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Trial registered on ANZCTR


Registration number
ACTRN12623000691640
Ethics application status
Approved
Date submitted
14/06/2023
Date registered
28/06/2023
Date last updated
21/01/2024
Date data sharing statement initially provided
28/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Impact of injection site on buprenorphine pharmacokinetics.
Scientific title
The impact of injection site on the pharmacokinetics of depot buprenorphine in people with opioid use disorder: An Open-label non-randomized cross-over trial .
Secondary ID [1] 309890 0
Protocol Number: X23-0103
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Opioid Dependence
 330354 0
Condition category
Condition code
Mental Health 327197 327197 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants currently on Buvidal (Buprenorphine Extended-Release) or Sublocade (Buprenorphine Extended-Release) will be administered their current prescribed monthly buprenorphine dose via sub-cutaneous Sublocade (Buprenorphine Extended-Release) injection. Sublocade is currently approved for abdominal sub-cutaneous injection, and participants will also receive sub-cutaneous injections in the thigh, buttock and deltoid as per the study protocol. Participants will be randomized initially to one of the 3 alternative sites (Thigh, buttock or deltoid) for their first trial dose, and subsequent doses will be given in the order of abdomen, thigh, buttock and deltoid, dependent on the initial injection site. Sublocade can only be administered by a trained nurse or medical staff member. An initial dose of 300mg Sublocade will be given at the first dose, and thereafter, 100mg or 300mg doses will be administered as decided by the site investigator in consultation with the patient. Participants will be encouraged to complete 3 doses for each injection site for a total of 12 Sublocade doses during the study period. Sublocade is administered in monthly injections, therefore overall maximum duration of study participation will be 12 months. Participant adherence and retention in treatment will be monitored through REDCap database and within secure patient logs in each site folder.
Intervention code [1] 326318 0
Treatment: Drugs
Comparator / control treatment
Because of the marked interindividual variability in buprenorphine pharmacokinetics observed in previous clinical studies, a cross-over design will be employed, allowing each individual to be their own control.
The relative risk of a subtherapeutic concentration in a novel injection site will be calculated, using the approved site (abdomen) as the control, and as such each participant serves is their own internal control.
Control group
Active

Outcomes
Primary outcome [1] 335084 0
To compare the pharmacokinetics of subcutaneous depot buprenorphine administered to four different injection sites. Pharmacokinetics examined include peak and trough blood concentrations and overall concentration-time profiles at steady state conditions.
Timepoint [1] 335084 0
At 12 months post study initiation all samples will be collected. Sample timepoints for collection after each treatment (Sublocade injection) are:
- 1-2 hours post injection
- 24 hours post injection
- 48 hours post injection
- 3 days post injection
- 5 days post injection
- 7 days post injection
- 14 days post injection
- 21 days post injection
Primary outcome [2] 335085 0
To examine dose adequacy using Clinical Opiate Withdrawal Scale (COWS) and Subjective Opiate Withdrawal Scale (SOWS).
Timepoint [2] 335085 0
At 1-2 hours, 24 hours, 48 hours, 3 days, 5 days, 7 days, 14 days, 21 days post injection.
Primary outcome [3] 335150 0
To examine treatment effect on withdrawal symptoms using Withdrawal visual analog scale.
Timepoint [3] 335150 0
At 1-2 hours, 24 hours, 48 hours, 3 days, 5 days, 7 days, 14 days, 21 days post injection.
Secondary outcome [1] 422961 0
To assess treatment effects on illicit opioid and other drug use through the use of the Australia Treatment Outcome Profiles (ATOP)
Timepoint [1] 422961 0
At 7 days and 28 days post each study dose and at exit from study (approx 12 months).
Secondary outcome [2] 422962 0
To assess treatment effects on general physical, mental and psychosocial functioning. This will be assessed using a Patient Satisfaction Visual Analogue Scale and a Patient Global Impression of Change Visual Analogue Scale. These measures will be assessed as a composite secondary outcome.
Timepoint [2] 422962 0
At 7 days and 28 days post each study dose and at exit from study (approx 12 months).
Secondary outcome [3] 423463 0
To assess treatment effects on opioid craving symptoms using a Craving Visual Analogue scale.
Timepoint [3] 423463 0
At 1-2 hours, 24 hours, 48 hours, 3 days, 5 days, 7 days, 14 days, 21 days post injection.

Eligibility
Key inclusion criteria
1. Aged greater than or equal to 18 years old.
2. Demonstrating sufficient English language ability and willing to provide written informed consent.
3. Willing and able to comply with requirements of the study.
4. Meets the criteria for opioid dependence as defined by Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM-5) for moderate to severe opioid use disorder.
5. Appropriate candidate for medically assisted treatment with partial/full opioid agonist treatment as determined by the Principal Investigator.
6. Stable on Sublocade treatment (i.e., 3rd dose for those on 100 mg/month maintenance or 4th dose for those on 300 mg/month maintenance or those stable on Buvidal after the 3rd dose).
7. Female patients of childbearing potential must be willing to use a highly effective method of contraception during the entire trial.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindications for partial/full opioid agonist treatment according to National Guidelines for Medication-Assisted Treatment of Opioid Dependence, 2014.
2. Current, severe medical condition (e.g., hepatic failure or respiratory insufficiency) assessed by Principal Investigator.
3. Any known hypersensitivity to buprenorphine or any component of the ATRIGEL® delivery system.
4. Participants with a serious untreated psychiatric comorbidity at the discretion of the Principal Investigator.
5. Recent history of suicidal ideation or active suicidal behaviour as based on clinical assessment.
6. Clinically significant laboratory abnormalities, which in the opinion of the Investigator may prevent the patient from safely participating in trial.
7. History of Torsades de Pointes or other heart arrhythmia or an electrocardiogram (ECG) demonstrating a clinically significant abnormality, as judged by the Investigator.
8. Participant requiring chronic use of agents that are strong inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4) such as some azole antifungals (e.g., ketoconazole), macrolide antibiotics (e.g., clarithromycin), or protease inhibitors (e.g., ritonavir, indinavir, and saquinavir).
9. Currently breastfeeding or pregnant.
10. Patients who have had an investigational new drug or device within the last 30 days.
11. Patients who have already participated in this study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
This is an exploratory study without any pilot data and hence we expect the sample size of up to 50 participants (with repeated measures) to be adequate to provide a signal of bioequivalence to ascertain if a further large-scale PK study is required. For other outcomes that are not adequately powered, this study will enable researchers to accurately estimate the effect sizes and determine the sample size and study design needed to achieve adequate power for these outcomes for further research.
Briefly, participants will be characterized on baseline demographic variables (age, sex, gender, education, etc), drug use history variables (e.g., years of use, prior treatments), pre-treatment opioid use frequency, craving, and on presence/absence of anxiety and/or depressive symptoms (DASS). These variables will be summarized by calculating means, standard deviations, and percentile ranges for all continuous variables and by calculating proportions for all categorical variables. A one-way analysis of variance (ANOVA) will be used to assess group differences for continuous variables. Nominal variables will be analysed via chi-square tests of independence.
Pharmacokinetic analysis for each injection site will be undertaken, where PK parameters (elimination half-life, peak and trough (pre-dose) concentration) of buprenorphine will be calculated based on blood levels. Concentration ranges for each dosing site will be compared to each other, based on (1) peak concentration, (2) trough concentration and (3) concentration range between 3-28 days post-injection using a one-way analysis of variance (ANOVA) to assess group differences. The proportion of buprenorphine concentrations that are below 2 ng/ml for each injection site will be described using a frequency evaluation. The relative risk of a subtherapeutic concentration in a novel injection site will be calculated, using the approved site (abdomen) as the control. The area under the buprenorphine concentration-time curve (AUC) will be calculated for each injection site and the potential impact of the number of samples in each dosing interval on the AUC will be discussed. The impact of duration of treatment on the results will be assessed using the trough (pre-dose) concentrations for each injection site separately by (1) visual inspection, and (2) linear regression and application of the F-test to determine if the slope is non-zero; these analyses will also be performed using trough levels from the entire dataset per patient to ascertain overall temporal trends.

A sub-group analysis will be conducted according to doses. A key outcome is the effect of site on the trajectory of buprenorphine concentrations, and as such each participant serves is their own internal control.

Recruitment
Recruitment status
Suspended
Date of first participant enrolment
Anticipated
31/08/2023
Actual
18/12/2023
Date of last participant enrolment
Anticipated
31/08/2024
Actual
18/12/2023
Date of last data collection
Anticipated
30/08/2025
Actual
Sample size
Target
50
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 24911 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 24912 0
Canterbury Hospital - Campsie
Recruitment hospital [3] 24914 0
The Langton Centre - Surry Hills
Recruitment hospital [4] 24915 0
Drug and Alcohol Clinical Services, Hunter New England Local Health District - Newcastle
Recruitment hospital [5] 24916 0
NSLHD Drug and Alcohol Service - St Leonards
Recruitment postcode(s) [1] 40563 0
2050 - Camperdown
Recruitment postcode(s) [2] 40564 0
2194 - Campsie
Recruitment postcode(s) [3] 40566 0
2010 - Surry Hills
Recruitment postcode(s) [4] 40567 0
2300 - Newcastle
Recruitment postcode(s) [5] 40568 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 314074 0
Commercial sector/Industry
Name [1] 314074 0
Indivior Pty Ltd
Country [1] 314074 0
Australia
Primary sponsor type
Government body
Name
Sydney Local Health District
Address
Level 11, King George V Building
Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 315998 0
Government body
Name [1] 315998 0
Hunter New England Local Health District (HNELHD)
Address [1] 315998 0
Lookout Road
New Lambton NSW 2305
Postal address:
Locked Bag 1
New Lambton NSW 2305
Country [1] 315998 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313214 0
Sydney Local Health District Ethics Review Committee
Ethics committee address [1] 313214 0
Ethics committee country [1] 313214 0
Australia
Date submitted for ethics approval [1] 313214 0
24/03/2023
Approval date [1] 313214 0
06/06/2023
Ethics approval number [1] 313214 0
2023/ETH00605

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127366 0
Prof Paul Haber
Address 127366 0
Drug Health Services Level 6 KGV Building, Missenden Road, CAMPERDOWN, NSW 2050
Country 127366 0
Australia
Phone 127366 0
+61 0295156419
Fax 127366 0
Email 127366 0
paul.haber@sydney.edu.au
Contact person for public queries
Name 127367 0
Paul Haber
Address 127367 0
Drug Health Services Level 6 KGV Building, Missenden Road, CAMPERDOWN, NSW 2050
Country 127367 0
Australia
Phone 127367 0
+61 0295156419
Fax 127367 0
Email 127367 0
paul.haber@sydney.edu.au
Contact person for scientific queries
Name 127368 0
Paul Haber
Address 127368 0
Drug Health Services Level 6 KGV Building, Missenden Road, CAMPERDOWN, NSW 2050
Country 127368 0
Australia
Phone 127368 0
+61 0295156419
Fax 127368 0
Email 127368 0
paul.haber@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not consented for by patients


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.