Endometriosis
Conditions
Keywords
endometriosis, pelvic pain, opioid, narcotic
Brief summary
The purpose of this study is to determine if the addition of Low Dose Naltrexone to standard endometriosis treatments will improve patient reported endometriosis associated pain.
Detailed description
The central hypothesis of the research study is that low dose naltrexone (LDN), in combination with hormonal suppression of endometriosis (standard of care), will lead to significant improvement of endometriosis-related pain. The proposal seeks to: 1. determine if the addition of LDN to standard endometriosis treatments will improve patient- reported endometriosis associated pain using daily Visual Analogue Scale (VAS) scores and 2. measure the impact of treatment on quality of life as measured by validated questionnaires including the Endometriosis Health Profile-30 (EHP30) and the Patient's Global Impression of Change (PGIC).
Interventions
DRUGNaltrexone
4.5mg daily dose, taken orally
5 - 15mg daily dose, taken orally
DRUGPlacebo
daily placebo pill, taken orally
Sponsors
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, Double Blind, Placebo Controlled Trial
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Premenopausal female ages 18 to 45 years old on the day of signing informed consent. * Must agree to use only study-specific analgesic medications during the study and is not known to be intolerant to them. * Diagnosed with endometriosis and has had, within the last 10 years prior to signing the informed consent, surgical diagnosis with direct visualization and/or histopathologic confirmation of endometriosis. * Is not expected to undergo gynecological surgery or other surgical procedures for treatment of endometriosis during the study period. * Agrees to use contraception if not surgically sterile during the entire study. * Patients using oral contraceptives, LARCs and/or GnRH agonists/antagonists for contraception and/or management of endometriosis, with a stable regimen, will be able to continue in the study, however, women using oral contraceptives and GnRH agonist/antagonists will be switched to Norethindrone acetate during the 1-2 week run-in period as prescribed by principle investigator.
Exclusion criteria
* Women that are pregnant, breastfeeding or trying to conceive. * Patients with chronic daily narcotic use and any chronic pain or frequently reoccurring pain condition, other than endometriosis, that is treated with opioids or requires analgesics for more than 7 days per month. * Patients with abnormal liver function tests (greater than 3x normal limit) in the past year or history of liver disease. Routine screening of liver function is not required. * Non-English speaking or inability to read and understand English secondary, in part, to the need to read and report daily results in English. * Undiagnosed vaginal bleeding * Patients with history of opioid, illicit drug or alcohol abuse * Patients currently taking thioridazine * Patients with a history of suicidality * Patients with current or history of unstable depression or other psychiatric disorder who, by PI judgement, are unstable or not well controlled * Known, suspected or history of cancer of the breast * Active deep vein thrombosis, pulmonary embolism or history of these conditions * Active or recent arterial thromboembolic disease (e.g., stroke, myocardial infarction)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Score Area Under the Curve (AUC) | 12 weeks | Pain is reported daily using the Visual Analog Scale, a 100mm horizontal line on which the patient's pain intensity is represented by a point between the extremities of 0 (no pain) and 100 (worst pain). The final outcome measure will be calculated as area under the curve from randomization through 12-weeks of intervention. AUC was calculated using the trapezoid rule. Calculated AUC per subject across this 12-week period can range from 0 - 8300. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PGIC Score (Painful Periods) | 4, 8, 12 and 16 weeks | Patient's Global Impression of Change (PGIC) scale will be used to rate painful periods. This is a 7 point scale ranging from 1 (much worse) to 7 (much better). |
| PGIC Score (Nonmenstrual Pelvic Pain) | 4, 8, 12 and 16 weeks | Patient's Global Impression of Change (PGIC) scale will be used to rate nonmenstrual pelvic pain. This is a 7 point scale ranging from 1 (much worse) to 7 (much better). |
| EHP-30 Score | Baseline, 4, 8, 12, and 16 weeks | Quality of life measured by the validated Endometriosis Health Profile (EHP-30) questionnaire. Scores range from 0 (best health status) to 100 (worst health status). |
| Ibuprofen Use | 12 weeks | Average # of ibuprofen 200 mg pills per week during the study treatment period |
| Oxycodone Use | 12 weeks | Number of subjects who used oxycodone at any time during the study |
