HM2008/00566/00. study and to obtain clinical experience with the use of this drug. Primary Outcome/Efficacy Variable(s): <Pharmacokinetics>

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: /182 Title: Clinical Evaluation of Ropinirole HCl (SK&F101468) as Monotherapy in Parkinson s Diseas e Phase III Open-label Uncontrolled Study Rationale: To evaluate the pharmacokinetics of ropinirole HCl administered three times daily for 16 weeks as monotherapy in subjects with Parkinson s dis ease in an open-label uncontrolled study and to obtain clinical experience with the use of this drug. Phase: III Study Period: 21 January 2002 to 9 July 2003 Study Design: Open-label Uncontrolled Study Centres: 6 medical centres in Japan Indication: Parkinson s dis ease (including juvenile Parkinsonism) Treatment: Three times daily after meals 1) Fixed titration stage: 4 weeks Subjects will be started at 0.75mg/day and take one ropinirole HCl 0.25 mg tablet three times daily after meals (except on Day 1 when subjects will start to take the investigational product after lunch). The dose will be increased weekly in 0.75 mg/day increments from 0.75 mg/day to 3 mg/day over Weeks 1 to 4. 2) Flexible titration and maintenance dose stage: 12 weeks From Weeks 5 to 16, the dose may be increased from 3mg/day to 15mg/day by 1.5mg at intervals of at least 1 week according to individual subject s t olerability until sufficient efficacy is achieved (up to a maximum of 15 mg/day). Once the subject reaches a dose level above which additional symptomatic improvement cannot be expected, he/she will be maintained on that dose. If the subject reports an adverse event that makes dose increase difficult but does not require dose reduction, he/she will be maintained on a dose level at which the adverse event is observed. If dose reduction is necessary, the subject will be down titrated until a tolerated dose is achieved and then will be maintained on that dose. The dose may be reduced to a minimum of 3 mg/day, the dose attained at the end of the fixed titration stage Objectives: To evaluate the pharmacokinetics of ropinirole HCl administered three times daily for 16 weeks as monotherapy in subjects with Parkinson s dis ease in an open-label uncontrolled study and to obtain clinical experience with the use of this drug. Primary Outcome/Efficacy Variable(s): <Pharmacokinetics> 1

2 Trough plasma concentration (Cmin) Maximum plasma concentration (Cmax) Time to reach Cmax (Tmax) Area under plasma concentration-time curve (AUC) Secondary Outcome/Efficacy Variable(s): <Safety> Adverse events Laboratory tests, ECGs, Vital signs <Efficacy> 1. UPDRS Part 3Total mean score for change from the Baseline 2. UPDRS Part 3 Responder Rate at final evaluation (percentage change from baseline of 20% and 30% or greater) 3. UPDRS Part 2 Total mean score for change from the Baseline 4. UPDRS Part 1 Total mean score for change from the Baseline 5. UPDRS Part Tot al mean score for change from the Baseline 6. Clinician s Global Impression of Efficacy Responder Rate (Improvement or better) 7. Distribution of Hoehn & Yahr Severity 2

3 Statistical Methods: The PMDA recommended that the present study should be designed to provide pharmacokinetic data and clinical experience of ropinirole administered three times daily. The sample size of 10 was selected for serial blood sampling for up to 8 hours post-dose, considering feasibility of pharmacokinetic evaluation and blood sampling, and a total of 30 subjects will be enrolled to ensure at least 10 evaluable subjects. : Four subject populations were evaluated: (1) Pharmacokinetic population c onsisting of all subjects who undergo blood sampling for pharmacokinetic analysis and do not have a major protocol deviation defined as follows. a) Subjects who do not meet the inclusion and exclusion criteria. b) Non-compliance with study medication or concomitant medication rules that may affect the pharmacokinetic assessment. c) Other deviations that may affect pharmacokinetic evaluation (2) Safety Population- consist of all subjects who take at least one tablet of the investigational product. (3) Full Analysis Population consisting of all subjects who enter the treatment phase and do not fall under any of the following conditions: a) Subjects who do not meet major eligibility criteria as measured objectively. b) Subjects who fail to take at least one dose of the investigational product. c) Subjects for whom all data are missing after the start of study treatment. (4) Per Protocol Population c onsisting of the subset of the FAS population who does not fall under the following condition Subjects who are considered ineligible for efficacy assessments because of protocol violations. Study Population: Inclusion criteria 1) Age: 20 years or older (at the time of informed consent) 2) Informed consent: Subjects who are able to give written informed consent in person (i.e. subjects who are capable of giving written informed consent). Exclusion Criteria: 1) Subjects who have been treated with another dopamine agonist or L-dopa within 4 weeks prior to the start of the treatment phase. 2) Subjects who have been treated with another investigational drug within 12 weeks prior to the start of the treatment phase. 3) Subjects who have or have a history of a serious heart disease. 4) Subjects who have or have a history of a serious hepatic or renal disorder. 3

