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    Summary
    EudraCT Number:2012-002408-42
    Sponsor's Protocol Code Number:RB-UK-12-0004
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-07-27
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2012-002408-42
    A.3Full title of the trial
    An Open-label, Randomised, Three -Way, Cross-Over Study to Assess the Pharmacokinetics, Safety and Tolerability of Two Formulations of RBP-6300 10mg in Healthy Volunteers under a Naltrexone Block in the Presence and Absence of Food.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-label, Randomised, Three -Way, Cross-Over Study to Assess the Pharmacokinetics, Safety and Tolerability of Two Formulations of RBP-6300 10mg in Healthy Volunteers under a Naltrexone Block in the Presence and Absence of Food.
    A.4.1Sponsor's protocol code numberRB-UK-12-0004
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorReckitt Benckiser Pharmaceuticals Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportReckitt Benckiser Pharmaceuticals Inc
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationReckitt Benckiser Pharmaceuticals Limited
    B.5.2Functional name of contact pointMark Hood
    B.5.3 Address:
    B.5.3.1Street AddressDansom Lane
    B.5.3.2Town/ cityHull
    B.5.3.3Post codeHU8 7DS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number004401482582226
    B.5.5Fax number004401482582603
    B.5.6E-mailmark.hood@reckittbenckiser.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRBP-6300 Formulation B
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBuprenorphine Hemiadipate Hydrochloride
    D.3.9.2Current sponsor codeRX778002A
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNaloxone hydrochloride dihydrate
    D.3.9.1CAS number 51481-60-8
    D.3.9.3Other descriptive nameNALOXONE HYDROCHLORIDE DIHYDRATE
    D.3.9.4EV Substance CodeSUB12168MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRBP-6300 Formulation A
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBuprenorphine Hemiadipate Hydrochloride
    D.3.9.2Current sponsor codeRX778002A
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNaloxone hydrochloride dihydrate
    D.3.9.1CAS number 51481-60-8
    D.3.9.3Other descriptive nameNALOXONE HYDROCHLORIDE DIHYDRATE
    D.3.9.4EV Substance CodeSUB12168MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Maintenance/substitution agent for the treatment of opioid dependence.
    E.1.1.1Medical condition in easily understood language
    Maintenance/substitution agent for the treatment of opioid dependence.
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level LLT
    E.1.2Classification code 10012346
    E.1.2Term Dependence on opiates
    E.1.2System Organ Class 100000004873
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the relative bioavailability of buprenorphine after oral administration of RBP 6300 (Formualtion A) 10 mg as compared to RBP 6300 (Formualtion B) 10 mg, when administered in the fasted state.

    To assess the relative bioavailability of buprenorphine after oral administration of RBP 6300 (Formulation A) 10 mg to subjects who have been fed a high-fat breakfast as compared to fasted.
    E.2.2Secondary objectives of the trial
    To assess the safety and tolerability of RBP 6300 (Formulation A) and RBP 6300 (Formulation B) administered to healthy subjects under a naltrexone blockade.

    To assess the plasma PK of naloxone, naloxone-3-glucuronide, buprenorphine, buprenorphine hemiadipate and norbuprenorphine after oral administration of RBP 6300 (Formulation A) 10 mg as compared to RBP 6300 (Formulation B) 10 mg, when administered in the fasted state.

    To assess the plasma PK of naloxone, naloxone-3-glucuronide, buprenorphine, buprenorphine hemiadipate and norbuprenorphine after oral administration of RBP 6300 (Formulation A) 10 mg to subjects who have been fed a high-fat breakfast as compared to fasted.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subject must be a male or non-pregnant, non-breastfeeding female.

    Subject must be between 18 and 55 years of age (inclusive) at screening.

    Subject’s Body Mass Index (BMI) must be between 18.5 and 30.0 kg/m2 (inclusive), and subject must weigh a minimum of 50 kg (110.23 lbs).

    Women of childbearing potential who agree to use adequate contraception methods (e.g., an oral or injectable hormonal contraceptive, an approved hormonal implant or topical patch, an intrauterine device, a double barrier method, or a barrier plus spermicide). A woman of childbearing potential is defined as any female who is less than 2 years post-menopausal or has not undergone a hysterectomy or surgical sterilization, e.g., bilateral tubal ligation, bilateral ovariectomy (oophorectomy). Post-menopausal status will be confirmed by a follicle stimulating hormone (FSH) test at initial screening.

    Male subjects of childbearing potential with partner(s) of childbearing potential must agree to take appropriate contraceptive precautions from screening until 3 months after receiving the last dose of study treatment and agree to use barrier contraception, in addition to their partner(s) using another method. Acceptable forms of contraception are as listed in criteria 4.2.4

    Male subjects must refrain from donating sperm and female subjects from donating eggs for 90 days after the end of the study.

    Subject must voluntarily consent to participate in this study and provide their written informed consent prior to start of any study-specific procedures.

    Subject must be willing and able to remain in the study unit for the entire duration of each confinement period.
    E.4Principal exclusion criteria
    Women of childbearing potential who are pregnant, lactating, seeking pregnancy, or who do not agree to use adequate contraceptive methods.

