A randomized, placebo-controlled, phase 2 study of the efficacy and safety of droxidopa in patients with intradialytic hypotension

Figures & data

Figure 1. Disposition of patients.

Table 1. Patient baseline/screening demographics, vital signs and medical history for the ITT population.

	Droxidopa dose		Placebo	Total
	600 mg	400 mg
n	32	30	23	85
Age, y
Mean (SD)	59.7 (15.0)	60.3 (12.7)	60.2 (16.0)	60.0 (14.3)
Median, (Range)	61 (31, 83)	59 (38, 86)	58 (24, 86)	60 (24, 86)
≥65 years, n (%)	14 (43.8)	12 (40.0)	10 (43.0)	36 (42.4)
Gender, n (%)
Male	15 (46.9)	14 (46.7)	9 (39.1)	38 (44.7)
Female	17 (53.1)	16 (53.3)	14 (60.9)	47 (55.3)
Race, n (%)
White	16 (50.0)	8 (26.7)	11 (47.8)	35 (41.2)
Black/African-American	15 (46.9)	19 (63.3)	12 (52.2)	46 (54.1)
Other	1 (3.1)	3 (10.0)	0	4 (4.7)
Weight, kg^a
Mean (SD)	87.5 (24.2)	91.5 (23.8)	92.1 (21.9)	90.2 (23.3)
Median (range)	84.6 (43.8, 148.0)	93.2 (45.1, 125.2)	93.3 (55.3, 125.8)	92.6 (43.8, 148.0)
Heart rate, bpm^a
Mean (SD)	78.1 (12.3)	81.8 (12.8)	84.1 (13.7)	81.0 (12.9)
Median (range)	79.5 (45, 101)	83.0 (58, 111)	80.0 (58, 117)	81.0 (45, 117)
Duration of ESRD,^b,c y
Mean (SD)	4.0 (4.7)^b	7.0 (5.1)	5.1 (3.8)	5.4 (4.7)
Median (Range)	2.5 (0, 21)^b	6.0 (1, 19)	4.6 (0, 14)	3.8 (0, 21)
Duration of HD,^b y
Mean (SD)	4.0 (4.6)	6.2 (4.7)	4.9 (3.6)	5.0 (4.5)
Median (Range)	2.5 (0, 21)	5.0 (1, 19)	4.6 (0, 14)	3.3 (0, 21)
Duration of IDH^b, mo
Mean (SD)	12.6 (14.5)	15.9 (19.9)	24.9 (36.4)	17.1 (24.2)
Median (Range)	9.9 (0, 58)	7.8 (1, 96)	11.1 (1, 156)	8.5 (0, 156)
Diabetes mellitus,^b n (%)	22 (68.8)	19 (63.3)	10 (43.5)	51 (60.0)
Cardiovascular disease,^b n (%)	28 (87.5)	27 (90.0)	21 (91.3)	76 (89.4)
Arterial hypertension	23 (71.9)	17 (56.7)	14 (60.9)	54 (63.5)
Prior CVA/stroke	5 (15.6)	4 (13.3)	7 (30.4)	16 (18.8)
Prior myocardial infarction	5 (15.6)	3 (10.0)	5 (21.7)	13 (15.3)
Antihypertensive concomitant medication,^b,d n (%)
ACE inhibitors and ARBs	11 (35.5)	8 (26.7)	7 (30.4)	26 (30.6)
Beta blockers	11 (35.5)	6 (20.0)	9 (39.1)	26 (30.6)
Calcium channel blockers	9 (29.0)	11 (36.7)	2 (8.7)	22 (25.9)
Diuretics	8 (25.8)	3 (10.0)	2 (8.7)	13 (15.3)
Other	5 (16.1)	3 (10.0)	2 (8.7)	10 (11.8)

^aAt screening.

^bDocumented during 3 months before enrollment.

^cDuration of ESRD not available for one patient in 600-mg group.

^dSome patients took more than one medication.

Abbreviations: ACE = Angiotensin-converting enzyme; ARB = Angiotensin receptor blockers; CVA = Cerebrovascular accident; ESRD = End-stage renal disease; HD = Hemodialysis; IDH = Intradialytic hypotension; ITT = Intent-to-treat; SD = Standard deviation.

Table 2. Patient baseline BP: pre-, intra- and post-HD.

