Low-Dose Naltrexone in Combination With Standard Treatment in Women With Endometriosis

• ClinicalTrials.gov Identifier: NCT03970330
• Recruitment Status: Terminated
• First Posted: May 31, 2019
• Results First Posted: November 3, 2022
• Last Update Posted: November 3, 2022
• Sponsor: Milton S. Hershey Medical Center
• Information provided by (Responsible Party): Kristin Riley, MD, Milton S. Hershey Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Endometriosis	Drug: Naltrexone; Drug: Norethindrone Acetate; Drug: Placebo	Phase 3

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, Double Blind, Placebo Controlled Trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-Blind Placebo-Controlled Trial to Assess the Effectiveness of Low-Dose Naltrexone in Combination With Standard Treatment in Women With Chronic Pelvic Pain Secondary to Endometriosis
• Actual Study Start Date: January 16, 2020
• Actual Primary Completion Date: June 21, 2021
• Actual Study Completion Date: June 21, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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	Drug: Naltrexone; 4.5mg daily dose, taken orally; Other Name: REVIA; Drug: Norethindrone Acetate; 5 - 15mg daily dose, taken orally
Placebo Comparator: Placebo; 12-week intervention period of daily placebo in combination with standard treatment of 5-15 mg daily norethindrone acetate	Drug: Norethindrone Acetate; 5 - 15mg daily dose, taken orally; Drug: Placebo; daily placebo pill, taken orally

Outcome Measures

Primary Outcome Measures :

1. Pain Score Area Under the Curve (AUC) [ Time Frame: 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 Outcome Measures :

1. EHP-30 Score [ Time Frame: 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).
2. PGIC Score (Painful Periods) [ Time Frame: 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).
3. PGIC Score (Nonmenstrual Pelvic Pain) [ Time Frame: 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).
4. PGIC Score (Dyspareunia) [ Time Frame: 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).
5. Ibuprofen Use [ Time Frame: 12 weeks ]
   Average # of ibuprofen 200 mg pills per week during the study treatment period
6. Oxycodone Use [ Time Frame: 12 weeks ]
   Number of subjects who used oxycodone at any time during the study

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Endometriosis is specifically associated to females.
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, Pennsylvania

Penn State Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

Sponsors and Collaborators

Milton S. Hershey Medical Center

Investigators

• Principal Investigator: Kristin Riley, MD; Milton S. Hershey Medical Center

  Study Documents (Full-Text)

Documents provided by Kristin Riley, MD, Milton S. Hershey Medical Center:

Study Protocol and Statistical Analysis Plan  [PDF] April 15, 2022

More Information

• Responsible Party: Kristin Riley, MD, Asst. Professor of Obstetrics and Gynecology, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT03970330
• Other Study ID Numbers: Study00011187
• First Posted: May 31, 2019
• Results First Posted: November 3, 2022
• Last Update Posted: November 3, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Participant data will be shared that underlie the results reported in this article, after deidentification. Documents that will be available are the study protocol, statistical analysis plan, informed consent. Analyses is to achieve the study aims in the approved proposal.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Data will be available one year after publication according to PMCID journal guidelines.
• Access Criteria: Data will plan to be published in a peer-reviewed journal and /or posted at clinicaltrials.gov websites or other websites per request of the NIH. Materials will also be accessible through email contact of Primary Investigator.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kristin Riley, MD, Milton S. Hershey Medical Center:

endometriosis; pelvic pain; opioid; narcotic

Additional relevant MeSH terms:

Endometriosis; Naltrexone; Norethindrone; Norethindrone Acetate; Alcohol Deterrents; Narcotic Antagonists; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents; Contraceptives, Oral, Hormonal; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Hormonal; Contraceptives, Oral, Synthetic