Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06408714 |
| Other study ID # |
UNM24-157 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2024 |
| Est. completion date |
December 31, 2026 |
Study information
| Verified date |
May 2024 |
| Source |
University of New Mexico |
| Contact |
Silas Bussman |
| Phone |
505-272-6370 |
| Email |
sibussman[@]salud.unm.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The goal of this clinical trial is to compare naloxone to nalmefene for the treatment of
opioid overdose in adults. The main questions it aims to answer are:
- Does nalmefene lower the number of doses of medicine participants need to treat opioid
overdose?
- When participants are given nalmefene instead of naloxone, do they have fewer
complications of opioid overdose such as being admitted to the hospital or having a
breathing tube inserted?
Researchers will compare nalmefene to naloxone for the treatment of opioid overdose.
Nalmefene and naloxone are both approved medicines to treat opioid overdose.
Participants who are brought to the emergency department after an opioid overdose will be
given a dose of either nalmefene or naloxone if their breathing slows down again after an
opioid overdose. Participants will:
- Stay in the emergency department for 8 hours after receiving a dose of nalmefene or
naloxone.
- Receive a phone call 7 days after their emergency department to check on how they are
doing.
Background information:
Naloxone (also known as Narcan) and nalmefene are opioid blocking medicines. When someone
overdoses on an opioid, such as heroin or fentanyl, their breathing slows down or stops and
they can die. By giving naloxone or nalmefene, the effect of the opioid can be blocked and
the person can start breathing again. Naloxone is the most commonly used medicine to reverse
an opioid overdose. The effect of naloxone lasts about an hour, and patients may need more
than one dose of naloxone to keep them breathing. Sometimes patients overdose, get a dose of
naloxone and wake up, and then some time later their breathing slows down again and they need
another dose of naloxone. This can happen because the effect of the opioid they took lasts
longer than the effect of the naloxone.
The effect of nalmefene lasts longer than naloxone, about four hours. If a person gets
nalmefene, their opioid may wear off before the nalmefene wears off and they might not need
any more doses of a reversal medicine. Both naloxone and nalmefene are approved medicines for
treating opioid overdose.
Often, when a person overdoses on an opioid, someone gives them naloxone right away and then
they are brought to the emergency department. In the emergency department, they are watched
for several hours to make sure they don't stop breathing again when their naloxone wears off.
If they do stop breathing again, they are given another dose of naloxone. In this study,
participants will be given either nalmefene or naloxone if their breathing slows down while
they are in the emergency department.
Description:
1. Study Design This is an open-label prospective randomized single center study comparing
nalmefene to naloxone in the treatment of recurrent respiratory depression from opioids.
2. Number of Subjects
We will enroll 37 patients in the nalmefene group and 37 patients in the naloxone group,
for a total of 74 patients.
Based upon our feasibility study of naloxone administrations in the ED, 344 patients
received naloxone in the ED during a two-year period (2021-2022), corresponding to
approximately 14 patients per month. (Note that this is likely their 2nd dose of
naloxone, as nearly all patients arrive via EMS and we presume received naloxone by
EMS.) We estimate that 75% of patients who receive opioid antagonist treatment during
EMS transport or shortly after ED arrival will be capable of providing informed consent
in the ED. We estimate that up to 50% may decline to participate. Based on these
parameters, we estimate enrolling 5.4 patients per month or 96 subjects over the 18
month enrollment period.
In our power and sample size analysis we estimated we would need to enroll 62 subjects.
We added a 20% increase in our sample size to account for subjects that might not stay
for the observation period, for a total of 74 patients.
To enroll 74 patients, we will screen 220 patients for eligibility and consent.
Sample size justification:
We conducted power analyses with varying scenarios for a noninferiority clinical trial
comparing nalmefene versus naloxone. For a redosing rate (p1) of 0.33 for naloxone and a
redosing rate (p2) of 0.05 for nalmefene, a significance level (alpha) of 0.025, and a
margin of noninferiority of -0.02, we would need 31 patients in each, respectively. This
would give us a total of 62 patients to achieve a power of 0.8. We will enroll 20% extra
patients, or 37 patients in each group, in anticipation of patients not completing the
observation period or the study, for a total of 74 patients.