	Droxidopa dose		Placebo
	600 mg	400 mg
n	32	30	23
SBP, mm Hg
Pre-HD
Mean (SD)	145.4 (23.7)	142.7 (21.3)	139.0 (21.3)
Median (range)	146.8 (102.5, 198.0)	139.2 (103.7, 183.3)	141.3 (87.8, 175.3)
Intra-HD
Mean (SD)	125.9 (20.9)	125.2 (17.9)	119.2 (20.7)
Median (range)	127.1 (82.5, 167.3)	127.9 (85.3, 164.4)	117.5 (85.7, 161.0)
Post-HD
Mean (SD)	124.8 (18.6)	126.9 (20.0)	119.0 (18.6)
Median (range)	124.8 (78.0, 156.3)	125.8 (91.3, 172.5)	118.7 (88.8, 168.8)
DBP, mm Hg
Pre-HD
Mean (SD)	73.2 (14.0)	74.4 (14.8)	74.4 (12.7)
Median (range)	73.1 (46.7, 108.7)	74.4 (45.0, 110.6)	76.7 (46.0, 108.7)
Intra-HD
Mean (SD)	64.4 (11.9)	66.3 (12.8)	63.7 (12.4)
Median (range)	65.8 (45.7, 86.0)	64.6 (42.6, 95.2)	62.7 (45.5, 96.3)
Post-HD
Mean (SD)	64.2 (11.2)	66.6 (13.1)	64.0 (9.7)
Median (range)	65.0 (41.7, 88.7)	62.1 (49.3, 98.7)	64.3 (47.5, 88.8)

Abbreviations: BP = Blood pressure; DBP = Diastolic blood pressure; HD = Hemodialysis; SBP = Systolic blood pressure; SD = Standard deviation.

Table 3. Primary endpoint: changes in intra-HD MAP (mm Hg) over the study period.

	Droxidopa dose		Placebo
	600 mg	400 mg
n	32	30	23
Baseline^a average intra-HD MAP
Mean (SD)	84.9 (14.0)	85.9 (13.8)	82.2 (14.6)
Median (Range)	86.4 (58.0, 108.2)	86.5 (60.4, 118.3)	79.5 (62.8, 117.9)
On-treatment^b average intra-HD MAP
Mean (SD)	85.3 (14.6)	86.1 (12.4)	83.8 (15.5)
Median (Range)	83.7 (61.2, 123.7)	88.4 (62.3, 107.7)	82.9 (64.8, 112.6)
Change from baseline
Mean (SD)	2.0 (6.6)	-0.1 (10.0)	1.6 (9.8)
Median (Range)	3.0 (-12.2, 17.6)	1.9 (-28.9, 13.5)	1.8 (-15.9, 24.5)
p-value (vs placebo)	0.81	0.69

^aAverage of visits 2–7.

^bAverage of visits 14–19.

Abbreviations: HD = Hemodialysis; MAP = Mean arterial pressure; SD = Standard deviation.

Figure 2. Mean changes in intra-HD MAP, nadir intra-HD SBP and nadir intra-HD DBP across visits by treatment. Abbreviations: DBP = Diastolic blood pressure; HD = Hemodialysis; MAP = Mean arterial pressure; SBP = Systolic blood pressure.

Table 4. Changes in average pre- versus post-HD arterial BP over the study period.

	Droxidopa dose		Placebo
	600 mg	400 mg
n	32	30	23
SBP, mm Hg
Baseline^a average difference in pre-/post-HD
Mean (SD)	-20.6 (17.4)	-16.1 (20.8)	-19.9 (17.8)
Median (Range)	-18.6 (-71.0, 7.7)	-11.3 (-73.2, 15.2)	-18.2 (-49.5, 10.5)
On-treatment^b average difference in pre-/post-HD
Mean (SD)	-16.6 (17.2)	-11.7 (21.8)	-24.3 (20.5)
Median (Range)	-15.4 (-62.2, 14.3)	-10.3 (-65.7, 38.2)	-20.3 (-67.2, 8.7)
Change from baseline
Mean (SD)	4.8 (11.6)	3.4 (13.1)	-4.4 (17.9)
Median (Range)	4.3 (-16.8, 30.5)	1.8 (-19.8, 26.7)	-2.0 (-57.7, 25.5)
LS Means (SE)	4.2 (2.5)	4.2 (2.6)	-4.6 (2.9)
95% CI of LS Means	-0.8, 9.2	-1.0, 9.4	-10.3, 1.0
p-value (vs placebo)	0.022	0.025
DBP, mm Hg
Baseline^a average difference in pre-/post-HD
Mean (SD)	-8.9 (8.1)	-8.4 (13.4)	-10.5 (11.3)
Median (Range)	-7.3 (-26.0, 5.5)	-6.2 (-62.0, 8.8)	-12.3 (-34.0, 12.7)
On-treatment^b average difference in pre-/post-HD
Mean (SD)	-6.3 (10.7)	-7.1 (10.6)	-12.3 (12.2)
Median (Range)	-7.9 (-32.5, 18.2)	-8.3 (-25.0, 9.5)	-16.2 (-32.5, 13.5)
Change from baseline
Mean (SD)	2.5 (9.6)	0.9 (12.7)	-1.8 (10.3)
Median (Range)	0.7 (-14.2, 24.8)	-0.9 (-23.3, 42.2)	-0.5 (-29.7, 16.7)
p-value (vs placebo)	0.057	0.150

