Table 7.

Summary of the clinical evidence of PPAR agonists in neurodegenerative diseases and neurological dysfunction.

Disease	Target	Drug Name	Clinical Phase (Sample size)	Main Findings/Primary Endpoint	Reference/Clinical Trial Identifier
Alzheimer′s Disease	PPARγ	Rosiglitazone	II (30)	▪ Better delayed recall and selective attention ▪ Stable plasma amyloid β-42 level at 6th month	[226]
			II (687)	▪ No significant differences of ADAS-Cog at week 24 ▪ APOE ɛ4-negative patients had improved cognitive functions ▪ Dose-dependent improvement of fasting plasma insulin in APOE ɛ4-negative patients	[228]
			II-completed (337)	▪ Primary endpoint: Evaluate the long-term safety and tolerability of rosiglitazone-extended release in subjects with mild to moderate Alzheimer′s disease	EUCTR2004-000985-12
			II (80)	▪ Increased cerebral metabolic rate for glucose ▪ No difference in decrease of whole brain volume ▪ No difference in clinical outcome measures of ADAS-Cog or CIBIC scores ▪ No difference in plasma glucose levels	[227]
			II-completed (40)	▪ Primary endpoint: Frequency of adverse events, safety and tolerability	NCT00381238
			III (639)	▪ No difference in cognition and global function of APOE-∊4-negative subjects ▪ Well-tolerated	[229]
			III (1496; 1485; 1461)	▪ No difference in cognitive function measurements	[230]
		Pioglitazone	III-terminated (3494)	▪ Primary endpoint: Time to diagnosis of mild cognitive impairment due to Alzheimer′s disease	NCT01931566
			II (78)	▪ No increase in oxygen uptake, HbA1c, fasting triglycerides, IL-6 levels ▪ Increased glucose disposal rate ▪ Decreased fasting insulin level and endurance of exercise ▪ No difference in cognitive performances ▪ Significant improvement in ADAS-Cog after endurance exercise	[231]
			II (25)	▪ Well-tolerated ▪ No effect on clinical outcome measures ▪ No change to blood glucose level in non-diabetic subjects	[232]
	PPARα	Gemfibrozil	I-ongoing (72)	▪ Primary endpoint: Safety, microRNA-107 levels, β-amyloid 1-40 and -42 levels	NCT02045056
Amyotrophic Lateral Sclerosis	PPARγ	Pioglitazone	II (219)	▪ Hazard ratio of 1.21, with a 21% increase in the pioglitazone group ▪ No difference in survival, functional rating, quality of life, and slow vital capacity.	[237]
			II (27)	▪ No effect on tau level	[238]
Multiple Sclerosis	PPARγ	Pioglitazone	I (24)	▪ No improvement in disability status score ▪ Reduced grey matter volume and fraction loss	[240]
		CHS-131	II (227)	▪ Dose-dependent reduction in new contrast-enhanced lesions and relapse rates	[241]
Drug-resistant Nocturnal Frontal Lobe Epilepsy	PPARα	Fenofibrate	II (12)	▪ Improved subjective measurements of daily seizure diaries and quality of life ▪ Reduced major events and minor motor events	[242]
Postherpetic Neuralgia	PPARγ	ATx08-001/FK614	II (61)	▪ Primary endpoint: Sum of the pain intensity difference in 6-h and 12-h pain intensity scores	NCT01318226
Friedreich′s Ataxia	PPARγ	Pioglitazone	III (40)	▪ No improvement in neurological functions	[243]