Table 3.

Clinical trial sample size estimates

Pre-symptomatic prevention trial (CDR®+NACC-FTLD Global = 0)
			Primary endpoint - Sample Size Estimates (50% Treatment Effect)
Genetic Group	Estimated number of eligible participants	Inclusion Criteria	CDR®+NACC-FTLD-SB		Neuropsychological Tests		NfL (log)		MRI Volume
			2 Yrs	4 Yrs	2 Yrs	4 Yrs	2 Yrs	4 Yrs	2 Yrs	4 Yrs
C9orf72 MRI=Temporal NP = Trails B	171	All CDR 0	>10000	4994	>10000	6784	3397	699	1639	394
	13	CDR 0 & NfL (log) > 3	582	334	1113	386	>10000	638	537	173
	38	CDR 0 & DA > −5	508	224	657	184	527	153	424	119
	20	CDR 0 & DA > −2.5	266	111	364	96	439	123	402	102
GRN MRI=Frontal NP=Trails A	168	All CDR 0	3144	1526	3844	1576	684	271	826	459
	7	CDR 0 & NfL (log) > 3	250	179	250	140	158	51	71	46
	26	CDR 0 & DA −5	297	182	267	130	99	30	52	27
	10	CDR 0 & DA −2.5	182	104	159	79	84	26	37	24
MAPT MRI=MTL NP=MINT	94	All CDR 0	7073	2733	>10000	3741	3059	802	1492	526
	4	CDR 0 & NfL (log) > 3	283	188	373	220	>10000	501	147	72
	19	CDR 0 & DA −5	362	190	641	265	595	149	108	39
	14	CDR 0 & DA −2.5	191	97	311	134	438	117	72	24
Early symptomatic treatment trial (All CDR®+NACC-FTLD Global = 1 enriched with 0 and 0.5 participants)
			Primary endpoint - Sample Size Estimates (50% Treatment Effect)
Genetic Group	Estimated number of eligible participants	Inclusion Criteria	CDR®+NACC-FTLD-SB		Neuropsychological Tests		NfL (log)		MRI Volume
			1.5 Yrs	2 Yrs	1.5 Yrs	2 Yrs	1.5 Yrs	2 Yrs	1.5 Yrs	2 Yrs
C9orf72 MRI=Temporal NP = Trails B	94	ALL CDR 0.5 and 1	188	129	340	203	811	483	639	367
	37	All CDR 1 & (CDR 0 & 0.5 if NfL > 3)	161	115	370	222	1806	782	645	358
	83	All CDR 1 & (CDR 0 & 0.5 if DA > −2.5)	176	124	400	207	740	423	678	360
	67	All CDR 1 & (CDR 0 & 0.5 if DA > 0)	117	79	275	161	628	384	669	359
GRN MRI=Frontal NP=Trails A	67	ALL CDR 0.5 and 1	76	66	115	79	133	76	44	30
	33	All CDR 1 & (CDR 0 & 0.5 if NfL > 3)	97	84	124	92	182	110	49	36
	48	All CDR 1 & (CDR 0 & 0.5 if DA > −2.5)	79	68	105	74	127	75	36	26
	38	All CDR 1 & (CDR 0 & 0.5 if DA > 0)	39	32	62	41	124	72	32	22
MAPT MRI=MTL NP=MINT	43	ALL CDR 0.5 and 1	175	136	300	196	845	437	124	74
	11	All CDR 1 & (CDR 0 & 0.5 if NfL > 3)	89	66	138	91	1719	769	95	59
	43	All CDR 1 & (CDR 0 & 0.5 if DA > −2.5)	164	120	244	163	779	419	109	63
	31	All CDR 1 & (CDR 0 & 0.5 if DA > 0)	96	66	150	104	627	359	83	48

Note. Sample size estimates (total n for a trial) are first presented for pre-symptomatic prevention trials in which all enrolled participants are presymptomatic based on CDR^®+NACC-FTLD = 0. Within each genetic group, sample sizes are estimated for trials enrolling all presymptomatic participants as well as three additional scenarios in which NfL or Disease Age are used to enroll high-risk participants likely to be proximal to symptom onset. In the bottom half of the table, estimates are presented for an early symptomatic trial in which all participants with a CDR^®+NACC-FTLD Global = 1 are eligible, and those with CDR^®+NACC-FTLD < 1 are included based on different inclusion criteria. The estimated number of eligible participants refers to the number of participants in the current dataset that meet the specified inclusion criteria. For each genetic group, we select a representative MRI and neuropsychological measures (displayed in the first column). Bolded cells indicate that the sample size estimates are less than or within 15 participants of the number eligible. All trial designs assume 1:1 randomization treatment vs. control, 10% attrition per year, and have a primary analysis of a change from baseline in the primary endpoint. Additional details of the assumptions underlying these simulations can be found in Table S9.

Abbreviations: CDR^®+NACC-FTLD-SB/CDR: Clinical Dementia Rating Scale plus National Alzheimer’s Coordinating Center’s Frontotemporal Lobar Degeneration Module Sum of Boxes; NfL(log): Log-transformed plasma neurofilament light chain; MRI: magnetic resonance imaging; NP: Group-specific neuropsychological measure; Trails A/B: Trail Making Test, Parts A & B; MTL: Medial Temporal Lobe; MINT: Multilingual Naming Test; DA = Disease Age