. 2020 Jun 5;2020(6):CD012906. doi: 10.1002/14651858.CD012906.pub2

1. Overview of trial populations.

Trial ID (trial design)	Intervention(s) and comparator(s)	Description of power and sample size calculation	Screened/eligible (N)	Randomised (N)	Analysed (N)	Finishing trial (N)	Randomised finishing trial (%)	Follow‐up
Bilezikian 2013 (parallel RCT)	I: metformin	"Sample size calculation was based on a 30% dropout rate and a SD of 4% for percentage change from baseline in femoral neck, ensuring that the 95% confidence interval will be the mean +‐ 0.9% for each treatment group"	316	112	111	85	75.9	52 weeks^a
	C1: rosiglitazone		316	114	114	77	67.5
	total:			226	225	162	71.7
Erem 2014 (parallel RCT)	I: metformin	—	—	20	19	19	95.0	52 weeks
	C1: gliclazide			20	19	19	95.0
	C2: pioglitazone			20	19	19	95.0
	total:			60	57	57	95.0
Derosa 2009 (parallel RCT)	I: metformin	"Considering as clinically significant a difference of at least 10% compared with the baseline and an α error of.05, the actual sample size is adequate to obtain a power higher than 0.80 for all variables related to glucose metabolism (HbA1c, FPG, PPG, FPI, PPI, GIR, and TGR)."	—	67	—	60	90.0	15 months
	C1: pioglitazone		—	69	—	60	87.0
	total:			136	—	120	88.2
Kahn 2006 (parallel RCT)	I: metformin	"We originally calculated that we would need to enroll 3600 patients to provide the study with a power of 90% to detect a 30% reduction in the risk of treatment failure for rosiglitazone, as compared with metformin and glyburide, at a significance level of P=0.05 (two‐sided, adjusted for two comparisons), assuming an event rate of 0.072 per year for metformin or glyburide and a rate of loss to follow‐up of 0.064 per year in each group. The protocol was amended in March 2002 to increase the number of patients to 4182 and in February 2004, to extend the follow‐up period beyond 4 years, in order to compensate for an overall rate of withdrawal that was greater than anticipated and an overall rate of primary outcome events that was lower than anticipated. The revised power estimate was 83%, assuming a rate of loss to follow‐up of 0.128 per year and a hazard rate for treatment failure of 0.035 per year."	6676	1455	1454	903	62.1	Median of 4 years (maximum 6.1)
	C1: rosiglitazone			1458	1456	917	62.9
	C2: glibenclamide			1447	1441	807	55.8
	total:			4360	4351	2627	60.2
Schweizer 2007 (parallel RCT)	I: metformin	"A planned sample size of 660 patients (in 2 : 1 allocation ratio to vildagliptin: metformin) was calculated assuming a 20% drop‐out rate, with 90% power and a one‐sided significance level of 0.025 to detect non‐inferiority of vildagliptin compared with metformin in reducing HbA1c after 52 weeks, with a noninferiority margin of 0.3% and an expected difference between the two treatment groups of 0.0%. Based on health authority feedback, the test of non‐inferiority was amended during the course of the study to utilize a non‐inferiority margin of 0.4%, which increased the statistical power to 99%"	1606	254 (158)^b	249 (158)^b	191 (142)^b	75.2 (55.9)^b	104 weeks^c
	C1: vildagliptin		1606	526 (305)^b	511 (304)^b	378 (260)^b	71.9 (49.4)^b
	total:			780 (463)^b	760 (462)^b	569 (402)^b	73.5 (52.7)^b
Umpierrez 2014 (parallel RCT)	I: metformin	"The study was designed with 90% power to detect noninferiority of dulaglutide 1.5 mg versus metformin on HbA1c change from baseline at the 26‐week primary end point with a margin of 0.4%, a SD of 1.3%, and a one‐sided a of 0.025, assuming no true difference between treatments. This corresponds to 251 patients per arm, with an assumed dropout rate of 11%. If noninferiority was met, superiority was assessed using a tree‐gatekeeping approach in which the type I error rate across all treatment comparisons for change from baseline in HbA1c at 26 weeks was strongly controlled at 0.025 (onesided). P values were adjusted so that each can be compared with 0.025 to assess significance while accounting for multiplicity adjustments. The analyses of efficacy and safety were based on the intent‐to‐treat population consisting of all randomized patients who received at least one dose of study treatment."	—	268	268	213	79.5	52 weeks
	C1: dulaglutide (1.5 mg/week)			269	269	220	81.8
	C2: dulaglutide (0.75 mg/week)			270	270	218	80.7
	total:			807	807	651	80.7
Kiyici 2009 (parallel RCT)	I: metformin	—	—	16	16	16	100	52 weeks
	C1: rosiglitazone			19	19	19	100
	C2: no intervention			15	15	15	100
	total:			50	50	50	100
Pfützner 2011 (parallel RCT)	I: metformin	"...each comparison was performed at the 0.027 alpha level from Dunnett’s adjustment so that the overall (family‐wise) type I error rate was controlled at the 0.05 significance level." "Based on the primary end‐point, the sample size afforded at least 90% power for both the combination comparisons and the individual components based on the min test by Laska and Meisner for normal case."	2936	328	328	219	66.8	76 weeks^d
	C1: saxagliptin		2936	335	335	209	62.4
	total:			663	663	428	64.6
Schernthaner 2004 (parallel RCT)	I: metformin	"A noninferiority design was used in this study. Sample size was based on the study objective to disprove the null hypothesis that pioglitazone was inferior to metformin in terms of reduction in HbA1c. Based on a 5% significance level and a statistical power of 90%, a sample size of 450 patients in each treatment group was required."	2145	— (597^e)	597	501	—	52 weeks
	C1: pioglitazone		2145	— (597^e)	597	499	—
	total:			1199	1194	1000	83.4
Yamanouchi 2005 (parallel RCT)	I: metformin	"Our pretrial calculation showed that a two‐sided comparison of the pioglitazone vs. the diet‐alone group in Japanese patients required at least 30 patients per group to detect a difference in mean HbA1c of at least 1% with 5% significance and 95% power"	—	39	37	37	94.9	52 weeks
	C1: pioglitazone			38	35	35	92.1
	C2: glimepiride			37	34	34	91.9
	total:			114	106	106	93.0
Williams‐Herman 2010 (parallel RCT)	I: metformin (1000 mg/day)	—	3427	182	—	95	52.2	104 weeks^f
	I2: metformin (2000 mg/day)			182	—	80	44.0
	C1: sitagliptin			179	—	65	36.3
	total:			543	—^g	240	44.2
Rahman 2011 (parallel RCT)	I: metformin	—	—	102	102	—	—	52 weeks
	C1: glimepiride	—	—	102	102	—	—
	total:			204	204	—	—
Campbell 1994 (parallel RCT)	I: metformin	—	—	24	24	24	100.0	52 weeks
	C1: glipizide	—	—	24	24	24	100.0
	total:			48	48	48	100.0
Derosa 2004 (parallel RCT)	I: metformin	"The power of the study was calculated with a Fisher's exact test, with a 0.050 two‐sided significance alpha level and a 90% power; to detect the difference between a glimepiride group proportion of 0.500 and a metformin group proportion of 0.750 the sample size in each group would be 85."	—	83	75	75	90.4	60 weeks
	C1: glimepiride		—	81	73	73	90.1
	total:			164	148	148	90.2
UKPDS 34 1998 (parallel RCT)	I: metformin	"Table 6 gives the likelihood of detecting a 20 % or 25 % reduction of endpoints by improved plasma glucose and blood pressure control. This reduction has been accepted as being a clinically significant gain, particularly as benefits from treatment are likely to be even greater over a longer period of therapy since complications develop over many years. Power calculations assumed 8 % loss to follow‐up and a 4% per annum increased number of events as the cohort ages"	4209	342	342	—	—	10.7 years
	C1: glibenclamide			277	277	—	—
	C2: insulin			409	409	—	—
	total:			1028	1028	—	—
Teupe 1991^h (parallel RCT)	I: metformin	—	—	50	25	25	50.0	2 years
	C1: no intervention	—	—	50	29	29	58.0
	total:			100	54	54	54.0
Onuchin 2010 (parallel RCT)	I: metformin	—	—	46	46	—	—	12 months
	C1: insulin	—	—	45	45	—	—
	total:			91	91	—	—
Derosa 2003 (parallel RCT)	I: metformin	—	—	56	56	49	87.5	14 months
	C1: repaglinide	—	—	56	56	53	94.6
	total:			112	102	102	91.1
Grand total	All interventions			4041ⁱ		2463^j
	All comparators			6639ⁱ		3732^j
	All interventions and comparators			10,680ⁱ		6195^j

