Korean Journal of Clinical Pharmacy

Table. 2.

Table. 2. Table 2

Studies on tertiary prevention of T1D

Drug	Study	population, age (years)	Time of diagnosis	Intervention	Time of primary endpoint	Primary endpoint	Outcome, p value
Anti-CD
Teplizumab (anti-CD3)	Herold anti-CD3^50,51) (phase 1/2)	n=42, 7-30	<6 weeks	IV infusion for 14 days	1 year	MMTT C-peptide AUC	103% vs. 49% of baseline (0.01)
	Protégé^52,53) (phase 2/3)	n=516, 8-35	<12 weeks	1. 14-day full-dose group (n=209): ~9034 μg/m²2. 14-day low-dose group (n=102): ~2985 μg m²3. 6-day full-dose group (n=99): ~2426 μg/m²	2 years	Insulin <0.5 U/kg + HbA1c <6.5%	NS
	ITN AbATE⁵⁴⁾(phase 2)	n=83, 8-30	<8 weeks	IV infusion for 14 days	2 years	MMTT C-peptide AUC change	-0.28 vs.-0.46 (0.002)
	DELAY⁵⁵⁾(phase 2)	n=63, 8-28	4-12 months	IV infusion for 14 days	1 year	MMTT C-peptide AUC	0.45 vs. 0.37 (0.03)
	PROTECT⁵⁶⁾(phase 3)	n=328, 8-17	<6 weeks	2 cycles of 12-day course IV infusion	18 months	MMTT C-peptideAUC change	-0.09 vs. -0.21 (<0.001)
Otelixizumab (anti-CD3)	Keymeulen anti-CD3^59,60)	n=80, 12-39	<4 weeks*	IV infusion for 6 daysday 1: 8 mg or 24 mg; day 2-6: 8 mg	48 months	insulin requirement change	+0.09 vs.+0.32 U/kg/day (<0.01)
	DEFEND-1⁵⁷⁾(DEFEND-2⁵⁸⁾)	n=281(179), 12-45(12-45)	<90 days	day 1: 0.1 mg; day 2: 0.2 mg; day 3: 0.3 mg; day 4-8: 0.5 mg IV infusion	1 year	MMTT C-peptideAUC change	NS
	Anti-CD3 dose-finding trial⁶¹⁾	n=28, 16-27	<32 days	cumulative 9 or 18 or 27 mg IV infusion for 6 days	18 months	1. Safety2. MMTT C-peptideAUC	1. Dose-related AEs, n/a2. Diff†: 0.39 (0.023)
Abatacept (anti-CD80/86)	TrialNet abatacept^62,63)	n=112, 6-45	<100 days	10 mg/kg (max: 1000 mg/dose) IV infusion day 1, 14, 28 and once a month for 2 years	2 years	MMTT C-peptide AUC	0.378 vs.0.238 (0.0029)
Alefacept (anti-CD2)	T1DAL-alefacept^64,65)	n=49, 12-35	<100 days	15 mg IV infusion per week, 12 times repeat after 12 weeks rest	1 year	MMTT C-peptide AUC change	+0.015 vs.-0.115 (0.065)
Rituximab (anti-CD20)	TrialNet anti-CD20^66,67)	n=87, 8-40	3 weeks-3 months	day 1, 8, 15, 22375 mg/m² IV infusion	1 year	MMTT C-peptide AUC	0.56 vs. 0.47 (0.03)
Iscalimab (anti-CD40)	Iscalimab CD40 blockade⁶⁸⁾	n=102, 12-21	<56 days	initial: IV infusion; subsequent: SC	1 year	1. Safety2. MMTT C-peptide	In progress
Cytokine-directed
Canakinumab (anti-IL-1β)	TrialNet canakinumab⁶⁹⁾	n=69, 6-45	<100 days	2 mg/kg (max: 300 mg) once a month SC for 12 months	1 year	MMTT C-peptide AUC	NS
Anakinra (anti-IL-1)	AIDA anakinra trial⁶⁹⁾	n=69, 18-35	<12 weeks	100 mg qd SC for 9 months	9 months	MMTT C-peptide AUC	NS
Tocilizumab (anti-IL-6)	EXTEND-children⁷⁰⁾ (adults⁷⁰⁾)	n=81(55), 6-17(18-45)	<100 days	10 mg/kg or 8 mg/kg (max: 800 mg) IV per 4 week for 24 weeks	52 weeks	MMTT C-peptide AUC	NS
Ladarixin (anti-IL-8)	Ladarixin⁷¹⁾	n=76, 18-46	<100 days*	400 mg PO bid, 14 days on/14 days off cycle, 3 cycles	13 weeks	MMTT C-peptide AUC change	NS
Ustekinumab (anti-IL-12/23)	UST1D2-adults⁷²⁾	n=66, 18-35	<100 days	week 0: 6 mg/kg IV (loading dose)week 8, 16, 24, 32, 40, 48: 90 mg SC	52 weeks	MMTT C-peptide AUC	In progress
	USTEK1D-adolescents⁷³⁾	n=72, 12-18	<100 days	week 0, 4, 12, 20, 28, 36, 44: 2 mg/kg or 90 mg SC	52 weeks	MMTT C-peptide AUC	In progress
Etanercept (anti-TNF-α)	Etanercept⁷⁴⁾	n=18, 7-18	<4 weeks	0.4 mg/kg (max: 25mg) SC twice a week for 24 weeks	24 weeks	MMTT C-peptide AUC change	+39% vs. -20% (0.05)
