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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Chelsea Therapeutics
ClinicalTrials.gov Identifier:
NCT00657046
First received: April 8, 2008
Last updated: May 27, 2014
Last verified: May 2014
  Purpose

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 Intervention Phase
Intradialytic Hypotension
Drug: Droxidopa
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Chelsea Therapeutics:

Primary Outcome Measures:
  • Change in Average Mean Arterial Blood Pressure During Hemodialysis [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    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:
  • Change in Average Mean Nadir Systolic Blood Pressures During Hemodialysis; [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    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).

  • Change in the Number of Hypotension-induced Interventions During Hemodialysis (HD) Sessions; [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    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).

  • Change in the Hypotension-induced Symptom Severity Score [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    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).


  • Daily Symptoms Associated With Hemodialysis [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    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).


  • Change in the Multidimensional Fatigue Inventory (MFI-20) [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    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:
  • Change in Systolic Blood Pressure From Pre-dialysis to Post-dialysis [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

    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).



Enrollment: 85
Study Start Date: December 2007
Study Completion Date: January 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.
  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  2. Taking anti-hypertensive medication on the day of dialysis;
  3. Currently taking selective norepinephrine re-uptake inhibitors;
  4. Current known or suspected drug or substance abuse;
  5. 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.
  6. 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;
  7. Women who are pregnant or breast feeding;
  8. Known or suspected hypersensitivity to the study medication or any of its ingredients;
  9. Have active atrial fibrillation (within the last 6 months) or, in the investigator's opinion, have any other significant cardiac arrhythmia;
  10. Any other significant systemic, hepatic or cardiac illness;
  11. Have a history of closed angle glaucoma;
  12. Have a known or suspected malignancy (other than basal cell carcinoma);
  13. Patients with known gastrointestinal illness or other gastrointestinal disorder that may, in the investigator's opinion, affect the absorption of study drug;
  14. In the investigator's opinion, have clinically significant abnormalities on clinical examination or laboratory testing;
  15. In the investigator's opinion, are unable to adequately cooperate because of individual or family situation;
  16. 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;
  17. Are not able or willing to comply with the study requirements for the duration of the study;
  18. 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;
  19. Previous enrollment in the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00657046

Locations
United States, Oregon
Rogue Valley Dialysis
Medford, Oregon, United States, 97504
Sponsors and Collaborators
Chelsea Therapeutics
Investigators
Principal Investigator: Rekha Halligan, MD Bayview Nephrology
  More Information

No publications provided

Responsible Party: Chelsea Therapeutics
ClinicalTrials.gov Identifier: NCT00657046     History of Changes
Other Study ID Numbers: Droxidopa IDH201
Study First Received: April 8, 2008
Results First Received: April 24, 2014
Last Updated: May 27, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hypotension
Vascular Diseases
Cardiovascular Diseases
Droxidopa
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 20, 2014