Conditions: Endometriosis
Keywords: endometriosis pelvic pain opioid narcotic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

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).

Arms:
arm 1: 12-week intervention period of 4.5 mg daily naltrexone in combination with standard treatment of 5-15 mg daily norethindrone acetate arm 2: 12-week intervention period of daily placebo in combination with standard treatment of 5-15 mg daily norethindrone acetate

Interventions: intervention 1: Naltrexone intervention 2: Norethindrone Acetate intervention 3: Placebo
Intervention descriptions: intervention 1: 4.5mg daily dose, taken orally intervention 2: 5 - 15mg daily dose, taken orally intervention 3: daily placebo pill, taken orally

Protocol document:
Prot_SAP_000.pdf: 
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HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol 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.
Principal Investigator:
Name: Kristin Riley, MD  
Department: Obstetrics and Gynecology Division of Minimally Invasive Gynecology Surgery 
E-mail Address: kriley@pennstatehealth.psu.edu 
Version Date:
April 15, 2022
Clinicaltrials.gov Registration #:
NCT03970330
Important Instructions for Using This Protocol Template:
1.
Add this completed protocol template to your study in CATS IRB (http://irb.psu.edu) on the “Basic Information” 
page, item 7. 
2.
This template is provided to help investigators prepare a protocol that includes the necessary information needed 
by the IRB to determine whether a study meets all applicable criteria for approval. 
3.
Type your protocol responses below the gray instructional boxes of guidance language.  If the section or item is 
not applicable, indicate not applicable.
4.
For research being conducted at Penn State Hershey or by Penn State Hershey researchers only, delete the 
instructional boxes from the final version of the protocol prior to upload to CATS IRB (http://irb.psu.edu).  For all 
other research, do not delete the instructional boxes from the final version of the protocol.
5.
When making revisions to this protocol as requested by the IRB, please follow the instructions outlined in the Study 
Submission Guide available in the Help Center in CATS IRB (http://irb.psu.edu) for using track changes. 
If you need help…
University Park and other campuses:
Office for Research Protections Human Research Protection Program
The 330 Building, Suite 205
University Park, PA 16802-7014
Phone: 814-865-1775
Fax: 814-863-8699
Email: irb-orp@psu.edu
College of Medicine and Hershey Medical Center:
Human Subjects Protection Office
90 Hope Drive, Mail Code A115, P.O. Box 855
Hershey, PA 17033
(Physical Office Location: Academic Support Building Room 1140)
Phone: 717-531-5687
Fax number: 717-531-3937
Email: irb-hspo@psu.edu
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Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Confidentiality, Privacy and Data Management
10.0
Data and Safety Monitoring Plan
11.0
Risks
12.0
Potential Benefits to Subjects and Others
13.0
Sharing Results with Subjects
14.0
Subject Stipend (Compensation) and/or Travel Reimbursements
15.0
Economic Burden to Subjects
16.0
Resources Available
17.0
Other Approvals
18.0
Multi-Site Research
19.0
Adverse Event Reporting
20.0
Study Monitoring, Auditing and Inspecting
21.0
Future Undetermined Research: Data and Specimen Banking
22.0
References
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1.0
Objectives
1.1
Study Objectives
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 100-point Visual Analogue Scale (VAS) scores and 
2) measure the impact of treatment on quality of life as measured by questionnaires 
including the Endometriosis Health Profile-30 (EHP30) and the Patient’s Global Impression of 
Change (PGIC), and Patient Global Assessments (PGA) specific to pain, dysmenorrhea, and 
non-menstrual pelvic pain. We propose a double-blind placebo-controlled randomized 
clinical trial to achieve the following aims:
Aim 1: Identify the impact of LDN on daily endometriosis associated pain. We hypothesize 
that LDN in combination with standard hormonal suppression of endometriosis will decrease 
endometriosis associated pain reported using the VAS as compared with hormonal suppression 
alone.
Aim 2: Identify the impact of LDN on quality of life among women with endometriosis. The EHP30 and 
PGIC are surveys used to measure quality of life outcomes. We hypothesize that LDN in combination 
with standard hormonal suppression of endometriosis will improve quality of life as compared with 
hormonal suppression alone 
1.2
Primary Study Endpoints
The primary study endpoint is the difference in endometriosis associated pain as reported in daily VAS 
between study groups.
1.3
Secondary Study Endpoints
The secondary study endpoints will include the following quality of life measures: 
1) Patient’s Global Impression of Change (PGIC) surveys 
2) Endometriosis Health Profile-30 (EHP 30) surveys
3) Patient Global Assessment (PGA)- pain, dysmenorrhea, non-menstrual pelvic pain 
Additional secondary outcomes will include pain medication use (opioid and non-opioid).  Subject 
reported daily analgesic use (NSAIDs and opioid) will be recorded and narcotic prescriptions will be 
verified using the state run Prescription Drug Monitoring Program monthly.  Subject reported side 
effects to medications will also be monitored. 
2.0
Background
2.1
Scientific Background and Gaps
Endometriosis is a significant public health problem. It is estimated to occur in 6-10% of the 
general female population.1,2,13 It is defined as the presence of endometrial glands and stroma 
located outside of the intra-uterine cavity.2,14 The primary symptoms of endometriosis are 
debilitating, cyclic pelvic pain and infertility.3,4 The prevalence of endometriosis among women 
with pelvic pain or infertility increases to 40% when compared to their healthy peers. Some 
experts suggest that endometriosis is present in over 70% of women with chronic pelvic pain. 
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The exact cause of endometriosis remains unknown; however, the major mechanism is thought 
to be retrograde menstruation, otherwise known as Sampson’s Theory.1,2 During menses the 
uterine lining, known as the endometrium, breaks down and begins to separate from the 
muscular portion of the uterine cavity.  This process results in bleeding.  The muscular portion 
of the uterus then contracts and expels the endometrial tissue and blood through the cervix 
into the vagina and out of the body.  For many women, a small amount of endometrial tissue 
and blood is expelled in a retrograde fashion through the fallopian tubes and into the 
abdominal cavity.1,2 The blood and endometrial tissue then settle into the dependent parts of 
the pelvis.  This theory is consistent with the clinical presentation of endometriosis, as the most 
common locations of endometriosis are the ovary, the recto-vaginal space, the pelvic sidewall 
along the course of the ureter and the bladder surface.1,2  
Endometriosis implants, although small, can have a major impact on the quality of life for many 
women.  Endometriosis is associated with pain that is disproportionate to cellular injury and 
seems to be hyper responsive to inflammatory processes.1,2,14 In addition, they are responsive 
to the changes in hormone levels, particularly estrogen and progesterone, which fluctuate 
during the menstrual cycle.1,2,4 These hormonal changes along with the significant inflammation 
that occurs immediately before and during menses play a large role in the symptoms of 
debilitating pain experienced by women.  Some women experience similar symptoms during 
other clinical situations leading to inflammation in their pelvis.  For example, constipation, 
diarrhea, or bladder infections are some of the many other causes of significant pain in 
endometriosis patients.
There are many challenges in the diagnosis and management of endometriosis.  Current 
standards require surgery with either pathologic confirmation of biopsied lesions or direct 
visualization of “classic” appearing lesions for diagnosis.  Endometriosis is not visualized via any 
current imaging techniques. Blood, urine and other body fluid evaluation cannot provide a 
diagnosis either.  The invasive nature of diagnostic testing often leads to a delay in diagnosis of 
6-11 years among women, including those with symptoms highly suggestive of endometriosis. 
Unfortunately, this leads to delays in treatment.  
Given the frequent delays in diagnosis, many women also have narcotic pain medications 
incorporated into their treatment plan secondary to the severity and recurrent nature of 
endometriosis-associated pain.1,3,9,15 This often occurs with or without a formal diagnosis of 
endometriosis.  Currently, I work at a regional referral center for the management of 
endometriosis.  Many patients present to our clinic already have been exposed to narcotic pain 
medications prior to their initial consultation.
Current literature reports that in 2014 alone US retail pharmacies dispensed 245 million 
prescriptions for opioid based narcotic pain relievers.15 Three to four percent (9.6-11.5 million) 
of the adults in the US population are prescribed long-term opioid therapy.15 Currently, there 
are no published data evaluating the utilization of long-term opioids in the endometriosis 
population.  Secondary to this knowledge gap we evaluated data from a national, longitudinal, 
claims-based database to evaluate opioid use in endometriosis patients.  We identified 706, 
863 women meeting inclusion criteria that had the diagnosis of endometriosis and also had at 
least 1 year of continuous data prior to and 2 years of continuous data following the diagnosis 
