| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039626 |
| E.1.2 | Term | Schizophrenia |
|
| 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 objectives of this study are to investigate, with JNJ-40411813 as monotherapy or as add-on to antipsychotics:
- Safety and tolerability in subjects with schizophrenia;
- Explore potent effect in subjects with schizophrenia; |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
- To assess the pharmacokinetics of JNJ-40411813 in a patient population using a population PK approach and explore its relationship with efficacy (e.g., change in Positive and Negative Syndrome Scale [PANSS] scores) and safety parameters |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female between 18 and 65 years of age, inclusive
2. Body Mass Index (BMI) between 18 and 35 kg/m2 inclusive (BMI =
weight/height2)
3. Medically stable on the basis of physical examination, medical history, vital
signs and 12-lead ECG performed at screening.
4. Medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel, hematology, or urinalysis are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal to not be clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the subject's source documents and initialed by the investigator.
5. In- or outpatients who have been diagnosed with schizophrenia according to
DSM-IV (295.10, 295.20, 295.30, 295.60, 295.90) at least 1 year prior to
screening.
6. Known by the recruiting or referring psychiatrist for at least 12 months.
7. Men must agree to use a double barrier method of birth control at each sexual
intercourse (at least a condom) and to not donate sperm during the study and
for 90 days after receiving the last dose of study drug.
8. Women must meet one of the following:
– postmenopausal (amenorrhoea for at least 12 months prior to screening or amenorrhoea for at least 6 months prior to screening and follicle stimulating hormone [FSH] concentrations of >40 mIU/mL),
– surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy),
– or if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method [e.g., condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel], male partner sterilization) as
local regulations permit, before entry, and must agree to continue to use the same method of contraception at least 3 months after the last intake of study drug.
9. Women of childbearing potential must have a negative serum pregnancy test
at screening and a negative urine pregnancy test at baseline before receiving
the study drug.
10. Must be able and willing to describe subjective experiences while receiving
JNJ-40411813.
11. Subjects themselves or the relatives they are living with have to be reachable
by phone on a regular basis.
12. Must be willing and able to adhere to the prohibitions and restrictions
specified in this protocol.
13. Must have agreed to frequent blood sampling during the course of the study.
14. Subjects (or their legally acceptable representative) must have signed a separate written ICF for pharmacogenomic (DNA) research indicating
willingness to participate in Part 1 (genetic analyses related to the study) of the pharmacogenomic component of the study; and indicating either consent or refusal for Part 2 (DNA storage for future research) (where local regulations permit). Subject participation in Part 1 is required. Subject participation in Part 2 is optional and refusal to participate in Part 2 will not result in ineligibility for the main study.
Inclusion criteria specific to Acute Subjects (Part A, JNJ-40411813
monotherapy)
15. Subjects preferring treatment with an antipsychotic with a novel mode-ofaction
over currently available antipsychotics. Subjects should not have received any oral antipsychotic for at least 5 days, and no long acting injectable antipsychotic for at least 3 months, before Day 1. Antipsychotic medication should not be removed for the purpose of making subjects eligible for enrollment into the study.
16. Total PANSS score: 70 to 120
17. Willing to be treated for at least 14 days as inpatient at the beginning of the
trial.
Inclusion criteria specific to Stable Subjects (Part B, JNJ-40411813 add-on
therapy)
18. Stable treatment for at least 3 months (minor changes are acceptable upon
confirmation by the sponsor representative).
19. Total PANSS score: 50 to 90
20. Willing to be treated as an inpatient if medically appropriate.
21. Clinically stable for at least 3 months with residual symptoms that are not
satisfactorily controlled with (or without) current treatments
22. Subjects with residual positive symptoms:
Should have positive symptoms like delusions, hallucinations, formal
thought disturbances, depersonalizations and/or catatonic symptoms like stereotypies for at least three months despite, currently receiving antipsychotic treatment (other than clozapine). PANSS positive subscale should be ≥15 and higher than the PANSS negative subscale.