    History or presence of any major health issues, including but not limited to: clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results.

    Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at screening.

    History or presence of allergic or adverse response to buprenorphine, naloxone, naltrexone or related drugs.

    Significantly abnormal diet, as determined by the PI or designee, during the 4 weeks preceding the first dose of study medication.

    Blood or plasma donation within 3 months prior to the first dose of study medication.

    Participation in another clinical trial (i.e., randomized subjects who received study medication) within 3 months prior to the first dose of study medication.

    Use of any over-the-counter (OTC) medication, including herbal and nutritional supplements, or grapefruit juice within 7 days prior to the first dose of study medication.

    Use of any prescription medication, except hormonal contraceptive or hormonal replacement therapy, within 14 days prior to the first dose of study medication.

    Treated with any known drugs that are moderate or strong inhibitors/inducers of CYP3A4 enzyme such as barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study medication. Appendix 4 contains a list of CYP3A4 inhibitors/inducers.

    Use of tobacco or nicotine containing products within 60 days prior to the first dose of study medication and during the duration of the trial period, or testing positive for Cotinine.

    Positive urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates, including buprenorphine) or any history of intravenous drug abuse or any history of abuse of opioids.

    Positive urine screen for ethanol.

    Positive results for human immunodeficiency virus (HIV-1 or HIV-2 antibodies by ELISA or EIA and reactive/positive results confirmed by HIV specific immunobloting or immunoprecipitation assays), hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), hepatitis B core antibodies (IgG anti-HBc or IgM anti-HBc) unless antibodies to HBsAg are positive in isolation, consistent with hepatitis B vaccination, hepatitis C antibody (anti-HCV), or hepatitis C viral RNA as assessed by PCR.

    Hemoglobin at screening of < 11.5 g/dl (if female subject) or < 12.5 g/dl (if male subject).

    Subject has, or has a history of, any significant disease, surgery or any condition known to interfere with the absorption, distribution, metabolism or excretion of drugs.
    E.5 End points
    E.5.1Primary end point(s)
    Pre-treatment AEs will be listed by subject. TEAEs will be listed and tabulated by treatment and by severity and causal relationship to study treatment. SAEs will be listed separately.

    Individual vital signs (supine BP, heart rate, respiration rate, oxygen saturation and aural temperature) will be listed per treatment and measurement time and summarised descriptively.

    ECG assessments will be listed by subject and measurement time.

    Individual clinical laboratory results (haematology, biochemistry and urinalysis) will be listed by subject and measurement time, including laboratory comments. Abnormal clinical laboratory values and associated repeats will be listed by subject and measurement time separately together with comments as to their clinical significance. A summary of the number of occurrences of abnormal clinical laboratory parameters will be tabulated.

    Individual virology results, results from ethanol urine, drugs of abuse and buprenorphine screens will be listed by subject.

    For the PK endpoints, plasma concentrations of naloxone, naloxone-3-glucuronide, buprenorphine, buprenorphine hemiadipate and norbuprenorphine will be tabulated separately for each treatment, gender and sampling time and summarised descriptively. Concentrations below the limit of quantification (BLQ) will be set to zero in the data summarisation and descriptive statistics.

    Individual plasma concentration-time profiles of naloxone, naloxone-3-glucuronide, buprenorphine, buprenorphine hemiadipate and norbuprenorphine will be plotted both on a semi logarithmic and a linear scale. Treatment means and associated standard deviations will also be presented graphically for each analyte, treatment and gender.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Adverse Events - Starting from 21 days prior first dosing every day until 5 to 10 days post final dose.

    Individual Vital signs (supine, BP, heartrate, respiration rate, oxygen saturation and oral temperature - measured after 3 minutes in a supine position, on Day 1 at 1, 2, 4, 8, 12 and 24 hours (Day 2) post-dose.

    Individual Clinical Laboratory results - Prior First dose, Day 1 and 5 to 10 days post final dose.

    Individual virology results - Prior first dose.

    PK end points - everyday during dose administration.
    E.5.2Secondary end point(s)
    Secondary Safety Endpoints

    Clinical laboratory results.
    12-lead ECG.
    Concomitant medication assessment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinical laboratory results - Prior First dose and 5 to 10 days after final dose.

    12-lead ECG - Prior first dose and 5 -10 days post final dose.

    Concomitant medication assessment - Prior initial dose administration, every day until 5 -10 days post final dose.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    To compare the tolerability of the two formulations of Buprenorphine Hemiadipate Hydrochloride in Healthy Volunteers.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study Yes
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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 subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 48
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state48
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will return to the Clinical Pharmacology Unit for a final post study medical visit 7 days after the last dose of study treatment. The post study medical visit will be scheduled in the morning (after an overnight fast of at least 8 hours). This visit will also be undertaken by subjects who withdraw from the study prematurely, whenever possible. If there are no clinically relevant AEs the subjects may be discharged.

    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-09-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-12-23
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