Clinical trial NCT02678000: Study of the Safety, Tolerability, and Pharmacokinetics of LHW090 in Patients With Moderately Impaired Renal Function
Official title: A Two Part Randomized, Double-blind, Parallel-group, Placebo-controlled Study to Evaluate the Renal Safety, Tolerability and Pharmacokinetics of LHW090 in Patients With Moderately Impaired Renal Function on Angiotensin Receptor Blockers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Kidney Disease (CKD)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-02-09
Enrollment: 84
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This was a randomized, double-blind, parallel group, placebo-controlled study, in two sequential parts that evaluated the renal safety, tolerability and pharmacokinetics of LHW090 in patients with moderately impaired renal function.


Eligibility criteria: Inclusion Criteria (all Parts):

* Written informed consent must be obtained before any assessment is performed.
* Male and female patients, age 40 to 85 years of age (inclusive) on a stable (at least 1 month) dose of an angiotensin receptor blocker (ARB) and stable moderately impaired renal function, defined here as an eGFR 30-59 mL/min/1.73m\^2 (inclusive) using the 4 variable MDRD Study equation for at least 3 months.
* At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the patient has rested for at least five minutes, and again after three minutes in the standing position. Sitting vital signs should be within the following ranges:

  * oral body temperature between 35.0-37.5 °C
  * systolic blood pressure, 100-170 mm Hg
  * diastolic blood pressure, 50-100 mm Hg
  * pulse rate, 50 - 95 bpm
* Patients should be excluded if their standing vital signs (relative to sitting) show findings which, in the opinion of the Investigator, are associated with clinical manifestation of postural hypotension (i.e. absence of any other cause). The Investigator should carefully consider enrolling patients with either a \> 20 mm Hg decrease in systolic or a \>10 mm Hg decrease in diastolic blood pressure, accompanied by a \> 20 bpm increase in heart-rate (comparing standing to sitting results).
* Patients must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 38 kg/m\^2. BMI = Body weight (kg) / \[Height (m)\]\^2.
* Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Exclusion criteria:

* History of angioedema, drug-related or otherwise, as reported by the patient.
* Use of angiotensin converting enzyme inhibitors (ACE inhibitors), mineralocorticoid receptor antagonists (e.g. spironolactone or eplerenone), aliskiren, vasopressin receptor antagonists (e.g. tolvaptan), or oral alkalinizing agents (e.g. sodium and potassium citrate or Shohl's solution). Note: Patients who discontinue their ACE-inhibitor and substitute with an angiotensin receptor blocker (ARB) may be eligible to be rescreened provided their medication regimen has been stable for at least 1 month and their renal function has been stable for at least 3 months. Any substitutions or changes to a patient's medication regimen must be done under the guidance of the patient's treating physician.
* History of a renal transplant.
* Known current significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or significant severe valvular disease on prior or current echocardiogram.
* A serum potassium ≤ 3.5 mmol/l or ≥ 5.2 mmol/l at screening.
* A previous history or previously diagnosed renal cystic disease such as autosomal dominant polycystic kidney disease (history of an incidental asymptomatic acquired renal cyst(s) is excepted); obstructive uropathy; renal stone(s) in the past 2 years; chronic interstitial nephropathy; drug induced nephropathy; residual renal insufficiency following an episode of acute kidney injury or acute tubular necrosis related to renal atheroembolic disease, septic shock or ischemic nephropathy; renal tubular acidosis requiring treatment; nephrotic syndrome or nephrotic range proteinuria; or renal artery stenosis.

Primary outcomes:
measure: Number of Patients With Reported Adverse Events Receiving Escalating Doses of LHW090 (Part 1)
timeFrame: Adverse events were collected from first dose of study treatment until end of study treatment, (12 days dosing period + 9 days follow up (PART 1) plus 30 days post treatment, up to maximum duration of approximately 20 months
measure: Pharmacokinetics of LHW090/LHV527 (Active Metabolite) in Plasma: Area Under the Plasma Concentration-time Curve From Time Zero Time 't' Where t is a Defined Time Point After Administration (AUC0-t) (PART 1)
timeFrame: Within 60 minutes prior to dosing, post dose +/- 10 min from greater or equal to 1 hr to 24 hrs.
measure: Number of Patients Who Developed a Renal Event (PART 2)
timeFrame: Baseline, within 24 to 48 hours of post-dose weekly for up to 8 weeks
Secondary outcomes:
measure: Cmax : Pharmacokinetics of LHW090/LHV527 (Active Metabolite) in Plasma: Observed Maximum Plasma Concentration Following Administration of LHW090 (PART 1/PART 2)
timeFrame: PART 1: within 60 minutes prior to dosing, post dose +/- 10 min from greater or equal to 1 hr to 24 hrs. PART 2: within 60 min +/- 10 min from greater or equal to 1 hr to 8 hours after 4 weeks dosing.
measure: AUC0-t: Pharmacokinetics of LHW090/LHV527 (Active Metabolite)in Plasma: Area Under the Plasma Concentration-time Curve From Time Zero Time 't' Where t is a Defined Time Point After Administration (PART 2)
timeFrame: PART 2: within 60 min +/- 10 min from greater or equal to 1 hr to 8 hours after 4 weeks dosing
measure: Tmax: Pharmacokinetics of LHW090/LHV527 in Plasma: Time to Reach the Maximum Concentration After Administration of LHW090 (PART 1/PART 2)
timeFrame: Part 1: within 60 minutes prior to dosing, post dose +/- 10 min from greater or equal to 1 hr to 24 hrs. Part 2: within 60 min +/- 10 min from greater or equal to 1 hr to 8 hours after 4 weeks dosing
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Novartis Investigative Site
state: California
city: Lakewood
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Miami Lakes
country: United States
facility: Novartis Investigative Site
state: Florida
city: Orlando
country: United States
facility: Novartis Investigative Site
state: Florida
city: New Orleans
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Minneapolis
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Saint Paul
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Elsterwerda
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: