GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases

Study Overview
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Brief Summary
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The purpose of this study it to determine whether the use of a gonadotropin releasing hormone (GnRH)-agonist (depot-leuprolide acetate) during cyclophosphamide (CYC) therapy in women with rheumatic diseases will provide greater ovarian protection than placebo.

Detailed Description
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Patients will be women ages 18-40 with either a severe rheumatic disease requiring cyclophosphamide or interstitial lung disease requiring cyclophosphamide to be administered either daily orally; monthly intravenously; or intravenously every 2 weeks for 6 doses. Because cyclophosphamide treatment may be required urgently for some indications, study entry may occur before either the first or second dose of cyclophosphamide for patients receiving cyclophosphamide intravenously. Of 16 participants who were screened, only 14 were randomized and only 7 participants actually completed the study. Due to this low number, follicle stimulating hormone (FSH) levels were not obtained. Secondary outcome measures that are not available include presence of menses and FSH.

Official Title
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GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases

Conditions
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Lupus Erythematosus, Systemic, Systemic Vasculitis, Isolated Angiitis of Central Nervous System, Lung Disease With Systemic Sclerosis, Lung Disease Interstitial Diffuse

Intervention / Treatment
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* Drug: depot leuprolide acetate 3.75 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Female, post menarche, not menopausal Ages 18-40 years inclusive at enrollment Diagnosis consistent with a rheumatic or autoimmune disease requiring 3-6 months of daily or intermittent cyclophosphamide therapy. This may include, but is not limited to: Systemic lupus Sjogren's syndrome Systemic vasculitis Isolated vasculitis of the central nervous system Other autoimmune neurologic diseases requiring cyclophosphamide including transverse myelitis, peripheral neuropathies, multiple sclerosis, neuromyelitis optica, and retinal vasculitis Behcet's syndrome Scleroderma Inflammatory myositis Interstitial lung disease, other autoimmune pulmonary diseases requiring cyclophosphamide Overlap connective tissue diseases not precisely fitting the above definitions clearly requiring cyclophosphamide for severe immune mediated organ damage Rheumatoid vasculitis Patients will have planned cyclophosphamide treatment according to any one of the following regimens: 3 to 6 months of daily oral cyclophosphamide: Lupron/placebo must be given within four (4) weeks of initiation of daily cyclophosphamide. The Eurolupus regimen consisting of 6 fortnightly biweekly boluses of 500 mg cyclophosphamide: First dose of Lupron/placebo must be given 10 days prior to the second dose of cyclophosphamide 3 to 6 monthly boluses of cyclophosphamide by the NIH regimen: First dose of Lupron/placebo must be given 10 days prior to the second dose of cyclophosphamide A satisfactory plan for contraception consistent with cyclophosphamide administration (when appropriate: depot progestins, IUD, combination oral contraception and/or dual barrier contraception). Exclusion Criteria: Symptoms consistent with ovarian failure based on gynecologic evaluation and confirmatory laboratory testing Prior unilateral or bilateral oophorectomy Cervical intraepithelial neoplasia (CIN 2, or more severe), that has not been adequately evaluated or is not being adequately treated Contraindications to use of GnRH-a (e.g., undiagnosed abnormal uterine bleeding) Prior adverse or allergic reaction to GnRH-a A history of severe psychiatric disorders, particularly severe depression that is currently not adequately treated History of significant noncompliance with medical treatment Patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants that have not already been addressed with appropriate measures to preserve bone mass. Pregnant or breastfeeding Significant thrombotic event requiring treatment that will not have received appropriate therapy for at least 4 weeks before initiation of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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 |
| --- | --- |
| Active Comparator: LUPRON<br>Monthly depot leuprolide acetate 3.75 mg injection during cyclophosphamide administration. First dose of study drug given at least 10 days before following dose of cyclophosphamide if cyclophosphamide is given in biweekly or monthly boluses | Drug: depot leuprolide acetate 3.75 mg<br>* Monthly depot leuprolide acetate 3.75 mg vs placebo during cyclophosphamide administration. First dose of study drug given at least 10 days before following dose of cyclophosphamide if cyclophosphamide is given in biweekly or monthly boluses<br>* Other names: LUPRON depot 3.75 mg;|
| Placebo Comparator: Placebo<br>Monthly placebo injection during cyclophosphamide administration. First dose of study drug given at least 10 days before following dose of cyclophosphamide if cyclophosphamide is given in biweekly or monthly boluses. | Drug: Placebo<br>* Monthly placebo during cyclophosphamide administration. First dose of study drug given at least 10 days before following dose of cyclophosphamide if cyclophosphamide is given in biweekly or monthly boluses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-mullerian Hormone (AMH) Measured as a Continuous Variable, Specifically Assessing the Intra-person Change From Study Entry (Day 0) to 6-month Post-intervention Visit | AMH was quantified in vitro a commercially available enzyme linked immunosorbent assay (ELISA) (Beckman Coulter; Marseille, France) was used for in vitro quantitative measurement of serum AMH. | Day 0 to 6-month post-intervention visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | AMH level ≤1.0 predicts onset of menopause within 5 years in normal women | baseline and 6 months | 
| Number of Participants With Either an AMH Level of >1 ng/mL OR Antral Follicle Count of >4. | An AMH level of >1 ng/ml and/or an antral follicle count of >4 in either ovary is a strong predictor of residual ovarian function | baseline and 6 months | 
| Mean Antral Follicle Count (AFC) | Mean antral follicle count (AFC) is the average number of follicles counted in each of 2 ovaries | baseline and 6 months | 
| Mean Ovarian Volume. | Mean ovarian volume reflects the preservation of ovarian tissue despite exposure to cyclophosphamide; reduced ovarian size is documented in cyclophosphamide treated patients | baseline and 6 months |