IDH201: Safety and Benefit Study of Droxidopa to Treat Patients With Intradialytic Hypotension

• Sponsor: Chelsea Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00657046
• Collaborator: (none)
• Enrollment: 85
• Location: 1
• Arms: 3
• Duration (Months): 13
• Patients Per Site Per Month: 6.5

Study Details

Study Description

Brief Summary

In clinical trials in Japan, droxidopa has been shown to be effective in affecting blood pressure changes upon orthostatic challenge in patients with autonomic dysfunction, as well as reducing the severity and frequency of symptoms of orthostatic hypotension in these patients. The efficacy of droxidopa in ameliorating symptoms in patients undergoing dialysis has also been demonstrated in the literature and clinical trials conducted in Japan. The current study will investigate the clinical efficacy of two different doses of droxidopa in patients with intradialytic hypotension over a 4 week treatment period with a placebo control. The clinical efficacy will be evaluated by changes in hypotension- related symptoms, as well as changes in blood pressure prior to, during and following, HD sessions as compared to their pre-treatment baseline values.

Condition or Disease	Intervention/Treatment	Phase
Intradialytic Hypotension	Drug: Droxidopa; Drug: Placebo	Phase 2

Detailed Description

This is a phase II, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of droxidopa in HD patients with intradialytic hypotension. The study will be conducted in up to 15 centers, with a sufficient number of patients enrolled to allow 75 patients to be randomized into 3 study groups (25 randomized to placebo, 25 randomized to 400 mg droxidopa, and 25 randomized to 600 mg droxidopa).

The study will consist of an initial screening period (up to 7 days) to confirm eligibility followed by a 2 week baseline, and a 4 week treatment period. During baseline and treatment visits SBP and DBP measurements will be collected using a consistent method immediately pre-, during and immediately post-dialysis. SBP, DBP and heart rate measurements will be taken every 20 minutes during HD sessions.

There will be 19 scheduled visits, not including the post-treatment follow-up visit, during this trial; Visit 1 (Screening), Visits 2 through 7 (baseline and randomization), Visits 8 through 19 (tri-weekly treatment visits). Each visit will coincide with the patient's normal dialysis treatments.

All patients will be followed for 30 days following the completion of the active treatment period (or premature withdrawal) to check for the occurrence of adverse events (AEs).

Patients will attend the study center as out-patients.

Eligible patients will be assigned a unique identification number at screening, and prior to the first treatment visit will be randomized to one of the following treatment groups:

Group A: Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) Group B: Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) Group C: Placebo (3 capsules with mannitol substituted for droxidopa) Each patient will take 3 capsules 1 hour prior to each dialysis procedure with approximately 100 mL (typically half a glass) of water.

The primary measure of efficacy will be the change from baseline (visits 2-7) in average mean arterial blood pressure compared to that during treatment (visit 14-19).

The secondary measures of efficacy will be:

• Change between baseline (visits 2-7) and treatment (visits 14-19) in average mean nadir systolic and diastolic blood pressures during hemodialysis;

• Change in the number of hypotension-induced interventions during hemodialysis (HD) sessions;

• Change in hypotension-induced symptoms measured during hemodialysis;

• Change in daily symptoms associated with hemodialysis;

• Change in fatigue using the Multidimensional Fatigue Inventory (MFI-20). The safety of droxidopa will be evaluated based on the occurrence of treatment-emergent adverse events (AE) and specific evaluation of blood pressure, heart rate (HR), ECG, and laboratory findings across the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multi-center, Randomized, Double-blind, Parallel-group, Placebo-controlled Study to Assess the Clinical Benefit and Safety of Droxidopa in Patients With Intradialytic Hypotension
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with Placebo)	Drug: Droxidopa; Capsules containing 200 mg droxidopa; Drug: Placebo; Capsules with mannitol substituted for droxidopa
Active Comparator: 2 Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa)	Drug: Droxidopa; Capsules containing 200 mg droxidopa
Placebo Comparator: 3 Placebo (3 capsules with mannitol substituted for droxidopa)	Drug: Placebo; Capsules with mannitol substituted for droxidopa

