Compound danshen dripping pills for diabetic retinopathy in patients with type 2 diabetes: A superiority, randomized controlled trial

Table 1 Detailed criteria for efficacy determination

Grading	FFA scale	Hemorrhage	Effusion (reference)
Marked effectiveness	Improvement in at least one evaluation point	Reduced > 50%	Absent/stable/reduced
	Improvement in at least 2 evaluation points	Absent/stable	Absent/stable/reduced
Effectiveness	Improvement in at least one evaluation point	Reduced ≤ 50%	Absent/stable/reduced
	Improvement in at least one evaluation point	Absent/stable	Absent/stable/reduced
	Stable	Reduced < 50%	Absent/stable/reduced
	Stable	Stable	Reduced ≥ 50%
Stability	Patients not meeting the criteria for marked effectiveness, effectiveness, or worsening
Worsening	Occurrence of worsening in one or more evaluation points	Increased	Absent/stable/increased
	Occurrence of worsening in two or more evaluation points	Absent/stable	Absent/stable/increased
	Or occurrence of IRMA/neovascularization/venous beading
	Stable	Increased	Absent/stable/increased
	Stable	Stable	Increased ≥ 50%

FFA: Fundus fluorescein angiography; IRMA: Intraretinal microvascular abnormalities.

Table 2 Baseline characteristics and demographics of randomized patients, n (%)

	CDDP (n = 362)	Placebo (n = 121)	P value
Demographics
Gender (male/female)	192/170	59/62	0.415
Age (years)	58.22 (8.13)	57.22 (8.01)	0.196
Positive pregnancy test (women only)	0 (0.00)	0 (0.00)	0.971
Height (m)	1.65 (0.08)	1.65 (0.08)	0.733
Weight (kg)	65.86 (10.70)	65.85 (10.10)	0.877
BMI (kg/m2)	24.11 (2.93)	24.24 (2.94)	0.662
Treatment for diabetes
Duration of diabetes (years)	10.42 (5.90)	10.01 (6.07)	0.382
Sulfonylureas preparation	98 (27.84)	29 (24.58)	0.489
Biguanides preparation	148 (42.05)	49 (41.53)	0.921
Alpha-glucosidase inhibitor	116 (32.95)	33 (27.97)	0.314
Insulin	179 (50.85)	62 (52.54)	0.751
Other diabetes medications	48 (13.64)	12 (10.17)	0.329
HbA1c (%)	6.89 (0.95)	6.96 (0.92)	0.454
Duration of DR (years)	2.31 (2.85)	2.44 (3.06)	0.662
Retinopathy level in worst eye (ETDRS scale)			0.437
No obvious diabetic retinopathy	0 (0.00)	0 (0.00)
Mild NPDR	127 (35.08)	48 (39.67)
Moderate NPDR	182 (50.28)	56 (46.28)
Severe NPDR	53 (14.64)	17 (14.05)
PDR	0 (0.00)	0 (0.00)
General ophthalmologic examination
Left eye’s corrected vision (Snellen's test-chart)	4.71 (0.47)	4.76 (0.46)	0.099
Right eye’s corrected vision (Snellen's test-chart)	4.72 (0.47)	4.78 (0.40)	0.113
Fundus changes
Microaneurysms	362 (100)	121 (100)	> 0.999
Hemorrhage	115 (34.53)	44 (38.94)	0.398
Hard exudates	137 (41.14)	39 (34.51)	0.213
Microvascular abnormalities			0.178
No abnormality	306 (84.53)	102 (84.30)
Mild abnormality	31 (8.56)	7 (5.79)
Severe abnormality	25 (6.91)	12 (9.92)
Venous beading	6 (1.66)	2 (1.65)	> 0.999
Diabetic macular edema	59 (21.15)	19 (21.59)	0.929
Neovascularization	0 (0.00)	0 (0.00)	> 0.999

BMI: Body mass index; DR: Diabetic retinopathy; ETDRS: Early treatment diabetic retinopathy study; NPDR: Non-proliferative diabetic retinopathy; PDR: Proliferative diabetic retinopathy.

