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

Primary Purpose

Lupus Erythematosus, Systemic, Systemic Vasculitis, Isolated Angiitis of Central Nervous System

Status
Terminated
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
depot leuprolide acetate 3.75 mg
Placebo
Sponsored by
Joseph Mccune
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lupus Erythematosus, Systemic

Eligibility Criteria

18 Years - 40 Years (Adult)FemaleDoes not accept healthy volunteers
  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.

Sites / Locations

  • University of Michigan
  • The Ohio State University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

LUPRON

Placebo

Arm Description

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

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
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
Mean Antral Follicle Count (AFC)
Mean antral follicle count (AFC) is the average number of follicles counted in each of 2 ovaries
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

Full Information

First Posted
December 9, 2010
Last Updated
May 23, 2017
Sponsor
Joseph Mccune
Collaborators
National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT01257802
Brief Title
GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases
Acronym
LUPRON
Official Title
GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Terminated
Study Start Date
May 2011 (undefined)
Primary Completion Date
October 2015 (Actual)
Study Completion Date
November 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Joseph Mccune
Collaborators
National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lupus Erythematosus, Systemic, Systemic Vasculitis, Isolated Angiitis of Central Nervous System, Lung Disease With Systemic Sclerosis, Lung Disease Interstitial Diffuse

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LUPRON
Arm Type
Active Comparator
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
depot leuprolide acetate 3.75 mg
Other Intervention Name(s)
LUPRON depot 3.75 mg
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Day 0 to 6-month post-intervention visit
Secondary Outcome Measure Information:
Title
Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL,
Description
AMH level ≤1.0 predicts onset of menopause within 5 years in normal women
Time Frame
baseline and 6 months
Title
Number of Participants With Either an AMH Level of >1 ng/mL OR Antral Follicle Count of >4.
Description
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
Time Frame
baseline and 6 months
Title
Mean Antral Follicle Count (AFC)
Description
Mean antral follicle count (AFC) is the average number of follicles counted in each of 2 ovaries
Time Frame
baseline and 6 months
Title
Mean Ovarian Volume.
Description
Mean ovarian volume reflects the preservation of ovarian tissue despite exposure to cyclophosphamide; reduced ovarian size is documented in cyclophosphamide treated patients
Time Frame
baseline and 6 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William J McCune, M.D.
Organizational Affiliation
Professor of Internal Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
The Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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