C-Path SWEDD vs DAT-Deficient slide (Conrado 2018), Summary from below percentages, Description table (intervention-based suppression of disease progression), WATCH-PD sample-size narrative, 2017 Simuni Table 1, 2018 Marek Column A table, TAK-341 IDP / ePOC / GBA GT PRC1 / 20210122_RSLT_GBA GT v2_GP rows
Rate of Motor Decline in SWEDD and DAT-Deficient Subjects was Different - Statistically and Clinically (slide)
Average monthly progression in the MDS-UPDRS part III (point/month):
- SWEDD = 0.05 (90% CI: -0.04, 0.13)
- DAT-deficient = 0.18 (90% CI: 0.14, 0.21)
- Difference = -0.13 (90% CI: -0.23, -0.04), one-tailed P-value = 0.01
Average difference in the change from baseline of motor scores at 24 months between SWEDD and DAT-deficient subjects (points):
- -3.16 (90% CI: -0.96, -5.42)
Conrado DJ, et al. Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson’s Disease Clinical Trials: A Disease Progression Modeling Analysis. Clin Transl Sci. 2018 Jan;11(1):63-70
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Summary from below
- Isradipine p3: 25%
- Joel p2: 40 (probably)%
- Inosine p3: 20%
- Prasinezumab P2: 37.5%
바람직한 description: x% (intervention-based) suppression (or reduction in) of disease progression (relative to placebo)
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| 'a trial would have 80% power to detect a difference of 5% in predicted FEV1, using a 1-sided test at the 10% level' 의미: i) , if the true drug effect was 5% better than placebo, then 10% of trials would erroneously declare statistical significance over placebo; ii) if the true effect in the active treatment was 5% better than placebo, 80% of trials would correctly declare active superior | ||||||||||||||||||||||||||||||||||||||||||||
| Efficacy variable |
- improvement in the CGI, QOL, or L-Dopa- savings is not recommended (2008 ema guideline). - (2016 Davis) in studies of motor progression, individuals should be examined in the off state, requiring individuals to undergo assessments in the off state becomes impractical with advancing disease and motor disability and might result in change in dropout bias | |||||||||||||||||||||||||||||||||||||||||||
| Tx duration | up to 24 m (2008 EMA GUIDELine) | |||||||||||||||||||||||||||||||||||||||||||
| Sample size calculation | ref: 2017 Biglan Isradipine P3, 36m |
주) updrs (not mds-updrs), Previous studies 29, 30, 41 support a standard deviation of 12.0 units for the primary outcome, total UPDRS from baseline to 36 months. The same data suggest an average change of 12 units in untreated PD patients of around 4.0 points over this same time period. However, it is deceiving, as the change would likely be much greater in the absence of symptomatic treatment. If we assume that treatment with levodopa or a dopaminergic agonist provides a "bonus" of 12 points, then the underlying true decline in function over this period would be approximately 16 points (js: 4+12), a value broadly consistent with the rate of change in total UPDRS in untreated patients. We have chosen to power our study to detect a 6-point effect, representing an overall 25% reduction in the underlying rate of progression. Using the above assumptions, a two-sided test with α = 0.05 and β = 0.8 and making allowance for 15% dropouts, the required sample size is 168 participants per group or 168 in total 336. We are also sufficiently powered to address our key secondary outcomes. Given the sample size above, we will be able to detect a 29% reduction in the rate of motor complications; an approximately 25% reduction in the dosage of ST; and an effect size of 1.5 points on the nonmotor experiences of daily living between treatment groups. CPP clinical trial simulator (DAT Neuroimaging-informed Early PD Clinical Trial Simulator): this uses 'Effect of Drug on Rate of Disease Progression (% Reduction) | ||||||||||||||||||||||||||||||||||||||||||
| WATCH-PD |
Based on current data from longitudinal studies in PD such as the PPMI study, it is estimated that using MDS-UPDRS measurement would require at minimum a study duration of at least 12-months with an estimated 156-208 early PD patients needed to have 80% power to detect a 50% intervention-based change in symptom progression relative to placebo To have at minimum 80% power to detect a 25% reduction relative to placebo would require over 800 patients. The sample size for this exploratory study was selected as a compromise between feasibility and having sufficient power to detect a mean change over 12 months for an endpoint that has superior responsiveness to that of the MDS-UPDRS (Part 3) — i.e., a larger ratio of mean change over 12 months to the variability (standard deviation) of change (standardized response mean). It has been reported that the mean change in MDS-UPDRS (Part 3) in untreated early PD patients from baseline to 1 year is 6.28 with an associated standard deviation (SD) of 6.93, based on the PPMI database (js: this is 2017 Simuni; but 2018 Simuni가 더 정확할 것), which utilized similar eligibility criteria to those in this study. With a sample size of 80 subjects, there would be greater than 95% power to detect a mean change of 6.28 units with an estimated SD of 6.93 using a one-sample t-test and a two-tailed P-value of 0.05 (or 0.025 to allow for multiple testing). For an endpoint that had a larger standardized response mean, sample size would therefore have higher power to detect a true mean change of 6.28 points in a sample of 30 subjects (whilst not accounting for multiple testing). Based on the PPMI database28, ~50% of subjects had initiated dopaminergic therapy by 12 months from recruitment, so conservatively it is expected that 60 subjects recruited would result in at least 30 subjects not starting dopaminergic therapy by 12 months. To account for potential drop-out during study conduct, the total sample size required for this study is targeting 75 enrolled subjects (a conservative 15% drop-out rate was based on a similar drop-out rate to 12 months from the PPMI study). As attrition could be higher in this planned study compared to the PPMI study (for example due to the additional use of devices), up to 100 subjects may be enrolled in this study. A drop-out of 12 months is observed to be larger than 15% during study conduct. | |||||||||||||||||||||||||||||||||||||||||||
| DATscan, MDS-UPDRS |
2017 Simuni raw data & SSE 봐라 Table 1. Sample Sizes Needed to Detect 1 Year Differences in Mean MDS-UPDRS, DATscan
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| 2018 Marek |
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| Datscan | 2018 Simuni raw data 봐라 | |||||||||||||||||||||||||||||||||||||||||||
| 20181001 TAK-341 IDP SECTION 5.22.1 | [p2/3] ., early PD patients with less than 1 year of 10 points (10.56) when not at 12 month has been set at MDS-UPDRS Part III ... (effect size = 0.31, alpha with Hahn's step down procedure = 0.05) (two-sided), and Power = 90%, the estimated number of subjects will be about 203 /arm for a 1-year study. | |||||||||||||||||||||||||||||||||||||||||||
| TAK-341 20190613 Joel ePOC presentation 061219 |
위 doc 의 data 와 동일. - MDS UPDRS Total Score (Parts I+II+III): N = 609 → 203 per arm, assuming rate of progression in untreated patients, Effect Size = 0.34 (note for the marker), 25 dropout rate. - DATscan: Mean (SD) 12 month change from baseline in striatal DaTscan signal among untreated patients = -15.1 - ePOC evaluation coincident in time with interim analysis for futility based on motor symptoms (UPDRS III) at the EOTm. - Both evaluations conducted when at least half of subjects have ≥ 244 days of treatment (~end of treatment am (244 total). | |||||||||||||||||||||||||||||||||||||||||||
| TAK-341 ePOC doc updated 060619 | 바로 위 (n=82 나온 것)와 동일 data 인데, 12 month change from baseline in mean striatum DaTscan signal was -0.15 (SD = 0.19); To detect a 50% reduction in decline, n = 59 patients per group are needed (one-sided test with alpha = 0.10; 80% power), or a total of n = 177 completing the 12-month study. | |||||||||||||||||||||||||||||||||||||||||||
| GBA GT PRC1 : Jaya's | ||||||||||||||||||||||||||||||||||||||||||||
| 20210122_RSLT_GBA GT v2_GP: | - PPMI data on early stage subjects with idiopathic PD (H&Y 1 and 2) not yet on dopaminergic therapy: Assuming one-sided alpha of 0.05, the total (2 arms) sample size required to demonstrate a 50% reduction in rate of progression of the MDS-UPDRS III (a standard endpoint in PD trials) would be 149 for a 1 year study (with quarterly visits) and 109 for a 2 year study (with annual visits) for idiopathic PD. assuming power = 80% and one-sided alpha = 5%. | |||||||||||||||||||||||||||||||||||||||||||
| Sample Size | Duration | Assessment frequency | Reduction in rate of decline |
|---|---|---|---|
| 109 | 2 year | annual | 50% |
| 111 | 2 year | quarterly | 40% |
→ 내 계산과 다름 (이게 two sided 라면 내 계산과 비슷한데)
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| 2017 Simuni table | most cells beyond Mean Change column are partially clipped | preserved as ... placeholders where the cell value is not visible in the photo crops. |
| TAK-341 IDP cell | MDS-UPDRS Part III ... (effect size = 0.31, alpha with Hahn's step down procedure = 0.05) | mid-cell ellipsis indicates a clipped passage; preserved verbatim. |
| Bottom annotation | → 내 계산과 다름 (이게 two sided 라면 내 계산과 비슷한데) | sentence is clipped at the bottom edge and continues with → if using the DAT score as an endpoint, the total (2-arm) required sample size would be 154 for a one year study and 108 for a two... in 20240722_182811. |