3. Study Timelines
- The duration of an individual subject's participation in the research: 7 days
- Initial visit: emergency department visit with observation of 8 hours after
emergency department arrival or until discharge, whichever comes first.
- Second evaluation: phone follow up at 7 days
- The duration anticipated to enroll all subjects: 1.5 years
8. Research Setting Study site: Single center study at the University of New Mexico Hospital
Adult Emergency Department. UNMH is the only academic medical center, Level I trauma center,
and stroke center in New Mexico. UNMH is also the safety net hospital for the greater
Albuquerque area. The UNMH ED saw over 102,000 patients in 2022, of whom ~58,000 were seen in
the adult ED.
Biological samples will be processed by TriCore Laboratories, the contracted laboratory
service for UNM HSC. Xylazine and nitazene testing will be performed at NMS Labs
(nmslabs.com).
9. Resources Available
The UNMH emergency department is staffed 24 hours a day with licensed emergency physicians
("attending physicians"). Attending physicians will be responsible for medical
decision-making and ordering and evaluation of necessary diagnostics and therapeutics for
study participants.
Resources:
The Department of Emergency Medicine maintains a workforce of full-time trained research
staff specializing in research subject identification and recruitment. All staff are trained
in human subject research, good clinical practices and Basic Science Laboratory level 1 and 2
(BSL 1-2) procedures. Staff are able to accommodate regular night and weekend coverage to
ensure adequate staffing to respond to potential subject enrollments.
All study personnel are required to maintain current human subject protections and good
clinical practices certifications and complete and document study specific training and
delegation on study training and delegation logs.
Pharmacy Resources: The UNMH investigational drug service is used in this study. The
investigational drug service allows for the secure storage and dispensation of
investigational drugs in accordance with applicable state and federal regulations and
institutional policies.
Laboratory resources: The UNM HSC Clinical and Translational Sciences Center (CTSC) contract
laboratory will be used for the processing and storage of research samples. The CTSC contract
laboratory provides secure 24-hour access to calibrated continuous temperature monitored
freezers, centrifuge and BSL-2 lab bench space. Quanititative Nalmefene and Xylazine testing
will be performed by NMS labs.
12. Study Procedures
- Screening: Study subjects will be recruited from the University of New Mexico Hospital
Emergency Department. Research Assistants (RAs) will identify patients seen in the ED by
reviewing the electronic medical record (EMR) tracking board, notification by secure
messaging system of arriving patients, and by provider referral.
- Informed Consent: Patients who are determined to meet all inclusion and none of the
exclusion criteria will be approached about informed consent by a trained IRB-approved
study team member. For additional detail on informed consent see Section 21 Consent
Process.
- Enrollment and Randomization: Patients who provide written informed consent are
considered enrolled in the study. Subjects will be asked to complete demographics,
medical history and prior and concomitant medications by survey at the time of
enrollment. Blood Alcohol Content (BAC) will be measured by Breathalyzer. Participants
will then be randomized using the UNM Health Sciences REDCap randomization tool to
either nalmefene or standard care (naloxone) treatment arms. Research staff will be
blinded to randomization.
- Blood Collection: Blood collection for serum testing for co-ingestants, xylazine, and
nitazenes will be performed after enrollment. Blood collection for research testing will
involve no more than 15 mL (1 tablespoon) in up to 3 tubes at one timepoint.
- Subject Follow-Up: RAs will remain present with the patient in the peri-dosing period to
observe and record any adverse events, including any occurrence of precipitated
withdrawal or recrudescence, for no less than 8 hours after emergency department arrival
or until emergency department discharge, whichever comes first. Subjects will be
contacted by phone 7 days (+/- 2 days) after enrollment to assess for recurrence of
opioid overdose symptoms, repeat emergency department visits or hospitalizations and
occurrence of adverse events.
- Data Acquisition: Demographics, medical history and prior and concomitant medications,
adverse events will be collected by subject interview/survey and/or observation in the
ED. All other data elements such as details related to medication, laboratory and
imagining results, diagnosis and information on subsequent discharge and/or
hospitalization or return visit to the emergency department will be captured from the
subjects EMR.