of endometriosis.  We found several strong correlations between endometriosis and opioid 
use.  Among women with endometriosis not only was there a significant increase in the 
percentage of subjects getting a prescription for opioids (56.3% vs 34.5%) in endometriosis 
patients vs. controls, but women with endometriosis who received opioids were more likely to 
receive multiple prescriptions and had a higher median cumulative dose of opioids that their 
matched controls (manuscript in preparation).  Due to the growing opioid epidemic and the 
limited effective treatments for endometriosis related pain, there is a dire need to understand 
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the extent of opioid utilization in this patient population.  We must continue to work to 
develop effective non-opioid based treatments that alleviate endometriosis-associated pain 
symptoms and decrease the use of narcotic pain medications for endometriosis. 
Naltrexone is an opioid antagonist that is FDA approved for the treatment of opioid and alcohol 
dependence.  Naltrexone is thought to act through competitive antagonism at the level of 
opioid receptors in the central nervous system.6,5 Naltrexone is absorbed orally and 
metabolized into its active metabolite 6-beta-naltrexone during its first pass through the liver.5 
It is widely distributed throughout the body giving it great bioavailability.  Naltrexone is 
primarily excreted in urine.5 There is emerging evidence that when used at a significantly 
reduced dose (approximately 1/10 the dose traditionally prescribed), naltrexone has different 
pharmacologic effects.6,5 Low dose naltrexone (LDN) has been used and studied in other 
chronic conditions.  Most of the data are related to multiple sclerosis, Crohn’s disease, and 
fibromyalgia.6,5 Current literature reports that LDN is well tolerated with minimal side effects.  
The most common side effect reported was vivid dreams.5 There is still a significant lack of 
randomized controlled trials for LDN use in any condition; however, both animal and human 
studies have demonstrated promising results.  
LDN is thought to function through multiple different mechanisms that would be expected to 
benefit women suffering with the chronic symptoms of endometriosis-associated pain.  Three 
of these mechanisms will be discussed here.  First, LDN causes upregulation of opioid receptors 
and increased endogenous opioid production.6,5,12 Second, it blocks toll-like receptor 4 (TLR4) in 
glial cells found in the central and peripheral nervous system.  Finally, LDN has been 
demonstrated to impact the production of peripheral inflammatory cytokines.
Dr. Ian Zagon and team have done significant amounts of work in this area using rodent 
models.  Their hypothesis of the mechanism of action of LDN is that is causes transient and 
incomplete blockade of opioid receptors.  This phenomenon has been demonstrated with both 
naltrexone and naloxone in multiple studies.  The consequence of exposure to LDN has been 
referred to as an opioid rebound effect.  This leads to improved endogenous analgesia through 
increased opioid production and sensitivity.6,5,12,16,17 The concept of inducing a paradoxical 
effect with variable doses of medication acting at opioid receptors is not novel to naltrexone; in 
fact it has been demonstrated previously with low-dose morphine.  Multiple previous studies 
have also demonstrated hyperalgesia in rats when exposed to morphine as low doses.5 The 
effect was routinely described at doses around 1/10 the standard dose given to treat pain.  The 
paradoxical effects of naltrexone also seem to present as doses around 1/10 the standard 
treatment doses.5
It is well know that inflammation is a key component in endometriosis-associated pain.1,2 Non-
steroidal anti-inflammatory medications are considered first line treatment for endometriosis, 
but often fall well short of providing adequate pain control.3,4 Evidence suggests that women 
with endometriosis can be thought of as having a pelvic inflammatory condition.2 Additionally, 
endometriosis lesions are associated with increased peritoneal vascularity and innervation.2 
This is thought to play a significant role in pain. It is hypothesized that the combination of 
increased nerve density along with recurrent inflammatory processes in the female pelvis (e.g. 
menses) cause devastating symptoms often presenting similar to neuropathic pain.1,2,14 The 
evidence that LDN has antagonistic effects on TLR4 in the glial cells suggests that it could be an 
ideal medication choice for endometriosis-associated pain.6,5 Activation of the microglia in the 
central nervous system has been shown to increase inflammatory and excitatory factors leading 
to pain sensitivity as well as other symptoms.  To the contrary, opioids have been shown in 
previous studies to stimulate TLR4 activity leading to opioid induced inflammation.6,5 This may 
be one explanation as to why opioid therapy has not demonstrated improved outcomes with 
chronic use in endometriosis or other chronic inflammatory conditions such as fibromyalgia.  
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These data are further supported by other studies performed using dextro-naltrexone.  This 
stereoisomer of naltrexone is active at the glial cell and not at the opioid receptor.  Dextro-
naltrexone demonstrated both analgesic and neuroprotective properties.5
Most research demonstrating the general anti-inflammatory effects of LDN have been 
completed in animal models, but there are some pilot studies demonstrating this effect in 
humans as well.  Multiple pilot studies have demonstrated decreased levels of inflammatory 
markers in women with fibromyalgia following administration of LDN.5,7,18 Fibromyalgia (similar 
to endometriosis) is considered an inflammatory disorder.  One study demonstrated that 
women with fibromyalgia and an elevated erythrocyte sedimentation rate (ESR), which is a 
serum marker for inflammation, had improved response rates to LDN as compared to women 
with fibromyalgia and a normal ESR.7 A separate 10-week crossover trial using LDN in women 
with fibromyalgia demonstrated significantly decreased plasma concentrations of multiple key 
pro-inflammatory cytokines as well as a 15% reported decrease in fibromyalgia associated 
pain.18
In summary, endometriosis is a devastating disease that impacts nearly 1:10 women in the 
reproductive years or their life.  The pathophysiology of endometriosis is not completely 
understood, however, there is strong evidence that inflammation plays a major role in the 
symptoms associate with endometriosis.  Current strategies for the management of 
endometriosis-associated pain often leave women seeking additional relief in the form of 
opioid-based treatments.  In light of the current opioid epidemic it is important that we 
continue seek non-opioid based therapies that can provide symptomatic relief while we 
continue to try and better understand this debilitating disease.  LDN has gained some 
popularity as an off-label treatment for inflammatory conditions such as multiple sclerosis, 
Crohn’s disease and fibromyalgia, but the literature has nothing to offer in the way of 
significant randomized controlled trials to adequately test the mounting evidence that LDN is 
beneficial in chronic inflammatory conditions to include endometriosis.
2.2
Previous Data
Our preliminary data includes a retrospective analysis of national claims data; we compared narcotic use 
in 706,863 women with endometriosis with age- and region-matched controls without endometriosis. In 
the two years following the diagnosis of endometriosis, 56.3% of women with endometriosis had filled a 
prescription for narcotic pain medication as compared to 34.5% of the controls over a similar two-year 
time frame (manuscript in preparation). It is critical that we find non-narcotic alternatives to symptom 
management for this group of women suffering during what should be the peak of their productive 
years of life.  We do not have preliminary data specific to the use of LDN.  The results of this study would 
potentially serve as preliminary data for future large-scale multi-center studies.  There is sufficient 
preliminary data (for alternative disease states) in the existing literature regarding the safety and 
potential efficacy of LDN to support the further study of LDN.  These studies are also discussed in more 
detail in the background section of the protocol.
2.3
Study Rationale
Naltrexone hydrochloride is a well-known, competitive opioid antagonist traditionally used to treat 
opioid overdose or addiction. At much lower doses, naltrexone has significantly different pharmacologic 
properties. Low-dose naltrexone (LDN) acts on non-opioid receptors in the central nervous system to 
decrease activation of microglial cells and decrease plasma levels of multiple inflammatory cytokines. 
LDN has also been shown to transiently block all three subtypes of opioid receptors (μ,κ,δ) resulting in 
an upregulation of not only opioid receptors, but also increasing endogenous opioid production. Early 
studies of LND in other inflammatory disorders, such as inflammatory bowel disease and fibromyalgia, 
have demonstrated promising results. Since the pelvic pain associated with endometriosis is due in part 
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to increased peritoneal inflammation, LND has the potential to provide non-narcotic analgesic relief by 
decreasing endometriosis-associated inflammation.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
Inclusion

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. 
3.2
Exclusion Criteria
Exclusion

Women that are pregnant, breastfeeding or trying to conceive. 

Patients with chronic daily opioid 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)
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
Subjects will be removed from the study for safety reasons.  Subjects will be evaluated for 
potential negative reactions to study medications at each visit.  Additionally, subjects will be 
advised to contact the study team with any new negative symptoms to arrange evaluation.  
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Additionally, unintended pregnancy during the study period will meet criteria for withdrawal 
from the study.
Withdraw of consent at any time during the study period will also constitute the withdrawal of 
study subjects.
3.3.2
Follow-up for withdrawn subjects
The statistical methods allow for withdraw/screen fails. Subjects will be asked to return the 
study drug to the site if withdrawn or removed from the study. No other safety follow-up 
planned.
If the subject is removed from the study for any of the above reasons, she will receive the 
appropriate treatment based on the decisions of her providing physician team. No further data 
will be collected on these patients.
4.0
Recruitment Methods
4.1
Identification of subjects
Potential subjects will be identified within our Minimally Invasive Gynecological (MIGS) Division 
Outpatient clinic location and others identified as having endometriosis within PennState Women’s 
Health department. We have created an endometriosis database, which we use to screen potential 
subjects that may qualify for this study.  We will also utilize an approved flyer, patient recruitment 
letter, StudyFinder and EIM report request to identify potentially eligible subjects.  In addition, we have 
developed a MIGS Research Patient Form to give clinic patients at their intake to gauge potential 
interest in any current studies within the Minimally Invasive Gynecologic Surgery Division.
4.2
Recruitment process
Subjects will be recruited from various MIGS and Women’s Health clinic locations within Penn State 
Health. Participation will be purely voluntary. Subjects will be compensated for their time and effort. 
Written informed consent will be obtained prior to the study.  We will use a study coordinator to assist 
us with contacting patients for their follow up visits and completing their surveys.
We do not anticipate having any difficulty recruiting these women into the study given our extensive 
experience with this to date.  We are currently one of the highest volume Minimally Invasive GYN 
Surgery groups in the region.  In 2016 we had 2700 patient encounters for endometriosis/female pelvic 
pain.  Additionally, 80% of these encounters involved patients located within 10 counties that included 
Dauphin County and those counties adjacent to Dauphin County within the Penn State Health region.  
The close proximity of the patients will help increase the likelihood of patient participation.  In the past 
12 months has seen 275 new patient consults, with nearly 900 total clinic visits and over 950 surgical 
procedures performed specifically for endometriosis or pelvic pain.
We will meet on a regular basis to discuss how well we are doing with recruitment and retention. We 
have designed an easy to follow study, thus we do not anticipate difficulty with retaining these subjects. 
Based on our previous clinical trials involving women with endometriosis, we assume an 80% retention 
rate and we will recruit an average of 64 subjects per year.
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4.3
Recruitment materials
The PI will monitor recruitment and retention rates for the study monthly to ensure that the goals are 
being met. In addition, we will collaborate with the Penn State Clinical Trials Office and Office of 
Marketing and Communications to promote the study and increase recruitment efforts. IRB approved 
flyers will be hung in our Minimally Invasive GYN Surgery and around campus at approved locations. The 
MIGS Research Patient Form will be given to patients at their clinic visits, collected by clinic staff, and 
then forwarded to study coordinators to contact patients with applicable study information.  Patient 
recruitment letters will be sent to previous study participants with endometriosis who wished to be 
contacted for future research opportunities to start. The letter will also be used to provide study 
information to all identified endometriosis patients within PennState Women’s Health (via EIM request).
We will also utilize StudyFinder, which is an online database that connects interested volunteers with a 
variety of studies, which University researchers are conducting. Visitors can browse by topic or search 
for a keyword to discover available studies at Penn State Hershey Medical Center. StudyFinder is also 
promoted to the community through Web advertising, Google search and billboards. We will also 
register this study at ClinicalTrials.gov. If recruitment and retention are inadequate, we will begin to 
advertise in the broader central Pennsylvania area and with offices known to refer endometriosis 
patients to our practice.
4.4
Eligibility/screening of subjects
When the study team receives information about a potential subject, follow-up is made to verify 
eligibility. If excluded, no further questions are asked and they are thanked for their time. If eligible the 
subject is scheduled for a visit. 
Follow-up includes a phone screen of the potential subject by asking questions such as, ensuring the 
subject is premenopausal and in between the ages of 18 and 45 years old, agree to only use study-
specific analgesic medications during the study and if intolerance to oxycodone and ibuprofen are 
known, agrees to use Norethindrone acetate and either their LARC or other barrier contraception while 
in the study, if the subject plans on becoming pregnant or trying to conceive at any point during the 
study, if the subject has any chronic daily narcotic use and any chronic pain other than endometriosis, 
and verify the subject is able to speak and read English to answer the surveys. We will also confirm that 
the subject is willing and able to be reliably contacted by email for study specific purposes.
If the participant passes the phone screen, the participant will be scheduled for a screening visit. After 
consent and receiving Norethindrone acetate, an email will be sent for the subject to complete the daily 
surveys for next 6-7 days. Upon completion of the surveys, the participant will pass or fail the screening 
process. 
5.0
Consent Process and Documentation
5.1
Consent Process 
 
5.1.1
Obtaining Informed Consent
5.1.1.1
Timing and Location of Consent
In accordance to HRP-090 SOP for the Informed Consent Process, the potential 
subject will be given a copy of the most current approved consent document for 
review in advance. The consent process will take place in a private room setting 
in the clinic or the Clinical Research Center (CRC).  The consent document will be 
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provided for review and discussion will take place. Consent will be obtained 
prior to any study procedures being done. 
5.1.1.2
Coercion or Undue Influence during Consent
The subject will be informed that their participation in the study is voluntary. 
The subject will receive a copy of the consent form to read at home prior to 
making a screening appointment.  At the time of consent, all sections of the 
informed consent will be thoroughly reviewed with the subject and all of the 
subject’s questions will be answered prior to signing. Once all questions have 
been answered and the subject verbalizes understanding of the study and its 
requirements and agrees to participate, the subject and coordinator sign the 
consent form. A copy of the signed consent form is provided to the subject. 
5.1.2
Waiver or alteration of the informed consent requirement
A waiver of the consent process is requested for recruitment purposes in pre-screening the 
medical record to identify eligible subjects for the study. The pre-screening is a phone screen of 
the potential subject to ask questions such as, ensuring the subject is premenopausal and in 
between the ages of 18 and 45 years old, agree to only use study-specific analgesic medications 
during the study and if intolerance to oxycodone and ibuprofen are known, agrees to use oral 
contraceptive Norethindrone acetate and other barrier contraception while in the study, if the 
subject plans on becoming pregnant or trying to conceive at any point during the study, if the 
subject has any chronic daily narcotic use and any chronic pain other than endometriosis, and 
verify the subject is able to speak and read English to answer the surveys. This ensures that we 
are giving the right subject a scheduled screening visit. 
5.2
Consent Documentation
5.2.1
Written Documentation of Consent
In accordance to HRP-091 SOP for Written Documentation of Consent,  The consent form will be 
the most currently approved watermarked version and in a language understandable to the 
subject.  All appropriate signatures will be obtained; one copy will be given to the subject and 
another will be place in the medical record. 
5.2.2
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.)
Not applicable. 
5.3
Consent – Other Considerations 
5.3.1
Non-English Speaking Subjects
Not applicable. Subjects who do not speak English will not be enrolled due to the need to 
consent and surveys are all in English, which would require the subjects to read and speak 
English. 
5.3.2
Cognitively Impaired Adults
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5.3.2.1 Capability of Providing Consent
Not applicable
5.3.2.2
Adults Unable To Consent
Not applicable 
5.3.2.3 Assent of Adults Unable to Consent
Not applicable
5.3.3
Subjects who are not yet adults (infants, children, teenagers) 
5.3.3.1 Parental Permission
Not applicable
5.3.3.2 Assent of subjects who are not yet adults
Not applicable
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
 
