Table 2.

Summary of clinical trials.

Author	Year	Study Design	SARM	Study Population	Study Arms and Total Subjects	Summary of Adverse Events
Marcantonio et al. [32]	2010	Randomized, double-blind, placebo-controlled, parallel group	MK-3984 and MK-2866	Healthy postmenopausal women	Placebo (N = 22) MK-2866 3 mg daily (N = 22) MK-3984 50 mg daily (N = 22) MK-3984 125 mg daily (N = 22) Total exposed = 66 Total N = 88	7/44 subjects receiving the 50 mg or 125 mg dose of MK-3984 had ALT elevation > 3 × ULN and were discontinued from the study, but no significant ALT elevation was reported for the 3 mg dose of MK-2866.
Meglasson et al. [33]	2010	Double-blind, placebo-controlled ascending single dose	LGD-4033	Healthy adult males	0.1–22 mg	No SAE’s reported.
Dalton et al. [34]	2011	Double-blind, placebo-controlled phase II trial	Enobosarm	Elderly men and postmenopausal women	Daily doses of placebo, 0.1, 0.3, 1, or 3 mg of Enobosarm for 86 days. (N = 24 per group, 50% male and female) Total Exposed = 96 Total N = 120	No SAE’s reported. ALT increased in dose-dependent fashion (8 total patients with 6 of 8 in highest dose 3 mg group). In these 7 patients, ALT elevations resolved while on drug. One subject discontinued (3 mg dose) due to ALT elevation of 4.2 X ULN and returned to normal after drug discontinuation. Dose-dependent reduction in HDL.
Yi et al. [35]	2012	Pharmacokinetic and Metabolism Study	LY2452473	Healthy males	15 mg (N = 6) Total Exposed N = 6 Total N = 6	No safety events reported.
Basaria et al. [36]	2013	Placebo-controlled ascending single and multiple dose PK	LGD-4033	Healthy adult males	Placebo (N = 33) 0.1 mg (N = 18) 0.3 mg (N = 11) 1 mg (N = 14) Total Exposed = 43 Total N = 76	No SAE’s, no study discontinuation due to adverse events, no clinically significant changes in liver enzymes. Dose-dependent reduction in HDL but returned to baseline 25 days post-last dose.
Papanicolaou et al. [21]	2013	Randomized placebo-controlled efficacy and safety	MK-0773	Females with sarcopenia	Placebo (N = 89) MK-0773 50 mg BID (N = 81) Total Exposed N = 81 Total N = 170	13.5% (N = 23) of participants had an AE possibly, probably or definitely related to study therapy. The most common AE leading to discontinuation was an increase in ALT (N = 5, 6.2%). This occurred within 6–8 weeks and all ALT returned to baseline with no clinical sequelae after stopping therapy. Hematocrit increases >3% were significantly more frequent in the MK-0773 group compared with placebo. Trend towards increased blood pressure in MK-0773 compared with placebo (5 mmgHg difference from baseline at 6 months in treatment vs. placebo group).
Bhattacharya et al. [37]	2016	Placebo-controlled ascending single and multiple dose PK	PF-06260414	Healthy adult males	Western: Placebo N = 17 SAD: 1–400 mg single dose (N = 6 per group) MAD: 3–100 mg BID (N = 6 per group) Japanese: Placebo (N = 2) 30 mg BID (N = 5) Total Exposed = 53 Total N = 72	No severe AE’s. A total of 42 of 67 treatment-emergent AE’s were considered treatment-related. Three subjects receiving SARM discontinued the study (anxiety, hypertension and ALT increase). ALT increase occurred in 10 subjects (9 SARM subjects and 1 placebo subject). Five subjects receiving 100 mg BID had ALT increases and 3 Japanese subjects receiving 30 mg BID had ALT increases. One subject in 100 mg BID cohort had ALT increases as early as day 6 with peak of 343 IU/L on day 14, which normalized by day 42 leading to discontinuation. Dose-dependent decreases in HDL
Coss et al. [38]	2016	Drug–drug interaction study, crossover design with 6 to 10-day washout period	Enobosarm	Healthy adult males	All subjects dosed with Enobosarm 3 mg. The following studies had two occasions of Enobosarm and one occasion of the additional drug: Itraconazole 200 mg (N = 12) Rifampin 600 mg (N = 12) Probenecid 500 mg (N = 15) The following two studies had one occasion of Enobosarm and two occasions of the following drugs: Celecoxib 200 mg (N = 42) Rosuvastatin 10 mg (N = 49) Total Exposed N = 132 Total N = 132	No SAE’s, 21% reported AE’s while taking Enobosarm, however only 8 subject’s AE’s were determined to be related to Enobosarm. The most common AE was headache.
Clark et al. [39]	2017	Placebo-controlled ascending single and multiple dose PK	GSK2881078	Healthy adult males and postmenopausal women	SAD: 0–0.2 mg, N = 10 all males) MAD: Placebo (N = 22) 0.05–0.75 mg (N = 67, 24 female subjects) Total Exposed N = 77 Total N = 99	Dose-dependent reductions in HDL. Female subject on active treatment developed a maculopapular rash and ALT increase to 2.9 X the ULN and discontinued the study. Another female developed and ALT elevation to 2.3 X the ULN. Two men on active treatment developed muscle soreness after demanding activity in the follow-up period 14 and 28 days, respectively, with elevation in CPK (17,841 and 4590 IU, respectively and mild elevations in ALT, both resolved over 3 weeks). No other subjects showed ALT ≥ 2 X ULN during treatment.
