Opioid Use Disorder
Conditions
Keywords
naltrexone, opioids, opioid use disorder, OLANI implant
Brief summary
This study will examine the pharmacokinetic profile and safety of the O'Neil Long Acting Naltrexone Implant (OLANI) overtime in healthy volunteers. All participants will be treated in an open label manner. No randomization will occur. It is hypothesized that the OLANI will provide sustained therapeutic doses of naltrexone (NTX) for periods up to 6 months via a single subcutaneous application of 2 OLANIs.
Detailed description
Naltrexone (NTX) is a nonspecific pure opioid antagonist with a high affinity for the µ-opioid receptor. It blocks the effects of opioids by competitive binding at opiate receptors. NTX is used primarily in the management of opiate and alcohol dependence. It is available in the United States (US) as 2 formulations; a once daily oral formulation (Revia) and a once monthly intramuscular injection (Vivitrol). While NTX is a potent antagonist and efficiently blocks the effects of exogenous opiates such as heroin, the success of NTX for the treatment of opiate dependence has been limited by poor patient compliance. Therefore, the development of a sustained release NTX formulation (in excess of 1 month) would be of great benefit for the treatment of opioid use disorder.
Interventions
1.8 g implant containing 60% naltrexone
Sponsors
National Institute on Drug Abuse (NIDA)
New York State Psychiatric Institute
Columbia University
Clinilabs, Inc.
Go Medical Industries Pty Ltd
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Men or women between the ages of 18 and 55 years old (inclusive) * Without The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) - Substance Related Disorders classification; in sustained remission is not exclusionary * Able and willing to comply with the requirements of the protocol * Able and willing to provide written informed consent * Willing to undergo a minor surgical procedure under local anesthetic to allow for investigational drug administration in the subcutaneous tissue * BMI inclusive of 18.5 to 30.0 * Have an initial weight between 45.3 and 81.6 kilograms (inclusive)
Exclusion criteria
* Positive urine drug screen (UDS) at screening for illicit substances. * Is currently on naltrexone medication. * Has had a naltrexone implant in the past 24 months. * Has received treatment with an extended naltrexone product (e.g. Vivitrol) in the past 12 months. * Has a condition which requires treatment with opioid based medication. * Has a known hypersensitivity to naltrexone. * Has a known hypersensitivity to poly-lactic based materials e.g. biodegradable sutures, surgical implants or previous biodegradable implants. * Has a known hypersensitivity to local anesthesia. * Is prone to skin rashes, irritation or has a skin condition such as recurrent eczema that is likely to impact the implant site area, or as determined by the evaluating physician. * Demonstrates any abnormal skin tissue in the proposed implantation area. * Is pregnant or planning to be. Women need to have negative blood pregnancy test at screening. Women need to agree to practice dual contraceptives. * Participant is breastfeeding or planning to be. * Has a current significant neurological (including cognitive and psychiatric disorders), hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, hematological or metabolic disease unless currently controlled and stable with protocol-allowed medication 30 days prior to proposed investigational product administration. * Any clinically important abnormal finding as determined by medical history, physical examination, ECG or clinical laboratory tests. * Any additional condition(s) that in the investigator's opinion would prohibit the participant from completing the study or would not be in the best interest of the participant. * Alanine aminotransferase (ALT) or aspartate transaminase (AST) \> 3 times the upper end of the laboratory normal range. * Any methadone use 14 days prior to screening, and up to Study Day 0. * Current DSM-5 diagnosis of schizophrenia, bipolar, anxiety, or depressive disorder, confirmed by The Mini International Neuropsychiatric Interview (MINI) diagnostic interview assessment, or currently treated with medications for anxiety or depression. Past history (in remission DSM-5 classification) of anxiety or depression is not exclusionary. * Any elevated risk for suicide measured using the Columbia Suicide Severity Rating Scale (C-SSRS), endorsing any of the items in the past month (C-SSRS, Lifetime) * Is participating or intending to participate in any other clinical trial during the duration of this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants That Maintain MEC | up to 540 days or until NTX blood levels become undetectable | Percentage of participants who maintain naltrexone (NTX) blood levels of ≥1.33 ng/mL for ≥180 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax of Naltrexone | pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days | Single-dose PK measurement of the time to reach the maximum (Tmax) naltrexone concentration after dosing on Day 1 |
| AUC of Naltrexone | pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days | Single-dose PK measurement of the area under the curve (AUC) for naltrexone after dosing on Day 1 |
| Median Cmax of 6β-naltrexol | pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days | Single-dose PK measurement of the peak plasma 6β-naltrexol concentration after dosing on Day 1 |
| Median Cmax of Naltrexone | pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days | Single-dose pharmacokinetic (PK) measurement of the plasma naltrexone concentration (Cmax) after dosing on Day 1 |
| Time>Minimum Effective Concentration | pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days | Time (T) naltrexone remains above the minimum effective concentration (MEC) of 1.33 |
| AUC of 6β-naltrexol | pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days | Single-dose PK measurement of the AUC for 6β-naltrexol concentration after dosing on Day 1 |
| Incidence of Adverse Events (AEs) | Up to 540 days or until NTX blood levels become undetectable | Incidence and Severity of AEs |
| Median Tmax of 6β-naltrexol | pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days | Single-dose PK measurement of the time to reach the maximum 6β-naltrexol concentration after dosing on Day 1 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OLANI (Naltrexone Implant) 2 OLANI containing 60% naltrexone (1.8 g total) administered one time subcutaneously
naltrexone implant: 1.8 g implant containing 60% naltrexone | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | OLANI (Naltrexone Implant) |
|---|---|
| Age, Continuous | 38.4 years STANDARD_DEVIATION 10.77 |
| Body Mass Index (kg/m^2) | 24.92 kg/m^2 STANDARD_DEVIATION 3.63 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 19 / 20 |
| serious Total, serious adverse events | 2 / 20 |
Outcome results
Primary
Percentage of Participants That Maintain MEC
Percentage of participants who maintain naltrexone (NTX) blood levels of ≥1.33 ng/mL for ≥180 days
Time frame: up to 540 days or until NTX blood levels become undetectable
Population: Per-Protocol Population consisted of all subjects who completed at least 75% valid PK blood samples including 2 consecutive undetectable values (defined as \<0.1 ng/mL) and those without any major protocol deviations.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OLANI (Naltrexone Implant) | Percentage of Participants That Maintain MEC | 10 Participants |
Secondary
AUC of 6β-naltrexol
Single-dose PK measurement of the AUC for 6β-naltrexol concentration after dosing on Day 1
Time frame: pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days
Population: Per-Protocol Population consisted of all subjects who completed at least 75% valid PK blood samples including 2 consecutive undetectable values (defined as \<0.1 ng/mL) and those without any major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OLANI (Naltrexone Implant) | AUC of 6β-naltrexol | 2856.50 day*ng/mL |
Secondary
AUC of Naltrexone
Single-dose PK measurement of the area under the curve (AUC) for naltrexone after dosing on Day 1
Time frame: pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days
Population: Per-Protocol Population consisted of all subjects who completed at least 75% valid PK blood samples including 2 consecutive undetectable values (defined as \<0.1 ng/mL) and those without any major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OLANI (Naltrexone Implant) | AUC of Naltrexone | 1440.5 day*ng/mL |
Secondary
Incidence of Adverse Events (AEs)
Incidence and Severity of AEs
Time frame: Up to 540 days or until NTX blood levels become undetectable
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Participants with at least One Treatment-Emergent Adverse Event | 19 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Implant site inflammation | 7 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Vomiting | 7 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Headache | 5 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Implant site pruritus | 4 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Nausea | 3 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Diarrhoea | 3 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Upper respiratory tract infection | 3 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Implant site pain | 2 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Back pain | 2 participants |
| OLANI (Naltrexone Implant) | Incidence of Adverse Events (AEs) | Weight increased | 2 participants |
Secondary
Median Cmax of 6β-naltrexol
Single-dose PK measurement of the peak plasma 6β-naltrexol concentration after dosing on Day 1
Time frame: pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days
Population: Per-Protocol Population consisted of all subjects who completed at least 75% valid PK blood samples including 2 consecutive undetectable values (defined as \<0.1 ng/mL) and those without any major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OLANI (Naltrexone Implant) | Median Cmax of 6β-naltrexol | 23.45 ng/mL |
Secondary
Median Cmax of Naltrexone
Single-dose pharmacokinetic (PK) measurement of the plasma naltrexone concentration (Cmax) after dosing on Day 1
Time frame: pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days
Population: Per-Protocol Population consisted of all subjects who completed at least 75% valid PK blood samples including 2 consecutive undetectable values (defined as \<0.1 ng/mL) and those without any major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OLANI (Naltrexone Implant) | Median Cmax of Naltrexone | 17.00 ng/mL |
Secondary
Median Tmax of 6β-naltrexol
Single-dose PK measurement of the time to reach the maximum 6β-naltrexol concentration after dosing on Day 1
Time frame: pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days
Population: Per-Protocol Population consisted of all subjects who completed at least 75% valid PK blood samples including 2 consecutive undetectable values (defined as \<0.1 ng/mL) and those without any major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OLANI (Naltrexone Implant) | Median Tmax of 6β-naltrexol | 49.70 day |
Secondary
Time>Minimum Effective Concentration
Time (T) naltrexone remains above the minimum effective concentration (MEC) of 1.33
Time frame: pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days
Population: Per-Protocol Population consisted of all subjects who completed at least 75% valid PK blood samples including 2 consecutive undetectable values (defined as \<0.1 ng/mL) and those without any major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OLANI (Naltrexone Implant) | Time>Minimum Effective Concentration | 270 days |
Secondary
Tmax of Naltrexone
Single-dose PK measurement of the time to reach the maximum (Tmax) naltrexone concentration after dosing on Day 1
Time frame: pre-dose, at 3, 6, and 12 hours (± 60 minutes) after dosing; 24 and 48 hours (± 2 hours) after dosing; day 4 (± 1 day), day 8 (± 2 days); days 14, 21, 28, 35, 42, 49 and 56 (± 3 days); then every 30 days (± 10 days) up to 540 days
Population: Per-Protocol Population consisted of all subjects who completed at least 75% valid PK blood samples including 2 consecutive undetectable values (defined as \<0.1 ng/mL) and those without any major protocol deviations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| OLANI (Naltrexone Implant) | Tmax of Naltrexone | 49.63 day |