^aAverage of visits 2–7.

^bAverage of visits 14–19.

Abbreviations: BP = Blood pressure; DBP = Diastolic blood pressure; HD = Hemodialysis; LS = Least squares (mean); SBP = Systolic blood pressure; SD = Standard deviation; SE = Standard error.

Table 5. Numbers of hypotension-induced interventions over the study period.

	Droxidopa dose		Placebo
	600 mg	400 mg
n	32	30	23
Change in body position
Baseline	13	11	8
Visits 8–13	10	7	6
Visits 14–19	11	5	5
Total (visits 8–19)	21	12	11
p-value^a	0.3701	0.7304
Reducing ultrafiltration rate/volume
Baseline	20	20	15
Visits 8–13	19	15	14
Visits 14–19	14	16	16
Total (visits 8–19)	33	31	30
p-value^a	0.0996	0.2688
Saline or hyperoncotic albumin use
Baseline	21	18	16
Visits 8–13	18	15	14
Visits 14–19	16	20	11
Total (visits 8–19)	34	35	25
p-value^a	1.0000	0.2606
Early termination of hemodialysis
Baseline	8	6	7
Visits 8–13	5	3	7
Visits 14–19	1	3	7
Total (visits 8–19)	6	6	14
p-value^a	0.0078	0.0817
Other
Baseline	5	4	5
Visits 8–13	8	4	4
Visits 14–19	7	1	6
Total (visits 8–19)	15	5	10
p-value^a	1	0.0344

^aFisher Exact test comparing active treatment to placebo.

Table 6. Summary of adverse events (AEs; Safety population, n = 84).

	Patients, n (%)
Description	Droxidopa dose		Placebo
	600 mg	400 mg
n	31	30	23
Experienced at least 1 AE	25 (80.6)	25 (83.3)	14 (60.9)
Severity
Mild	18 (58.1)	15 (50.0)	10 (43.5)
Moderate	15 (48.4)	16 (53.5)	9 (39.1)
Severe	9 (29.0)	14 (46.7)	7 (30.4)
Relation to study drug
Possibly related	2 (6.5)	2 (6.7)	2 (8.7)
Unlikely to be related	9 (29.0)	5 (16.7)	3 (13.0)
Not related	23 (74.2)	25 (83.3)	13 (56.5)

Table 7. Most common adverse events (AEs) reported by ≥15% of patients in treatment group (safety population).

AE, n (%)	Droxidopa dose
	600 mg		400 mg		Placebo
	Patients	Events	Patients	Events	Patients	Events
	31 (80.6)	102 (100)	25 (83.3)	99 (100)	14 (60.9)	72 (100)
Nausea	6 (19.4)	9 (8.8)	5 (16.7)	6 (6.1)	3 (13.0)	5 (6.9)
Fatigue	6 (19.4)	7 (6.9)	4 (13.3)	4 (4.0)	2 (8.7)	2 (2.8)
Headache	5 (16.1)	7 (6.9)	5 (16.7)	5 (5.1)	2 (8.7)	2 (2.8)
Muscle spasms	4 (12.9)	6 (5.9)	6 (20.0)	9 (9.1)	2 (8.7)	2 (2.8)
Poor quality sleep	4 (12.9)	6 (5.9)	6 (20.0)	7 (7.1)	1 (4.3)	1 (1.4)
Dizziness	2 (6.5)	3 (2.9)	6 (20.0)	7 (7.1)	2 (8.7)	3 (4.2)
Pruritus	3 (9.7)	3 (2.9)	6 (20.0)	9 (9.1)	1 (4.3)	1 (1.4)