E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
High blood pressure not controlled |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015491 |
E.1.2 | Term | Essential hypertension, unspecified |
E.1.2 | System Organ Class | 100000004866 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether LHW090 displays the clinical safety and efficacy profile to support further development in patients with resistant hypertension: i.e
- To assess the safety and tolerability of LHW090 for 4 weeks on a background of conventional anti-hypertensive medications in patients with resistant hypertension.
- To evaluate the effect of LHW090 on placebo-adjusted mean daytime systolic blood pressure (SBP) after 4 weeks in patients with resistant hypertension.
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E.2.2 | Secondary objectives of the trial |
To evaluate the pharmacokinetics (PK) of LHW090 and its active metabolite LHV527 in patients with resistant hypertension. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients, age 40 to 85 years inclusive.
3. Demonstrating a ≥ 80% medication compliance rate during the single-blind run-in period.
4. Patients with uncontrolled hypertension (here defined as having a daytime systolic BP ≥ 135 mmHg by ABPM at screening) despite treatment with a stable (at least 1 month) regimen that includes an optimal doses of an ARB plus a diuretic (thiazide or loop) plus at least one class of anti-hypertensive medication
For the purposes of this trial, optimal doses of anti-hypertensive medications are defined as:
a) the highest dose listed in the clinical practice guideline from the American Society for Hypertension and the International Society for Hypertension [Weber, et al. 2014] or
b) the highest allowable prescribed dose per the manufacturer's label or
c) the highest dose tolerated by an individual patient or
d) the highest dose appropriate for an individual patient in the judgment of the Investigator
5. Subjects must weigh at least 45 kg to participate in the study and must have a body mass index
(BMI) within the range of 18-40 kg/m2.
6. Able to communicate well with the investigator, to understand and comply with the requirements of
the study.
Other protocol defined inclusion criteria may apply |
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E.4 | Principal exclusion criteria |
Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives
of enrollment, whichever is longer; or longer if required by local regulations, and for
any other limitation of participation in an investigational trial based on local regulations.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical
classes.
3. Patients with an estimated GFR <60 ml/min/1.73m2 at screening using the MDRD
equation.
4. Use of angiotensin converting enzyme inhibitors (ACE-inhibitors).
Note: Patients who discontinue their ACE-inhibitor and substitute with an angiotensin
receptor blocker may be eligible to be re-screened provided their anti-hypertensive
regimen has been stable for at least 1 month. Any substitutions or changes to a patient's
anti-hypertensive regimen should be done under the guidance of the patient's treating
physician.
5. History of angioedema, drug related or otherwise, as reported by the patient.
6. Clinically significant ECG abnormalities at screening as determined by the Investigator.
7. Severe hypertension as defined by an office systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg at screening or baseline.
8. A history of secondary hypertension of any etiology including but not limited to unilateral
or bilateral renal artery stenosis, polycystic kidney disease, coarctation of the aorta,
primary hyperaldosteronism, Cushing's disease, pheochromocytoma, and drug-induced
hypertension. If the patient has not been evaluated for secondary HT, investigators are responsible to evaluate all potential secondary causes of hypertension considering clinical history, physical examination, laboratory investigations or other relevant diagnostic measures in accordance with current practices and clinical guidelines before entering the patient into the study.
9. Known current significant left ventricular outflow obstruction, such as obstructive
hypertrophic cardiomyopathy or significant severe valvular disease on prior or current
echocardiogram).
10. A history of known moderate or malignant hypertensive retinopathy defined as moderate (retinal signs
of hemorrhage), microaneurysms, cotton-wool spots, hard exudates, or a combination
thereof) or malignant (signs of moderate retinopathy plus swelling of the optic disk). Patients with a stable ophthalmologic history in the past 6 months are eligible. Any new or progressive retinal changes, acute glaucoma or other ophthalmologic conditions within the past 6 months should be evaluated by the treating ophthalmologist during screening.
11. To facilitate ABPM assessment of daytime readings, an upper arm circumference greater
than 42 cm or third shift or overnight workers.
12. History within the previous 6 months of myocardial infarction, coronary artery bypass
graft (CABG), percutaneous coronary intervention (PCI), hypertensive encephalopathy,
stroke, or transient ischemic attack (TIA).
13. Hemoglobin levels below 9.0 g/dL at screening.
14. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin or in-situ cervical cancer), treated or untreated, within the past 1 year, regardless
of whether there is evidence of local recurrence or metastases.
15. Donation or loss of 400 mL or more of blood within 8 weeks prior to initial dosing, or
longer if required by local regulation.
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
17. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant
18. Sexually active males must use a condom during intercourse while taking drug and for
1 week after stopping study medication and should not father a child in this period.
A condom is required to be used also by vasectomized men in order to prevent delivery of
the drug via seminal fluid.
19. Any surgical or medical condition, which in the opinion of the investigator, may place the
patient at higher risk from his/her participation in the study, or is likely to prevent the
patient from complying with the requirements of the study or completing the study.
20. On the Columbia-Suicide Severity Rating Scale score "yes" on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or "yes" on any item of the Suicidal Behavior section, except for the "Non-Suicidal Self Injurious Behavior" (question also included in the Suicidal Behavior section), if this behavior occured in the past 2 years. Any patient meeting this exclusion criterion should be referred to a mental health care professional.
21. Vulnerable subjects, e.g. subjects kept in detention, soldiers and employees of the sponsor
or a clinical research organization, involved in this study.
Other protocol defined exclusion criteria may apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety endpoints (adverse events, serious adverse events) will be measured up to and including end of study assessments
The primary efficacy variable will be the change in the 12 hour average of systolic blood pressure
measured by ambulatory blood pressure monitoring (ABPM) 28 days following the start of treatment
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Efficacy and Safety parameters will be routinely evaluated over the 4 weeks of treatment as defined in the protocol
-ABPM measured at baseline and at the end of the treatment at day 28 |
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E.5.2 | Secondary end point(s) |
Pharmacokinetics (PK) parameters of LHW090 and its active metabolite LHV527 in patients with resistant hypertension.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As defined in the protocol : PK parameters will be measured on Day 28 (Cmax, Tmax, AUClast, AUC0-t) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Denmark |
France |
Germany |
Netherlands |
Switzerland |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 12 |
E.8.9.2 | In all countries concerned by the trial days | 19 |