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Trial registered on ANZCTR


Registration number
ACTRN12616000394448
Ethics application status
Approved
Date submitted
29/01/2016
Date registered
24/03/2016
Date last updated
27/10/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy of a maintenance therapy with supplements containing indole-3-carbinol (I3C) and epigallocatechin-3-gallate (EGCG) in ovarian cancer patients
Scientific title
An open randomized controlled clinical trial to evaluate the efficacy of a maintenance therapy with supplements containing I3C and EGCG in ovarian cancer patients
Secondary ID [1] 288343 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian cancer 297331 0
Condition category
Condition code
Cancer 297528 297528 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1
Patients of Arm 1 received neoadjuvant chemotherapy consisted of 2–4 cycles of TP regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: cisplatin 75-100 mg/m^2 by intravenous >= 1-h infusion with hyper-hydration) or TC regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: carboplatin AUC 5 by intravenous >= 1-h infusion), every 21 days. Surgical treatment (panhysterectomy with subtotal resection of the greater omentum and the maximum removal of disseminated tumor foci) was carried out 24 days after the last cycle of neoadjuvant chemotherapy. 14 days after surgery patients were treated with postoperative adjuvant chemotherapy consisted of 5-6 cycles of TP regimen or TC regimen every 21 days. Maintenance therapy with oral administration of Indinol Forto (Registered Trademark) (200 mg of I3C 2 times a day continuously) was started 14 days before the primary neoadjuvant therapy and continued after completion of postoperative adjuvant chemotherapy for 5 years of the study.
The number of cycles of chemotherapy depends on time of achieved CA-125 level =<35 U/mL and general declining profile of CA-125; the number of cycles of chemotherapy also varied depending on set of clinical and laboratory data, including physical condition.

Arm 2
Patients of Arm 2 received neoadjuvant chemotherapy consisted of 2–4 cycles of TP regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: cisplatin 75-100 mg/m^2 by intravenous >= 1-h infusion with hyper-hydration) or TC regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: carboplatin AUC 5 by intravenous >= 1-h infusion), every 21 days. Surgical treatment (panhysterectomy with subtotal resection of the greater omentum and the maximum removal of disseminated tumor foci) was carried out 24 days after the last cycle of neoadjuvant chemotherapy. 14 days after surgery patients were treated with postoperative adjuvant chemotherapy consisted of 5-6 cycles of TP regimen or TC regimen every 21 days. Maintenance therapy with oral administration of Promisan (Registered Trademark) (200 mg of I3C + 100 mg of EGCG 2 times a day continuously) was started 14 days before the primary neoadjuvant therapy and continued after completion of postoperative adjuvant chemotherapy for 5 years of the study.
The number of cycles of chemotherapy depends on time of achieved CA-125 level =<35 U/mL and general declining profile of CA-125; the number of cycles of chemotherapy also varied depending on set of clinical and laboratory data, including physical condition.



Arm 3
Patients of Arm 3 received neoadjuvant chemotherapy consisted of 2–4 cycles of TP regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: cisplatin 75-100 mg/m^2 by intravenous >= 1-h infusion with hyper-hydration) or TC regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: carboplatin AUC 5 by intravenous >= 1-h infusion), every 21 days. Surgical treatment (panhysterectomy with subtotal resection of the greater omentum and the maximum removal of disseminated tumor foci) was carried out 24 days after the last cycle of neoadjuvant chemotherapy. 14 days after surgery patients were treated with postoperative adjuvant chemotherapy consisted of 5-6 cycles of TP regimen or TC regimen every 21 days. Patients also received long-term chemotherapy TP regimen or TC regimen after the last cycle of postoperative adjuvant chemotherapy every 2-3 months for 5 years of the study. Maintenance therapy with oral administration of Promisan (Registered Trademark) (200 mg of I3C + 100 mg of EGCG 2 times a day continuously) was started 14 days before the primary neoadjuvant therapy and continued after completion of postoperative adjuvant chemotherapy for 5 years of the study.
The number of cycles of chemotherapy depends on time of achieved CA-125 level =<35 U/mL and general declining profile of CA-125; the number of cycles of chemotherapy also varied depending on set of clinical and laboratory data, including physical condition.