23. Subjects with residual negative symptoms: (see protocol for details)
24. Subjects partially responsive to clozapine treatment: (see protocol for details)
|
|
| E.4 | Principal exclusion criteria |
1. A current DSM-IV axis I diagnosis other than schizophrenia
2. A DSM-IV diagnosis of substance abuse or dependence within 6 months prior to screening evaluation (nicotine and caffeine dependence are not exclusionary; subjects with a positive drug screen at screening may be included provided use does not lead to a DSM-IV diagnosis of substance dependence and subjects should be encouraged to abstain from alcohol and illegal drugs within 3 days prior to Day 1 and at any time during the study)
3. Any medical condition that could potentially alter the absorption, metabolism, or excretion of the study medication, such as Crohn’s disease, liver disease, or renal disease
4. Relevant history of any significant and/or unstable cardiovascular, respiratory, neurologic (including seizures or significant cerebrovascular disorders), renal, hepatic, endocrine, or immunologic diseases
5. PANSS score <50 or >120
6. Other significant and/or unstable systemic illnesses
7. Allergy or hypersensitivity to any known antipsychotic compounds
8. Inability to swallow the study medication whole with the aid of water
(subjects may not chew, divide, dissolve, or crush the study medication, as
this may affect the release profile)
9. Subjects who have never been treated with antipsychotics
10. Exposure to an experimental drug or experimental medical device within
90 days before screening
11. Significant risk of suicidal or violent behavior
12. Female subjects who are pregnant or breastfeeding
13. Clinically significant abnormal values for clinical chemistry, hematology or urinalysis at screening or admission. It is expected that laboratory values will generally be within the normal range for the laboratory, though minor deviations, which are not considered to be of clinical significance to the investigator, are acceptable. Values of ALT/AST <2 fold the upper limit of normal will be allowed
14. Serology positive for hepatitis B surface antigen (HBsAg), hepatitis C
antibodies or HIV antibodies at screening
15. Clinically significant abnormal physical examination, vital signs or 12-lead ECG at screening. Minor deviations in ECG, which are not considered to be of clinical significance to the investigator, are acceptable.
16. Clinically significant abnormal observations in ECG defined as:
– A confirmed screening visit QTcB interval ≥470 msec
– A history of additional risk factors for torsades des pointes (e.g. heart
failure, hypokalemia, family history of Long QT Syndrome)
17. Use of monoamine oxidase inhibitors within 4 weeks or fluoxetine within
5 weeks before screening. Use of all tricyclic antidepressants within 2 weeks before screening
18. Use of mood stabilizers (e.g., anticonvulsants and/or lithium) within
2 weeks before Day 1.
19. Received electroconvulsive therapy within 3 months before screening
20. Have been involuntarily committed to psychiatric hospitalization
21. Alcohol dependence and/or illicit drug use
22. Any condition that, in the opinion of the investigator, would compromise
the well-being of the subject or the study or prevent the subject from
meeting or performing study requirements
23. Donation of 1 or more units (approximately 450 mL) of blood or acute
loss of an equivalent amount of blood within 90 days prior to study drug
administration
24. Employees of the investigator or study center, with direct involvement in
the proposed study or other studies under the direction of that investigator
or study center, as well as family members of the employees or the
investigator
25. Any concomitant drug with CYP3A4 inhibiting or inducing properties
(see Attachment 15).
Medication exclusion criteria specific to (Sub)acute Subjects (Part A,
monotherapy)
26. Subjects currently taking antipsychotics or any antidepressant.
Medication exclusion criteria specific to Stable Subjects (Part B, JNJ-40411813
add-on therapy)
27. Subjects with residual positive and negative symptoms:
- Currently receiving clozapine treatment (otherwise can be in the
clozapine treated subgroup)
28. Subjects partially responsive to clozapine
- No specific exclusion criteria
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Endpoints:
Potential clinical efficacy of JNJ-40411813 will be evaluated using the PANSS, Clinical Global Impression- Schizophrenia scale (CGI-SCH) and the short version of the Subjective Well-Being under Neuroleptics Scale (SWN) for all the subjects. Some scales will only be used for the stable subjects who are clinically judged as
having relevant symptoms in the evaluated dimensions; the Calgary Depression Scale for Schizophrenia (CDSS), the Hamilton Anxiety Rating Scale (HAM-A), and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).
Safety Endpoints:
Safety and tolerability scales for all subjects will include the Udvalg for Klinische
Undersogelser (UKU) side effect rating scale, vital signs, body weight, lab tests
(including biomarkers and prolactin [PRL]) and a suicidality scale (Columbia Suicide
Severity Rating Scale [CSSRS]).
Furthermore, a detailed written report on each subject will be prepared by the
investigator based on her/his observations and an interview with the subject at the end of the trial. These narratives will be used to support the efficacy evaluation. |
|
| 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 | Yes |
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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 | 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
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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