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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.
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Active Comparator | Droxidopa at 400 mg (2 capsules each containing 200 mg droxidopa plus one capsule with Placebo) |
|
| 2 | Active Comparator | Droxidopa at 600 mg (3 capsules each containing 200 mg droxidopa) |
|
| 3 | Placebo Comparator | Placebo (3 capsules with mannitol substituted for droxidopa) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Droxidopa | Drug | Capsules containing 200 mg droxidopa |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Average Mean Arterial Blood Pressure During Hemodialysis | 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. | 6 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Average Mean Nadir Systolic Blood Pressures During Hemodialysis; | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Systolic Blood Pressure From Pre-dialysis to Post-dialysis | 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). |
Inclusion Criteria:
Exclusion Criteria:
Currently taking ephedrine or midodrine;
Taking anti-hypertensive medication on the day of dialysis;
Currently taking selective norepinephrine re-uptake inhibitors;
Current known or suspected drug or substance abuse;
Women of childbearing potential who are not using a medically accepted contraception;
Subject Restrictions:
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;
Women who are pregnant or breast feeding;
Known or suspected hypersensitivity to the study medication or any of its ingredients;
Have active atrial fibrillation (within the last 6 months) or, in the investigator's opinion, have any other significant cardiac arrhythmia;
Any other significant systemic, hepatic or cardiac illness;
Have a history of closed angle glaucoma;
Have a known or suspected malignancy (other than basal cell carcinoma);
Patients with known gastrointestinal illness or other gastrointestinal disorder that may, in the investigator's opinion, affect the absorption of study drug;
In the investigator's opinion, have clinically significant abnormalities on clinical examination or laboratory testing;
In the investigator's opinion, are unable to adequately cooperate because of individual or family situation;
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;
Are not able or willing to comply with the study requirements for the duration of the study;
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;
Previous enrollment in the study.
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| Name | Affiliation | Role |
|---|---|---|
| Rekha Halligan, MD | Bayview Nephrology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rogue Valley Dialysis | Medford | Oregon | 97504 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Droxidopa 400mg | 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. |
| FG001 | Droxidopa 600mg | 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. |
| FG002 | Placebo | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Droxidopa 400mg | 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. |
| BG001 | Droxidopa 600mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Average Mean Arterial Blood Pressure During Hemodialysis | 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. | 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. | Posted | Mean | Standard Deviation | mmHg | 6 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Droxidopa 400mg | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Renal Transplane | Surgical and medical procedures |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Procedural Nausea | Gastrointestinal disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Scientific Officer | Chelsea Therapeutics Inc. | 704-973-4202 | hewitt@chelsearx.com |
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| ID | Term |
|---|---|
| D015103 | Droxidopa |
| ID | Term |
|---|---|
| D009638 | Norepinephrine |
| D002395 | Catecholamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
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| Placebo |
| Drug |
Capsules with mannitol substituted for droxidopa |
|
| 6 weeks |
| Change in the Number of Hypotension-induced Interventions During Hemodialysis (HD) Sessions; | 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). | 6 weeks |
| Change in the Hypotension-induced Symptom Severity Score | 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). | 6 weeks |
| Daily Symptoms Associated With Hemodialysis | 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). | 6 weeks |
| Change in the Multidimensional Fatigue Inventory (MFI-20) | 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). | 6 weeks |
| 6 weeks |
| Withdrawal by Subject |
|
| Death |
|
| Surgery |
|
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. |
| BG002 | Placebo | 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. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
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.