Outcome Measures

Primary Outcome Measures

1. Change in Average Mean Arterial Blood Pressure During Hemodialysis [6 weeks]

   Change between average baseline (visits 2-7) mean arterial blood pressure during hemodialysis and average treatment (visits 14-19) mean arterial blood pressure during hemodialysis. The calculation of MAP was based on the systolic (SBP) and diastolic (DBP) blood pressure measurements taken during each valid HD session, using the traditional formula: MAP = (SBP+2*DBP)/3 for each time-point. The mean of the intradialytic measurements was calculated for each valid HD session, and these daily mean values were averaged across the visits within each period.

Secondary Outcome Measures

1. Change in Average Mean Nadir Systolic Blood Pressures During Hemodialysis; [6 weeks]

   Change between baseline (visits 2-7) and treatment (visits 14-19) in average mean nadir systolic blood pressures during hemodialysis. The baseline value will be the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value will be defined as the average of the values collected at each of the last six treatment visits (visits 14-19).

2. Change in the Number of Hypotension-induced Interventions During Hemodialysis (HD) Sessions; [6 weeks]

   Evaluate the efficacy of droxidopa as measured by change in the number of hypotension-induced interventions during hemodialysis (HD) sessions between baseline (visits 2-7) and treatment (visits 14-19). The baseline value will be the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value will be defined as the average of the values collected at each of the last six treatment visits (visits 14-19).

3. Change in the Hypotension-induced Symptom Severity Score [6 weeks]

   The hypotension-induced symptom severity score is the sum of a 6 question scale (each rated 0 [asymptomatic] to 4 [severe]). The questions look at cramps, dizziness, headache, nausea, itchiness, and restless legs syndrome experienced during dialysis. The outcome looks at the difference between the average baseline score (visits 2-7) and the average on-treatment scores (visits 14-19). The baseline value will be the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value will be defined as the average of the values collected at each of the last six treatment visits (visits 14-19).

4. Daily Symptoms Associated With Hemodialysis [6 weeks]

   The Daily symptoms associated with hemodialysis score is the sum of an 8 question scale (each rated 0 [asymptomatic] to 4 [severe]). The questions look at fatigability, malaise/weakness, physical disturbance on standing, coldness of limbs, dizziness/lightheadedness, dizziness on standing, general bad feeling, and sleep disorders and asks how each of these items affected the patients daily activities on that day. The outcome looks at the difference between the average baseline score (visits 2-7) and the average on-treatment scores (visits 14-19). The baseline value will be the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value will be defined as the average of the values collected at each of the last six treatment visits (visits 14-19).

5. Change in the Multidimensional Fatigue Inventory (MFI-20) [6 weeks]

   Fatigue will be measured by the general fatigue domain (items 1, 5, 12 and 16) of MFI-20 and will be summarized by treatment group and treatment period. The scores per item run from 1 to 5. A higher score indicates more fatigue. Therefore, the items indicative for fatigue need to be recoded (1=5, 2=4, 3=3, 4=2, 5=1). This concerns item: 5 and 16. A total score is calculated by summation of the scores of the individual items. Scores can range from the minimum of 4 to the maximum of 20. The value at baseline (visit 7) will be subtracted from the value on treatment (visit 19 or visit 13 if visit 19 is not available).

