Safety and Efficacy Study of LHW090 in Resistant Hypertension Patients

A Randomized, Sponsor Open, Site and Subject Double Blind, Parallel Group, Placebo-controlled Study to Evaluate the Safety and Efficacy of LHW090 After 4 Weeks Treatment in Patients With Resistant Hypertension

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02515331

Enrollment

Registered

2015-08-04

Start date

2015-11-04

Completion date

2017-08-17

Last updated

2021-01-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Patients, Resistant Hypertension

Keywords

resistant hypertension

Brief summary

The purpose of the present study was to determine whether LHW090 displays the clinical safety and efficacy profile to support further development in patients with resistant hypertension.

Interventions

DRUGLHW090

Capsule - oral dose

DRUGPlacebo

Capsule - oral dose

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

40 Years to 85 Years

Healthy volunteers

Inclusion criteria

* Male and female patients, age 40 to 85 years inclusive. * • Patients with uncontrolled hypertension (here defined as having a mean daytime systolic BP ≥ 135 mmHg by ABPM at screening) despite treatment with a stable (at least 1 month) regimen that includes an optimal dose of an ARB plus a diuretic plus at least one additional class of anti-hypertensive medication. For the purposes of this trial, optimal doses of anti-hypertensive medications are defined as: * the highest dose listed in the clinical practice guideline from the American Society for Hypertension and the International Society for Hypertension or * the highest allowable prescribed dose per the manufacturer's label or * the highest dose tolerated by an individual patient or * the highest dose appropriate for an individual patient in the judgment of the Investigator * Subjects must weigh at least 45 kg to participate in the study and must have a body mass index (BMI) within the range of 18-38 kg/m\^2.

Exclusion criteria

* Patients with an estimated GFR \<60 ml/min/1.73m\^2. * 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. * Severe hypertension as defined by systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg at screening. * 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. * Known current significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or significant severe valvular disease on prior or current echocardiogram). * A history of known moderate or malignant 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. * To facilitate ABPM assessment, an upper arm circumference greater than 42 cm. * 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). 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. • Women of child-bearing potential

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	6 months	Number of participants with AEs, SAEs and deaths were assessed.
Change From Baseline in Mean Daytime Blood Pressure	Baseline, day 27	Change in the 12 hour average of systolic blood pressure (SBP) measured by ambulatory blood pressure was defined as the 12 hour daytime average SBP on Day 28 minus the 12 hour daytime average SBP on Day -1. monitoring (ABPM). A negative change from baseline indicates improvement.

Secondary

Measure	Time frame	Description
Pharmacokinetics of LHW090/LHV527 in Plasma: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast)	Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs up to 12 hrs on Day 1 and Day 28	Blood samples were collected to assess AUClast.
Pharmacokinetics of LHW090/LHV527 in Plasma: Observe Maximum Plasma Concentration Following LHW090 at Steady State in Patients (Cmax)	Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs up to 12 hrs on Day 1 and Day 28	Blood samples were collected to assess Cmax.
Pharmacokinetics of LHW090/LHV527 in Plasma:Tlast	Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs up to 12 hrs on Day 1 and Day 28	Blood samples were collected to assess Tlast.
Pharmacokinetics of LHW090/LHV527 in Plasma: Last Measurable Plasma Concentration (Clast)	Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs up to 12 hrs on Day 1 and Day 28	Blood samples were collected to assess Clast.
Pharmacokinetics of LHW090/LHV527 in Plasma: Time to Reach the Maximum Concentration After Administration of LHW090 (Tmax)	Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs up to 12 hrs on Day 1 and Day 28	Blood samples were collected to assess Tmax.

Countries

Denmark, France, Germany, Netherlands, Switzerland, United States

Participant flow

Pre-assignment details

Participants were randomized in a 1:1:2 ratio to LHW090 100 mg, LHW090 200 mg and placebo, respectively.

Participants by arm

Arm	Count
LHW090 100 mg LHW090 100 mg once daily for 28 days	17
LHW090 200 mg LHW090 200 mg once daily for 28 days	15
Placebo Matching placebo to LHW090 oral dose for 28 days	32
Total	64

Withdrawals & dropouts

Period	Reason	FG000	FG002
Overall Study	Adverse Event	2	0
Overall Study	Protocol deviation	0	3
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	LHW090 100 mg	LHW090 200 mg	Placebo	Total
Age, Continuous	64.2 Years STANDARD_DEVIATION 8.42	61.8 Years STANDARD_DEVIATION 5.16	64.4 Years STANDARD_DEVIATION 9.56	63.8 Years STANDARD_DEVIATION 8.38
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	4 Participants	7 Participants	14 Participants	25 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants	2 Participants
Race (NIH/OMB) White	11 Participants	7 Participants	18 Participants	36 Participants
Sex: Female, Male Female	4 Participants	9 Participants	13 Participants	26 Participants
Sex: Female, Male Male	13 Participants	6 Participants	19 Participants	38 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 17	0 / 15	0 / 32
other Total, other adverse events	12 / 17	3 / 15	14 / 32
serious Total, serious adverse events	0 / 17	0 / 15	0 / 32

Outcome results

Primary

Change From Baseline in Mean Daytime Blood Pressure

Change in the 12 hour average of systolic blood pressure (SBP) measured by ambulatory blood pressure was defined as the 12 hour daytime average SBP on Day 28 minus the 12 hour daytime average SBP on Day -1. monitoring (ABPM). A negative change from baseline indicates improvement.

Time frame: Baseline, day 27

Population: The primary pharmacodynamics (PD) analysis set, which included patients that received study drug with any available PD data, was considered for the analysis. Only patients with values on both baseline and day 27 were analyzed.

Arm	Measure	Value (MEAN)	Dispersion
LHW090 100 mg	Change From Baseline in Mean Daytime Blood Pressure	-9.41 mmHg	Standard Deviation 8.379
LHW090 200 mg	Change From Baseline in Mean Daytime Blood Pressure	-16.84 mmHg	Standard Deviation 7.678
Placebo	Change From Baseline in Mean Daytime Blood Pressure	-0.79 mmHg	Standard Deviation 10.555

p-value: 0.00295% CI: [-14.388, -2.722]Longitudinal repeated measures mixed eff

p-value: <0.00195% CI: [-20.852, -8.602]Longitudinal repeated measures mixed eff

Primary

Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths

Number of participants with AEs, SAEs and deaths were assessed.

Time frame: 6 months

Population: Safety analysis set: included all participants who were randomized.

Arm	Measure	Group	Value (NUMBER)
LHW090 100 mg	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	SAEs	0 Participants
LHW090 100 mg	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	AEs	12 Participants
LHW090 100 mg	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	Deaths	0 Participants
LHW090 200 mg	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	SAEs	0 Participants
LHW090 200 mg	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	AEs	3 Participants
LHW090 200 mg	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	Deaths	0 Participants
Placebo	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	AEs	14 Participants
Placebo	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	Deaths	0 Participants
Placebo	Number of Participants With Reported Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths	SAEs	0 Participants

Secondary