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1 Plan to protect PHI from improper use or disclosure
Information is included in the “Confidentiality, Privacy and Data Management” 
section of this protocol.
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6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers 
Subjects who are identified through review of PHI will be contacted and offered 
information about the study. If they are not interested, we will not keep any of 
their PHI on any paper or electronic screening logs, they will only be identified by 
initials and date they were contacted. Those who do agree to participate will have 
their PHI retained as described for this study.
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
This protocol has strict and specific inclusion/exclusion criteria for subjects to qualify.  Access to 
PHI in the medical record of a potential subject is necessary to assess eligibility prior to giving 
study information and the consent process.  Discussion about the research will take place only if 
the patient appears to be eligible based on pre-screening efforts. 
6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
The waiver is requested during pre-screening efforts and pre-enrollment to assess and identify 
only those women potentially eligible as well as the ability of the patient to be compliant to 
daily surveys. 
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations. 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
We propose to conduct a randomized double-blind placebo-controlled trial to evaluate the 
effectiveness of low-dose naltrexone (4.5 mg daily) in combination with a standard treatment 
(norethindrone acetate daily) on management of endometriosis-associated pain.  Potential 
subjects will be screened in the Penn State Minimally Invasive GYN Surgery clinic for 
endometriosis-associated pain for greater than 6 months.  Subjects will be screened from new 
and existing patients in the Minimally Invasive GYN Surgery clinic as well as from referral sites 
including surrounding general OBGYN and Primary Care practices.  Those meeting all inclusion 
and exclusion criteria that are willing to participate will receive a detailed history and physical 
exam.  Baseline survey data will be collected and entered into the RedCap secured database.  
At this time subjects will be set up for daily emails to complete VAS scores directly into RedCap.  
The first visit will be scheduled 1 week following the screening visit.
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During the first visit subjects will be screened for daily reporting compliance.  Subjects having 
completed 5 or fewer daily VAS scores and surveys during the baseline collection will be offered 
one additional 7-day period to improve compliance.  If at the conclusion of the second 7-day 
run-in period of gathering daily baseline VAS scores and survey responses they continue to 
have 5 or fewer entries per week they will be considered a screen failure and withdrawn from 
the study.  Those subjects meeting the 6 entry or more threshold of daily reporting at either 
visit 1 or following the second 7 day run in period will be randomized in the study.  
Randomized subjects will receive norethindrone acetate 5 mg (up to 15 mg depending on 
subject’s needs) daily plus LDN 4.5 mg daily or norethindrone acetate 5 mg (up to 15 mg) daily 
plus placebo.  If the subject is taking norethindrone acetate prior to the study, she will remain 
on her current dose to start the study. Dose adjustments will be made, if needed, to achieve 
amenorrhea or minimize uterine bleeding. Menstrual status will be assessed and documented 
in a progress note if this should occur either in person at a study visit or via telephone in the 
interim. Norethindrone acetate is provided in 5mg tablets; if dosing adjustment is needed, the 
study staff will arrange to ship additional study drug via FedEx.
The study will include a 12-week intervention period during which subjects will be asked to 
record daily electronic VAS scores, report daily analgesic use (NSAIDs and opioids) and 
complete surveys every 4 weeks.  VAS scores will be reported daily. Patient Global Impression 
of Change (PGIC), Patient Global Assessments (for pain, dysmenorrhea, nonmenstrual pelvic 
pain and function) (PGAs) and Endometriosis Health Profile-30 (EHP 30) surveys will be 
completed at 4-week intervals during the intervention (0, 4, 8, and 12 weeks).  Subjects will be 
asked to complete a brief telephone interview visit at 16 weeks to complete final quality of life 
surveys (EHP 30, PGAs and PGIC).
Subjects will be screened for side effects and asked to record pain medication use throughout 
the duration of the study. Subjects will be dispensed a 4-week supply of medications from the 
Investigational Pharmacy. They will be required to bring medication bottles to each visit for 
counting and drug accountability.  Any remaining capsules will be returned to the pharmacy.  
All study subjects and investigators will remain blinded to the study group until the completion 
of the study. In the event subjects cannot attend study visits in-person due to extenuating 
circumstances (e.g. related to COVID-19 pandemic), remote visits can be completed via 
telephone for which questionnaires will be sent via REDcap and IDS will ship of study drug. Drug 
accountability and monitoring for side effects can also be done via telephone.
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7.2
Study Procedures
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Visit Table Summary of Study Procedures
 (*) – these asterisked visits can be done remotely via telephone, if warranted due to extenuating circumstances.
7.2.1
Screening visit:
Screening Visit 1: 
Pre-screening will take place over the phone with women identified as potential candidates for 
study participation via clinic visits or other previously discussed methods of subject recruitment.  
Initial contact will be made via the telephone to assess women’s interest in participation. As per 
standard of care, narcotic usage is assessed during routine clinic visits. 
If the subject meets all pre-screening criteria, the subject will be scheduled for a screening visit. At 
the screening visit, the informed consent will be reviewed and the subject will be given ample time 
to ask any questions or concerns about the study. Once informed consent is signed, the subject 
information will be placed in redcap and a test email will be sent to the subject. Those meeting all 
inclusion and exclusion criteria that are willing to participate will receive a detailed past medical 
history and physical exam. Baseline surveys and any adverse events will be collected and 
entered into the RedCap secured database.  
The subject will complete the WERF survey, VAS score, EHP-30 and PGAs during the visit to ensure 
understanding and allow the coordinator to help with any questions. The subject will be given a 2 
week supply of Norethindrone acetate to start during the run-in period and given instruction on 
how to complete the daily VAS scores and study questions. It will be explained to the subject that 
they must complete at least 6 out of the 7 days of surveys to be enrolled into the study. If the 
subject is unable to complete the 6 out of 7 days of surveys, the subject will be given one additional 
week to determine if compliance is attainable. (This will ensure provide ample opportunity for 
Procedure
Pre-
screen
Screening 
Visit
(beginning of 
Run-in week)
Visit 1
Enrollment – 
Randomization
(Day 1)
Visit 2*
4-weeks
(Day 28-
30)
Visit 3*
8-weeks
(Day 56-
58)
Visit 4*
12-weeks
(Day 84-
86)
Visit 5
16-weeks 
Phone f/u
(Day 114-
121
Screening Criteria
X
Informed Consent 
X
WERF Questionnaire
X
Physical 
X
Past Medical History
X
EHP-30 
X
X
X
X
X
X
PGIC
X
X
X
X
PGAs
X
X
X
X
X
X
Study Drug Dispensed & 
Compliance 
X (Only 
Norethindrone 
Acetate given, 
if needed)
X
X
X
X
Daily Pain, Analgesic 
and Study  
Medication 
Assessment
X (6-7 days)
X (Daily)
X 
(Daily)
X (Daily)
X (Daily)
X (Daily)
Screening/Assessment 
of Adverse Events
X
X
X
X
X
X
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enrollment for potential subjects with unpredictable barriers to completion in the first 7 days.)  If 
the subject is unable to do so, they will be a screen fail.  Those completing greater than or equal to 
6 entries in either of the 7-day periods will be eligible for enrollment in the study.  In the event of 
needing an additional 7-day run-in period, data points during the screening period will not be 
assessed in aggregate for eligibility.   
7.2.2
Study Visit 1: Randomization/ Enrollment 
The subject will be scheduled for a randomization/ enrollment visit one week after the screening visit. 
At this visit, the subject will be randomized into group A or B by IDS as long as the subject has met all 
the criteria for enrollment.  This study will compare low dose naltrexone with a placebo, or sugar pill.  
Both study groups will receive norethindrone acetate for treatment of their endometriosis during the 
study period.  Dosing for norethindrone acetate will be 5 mg to 15 mg depending on the subject’s 
needs and will be adjusted as needed to achieve amenorrhea or minimize uterine bleeding as this 
standard treatment for endometriosis. The 2 groups are listed below:
Group
Treatment
A
Norethindrone acetate (daily) + Placebo (4.5 mg daily)
B
Norethindrone acetate (daily) + Naltrexone (4.5 mg daily)
The subject will be given 1-month supply of Norethindrone acetate and 1-month (30 day) supply of 
study medication and instructed to take it once a day. The subject will take the first dose of study 
drug in clinic with study personnel present.
Study subjects will receive education on analgesics approved for use in the study which are also 
within the standard of care for the management of pelvic pain associated with endometriosis.  As 
standard of care for these patients, study subjects will be instructed to take ibuprofen as first time 
treatment and acetaminophen if additional pain relief is needed, both of which are available over the 
counter. Only if requested will a stronger medication be prescribed like oxycodone.   If needed, to 
relieve pain, the subject will be advised to take first the ibuprofen 600 mg every 6 hours as needed 
for pain with food, then acetaminophen 1000mg every 6 hours as needed for pain. Subjects needing 
additional pain relief will need to discuss this with the study team in which oxycodone 5 mg every 6 
hours as needed for pain will be prescribed. Refill prescriptions for opioid pain medication will be 
provided using the same dose and quantity beyond the screening visit on an as needed basis and will 
not be routinely provided at any subsequent study visits unless there is a documented need.  The 
subject will complete an EPH-30 and PGAs surveys at the visit. The subject will be instructed to 
complete their daily surveys which include the VAS and medication compliance. We will also review 
and record any adverse events.  At this time, we will also review compliance of daily reporting since 
the previous visit.  Surveys will be sent via email through a secure link with RedCap and completed 
on-site during the visit.   
7.2.3
Study visit 2: 4-week treatment 
The subject will return in 4 weeks for a follow up visit. At this visit the subject will be given time 
to ask any questions or concerns they may have had over the past 4 weeks. The subject’s 
compliance with daily surveys and medication compliance will be reviewed. The subject’s 
medications will be counted and returned if needed. 
The subject will be given another 1-month supply of Norethindrone acetate and 1-month supply of 
study medication.  They will be instructed to take each once a day. To relieve pain, the subject will 
be advised to take Ibuprofen and acetaminophen as needed and oxycodone (if applicable). The 
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subject will complete the EPH-30, PGAs and PGIC survey prior to being discharged from the visit.  
We will also review and record any adverse events.  The subject will be instructed to complete their 
daily surveys which include the VAS and medication compliance.  Surveys will be sent via email 
through a secure link with RedCap and completed on-site during the visit.   
7.2.4
Study visit 3: 8-week treatment 
The subject will return in 4 weeks for a second follow up visit. At this visit, the subject will be 
given time to ask any questions or concerns they may have had over the past 4 weeks. The 
subject’s compliance with daily surveys and medication compliance will be reviewed. The 
subject’s medications will be counted and returned if needed. 
The subject will be given another 1-month supply of Norethindrone acetate and 1-month supply of 
study medication and instructed to take it once a day. To relieve pain, the subject will be advised to 
take Ibuprofen and acetaminophen as needed and oxycodone (if applicable).. The subject will 
complete the EPH-30, PGAs and PGIC survey prior to being discharged from the visit.  We will also 
review and record any adverse events.  The subject will be instructed to complete their daily 
surveys which include the VAS and medication compliance. Surveys will be sent via email through a 
secure link with RedCap and completed on-site during the visit.   
7.2.5
Study visit 4: 12-week treatment 
The subject will return in 4 weeks for a final follow up visit. At this visit the subject will be given 
time to ask any questions or concerns they may have had over the past 4 weeks. The subject’s 
compliance with daily surveys and medication compliance will be reviewed. The subject’s 
medications will be counted and collected as the treatment period is completed. The subject will 
complete the EPH-30, PGAs and PGIC survey prior to being discharged from the visit. We will also 
review and record any adverse events.  The subject will be instructed to complete their daily survey 
which is the VAS and pain medication consumption. Surveys will be sent via email through a secure 
link with RedCap and completed on-site during the visit.  
Subjects will be offered continuation of norethindrone acetate daily and a prescription for this 
