GBA GT v2_GP sample-size tail, 20190423 Sclareol-NS imaging strategy 4-panel chart, Sample size calculation (proportion / Visions Pharmaceutical 2021 #1755 / Lundkya 2013), Innovative design / Interim analysis / β regression model / FDA-EMA principle, C-Path DAT Enrichment slide, Delayed start design (Liu-Seifert 2015 sketch), MEAN STRIATUM DAT vs AV133 table

Sample Size	Duration	Assessment frequency	Reduction in rate of decline
149	1 year	quarterly	50%
109	2 year	annual	50%
111	2 year	quarterly	40%

→ 내 계산과 다름 (이게 two sided 라면 내 계산과 비슷한데)

→ if using the DaT scan as an endpoint, the total (2-arm) required sample size would be 154 for a one year study and 108 for a two year study (with quarterly visits) and 100 for a 2 year (with annual visits) for idiopathic PD assuming alpha = 0.05, the total (2 arm) sample size required to demonstrate a 50% reduction in rate of progression of the MDS-UPDRS III using the 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).

	row label	row content
	20190423 Sclareol-NS imaging strategy	PD: The sample sizes shown here are calculated for a 50% slowing of dopamine signal decrease over 12 months. These calculations are based on N=345 subjects for DaTscan but only N=17 for [18F]AV-133. 위의 alpha effect size 봤더니 보고된 적은 자료가 적은 듯, 이중 sample size 봐서 효과적인 주영태 알 (=1, two sided) 하면 sample N. tor arm/arm 이 1 total 만
	Effect size	P arm (two sided)
Sample size calculation - proportion	Visions Pharmaceutical, 2021 #1755	With 270 randomized participants, the study was designed to have 80% power to detect a 25% reduction by inosine in the expected rate of progression, ie, a reduction in the 2-year increase in MDS-UPDRS parts I-III by 6.0 points, which corresponds with patient assessment of a minimum clinically important difference[18, 19] (Section 10.5.1 in the study protocol clipperment). Assuming that 30% of the subjects in the population have the factor, the study would require a sample size of 38 for estimating the expected proportion with 70% absolute precision (Margin of Error) and 80% confidence. We would expect a proportion of 30%, then a sample size of 73 would be sufficient. In other words, if you need to ascertain a sample of 38 from a population, and determine that 36% of subjects have the factor of interest, you would be 80% confident that between 26% and 46% of subjects in the population have the factor of interest. My description: from the visual assessment of Lundkya 2013 (fig 19), approximately 36% of idiopathic PD showed 50% reduced soluble parkin protein of average healthy controls. A study would require a sample size of 38 for estimating the expected proportion (36%) with 70% margin of error and 80% confidence. 2017 Biglan
Innovative design
Interim analysis		ref: 2017 Biglan
Many good examples of GLP1 agonist trials in [Mc/aritmu, 2020 #1542], [Ahsmed, 2020 #2341]		- Inosine P3 (Parkinson Study Group 2014 #682): 70% of changes of placebo group. - Inosine p3
β regression model		Figure 4A. The sample size required per arm decreased with the increase of the drug effect size to achieve 80% power. Specifically, in order to achieve 80% power, a PD therapeutic response with a disease modifying effect of 20%, 30%, 40% or 50% will require 400, 180, 100 and 70 subjects per arm, respectively. Figure 4B shows that the sample size required to achieve 90% power for a 50% reduction in progression rate decreases with an increase in trial duration. In order to achieve 90% power, 480, 160 and 70 subjects per arm will be required for clinical trials with 12, 18 and 24 months treatment duration, respectively.
Review and numerous examples: (Ahmed et al. 2014, PMID)
FDA	(MJF Roadmap for PD TREATMENTS 2018, ?9)	Adornisant them in all FDA guidance is the principle of clinical meaningfulness. The change in UPDRS may be evaluated by a slope analysis. Extrapolation of the slope beyond the observation period requires a linear progression rate. This assumption needs to be justified and might be different depending on the population included and duration of observation. Hence the clinical relevance of difference in slope may be difficult to interpret. Also, the slope in the placebo group is dependent on the population selected. Given these reservations with respect to the slope analysis, alternative analyses, if justified, may be more appropriate.
EMA

여기까지 SWEDD 빼면 N 이 11/3,4 위치/2

DAT Enrichment allows ~24% Reduction of Trial Size to Detect a Disease modifying Drug Effect with 80% Power (slide)

Under these assumptions:

• 24 month placebo-controlled trials
• Enriched trials had only subjects with DAT deficit, while non-enriched trials included 33% of SWEDD.
• Disease modifying drug effect of 50% reduction in the progression rate.
• Power was calculated as the proportion of trials for which the parameter estimate for the interaction between time and treatment showed a beneficial drug effect with a two-tailed P-value < 0.05.

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

Confidential

Delayed start design

{Liu-Seifert, 2015 #2848}

Rationale: if delayed start patients catch up with the early start patients at the end of the delayed start period, the drug is symptomatic; if not, then disease-modifying.

Challenge: operational challenges and absence of a robust statistical method.

MEAN STRIATUM DAT vs AV133

DaTscan (N=345)	TIME	Mean (SD) Change From Baseline in Mean striatum	Power	Reduce By 100%	Reduce by 50%	Reduce by 25%
	1 Year	-11.7% (12.1)	80% 90%	35 50	140 180	540 720
	2 Year	-20.9% (16.1)	80% 90%	10 32	34 42	140 160
AV133 (N=17)	— Mean (SD) Change From …

Uncertain Spans

location	transcription	uncertainty
Adornisant them in all FDA guidance	reads as written (likely OCR garble of Adamant theme in all FDA guidance or similar); preserved verbatim.
[Mc/aritmu, 2020 #1542], [Ahsmed, 2020 #2341]	reference labels	OCR-rendered; preserved verbatim with bracket and comma artefacts.
Sclareol-NS imaging strategy	샘플 N. tor arm/arm 이 1 total 만	trailing tor arm/arm 이 1 total 만 is partly clipped; preserved verbatim.