| PGIC Score (Dyspareunia) | 4, 8, 12 and 16 weeks | Patient's Global Impression of Change (PGIC) scale will be used to rate pelvic pain during sex. This is a 7 point scale ranging from 1 (much worse) to 7 (much better). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low-Dose Naltrexone 12-week intervention period of 4.5 mg daily naltrexone in combination with standard treatment of 5-15 mg daily norethindrone acetate
Naltrexone: 4.5mg daily dose, taken orally
Norethindrone Acetate: 5 - 15mg daily dose, taken orally | 5 |
| Placebo 12-week intervention period of daily placebo in combination with standard treatment of 5-15 mg daily norethindrone acetate
Norethindrone Acetate: 5 - 15mg daily dose, taken orally
Placebo: daily placebo pill, taken orally | 4 |
| Total | 9 |
Baseline characteristics
| Characteristic | Placebo | Total | Low-Dose Naltrexone |
|---|---|---|---|
| Age, Continuous | 27.5 years STANDARD_DEVIATION 3.4 | 28.9 years STANDARD_DEVIATION 6.8 | 30 years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 9 Participants | 5 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 | 0 Participants | 0 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 | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 5 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 / 5 | 0 / 4 |
| other Total, other adverse events | 3 / 5 | 4 / 4 |
| serious Total, serious adverse events | 0 / 5 | 0 / 4 |
Outcome results
Primary
Pain Score Area Under the Curve (AUC)
Pain is reported daily using the Visual Analog Scale, a 100mm horizontal line on which the patient's pain intensity is represented by a point between the extremities of 0 (no pain) and 100 (worst pain). The final outcome measure will be calculated as area under the curve from randomization through 12-weeks of intervention. AUC was calculated using the trapezoid rule. Calculated AUC per subject across this 12-week period can range from 0 - 8300.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-Dose Naltrexone | Pain Score Area Under the Curve (AUC) | 2461 units on a scale*days | Standard Deviation 1445 |
| Placebo | Pain Score Area Under the Curve (AUC) | 1338 units on a scale*days | Standard Deviation 697 |
p-value: 0.295% CI: [-755, 3000]t-test, 2 sided
Secondary
EHP-30 Score
Quality of life measured by the validated Endometriosis Health Profile (EHP-30) questionnaire. Scores range from 0 (best health status) to 100 (worst health status).
Time frame: Baseline, 4, 8, 12, and 16 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low-Dose Naltrexone | EHP-30 Score | Week 8 | 34.9 score on a scale | Standard Deviation 22.8 |
| Low-Dose Naltrexone | EHP-30 Score | Week 12 | 34.1 score on a scale | Standard Deviation 26.6 |
| Low-Dose Naltrexone | EHP-30 Score | Week 4 | 35.5 score on a scale | Standard Deviation 16.6 |
| Low-Dose Naltrexone | EHP-30 Score | Week 16 | 35.7 score on a scale | Standard Deviation 28 |
| Low-Dose Naltrexone | EHP-30 Score | Baseline | 56.5 score on a scale | Standard Deviation 18.3 |
| Placebo | EHP-30 Score | Week 16 | 28.9 score on a scale | Standard Deviation 23.3 |
| Placebo | EHP-30 Score | Baseline | 27.6 score on a scale | Standard Deviation 19.4 |
| Placebo | EHP-30 Score | Week 4 | 25.1 score on a scale | Standard Deviation 17.1 |
| Placebo | EHP-30 Score | Week 12 | 18.6 score on a scale | Standard Deviation 15.8 |
| Placebo | EHP-30 Score | Week 8 | 16.0 score on a scale | Standard Deviation 8 |
Comparison: Comparison of treatment groups at BASELINEp-value: 0.0695% CI: [-1.9, 59.6]Mixed Models Analysis
Comparison: Comparison of treatment groups at WEEK 4p-value: 0.4895% CI: [-20.3, 41.2]Mixed Models Analysis
Comparison: Comparison of treatment groups at WEEK 8p-value: 0.2195% CI: [-11.8, 49.6]Mixed Models Analysis
Comparison: Comparison of treatment groups at WEEK 12p-value: 0.395% CI: [-15.2, 46.2]Mixed Models Analysis
Comparison: Comparison of treatment groups at WEEK 16p-value: 0.6595% CI: [-24, 37.5]Mixed Models Analysis
Secondary
Ibuprofen Use
Average # of ibuprofen 200 mg pills per week during the study treatment period
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low-Dose Naltrexone | Ibuprofen Use | 5.5 pills/week | Standard Deviation 3.9 |
| Placebo | Ibuprofen Use | 1.2 pills/week | Standard Deviation 1.3 |
p-value: 0.0895% CI: [-0.6, 9.2]t-test, 2 sided
Secondary
Oxycodone Use
Number of subjects who used oxycodone at any time during the study
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low-Dose Naltrexone | Oxycodone Use | 0 Participants |
| Placebo | Oxycodone Use | 0 Participants |
Secondary
PGIC Score (Dyspareunia)
Patient's Global Impression of Change (PGIC) scale will be used to rate pelvic pain during sex. This is a 7 point scale ranging from 1 (much worse) to 7 (much better).