medication will be provided if needed as continued management of endometriosis at the conclusion 
of the study.   No additional study medication will be provided at this visit.  Subjects will be asked to 
continue to complete daily reports throughout the next 4-week period to assess symptoms following 
discontinued use of the study drug.
7.2.6
Follow up phone visit: 4-weeks after completion of study medication. 
The subject will receive a follow-up phone call from the study coordinator 4 weeks after the 
completion of the study medication. At this visit the subject will be given time to ask any 
questions or concerns they may have had over the past 4 weeks. The subject’s compliance with 
daily surveys will be reviewed. The subject will be emailed the EPH-30, PGAs and PGIC surveys 
via email through a secure link with RedCap. We will also review and record any adverse events.  
The subject will be thanked for participating in the study.   
7.3
Duration of Participation
16 weeks 
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7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
Naltrexone is an opioid antagonist that is FDA approved for the treatment of opioid and alcohol 
dependence. Naltrexone is thought to act through competitive antagonism at the level of opioid 
receptors in the central nervous system.6,5 Naltrexone is absorbed orally and metabolized into its 
active metabolite 6-beta-naltrexone during its first pass through the liver.5 It is widely 
distributed throughout the body giving it great bioavailability. Naltrexone is primarily excreted in 
urine.5 There is emerging evidence that when used at a significantly reduced dose 
(approximately 1/10 the dose traditionally prescribed), naltrexone has different pharmacologic 
effects.6,5 Low dose naltrexone (LDN) has been used and studied in other chronic conditions. 
Most of the data are related to multiple sclerosis, Crohn’s disease, and fibromyalgia.6,5 Current 
literature reports that LDN is well tolerated with minimal side effects. The most common side 
effect reported was vivid dreams.5
7.4.2
Treatment Regimen
Arm A:  Placebo: In Arm A, the participant will be placed on the daily placebo and standard 
endometriosis treatment (norethindrone acetate 5 to 15mg daily dose) medication. All 
medications will be taken orally.  Pill counts (or case packet counts) will be monitored at each in 
patient study visit. Norethindrone will be taken for up to 14 weeks during the study period and 
the study drug will be taken for up to 12 weeks during the study period.
Arm B: Low dose naltrexone:  In Arm B, the participant will be placed on daily low dose 
naltrexone (4.5 mg daily) and standard endometriosis treatment (norethindrone acetate 5 to 
15mg daily dose). All medications will be taken orally.  Pill counts (or case packet counts) will be 
monitored at each in patient study visit.  Norethindrone will be taken for up to 14 weeks during 
the study period and the study drug will be taken for up to 12 weeks during the study period.
7.4.3
Method for Assigning Subject to Treatment Groups
Randomization is a critical feature of a clinical trial because it prevents treatment-selection 
biases. The statistician involved in this study will develop the programs necessary for the 
random number generator to create the randomization; however, the final random seeds used 
to generate the randomization scheme will be prepared by a statistician in PSU’s Department of 
Public Health Sciences independent of the study in order to keep this study’s statisticians 
blinded as well. The randomization scheme for this study will use variable-size, random 
permuted blocks to ensure that ensure the number of participants in each treatment arm.  IDS 
will be performing randomization to ensure proper blinding of the study team.  They will also be 
responsible for distributing the study medications according to assigned group as per there 
standard operating procedure.  
7.4.4
Subject Compliance Monitoring
For daily low dose naltrexone or placebo and norethindrone acetate, study team will be 
dispensing study medication on visits. Study team will count study medication on visits. 
Participants are to bring study medication with them to each visit for compliance calculation.  
7.4.5
Blinding of the Test Article
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The naltrexone, norethindrone acetate, and placebo will be provided in individual packets that 
will be identical. The drug will be kept and dispensed in the Investigational Pharmacy at Penn 
State Hershey Medical Center and they will hold the randomization and unblinding key as 
needed.  The investigators and biostatisticians will remain blinded to the allocation sequence 
and patient assignment.
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
The naltrexone, norethindrone acetate, and placebo will be monitored and 
dispensed by our Investigational Drug Services (IDS) Pharmacy. IDS will hold the 
randomization and unblinding key as needed. Participants will be given study 
drug to take one daily as prescribed. 
7.4.6.2
Storage
Stability will be monitored and appropriate storage conditions will be assured by 
IDS Pharmacy.  The drug will be kept and dispensed in the Investigational 
Pharmacy at Pennsylvania State Hershey Medical Center. 
7.4.6.3
Preparation and Dispensing
The Investigational Pharmacy at Penn State Hershey Medical Center will 
dispense the study drug and placebo per institutional policy.
7.4.6.4
Return or Destruction of the Test Article
The Investigational Pharmacy at Penn State Hershey Medical Center will destroy 
returned study drug packets as per institutional policy.
7.4.6.5
 Prior and Concomitant Therapy
All concomitant medications will be documented. There are no prohibited 
medications or therapies throughout the study.
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
We plan to enroll 160 subjects over approximately 3 years of the 5-year study. Based on our previous 
clinical trials involving women with endometriosis, we assume an 80% retention rate and will recruit an 
average of 64 subjects per year (5-6 per month).  We will have access to patients from a referral 
network that in the past 12 months has seen 275 new patient consults, with nearly 900 total clinic visits 
and over 950 surgical procedures performed specifically for endometriosis or pelvic pain.  To maximize 
the success of the proposed study, we will monitor recruitment and retention rates for the study 
monthly to ensure that the goals are being met.  In addition, we will collaborate with the Penn State 
Clinical Trials Office and Office of Marketing and Communications to promote the study and increase 
recruitment efforts.  
We would anticipate a 50% screen failure rate secondary to the requirement of 85% compliance with 
daily electronic reporting during the one week run in period prior to randomization in the study.  We 
have multiple on-going endometriosis studies that have scree-failure rates of less than 10% without the 
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stringent requirement of compliance, however, secondary to the nature of this study design, maximal 
compliance with daily reporting in necessary.  Based on these estimates we would anticipate screening 
320-350 patients to enroll our target of 160 subjects.  
8.2
Sample size determination
The primary outcome will be the average area under the curve (AUC) as determined by the daily VAS 
scores collected per participant over the course of the trial. Previous studies have demonstrated that a 
10 mm change in VAS scores and demonstrated a standard deviation of 20 mm. Using these previously 
published data as a guide for our sample size estimation, we believe a standardized effect size (i.e., the 
difference in the AUC VAS score means between the two intervention groups divided by the standard 
deviation) of 0.5 will be clinically relevant to detect. Furthermore, based on our prior research with 
endometriosis patients, we anticipate a withdrawal rate of 20%. Therefore, we propose a target sample 
size of 160 (80 per intervention) randomized participants for this trial.  Such a sample size yields 80% 
statistical power with a two-sided, 0.05 significance level test to detect a standardized effect size of 0.5, 
while accounting for the 20% withdrawal rate. The true statistical power actually may exceed 80% 
because our statistical methodology will include partial data for those participants who withdraw (up to 
the point in time at which they withdraw).
8.3
Statistical methods
The VAS scores will be collected daily from 1-week pre-intervention to 12 weeks post-
intervention. Prior to analysis, the AUC VAS scores will be calculated per participant separately 
for the 1-week pre-intervention period and the randomization to 12 weeks post-intervention 
period. Subsequently, the AUC VAS score data will be normalized per participant to an average 
AUC VAS score per week (i.e., 7 days) to account for participants that withdraw early from the 
study.  The primary outcome of interest is the AUC VAS scores from randomization to 12 weeks 
post-intervention period. For this primary outcome, a linear mixed-model will be used to 
compare the average AUC VAS scores from randomization to 12 weeks post-intervention 
between the two intervention groups, adjusting for the covariate of opioid intake during the 
12-week trial as measured in morphine equivalent units (MEUs)) and using the subject as a 
random effect in the model. 
A secondary analysis with AUC VAS scores as the outcome will use a linear mixed-effects model 
having intervention group, the repeated factor of time period (1-week pre-intervention and 
randomization to 12 weeks post-intervention), the interaction of intervention group and time 
period, and the covariate of opioid intake during the trial as fixed effects and the participant as 
a random effect. Contrasts will be constructed from this mixed model to compare within and 
between the intervention groups with respect to AUC VAS scores. Similarly, linear mixed-effects 
models will be used to compare the two interventions over time with respect to the outcomes 
of PGIC and EHP30 which are collected at 4-week intervals over the course of the trial.  Another 
secondary analysis will fit a linear random coefficients model to the weekly VAS scores (i.e., not 
AUC) to generate linear trajectories for each intervention group, adjusting for the covariate of 
opioid intake. From these trajectories, estimates for the rate of change (i.e., slope) over time in 
VAS scores will be compared between the two intervention groups. In the event linear 
trajectories do not fit the data well, higher order polynomials (e.g., quadratic) will be 
considered to estimate the curve trajectory per intervention.
9.0
Confidentiality, Privacy and Data Management 
9.1
Confidentiality
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9.1.1
Identifiers associated with data and/or specimens
See HRP-598 Research Data Plan Review Form
9.1.1.1 Use of Codes, Master List
See HRP-598 Research Data Plan Review Form
9.1.2
Storage of Data and/or Specimens
See HRP-598 Research Data Plan Review Form
9.1.3
Access to Data and/or Specimens
See HRP-598 Research Data Plan Review Form
9.1.4
Transferring Data and/or Specimens
See HRP-598 Research Data Plan Review Form
9.2
Subject Privacy
See HRP-598 Research Data Plan Review Form
10.0 Data and Safety Monitoring Plan
10.1
Periodic evaluation of data
Adverse event reporting will be reviewed at regular research meetings led by principle investigator.   
Annual reports will be made to the Penn State IRB as per the current protocol.
10.2
Data that are reviewed
Adverse events are defined as unfavorable medical changes that occur during or after the study 
initiation, that may or may not be related to or caused by study participation. Adverse events are not 
procedures or surgeries (the medical condition that caused the need for the procedure or surgery is the 
adverse event or pre-existing conditions or illnesses that do not worsen during the study period. The 
intensity of the event will be evaluated and recorded as one of the following:
Mild intensity – events may or may not be volunteered by the patient. The patient is aware of 
the event but it is easily tolerated.
Moderate intensity – signifies discomfort sufficient to interfere with normal activities. A change 
in therapy may or may not be indicated.
Severe intensity – side effects are almost always brought up by the patient, definitely interfere 
with functioning, and require a medical intervention.
The investigator will be obligated to pursue and provide information as requested by the FDA, when 
applicable. In general, this will require a description of the event in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible causality. 
Information on other possible causes of the event, including concomitant medications and illnesses, 
must be provided. The investigator’s assessment of causality must also be provided. If causality is 
unknown, it should be attributed to study participation. The certainty of the relationship of the event to 
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study participation will be recorded as “Possible Related” or Not Possibly Related.” The situation 
surrounding the event should be assessed to determine whether it is related to the study.
10.3
Method of collection of safety information
Study data will be managed using REDCap (Research Electronic Data Capture), a secure web application 
designed to support data capture for research studies, providing user-friendly web-based case report 
forms, real-time data entry validation (e.g., for data types and range checks), audit trails, a 
randomization module, and a de-identified data export mechanism to common statistical packages 
(SPSS, SAS, Stata, R/S-Plus). 
Well-designed data collection forms (i.e. CRFs) will be developed to minimize data collection and 
recording errors.  Separate data collection forms will be designed based on who is collecting the data 
and when and where the data are collected. Forms will be designed to collect cumulative information 
such as adverse events and the use of concomitant medications.
  