Other Outcome Measures

1. Change in Systolic Blood Pressure From Pre-dialysis to Post-dialysis [6 weeks]

   Change from baseline (visits 2-7) to end of study (HD visits 14-19) in the drop in systolic blood pressure from pre-hemodialysis to 5 minutes post-hemodialysis. The baseline value was the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value was defined as the average of the values collected at each of the last six treatment visits (visits 14-19).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female and aged 18 years or over;

2. Clinical diagnosis of ESRD;

3. Demonstrated requirement to undergo maintenance HD 3 times per week for sessions at least 3 hours in duration;

4. Medical history consistent with IDH existing for at least 1 month;

5. Observed symptomatic intradialytic hypotension in 3 of 6 HD sessions during screening, as defined by as a decrease in systolic blood pressure by ≥20 mm Hg or a decrease in MAP by 10 mm Hg associated with symptoms that include: abdominal discomfort; yawning; sighing; nausea; vomiting; muscle cramps; restlessness; dizziness or fainting; and anxiety (definition according to: National Kidney Foundation 2007) ;

6. Provide written informed consent to participate in the study and understand that they may withdraw their consent at any time without prejudice to their future medical care.

Exclusion Criteria:

1. Currently taking ephedrine or midodrine;

• Patients taking ephedrine or midodrine may enroll after a minimum 7 day washout period

1. Taking anti-hypertensive medication on the day of dialysis;

2. Currently taking selective norepinephrine re-uptake inhibitors;

3. Current known or suspected drug or substance abuse;

4. Women of childbearing potential who are not using a medically accepted contraception;

Subject Restrictions:

• Reproductive potential: Female subjects should be either post-menopausal (amenorrhea for at least 12 consecutive months), surgically sterile, or women of child-bearing potential (WOCP) who are using or agree to use acceptable methods of contraception. Acceptable contraceptives include intrauterine devices (IUDs), hormonal contraceptives (oral, depot, patch or injectable) and double barrier methods such as condoms or diaphragms with spermicidal gel or foam.

• For WOCP a urine/serum beta HCG pregnancy test must be conducted at screening and study termination, and a urine/serum pregnancy test must be conducted at baseline; the results must be negative at screening and at baseline. WOCP must be advised to use acceptable contraceptives throughout the study period and for 30 days after the last dose of investigational product. If hormonal contraceptives are used they should be taken according to the package insert. WOCP who are not currently sexually active must agree to use acceptable contraception, as defined above, if they decide to become sexually active during the period of the study and for 30 days after the last dose of investigational product.

1. Sexually active males whose partner is a WOCP must agree to use condoms for the duration of the study and for 30 days after the last dose;

2. Women who are pregnant or breast feeding;

3. Known or suspected hypersensitivity to the study medication or any of its ingredients;

4. Have active atrial fibrillation (within the last 6 months) or, in the investigator's opinion, have any other significant cardiac arrhythmia;

5. Any other significant systemic, hepatic or cardiac illness;

6. Have a history of closed angle glaucoma;

7. Have a known or suspected malignancy (other than basal cell carcinoma);

8. Patients with known gastrointestinal illness or other gastrointestinal disorder that may, in the investigator's opinion, affect the absorption of study drug;

9. In the investigator's opinion, have clinically significant abnormalities on clinical examination or laboratory testing;

10. In the investigator's opinion, are unable to adequately cooperate because of individual or family situation;

11. In the investigator's opinion, are suffering from a mental disorder that interferes with the diagnosis and/or with the conduct of the study, e.g. schizophrenia, major depression, dementia;

12. Are not able or willing to comply with the study requirements for the duration of the study;

13. Have participated in another clinical trial with an investigational agent (including named patient or compassionate use protocol) within 30 days before the start of the study;

14. Previous enrollment in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rogue Valley Dialysis	Medford	Oregon	United States	97504

Sponsors and Collaborators

• Chelsea Therapeutics

Investigators

• Principal Investigator: Rekha Halligan, MD, Bayview Nephrology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Chelsea Therapeutics
• ClinicalTrials.gov Identifier: NCT00657046
• Other Study ID Numbers: Droxidopa IDH201
• First Posted: Apr 14, 2008
• Last Update Posted: Jun 27, 2014
• Last Verified: May 1, 2014