13. Data Analysis Plan We will use an intention-to-treat analysis. For the primary
outcome, we will compare the proportion of subjects experiencing the primary endpoint
(respiratory depression requiring opioid antagonist treatment) using the Newcombe's
method for the difference between two proportions1, adjusted for a non-inferiority
framework as the initial analysis.
As we expect that the time to event (respiratory depression) will differ between the two
treatment arms, we will also compare the risk of recurrent respiratory depression using a
failure time analysis. Failure time analysis (also known as survival analysis) allows us to
assess the risk of a failure event (here, recurrent respiratory depression) while adjusting
for observations that are time dependent and of varying length. Failure time analyses also
correctly account for incomplete observations because of a study ending or loss of subjects
to follow-up (we anticipate that some subjects may not stay for the full observation period).
For the initial analysis, we anticipate using nonparametric techniques, such as Kaplan-Meier
curve estimation and log-rank tests to assess for differences in recurrent respiratory
depression between the two arms. Most frequently, failure time analysis is used in situations
where only one event occurs (such as a diagnostic endpoint, disease cure, or death) and the
subject then is withdrawn from the study. In the proposed study, subjects can experience
multiple failure events (recurrent episodes of respiratory depression) because a rescue
therapy (naloxone or nalmefene) is available. After completing the initial non-parametric
analyses, we propose an additional analysis that will allow us to take advantage of the
likelihood that subjects may have more than one endpoint. Since multiple events can occur
within the same subject, calculation of standard errors and statistical inference need to
account for the correlation between observations in the same individual. The method we
propose using does this precisely and we have used this method for a different
poisoning/antidote study.2,3 With this method, the point estimate of the relative risk is not
affected by the correlation between repeat measurements within the same individual, and
therefore can be calculated using a proportional hazards model. All analyses will use the R
statistical language.
14. Provisions to Monitor the Data to Ensure the Safety of Subjects Data monitor services
will be provided by the University of New Mexico Hospitals Clinical Trials Operations Office
and supervised by Leslie Byatt, BA, CCRC, PCP. The study data monitor is not directly
affiliated with the study.
Safety monitoring will be provided by Snehal Bhatt, MD. Dr Bhatt is an experienced addiction
medicine physician. Dr Bhatt is affiliated with the University of New Mexico School of
Medicine.
All study subjects will be asked to stay in the UNMH Emergency Department for the duration of
the 8 hour observation period. All adverse events will be recorded for the duration of the 8
hour observation period. All adverse event information will be prepared in summary,
deidentified, and provided to the safety monitor on the following schedule for review:
Review 1: After completion of the 3rd subject enrollment (4% of subjects enrolled) Review 2:
After completion of the 10th subject enrollment (14% of subjects enrolled) Review 3: After
completion of the 26th subject enrollment (35% of subjects enrolled) Review 4: After
completion of the 42nd subject enrollment (57% of subjects enrolled) Review 5: After
completion of the 74th and final subject enrollment (100% of subjects enrolled) This safety
monitor review schedule is subject to change in the event that the safety monitor raises
concerns that merit more frequent reviews.
All serious adverse events will be gathered through the day 7 follow-up. In the event of a
serious adverse event (SAE) that is determined to be unexpected and possibly or probably
related to the investigational product, enrollment will be temporarily stopped until the
safety monitor has reviewed and provided recommendations related to ongoing study conduct.
Once any recommendations, if any, have been addressed, the study may continue. Initial SAE
reports have to be reported within 24 hours of the identification of an SAE, follow-up
attempts will be made as needed within 3 days or no later than 14 days from the initial
report, if additional information becomes available this will be processed as per our
procedures. . All SAE's will be followed to resolution. All SAE information will be gathered
in a detailed summary report and transmitted to the safety monitor for review. Only SAEs will
be forwarded to Drug Safety mailbox at AEreport2@pharma.com. The investigator will be using
the following definitions for AEs, SAEs and reportable new information. The SAE report from
will include start and stop date, whether or not it was unexpected, concise identification
according to the Common Terminology for the Categorization of Adverse Events (CTCAE),
detailed narrative description including why it is determine to meet the SAE definition
below, any medical interventions to address the SAE, the events relationship to the study
intervention, and report type (initial, follow-up or final). All SAE's must be reviewed by
the principal investigator prior to submission to the safety monitor for review.
Adverse Event (AE): Any untoward or unfavorable medical occurrence in a human study
participant, including any abnormal sign (e.g. abnormal physical exam or laboratory finding),
symptom, or disease, temporally associated with the participants' involvement in the
research, whether or not considered related to participation in the research.
Serious Adverse Event (SAE): Any adverse event that:
- Results in death
- Is life threatening, or places the participant at immediate risk of death from the event
as it occurred
- Requires or prolongs hospitalization
- Causes persistent or significant disability or incapacity
- Results in congenital anomalies or birth defects
- Is another condition which investigators judge to represent significant hazards
A pregnancy is not by definition an SAE but is handled as an SAE because it is not a
condition that should occur during the clinical trial, requires the subject to be
discontinued from the study, and requires ongoing monitoring of the pregnancy by the PI.
Abnormal pregnancy outcomes are considered as reportable SAEs. SAEs associated with pregnancy
outcome include, but are not limited to:
- Pregnancy losses (e.g., spontaneous abortion, late fetal death, elective termination)
- Life-threatening developments (e.g., placental abruption, fetal distress) • Congenital
anomalies
- Neonatal fatality, any event resulting in maternal hospitalization /prolonged
hospitalization or maternal fatality.
Any female subject who becomes pregnant while participating will be withdrawn from the study
but will be contacted to determine the pregnancy outcome.
The study team will promptly report all unanticipated problems that meet the following
criteria to the UNM HSC HRRC within 5 business days of identification as reportable
information. Defined by DHHS 45 CFR part 46 as any incident, experience, or outcome that
meets all of the following criteria:
- unexpected, in terms of nature, severity, or frequency, given (a) the research
procedures that are described in the protocol-related documents, such as the
IRB-approved research protocol and informed consent document; and (b) the
characteristics of the study population;
- related or possibly related to participation in the research (in this guidance document,
possibly related means there is a reasonable possibility that the incident, experience,
or outcome may have been caused by the procedures involved in the research);
- suggests that the research places participants or others at a greater risk of harm
(including physical, psychological, economic, or social harm) than was previously known
or recognized.
Subjects in the trial will receive clinical care in the UNM Hospital Emergency Department. As
subjects are also patients being treated for the effects of opioid intoxication, all will
receive standard of care. Standard care includes: establishing intravenous access to provide
additional medication to reverse respiratory depression, end-tidal carbon dioxide monitoring,
pulse oximetry, electrocardiographic monitoring, and vital sign monitoring. All subjects will
receive care from the ED treatment team. The ED team consists of a board-certified EM faculty
member, resident physicians, advanced practice providers, emergency medicine pharmacists, and
registered nurses. All subjects in the trial will be treated in appropriate clinical spaces
within the ED. A full spectrum of standard emergency equipment is readily available (e.g.,
airway adjuncts, advanced monitoring, etc.
15. Withdrawal of Subjects The study medical clinician must apply their clinical judgement to
determine if an adverse event is of sufficient severity to require that the participant be
withdrawn from further study participation. The study medical clinician should consult with
the site Principal Investigator, the Co-Investigator, and/or Medical Monitor as needed. If
necessary, a study medical clinician may suspend any trial treatments and institute the
necessary medical therapy to protect a participant from any immediate danger.
A participant may also voluntarily withdraw from treatment due to what they perceive as an
intolerable adverse event or for any other reason. If a voluntary withdrawal is requested,
the participant will be asked to complete an end-of-medication visit to assure safety and to
document end-of-medication outcomes and will be given recommendations for medical care and/or
referrals to treatment as necessary.
A participant may withdraw from any portion of the protocol (e.g. serum collection for
expanded toxicology testing) but complete other aspects of the study.
A participant may withdraw from the study at any time.
16. Data Management/Confidentiality All study data will be stored in accordance with all
applicable state and federal regulations and in accordance with institutional requirements.
All subject source information will be stored N:\Research-Studies network drive.
The research team will have access to the patient's medical record to abstract elements from
the patient's chart relevant to the study, including patient disposition and additional AE
and SAE's and 7 day follow-up data.
Zip codes will not be recorded. Information abstracted as part of the research study will not
include direct patient identifiers (i.e., name, MRN, FIN, address). Subjects will be
identified by a unique study number. A link between the patient's identifying information
will remain secured and stored apart from study data on the N: drive. This data will include
substance abuse information.
Data from this study will not be publicly available.
All study data will be entered into UNM Health Sciences REDcap, a secure web application for
building and managing online surveys and databases. After study closure all data will be
stored in the N:\Research-studies network drive.
All study specimens will be labeled with a unique study ID only and stored only for the
duration of testing described in this protocol. Specimens will not be banked for this study
and will only be accessible to IRB approved members of the study team.
No data will be collected by audio or video recording. Data will not include photographs.
This study is not funded by the NIH. Data will be retained for a period of 6 years from the
date the study is complete and then destroyed. No minors will be included in this study.
17. Data and Specimen Banking Neither data nor specimens will be banked for this study.
18. Risks to Subjects
Study related risks include medication risks, study procedures risks and loss of
confidentiality.
Medication risks associated with the use of naloxone and nalmefene are very similar and may
include precipitation of severe opioid withdrawal, recurrent respiratory and central nervous
system depression, nausea, vomiting, fever, dizziness, headache, chills, and vasodilation
(relaxing/dilation of blood vessels). Other risks associated with reversal of opioid overdose
include cardiac related risks such as pulmonary edema (fluid in the lungs), cardiovascular
instability, hypotension (low blood pressure, hypertension (high blood pressure), tachycardia
(fast heart rate), ventricular fibrillation (irregular heart beat). Risks associated with the
use of nalmefene and naloxone in pregnant people include precipitated withdrawal in the
fetus.
Risks associated with study procedures, which include a study blood draw are minimal. They
include pain, bruising, infection, lightheadedness, fainting, blood clots, and bleeding or
other discomforts at the draw site.
Risks associated with the possible loss of confidentiality may include emotional discomfort
or stress.
19. Potential Benefits to Subjects There are no known benefits to subjects.
20. Recruitment Methods Potential subjects will be identified for participation in the study
after presentation to the UNM ED for suspected acute opioid overdose. Based upon our
feasibility analyses, we expect that most subjects will arrive via EMS. Our dispatch team
uses a secure text messaging system (TigerConnect, https://tigerconnect.com/) to alert
designated staff members of pending patient arrivals based off EMS radio reports. These
messages typically provide a very brief description of the patient and their condition. A
typical message might say: "32 M with RR 4 and sat 80%, now RR 16 and 95% after Narcan. ETA
10 minutes". These messages give the research team the opportunity to proactively identify
potential subjects. We currently use a cadre of trained research assistants to monitor our ED
tracking board and EMS message alerts, and to provide just-in-time reminders to clinical
staff about current studies. We will use these research assistants to aid in subject
identification. These RAs are typically able to consent subjects for most studies. Due to the
acuity of the event and our current crowded ED state, nearly all patients with an opioid OD
requiring active management (supplemental oxygen, BVM, naloxone administration) are moved to
our resuscitation area for rapid assessment and stabilization. Once stabilized, patients can
be relocated to other spaces in the ED.
Potential subjects will be identified by
- Notification of the study team by a treating physician when a potentially eligible
patient presents to the emergency department.
- Research assistants will monitor patient arrival alerts in TigerConnect for potentially
eligible patients.
- Research assistants will monitor the UNMH ED tracking board for potentially eligible
patients.
21. Provisions to Protect the Privacy Interests of Subjects Potential subjects will be
recruited from the UNM ED. Whenever possible, subjects will be approached in a private
setting. The IRB-approved study personnel responsible for approaching the potential
subject about informed consent will be responsible for confirming with the patient that
they are willing to discuss study participation prior to attempting to obtain informed
consent. All study data will be gathered directly from the subject or the subject's
chart in a standard patient care area within the UNMH ED or by phone for the 7 day
follow-up. If the potential patient expresses privacy concerns before or during
participation, it will be the IRB-approved research team member's responsibility to
address that concern to the best of their ability and to document any steps taken to
address these concerns on a study notes page. Study personnel may have limited ability
to address privacy concerns in certain circumstances and if they are unable to address
the potential subject's privacy concerns the potential subject will be excluded from
participation.
22. Economic Burden to Subjects Subjects will be responsible for all costs associated
with standard care they receive as part of the emergency department visit. The research
will cover all costs associated with research procedures. UNM will not charge study
subjects, insurers or any other third parties for any study activities covered by the
protocol and paid for by Purdue Pharma. Purdue Pharma shall not be responsible for the
care or treatment of any illness or injury occurring to any study subject regardless of
whether such costs are otherwise covered by such study subject's medical or hospital
insurance, government program or other third party payor.
24. Compensation for Research-Related Injury Research related injury is not expected in
this study. We do not expect to see higher rates of research related injury in the
nalmefene or naloxone treatment arms, as such there are not funds set aside for
compensation in the event of research related injury. In the event of research related
injury subjects are responsible for seeking care. UNM Hospital will provide care in the
event of research related injury but subjects may seek or request care elsewhere.
Subjects will be responsible for the cost of that care. Purdue Pharma shall not be
responsible for the care or treatment of any illness or injury occurring to any Study
subject regardless of whether such costs are otherwise covered by such Study subject's
medical or hospital insurance, government program or other third party payor.
25. Consent Process Subjects are considered enrolled once they have signed and dated the
IRB-approved informed consent form. The consent process will take place in patient care
areas in the UNMH ED. Details related to maintaining patients' privacy are described in
Section 21. Provision to Protect the Privacy Interests of Subjects. Consent will be
obtained by IRB-approved study team members who are trained and delegated this task on
study training and delegation logs. The IRB-approved study team member obtaining
informed consent will be responsible for documenting their consent discussion with the
potential participant on a study notes page and confirm the subject's ability to give
informed consent by completing the UCSD Brief Assessment of Capacity to Consent
(attached). Only English-speaking subjects will be enrolled in the study. Spanish-only
speaking subjects will not be enrolled because it is rare for patients in the population
being studied to only speak Spanish.The study will not permit consent by a legally
authorized representative and will not be enrolling those who are cognitively impaired
or unable to give consent. This study will not include minors under the age of 18 years.
26. Documentation of Consent Subject consent will be documented on a hard copy informed
consent form. Details of the circumstances of informed consent will be recorded on a
study notes page. Information substantiating a subject's ability to give informed
consent will be recorded on a UCSD Brief Assessment of Capacity to Consent for each
subject at the time of consent.
27. Study Test Results/Incidental Findings Individual subject research specific
information will not be shared with subjects. Any information relevant to their medical
care will be provided by their care team. The study will not generate any incidental
findings that are relevant to the subjects' care.
28. Sharing Study Progress or Results with Subjects We do not intend to provide subjects
with a summary of the trial progress while the study remains underway. We do not intend
to provide subjects with a summary of the study results after the study is complete.
29. Inclusion of Vulnerable Populations As this study involves subjects who have
experienced a suspected opioid overdose, it is likely that the sample will be enriched
with subjects who are economically or educationally disadvantaged. The informed consent
form is specifically composed to minimize use of complicated language to the greatest
degree possible. IRB approved study team members obtaining informed consent are
responsible for ensuring the voluntariness of participation by reiterating the
voluntariness of participation, confirming subject understanding and eliciting questions
during the process of informed consent.
33. Drugs or Devices The UNMH investigational drug service is used in this study. The
investigational drug service allows for the secure storage and dispensation of
investigational drugs in accordance with applicable state and federal regulations and
institutional policies. The drugs used in this investigation will be used on-label. The
investigational drug service will also ensure that the subjects are not billed for the
investigational product.
