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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Fertility Preservation, Alkylating Agents, Lymphoma

Intervention / Treatment
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* Drug: Triptorelin
* Drug: Norethisterone acetate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (GnRha arm)<br>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<br>* Triptorelin: intramusculAR injection every 3 months<br>* Other names: Decapeptyl;Drug: Norethisterone acetate<br>* 5 mg/day per os until during chemotherapy<br>* Other names: Primolut;|
| Active Comparator: Arm B (control Arm)<br>Norethisterone acetate alone, 5mg par day, (ARM B) until the end of the chemotherapy. | Drug: Norethisterone acetate<br>* 5 mg/day per os until during chemotherapy<br>* Other names: Primolut;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Premature ovarian failure rate | 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. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of the flare-up effect of Triptorelin | 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. | 2 years | 
| Ovarian function during the treatment | 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. | 1 year | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | 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. | 1 year | 
| Add back therapy effect | 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. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ovarian failure, chemotherapy, lymphoma, GnRH agonist