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

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

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:

• 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.

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.