PROtecting Ovaries and Fertility During Chemotherapy - The PROOF Trial

Study Overview
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Brief Summary
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The purpose of this study is to determine whether gonadotropin releasing hormone agonists (medical therapy) will protect against ovarian failure in reproductive aged women undergoing sterilizing chemotherapy.

Detailed Description
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Fertility preservation is defined as the maintenance of one's ability to reproduce. The hypothesis for this study is that medical treatment (GnRHa) will help female cancer patients, receiving sterilizing chemotherapy, preserve their ovarian function and therefore fertility. This study is a feasibility trial of the drug (GnRHa)vs placebo in female cancer patients receiving gonadotoxic chemotherapy between the ages of 18 and 38 who wish to participate. The objective of the feasibility trial is to determine the feasibility of a definitive study to answer this question and also to define the required parameters needed to design the definitive study such as the observable difference in ovarian failure between the drug and placebo groups. The same protocol will be followed as proposed for the definitive trial but with a smaller sample size. This pilot study will be conducted at the Ottawa Hospital Regional Cancer Centre/Division of Reproductive Medicine of Department of Obstetrics and Gynecology, University of Ottawa and the Cancer Centre of Southeastern Ontario/Division of Reproductive Medicine of Department of Obstetrics and Gynecology, University of Ottawa. The planned trial intervention is trimonthly (every 3 months) administration of depot GnRHa (Leuprolide acetate (LA) 11.25 mg intramuscularly) or placebo. Injections would start prior to initiation of chemotherapy, in the luteal phase of the menstrual cycle preceding chemotherapy, and will continue until cessation of chemotherapy (maximum of 6 months or 2 injections). Since only adjuvant/curative chemotherapy patients will be enrolled, chemotherapy will last a maximum of six months. Subjects will be randomized, with concealed allocation, to either GnRHa or placebo. Subjects and investigators will be blinded to the intervention administered. Inclusion criteria: Women who are between ages 18 to 38; who will be undergoing gonadotoxic (sterilizing) curative/ adjuvant chemotherapy for early stage disease; and have provided informed consent. All subjects will be enrolled from the Ottawa Hospital Regional Cancer Institute (OHRCC) and the Cancer Center of South Eastern Ontario at Kingston General Hospital (CCSEO). Gonadotoxic chemotherapy includes alkylating / anthracycline agents eg. cyclophosphamide. Exclusion criteria: Women who; have advanced stage disease and/or whose median survival is expected to be less than 6 months have cancer of the ovaries, uterus, or fallopian tubes; have clinical or biochemical evidence of diminished ovarian reserve (recent shortening of cycles &lt; 24 days between menses, age &gt; 38, elevated serum FSH (follicular stimulating hormone)&gt; 15 IU/L, or low antral follicle count (AFC- number of follicles less than 10 mm on day 2 or 3 of natural menses) on baseline pelvic ultrasound (&lt;5) or elevated day 2 or 3 estradiol (&gt; 280 pmol/ml); have previously received chemotherapy or abdominal/pelvic radiation or have planned to receive abdomino/pelvic radiation; are pregnant; have contraindications to intramuscular injections; or 7) have a history of fractures secondary to/or documented osteoporosis. Outcomes: Subjects will be assessed at baseline, monthly (for adverse effects only) during active intervention, and at 0, 3, 6, 9, and 12 months post cessation of chemotherapy and treatment (GnRHa/ placebo) for predictors of ovarian reserve. The primary outcome is protection against ovarian failure at 12 months post chemotherapy. This is measured by resumption of regular menstrual cycles (every 24 -35 days) with documentation of ovulation by biochemistry (progesterone levels) over a minimum of three months. Secondary outcomes will include sonographic (biophysical) and biochemical markers of ovarian reserve.

Official Title
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PROtecting Ovaries and Fertility During Chemotherapy - The PROOF Trial: A Randomized Controlled Trial of Gonadotropin Releasing Hormone Agonist (GnRHa) for Fertility Preservation in Oncology Patients

Conditions
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Fertility Preservation, Cancer

Intervention / Treatment
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* Drug: Leuprolide acetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women who are: between ages 18 to 38; who will be undergoing gonadotoxic (sterilizing) curative/ adjuvant chemotherapy for early stage disease; and have provided informed consent. All subjects will be enrolled from the Ottawa Hospital Regional Cancer Institute (OHRCC) and the Cancer Center of South Eastern Ontario at Kingston General Hospital (CCSEO). Exclusion Criteria: Women who: have advanced stage disease and/or whose median survival is expected to be less than 6 months have cancer of the ovaries, uterus, or fallopian tubes; have clinical or biochemical evidence of diminished ovarian reserve (recent shortening of cycles &lt; 24 days between menses, age &gt; 38, elevated serum FSH (follicular stimulating hormone)&gt; 15 IU/L, or low antral follicle count (AFC- number of follicles less than 10 mm on day 2 or 3 of natural menses) on baseline pelvic ultrasound (&lt;5) or elevated day 2 or 3 estradiol (&gt; 280 pmol/ml); have previously received chemotherapy or abdominal/pelvic radiation or have planned to receive abdomino/pelvic radiation; are pregnant; have contraindications to intramuscular injections; or have a history of fractures secondary to/or documented osteoporosis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 38 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Leuprolide acetate<br> <br> |
| Active Comparator: depot GnRHa (Leuprolide acetate (LA) 11.25 mg intramuscularly)<br> | Drug: Leuprolide acetate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protection against ovarian failure |  | 12 months post Chemo therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sonographic (biophysical) and biochemical markers of ovarian reserve |  | 3,6,9,12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gonadotropin releasing hormone agonist, GnRH, Fertility, Fertility preservation, Oncology, Cancer, Chemotherapy