10.4
Frequency of data collection
All data collection will begin immediately upon enrollment.
10.5
Individuals reviewing the data
The PI will receive immediate notification of all serious adverse events, and a regular report 
summarizing recruitment and all other adverse events.   The required offices will be notified 
immediately of SAEs as per our safety plan and a summary of the reported adverse events will be 
presented per policy.
10.6
Frequency of review of cumulative data
Refer to section 10.5 
10.7
Statistical tests
Refer to section 10.2 
10.8
Suspension of research
Not applicable 
11.0 Risks
Risks of Norethindrone: Serious adverse reactions with the use of norethindrone are serious 
cardiovascular events and stroke, vascular events, and liver disease. Adverse reactions commonly 
reported by norethindrone users are: Irregular uterine bleeding, nausea, breast tenderness, and 
headache
Risks of Low Dose naltrexone: Adverse reactions to low dose naltrexone can include hepatotoxicity, 
depression and suicidality, allergic reactions, eosinophilic pneumonia, muscle cramps, dizziness or 
syncope, somnolence or sedation, decreased appetite, and insomnia. 
Everyone taking part in the study will be watched carefully for side effects; however, doctors do not 
know all the discomforts and risks that may happen.  With all drugs there is the possibility of 
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complications and side effects that are not known at this time.  These may be mild or serious, and in 
some cases may be very serious, long-lasting, or may never go away.  There is also a risk of death.
If you experience any side effect (or other health issues) during this study, let your study doctor know 
immediately.  If you are not honest about your side effects, you may harm yourself by staying in this study.  
If you do not understand what any of these side effects mean, please ask the study doctor or study staff 
to explain the words to you.
Common side effects of naltrexone at higher doses include:

