Study Evaluating Efficacy and Safety of OSU6162 in the Treatment of Residual Symptoms After Stroke

Following stroke, a recovery process is promptly initiated, which leads to a partial rehabilitation. However, a number of disabling residual symptoms may persist for years and include mental fatigue, depression, cognitive deficits, neurological problems and more. In the lack of an effective treatment these symptoms will lead to major consequences for the individual and the surrounding society. OSU6162 has in earlier clinical studies of stroke patients shown evidence of a favorable effect on residual symptoms, especially mental fatigue, together with a mild side effect profile.

In this phase II, randomized, placebo-controlled, two-armed study, a 16 week OSU6162 treatment will be compared to an equally long placebo treatment in patients with residual symptoms following stroke.

Main objectives of this study are to evaluate the efficacy and safety of OSU6162 compared to placebo with respect to treatment response in post stroke patients.

Endpoints:

Primary endpoint is Clinical Global Impression of Change (CGI-C) after 16 weeks of treatment.

Secondary endpoints are:

CGI-C score after 4, 8 and 12 weeks of treatment. FAI; MFS; FSS; BDI; SF-36 scores after 4, 8, 12 and 16 weeks of treatment. Correlation between plasma concentration of OSU6162 and therapeutic response after 4 and 16 weeks of treatment.

Safety variables: AE/SAE, physical and neurological examinations, vital signs (blood pressure and puls) and laboratory test.

Study Design:

The treatment period is 16 weeks, during which all patients will make 7 study visits and have 4 telephone interviews.

Study visits include:

Visit 1: screening at week -2, Days -14 to -5 Visit 2: baseline at week 0 Visit 4: week 4 ± 3 days Visit 6: week 8 ± 3 days Visit 8: week 12 ± 3 days Visit 10: week 16 ± 3 days Visit 11: follow up at week 20 ± 7 days

Randomization and start of treatment with OSU6162 or placebo at baseline, visit 2, week 0. Study medication administered during all study visits from baseline at visit 2 to visit 8 at week 12.

Physical and neurological examinations, vital signs and weight recording during all study visits.

ECG recorded during visits 1 (week -2) and 10 (week 16). Blood (and urine) sampling for safety labs during visits 1 (week -2), visit 4 (week 4), visit 10 (week 16). Pregnancy test at visit 1 and 10.

Blood sampling for analysis of plasma OSU6162 concentration at visit 4 and 10.

Primary outcome measures and secondary outcome self-assessment tests performed during all study visits.

Telephone interviews at visit: 3 (week 2 ± 3 days), 5 (week 6 ± 3 days), 7 (week 10 ± 3 days) and 9 (week 14 ± 3 days.

Concomitant medication, adverse events and drug compliance are recorded during all visits and telephone interviews.

Dosing:

All patients in the OSU6162 group start with a dose of 15 mg BID. The dose is increased to a maximum of 30 mg BID after 4 weeks of treatment. Intermediate doses are allowed and the final dose is individually flexible, depending on the therapeutic response and presence of AE. In the placebo group patients receive tablets with identical appearance to active treatment tablets (OSU6162 15 mg), administered according to the same dosing regime as active treatment.

Data analysis and statistics:

Efficacy analyses will be based on Mixed Models for Repeated Measures (MMRM) analyses. The MMRM analyses use all the longitudinal observations at each post-baseline visit for the study period of interest. Significance tests will be based on estimated population marginal means and Type III test of fixed effects, using a two-sided test with the significance level of 0.05. Differences in distributions of categorical variables will be tested using the Chi-square test or Fisher's exact test.

Due to the large number of variables engendered, multivariate statistical evaluations will be performed as a complement to the above-mentioned statistical methods.

Before unblinding of the study data, a separate Statistical Analysis Plan (SAP) will be prepared.

Patient and data safety:

This study is conducted in accordance with the study protocol, the Declaration of Helsinki, ICH E6 GCP, the European Clinical Trials Directive 2001/20/EC and applicable local laws and regulations.

The Investigator is responsible for ensuring the accuracy, completeness, legibility and timeliness of the data recorded in the CRFs. Data recorded in the CRF that are derived from source documents should be consistent with the source documents or the discrepancies should be explained. Signed sections of CRFs are monitored and collected on a regular basis.

An individual secrecy agreement is established for all Sponsor, site personnel, independent auditors, and representatives from Competent Authorities that will have access to the information in the medical records for the participating patients.

Eligibility Criteria:
Inclusion Criteria:

1. Signed written informed consent
2. Between 18-80 years
3. Stroke \>12 months prior to the start of the study. Patients must have had the location of their stroke evaluated through a CT scan, noted in their hospital notes
4. Anamnestic evidence of post stroke residual symptoms at least 3 months prior to the start of the study
5. At least 10.5 points on Mental Fatigue scale at the screening visit 1 (week -2)

Exclusion Criteria:

1. Residual symptoms following other pathologies than stroke
2. Active substance abuse (drug screen taken at visit1)
3. Other serious somatic or psychiatric disease
4. Beck Depression Inventory \>30 at visit1 and 2
5. Current pregnancy or breast-feeding, or intention to become pregnant within 3 months after the last dose
6. Female patients of childbearing potential not using adequate contraceptives. Female patients of childbearing potential must, for inclusion, use a highly efficient method of contraception, i.e. a method with a failure rate of less than 1% (e.g. sterilisation, hormone implants, hormone injections, some intrauterine devices, or vasectomy in partner). Male patients must agree to use condoms during the study and for 2 weeks after the end of the study/last dose of IMP, unless their partner is using a highly efficient method of contraception, as described above.
7. Pathologic ECG, as assessed by the investigator. Max QTc time on ECG: 450 ms in men and 460 ms in women
8. Abnormal laboratory values of such severity that participation in the study, in the opinion of the investigator, is questionable
9. Patients who are so debilitated by their disease that they are not assumed to be able to perform the assessments or handle the instruments used for evaluation of effect
10. Current participation in other Clinical trials
11. Previous treatment with OSU6162
12. Clinically significant liver disease which may prevent the patient from completing the study and/or an elevation in either total bilirubin, alkaline phosphatase, AST, ALT of \>2 times the laboratory reference
13. Clinically significant renal disease which may prevent the patient from completing the study and/or an elevation in serum creatinine of \>1.5 times the laboratory reference.
14. Any surgical or medical condition which, in the opinion of the investigator, might interfere with the absorption, distribution, metabolism or excretion of OSU6162
15. Patients treated with Modiodal, Xyrem, Mirtazapine, Mianserin or metabolic enzyme inhibitors (with the exception of antidepressants other than Mirtazapine and Mianserin) or inducers, or drugs with a narrow treatment window (e.g. warfarin, antiepileptics, cyclosporine) and individually modelled drugs such as lithium.
16. Use of drugs capable of inducing hepatic enzyme metabolism (e.g., barbiturates, rifampicin, carbamazepine, phenytoin, primidone) within 30 days prior to the start of the study (or 5 half-lives of the inducing agent, whichever is longer)
17. Antipsychotic treatment
18. Patients treated with "unstable therapies", i.e., treatments that have not been at the same dose for at least 6 weeks prior to inclusion in this study. The treatment must also remain unchanged during the study period. Insomnia medication and other PRN medications are allowed
19. Use of acute or chronic medications for other medical conditions are allowed based on the investigator's judgement. Occasional use of over-the-counter (OTC) medication is allowed at the investigator's discretion
20. Supplements from health food stores and naturopathic preparations (dietary supplements, natural remedies) are not allowed during the course of the study or 4 weeks before study start.