Neil et al. [40]	2018	Randomized double-blinded, placeb0-controlled dose-escalation PKPD	GSK2881078	Healthy elderly men and women	Cohort 1: Males: 0.75 mg or 1.5 mg Females: 0.5 mg or 0.75 mg Dosed twice daily for 3 days followed by daily for 28 days. (N = 10 each dosing group, 2:1 placebo) Cohort 2: Males: 4 mg daily for 56 days Females: 0.35 mg daily for 28 days followed by 1.5 mg daily for 28 days (N = 10 in each dosing group, 2:1 placebo) Total exposed N = 62 Total N = 93	62.9% receiving SARM compared with 13.3% placebo had ALT elevations. All elevations in ALT were transient occurring from approximately day 14 beginning to resolve and returning to baseline by day 28 of dosing. ALT incidence was most frequent in highest dose group 4 mg, with 2 individuals having a 5–10 X ULN elevation in ALT.
Peters et al. [41]	2018	Single arm, non-randomized efficacy study	GTX-024 (Enobosarm)	Postmenopausal females with stress incontinence	3 mg daily Total Exposed N = 19 Total N = 19	Minimal adverse events with none above Grade I. Elevated ALT in 1 of 19 subjects.
Ristic et al. [42]	2018	Randomized placebo-controlled study	VK5211 (ligandrol)	Patients >65 recovering from hip fracture 3–7 weeks prior	Placebo 0.5 mg daily 1 mg daily 2 mg daily Total N = 108, number in each arm not specified.	No SAE’s reported.
NCT01401543 [43]	2019	Bioavailability study crossover design	LY2452473	Healthy male	5 mg LY2452473 + 5 mg tadalafil standard and at three different particle sizes (10, 40 and 90 microns) single dose Total Exposed = 24 Total N = 24	No SAE’s, most common AE was headache, no report of liver enzymes.
NCT01160289 [44]	2019	Randomized placebo-control trial	LY2452473	Males with erectile dysfunction	5 mg tadalafil + placebo (N = 87) 10 mg tadalafil + placebo (N = 89) 1 mg LY2452473 + tadalafil daily (N = 85) 5 mg LY2452473 + tadalafil daily (N = 97) 5 mg LY2452473 + placebo (N = 52) Total Exposed N = 234 Total N = 410	SAE’s occurred slightly more commonly in patients randomized to LY2452473 (4 of 234 subjects) compared with 0 of 176 subjects randomized to a placebo group. SAE’s included humerus fracture, pulmonary embolus, tubular interstitial nephritis, arrythmia, lobar pneumonia and cardiac arrest. Association with SARM not noted. Other AE’s occurred at similar rates between SARM and placebo groups (20–30% of patients). No patient in the SARM groups had AST elevation.
NCT03241342 [45]	2020	Randomized placebo-controlled study	GTX-024	Females 18–80 years old with stress incontinence	Placebo (N = 165) GTX-024 1 mg daily (N = 163) GTX-024 3 mg daily (N = 163) Total Exposed N = 326 Total N = 491	5 total SAE’s in GTX-024 groups vs. 4 in placebo. SAE’s included hip fracture, dysesthesia, myocardial infarction, cerebral vascular accident and goiter. Non-SAE’s were also similar in GTX-024 vs. placebo group. Only 2 of 326 subjects experienced increased ALT.
Efimenko et al. [46]	2021	Cross-sectional survey study in SARM users	LGD-4033 RAD-140 MK-2866	Most commonly healthy adult men (98.5%) that were 18–29 (72.3%) years old	Total survey responders N = 343	54.5% of users reported adverse effects related to SARM use. The most common were mood swings (22.4%), decreased testes size (20.7%) and acne (15.2%). The proportion of responders reporting a side effect increased significantly with longer reported exposure times to SARM.
Pencina et al. [47]	2021	Randomized placebo-controlled, double blind	OPK-88004	Prostate cancer survivors	Placebo N = 36 1 mg daily N = 28 5 mg daily N = 14 15 mg daily N = 14 Total Exposed N = 78 Total N = 114	3 SAE’s not considered treatment-related were coronary artery bypass grafting, renal cancer and lung and liver cancer. Dose-dependent increases in AST and ALT with only one participant in the 15-mg group having AST and ALT elevations above the ULN. Dose-dependent decreases in HDL.
NCT03297398 [48]	2021	Randomized placebo control trial	OPK-88004	Males with symptoms of benign prostatic hyperplasia	Placebo (N = 38) OPK-88004 15 mg (N = 40) OPK-88004 25 mg (N = 38) Total Exposed N = 78 Total N = 114	2 subjects had SAE’s in 25 mg group (coronary artery disease, biliary obstruction and cholangitis)—association not noted. Other AE’s occurred at much higher rates in SARM groups (60–70%) compared with placebo (10–15%). This appeared to be heavily driven from lab abnormalities such as decreased testosterone, decreased LDL and decreased HDL. ALT increased in 4 subjects randomized to SARM (3/40 and 1/38 in the 15 mg and 25 mg groups, respectively).