Nausea, vomiting, diarrhea or constipation

Stomach pain or cramping

Loss of appetite

Headache

Dizziness

Nervousness, irritability, or anxiety

Tearfulness

Increased or decreased energy
This study plans on using low dose naltrexone at a much lower dose than typically available. Multiple 
studies have used similar doses of naltrexone (3 – 4.5 mg) in both adult and children with no significant 
adverse reactions.  There is no evidence reported of interactions of low dose naltrexone with other 
medications. The most commonly reported side effects in studies using low dose naltrexone include:

Difficulty falling and/or staying asleep (insomnia)

Vivid dreams

Headaches.
Though it is an uncommon event, there is a risk of unexpected allergic reaction to the study drug which 
may include hives, rash, swelling or difficulty breathing. If one of the mentioned symptoms appears, stop 
taking your study drug(s) and seek immediate medical help.
Risk of Loss of Confidentiality: There is a slight risk of loss of confidentiality associated with participation 
in the study. To mitigate this risk, all subjects will be assigned a unique study ID that will be used 
throughout the study to identify each subject. The list linking identifiable information from the study ID 
will be maintained in the REDCap database designed for this study. REDCap uses secure passwords and 
access to the database would be restricted to study personnel.
12.0 Potential Benefits to Subjects and Others
12.1
Potential Benefits to Subjects
The potential benefits to subject may be a decrease in pain and narcotic use.
12.2
Potential Benefits to Others
Endometriosis is a devastating disease that impacts nearly 1:10 women in the reproductive years or 
their life. The pathophysiology of endometriosis is not completely understood, however, there is strong 
evidence that inflammation plays a major role in the symptoms associate with endometriosis. Current 
strategies for the management of endometriosis-associated pain often leave women seeking additional 
relief in the form of opioid-based treatments. In light of the current opioid epidemic it is important that 
we continue seek non-opioid based therapies that can provide symptomatic relief while we continue to 
try and better understand this debilitating disease. LDN has gained some popularity as an off-label 
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treatment for inflammatory conditions such as multiple sclerosis, Crohn’s disease and fibromyalgia, 
which can potentially be utilized in endometriosis as well. 
13.0 Sharing Results with Subjects
There is no information for the patient to receive as no diagnostics will be done. 
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements
Subject will receive $25 at the completion of the screening visit and $100 additional at the completion of the 
study for a total of $125.  We will not be providing travel reimbursement as part of this study protocol. 
15.0 Economic Burden to Subjects
15.1
Costs 
All tests and procedures required for participation in the study will be paid for by the sponsor. There are 
no additional costs to subjects participating in the research. Analgesics taken during the study will be 
paid for by the subject and/or her insurance.
15.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers.
16.0 Resources Available
16.1
Facilities and locations
Locations for study visits may include the Penn State Women’s Health Clinic at Hope Drive and the 
Clinical Research Center at the Penn State Hershey Medical Center.
16.2
Feasibility of recruiting the required number of subjects
The PI sees approximately 10 patients each week with endometriosis; approximately 30-40 are seen 
total within the Minimally Invasive GYN Surgery practice.
16.3
PI Time devoted to conducting the research
The PI has dedicated research time and is available to see study patients 2-3 days/week and the co-
Investigator on the study asback up. 
16.4
Availability of medical or psychological resources
Resources will be made available at the Penn State Hershey Medical Center, if warranted.
16.5
Process for informing Study Team
The PI, study coordinator(s) and other study team delegates will complete required study specific 
sponsor training throughout the conduct of the trial. OBGYN Research study team meeting occur on a 
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weekly basis to inform all members of the study status, responsibilities and trainings can take place.  On-
going communication via email and telephone will also take place.
17.0 Other Approvals
17.1
Other Approvals from External Entities
Not applicable 
17.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library.
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or 
gene therapy). 
  Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had 
been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of HRP-901 
- Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library.
  Clinical Research Center (CRC) Advisory Committee– All campuses – Research involves the use of 
CRC services in any way.  
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a copy 
of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library.
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research Center 
Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific Review 
Committee is required if the study involves cancer prevention studies or cancer patients, records and/or 
tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator 
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18.0 Multi-Site Research
18.1
Communication Plans
Not applicable 
18.2
Data Submission and Security Plan
Not applicable 
18.3
Subject Enrollment
Not applicable 
18.4
Reporting of Adverse Events and New Information
Not applicable
18.5
Audit and Monitoring Plans
Not applicable 
19.0 Adverse Event Reporting
19.1
Adverse Event Definitions
For drug studies, incorporate the following definitions into the below responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected adverse 
reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Serious adverse 
event or Serious 
suspected adverse 
reaction
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
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have caused death.
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.  
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified.
19.2
Recording of Adverse Events
Research subjects will be routinely questioned about adverse events at study visits or survey completion 
days. All adverse events (serious or non-serious) and abnormal test findings observed or reported to 
study team believed to be associated with the study drug will be followed until the event (or its 
sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable to the investigator. 
An abnormal test finding will be classified as an adverse event if one or more of the following criteria are 
met:

