Table 2.

Novel agents targeting inflammation

Name	Mechanism	Trial phase, type, NTC #	Primary end points	Status	Results and comments
Glutamine	NADH producer	3, RDBPC, NCT01179217	N of crises	FDA approved	Age >5 y; reduction in VOCs77
Omega-3 fatty acids	Reduces endothelial activation; improved sRBC membrane and NO production	2, RDBPC, ISRCTN80844630	Annualized rate of VOC hospitalizations	Completed	Age 2-24 y; improved rates of VOC, anemia, and number of transfusions23
		1/2, open label single arm, NCT02947100	Safety in dose escalation, reduction in thermal sensitivity	Recruiting	Age 8-25 y
		3, RPC triple blind, NCT02525107	Frequency and severity of VOCs, duration of hospitalization	Not yet recruiting	Age 13-70 y
		2, RDBPC, NCT02973360	Change in baseline blood cells omega-3 fatty acid index	Completed	All SCD genotypes; age 5-17 y; advanced lipid technologies
					Well tolerated with reduction in diary-reported home-managed SCD pain78
		3, RPC triple blind, NCT02604368	Annualized VOC rate	Not yet recruiting	All SCD genotypes; using advanced lipid technologies for improved bioavailability
N-acetylcysteine	Reduces oxidative stress and increases glutathione	3, RDBPC, NCT01849016	Rate of pain d per y (diary)	Completed	All SCD genotypes; trends toward lower rates of pain, VOCs, did not reach significance; study limited by poor adherence28
		1/2, single arm open label, NCT01800526	VWF activity	Enrolling by invitation
NKTT120		1, open label single arm, NCT01783691	Safety	Completed	Well tolerated; depleted iNKTs for 2-5 mo33
Arginine*	NO substrate	2, RDBPC, NCT01796678	Length of stay	Completed	All SCD genotypes; single center; trend toward decreased length of stay
					Reduction in total parenteral opioid use by 54% (P = .02)37
		2, RDBPC, NCT02536170	Total parenteral opioid use	Recruiting	All SCD genotypes; age 3-21 y; multicenter
		1/2, open label randomized crossover design, NCT02447874	PK and change in NO metabolites	Enrollingby invitation	Age 7-21 y
		2, randomized open label, NCT00004412	Leg ulcer healing	Completed	All SCD genotypes; improved leg ulcer healing79
Citrulline*	Precursor to arginine	1, open label, NCT02314689/NCT02697240	AEs and citrulline level	Completed	All SCD genotypes; age 6-50 y; IV formulation; well tolerated40
Riociguat	Stimulates soluble guanylate cyclase	2, RDCPC, NCT02633397	Treatment-related SAEs	Recruiting	All SCD genotypes
IW-1701	Stimulates soluble guanylate cyclase	2, RDBPC, NCT03285178	Treatment-emergent AEs	Recruiting	All SCD genotypes; age 16-70 y
IMR-687	PDE9 inhibitor	2a, RDBPC, NCT03401112	Treatment-related AEs	Recruiting	All SCD genotypes
Simvastatin	Upregulates NOS, reduces endothelial dysfunction	1/2, open label single arm, NCT00508027	Change in baseline labs	Completed	All SCD genotypes; increased NO metabolites, decreased CRP and IL-645
		1/2, open label single arm, NCT01702246	Change in frequency of vasoocclusive pain events	Completed	Decreased rates of pain and analgesic use; improved inflammatory markers46
Atorvastatin	Upregulates NOS	2, RDBPC crossover, NCT01732718	Change in endothelial function on USG imaging	Completed
Montelukast	Cysteinyl leukotriene receptor antagonist	2, RDBPC, NCT01960413	Improvement in soluble VCAM	Completed	Age 16-70 y
Zileuton	5-lipoxygenase inhibitor	1, open label single arm, NCT01136941	AEs	Completed	All SCD genotypes; age >12 y; well tolerated49
Mometasone	Inhaled corticosteroid	2, RDBPC, NCT02061202	Feasibility	Completed	Age ≥15 y; decreased soluble VCAM and daily pain50
Ambrisentan	Endothelin receptor antagonist	1, RPC, NCT02712346	Safety and tolerability	Recruiting

Unless otherwise specified, study included only adult patients with HbSS or HbSβ0.

AE, adverse event; FDA, US Food and Drug Administration; RDBPC, randomized double blind placebo controlled; SAE, serious AE; USG, ultrasound guided.

^*Study drug administered during acute VOC.