Table 3 Changes in bead-like, intraretinal microvascular abnormality and fundus neovascularization, n (%)

	CDDP (n = 362)	Placebo (n = 121)	P value
Bead-like
Baseline			> 0.999
None	356 (98.34)	119 (98.35)
Present	6 (1.66)	2 (1.65)
12 weeks			> 0.999
None	356 (98.34)	119 (98.35)
Present	6 (1.66)	2 (1.65)
24 weeks			> 0.999
None	356 (98.34)	119 (98.35)
Present	6 (1.66)	2 (1.65)
Intraretinal microvascular abnormalities
Baseline			0.578
No abnormality	306 (84.53)	102 (84.30)
Mild abnormality	31 (8.56)	7 (5.79)
Severe abnormality	25 (6.91)	12 (9.92)
12 weeks			0.716
No abnormality	305 (84.25)	104 (85.96)
Mild abnormality	32 (8.84)	5 (4.13)
Severe abnormality	25 (6.91)	12 (9.92)
24 weeks			0.394
No abnormality	305 (84.25)	100 (82.64)
Mild abnormality	30 (8.29)	9 (7.44)
Severe abnormality	27 (7.46)	12 (9.92)
Fundus neovascularization
Baseline
None	362 (100)	121 (100)
Present	0 (0.00)	0 (0.00)
12 weeks			0.999
None	360 (99.45)	120 (99.17)
Present	2 (0.55)	1 (0.83)
24 weeks			0.999
None	360 (99.45)	120 (99.17)
Present	2 (0.55)	1 (0.83)

CDDP: Compound danshen dripping pill.

Table 4 Rates of adverse events

	CDDP group (n = 362)			Placebo group (n = 121)			P value
	Number of times	Number of cases	Percentage (%)	Number of times	Number of cases	Percentage (%)
Adverse events	143	92	25.41	65	36	29.75	0.344
Mild	108	73	20.17	50	32	26.45	0.162
Moderate	32	26	7.18	14	11	9.09	0.554
Severe	3	3	0.83	1	1	0.83	> 0.999
Serious adverse events	6	6	1.66	1	1	0.83	0.686
Adverse events occurring in at least 1% of participants in one or more groups
Infections	21	18	4.97	7	6	4.96	1.000
Urinary tract infection	6	6	1.66	4	4	3.31	0.278
Upper respiratory tract infection	8	7	1.93	1	1	0.83	0.686
Nervous system disorders	2	2	0.55	8	8	6.61	0.000
Dizziness	2	2	0.55	4	4	3.31	0.037
Blood and lymphatic system disorders	3	3	0.83	2	2	1.65	0.603
Coagulation disorder	3	3	0.83	2	2	1.65	0.603
Investigations	52	39	10.77	26	16	13.22	0.509
Increased gamma-glutamyl transferase	2	2	0.55	2	2	1.65	0.262
Positive urine leukocytes	5	5	1.38	8	6	4.96	0.033
Increased blood creatine phosphokinase	5	5	1.38	3	3	2.48	0.420
Increased blood creatinine	5	4	1.10	1	1	0.83	1.000
Decreased blood glucose	5	5	1.38	1	1	0.83	1.000
Increased blood glucose	9	8	2.21	1	1	0.83	0.461
Decreased platelet count	0	0	0.00	2	2	1.65	0.062

CDDP: Compound danshen dripping pill.

Table 5 Subgroup results of efficacy rate, n (%)

Overall efficacy rate	Subgroup	n (CDDP/placebo)	CDDP	Placebo	Between-group difference in overall efficacy rate (95%CI)	Test statistic (CMH)	P value
NPDR severity	Mild	127/48	101 (79.53)	30 (62.5)	0.016-0.324	5.899	0.015
	Moderate	182/56	139 (76.37)	27 (48.21)	0.076-0.341	15.655	< 0.001
	Severe	53/17	39 (73.58)	8 (47.06)	0.000-0.531	1.759	0.185
HbA1c	< 7%	197/64	158 (80.20)	38 (59.38)	0.076-0.341	15.155	< 0.001
	≥ 7%	163/55	121 (74.23)	26 (47.27)	0.122-0.418	12.202	< 0.001
Duration of diabetes	< 5 years	57/23	46 (80.70)	13 (56.52)	0.015-0.469	2.963	0.085
	≥ 5 years	305/98	233 (76.39)	52 (53.06)	0.124-0.343	18.615	< 0.001

NPDR: Non-proliferative diabetic retinopathy; CDDP: Compound danshen dripping pill; CMH: Cochran-Mantel-Haenszel.

