program discontinued

This clinical trial is being conducted to compare concentrations of hydrocodone and acetaminophen in the blood after administration of different amounts of tablets of a new and a marketed tablet formulation in healthy adults.

Part 1 is a randomized, single-site, open-label, 4-treatment, 4-period crossover, single oral dose Phase I trial in 32 healthy male and female subjects. Part will consist of an Enrollment Visit, 4 treatment periods (each lasting approximately 90 hours), and a Final Examination. The treatment periods will be separated by a washout period each lasting at least 7 days.

Part 2 is optional and depending on pharmacokinetic data review after Part 1. It is a randomized, single-site, open-label, 2-treatment, 2-period crossover, single oral dose part in healthy male and female subjects. Part 2 will consist of an Enrollment Visit, 2 treatment periods (each lasting approximately 90 hours) and a Final Examination. The treatment periods will be separated by a washout period lasting at least 7 days.

Participants must fast for approximately 10 hours prior to administration of Investigational medicinal product (IMP) and until approximately 4 hours after the administration of the IMP.

Inclusion Criteria:

• Subjects have given written informed consent to participate.

• Body mass index between 20 kg/m2 and 30 kg/m2 inclusive, with a minimal body weight of 60 kg.

• Subjects must be in good health as determined by the medical history, physical and laboratory examinations and must not show any clinically significant deviations from reference ranges as determined by 12-lead electrocardiogram (ECG), vital signs (blood pressure, pulse rate, respiratory rate), body temperature, oxygen saturation, and safety laboratory parameters (hematology, clinical chemistry, clotting, and urinalysis).

• From the first administration of IMP until at least 4 weeks (for women)/90 days (for men) after the Final Examination, subjects must agree to use highly effective contraception with a low failure rate defined as <1% per year.

• For female subjects of childbearing potential:

  • Combined (estrogen and progestogen containing) hormonal contraception.
  • Progestogen-only hormonal contraception associated with inhibition of ovulation.
  • An intra-uterine device (hormone-free).
  • An intra-uterine hormone releasing system (IUS).
  • Bilateral tubal occlusion.

Women of non-childbearing potential may be included if surgically sterile (i.e., after hysterectomy or bilateral oophorectomy) or post-menopausal for at least 12 months (i.e., spontaneous amenorrhea at least 1 year prior to screening with confirmed follicle-stimulating hormone level >40 IU/L).

For male subjects:

Male subjects have to use barrier contraception (condom) during sexual intercourse with women of childbearing potential from the first application of IMP until at least 90 days after the Final Examination. The male subject has to be willing to ensure that the female sexual partner uses at least 1 additional method of contraception with a low failure rate defined as <1% per year until at least 90 days after the Final Examination.

Exclusion Criteria:

• Withdrawal of informed consent.

• Received forbidden medication or an investigational medical device since the Enrollment Visit.

• Any relevant deterioration in the health of the subject since the Enrollment Visit possibly impacting participation in the trial at the discretion of the investigator, including: adverse events; vital signs (relevant out-of-reference blood pressure or pulse rate if technical failure can be excluded and result is confirmed by at least 1 additional measurement); physical examination, 12-lead ECG (relevant QTc prolongation if result is confirmed by 1 additional ECG measurement and manual re-evaluation by the investigator); other safety parameters.

• Blood loss of 100 mL or more since enrollment in this trial (excluding blood taken for this trial).

• Resting pulse rate <50 beats per minute or >90 beats per minute.

• Resting systolic blood pressure <90 mmHg or >140 mmHg. Resting diastolic blood pressure >90 mmHg.

• Prolongation of corrected QT interval (according to Fridericia's formula; QTcF), i.e., QTcF >450 ms or presence of other of risk factors for torsade de pointes.

• Evidence for thyroid disease based on clinical and safety laboratory findings, including thyroid-stimulating hormone.

• Any laboratory value (from blood samples taken at the Enrollment Visit) meeting the following criteria:

  • Out-of-reference range value for alanine transaminase, aspartate transaminase, alkaline phosphatase, total bilirubin, glucose (fasted), gamma-glutamyl transferase, serum creatinine, prothrombin time, and international normalized ratio.
  • Exclusion range met for urinalysis or lactate dehydrogenase, potassium, total protein, sodium, calcium, hemoglobin, hematocrit, white blood cell count, or platelets.
  • Out-of-reference range value for any other safety laboratory parameter that is judged as clinically relevant by the investigator.
  • A single repeat laboratory test (for each out-of-range parameter) is allowed to rule out laboratory error.

• Positive or missing virus serology test (in blood sample taken at the Enrollment Visit) for human immunodeficiency virus Type 1 or Type 2 antibodies, hepatitis B surface antigen, (HBsAg), hepatitis B core antigen antibodies (anti-HBc), or hepatitis C virus antibodies.

• For women of childbearing potential only: positive or missing pregnancy test.

• Subject received IMP in another clinical trial (when assessing for Part 2, excludes IMP received in Part 1 of this trial) within 30 days before the Enrollment Visit. Depending on the nature of the previous IMP, a longer washout may be needed.

• Diseases or conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs.

• History of orthostatic hypotension.

• History of, or at risk of seizures (i.e., head trauma, epilepsy in family history, unclear loss of consciousness).

• Definite or suspected hypersensitivity to the active substance or to any of the excipients of the IMP; especially known hypersensitivity/intolerance or contraindications to opioids, opioid antagonists, acetaminophen or any excipients of the drug formulation.

• Evidence or history of alcohol or drug abuse including positive or missing alcohol breath test or drugs of abuse test.

• Unable to abstain from regular use of any medication, including herbal remedies or over-the-counter medication within 2 weeks prior to the Enrollment Visit and anticipated use during the course of the trial, excluding oral contraceptives in women of childbearing potential and topical medications or nasal sprays without systemic effect.

• Lactating or breastfeeding women.

• Habitually smoking more than 10 cigarettes, 2 cigars, or 2 pipes of tobacco per day within the last 6 months before enrollment in this trial.

• Unable to refrain from smoking during the stay at the trial site in each treatment period.

• Not willing or able to abstain from consumption of:

  • Beverages or food containing methylxanthines (tea, coffee, cola, chocolate, etc.) from 48 hours prior to the planned first administration of IMP until discharge from the trial site in each treatment period.
  • Beverages or food containing quinine (bitter lemon, tonic water), grapefruit juice (sweet or sour), Seville oranges, or alcohol from 72 hours prior to the planned first administration of IMP until discharge from the trial site in each treatment period.

• Known or suspected of not being able to comply with the requirements of the trial protocol or the instructions of the trial site staff.

• Not able to communicate meaningfully with the trial site staff.

• Employee of the investigator or trial site, with direct involvement in the proposed trial or other trials under the direction of that investigator or trial site, as well as family members of the employees or the investigator.

• Blood loss of 500 mL or more within 45 days before enrollment in this trial.

• Unable to establish reliable venous access.

• Medical history of bronchial asthma, Addison's disease, prostatic hypertrophy, or urethral stricture.

Details available at:

http://www.grunenthal.com/grt-web/Grunenthal\_Group/Research\_Development/Grunenthal\_Clinical\_Trials/Data\_Sharing/296200025.jsp