4 5) Subjects with symptomatic postural hypotension. 6) Subjects with disturbance of consciousness. 7) Subjects who have had serious psychiatric symptoms (including those caused by anti- Parkinson drugs), such as confusion, hallucination, delusion and abnormal behavior, within 6 months (26 weeks) prior to giving informed consent. 8) Women who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study or within 30 days of the last dose of study medication. 9) Subjects with a history of allergy to ropinirole HCl. 10) Subjects who have undergone any surgical procedure for PD (e.g. pallidectomy, deep brain stimulation). 11) Others whom the investigator or subinvestigator considers ineligible for the study. Number of Subjects: Planned, N 30 Entered, N 32 Completed, n (%) 27(84.4) Total Number Subjects Withdrawn, N (%) 5(15.6) Withdrawn due to Adverse Events n (%) 5(15.6) Withdrawn due to Lack of Efficacy n (%) 0 Withdrawn for other reasons n (%) 0 Demographics N (ITT) 32 Females: Males 72.4:27.6 Mean Age, years (SD) 65.1±6.01 Pharmacokinetic Results: C max (Mean±SD ng/ml) (n) 4.3±1.3 (10) C min (Mean±SD ng/ml) (n) 2.1±0.9 (29) AUC 0-8 (Mean±SD hng /ml) (n) 25.5±8.1 (10) T max (Median [Range]) (n) 3.0 [ ] (10) T 1/2 (Mean±SD hr) (n) 5.0±1.7 (10) SK&F C max (Mean±SD ng/ml) (n) 3.3±0.8 (10) C min (Mean±SD ng/ml) (n) 2.0±0.6 (29) AUC 0-8 (Mean±SD hng /ml) (n) 21.9±4.4 (10) T max (Median [Range]) (n) 3.0[ ] (10) T 1/2 (Mean±SD hr) (n) 10.8±6.3 (10) SK&F C max (Mean±SD ng/ml) (n) 0.15±0.05 (10) C min (Mean±SD ng/ml) (n) 0.08±0.04 (29) AUC 0-8 (Mean±SD hng /ml) (n) 0.89±0.30 (10) T max (Median [Range]) (n) 2.0 [ ] (10) T 1/2 (Mean±SD hr) (n) 8.4±7.4 (10) 4

5 Efficacy Results: 1.UPDRS Part 3 Total mean score for change from the Baseline (SE) ± % Confidence Interval -16, UPDRS Part 3 Responder Rate at final evaluation ( 20% or 30% changes from baseline) UPDRS Part 3 On R esponder Rate (20%) % CI 72.6,97.8 UPDRS Part 3 On R esponder Rate (30%) % CI 72.6, UPDRS Part 2 Total mean score for change from the Baseline (SE) -3.8±3.4 95% CI -5.1, UPDRS Part 1 Total mean score for change from the Baseline (SE) -0.6± % CI -1.2, 0 5. UPDRS Part 4 Total mean score for change from the Baseline (SE) -0±0.5 95% CI -0.2, Clinician s Global Impression of Efficacy Responder Rate (Improvement or better)(95% CI) 82.8(64.2, 94.2) 7. Hoehn & Yahr Severity at baseline and endpoint n(%) Stage 1 6(20.7) Stage 2 20(69.0) Stage 3 3(10.3) at final evaluation n(%) Stage 1 23(79.3) Stage 2 5(17.2) Stage 3 1(3.4) Safety Results: Most Frequent Adverse Events On-Therapy N (%) Subjects with any AE(s), n(%) 20(66.7) Extrasystoles supraventricular 1(3.3) Positional dizziness 1(3.3) Mucosal hemorrhage 1(3.3) Diarrhea NOS 1(3.3) Nausea 7(23.3) Stomach discomfort 1(3.3) Vomiting NOS 1(3.3) Hypoaesthesia ora 1(3.3) 5

6 Skin tear 1(3.3) Creatine phosphokinase increased 1(3.3) Abnormal LFTs 1(3.3) Dehydration 1(3.3) Back pain 1(3.3) Myelodysplastic syndrome 1(3.3) Headache 1(3.3) Mental disability NOS 1(3.3) Somnolence 7(23.3) Tremor 2(6.7) Hallucination visual 1(3.3) Breathing difficult 1(3.3) Upper respiratory tract inflammation 2(6.7) Eczema 1(3.3) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 1 n (%) [related] Myelodysplastic syndrome 1(3.3)[0] Subjects with fatal SAEs, n (%) 0 Conclusion: In this open trial of ropinirole in monotherapy Parkinson disease subjects, ropinirole appeared to be effective as meansured by decrease in UPDRS and was generally well tolerated. No safety problems were identified. Ropinirole was administered orally three times per day for 16 weeks, according to a gradually increasing dose schedule Publications: No Publication Date Updated: 14-Oct