| OG001 | Droxidopa 600mg | 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. |
| OG002 | Placebo | 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. |
|
|
|
| Secondary | Change in Average Mean Nadir Systolic Blood Pressures During Hemodialysis; | 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). | 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. | Posted | Mean | Standard Deviation | mmHg | 6 weeks |
|
|
|
|
| Secondary | Change in the Number of Hypotension-induced Interventions During Hemodialysis (HD) Sessions; | 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). | Patients must have completed visits in the visit 14-19 timeframe. | Posted | Mean | Standard Deviation | average interventions per session | 6 weeks |
|
|
|
|
| Secondary | Change in the Hypotension-induced Symptom Severity Score | 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). | Patients must have completed visits in the visit 14-19 time frame. | Posted | Mean | Standard Deviation | units on a scale | 6 weeks |
|
|
|
|
| Secondary | Daily Symptoms Associated With Hemodialysis | 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). | 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. | Posted | Mean | Standard Deviation | units on a scale | 6 weeks |
|
|
|
|
| Secondary | Change in the Multidimensional Fatigue Inventory (MFI-20) | 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). | Patients must have completed at least visit 14. Three placebo patients did not complete their Multidimensional Fatigue Inventory during this visit. | Posted | Mean | Standard Deviation | units on a scale | 6 weeks |
|
|
|
|
| Post-Hoc | Systolic Blood Pressure Difference Between Pre-Hemodialysis and Nadir | Change from baseline to end of study (HD visits 14-19) in systolic blood pressure difference between pre-hemodialysis and nadir. | 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. | Posted | Mean | Standard Deviation | mmHg | 6 weeks |
|
|
|
|
| Other Pre-specified | Change in Systolic Blood Pressure From Pre-dialysis to Post-dialysis | 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). | Patients must have completed visits in the visit 14-19 timeframe. | Posted | Mean | Standard Deviation | mmHg | 6 weeks |
|
|
|
|
| Post-Hoc | Number Patients With Hypotension Induced Early Termination of Dialysis Procedure | Patients had to have at least one post baseline visit (visit 8 and beyond). | Posted | Number | participants | 6 weeks |
|
|
|
|
| 3 |
| 30 |
| 20 |
| 30 |
| EG001 | Droxidopa 600mg | 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. | 5 | 31 | 18 | 31 |
| EG002 | Placebo | 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. | 6 | 23 | 8 | 23 |
| Sepsis | Infections and infestations |
|
| Catheter Sepsis | Injury, poisoning and procedural complications |
|
| Pancreatitis | Gastrointestinal disorders |
|
| Urinary Tract Infection | Infections and infestations |
|
| Uremia | Renal and urinary disorders |
|
| thrombosis | Injury, poisoning and procedural complications |
|
| Hip Fracture | Injury, poisoning and procedural complications |
|
| Death | General disorders |
|
| Colitis Ischaemic | Gastrointestinal disorders |
|
| Indwelling Catheter Management | Surgical and medical procedures |
|
| Humerous Fracture | Injury, poisoning and procedural complications |
|
| Peripheral Artery Angioplasty | Surgical and medical procedures |
|
| Vomiting | Gastrointestinal disorders |
|
| Asthenia | General disorders |
|
| Fatigue | General disorders |
|
| Feeling Abnormal | General disorders |
|
| Malaise | General disorders |
|
| Post Procedural Discomfort | General disorders |
|
| Pyrexia | General disorders |
|
| Muscle Spasms | Musculoskeletal and connective tissue disorders |
|
| Dizziness | Nervous system disorders |
|
| Dizziness Postural | Nervous system disorders |
|
| Headache | Nervous system disorders |
|
| Poor Quality Sleep | Nervous system disorders |
|
| Restless Leg Syndrome | Nervous system disorders |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders |
|
| Pruritus | Skin and subcutaneous tissue disorders |
|
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| D002396 |
| Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D012694 | Serine |
| D021542 | Amino Acids, Neutral |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| 0.230 |
| No |
| Superiority or Other |
| 0.607 |
| No |
| Superiority or Other |
| 0.940 |
| No |
| Superiority or Other |
| 0.903 |
| No |
| Superiority or Other |
| 0.408 |
| No |
| Superiority or Other |
| 0.030 |
| No |
| Superiority or Other |
| 0.022 |
| No |
| Superiority or Other |
| No |
| Superiority or Other |