Therapeutic Instillation of Mistletoe (TIM)

Intravesical Mistletoe Extract in Superficial Bladder Cancer: A Phase III Efficacy Study

The aim of this phase III study is to assess the efficacy of abnobaVISCUM® 900 compared with Mitomycin C (MMC) monotherapy in patients with superficial bladder carcinoma by evaluation of the time to tumor recurrence. Secondary objective is to evaluate the safety of abnobaVISCUM® 900, in particular, to compare the toxicity of the two treatments. Another secondary objective is the treatment efficacy as measured by calculated prognosis for recurrence and progression after 1 year, the tumor grading in case of a recurrence and by measurement of Quality of Life.

Study Overview

• Status: Recruiting
• Conditions: Superficial Bladder Cancer
• Intervention / Treatment: Drug: abnobaVISCUM 900; Drug: Mitomycin C

Detailed Description

This is a randomized, open-label, active-controlled, prospective, multinational Phase III confirmative study with 2 treatment groups and an adaptive design (Bauer and Köhne, 1994). The study is designed to compare the efficacy of treatment with abnobaVISCUM® 900 with Mitomycin C (MMC). Patients with completely resected superficial bladder carcinoma (Stage Ta) with an intermediate risk classification according to the European Association of Urology (EAU, update 2013) and with one immediately post operative MMC 40 mg or Epirubicin 50 mg intravesical instillation will be eligible for inclusion in the study.

The study comprises a screening period of not more than 6 weeks, a treatment period of 12 months for abnobaVISCUM® 900 and MMC and a follow-up period of 12 months. Patients will be screened within 6 weeks after the transurethral resection of the bladder (TURB) and the immediately post operative MMC 40 mg or Epirubicin 50 mg intravesical instillation. A re-resection should be performed before inclusion if indicated. Every patient is to provide written informed consent before any study related procedures will be performed.

• Study Type: Interventional
• Enrollment (Estimated): 548
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Juergen Eisenbraun, Dr.; Phone Number: +49 7233 7043 200; Email: eisenbraun@abnoba.de

Study Locations

• Egypt
  • Giza, Egypt, 12411
    • Recruiting
    • Theodor Bilharz Research Institute
    • Contact: Tarek El Leithy, Prof. Dr.; Phone Number: +2 01222117206
    • Principal Investigator: Tarek El Leithy, Prof. Dr.
    • Sub-Investigator: Hani Nour, Dr.
• Germany
  • Essen, Germany, 45122
    • Recruiting
    • Clinic of Urology of the University Hospital of Essen
    • Contact: Jochen Hess, Prof. Dr.; Phone Number: +49 201 7233260
    • Principal Investigator: Jochen Hess, Prof. Dr.
    • Sub-Investigator: Boris Hadaschik, Prof. Dr.
  • Heinsberg, Germany, 52525
    • Recruiting
    • Urologische Gemeinschaftspraxis
    • Contact: Aloys Lappenküper; Phone Number: +49 2452 3113
    • Principal Investigator: Aloys Lappenküper, MD
    • Sub-Investigator: Thomas Kretz, MD
  • Herzberg, Germany, 37412
    • Recruiting
    • Urologische Praxis
    • Contact: Thorsten Werner, Dr.; Phone Number: +49 5521 71212
    • Principal Investigator: Thorsten Werner, Dr.
    • Sub-Investigator: Arian Farid, Dr.
  • Würselen, Germany, 52146
    • Recruiting
    • Urologische Facharztpraxis
    • Contact: Thomas Pulte, Dr.; Phone Number: +49 2405 452680
    • Principal Investigator: Thomas Pulte, Dr.
    • Sub-Investigator: Stephan Wolter, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed and dated written informed consent for data protection and willingness to participate and comply with the study protocol prior to any study-related procedures
• Completely resected (detrusor muscle in the TUR specimen according to need) superficial bladder carcinoma (Stage Ta) with classification as intermediate-risk according to the EAU (update 2013) and one immediately post operative intravesical MMC 40 mg or Epirubicin 50 mg instillation, completed re-resection if indicated
• Karnofsky Performance Status of 50% to 100% (corresponding to Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2)
• Life expectancy of ≥ 2 years at the time point of study inclusion
• Normal renal and liver function, normal cardiac and hematology profiles (patients with laboratory values slightly outside the reference range may be included, unless the investigator considers the abnormality as clinically significant)
• Female patients of childbearing potential must have a negative pregnancy test (β-human chorionic gonadotropin test) at Screening. Pregnancy during the treatment period including 12 weeks after the last instillation has to be excluded

