tc-5214 as augmentation therapy in patients with refractory hypertension

Conditions: Refractory Hypertension

Summary: a pilot study of subjects with refractory hypertension (on 3 concomitant agents with sbp \> 140 mmhg and a dbp \> 90 mmhg) randomized in a double-blind fashion to receive 4 single escalating doses of study medication in clinic.

12 subjects with refractory hypertension will be randomized in a double-blind fashion to receive single escalating doses of study medication in-clinic: on day 1 (1mg), day 8 (2mg), day 15 (4mg) and day 22 (8mg). on each of these 4 days, 10 subjects will receive tc-5214, and 2 subjects will receive placebo. placebo treatments will be pooled across the 4 days of single-dose to produce an equivalent reference cohort (n = 8) for each treatment dose (n=10). following the single-dose administration of 8mg in the clinic on day 22, subjects will continue with two weeks (days 23 - 35) of outpatient self-administration of tc-5214 (4mg bid; n = 6), or matching placebo (bid; n = 6). on day 36, subjects will return for a final in-clinic dose of either tc-5214 (4mg, n = 6) or placebo (n = 6). there will be a 1-week follow-up period at the end of the treatment period.

Eligibility criteria:
inclusion criteria: 1. refractory hypertension, defined as a sbp of \>140mmhg and a dbp \> 90mmhg, on stable doses of at least 3 concomitant antihypertensive treatment (which must include a diuretic and an acei, arb or ra) for 8 weeks prior to screening. all approved antihypertensive treatments are allowed except for alpha-adrenergic blockers, hydralazine, clonidine, guanethidine, guanadrel, and rauwolfia alkaloids. 2. stable hypertension, as defined by: a. mean sbp on day -7 that is within 20mmhg of the mean sbp on day 1, with both mean sbps \> 140mmhg; and b. mean dbp on day -7 that is within 10mm of the mean dbp on day 1, with both mean dbps \> 90mmhg. 3. outpatient with stable housing. 4. subjects must be able to stay in the clinic for 8 hrs on day 1, day 8, day 15, day 22, and day 36. 5. able to give and to sign informed consent. exclusion criteria: 1. any unstable medical condition other than hypertension; 2. stage 3 hypertension (sbp \> 180mmhg and/or dbp \> 110mmhg); 3. heart rate \> 100 beats per minute; 4. wocbp who is pregnant or who is planning to become pregnant during the study; 5. history within past year of alcohol or illicit drug abuse; 6. unable to comply with study procedures in opinion of investigator; 7. concomitant medications for any medical condition that is uncontrolled for more than 2 weeks prior to study entry; 8. current use of alpha-adrenergic blocker, hydralazine, clonidine, guanethidine, guanadrel, or rauwolfia alkaloids; 9. history of myocardial infarction or angina pectoris; 10. current seizure disorder; 11. renal insufficiency as defined by a serum creatinine \> 2.0; 12. uncontrolled hypothyroidism, vitamin b12 or folic acid deficiency; 13. history of or concurrent ileus, glaucoma, or urinary retention; 14. inability of subject to understand and sign the icf; 15. known systemic infection (hbv, hcv, hiv, tb); 16. current use of smoking cessation therapy within 4 weeks of screening; 17. use of herbal supplements; 18. clinically significant finding on physical exam; 19. clinically significant laboratory or ecg abnormality, including qtcf \> 460 msec; 20. participation in another clinical trial in last month; 21. body mass index (bmi) \> 35. 22. body weight \< 100 pounds. 23. site staff or family member of study site staff.

Keywords: refractory hypertension hypertension