TP or TC regimen was chosen randomly. Adherence to the intervention was measured by counting returned tablets and checking diaries of self-control.
Intervention code [1] 293650 0
Treatment: Other
Intervention code [2] 293983 0
Treatment: Drugs
Comparator / control treatment
Control Arm 4
In control Arm 4 patients received surgical treatment (panhysterectomy with subtotal resection of the greater omentum and the maximum removal of disseminated tumor foci) followed by postoperative adjuvant chemotherapy consisted of 5-6 cycles of TP regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: cisplatin 75-100 mg/m^2 by intravenous >= 1-h infusion with hyper-hydration) or TC regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: carboplatin AUC 5 by intravenous >= 1-h infusion) every 21 days.
The number of cycles of chemotherapy depends on time of achieved CA-125 level =<35 U/mL and general declining profile of CA-125; the number of cycles of chemotherapy also varied depending on set of clinical and laboratory data, including physical condition.

Control Arm 5
In control Arm 5 patients received neoadjuvant chemotherapy consisted of 2–4 cycles of TP regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: cisplatin 75-100 mg/m^2 by intravenous >= 1-h infusion with hyper-hydration) or TC regimen (1st day: paclitaxel 175 mg/m^2 by intravenous 3-h infusion with pre-medication; 2nd day: carboplatin AUC 5 by intravenous >= 1-h infusion) every 21 days. Surgical treatment (panhysterectomy with subtotal resection of the greater omentum and the maximum removal of disseminated tumor foci) was carried out 24 days after the last cycle of neoadjuvant chemotherapy. 14 days after surgery patients were treated with postoperative adjuvant chemotherapy consisted of 5-6 cycles of TP regimen or TC regimen every 21 days.
The number of cycles of chemotherapy depends on time of achieved CA-125 level =<35 U/mL and general declining profile of CA-125; the number of cycles of chemotherapy also varied depending on set of clinical and laboratory data, including physical condition.

TP or TC regimen was chosen randomly. Adherence to the intervention was measured by counting returned tablets and checking diaries of self-control.
Control group
Active

Outcomes
Primary outcome [1] 297084 0
Overall survival defined as the interval between date of diagnosis to the date of death
Timepoint [1] 297084 0
5 years post standard treatment commencement
Secondary outcome [1] 320002 0
Progression-free survival defined as the earliest disease progression per clinical progression, RECIST, CA-125 progression, or death. CA-125 determination and ultrasonography (US) were conducted every month. Tomographic studies were conducted every 3-4 months.
Timepoint [1] 320002 0
5 years post standard treatment commencement
Secondary outcome [2] 320003 0
Rate of patients with recurrent ovarian cancer with ascite formation. Detection of ascite formation has been defined by US, tomographic studies, and intraoperative findings.
Timepoint [2] 320003 0
5 years post standard treatment commencement

Eligibility
Key inclusion criteria
1) diagnosis of histologically confirmed International Federation Gynecology Obstetrics (FIGO) stage III serous ovarian cancer
2) patients with a general condition corresponding to WHO 0-2
3) absolute granulocyte count >= 1.5 x 10^3/mm^3; platelets >= 100 x 10^3/mm^3
4) adequate liver and renal function (bilirubin, creatinine within normal limits; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.0 times upper normal limit;
AST and ALT must be < 5.0 times upper normal limit if liver metastases present)
5) absence of significant coexisting diseases (documented history of gastric/duodenal ulcer within last 12 months, polyneuropathy, decompensated diabetes, heart attack within 1 year ago)
6) written informed consent
Minimum age
39 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1) point mutations in the BRCA genes
2) malignant tumors of other localizations
3) positive RW or HIV tests, alcohol or drug abuse
4) pregnancy or lactation
5) organizational problems which could impair the ability to commit treatment and monitoring (remote accommodation etc.)
6) psychiatric illness or uncontrolled psychiatric condition which may hamper compliance with the trial protocol
7) severe coexisting disease which may, in the opinion of the investigator influence the patient's ability to participate in the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 7535 0
Russian Federation
State/province [1] 7535 0
Moscow

