| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non muscle invasive bladder cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10005006 |
| E.1.2 | Term | Bladder cancer stage 0, with cancer in situ |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10005007 |
| E.1.2 | Term | Bladder cancer stage 0, without cancer in situ |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10005008 |
| E.1.2 | Term | Bladder cancer stage I, with cancer in situ |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10005009 |
| E.1.2 | Term | Bladder cancer stage I, without cancer in situ |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The aim of the trial is to determine whether Hyperthermia plus the chemotherapy drug mitomycin is an effective therapy for patients with non-muscle invasive bladder cancer who have tumour recurrence following bacillus Calmette-Guerin (BCG) therapy. To do this we will be looking at disease-free survival in all patients; and the complete response rate after three months of treatment for those patients who entered the trial with Carcinoma In-Situ (a difference form of non-muscle invasive bladder cancer). |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to assess the length of progression-free survival, overall survival, the safety and tolerability of both treatments, patient quality of life, treatment costs, and overall cost-effectiveness of the new treatment. A translational aspect will also be included in the trial, collecting blood, urine and tumour samples for future research to assess if there are any biomarkers of response to standard and the investigational treatments. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
HYMN -Quality of Life (covered in main study protocol) v2, date 12/08/10. Questionaires given at baseline, 3, 6, 9 and 12months. This will also be used to asses cost effectiveness.
HYMN-T (covered in the main protocol)v2, date 12/08/10
Blood, tissue and urine samples collected at baseline and further tissue and urine at recurrence. Samples will be used to look for molecular phenotypes of response. |
|
| E.3 | Principal inclusion criteria |
Inclusion Criteria
1. Previous BCG induction or maintenance therapy for NMIBC.
2. Recurrence of disease following induction or maintenance BCG defined as;
• Grade 3 or grade 2 stage Ta or T1 disease.
• CIS with grade 3, grade 2 or grade 1 stage Ta or T1 disease
• Carcinoma in situ (CIS) alone
3. Have undergone a re-resection of all T1 disease to exclude muscle invasive disease.
4. Age 18 yrs or older
5. WHO performance status 0, 1, 2, 3 or 4
6. Normal kidneys and ureters on imaging study within the past 12 months
7. Pre-treatment haematology and biochemistry values within acceptable limits:
- haemoglobin equal or greater than 10 g/dL
- platelets equal or greater than 100 x 10^9/L
- WBC equal or greater than 3.0 x 10^9/L or ANC equal or greater than 1.5 x 10^9/L
- Serum creatinine less than 1.5 x UNL
8. Negative pregnancy test for women of child-bearing potential.
9. Available for long-term follow-up.
10. Unfit or unwilling to have a full or partial cystectomy
11. Written informed consent.
|
|
| E.4 | Principal exclusion criteria |
Exclusion criteria
Patients with any of the following are not eligible for the trial:
1. Recurrence of grade 1 UCC withour CIS following BCG induction.
2. Previous intravesical chemotherapy in the past 6 months, other than single instillation post-TUR.
3. UCC involving the prostatic urethra or upper urinary tract.
4. T2 or higher stage UCC
5. Known or suspected reduced bladder capacity (less than 250 mls)
6. Significant bleeding disorder.
7. Pregnant or lactating women or women of childbearing potential unwilling or unable to use adequate non-hormonal contraception.
8. Current or long-term use of oral corticosteroids, or patients with an immunocompromised state for any reason.
9. Other malignancy within the past five years, except: non-melanomatous skin cancer cured by excision, adequately treated carcinoma in situ of the cervix or DCIS/LCIS of the breast or stable prostate cancer (under active surveillance or hormone control) with a life expectancy of more than >5 years.
10. Concurrent chemotherapy or any previous HM treatment.
11. Any known allergy or adverse event that would prevent them receiving a treatment that they may be randomised to within the trial.
12. Active or intractable UTI
13. Urethral stricture, or any situation impeding the insertion of a 20F catheter.
14. Bladder diverticular >1cm.
15. Significant Urinary incontinence
16. History of pelvic irradiation
17. Patients with implanted electronic devices (such as cardiac pacemakers) or metallic implants within the pelvis, lower torso, spine, hip or upper femur.
18. Suitable and willing to have, or have had, a full or partial cystectomy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objectives of the trial are to compare the treatments in terms of disease-free survival in all patients; and in terms of complete response rate at three months for those patients with CIS. Therefore the primary outcome measures will be the presence or absence of NMIBC at the two year surveillance assessment and the present or absence of CIS, in patients with CIS disease upon randomisation, at the 3 month surveillance assessment.
Disease-free survival time. Defined as the interval in whole days between the date of randomisation into the trial and the earliest of date of detection of recurrent disease, or date of death from any cause. Disease recurrence is defined as the presence of urothelial cell carcinoma or positive cytology. Disease progression is defined as T2 disease or evidence of extravesical disease. For those patients who do not have recurrent disease or die during the course of the trial, disease-free survival times will be censored at the last follow-up date. Patients who experience a distant upper-tract recurrence will be censored at the last available assessment.
Complete-response rate at 3 months. For patients with CIS, complete response at 3 months is defined as absence of visible tumour recurrence at cystoscopy, negative cytology and no evidence of CIS on random (4 quadrant) biopsy of the bladder.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life, identify biomarker of response |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 23 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| For the purposes of Clinical Trial Authorisation (CTA) under the European Union Directive 2001/20/EC, the trial is deemed to have ended 60 days after the trial office is notified that a total of 81 events in each arm(recurrent disease or death) have occurred and the last patient recruited has been followed-up for at least two years. This will allow for sufficient data to be collected for the completion of the final report. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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