Golimumab (anti-TNF-α)	T1GER⁷⁵⁾	n=84, 6-21	<100 days	60 mg/m² or 100 mg SC in week 0 and 2; 30 mg/m² or 50 mg SC per 2 weeks from week 4	52 weeks	MMTT C-peptide AUC	0.64 vs. 0.43 (<0.001)
IL-2	DF-IL2-Child⁷⁷⁾	n=24, 7-14	<3 months	0.125 or 0.250 or 0.500 MIU/m² SC qd for 5 days	436 days	T_regnumber	Dose-dependent increase (n/a)
Others
Verapamil	Verapamil⁸⁰⁾	n=24, 18-44	<3 months	360 mg/day PO	1 year	MMTT C-peptide AUC	Diff=0.28 (0.0186)
	CLVer⁸¹⁾	n=88, 7-17	<31 days	initial: 60 mg/day or 120 mg/day PO titration (max: 360 mg/day) for 2-4 weeks	1 year	MMTT C-peptide AUC	Diff=0.14 (0.04)
	Ver-A-T1D⁸²⁾	n=138, 18-45	<6 weeks	day 0~week 4: 120 mg qd POweek 4~week 8: 240 mg qd POweek 8~month 12: 360 mg qd PO	1 year	MMTT C-peptide AUC	In progress
Imatinib (TKI)	Imatinib trial⁸³⁾	n=67, 18-45	<100 days	100 mg qd PO for 26 weeks	1 year	MMTT C-peptide AUC	0.583 vs. 0,489 (0.048)
Baricitinib (JAK inhibitor)	BANDIT^84,85)	n=91, 10-30	<100 days	4 mg qd PO for 48 weeks	48 weeks	MMTT C-peptide AUC	0.65 vs. 0.43 (0.001)
Atorvastatin	DIATOR^86,87)	n=89, 18-39	2 weeks-3 months	40 mg qd PO for first 4 weeks, then 80 mg qd PO	18 months	MMTT C-peptide AUC	0.78 vs. 0.41 (NS)
1. T_reg+ rituximab2. T_reg	Treg ± anti-CD20⁸⁸⁾	n=36, 8-16	n/a	1. T_reg + rituximab2. T_reg + placebo	2 years	MMTT C-peptideAUC Treatment Ratio	1. 1.770 (Sig.)2. 1.893 (Sig.)
MSCs	MSCs – Uppsala⁸⁹⁾	n=20, 18-40	<3 weeks	2.1-3.6×10⁶ autologous cells/kg (median 2.75×10⁶ cells/kg) IV infusion without premedication	1 year	MMTT C-peptide AUC change	Increase vs. 13% decrease (<0.05)
1. Anti-IL-21 + liraglutide2. Anti-IL-21 alone3. Liraglutide alone	Anti-IL-21 ± liraglutide⁹⁰⁾	n=308, 18-45	<20 weeks	anti-IL-21: 12 mg/kg IV per 6 weeksliraglutide: initial 0.6 mg SC qd,increase 0.6 mg per 2 weeks until 1.8 mg1. Anti-IL-21 + liraglutide2. Anti-IL-21 alone3. Liraglutide alone	1 year	MMTT C-peptide AUC change	1. -10% vs. -39% (0.0017)2. -25% vs. -39% (0.093)3. -32% vs. -39% (0.38)
Pleconaril + ribavirin	DiViDInt⁹¹⁾	n=96, 6-15	<3 weeks*	pleconaril: 5 mg/kg PO bid (max: 600 mg/day) ribavirin: 7.5 mg/kg PO bid (max: 1000 mg/day if <75 kg; else 1200 mg/day)	1 year	MMTT C-peptide AUC	average marginal effect=0.057 (0.037)
ATG ± GCSF	ATG + GCSF trial^92,93)	n=25, 12-45	4 months-2 years	ATG: 0.5 kg/mg IV on day 1;2 mg/kg IV on day 2pegylated GCSF: 6 mg SC per 2 weeks, total 6 times	1 year	MMTT C-peptide AUC	0.74 vs. 0.43 (0.05)
	TrialNet ATG ± GCSF trial^94,95)	n=89, 12-45	<100 days	1. ATG alone2. ATG + GCSF	1 year	MMTT C-peptide AUC	1. 0.646 vs. 0.406 (0.0003)2. NS
Rituximab ± abatacept	RAPTOR Pilot⁹⁶⁾	n=36, 8-45	<100 days	rituximab-pvvr: 375 mg/m² IV qw, week 1-4 abatacept: SC qw for 20 months, from week 16 control group: Rituximab + placebo experimental group: Rituximab + Abatacept	2 years	MMTT C-peptide AUC	In progress

*time of insulin requirement; ^†difference between 9 mg and placebo group. Abbreviations: AEs, adverse events; ATG, anti-thymocyte globulin; AUC, area under curve; bid, twice a day; CI, confidence interval; Diff, difference between experimental and placebo; GCSF, granulocyte colony-stimulating factor; HR, hazard ratio; IV, intravenous; JAK, janus kinase; MMTT, mixed meal tolerance test; MSCs, mesenchymal stem cells; n/a, not applicable; NS, not Significant; PO, per oral; qd, once a day; qw, once a week; SC, subcutaneous; Sig., Significant; T1D, type 1 diabetes; TKI, tyrosine kinase inhibitor

Korean J Clin Pharm 2024;34:210-21 https://doi.org/10.24304/kjcp.2024.34.4.210