• Additional relevant MeSH terms: Hypotension; Droxidopa

Study Results

Participant Flow

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Period Title: Overall Study
STARTED	30	32	23
Had at Least 1 Post Baseline Visit	30	31	23
Had Visits up to Visit 18	28	30	23
COMPLETED	26	29	21
NOT COMPLETED	4	3	2

Baseline Characteristics

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo	Total
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Total of all reporting groups
Overall Participants	30	32	23	85
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.3 (12.71)	59.7 (14.98)	60.2 (16.00)	60.0 (14.34)
Sex: Female, Male (Count of Participants)
Female	16 53.3%	17 53.1%	14 60.9%	47 55.3%
Male	14 46.7%	15 46.9%	9 39.1%	38 44.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	19 63.3%	15 46.9%	12 52.2%	46 54.1%
White	11 36.7%	17 53.1%	11 47.8%	39 45.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	30 100%	32 100%	23 100%	85 100%

Outcome Measures

1. Primary Outcome

Title	Change in Average Mean Arterial Blood Pressure During Hemodialysis
Description	Change between average baseline (visits 2-7) mean arterial blood pressure during hemodialysis and average treatment (visits 14-19) mean arterial blood pressure during hemodialysis. The calculation of MAP was based on the systolic (SBP) and diastolic (DBP) blood pressure measurements taken during each valid HD session, using the traditional formula: MAP = (SBP+2*DBP)/3 for each time-point. The mean of the intradialytic measurements was calculated for each valid HD session, and these daily mean values were averaged across the visits within each period.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients must have blood pressure data from baseline and from visits 14-19. One droxidopa 400mg patient did not have blood pressure data for visit 14-19 and was excluded from the analysis.

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	27	30	23
Mean (Standard Deviation) [mmHg]	-0.12 (10.017)	1.95 (6.637)	1.60 (9.843)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.693
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.807
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate.

2. Secondary Outcome

Title	Change in Average Mean Nadir Systolic Blood Pressures During Hemodialysis;
Description	Change between baseline (visits 2-7) and treatment (visits 14-19) in average mean nadir systolic blood pressures during hemodialysis. The baseline value will be the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value will be defined as the average of the values collected at each of the last six treatment visits (visits 14-19).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients must have blood pressure data from baseline and from visits 14-19. One droxidopa 400mg patient did not have blood pressure data for visit 14-19 and was excluded from the analysis.

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	27	30	23
Mean (Standard Deviation) [mmHg]	3.09 (16.065)	2.60 (9.988)	-0.35 (14.695)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.212
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.230
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate.

3. Secondary Outcome

Title	Change in the Number of Hypotension-induced Interventions During Hemodialysis (HD) Sessions;
Description	Evaluate the efficacy of droxidopa as measured by change in the number of hypotension-induced interventions during hemodialysis (HD) sessions between baseline (visits 2-7) and treatment (visits 14-19). The baseline value will be the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value will be defined as the average of the values collected at each of the last six treatment visits (visits 14-19).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients must have completed visits in the visit 14-19 timeframe.

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	28	30	23
Mean (Standard Deviation) [average interventions per session]	-0.2 (0.86)	-0.2 (0.71)	-0.1 (0.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.712
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.607
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate.

4. Secondary Outcome

Title	Change in the Hypotension-induced Symptom Severity Score
Description	The hypotension-induced symptom severity score is the sum of a 6 question scale (each rated 0 [asymptomatic] to 4 [severe]). The questions look at cramps, dizziness, headache, nausea, itchiness, and restless legs syndrome experienced during dialysis. The outcome looks at the difference between the average baseline score (visits 2-7) and the average on-treatment scores (visits 14-19). The baseline value will be the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value will be defined as the average of the values collected at each of the last six treatment visits (visits 14-19).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients must have completed visits in the visit 14-19 time frame.

