A Study To Evaluate The Dose-Related Efficacy and Safety of PS433540 in Subjects With Hypertension

• irbesartan (Drug), also known as Avapro: 300 mg (2 x 150 mg capsules) once daily for 12 weeks
• placebo (Drug): placebo capsules once daily for 12 weeks
• PS433540 (Drug): 200 mg (2 x 100 mg capsules) once daily for 12 weeks
• PS433540 (Drug): 400 mg (4 x 100 mg capsules) once daily for 12 weeks
• PS433540 (Drug): 800 mg (8 x 100 mg capsules) once daily for 12 weeks

Primary outcomes

• Change From Baseline in Mean Seated Systolic Blood Pressure (SBP) Following 12 Weeks of Treatment With PS433540 200 mg, 400 mg, 800 mg and Placebo. [12 weeks]

Secondary outcomes

• Change From Baseline in Mean Seated Diastolic Blood Pressure (DBP) Following 12 Weeks of Treatment With PS433540 200 mg, 400 mg, 800 mg and Placebo. [12 weeks]
• The Percentage of Patients Treated With Each Dose of PS433540 Who Achieved Blood Pressure Control, Defined as <140/90 mmHg, After 12 Weeks of Treatment. [12 weeks]

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Males or females 18 - 70 years
* Mean seated Systolic Blood Pressure (SBP) ≥ 140 mmHg and < 180 mmHg and mean seated Diastolic Blood Pressure (DBP) > 90 and < 109 mmHg at two consecutive qualifying visits (Visits 3/3.5 and Visit 4). The mean difference in DBP between the two consecutive qualifying visits must be ≤ 10 mmHg.
* Women of child-bearing potential (WOCBP) must use two reliable forms of contraception if sexually active. Alternatively, female subjects must be postmenopausal (for at least 1 year).

Exclusion Criteria:

* Subjects with serious disorders which may limit the ability to evaluate the efficacy or safety of PS433540, including cardiovascular (includes subjects who are known to have coronary artery disease), renal (including the absence of one kidney), pulmonary, hepatic, gastrointestinal (including clinically significant malabsorption), endocrine/metabolic, hematologic, neurologic and psychiatric diseases.
* History of malignancy other than adequately treated basal cell or squamous cell skin cancer.
* Subjects with a history of myocardial infarction or New York Heart Association (NYHA) class II-IV heart failure.
* Subjects with a history of cerebrovascular accident or transient ischemic attack.
* Subjects with clinically significant cardiac conduction defects, including second or third degree Atrioventricular Block (AV block), left bundle branch block, sick sinus syndrome, atrial fibrillation, atrial flutter, an accessory bypass tract, or any arrhythmia requiring medication.
* Subjects with hemodynamically significant valvular disease.
* Subjects with history of type 1 diabetes mellitus and subjects with a history of type 2 diabetes mellitus using antihyperglycemic medication (oral medication, insulin, or exenatide) are excluded.

Participant flow

Outcome results

• Change From Baseline in Mean Seated Systolic Blood Pressure (SBP) Following 12 Weeks of Treatment With PS433540 200 mg, 400 mg, 800 mg and Placebo. (Primary), Mean, mm Hg: Irbesartan 300mg -10.7 +/- 14.32; Placebo 1.8 +/- 14.16; PS433540 200mg -13.2 +/- 13.61; PS433540 400mg -14.2 +/- 11.90; PS433540 800mg -23.4 +/- 18.70
• Change From Baseline in Mean Seated Diastolic Blood Pressure (DBP) Following 12 Weeks of Treatment With PS433540 200 mg, 400 mg, 800 mg and Placebo. (Secondary), Mean, mm Hg: Irbesartan 300mg -7.1 +/- 9.19; Placebo 0.2 +/- 9.68; PS433540 200mg -7.2 +/- 8.34; PS433540 400mg -9.2 +/- 9.10; PS433540 800mg -14.3 +/- 10.53
• The Percentage of Patients Treated With Each Dose of PS433540 Who Achieved Blood Pressure Control, Defined as <140/90 mmHg, After 12 Weeks of Treatment. (Secondary), Number, participants: Irbesartan 300mg 17; Placebo 5; PS433540 200mg 21; PS433540 400mg 28; PS433540 800mg 16

Adverse events

Serious adverse events by term

Other adverse events by term

Limitations and caveats: The 800mg dose level was discontinued from further enrollment per protocol amendment due to findings from another PS433540 trial that suggested clinical benefit beyond 500mg was expected to be limited.

• Rene Belder, MD, Study director, Ligand Pharmaceuticals
• Joel Neutel, MD, Principal investigator, Orange County Research Center