—: denotes not reported ^aAfter 52 weeks of metformin versus rosiglitazone all participants received open‐label metformin for an additional 24 weeks, which was not of interest to this review ^bParticipants also completing the 52‐week extension ^cThe trial consisted of a 52‐week intervention followed by a 52‐week extension period in which participants continued their allocated intervention ^dThe trial consisted of a 24‐week intervention followed by a 52‐week extension period in which participants continued their allocated intervention ^eAt least 597 participants were randomised to either arm. It is unclear which arm the remaining 5 participants were randomised to ^fThe trial consisted of a 24‐week intervention followed by a 30‐week extension period followed by an additional 52‐week extension period in which participants continued their allocated intervention ^gVariation in number of participants analysed depending on outcome measure ^hResults are after 2 years of intervention and follow‐up ⁱFor Schweizer 2007 numbers outside parentheses were used, for Schernthaner 2004 numbers in parentheses were used ^jFor Rahman 2011, UKPDS 34 1998 and Onuchin 2010 no numbers were available and thus not included in calculation

C: comparator; I: intervention; GIR: glucose infusion rate; ITT: intention‐to‐treat; RCT: randomised controlled trial; SD: standard deviation; HbA1c: glycosylated haemoglobin A1c; FPG: fasting plasma glucose; FPI: fasting plasma insulin; PPG: post prandial glucose; PPI: post prandial insulin.