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Trial registered on ANZCTR


Registration number
ACTRN12610000785000
Ethics application status
Approved
Date submitted
2/07/2010
Date registered
21/09/2010
Date last updated
25/05/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
Do gonadotrophin-releasing hormone (GnRH) agonists protect ovarian function in patients with Non-Hodgkin’s Lymphoma?
Scientific title
A randomized controlled trial evaluating the protective effect of a gonadotrophin-releasing hormone agonist on ovarian function in young women with Non-Hodgkin’s Lymphoma receiving a 14 day regimen of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisone (R-CHOP-14).
Secondary ID [1] 252142 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian function following chemotherapy 257674 0
Non-Hodgkin's Lymphoma 257681 0
Condition category
Condition code
Cancer 257852 257852 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Metabolic and Endocrine 257855 257855 0 0
Normal metabolism and endocrine development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
- Zoladex 3.6mg will be administered subcutaneously in the anterior abdominal wall. Ideally this will first occur up to 10-14 days prior to commencement of treatment with chemotherapy; however patients will be accepted onto the trial providing the first dose of Zoladex is given no later than one week following the start of the first course of chemotherapy

- Zoladex will be given every 28-32 days as required to cover the duration of the chemotherapy (expected four injections).

The patients will also receive the "progesterone-only" pill and calcium supplements.

The progesterone-only pill - 0.35mg of norethisterone, daily from day 1 of chemotherapy to the end of chemotherapy. This is the only contraception allowed during chemotherapy however it maybe continued post chemotherapy if so desired.

Calcium supplements - 600mg once daily from day 1 of chemotherapy to the end of chemotherapy.
Intervention code [1] 256742 0
Treatment: Drugs
Intervention code [2] 256894 0
Prevention
Comparator / control treatment
The "control" group will receive the “progesterone-only pill”.
Control group
Active

Outcomes
Primary outcome [1] 258715 0
Follicle stimulating hormone (FSH) assessed by blood serum analysis
Timepoint [1] 258715 0
6 months and 3 years post chemotherapy treatment
Primary outcome [2] 258716 0
anti-mullerian hormone (AMH) assessed by blood serum analysis
Timepoint [2] 258716 0
6 months and 3 years post chemotherapy treatment
Secondary outcome [1] 264747 0
oestradiol (E2) assessed by blood serum analysis
Timepoint [1] 264747 0
6 months post chemotherapy, and then yearly for 5 years post chemotherapy treatment
Secondary outcome [2] 264748 0
inhibin B assessed by blood serum analysis
Timepoint [2] 264748 0
baseline, 6 months, 3 years post chemotherapy treatment
Secondary outcome [3] 264749 0
antral follicle counts and ovarian volume assessment by ultrasound
Timepoint [3] 264749 0
6 months post chemotherapy, and then yearly for 5 years post chemotherapy treatment
Secondary outcome [4] 264750 0
menstrual regularity diary
Timepoint [4] 264750 0
6 months post chemotherapy, and then yearly for 5 years post chemotherapy treatment
Secondary outcome [5] 264751 0
bone mineral density will be assesed using a calibrated and validated dual energy x-ray absorptiometry (DEXA) scan.
Timepoint [5] 264751 0
baseline, before chemotherapy treatment and at the end of chemotherapy treatment

Eligibility
Key inclusion criteria
- women anticipated to receive 6 cycles of R-CHOP-14 with curative intent for Non-Hodgkin's Lymphoma (NHL)

- resident in Australia for the duration of trial participation

- a minimum of 12 months post-menarche and be less than or equal to 38 years at the start of treatment

- premenopausal state, as demonstrated by greater than and equal to 3 spontaneous menstrual cycles in the last 6 months or by non-menopausal levels of FSH or oestradiol at baseline

- ability to administer the first dose of Zoladex no later than 1 week after commencing chemotherapy

- consent to utilizing a progesterone-only contraceptive during their chemotherapy and also barrier contraception for 8 weeks prior to each follow up blood test

- ability to give informed consent. For patients under 18 years parental consent must be given, with patient assent where appropriate
Minimum age
13 Years
Maximum age
38 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- known contraindication to the use of a GnRH analogue (e.g. pregnancy or hypersensitivity) or a progesterone-only contraceptive

- anticipated requirement for pelvic irradiation as part of therapy

- radiological evidence of ovarian involvement with NHL

- prior cytotoxic chemotherapy for this or any other diagnosis

- contraindication to use of a progesterone-only contraceptive pill (e.g. previous history of thromboembolic disease)

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
- Patients will be referred to a fertility specialist by their treating oncologist. If the patient is eligible they will then be invited to participate in the study.

- the protocol is designed as a multi-centre, randomized, controlled trial, with a 1:1 randomization to GnRH analogue treatment and progesterone-only contraception (POP) during chemotherapy, compared to POP only during chemotherapy.

Allocation involved contcting the holder of the allocation schedule who was "off-site" or at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
randomization will be done by using a computer generated system
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
30/10/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 257229 0
Self funded/Unfunded
Name [1] 257229 0
Country [1] 257229 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Melbourne in vitro fertilization (IVF)
Address
Suite 10/320 Victoria Parade, EAST MELBOURNE, VICTORIA, 3002
Country
Australia
Secondary sponsor category [1] 256478 0
None
Name [1] 256478 0
Address [1] 256478 0
Country [1] 256478 0
Other collaborator category [1] 251357 0
Other Collaborative groups
Name [1] 251357 0
IVF Australia
Address [1] 251357 0
Level 2, 176 Pacific Hwy
Greenwich NSW 2065
Country [1] 251357 0
Australia
Other collaborator category [2] 251358 0
Other Collaborative groups
Name [2] 251358 0
Queensland Fertility Group
Address [2] 251358 0
199 Grey St
South Brisbane QLD 4101
Country [2] 251358 0
Australia
Other collaborator category [3] 251359 0
Other Collaborative groups
Name [3] 251359 0
Fertility Specialists of WA
Address [3] 251359 0
Bethesda Hospital
25 Queenslea Drive
Claremont WA 6010
Country [3] 251359 0
Australia
Other collaborator category [4] 251360 0
Other Collaborative groups
Name [4] 251360 0
Fertility SA
Address [4] 251360 0
120 Hutt Street, Adelaide, South Australia, 5000
Country [4] 251360 0
Australia
Other collaborator category [5] 251361 0
Other Collaborative groups
Name [5] 251361 0
Reproductive Services, The Royal Women's Hospital
Address [5] 251361 0
Locked Bag 300
Grattan St & Flemington Rd
Parkville VIC 3052
Country [5] 251361 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259249 0
The Royal Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 259249 0
The Royal Women's Hospital

Locked Bag 300
Grattan St & Flemington Rd
Parkville VIC 3052
AUSTRALIA
Ethics committee country [1] 259249 0
Australia
Date submitted for ethics approval [1] 259249 0
07/07/2010
Approval date [1] 259249 0
Ethics approval number [1] 259249 0

Summary
Brief summary
Non-Hodgkin’s lymphoma (NHL) is one of the most common cancers diagnosed in young women, with approximately 105 women under 40 years diagnosed in Australia annually (2005 data), most of whom will have aggressive histology.

In aggressive NHL, standard treatment is 6 cycles of R-CHOP-q21. Recently, an accelerated protocol (R-CHOP-q14) has been widely adopted. This regimen has been demonstrated to produce sustained remissions in at least 75% of women aged <40 (J Connors 2010, personal communication). The risk of early ovarian failure with regimens of variable intensity used in NHL (including CHOP) is estimated to be 10-40% (Avishay et al, 2006; Dolmans et al, 2005). Currently, however, there are no specific data available about the short or long-term effects of R-CHOPq14 on fertility, (Pfreundschuh 2008, personal communication) but the more intensive regimen may be expected to induce a higher incidence of ovarian damage than the q21 protocol. It is important, therefore, that the impact of this chemotherapy on fertility be evaluated in this patient population of child-bearing age with a high survival rate (Nicosia et al, 1985), as interventions aiming to protect fertility are worthy of study.

There is increasing evidence that fertility protection may be achieved with a GnRH agonist during chemotherapy. Two recent meta-analyses, despite showing benefit from use of GnRH agonists (p<0.05 in one analysis), concluded that because of the lack of randomization in various studies, there was not yet enough evidence to definitively resolve the issue (Beck-Fruchter et al, 2008; Blumenfeld et al, 2008). More recently, results of a randomized controlled trial in patients with breast cancer found a statistically significant reduction in ovarian failure in patients who received concomitant GnRH agonist (Badawy et al, 2009).

The lack of data regarding ovarian failure risk with treatment of NHL, and the absence of specific previous trials assessing ovarian protection in this context, both provide the rationale for further evaluation of a GnRH agonist in a rigorous, Australia-wide, clinical trial setting.

This randomized, controlled study aims to identify:
(1) the underlying risk of temporary and more permanent ovarian failure for patients receiving an accelerated protocol, R-CHOP –q14.
(2) whether there is any ovarian protective effect from concurrent administration of a GnRH agonist.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31356 0
Address 31356 0
Country 31356 0
Phone 31356 0
Fax 31356 0
Email 31356 0
Contact person for public queries
Name 14603 0
Franca Agresta
Address 14603 0
Suite 20/320 Victoria Parade
EAST MELBOURNE VIC 3002
Country 14603 0
Australia
Phone 14603 0
+ 61 (03) 9473 4570
Fax 14603 0
Email 14603 0
franca.agresta@mivf.com.au
Contact person for scientific queries
Name 5531 0
Dr Kate Stern
Address 5531 0
Suite 20/320 Victoria Parade
EAST MELBOURNE VIC 3002
Country 5531 0
Australia
Phone 5531 0
+ 61 (03) 9415 1838
Fax 5531 0
Email 5531 0
kate.stern@mivf.com.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

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