| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10043882 |
| E.1.2 | Term | Tinnitus |
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| 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 |
| To measure the change in tinnitus loudness (VAS) after single (Day 1) and repeated (Day 14) administration of either vestipitant-paroxetine combination, or vestipitant alone vs. placebo. |
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| E.2.2 | Secondary objectives of the trial |
To measure the change in tinnitus subjective features (i.e., tinnitus pitch and distress, and general alertness/anxiety levels), audiometry, psychoacoustic assessment of tinnitus pitch, timbre, loudness using an automated system, emotional/alertness level (i.e., visual scales, heart rate and blood pressure), clinical scores (i.e., Tinnitus Handicap Inventory and Annoyance of Hyperacusis; Diary for tinnitus, hyperacusis, and sleep).
To evaluate safety and tolerability of vestipitant alone and the combination paroxetine-vestipitant at single dose.
To evaluate the PK/PD relationships between steady state exposure of vestipitant and paroxetine-vestipitant combination with each of the various pharmacodynamic endpoints
To measure the change in Diary parameters of tinnitus and hyperacusis during the treatment period between the vestipitant-paroxetine combination and placebo.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
•Male or female subjects diagnosed with tinnitus according to a standard audiology visit and examination, including otoscopy and audiograms
•Subject with a THI severity grade of mild or greater (THI >= 18, [Newman, 1998]).
•Subjects must be 18-65 years of age inclusive.
•The subject must have the ability to comprehend the key components of the consent form and must have given written informed consent to participate in the study prior to commencing any study specific procedures.
•Women of childbearing potential, who have a negative urine pregnancy test result at screening and pre-dose on Day 1 for all the 3 treatment sessions, must be able to commit to either of the following:
Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug,
OR
Agrees to consistent and correct use of an acceptable method of birth control; GSK acceptable Contraceptive Methods, when used consistently and in accordance with both the product label and the instructions of a physician, are as follows:
a.Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject, or
b.Oral contraceptives (either combined or progestogen only);
Double-barrier method of contraception consisting of condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository);
IUD with a documented failure rate of less than 1% per year;
If subjects indicate they will remain abstinent during the period described above, they must agree to follow GSK guidelines for the consistent and correct use of an acceptable method of birth control should they become sexually active.
•Women of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal. For purposes of this study, postmenopausal is defined as one year without menses).
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply - see protocol for full list of criteria:
• Subject with a THI of grade of “No handicap” [Newman, 1998] i.e. THI score of less than 18.
• Subjects with one of the following medical conditions:
a. Subjects with any serious medical disorder or condition that would, in the investigator's opinion, preclude the administration of vestipitant or paroxetine
b. Existence of any surgical or medical condition which, in the judgement of the investigator, might interfere with the absorption, distribution, metabolism or excretion of the drug
c. Subjects with known Meniere Disease or Otosclerosis.
d. Subjects with a 12-lead ECG at screening, which in the opinion of the Principal Investigator or physician designee has abnormalities that will compromise safety in this study. Specific exclusion criteria with regard to QT interval (either QTcb or QTcf, machine or manual over-read, males or females) are as follows:
• QTc >=450 msec, based on single or average QTc value of triplicate ECGs obtained over a brief recording period.
e. Subjects with laboratory parameters outside the reference range for this age group will only be included if the Principal Investigator or designe considers that such findings will not introduce additional risk factors. In any case, liver function tests (bilirubin, ALT, AST or alkaline phosphatase) must be below 1.5 fold higher than the upper limit of normal at screening.
f. Subjects positive for hepatitis C antibody or hepatitis B surface antigen
g. Subjects who are not euthyroid based on clinical examination and laboratory results at the Screening Visit. Subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit.
h. Subjects with current or past history of clinically significant hepatic (subjects with hepatic impairment [ALT, AST, bilirubin, alkaline phosphatase, GGT must be below 1.5 fold higher than hte upper limit of normal screening] or a history of liver dysfunction), cardiac, renal (serum creatinine higher than 124umol/l), neurologic, cerebrovascular, metabolic, pulmonary disease or gastrointestinal bleeding.
i. Subjects with a current condition of, or history of psychosis.
j. Subjects who have had a myocardial infarction within 1 year prior to screening visit.
k. Subjects with current or past history of seizure disorders (except for febrile seizures in childhood).
l. Subjects with known or past history of cancer
m. Subjects with current or past clinically significant history of drug or other allergy (atopy) which, in the opinion of the Investigator, contraindicates the subject's participation in the study.
• Current or history of (within 6 months of study) regular alcohol consumption defined as:
- For males: an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units.
- For females: an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units.
-One unit is equivalent to a half-pint (220mL) of beer or 1 (125 mL) measure of spirits or 1 glass (125mL) of wine.
• Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive alcohol breath test at the Screening Visit. Subjects must be told to avoid consumption of alcoholic beverages for at least 24 hours prior to their Screening Visit. If a subject has a positive alcohol breath test or positive urine illicit drug screen, this subject will be excluded and the test may not be repeated.
• Subjects who have taken psychotropic drugs or antidepressants within the time frames specified below:-
• MAOIs or Fluoxetine –4 weeks prior to Screening Visit 1
• Antidepressants other than MAOIs or fluoxetine (e.g. TCAs, SSRIs, NSRIs), anxiolytics, lithium, other mood stabilisers (including anticonvulsants) and oral antipsychotics –14 days prior to Screening Visit 1
• Beta-adrenergic blockers if used to treat anxiety or its physical manifestations (e.g. tremor) –14 days prior to Screening Visit 1. Subjects prescribed Beta-adrenergic blockers may also be excluded due to potential drug-drug interactions.
• Opiates, hypnotics, benzodiazepines, and all other sedatives (including sedating antihistamines) – 5 half-lives or 14 days, whichever is longer prior to Screening Visit 1
• Any herbal/natural supplement or preparation known or thought to have any psychoactive effects –14 days prior to Screening Visit 1
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Visual Analog Scales (VAS) to measure the change in tinnitus loudness as perceived at the moment of the measurement at 2 hrs after dosing (or at any other time point vs. pre-dose baseline in their respective treatment session). |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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.8.5 | The trial involves multiple Member States | No |
| 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 | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | |
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