Endometriosis
Conditions
Keywords
Endometriosis, Adolescents, Bone density, GnRH Agonist, Add-back therapy
Brief summary
The purpose of this study is to determine whether a regimen of norethindrone acetate + placebo or norethindrone acetate + conjugated estrogens is superior in maintaining skeletal health and quality of life in adolescents treated with a GnRH agonist for endometriosis.
Detailed description
Endometriosis has become increasingly recognized as a chronic illness which begins during adolescence. Untreated endometriosis may lead to chronic pain and infertility. As recognition of the need for prompt therapy increases, so does the length of time patients will be exposed to treatments. As a result, there exists a pressing need to evaluate adjunctive measures that may limit the associated negative health consequences of treatment. A gonadotropin-releasing hormone (GnRH) agonist is one medication utilized for patients who have failed other treatments. While GnRH-agonists are effective in relieving symptoms, their long-term use is problematic. GnRH agonists induce a low-estrogen state, causing deleterious effects on bone mineralization. These negative consequences are especially important for our pediatric patients. Adolescence is the critical period in a woman's life for bone acquisition and attainment of peak bone mass. Anything that interferes with this process puts patients at risk for lifelong low bone density and future fracture. Add-back therapy appears to be a promising adjunct to treatment for prevention of this bone loss. Daily therapy with low-doses of hormones preserves bone density in adult patients, without altering the efficacy of the GnRH-agonist. However, no data exist on the effect of add-back therapy in adolescents. The aim of the current study is to evaluate the safety and efficacy of two add-back regimens, norethindrone acetate + placebo or norethindrone acetate + conjugated estrogens, for the preservation of skeletal health and quality of life in adolescents with endometriosis treated with a GnRH-agonist.
Interventions
DRUGNorethindrone acetate + estrogens
Norethindrone acetate 5 mg by mouth daily + Conjugated equine estrogens 0.625 mg by mouth daily
DRUGnorethindrone acetate + placebo
norethindrone acetate 5 mg by mouth daily + Placebo capsule 1 pill by mouth daily
Sponsors
Brigham and Women's Hospital
Boston Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
13 Years to 22 Years
Healthy volunteers
No
Inclusion criteria
* Age 13-22 years, at least two years post-menarche * Body mass index (BMI, kg/m2) between 18 -30 kg/m2 * Surgical diagnosis of endometriosis * Clinical decision to treat with a GnRH agonist, leuprolide depot (Lupron Depot®; TAP Pharmaceuticals, Inc.) 11.25 mg intra-muscular every 3 months
Exclusion criteria
* Concomitant chronic diseases which affect bone health, such as cystic fibrosis, inflammatory bowel disease, renal disease, or diabetes mellitus * Markedly impaired liver function or liver failure * Personal history of thromboembolic event (such as deep venous thrombosis) * Medication use known to affect bone metabolism: * Glucocorticoid therapy (including inhaled steroids) or anticonvulsants used in the last 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bone Mineral Density | Baseline to 12 months | Adjusted mean change in total body areal bone mineral density (aBMD) over the 12 month trial |
Secondary
| Measure | Time frame |
|---|---|
| Total Body Bone Mineral Content (BMC) | Baseline to 12 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention Group Conjugated equine estrogens: Conjugated estrogens 0.625 mg PO daily
Norethindrone acetate: Norethindrone acetate 5 mg PO daily | 25 |
| Placebo Group Placebo: Placebo capsule 1 pill PO daily
Norethindrone acetate: Norethindrone acetate 5 mg PO daily | 26 |
| Total | 51 |
Baseline characteristics
| Characteristic | Intervention Group | Total | Placebo Group |
|---|---|---|---|
| Age, Continuous | 17.7 years STANDARD_DEVIATION 1.4 | 17.9 years STANDARD_DEVIATION 1.7 | 18.1 years STANDARD_DEVIATION 1.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 51 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 49 Participants | 26 Participants |
| Region of Enrollment United States | 25 participants | 51 participants | 26 participants |
| Sex: Female, Male Female | 25 Participants | 51 Participants | 26 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 | — / — | — / — |
| other Total, other adverse events | 15 / 25 | 13 / 26 |
| serious Total, serious adverse events | 8 / 25 | 5 / 26 |
Outcome results
Primary
Bone Mineral Density
Adjusted mean change in total body areal bone mineral density (aBMD) over the 12 month trial
Time frame: Baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention Group | Bone Mineral Density | 0.01 g/cm^2 | Standard Error 0.006 |
| Placebo Group | Bone Mineral Density | -0.11 g/cm^2 | Standard Error 0.006 |
Comparison: Analysis followed the intention-to-treat principle. The time course of each measurement from baseline to 3, 6, 9, and 12 months was compared between arms by repeated-measures analysis of variance (RM-ANOVA), with an autoregressive covariance model to account for visit-to-visit correlation within subjects.~The primary test of treatment efficacy was time × treatment interaction. Adjusted changes over time and differences between trial arms were constructed from parameters of the RMANOVA.p-value: 0.1RMANOVA
Secondary
Total Body Bone Mineral Content (BMC)
Time frame: Baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention Group | Total Body Bone Mineral Content (BMC) | 37 g | Standard Error 10 |
| Placebo Group | Total Body Bone Mineral Content (BMC) | 15 g | Standard Error 11 |
Comparison: The time course of each measurement from baseline to 3, 6, 9, and 12 months was compared between arms by repeated-measures analysis of variance (RM-ANOVA), with an autoregressive covariance model to account for visit-to-visit correlation within subjects.~The primary test of treatment efficacy was time × treatment interaction. Adjusted changes over time and differences between trial arms were constructed from parameters of the RMANOVA.p-value: 0.02RMANOVA