Exclusion Criteria:

• Locally infiltrative or metastatic bladder tumor (Stage T2 or greater), low-risk Ta tumor (primary, solitary, LG/G1, <3 cm, no CIS) or high-risk tumors according to EAU classification, update 2013 (T1; HG/G3; CIS; multiple and recurrent and large [>3 cm] Ta G1/G2 tumors [all conditions must be present at this point], presence of upper urinary tract tumors or lesions which were not completely removed by TURB
• Urinary tract infection, benign prostatic obstruction grade II or III, neurogenic bladder, stress incontinence, bladder or urethral diverticula, fistulas or urethral stenosis
• Patients with acute systemic illness, such as inflammatory infections with fever > 38°C
• Patients with previous recurrence of a superficial bladder cancer or radiotherapy of the bladder or other intravesical treatment within the last 6 months, or patients with previous mistletoe therapy
• Patients with other previous or co-existing malignancies or CIS
• Patients having any previous or concurrent therapy with a systemic chemo- / immunotherapeutical treatment regimen, in particular vinca alkaloids, bleomycine and doxorubicine, or patients who are treated with pyroxidine hydrochloride (vitamin B6)
• Untreated coagulation disorders or inadequate anticoagulation therapy
• Leukocyte count < 4,000/mm3 or platelet count < 100,000/mm3
• Serum creatinine > 1.7 mg/dL
• Patients with known hypersensitivity to the excipients of the study medication (monosodium phosphate, disodium phosphate, ascorbic acid)
• Patients with a known hypersensitivity to mistletoe products and MMC
• Patients who were administered within a 4-week period before Visit 1 any other experimental drug under investigation
• Male patients planning to father a child or sperm donation from the first administration of study medication until 3 months after the last administration of the study medication
• Male patients unwilling to use barrier contraception ie, condoms and spermicide, from the day of first administration of the study medication until 12 weeks after administration of the study medication. In case the sexual relation is restricted to women fulfilling one of the criteria listed under inclusion criteria for female patients the barrier contraception is not necessary.
• Patients with a history of alcohol and / or drug abuse
• Patients who are unable to be regularly observed, not permitting adequate follow-up and compliance to the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: abnobaVISCUM 900; intravesical instillation of abnobaVISCUM 900	Drug: abnobaVISCUM 900; intravesical instillation of abnobaVISCUM 900 13 times during treatment period; Other Names: viscum album extract; mistletoe extract; abnobaVISCUM
Active Comparator: Mitomycin C; intravesical instillation of Mitomycin C	Drug: Mitomycin C; intravesical instillation of Mitomycin C 10 times during treatment period; Other Names: Mitomycin; MMC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to tumor recurrence	The primary objective of the study is to assess the efficacy of abnobaVISCUM® 900. Primary efficacy criterion will be the time to tumor recurrence.	up to two years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity and tolerability of the study medication	The secondary objective, namely safety including toxicity and tolerability of the study medication, will be assessed by the monitoring of adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE), laboratory assessments (hematology, biochemistry and urinalysis) and a global judgment of tolerability.	up to two years
Prognosis after 1 year for recurrence and progression	A secondary efficacy endpoint is prognosis after 1 year for recurrence and progression, estimated by the European Organization for Research and Treatment of Cancer (EORTC) Bladder Cancer Calculator.	1 year
Quality of Life with the EORTC QLQ-C30 and BLS24 Quality of Life Questionnaires	A secondary efficacy endpoint is measurement of Quality of Life with the EORTC QLQ-C30 and BLS24 questionnaires.	up to two years
Tumor grading	A secondary efficacy endpoint is the tumor grading in case of a recurrence by cytology, ultrasound, and cystoscopy.	up to two years

Collaborators and Investigators

• Sponsor: Abnoba Gmbh
• Investigators: Principal Investigator: Jochen Hess, Prof. Dr., Chief Medical Officer of the Urological Clinic of the University Hospital Essen

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: April 4, 2014
• First Submitted That Met QC Criteria: April 4, 2014
• First Posted (Estimated): April 8, 2014

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: recurrence rate; superficial bladder cancer; mistletoe extract; viscum album extract; abnobaVISCUM
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Urinary Bladder Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Alkylating Agents; Antibiotics, Antineoplastic; Mitomycins; Mitomycin; Viscum album peptide
• Other Study ID Numbers: AB03; 2013-003446-16 (EudraCT Number); 2023-503718-66-00 (Other Identifier: EU CT No.)