Test finding is accompanied by clinical symptoms 

Test finding necessitates additional diagnostic evaluation or medical/surgical 
intervention; including significant additional concomitant drug treatment or other 
therapy. 
19.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event.
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
19.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
19.4.1 Written IND/IDE Safety Reports
The Sponsor-Investigator will submit a written IND Safety Report (i.e., completed FDA Form 
3500A) to the responsible new drug review division of the FDA for any observed or volunteered 
adverse event that is determined to be a serious and unexpected, suspected adverse reaction.  
Each IND Safety Report will be prominently labeled, “IND Safety Report”, and a copy will be 
provided to all participating investigators (if applicable) and sub-investigators.
Written IND Safety Reports will be submitted to the FDA as soon as possible and, in no event, 
later than 15 calendar days following the Sponsor-Investigator’s receipt of the respective 
adverse event information and determination that it meets the respective criteria for reporting.
For each written IND Safety Report, the Sponsor-Investigator will identify all previously 
submitted IND Safety Reports that addressed a similar suspected adverse reaction experience 
and will provide an analysis of the significance of newly reported, suspected adverse reaction in 
light of the previous, similar report(s) or any other relevant information.
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Relevant follow-up information to an IND Safety Report will be submitted to the applicable 
review division of the FDA as soon as the information is available and will be identified as such 
(i.e., “Follow-up IND Safety Report”).
If the results of the Sponsor-Investigator’s follow-up investigation show that an adverse event 
that was initially determined to not require a written IND Safety Report does, in fact, meet the 
requirements for reporting; the Sponsor-Investigator will submit a written IND Safety Report as 
soon as possible, but in no event later than 15 calendar days, after the determination was made.
19.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
In addition to the subsequent submission of a written IND Safety Report (i.e., completed FDA 
Form 3500A), the Sponsor-Investigator will notify the responsible review division of the FDA by 
telephone or facsimile transmission of any unexpected, fatal or life-threatening suspected 
adverse reaction. 
The telephone or facsimile transmission of applicable IND Safety Reports will be made as soon 
as possible but in no event later than 7 calendar days after the Sponsor-Investigator’s receipt of 
the respective adverse event information and determination that it meets the respective criteria 
for reporting.
19.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
19.6
Unblinding Procedures
The Investigational Pharmacy at Penn State Hershey Medical Center and they will hold the 
randomization and unblinding key as needed.  The investigators and biostatisticians will remain blinded 
to the allocation sequence and patient assignment. Investigator will have the discretion of unblinding 
the physicians at any time if it is warranted for safety and/or scientific reasons.
19.7
Stopping Rules
The principle investigator will receive immediate notification of all serious adverse events, and a regular 
report, at six month intervals, summarizing recruitment and all adverse events, by treatment in a 
blinded fashion. The principle investigator will meet with research team after the receipt of the 
scheduled reports or after any major serious adverse event.
20.0 Study Monitoring, Auditing and Inspecting
20.1
Study Monitoring Plan
20.1.1 Quality Assurance and Quality Control
The study will be monitored by the Clinical Trial Monitoring Team from the Department of 
Public Health Sciences at Penn State Hershey College of Medicine. The monitors will provide an 
independent review of the regulatory and subject records and the data collected to assure 
compliance with the protocol, GCP, and applicable federal regulations. The monitoring will occur 
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at regular intervals after the enrollment of the first subject and the times will be predetermined 
by the monitoring plan developed by the Clinical Trial Monitoring Team. 
20.1.2 Safety Monitoring
See Section 10.0 for data and safety monitoring plan. 
21.0 Future Undetermined Research: Data and Specimen Banking
21.1
Data and/or specimens being stored
Not applicable
21.2
Location of storage
Not applicable
21.3
Duration of storage
Not applicable
21.4
Access to data and/or specimens
Not applicable
21.5
Procedures to release data or specimens
Not applicable
21.6
Process for returning results
Not applicable
22.0 References
1. 
Giudice LC. Endometriosis. N Engl J Med. 2010;362(25):2389-2398. doi:10.1056/NEJMcp1000274.
2. 
Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 
2012;98(3):511-519. doi:10.1016/j.fertnstert.2012.06.029.
3. 
Practice Committee of the American Society for Reproductive M. Treatment of pelvic pain associated 
with endometriosis: a committee opinion. Fertil Steril. 2014;101(4):927-935. 
doi:10.1016/j.fertnstert.2014.02.012.
4. 
Brown J, Farquhar C. An overview of treatments for endometriosis. JAMA. 2015;313(3):296-297. 
doi:10.1001/jama.2014.17119.
5. 
Patten DK, Schultz BG, Berlau DJ. The safety and efficacy of low-dose naltrexone in the management of 
chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn’s disease, and other chronic 
pain disorders. Pharmacother J Hum Pharmacol Drug Ther. January 2018. doi:10.1002/phar.2086.
6. 
Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory 
treatment for chronic pain. Clin Rheumatol. 2014;33(4):451-459. doi:10.1007/s10067-014-2517-2.
7. 
Younger J, Mackey S. Fibromyalgia Symptoms Are Reduced by Low-Dose Naltrexone: A Pilot Study. Pain 
Med. 2009;10(4):663-672. doi:10.1111/j.1526-4637.2009.00613.x.
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8. 
Gerlinger C, Schumacher U, Faustmann T, Colligs A, Schmitz H, Seitz C. Defining a minimal clinically 
important difference for endometriosis-associated pelvic pain measured on a visual analog scale: 
analyses of two placebo-controlled, randomized trials. Health Qual Life Outcomes. 2010;8(1):138. 
doi:10.1186/1477-7525-8-138.
9. 
Siedentopf F, Sillem M. [Chronic pelvic pain in women]. Schmerz. 2014;28(3):300-304. 
doi:10.1007/s00482-014-1408-4.
10. 
Parkitny L, Younger J. Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone 
for Fibromyalgia. 2017. doi:10.3390/biomedicines5020016.
11. 
Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose 
Naltrexone (LDN). doi:10.1007/s11481-013-9451-y.
12. 
Zagon IS, McLaughlin PJ. Naltrexone modulates body and brain development in rats: A role for 
endogenous opioid systems in growth. Life Sci. 1984. doi:10.1016/0024-3205(84)90563-0.
13. 
Simoens S, Dunselman G, Dirksen C, et al. The burden of endometriosis: Costs and quality of life of 
women with endometriosis and treated in referral centres. Hum Reprod. 2012;27(5). 
doi:10.1093/humrep/des073.
14. 
Burney RO. The genetics and biochemistry of endometriosis. Curr Opin Obs Gynecol. 2013;25(4):280-
286. doi:10.1097/GCO.0b013e3283630d56.
15. 
Longo DL, Volkow ND, McLellan AT. Opioid Abuse in Chronic Pain — Misconceptions and Mitigation 
Strategies. N Engl J Med. 2016;374(13):1253-1263. doi:10.1056/NEJMra1507771.
16. 
Zagon IS, McLaughlin PJ. Naltrexone Modulates Tumor Response in Mice with Neuroblastoma. Science 
(80- ). 1983. doi:10.2307/1691194.
17. 
Zagon IS, McLaughlin PJ. Naltrexone modulates growth in infant rats. Life Sci. 1983. doi:10.1016/0024-
3205(83)90639-2.
18. 
Parkitny L, Younger J. Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone 
for Fibromyalgia. Biomedicines. 2017;5(2):16. doi:10.3390/biomedicines5020016.
19. 
Jenkinson C, Kennedy S, Jones G. Evaluation of the American version of the 30-item Endometriosis 
Health Profile (EHP-30). Qual Life Res. 2008;17(9):1147-1152. doi:10.1007/s11136-008-9403-9.
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