Table 6 Subgroup results of fluorescein angiography scale evaluation, mean ± SD

Fluorescein angiography scale evaluation	Subgroup	n (CDDP/placebo)	CDDP changes from 24 weeks to baseline	Placebo changes from 24 weeks to baseline	Within-group comparison statistic (Wilcoxon rank-sum test)	95%CI	P value
NPDR severity	Mild	127/48	-0.35 ± 1.63	0.00 ± 0.77	2.114	-0.83 to 0.14	0.034
	Moderate	182/56	-0.26 ± 1.98	0.02 ± 1.97	0.753	-0.87 to 0.32	0.451
	Severe	53/17	-0.40 ± 2.78	0.35 ± 1.22	0.779	-2.14 to 0.64	0.431
HbA1c	< 7%	197/64	-0.41 ± 1.97	0.00 ± 1.83	1.109	-0.96 to 0.14	0.267
	≥ 7%	163/55	-0.19 ± 2.04	0.09 ± 1.01	1.484	-0.85 to 0.28	0.138
Duration of diabetes	< 5 years	57/23	-0.49 ± 3.08	-0.22 ± 0.52	0.343	-1.57 to 1.02	0.727
	≥ 5 years	305/98	-0.28 ± 1.73	0.12 ± 1.63	2.239	-0.79 to -0.01	0.025

NPDR: Non-proliferative diabetic retinopathy; CDDP: Compound danshen dripping pill.

Table 7 Subgroup results of fundus photography hemorrhage evaluation, mean ± SD

Fundus photography hemorrhage evaluation	Subgroup	n (CDDP/placebo)	CDDP changes from 24 weeks to baseline	Placebo changes from 24 weeks to baseline	Within-group comparison statistic (Wilcoxon rank-sum test)	95%CI	P value
NPDR severity	Mild	127/48	0.01 ± 0.09	0.13 ± 0.46	2.673	-0.21 to -0.04	0.007
	Moderate	182/56	-0.40 ± 1.34	0.57 ± 2.20	3.581	-1.46 to -0.49	< 0.001
	Severe	53/17	-0.63 ± 1.46	0.43 ± 1.83	0.211	-2.05 to -0.06	0.004
HbA1c	< 7%	197/64	-0.27 ± 1.04	-0.05 ± 1.28	1.448	-0.54 to 0.10	0.147
	≥ 7%	163/55	-0.31 ± 1.20	0.88 ± 1.97	5.717	-1.65 to -0.73	< 0.001
Duration of diabetes	< 5 years	57/23	-0.51 ± 1.36	-0.14 ± 1.42	2.106	-1.07 to 0.32	0.035
	≥ 5 years	305/98	-0.23 ± 1.05	0.51 ± 1.72	4.884	-1.04 to -0.44	< 0.001

NPDR: Non-proliferative diabetic retinopathy; CDDP: Compound danshen dripping pill.

Table 8 Subgroup results of safety³

	CDDP			Placebo			P value
	Cases	n	%2	Cases	n	%2
Adverse event1	143	92	25.41	65	36	29.75	0.344
< 60 (year)	70	49	25.93	36	23	34.33	0.207
≥ 60 (year)	73	43	24.86	29	13	24.07	1.000
Serious adverse events	6	6	1.66	1	1	0.83	0.686
< 60 (year)	3	3	1.59	1	1	1.49	1.000
≥ 60 (year)	3	3	1.73	0	0	0.00	1.000
Withdrawn due to adverse events	7	7	1.93	2	1	0.83	0.686
< 60 (year)	4	4	2.12	2	1	1.49	1.000
≥ 60 (year)	3	3	1.73	0	0	0.00	1.000

¹Adverse reactions refer to three types of reactions that are positively related, possibly related, or undetermined to the investigational drug.

²Percentage = number of safety incidents occurring in each group and layer/total number of subjects in each group and layer.

³The total number of safety set participants in the experimental group was 362 (189 for those under 60 years old and 173 for those over 60 years old); The total number of safety set participants in the control group was 121 (67 for those under 60 years old and 54 for those over 60 years old).

CDDP: Compound danshen dripping pill.