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	28	30	23
Mean (Standard Deviation) [units on a scale]	-0.9 (0.92)	-1.2 (1.32)	-1.2 (1.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4602
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.940
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

5. Secondary Outcome

Title	Daily Symptoms Associated With Hemodialysis
Description	The Daily symptoms associated with hemodialysis score is the sum of an 8 question scale (each rated 0 [asymptomatic] to 4 [severe]). The questions look at fatigability, malaise/weakness, physical disturbance on standing, coldness of limbs, dizziness/lightheadedness, dizziness on standing, general bad feeling, and sleep disorders and asks how each of these items affected the patients daily activities on that day. The outcome looks at the difference between the average baseline score (visits 2-7) and the average on-treatment scores (visits 14-19). The baseline value will be the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value will be defined as the average of the values collected at each of the last six treatment visits (visits 14-19).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients must have completed visits in the visit 14-19 timeframe. Three placebo patients and one droxidopa 600mg patient did not complete their Daily Symptoms Assessments during these visits.

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	28	29	20
Mean (Standard Deviation) [units on a scale]	-0.13 (3.843)	-1.33 (3.724)	-1.34 (3.504)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.376
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.903
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

6. Secondary Outcome

Title	Change in the Multidimensional Fatigue Inventory (MFI-20)
Description	Fatigue will be measured by the general fatigue domain (items 1, 5, 12 and 16) of MFI-20 and will be summarized by treatment group and treatment period. The scores per item run from 1 to 5. A higher score indicates more fatigue. Therefore, the items indicative for fatigue need to be recoded (1=5, 2=4, 3=3, 4=2, 5=1). This concerns item: 5 and 16. A total score is calculated by summation of the scores of the individual items. Scores can range from the minimum of 4 to the maximum of 20. The value at baseline (visit 7) will be subtracted from the value on treatment (visit 19 or visit 13 if visit 19 is not available).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients must have completed at least visit 14. Three placebo patients did not complete their Multidimensional Fatigue Inventory during this visit.

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	29	30	20
Mean (Standard Deviation) [units on a scale]	-0.1 (4.22)	-0.3 (2.93)	0.6 (2.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.319
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.408
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

7. Post-Hoc Outcome

Title	Systolic Blood Pressure Difference Between Pre-Hemodialysis and Nadir
Description	Change from baseline to end of study (HD visits 14-19) in systolic blood pressure difference between pre-hemodialysis and nadir.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients must have completed visits in the visit 14-19 timeframe. One droxidopa 400 mg patient did not have the required nadir blood pressure information for visits 14-19 and was excluded from the analysis.

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	27	30	23
Mean (Standard Deviation) [mmHg]	-5.88 (13.638)	-3.33 (11.666)	4.92 (18.180)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

8. Other Pre-specified Outcome

Title	Change in Systolic Blood Pressure From Pre-dialysis to Post-dialysis
Description	Change from baseline (visits 2-7) to end of study (HD visits 14-19) in the drop in systolic blood pressure from pre-hemodialysis to 5 minutes post-hemodialysis. The baseline value was the arithmetic average of the values collected at each of the six baseline visits (visits 2-7). The on treatment value was defined as the average of the values collected at each of the last six treatment visits (visits 14-19).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients must have completed visits in the visit 14-19 timeframe.

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	28	30	23
Mean (Standard Deviation) [mmHg]	3.41 (13.112)	4.77 (11.556)	-4.39 (17.860)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	ANCOVA
	Comments	GLM model with baseline as a covariate.

9. Post-Hoc Outcome

Title	Number Patients With Hypotension Induced Early Termination of Dialysis Procedure
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Patients had to have at least one post baseline visit (visit 8 and beyond).

