GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases (LUPRON)

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.

Study Overview

• Status: Terminated
• Conditions: Lupus Erythematosus, Systemic; Systemic Vasculitis; Lung Disease With Systemic Sclerosis; Isolated Angiitis of Central Nervous System; Lung Disease Interstitial Diffuse
• Intervention / Treatment: Drug: depot leuprolide acetate 3.75 mg; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: LUPRON; 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; 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; Other Names: LUPRON depot 3.75 mg
PLACEBO_COMPARATOR: Placebo; 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; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Joseph Mccune
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH)
• Investigators: Principal Investigator: William J McCune, M.D., Professor of Internal Medicine

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): November 1, 2015

Study Registration Dates

• First Submitted: December 9, 2010
• First Submitted That Met QC Criteria: December 9, 2010
• First Posted (ESTIMATE): December 10, 2010

Study Record Updates

• Last Update Posted (ACTUAL): June 27, 2017
• Last Update Submitted That Met QC Criteria: May 23, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Respiratory Tract Diseases; Immune System Diseases; Autoimmune Diseases; Musculoskeletal Diseases; Connective Tissue Diseases; Lung Diseases; Lupus Erythematosus, Systemic; Scleroderma, Systemic; Rheumatic Diseases; Collagen Diseases; Lung Diseases, Interstitial; Vasculitis; Systemic Vasculitis; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Leuprolide
• Other Study ID Numbers: HUM00043071; 5R01HD066139 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO