TC-5214 as Augmentation Therapy in Patients With Refractory Hypertension

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Double-blind, Randomized, Placebo-controlled, Sequential Group Pilot Study to Assess Safety, Tolerability, and Effectiveness of TC-5214 as Augmentation Therapy in Patients With Refractory Hypertension

Conditions
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Refractory Hypertension

Intervention / Treatment
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* Drug: Placebo
* Drug: TC-5214


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. Outpatient with stable housing. Subjects must be able to stay in the clinic for 8 hrs on Day 1, Day 8, Day 15, Day 22, and Day 36. Able to give and to sign informed consent. Exclusion Criteria: Any unstable medical condition other than hypertension; Stage 3 hypertension (SBP > 180mmHg and/or DBP > 110mmHg); Heart rate > 100 beats per minute; WOCBP who is pregnant or who is planning to become pregnant during the study; History within past year of alcohol or illicit drug abuse; Unable to comply with study procedures in opinion of investigator; Concomitant medications for any medical condition that is uncontrolled for more than 2 weeks prior to study entry; Current use of alpha-adrenergic blocker, hydralazine, clonidine, guanethidine, guanadrel, or rauwolfia alkaloids; History of myocardial infarction or angina pectoris; Current seizure disorder; Renal insufficiency as defined by a serum creatinine > 2.0; Uncontrolled hypothyroidism, vitamin B12 or folic acid deficiency; History of or concurrent ileus, glaucoma, or urinary retention; Inability of subject to understand and sign the ICF; Known systemic infection (HBV, HCV, HIV, TB); Current use of smoking cessation therapy within 4 weeks of screening; Use of herbal supplements; Clinically significant finding on physical exam; Clinically significant laboratory or ECG abnormality, including QTcF > 460 msec; Participation in another clinical trial in last month; Body Mass Index (BMI) > 35. Body weight < 100 pounds. Site staff or family member of study site staff.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects may receive a single, oral dose of placebo (capsule) in one of 4 crossover periods. Also, subjects may receive placebo orally, twice daily for 14 days in the last phase of the study. | Drug: Placebo<br>* Matching placebo<br>|
| Experimental: 1 mg TC-5214<br>Subjects may receive a single, oral capsule of 1 mg TC-5214 in one of 4 crossover periods. | Drug: TC-5214<br> <br> |
| Experimental: 2 mg TC-5214<br>Subjects may receive a single, oral capsule of 2 mg TC-5214 in one of 4 crossover periods. | Drug: TC-5214<br> <br> |
| Experimental: 4 mg TC-5214<br>Subjects may receive a single, oral capsule of 4 mg TC-5214 in one of 4 crossover periods. Also, subjects may receive 4 mg TC-5214 orally, twice daily for 14 days in the last phase of the study. | Drug: TC-5214<br> <br> |
| Experimental: 8 mg TC-5214<br>Subjects may receive a single, oral capsule of 8 mg TC-5214 in one of 4 crossover periods. | Drug: TC-5214<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean difference between TC-5214 and placebo in change at 3 hours from baseline SBP |  | Following dosing, 3 manual seated BP measurements and orthostatic BP measurements will be obtained in an identical fashion, at 30 minutes post-dose and at 1, 2, 3, 4, 5, 6, 7, and 8 hrs post-dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of TC-5214 in patients with refractory hypertension and obtain preliminary dose-response estimates |  | Days 1, 8, 15, 22 and 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory hypertension, hypertension