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

• Sponsor: Joseph Mccune (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01257802
• Collaborator: National Institutes of Health (NIH) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 14
• Locations: 2
• Arms: 2
• Duration (Months): 54
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Lupus Erythematosus, Systemic; Systemic Vasculitis; Isolated Angiitis of Central Nervous System; Lung Disease With Systemic Sclerosis; Lung Disease Interstitial Diffuse	Drug: depot leuprolide acetate 3.75 mg; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: GnRH-a for Ovarian Protection During CYC Therapy for Rheumatic Diseases
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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

4. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

1. 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

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan	Ann Arbor	Michigan	United States	48109
2	The Ohio State University	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Joseph Mccune
• National Institutes of Health (NIH)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: William J McCune, M.D., Professor of Internal Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Joseph Mccune, Michael H. and Marcia S. Klein Professor of Rheumatic Diseases and Director, Lupus Clinic, University of Michigan
• ClinicalTrials.gov Identifier: NCT01257802
• Other Study ID Numbers: HUM00043071; 5R01HD066139
• First Posted: Dec 10, 2010
• Last Update Posted: Jun 27, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Rheumatic Diseases; Lung Diseases; Lung Diseases, Interstitial; Vasculitis; Systemic Vasculitis; Scleroderma, Systemic; Collagen Diseases; Lupus Erythematosus, Systemic; Leuprolide

Study Results

Participant Flow

Pre-assignment Detail	2 of the 16 consented individuals were screen fails and therefore were not randomized.

Arm/Group Title	LUPRON	Placebo
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	6	8
6 Month / 24 Week Visit	5	2
COMPLETED	5	2
NOT COMPLETED	1	6

Baseline Characteristics

Arm/Group Title	LUPRON	Placebo	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	6	8	14
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	27.5	28.25	27.93
Sex: Female, Male (Count of Participants)
Female	6 100%	8 100%	14 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	6 100%	8 100%	14 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	LUPRON	Placebo
Arm/Group Description	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	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
Measure Participants	6	7
Baseline AMH (ng/ml)	2.07 (1.92)	3.87 (4.00)
6 month AMH (ng/ml)	0.72 (1.07)	0.24 (0)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	LUPRON	PLACEBO
Arm/Group Description	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	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
Measure Participants	6	7
Baseline AMH level ≤1.0 ng/ml	3 50%	6 75%
Baseline AMH level >1 ng/ml	3 50%	1 12.5%
6 Month AMH level ≤1.0 ng/ml	4 66.7%	1 12.5%
6 Month AMH level >1 ng/ml	1 16.7%	0 0%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	LUPRON	PLACEBO
Arm/Group Description	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	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
Measure Participants	6	7
Baseline AMH >1 ng/ml or AFC>4	4 66.7%	6 75%
6 Month AMH >1 ng/ml or AFC>4	1 16.7%	0 0%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	LUPRON	PLACEBO
Arm/Group Description	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	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
Measure Participants	6	7
Baseline Mean antral follicle count (AFC)	10.3 (9.29)	14.4 (12.4)
6 Month Mean antral follicle count (AFC)	2.5 (1.29)	17.7 (21.1)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	LUPRON	PLACEBO
Arm/Group Description	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	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
Measure Participants	6	7
Baseline mean ovarian volume	9.59 (2.69)	7.68 (3.50)
6 Month mean ovarian volume	4.26 (1.93)	6.97 (5.54)

Adverse Events

Time Frame	adverse events were collected from the time of randomization/baseline to the 6 month (24 week) follow up period The total interval of time for subjects in which AE's were collected spans approximately 6 months/24 weeks for each subject
Arm/Group Title	LUPRON		Placebo
Arm/Group Description	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		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
All Cause Mortality
	LUPRON		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/8 (0%)
Serious Adverse Events
	LUPRON		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		1/8 (12.5%)
Infections and infestations
clostridium difficile infection	1/6 (16.7%)	1	0/8 (0%)	0
Musculoskeletal and connective tissue disorders
chest pain	0/6 (0%)	0	1/8 (12.5%)	2
Hospitalization for items listed below:	0/6 (0%)	0	1/8 (12.5%)	1
Hospitalization for items listed below	0/6 (0%)	0	1/8 (12.5%)	1
Other (Not Including Serious) Adverse Events
	LUPRON		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		5/8 (62.5%)
Blood and lymphatic system disorders
pancytopenia	0/6 (0%)	0	1/8 (12.5%)	1
Gastrointestinal disorders
stool incontinence	0/6 (0%)	0	1/8 (12.5%)	1
abdominal pain	1/6 (16.7%)	1	0/8 (0%)	0
bacterial overgrowth - GI related	0/6 (0%)	0	1/8 (12.5%)	1
nausea and vomiting	0/6 (0%)	0	1/8 (12.5%)	1
General disorders
Insomnia	0/6 (0%)	0	1/8 (12.5%)	1
Infections and infestations
viral upper respiratory infection	0/6 (0%)	0	1/8 (12.5%)	1
Musculoskeletal and connective tissue disorders
pain in right hip	0/6 (0%)	0	1/8 (12.5%)	1
pain in right forearm	0/6 (0%)	0	1/8 (12.5%)	1
arthralgias	0/6 (0%)	0	1/8 (12.5%)	1
Renal and urinary disorders
fluid retention	1/6 (16.7%)	1	0/8 (0%)	0
worsening hypertension	1/6 (16.7%)	1	0/8 (0%)	0
edema of left calf, foot, and hand	0/6 (0%)	0	1/8 (12.5%)	1
Reproductive system and breast disorders
hot flashes	2/6 (33.3%)	2	4/8 (50%)	4
hot and cold flashes	0/6 (0%)	0	1/8 (12.5%)	1
increased sweating	0/6 (0%)	0	1/8 (12.5%)	1
2 menstruations in 28 day cycle	0/6 (0%)	0	1/8 (12.5%)	1
menstrual spotting in between cycles	1/6 (16.7%)	1	0/8 (0%)	0
night sweats	0/6 (0%)	0	1/8 (12.5%)	1
Skin and subcutaneous tissue disorders
leg striae	0/6 (0%)	0	1/8 (12.5%)	1
facial rash	0/6 (0%)	0	1/8 (12.5%)	1
Surgical and medical procedures
bleeding at catheter site	1/6 (16.7%)	1	0/8 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.