Funding & Sponsors
Funding source category [1] 292706 0
Other
Name [1] 292706 0
Russian Scientific Center of Roentgenoradiology
Address [1] 292706 0
86 Profsoyuznaya St., Moscow, 117997, Russia
Country [1] 292706 0
Russian Federation
Primary sponsor type
Other
Name
Russian Scientific Center of Roentgenoradiology
Address
117997 Moscow, Profsoyuznaya str., 86
Country
Russian Federation
Secondary sponsor category [1] 291438 0
None
Name [1] 291438 0
Address [1] 291438 0
Country [1] 291438 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294192 0
The Medical Ethics Committee of the Russian Research Centre of Roentgenology and Radiology
Ethics committee address [1] 294192 0
86 Profsoyuznaya St., Moscow, 117997, Russia.
Ethics committee country [1] 294192 0
Russian Federation
Date submitted for ethics approval [1] 294192 0
Approval date [1] 294192 0
03/02/2003
Ethics approval number [1] 294192 0

Summary
Brief summary
An open randomized controlled clinical trial in five arms. The purpose of the trial was to evaluate the efficacy of a maintenance therapy with supplements containing indole-3-carbinol (I3C) and epigallocatechine-3-gallate (EGCG) in ovarian cancer patients.
284 patients >= 39 years with histologically confirmed International Federation Gynecology Obstetrics (FIGO) stage III serous ovarian cancer who met the study criteria were randomized into five arms.
Active therapy was conducted for 5 years of the study with control visits at the beginning of the study and then every month.
The primary endpoint was overall survival (OS), defined as the interval between date of diagnosis to the date of death. Timepoint: 5 years post standard treatment commencement. Secondary endpoints were progression-free survival (PFS) and rate of patients with recurrent ovarian cancer with ascite formation. PFS was defined as the interval between date of the start of treatment to first documentation of disease progression or death resulting from any cause, including toxic complications. A PFS event defined as the earliest disease progression per clinical progression, RECIST, CA-125 progression, or death. CA-125 determination and ultrasonography (US) were conducted every month. Tomographic studies were conducted every 3-4 months.
Detection of ascite formation has been defined by US, tomographic studies, and intraoperative findings.
Timepoints of secondary endpoints: 5 years post standard treatment commencement.

5-year survival rate has been increased in the active groups of patients who took the combination of standard chemotherapy, surgery and maintenance therapy with I3C and EGCG (or only I3C). Ovarian cancer patients should be advised the long-term maintenance therapy with indole-3-carbinol and epigallocatechin-3-gallate to reduce the relapse rate and improve tumor susceptibility to standard chemotherapy.
Trial website
Trial related presentations / publications
L.A. Ashrafyan, I.B. Antonova, O.I. Aleshikova, E.V. Gerfanova. ESGO-0560. Indole-3-carbinol and epigallocatechin-3-gallate in combination therapy of ovarian cancer. ´International Journal of Gynecological Cancer´ (IJGC): Vol 25, Supplement 2, October 2015.
Public notes

Contacts
Principal investigator
Name 62822 0
Prof Levon Ashrafyan
Address 62822 0
Russian Scientific Center of Roentgenoradiology
86 Profsoyuznaya St., Moscow, 117997, Russia.
Country 62822 0
Russian Federation
Phone 62822 0
+7 (495) 333-91-20
Fax 62822 0
Email 62822 0
levaa2004@yahoo.com
Contact person for public queries
Name 62823 0
Ms Evgeniya Gerfanova
Address 62823 0
Russian Scientific Center of Roentgenoradiology
86 Profsoyuznaya St., Moscow, 117997, Russia.
Country 62823 0
Russian Federation
Phone 62823 0
+7 (495) 333-91-20
Fax 62823 0
Email 62823 0
evgeniyagerf@gmail.com
Contact person for scientific queries
Name 62824 0
Ms Evgeniya Gerfanova
Address 62824 0
Russian Scientific Center of Roentgenoradiology
86 Profsoyuznaya St., Moscow, 117997, Russia.
Country 62824 0
Russian Federation
Phone 62824 0
+7 (495) 333-91-20
Fax 62824 0
Email 62824 0
evgeniyagerf@gmail.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary