| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Maintenance/substitution agent for the treatment of opioid dependence
|
|
| E.1.1.1 | Medical condition in easily understood language |
Maintenance/substitution agent for the treatment of opioid dependence
|
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012346 |
| E.1.2 | Term | Dependence on opiates |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to demonstrate that RBP-6300 is not inferior to Subutex®/Suboxone® as assessed by the peak change from baseline in the pre-dose Clinical Opiate Withdrawal Scale (COWS) score during the Double-Blind Transfer Phase. |
|
| E.2.2 | Secondary objectives of the trial |
Overall clinical response to RBP-6300 with respect to:
• Mean change from baseline (D1) in pre-dose COWS score during Double-Blind Transfer Phase
• Mean change from baseline (D1) in the COWS score during first 2h post-dosing on D1 of Double-Blind Transfer Phase
• Mean change from baseline (D8) in pre-dose COWS score during Single-Blind Transition Phase
• Mean change from baseline (D8) in COWS score during first 2h post-dosing on D8 (D1 of Single-Blind Transition Phase)
• Peak and mean change from baseline in pre-dose SOWS
• Illicit opioid and non-opioid drug use as measured by UDS
• Drug craving as assessed using a 100 mm VAS
• Illicit opioid and non-opioid drug use as measured by self-reporting on the SUI
• Incidence of withdrawal due to clinically significant difficulties
• Treatment compliance rate
• Treatment retention rate
For further secondary objectives please refer to protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects must be male or non-pregnant, non-lactating females.
2. Subjects must be at least 18 years of age.
3. Subjects must provide written informed consent and must be willing that their general practitioners be notified of their participation in the study.
4. Women of childbearing potential must use a medically acceptable means of birth control and agree to continue its use during the study and for at least 3 months after the last dose of study drug. Women of childbearing potential are defined as all women who have not had a complete surgical hysterectomy or who cannot be documented as being at least 1 year postmenopausal. Medically acceptable forms of birth control include oral contraceptives, injectable or implantable methods, intrauterine devices, tubal ligation (if performed more than 1 year before screening), or double-barrier contraception. Use of two medically acceptable methods of birth control, one of which being a barrier method, may be needed according to local requirements or regulations (this will be reflected in the local informed consent form). Sexually active men must agree to use a medically acceptable form of contraception during the study and continue its use for at least 3 months after the last dose of study drug.
5. Subjects must be able to communicate well with the investigator, understand and comply with the requirements of the study, and understand the written informed consent.
6. Subjects must meet Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria for opioid dependence at screening.
7. Subjects must have been receiving maintenance treatment with Suboxone® or Subutex® at stable daily doses of 8, 16, or 24 mg/day for ≥30 days prior to screening and must be
considered by the investigator to be suitable for continuing such treatment.
8. Female subjects of childbearing potential must have a negative urine β-hCG or plasma (dependent on local regulations) test prior to enrolment into the study. |
|
| E.4 | Principal exclusion criteria |
1. Subjects who are unwilling or unable to comply with the requirements of the protocol or who are in a situation or have a condition that, in the opinion of the investigator, may interfere with participation in the study.
2. Subjects who, within 2 months prior to signing the informed consent document, participated in any other clinical study in which medications were delivered or who plan to participate in any other clinical study prior to the Follow-up Visit of the present trial.
3. Subjects who are receiving treatment for opioid dependence by court order.
4. Subjects with known allergy or sensitivity to buprenorphine or naloxone or to any of the excipients of Subutex®/Suboxone® or RBP-6300.
5. Subjects who are staff personnel or are affiliated with or a family member of staff personnel directly involved in the study.
6. Subjects with serious untreated Axis I DSM-IV-TR psychiatric co-morbidity (for example, those who are actively suicidal as per C-SSRS or have untreated schizophrenia).
7. Subjects with significant benzodiazepine use requiring medical detoxification or alcohol dependence requiring medical detoxification. Current polysubstance abuse or dependence is not a reason for exclusion.
8. Subjects with a current diagnosis of chronic pain requiring opioid treatment.
9. Subjects with an ECG result that shows a repeated demonstration of a QTc interval >450ms or a history of risk factors of Torsades de Pointes (eg heart failure, hypokalemia,
family history of Long QT Syndrome)
10. Subjects with aspartate aminotransferase (AST) levels ≥3 × upper limit of normal (ULN), alanine aminotransferase (ALT) levels ≥3 × ULN, or total bilirubin levels ≥1.5 × ULN.
11. Subjects with uncontrolled medical or psychiatric illness.
12. Subjects currently using opioid treatment (except buprenorphine), other opioid derivatives (e.g., methadone and analgesics), clonidine and related substances and clinically relevant CYP3A4 inhibitors or inducers.
13. Subjects with an opioid-positive (other than for buprenorphine) UDS result, a COWS score > 12, or a drug-craving VAS > 20 mm at screening or during the Open-Label Runin Phase.
14. Subjects positive for human immunodeficiency virus (HIV), or showing evidence of acute hepatitis B or C infection—acute infection is defined as subjects positive for hepatitis B surface antigen (HBsAg) and immunoglobulin M antibodies to hepatitis B core antigen (anti-HBc IgM),
and those with clinical evidence of either acute hepatitis B infection or hepatitis C infection. Subjects with chronic active hepatitis should also be excluded Subjects with asymptomatic hepatitis B or C infection and those asymptomatic currently being treated may be enrolled.
15. Subjects for whom treatment with Subutex®/Suboxone® is a contraindication as per the Summary of Product Characteristics (SmPC), such as subjects with severe respiratory insufficiency or severe hepatic insufficiency. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the peak change from baseline in the pre-dose COWS score over the 7-day Double-Blind Transfer Phase (i.e., in the pre-dose COWS scores recorded on Days 2 to 8). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| COWS will be performed pre-dose and 1 and 2 hours (± 15 minutes) post-dose on Days 1 and 8 and pre-dose on all other days throughout the study (except for Visit 14, FU). |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
-mean change from baseline in COWS score during the Double-Blind Transfer Phase and the Single-Blind Transition Phase
-The peak and mean change from baseline in SOWS score
-number and percentage of subjects with a drug-free UDS
- drug-craving VAS and SUI
- incidence of withdrawal due to clinically significant difficulties
- compliance rate
- treatment retention rate
Further secondary endpoints:
- pharmacokinetics
- safety |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-COWS, SOWS and drug-craving VAS will be performed pre-dose and 1 and 2 hours (± 15 minutes) post-dose on Days 1 and 8 and pre-dose on all other days throughout the study (except for Visit 14, FU).
- UDS and SUI will be performed at all visits (except for Visit 14, FU) throughout the study
- compliance rate, treatment retention rate and safety will be assessed throughout the study
- PK blood draws will be taken from Visit 3 to Visit 10
- compliance rate, treatment retention rate and safety will be assessed throughout the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Double-dummy, open-label run-in, Double-blind Transfer Phase, Single-Blind Transition Phase |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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