma PK sampling: Time 0 (prior to instillation), 30min, 1, 2, 3, 4, 5 and 6 hr post instillation. For the sampling of 30 min. post treatment the deviation is ±5 minute. For sampling of 1-6 hours post treatment, allowed window is ±9 minutes.  
2. *Attention! Mitomycin C is sensitive to light!!*
At each time point collect 3mL of blood into K2EDTA tube (supplied by UroGen) and place immediately in Ice (2-8°C) inside a closed cooling box protected from light. If the cooling box is unprotected from light, make sure to cover the collecting tubes with aluminum foil immediately after collection and then place them in ice.  
3. Centrifuge the tubes immediately after collection. If this not possible, maintain the tubes prior to centrifugation in ice (2-80C) for no longer than 1 hour 4. Use refrigerated centrifuge for plasma separation. Centrifuge at 3000 RPM for 10 min. 5. Transfer the plasma from each collecting tube using a disposable plastic pipette into 2 X 2mL
Eppendorf tubes (one will be shipped later to central lab, the second will be left at the site as a backup)
6. Place the samples in a box protected from light (supplied by UroGen)
7. Immediately store the box in -700C deep freeze.  
8. The shipping of the samples to central lab will be done in coordination with the CRA.
appendix iv questions 24-32 hours
labeling of plasma collecting tubes

Prior to each blood collection verify you have collecting tube and matching Eppendorf tubes of the required time point. *Plasma labels Example:*
Pre dose Post dose, time 0.5 hour TC-UT-03 **Plasma** MMC
PK: 0.5 h Time: __ : __ Site / Pt. Number: __/__ Date: __/___/__  
  
TC-UT-03 **Plasma** MMC
Pre-dose Time: __ : __  
  
Site / Pt. Number: __/__  
 Date: __/___/__
Page 122 of 130
appendix iv questions 24-32 hours
appendix viii ctacae 4.03 severity

Grades Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL*.  
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**.  
Grade 4 Life-threatening consequences; urgent intervention indicated.  
Grade 5 Death related to AE.  
Activities of Daily Living (ADL) * Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.  
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.  
Source: (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf)