Erasme-POF: Efficiency of Gonadotropin-releasing Hormone (GnRH) Agonist in Preventing Chemotherapy Induced Ovarian Failure

Sponsor

Erasme University Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT01160315

Collaborator

Fonds National de la Recherche Scientifique (Other), Ipsen (Industry)

118

Enrollment

Locations

Arms

159

Duration (Months)

7.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Chemotherapy drugs like alkylating agents are frequently used in various combined regimens to treat neoplastic and benign diseases. These drugs are definitely associated with premature ovarian failure (POF), resulting in an important decrease of the long-term quality of life and an increase of morbidity. A recent study showed that the patients treated by alkylating agents had a 4.52 fold higher risk to lose their ovarian function compared with those who were treated by other agents. The rate of POF after treatment ranged from 40 to 80%, according to the age of the patients and the total doses administered.

Young women who experience POF have to face with the prospects of infertility and to consider years of hormonal replacement therapy. The possibility of minimizing gonadal damage by administering of protective therapy during chemotherapy represents an attractive option for these patients.

The aim of this study is to evaluate the protective effect on the ovarian function of the gonadotropin-releasing hormone agonist (GnRha) administered concomitantly to alkylating agents. Preliminary data in the literature on animals (rat and monkeys) are promising. Data in human are, however, highly controversial.

Condition or Disease	Intervention/Treatment	Phase
Fertility Preservation Alkylating Agents Lymphoma	Drug: Triptorelin Drug: Norethisterone acetate	Phase 2/Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

118 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

A Prospective Open Randomized Trial on the Efficacy of Gonadotropin-releasing Hormone Agonist Depot-Triptorelin- to Prevent Chemotherapy Induced Premature Ovarian Failure in Lymphoma Patients.

Study Start Date :

Jul 1, 2002

Actual Primary Completion Date :

Jun 1, 2010

Actual Study Completion Date :

Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (GnRha arm) IM injection of Triptorelin -Decapeptyl PR 11.25mg- (every 3 months) and Norethisterone acetate- Primolut-Nor 5 mg- per os continuously until the end of the chemotherapy	Drug: Triptorelin Triptorelin: intramusculAR injection every 3 months Other Names: Decapeptyl Drug: Norethisterone acetate 5 mg/day per os until during chemotherapy Other Names: Primolut
Active Comparator: Arm B (control Arm) Norethisterone acetate alone, 5mg par day, (ARM B) until the end of the chemotherapy.	Drug: Norethisterone acetate 5 mg/day per os until during chemotherapy Other Names: Primolut

Arm

Intervention/Treatment

Experimental: Arm A (GnRha arm)

IM injection of Triptorelin -Decapeptyl PR 11.25mg- (every 3 months) and Norethisterone acetate- Primolut-Nor 5 mg- per os continuously until the end of the chemotherapy

Drug: Triptorelin

Triptorelin: intramusculAR injection every 3 months

Other Names:

Decapeptyl

Drug: Norethisterone acetate

5 mg/day per os until during chemotherapy

Other Names:

Primolut

Active Comparator: Arm B (control Arm)

Norethisterone acetate alone, 5mg par day, (ARM B) until the end of the chemotherapy.

Drug: Norethisterone acetate

5 mg/day per os until during chemotherapy

Other Names:

Primolut

Outcome Measures

Primary Outcome Measures

Premature ovarian failure rate [5 years]
Primary endpoint is to evaluate the short and long-term efficacy of triptorelin depot plus progestin versus progestin alone to prevent POF induced by chemotherapy treatment. The ovarian function (FSH, E2, Progesterone, and AMH, presence of spontaneous menstrual cycle and pregnancies) will be evaluated every 3 months during the first 6 months after the end of chemotherapy, every 6 months during the next 18 months and once a year during an additional 5 years. All hormonal treatment has to be interrupted 10 days before the blood test.

Secondary Outcome Measures

Impact of the flare-up effect of Triptorelin [2 years]
The Triptorelin/Norethisterone treatment has to start if possible 10 days before the beginning of the chemotherapy (time necessary to obtain the inhibitory effect of the Gn-Rha on the ovarian function)and at least the same day. The impact of the interval between the triptorelin/noresthisterone treatment and the start of the chemotherapy on the efficacy to protect ovarian function (FSH level at 2 years of follow-up) will be evaluated.
Ovarian function during the treatment [1 year]
Evaluation of the inhibitory action of the treatment on ovarian function during the chemotherapy: the hormonal profile (FSH and estradiol levels) will be evaluated 10 days after the triptorelin/Norethisterone treatment start, before the second injection (3 months) and at the end of the chemotherapy. Adverse effects due to the injection are evaluated 7-10 days after each injection.
Number of Participants with Adverse Events as a Measure of Safety and Tolerability [1 year]
Anamnesis including the compliance of the treatment (possible treatment interruption or dosage modification) and the adverse events are performed at each visit. All events expected and directly related to the chemotherapy or the initial pathology will be documented in the Case Report Form adverse events. Specific anamnesis concerning the possible adverse events due to treatment must be completed for each follow-up visit.
Add back therapy effect [1 year]
Evaluation of the efficacy of concomitant administration of progestin alone as "Add Back Therapy" during the treatment: specific anamnesis including estrogen-deficiency symptoms (hot flushes, vaginal dryness...) is reported at each visit during the treatment. Osteodensitometry is performed after 1 year follow-up.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Women between 18 and 45 years old with lymphoma.
Menarche >2year
Subject treated by chemotherapy-induced ovarian failure including alkylant agents (except less than 8 ABVD)
Presence of both ovaries (ovarian biopsy or hemiovariectomy for cryopreservation before treatment is accepted).
Ability to give written informed consent

Exclusion Criteria:

Hormonal-sensible malignancy
Chemotherapy or radiotherapy before the inclusion in the study
Pelvic irradiation including the ovaries or TBI
Pregnancy
Patient weight above 110 kg
Anamnesis of thrombo-embolic processes
Severe hepatic or renal insufficiency
Systolic blood pressure >15mmHg or diastolic blood pressure > 90mmHg
Contraindication of IM injection
Relevant ovarian abnormalities (Functional follicular cyst are tolerated)
Anamnesis of premature ovarian failure or irregular cycle (repeated amenorrhoea >2 months)
Dubin-Johnson and Rotor Syndrome

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Algemeen Ziekenhuis Stuivenberg	Antwerpen	Belgium	2060
2	AZ St Jan	Brugges	Belgium	8000
3	Bordet	Brussels	Belgium	1000
4	Erasme Hospital	Brussels	Belgium	1070
5	AZ-VUB	Brussels	Belgium	1090
6	St Luc University	Brussels	Belgium	1200
7	CHRU Lille	Lille	Belgium	59037
8	CHU Dijon	Dijon	France	21034
9	CHU Nancy	Nancy	France	54511
10	Henry-Mondor Hospital	Paris-Creteil	France	94010
11	Hôpital Hotel Dieu	Paris	France	75004
12	St Louis Hospital	Paris	France	75475
13	CHU St Antoine	Paris	France	75571
14	Centre Henri Beckerel	Rouen	France	76038
15	Instituto Europeo di oncologia	Milano	Italy	1-20141