Time frame: 4, 8, 12 and 16 weeks
Population: This measure was only assessed in patients who had intercourse during study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Low-Dose Naltrexone | PGIC Score (Dyspareunia) | Week 4 | 4.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Dyspareunia) | Week 8 | 4.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Dyspareunia) | Week 12 | 4.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Dyspareunia) | Week 16 | 4.0 units on a scale |
| Placebo | PGIC Score (Dyspareunia) | Week 16 | 5.0 units on a scale |
| Placebo | PGIC Score (Dyspareunia) | Week 4 | 6.0 units on a scale |
| Placebo | PGIC Score (Dyspareunia) | Week 12 | 6.0 units on a scale |
| Placebo | PGIC Score (Dyspareunia) | Week 8 | 6.0 units on a scale |
Comparison: Comparison of treatment groups at WEEK 4p-value: 0.37Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 8p-value: 0.39Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 12p-value: 0.37Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 16p-value: 0.39Wilcoxon (Mann-Whitney)
Secondary
PGIC Score (Nonmenstrual Pelvic Pain)
Patient's Global Impression of Change (PGIC) scale will be used to rate nonmenstrual pelvic pain. This is a 7 point scale ranging from 1 (much worse) to 7 (much better).
Time frame: 4, 8, 12 and 16 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Low-Dose Naltrexone | PGIC Score (Nonmenstrual Pelvic Pain) | Week 4 | 5.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Nonmenstrual Pelvic Pain) | Week 8 | 4.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Nonmenstrual Pelvic Pain) | Week 12 | 4.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Nonmenstrual Pelvic Pain) | Week 16 | 4.0 units on a scale |
| Placebo | PGIC Score (Nonmenstrual Pelvic Pain) | Week 16 | 5.5 units on a scale |
| Placebo | PGIC Score (Nonmenstrual Pelvic Pain) | Week 4 | 6.5 units on a scale |
| Placebo | PGIC Score (Nonmenstrual Pelvic Pain) | Week 12 | 6.5 units on a scale |
| Placebo | PGIC Score (Nonmenstrual Pelvic Pain) | Week 8 | 6.5 units on a scale |
Comparison: Comparison of treament groups at WEEK 4p-value: 0.29Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 8p-value: 0.24Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 12p-value: 0.2Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 16p-value: 0.53Wilcoxon (Mann-Whitney)
Secondary
PGIC Score (Painful Periods)
Patient's Global Impression of Change (PGIC) scale will be used to rate painful periods. This is a 7 point scale ranging from 1 (much worse) to 7 (much better).
Time frame: 4, 8, 12 and 16 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Low-Dose Naltrexone | PGIC Score (Painful Periods) | 4 weeks | 4.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Painful Periods) | 8 weeks | 4.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Painful Periods) | 12 weeks | 4.0 units on a scale |
| Low-Dose Naltrexone | PGIC Score (Painful Periods) | 16 weeks | 4.0 units on a scale |
| Placebo | PGIC Score (Painful Periods) | 16 weeks | 4.5 units on a scale |
| Placebo | PGIC Score (Painful Periods) | 4 weeks | 6.5 units on a scale |
| Placebo | PGIC Score (Painful Periods) | 12 weeks | 6.5 units on a scale |
| Placebo | PGIC Score (Painful Periods) | 8 weeks | 6.5 units on a scale |
Comparison: Comparison of treatment groups at WEEK 4p-value: 0.07Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 8p-value: 0.07Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 12p-value: 0.06Wilcoxon (Mann-Whitney)
Comparison: Comparison of treatment groups at WEEK 16p-value: 1Wilcoxon (Mann-Whitney)