Isolated Angiitis of Central Nervous System, Lung Disease Interstitial Diffuse, Lung Disease With Systemic Sclerosis, Lupus Erythematosus, Systemic, Systemic Vasculitis
Conditions
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.
Interventions
DRUGdepot 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
DRUGPlacebo
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
Sponsors
National Institutes of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Joseph Mccune
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | baseline and 6 months | 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. | baseline and 6 months | 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) | baseline and 6 months | Mean antral follicle count (AFC) is the average number of follicles counted in each of 2 ovaries |
| Mean Ovarian Volume. | baseline and 6 months | Mean ovarian volume reflects the preservation of ovarian tissue despite exposure to cyclophosphamide; reduced ovarian size is documented in cyclophosphamide treated patients |
Countries
United States
Participant flow
Pre-assignment details
2 of the 16 consented individuals were screen fails and therefore were not randomized.
Participants by arm
| Arm | Count |
|---|---|
| LUPRON 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 | 6 |
| Placebo 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
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 | 8 |
| Total | 14 |
Baseline characteristics
| Characteristic | LUPRON | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 27.5 years | 28.25 years | 27.93 years |
| Region of Enrollment United States | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 8 |
| other Total, other adverse events | 5 / 6 | 5 / 8 |
| serious Total, serious adverse events | 1 / 6 | 1 / 8 |
Outcome results
Primary
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.
Time frame: Day 0 to 6-month post-intervention visit
Population: 8 subjects are listed in the breakdown of baseline characteristics. Samples were missing from one subject enrolled in the Placebo arm - therefore analysis throughout the majority of the reporting will include only 7 samples instead of 8 in the Placebo arm
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LUPRON | 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 | Baseline AMH (ng/ml) | 2.07 ng/ml | Standard Deviation 1.92 |
| LUPRON | 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 | 6 month AMH (ng/ml) | 0.72 ng/ml | Standard Deviation 1.07 |
| Placebo | 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 | Baseline AMH (ng/ml) | 3.87 ng/ml | Standard Deviation 4 |
| Placebo | 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 | 6 month AMH (ng/ml) | 0.24 ng/ml | Standard Deviation 0 |
Secondary
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
Time frame: baseline and 6 months
Population: 4 of the 7 subjects in the placebo arm dropped out of the study and 2 of the remaining subjects failed to have blood drawn at the 24 week (6 month) milestone, and 1 subject of the 6 subjects receiving active drug dropped out of the study before reaching the 24 week (6 month) milestone
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LUPRON | Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | Baseline AMH level ≤1.0 ng/ml | 3 Participants |
| LUPRON | Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | Baseline AMH level >1 ng/ml | 3 Participants |
| LUPRON | Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | 6 Month AMH level ≤1.0 ng/ml | 4 Participants |
| LUPRON | Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | 6 Month AMH level >1 ng/ml | 1 Participants |
| Placebo | Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | 6 Month AMH level >1 ng/ml | 0 Participants |
| Placebo | Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | Baseline AMH level ≤1.0 ng/ml | 6 Participants |
| Placebo | Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | 6 Month AMH level ≤1.0 ng/ml | 1 Participants |
| Placebo | Count of Patients With AMH of ≤1.0 ng/mL vs >1 ng/mL, | Baseline AMH level >1 ng/ml | 1 Participants |
Secondary
Mean Antral Follicle Count (AFC)
Mean antral follicle count (AFC) is the average number of follicles counted in each of 2 ovaries
Time frame: baseline and 6 months
Population: 4 of the 7 subjects in the placebo arm dropped out of the study before reaching the 24 week (6 month) milestone, and 2 subjects of the 6 subjects receiving active drug did not have ultrasound performed at the 24 week (6 month) milestone
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LUPRON | Mean Antral Follicle Count (AFC) | Baseline Mean antral follicle count (AFC) | 10.3 # of ovarian follicles | Standard Deviation 9.29 |
| LUPRON | Mean Antral Follicle Count (AFC) | 6 Month Mean antral follicle count (AFC) | 2.5 # of ovarian follicles | Standard Deviation 1.29 |
| Placebo | Mean Antral Follicle Count (AFC) | Baseline Mean antral follicle count (AFC) | 14.4 # of ovarian follicles | Standard Deviation 12.4 |
| Placebo | Mean Antral Follicle Count (AFC) | 6 Month Mean antral follicle count (AFC) | 17.7 # of ovarian follicles | Standard Deviation 21.1 |
Secondary
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
Time frame: baseline and 6 months
Population: 4 of the 7 subjects in the placebo arm dropped out of the study before reaching the 24 week (6 month) milestone, and 2 subjects of the 6 subjects receiving active drug did not have ultrasound performed at the 24 week (6 month) milestone
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LUPRON | Mean Ovarian Volume. | Baseline mean ovarian volume | 9.59 cubic centimeters | Standard Deviation 2.69 |
| LUPRON | Mean Ovarian Volume. | 6 Month mean ovarian volume | 4.26 cubic centimeters | Standard Deviation 1.93 |
| Placebo | Mean Ovarian Volume. | Baseline mean ovarian volume | 7.68 cubic centimeters | Standard Deviation 3.5 |
| Placebo | Mean Ovarian Volume. | 6 Month mean ovarian volume | 6.97 cubic centimeters | Standard Deviation 5.54 |
Secondary
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
Time frame: baseline and 6 months
Population: 4 of the 7 subjects in the placebo arm dropped out of the study and 2 of the remaining subjects failed to have blood drawn at the 24 week (6 month) milestone, and 1 subject of the 6 subjects receiving active drug dropped out of the study before reaching the 24 week (6 month) milestone
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LUPRON | Number of Participants With Either an AMH Level of >1 ng/mL OR Antral Follicle Count of >4. | Baseline AMH >1 ng/ml or AFC>4 | 4 Participants |
| LUPRON | Number of Participants With Either an AMH Level of >1 ng/mL OR Antral Follicle Count of >4. | 6 Month AMH >1 ng/ml or AFC>4 | 1 Participants |
| Placebo | Number of Participants With Either an AMH Level of >1 ng/mL OR Antral Follicle Count of >4. | Baseline AMH >1 ng/ml or AFC>4 | 6 Participants |
| Placebo | Number of Participants With Either an AMH Level of >1 ng/mL OR Antral Follicle Count of >4. | 6 Month AMH >1 ng/ml or AFC>4 | 0 Participants |