Arm/Group Title	Droxidopa 400mg	Droxidopa 600mg	Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.	Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
Measure Participants	30	31	23
Number [participants]	3 10%	1 3.1%	7 30.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 400mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Droxidopa 600mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Arm/Group Title	Droxidopa 400mg		Droxidopa 600mg		Placebo
Arm/Group Description	Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.		Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.		Placebo (3 capsules with mannitol substituted for droxidopa) taken 1 hour (+/-15 minutes) prior to each hemodialysis session. Study treatments were administered over 4 weeks.
All Cause Mortality
	Droxidopa 400mg		Droxidopa 600mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Droxidopa 400mg		Droxidopa 600mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/30 (10%)		5/31 (16.1%)		6/23 (26.1%)
Gastrointestinal disorders
Pancreatitis	1/30 (3.3%)	1	0/31 (0%)	0	1/23 (4.3%)	1
Colitis Ischaemic	0/30 (0%)	0	1/31 (3.2%)	1	0/23 (0%)	0
General disorders
Death	0/30 (0%)	0	0/31 (0%)	0	1/23 (4.3%)	1
Infections and infestations
Sepsis	1/30 (3.3%)	1	0/31 (0%)	0	0/23 (0%)	0
Urinary Tract Infection	0/30 (0%)	0	0/31 (0%)	0	1/23 (4.3%)	1
Injury, poisoning and procedural complications
Catheter Sepsis	0/30 (0%)	0	1/31 (3.2%)	1	0/23 (0%)	0
thrombosis	0/30 (0%)	0	1/31 (3.2%)	1	1/23 (4.3%)	1
Hip Fracture	1/30 (3.3%)	1	0/31 (0%)	0	0/23 (0%)	0
Humerous Fracture	0/30 (0%)	0	1/31 (3.2%)	1	0/23 (0%)	0
Renal and urinary disorders
Uremia	1/30 (3.3%)	1	0/31 (0%)	0	0/23 (0%)	0
Surgical and medical procedures
Renal Transplane	0/30 (0%)	0	0/31 (0%)	0	1/23 (4.3%)	1
Indwelling Catheter Management	0/30 (0%)	0	0/31 (0%)	0	1/23 (4.3%)	1
Peripheral Artery Angioplasty	0/30 (0%)	0	1/31 (3.2%)	1	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	Droxidopa 400mg		Droxidopa 600mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/30 (66.7%)		18/31 (58.1%)		8/23 (34.8%)
Gastrointestinal disorders
Procedural Nausea	5/30 (16.7%)	6	6/31 (19.4%)	9	3/23 (13%)	5
Vomiting	2/30 (6.7%)	3	1/31 (3.2%)	1	2/23 (8.7%)	2
General disorders
Asthenia	4/30 (13.3%)	4	4/31 (12.9%)	4	2/23 (8.7%)	2
Fatigue	4/30 (13.3%)	4	6/31 (19.4%)	7	2/23 (8.7%)	2
Feeling Abnormal	4/30 (13.3%)	4	3/31 (9.7%)	3	2/23 (8.7%)	2
Malaise	4/30 (13.3%)	4	4/31 (12.9%)	4	1/23 (4.3%)	2
Post Procedural Discomfort	4/30 (13.3%)	4	2/31 (6.5%)	2	2/23 (8.7%)	2
Pyrexia	1/30 (3.3%)	1	2/31 (6.5%)	3	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle Spasms	5/30 (16.7%)	8	4/31 (12.9%)	6	2/23 (8.7%)	2
Nervous system disorders
Dizziness	6/30 (20%)	7	3/31 (9.7%)	3	2/23 (8.7%)	3
Dizziness Postural	2/30 (6.7%)	2	0/31 (0%)	0	2/23 (8.7%)	2
Headache	5/30 (16.7%)	5	5/31 (16.1%)	7	2/23 (8.7%)	2
Poor Quality Sleep	6/30 (20%)	7	4/31 (12.9%)	6	1/23 (4.3%)	1
Restless Leg Syndrome	4/30 (13.3%)	4	1/31 (3.2%)	1	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/30 (0%)	0	2/31 (6.5%)	2	0/23 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	6/30 (20%)	9	3/31 (9.7%)	3	1/23 (4.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.