Clinical trial NCT01257802: GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases
Official title: GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Lupus Erythematosus, Systemic
Systemic Vasculitis
Isolated Angiitis of Central Nervous System
Lung Disease With Systemic Sclerosis
Lung Disease Interstitial Diffuse
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2010-12-10
Enrollment: 14
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 1. Female, post menarche, not menopausal
2. Ages 18-40 years inclusive at enrollment
3. 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
4. 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
5. A satisfactory plan for contraception consistent with cyclophosphamide administration (when appropriate: depot progestins, IUD, combination oral contraception and/or dual barrier contraception).

Exclusion Criteria:

1. Symptoms consistent with ovarian failure based on gynecologic evaluation and confirmatory laboratory testing
2. Prior unilateral or bilateral oophorectomy
3. Cervical intraepithelial neoplasia (CIN 2, or more severe), that has not been adequately evaluated or is not being adequately treated
4. Contraindications to use of GnRH-a (e.g., undiagnosed abnormal uterine bleeding)
5. Prior adverse or allergic reaction to GnRH-a
6. A history of severe psychiatric disorders, particularly severe depression that is currently not adequately treated
7. History of significant noncompliance with medical treatment
8. 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.
9. Pregnant or breastfeeding
10. Significant thrombotic event requiring treatment that will not have received appropriate therapy for at least 4 weeks before initiation of study drug.

Primary outcomes:
measure: 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
timeFrame: Day 0 to 6-month post-intervention visit
Secondary outcomes:
measure: Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL,
timeFrame: baseline and 6 months
measure: Number of Participants With Either an AMH Level of >1 ng/mL OR Antral Follicle Count of >4.
timeFrame: baseline and 6 months
measure: Mean Antral Follicle Count (AFC)
timeFrame: baseline and 6 months
measure: Mean Ovarian Volume.
timeFrame: baseline and 6 months
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
Study officials:
affiliation: Professor of Internal Medicine
name: William J McCune, M.D.
role: PRINCIPAL_INVESTIGATOR
References: