Opiate Substitution Treatment, Opioid-Related Disorders
Conditions
Keywords
Opiate treatment, Opioid treatment, Glucagon-Like Peptide-1 Agonist, Opioid use disorder, Liraglutide
Brief summary
This research is being done to find out if liraglutide (brand name is Saxenda®) can safely and effectively reduce craving for opioids in patients with opioid use disorder, a primary factor contributing to early relapse.
Detailed description
The rationale for the proposed research is to develop an acute intervention that can improve treatment outcomes in opioid use disorder (OUD) by reducing craving, a primary factor contributing to early relapse. Although liraglutide was approved for human use in 2010, there are no data testing the effectiveness in patients with an OUD. The objective of the proposed research is to test whether treatment with a GLP-1R agonist can reduce craving in humans with OUD. Understanding how a 'satiety' agent may affect craving and brain responses to drug cues in an OUD population would provide entirely novel information. If liraglutide shows a trend towards efficacy, and safety of the GLP-1R agonist is demonstrated in this population, it would provide an indication to run the second phase, multi-center clinical trial of GLP-1R agonist in OUD patients.
Interventions
Liraglutide will be provided using an injection pen provided by the manufacturer
DRUGPlacebo
Placebo injection pen
Sponsors
National Institutes of Health (NIH)
National Institute on Drug Abuse (NIDA)
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 75 years * Diagnosed with an OUD seeking treatment at Caron Treatment Centers (CaronTC) and planning on being enrolled in a residential treatment plan for a minimum of 4 weeks * Women of childbearing potential must consent to use a medically accepted method of birth control or to abstain from sexual intercourse while in the study * Able and willing to provide informed consent prior to any study-related activities * Must be able to read and communicate in English sufficiently to complete all study requirements, including Ecology Momentary Assessment (EMA)
Exclusion criteria
* Age \< 18 or \> 75 years * Women who are pregnant, planning pregnancy, breastfeeding, or unwilling to use adequate contraceptive measures * History of angioedema, serious hypersensitivity reaction, or anaphylactic reaction to liraglutide or another glucagon-like peptide-1 receptor (GLP1R) agonist * Personal or family history of medullary thyroid carcinoma (MTC) or patients with multiple endocrine neoplasia syndrome type 2 (MEN 2) or thyroid nodule * Type I diabetes or history of diabetic ketoacidosis * Type II diabetes mellitus * Hypoglycemia on intake visit (blood glucose \< 70 mg/dL) * End-stage renal failure on dialysis or glomerular filtration rate (GFR) \<30 mL/min per 1.73 square meters or previous renal transplant * Severe hepatic impairment (AST or ALT levels \> 3 times upper limit of normal range) or previous liver transplant * Current or past diagnosis of pancreatitis, gastroparesis, or other severe gastrointestinal disease * Current or past diagnosis of gallbladder disease or gallstones * Serious cardiovascular disease within the past 6 months (e.g. uncontrolled hypertension, heart failure, significant cardiac arrhythmias, myocardial infarction, presence of angina pectoris, symptomatic coronary artery disease, deep vein thrombosis, pulmonary embolism, second- or third-degree heart block, mitral valve or aortic stenosis, hypertrophic cardiomyopathy, stroke) * Severe co-occurring psychiatric disorder (e.g., bipolar disorder, psychotic disorder, schizophrenia) that would, in the opinion of the Principle Investigator or study physician, interfere with participating in the study, such as if the patient needs a higher or different level of care and is going to be transferred out of Caron. * Suicidal ideation within the past 1 month, or history of suicide attempts within the past 1 year, unless participation is cleared by clinician assessment and/or judgement. * Treatment with any investigational drug in the one-month preceding the study * Previous randomization for participation in this trial * Abnormal physical exam findings, vital signs (blood pressure, heart rate, respiratory rate, body temperature), EKG measurements, and safety lab values that are deemed clinically significant by study physician
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Self-reported Cue-elicited Drug Craving as Measured by Visual Analog Scale (VAS) | Baseline (Day 1), End of the target drug dose (Day 19) | Scores are measured on a 0-100 point VAS, where 0= no craving, 100= maximum craving. |
| Change in Ambient Drug Craving Over Time as Measured by Visual Analog Scale (VAS) | Baseline (Day 1), Treatment Days (Days 2-19) | Scores are measured on a 0-4 point VAS, where 0= no craving, 4= maximum craving. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Respiratory Rate | Baseline (Day 1); beginning of each study drug dose (Days 2, 8, 14) | Respiratory rate in breaths per minute. |
| Absolute Change in Body Weight | From Day 1 to Day 19 | Body weight will be measured in kilograms (kg). |
| Percent Change in Body Weight | From Day 1 to Day 19 | Body weight will be measured in kilograms (kg) and change will measured in %. |
| Change in Fasting Blood Samples for Fructosamine | From Day 2 to Day 19 | Fructosamine is measured in umol/L |
| Change in Fasting Blood Samples for HA1c | From Day 2 to Day 19 | HA1c is measured in % |
| Frequency of Adverse Events (AE) and Serious Adverse Events (SAE) | Days 1-21 and at 30 days post-intervention (Day 49). | Number of participants affected by probable drug-related adverse events. |
| Change in Blood Pressure | Baseline (Day 1); beginning of each study drug dose (Days 2, 8, 14) | Blood pressure measurements in mmHg. Both systolic and diastolic pressures will be assessed during the study period. |
| Change in Heart Rate | Baseline (Day 1); beginning of each study drug dose (Days 2, 8, 14) | Heart rate measurements in beats per minute. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rebound Change in Heart Rate | From end of the target drug dose (Day 19) to rebound follow up (Day 21). | Heart rate measurements in beats per minute |
| Rebound Change in Respiratory Rate | From end of the target drug dose (Day 19) to rebound follow up (Day 21). | Respiratory rate in breaths per minutes. |
| Rebound Change in Ambient Drug Craving Over Time as Measured by Visual Analog Scale (VAS) | Treatment (averaged across Days 2-19), Rebound follow up (averaged across Days 20-21) | Scores are measured on a 0-4 point VAS, where 0= no craving, 4= maximum craving. Treatment score is the average scores across Days 2-19. Rebound follow up score is the average scores across Days 20-21. |
| Rebound Change in Blood Pressure | From end of the target drug dose (Day 19) to rebound follow up (Day 21). | Blood pressure measurements in mmHg. Both pressures will be assessed during the study period. |
| Change in Blood Oxygenation Level Response to Visual Opioid Drug Cues in Prefrontal Cortex Using Functional Near Infrared Spectroscopy (fNIRs) | Baseline (Day 1), end of the target drug dose (Day 19) | fNIRs indexes regional cerebral oxygenation saturation (%) by optical density (OD). Increased OD indicates increased blood oxygen saturation. |
Countries
United States
Participant flow
Recruitment details
Protocol was approved for a 3-dose intervention that could continue as a 5-dose intervention; no participants received the latter. All outcomes are reported as the 3-dose intervention.
Pre-assignment details
Two participants were not randomized due to screening after consent and prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Investigational Group Participants randomized to liraglutide will be started at a low dose (0.6 mg once per day) which will be gradually increased until 1.8 mg/day is reached for the 3-dose intervention and 3 mg/day is reached for the 5-dose intervention. Liraglutide will be administered by injection pen.
Liraglutide Pen Injector: Liraglutide will be provided using an injection pen provided by the manufacturer | 12 |
| Control Group Participants in the control group will have placebo administered by injection pen following the same low dose titration to 3.0 mg once per day.
Placebo: Placebo injection pen | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Early withdraw criteria met | 0 | 1 |
| Overall Study | Non-compliance/difficulty with staff | 2 | 0 |
| Overall Study | Screen fail after consent | 0 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 3 |
Baseline characteristics
| Characteristic | Control Group | Total | Investigational Group |
|---|---|---|---|
| Age, Continuous | 32.03 years STANDARD_DEVIATION 2.19 | 33.57 years STANDARD_DEVIATION 1.51 | 35.23 years STANDARD_DEVIATION 2.04 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 24 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 22 Participants | 12 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 10 Participants | 21 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 13 |
| other Total, other adverse events | 10 / 12 | 8 / 13 |
| serious Total, serious adverse events | 2 / 12 | 1 / 13 |
Outcome results
Primary
Change in Ambient Drug Craving Over Time as Measured by Visual Analog Scale (VAS)
Scores are measured on a 0-4 point VAS, where 0= no craving, 4= maximum craving.
Time frame: Baseline (Day 1), Treatment Days (Days 2-19)
Population: n=1 did not complete entire EMA. n=7 instead of n=8 reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Change in Ambient Drug Craving Over Time as Measured by Visual Analog Scale (VAS) | -0.55 score on a scale | — |
| Control Group | Change in Ambient Drug Craving Over Time as Measured by Visual Analog Scale (VAS) | -1.41 score on a scale | Standard Deviation 0.99 |
Primary
Change in Self-reported Cue-elicited Drug Craving as Measured by Visual Analog Scale (VAS)
Scores are measured on a 0-100 point VAS, where 0= no craving, 100= maximum craving.
Time frame: Baseline (Day 1), End of the target drug dose (Day 19)
Population: In control group, n=1 did not complete the measure due to technical difficulties. n=7 instead of n=8 reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Change in Self-reported Cue-elicited Drug Craving as Measured by Visual Analog Scale (VAS) | -5.00 score on a scale | — |
| Control Group | Change in Self-reported Cue-elicited Drug Craving as Measured by Visual Analog Scale (VAS) | -13.34 score on a scale | Standard Deviation 19.58 |
Secondary
Absolute Change in Body Weight
Body weight will be measured in kilograms (kg).
Time frame: From Day 1 to Day 19
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Absolute Change in Body Weight | 0.27 kg | — |
| Control Group | Absolute Change in Body Weight | 1.05 kg | Standard Deviation 1.86 |
Secondary
Change in Blood Pressure
Blood pressure measurements in mmHg. Both systolic and diastolic pressures will be assessed during the study period.
Time frame: Baseline (Day 1); beginning of each study drug dose (Days 2, 8, 14)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Investigational Group | Change in Blood Pressure | Systolic Pressure, from Day 2 | 4.00 mmHg | — |
| Investigational Group | Change in Blood Pressure | Systolic Pressure, from Day 8 | 9.00 mmHg | — |
| Investigational Group | Change in Blood Pressure | Systolic Pressure, from Day 14 | 3.75 mmHg | — |
| Investigational Group | Change in Blood Pressure | Diastolic Pressure, from Day 2 | 3.00 mmHg | — |
| Investigational Group | Change in Blood Pressure | Diastolic Pressure, from Day 8 | 2.25 mmHg | — |
| Investigational Group | Change in Blood Pressure | Diastolic Pressure, from Day 14 | 2.75 mmHg | — |
| Control Group | Change in Blood Pressure | Diastolic Pressure, from Day 8 | 3.34 mmHg | Standard Deviation 6.61 |
| Control Group | Change in Blood Pressure | Systolic Pressure, from Day 2 | -0.59 mmHg | Standard Deviation 4.69 |
| Control Group | Change in Blood Pressure | Diastolic Pressure, from Day 2 | 2.56 mmHg | Standard Deviation 6.17 |
| Control Group | Change in Blood Pressure | Systolic Pressure, from Day 8 | 2.75 mmHg | Standard Deviation 6.67 |
| Control Group | Change in Blood Pressure | Diastolic Pressure, from Day 14 | 4.19 mmHg | Standard Deviation 7.51 |
| Control Group | Change in Blood Pressure | Systolic Pressure, from Day 14 | 2.13 mmHg | Standard Deviation 8.13 |
Secondary
Change in Fasting Blood Samples for Fructosamine
Fructosamine is measured in umol/L
Time frame: From Day 2 to Day 19
Population: In control group, n=1 could not obtain blood draw for measure. n=7 instead of n=8 reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Change in Fasting Blood Samples for Fructosamine | -14.00 umol/L | — |
| Control Group | Change in Fasting Blood Samples for Fructosamine | 2.71 umol/L | Standard Deviation 21.48 |
Secondary
Change in Fasting Blood Samples for HA1c
HA1c is measured in %
Time frame: From Day 2 to Day 19
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Change in Fasting Blood Samples for HA1c | -0.10 % of total hemoglobin in the blood | — |
| Control Group | Change in Fasting Blood Samples for HA1c | 0 % of total hemoglobin in the blood | Standard Deviation 0.11 |
Secondary
Change in Heart Rate
Heart rate measurements in beats per minute.
Time frame: Baseline (Day 1); beginning of each study drug dose (Days 2, 8, 14)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Investigational Group | Change in Heart Rate | Day 14 change from baseline | 9.75 beats per minute | — |
| Investigational Group | Change in Heart Rate | Day 02 change from baseline | 10.75 beats per minute | — |
| Investigational Group | Change in Heart Rate | Day 08 change from baseline | 20.00 beats per minute | — |
| Control Group | Change in Heart Rate | Day 08 change from baseline | -2.63 beats per minute | Standard Deviation 10.98 |
| Control Group | Change in Heart Rate | Day 14 change from baseline | -3.09 beats per minute | Standard Deviation 11.2 |
| Control Group | Change in Heart Rate | Day 02 change from baseline | -5.78 beats per minute | Standard Deviation 5.1 |
Secondary
Change in Respiratory Rate
Respiratory rate in breaths per minute.
Time frame: Baseline (Day 1); beginning of each study drug dose (Days 2, 8, 14)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Investigational Group | Change in Respiratory Rate | Day 02 change from baseline | -1.00 breaths per minute | — |
| Investigational Group | Change in Respiratory Rate | Day 08 change from baseline | 0.67 breaths per minute | — |
| Investigational Group | Change in Respiratory Rate | Day 14 change from baseline | 1.33 breaths per minute | — |
| Control Group | Change in Respiratory Rate | Day 02 change from baseline | 0.08 breaths per minute | Standard Deviation 2.83 |
| Control Group | Change in Respiratory Rate | Day 08 change from baseline | -1.08 breaths per minute | Standard Deviation 2.74 |
| Control Group | Change in Respiratory Rate | Day 14 change from baseline | -0.13 breaths per minute | Standard Deviation 2.49 |
Secondary
Frequency of Adverse Events (AE) and Serious Adverse Events (SAE)
Number of participants affected by probable drug-related adverse events.
Time frame: Days 1-21 and at 30 days post-intervention (Day 49).
Population: Randomized participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Investigational Group | Frequency of Adverse Events (AE) and Serious Adverse Events (SAE) | Participants with drug-related AEs | 5 Participants |
| Investigational Group | Frequency of Adverse Events (AE) and Serious Adverse Events (SAE) | Participants with drug-related SAEs | 1 Participants |
| Control Group | Frequency of Adverse Events (AE) and Serious Adverse Events (SAE) | Participants with drug-related AEs | 3 Participants |
| Control Group | Frequency of Adverse Events (AE) and Serious Adverse Events (SAE) | Participants with drug-related SAEs | 0 Participants |
Secondary
Percent Change in Body Weight
Body weight will be measured in kilograms (kg) and change will measured in %.
Time frame: From Day 1 to Day 19
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Percent Change in Body Weight | 0.33 % change | — |
| Control Group | Percent Change in Body Weight | 1.38 % change | Standard Deviation 2.39 |
Other Pre-specified
Change in Blood Oxygenation Level Response to Visual Opioid Drug Cues in Prefrontal Cortex Using Functional Near Infrared Spectroscopy (fNIRs)
fNIRs indexes regional cerebral oxygenation saturation (%) by optical density (OD). Increased OD indicates increased blood oxygen saturation.
Time frame: Baseline (Day 1), end of the target drug dose (Day 19)
Population: In placebo group, processing difficulties limited analysis. N=5 reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Change in Blood Oxygenation Level Response to Visual Opioid Drug Cues in Prefrontal Cortex Using Functional Near Infrared Spectroscopy (fNIRs) | -3.10 Optical density (OD) | — |
| Control Group | Change in Blood Oxygenation Level Response to Visual Opioid Drug Cues in Prefrontal Cortex Using Functional Near Infrared Spectroscopy (fNIRs) | -0.58 Optical density (OD) | Standard Deviation 0.65 |
Other Pre-specified
Rebound Change in Ambient Drug Craving Over Time as Measured by Visual Analog Scale (VAS)
Scores are measured on a 0-4 point VAS, where 0= no craving, 4= maximum craving. Treatment score is the average scores across Days 2-19. Rebound follow up score is the average scores across Days 20-21.
Time frame: Treatment (averaged across Days 2-19), Rebound follow up (averaged across Days 20-21)
Population: n=1 did not complete entire EMA. n=7 instead of n=8 reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Rebound Change in Ambient Drug Craving Over Time as Measured by Visual Analog Scale (VAS) | -0.11 score on a scale | — |
| Control Group | Rebound Change in Ambient Drug Craving Over Time as Measured by Visual Analog Scale (VAS) | -0.15 score on a scale | Standard Deviation 0.47 |
Other Pre-specified
Rebound Change in Blood Pressure
Blood pressure measurements in mmHg. Both pressures will be assessed during the study period.
Time frame: From end of the target drug dose (Day 19) to rebound follow up (Day 21).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Investigational Group | Rebound Change in Blood Pressure | Change in systolic pressure | 11.00 mmHg | — |
| Investigational Group | Rebound Change in Blood Pressure | Change in diastolic pressure | 10.25 mmHg | — |
| Control Group | Rebound Change in Blood Pressure | Change in systolic pressure | -0.56 mmHg | Standard Deviation 12.45 |
| Control Group | Rebound Change in Blood Pressure | Change in diastolic pressure | -1.59 mmHg | Standard Deviation 6.27 |
Other Pre-specified
Rebound Change in Heart Rate
Heart rate measurements in beats per minute
Time frame: From end of the target drug dose (Day 19) to rebound follow up (Day 21).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Rebound Change in Heart Rate | 8.50 beats per minute | — |
| Control Group | Rebound Change in Heart Rate | -6.31 beats per minute | Standard Deviation 8.41 |
Other Pre-specified
Rebound Change in Respiratory Rate
Respiratory rate in breaths per minutes.
Time frame: From end of the target drug dose (Day 19) to rebound follow up (Day 21).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigational Group | Rebound Change in Respiratory Rate | -6.33 breaths per minute | — |
| Control Group | Rebound Change in Respiratory Rate | -0.67 breaths per minute | Standard Deviation 2.83 |