A phase II, randomized, double-blind, placebo controlled, multi-center study to evaluate the effects of LCI699 on cortisol in patients with hypertension.

• Conditions: hypertension; MedDRA version: 9.1Level: LLTClassification code 10020772Term: Hypertension

• Registration Number: EUCTR2008-007337-49-IS
• Lead Sponsor: ovartis Pharma Services AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2009-01-07
• Last Update Posted: 19 March 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 90

Inclusion Criteria

1. Able and willing to provide written informed consent prior to study participation.
2. An established diagnosis of hypertension with mean systolic and/or mean diastolic sitting OBP > 140/90 mmHg and < 180/110 mmHg on current antihypertensive treatment measured at screening (Visit 1) and within two (2) weeks of randomization (Visit 2).
3. Male or female patients 18 to 75 years of age (inclusive)
o Female subjects must have been surgically sterilized (oophorectomy with or without hysterectomy) at least 6 months prior to screening and negative pregnancy test. Surgical sterilization procedures must be supported with clinical documentation made available to sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the CRF.

OR:
o Postmenopausal women must have no regular menstrual bleeding for at least 1 year prior to inclusion. Menopause will be confirmed by a plasma FSH level of =40 IU/L

OR:
o Male subjects must be willing to use a double-barrier local contraception, i.e., spermicidal gel plus condom, for the entire duration of the study, up to Study Completion visit, and refrain from fathering a child or donating sperm in the three (3) months following last study drug administration.
4. Subjects must weigh at least 50 kg to participate in the study.
5. Morning plasma cortisol (sampled between 08:00 and 09:00) > 250 nM and 30 or 60 min post-ACTH plasma cortisol > 500 nM at the run in visit (Visit 2).
6. Ability to communicate and willingness to comply with all study requirements.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

For full list, please refer to the protocol.

1. Recent history (within last 6 months) of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack (TIA).
2. Clinically significant cardiac conduction defects (e.g., 3rd degree atrioventricular [AV] block, left bundle branch block [LBBB], sick sinus syndrome, atrial fibrillation or flutter); familial long QT syndrome or torsades de pointe.
3. Patients with renal impairment (estimated creatinine clearance < 50 mL/min by the MDRD formula).
4. Use of oral, parenteral, topical, inhaled or ophthalmic corticosteroids within 4 weeks of randomization.
5. Pregnant or nursing women, where pregnancy is confirmed by an hCG >5mIU/mL at screening (Visit 1).
6. Use of any of the following medications within four (4) weeks of randomization:
o Aldosterone receptor inhibitors (i.e., eplerenone & spironolactone)
o Potassium sparing diuretics (i.e., triamterene & amiloride)
o Direct renin inhibitors (i.e. aliskiren)
o Potassium supplements
o Thyroid medication (except on a stable regimen for at least 3 months prior to Visit 1 and is not expected to change during the course of study), estrogen-based and/or androgen-based hormone replacement therapies.
o Cholestyramine and colestipol resins.
o Systemically available non-steroidal anti-inflammatory agent. Topical NSAIDs and daily low dose aspirin (< 81 mg/day) are allowed.
o Growth hormone or similar drugs
o Class Ia, Ib and Ic or III anti-arrhythmics
o Any antidepressant drugs in the MAO inhibitor class, tricyclics, and venafaxine, duloxetine, and bupropion. Other psychotropic drugs such as benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) are allowed if well tolerated when previously taken and the patient has been on a stable dose for the previous 3 months.
o Chronic administration (defined as > 3 days per week) of sympathomimetic drugs such as those found in nasal decongestants, oral decongestants, diet aids and bronchodilators. Doses of sympathomimetic drugs used occasionally are prohibited 24 hours prior to the study visit.
o Ergot and serotonin (5-hydroxytryptamine) receptor agonist preparations.
o Drugs for the treatment of attention deficit hyperactivity disorder (ADHD), including bupropion, desipramine, methylphenidate, amphetamine and atomoxetine.
o Tamsulosin hydrochloride or other a-blockers.
o Nitrates of any kind.
o Sildenafil and vardenafil are disallowed within 24 hours prior to any scheduled visits. Tadalafil is disallowed within 48 hours prior to any scheduled visit. These drugs may be taken outside of this window.
o Any drug with a known and frequent toxicity to a major organ system within the past 3 months (i.e., cytostatic drugs)
7. Participation in any clinical investigation within 4 weeks prior to randomization or longer if required by local regulations.
8. Any blood donation or significant loss within 4 weeks of randomization; donation of plasma within 7 days prior to randomization.
9. History of malignancy of any organ system within the past 5 years with the exception of localized basal cell skin cancer.
10. Any surgical or medical condition which may significantly alter the absorption, of any drug substance, including but not limited to, any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resectio

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To determine the maximum tolerated dose (MTD) of LCI699 with respect to cortisol suppression following ACTH stimulation in hypertensive patients;Primary end point(s): The objectives of the study are to characterize the LCI699 concentration response relationship following ACTH stimulation, and to determine the MTD of LCI699 with respect to cortisol suppression following ACTH stimulation.;Secondary Objective: • To characterize the LCI699 exposure-response relationship on cortisol levels following ACTH stimulation in hypertensive patients<br>• To characterize the pharmacokinetics of LCI699 in hypertensive patients<br>• To assess the safety and tolerability of LCI699 in hypertensive patients<br>• To explore the proportion of patients achieving a successful BP response and BP control in all treatment groups for 23-26 hour post dose (11-14 hour post dose for BID regimen) MSSBP and MSDBP after 6 weeks treatment.