- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01846468
An Ascending Dose Study to Assess Safety, Tolerability, PK/PD of LHW090 in Healthy Volunteers and in Subjects With Renal Dysfunction
A Partially-blinded, Randomized, Placebo-controlled, Adaptive Single and Multiple Ascending Dose Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LHW090 in Healthy Volunteers and in Subjects With Renal Dysfunction
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Florida
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Orlando, Florida, United States, 32809
- Novartis Investigative Site
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Tennessee
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Knoxville, Tennessee, United States, 37920
- Novartis Investigative Site
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria: For Stage 1, 2 and 3 subjects only:
Subjects eligible for inclusion in these stages of the study have to fulfill all of the following criteria at screening:
- Healthy male and female subjects age 18 to 45 years of age included, and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
- At screening, and first baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes, and again (when required) 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, 90-140 mm Hg diastolic blood pressure, 50-90 mm Hg pulse rate, 40 - 90 bpm
For Stage 4 subjects only:
- Male and female subjects, age 18 to 75 years of age included, with previously identified chronic renal insufficiency (estimated or measured GFR ≤ 45ml/min/1.73m2, or diabetic with estimated or measured GFR ≤ 60ml/min/1.73m2.) Diabetes can be established by the prescription and current use of anti-glycemic drugs, a random fasting glucose level of ≥ 144mg/dl or a hemoglobin A1c of ≥ 6.5%
- At screening, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes, and again (when required) 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, 90-179 mm Hg diastolic blood pressure, 50-100 mm Hg pulse rate, 40 - 95 bpm
Exclusion Criteria:
For Stages 1, 2 and 3, subjects fulfilling any of the following additional criteria are not eligible for inclusion in this study:
- An active history of clinically significant ECG abnormalities as determined by the Investigator, or any of the following ECG abnormalities at Screening or Baseline:
- Long QT syndrome
- QTcF > 450 msec (males; at screening)
- QTcF > 460 msec (females; at screening)
- Known history of current clinically significant arrhythmias.
- Use of phosphodiesterase-5 inhibitors, UNLESS subjects agree to discontinue use of the drug for the duration of the study.
- 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, defined as all women physiologically capable of becoming pregnant
- Smokers (use of tobacco products in the previous 3 months). Urine cotinine levels will be measured during screening and at each baseline for all subjects. Smokers will be defined as any subject who reports tobacco use and/or who has a urine cotinine ≥ 500 ng/ml.
- Hemoglobin levels below 11.0 g/dl at screening.
- Subjects in Stage 3 only of the study will be excluded if they have any of the following:
- A history of allergy to topical anesthetic drops
- A history of corneal disease
- A history of eye surgery within three months prior to screening
- A history of corneal surgery (including refractive surgery and corneal transplantation)
For Stage 4, subjects fulfilling any of the following additional criteria are not eligible for inclusion in this study:
- An active history of clinically significant ECG abnormalities as determined by the Investigator, or any of the following ECG abnormalities at Screening or Baseline:
- Long QT syndrome
- QTcF > 480 msec at screening
- Use of phosphodiesterase-5 inhibitors, UNLESS subjects agree to discontinue use of the drug for the duration of the study.
- 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, defined as all women physiologically capable of becoming pregnant
- Significant smokers. Significant smokers who are unable to tolerate using no more than 4 cigarettes a day should be excluded
- History of right ventricular dysfunction within the last 12 months
- Hemoglobin levels below 9.0 g/dl at screening.
- Use of angiotensin converting enzyme inhibitors (ACEi), UNLESS subjects agree to either a withholding of their ACEi, or a switch to an angiotension receptor blocker, starting 5 days (or 5 half-lives which ever is longer) prior to initiation of study and extending to the end-of-study visit. Patient who withhold their ACEi for the specified duration must first consult with their primary physician to determine their suitability and safety for this temporary withholding of ACEi.
- Diuretic-dependence, i.e. unable to produce urine without diuretics, or at high risk of flash pulmonary edema without diuretics. Use of diuretics will exclude subjects UNLESS subjects agree to withhold diuretics starting the day prior to check-in and extending to discharge. Consultation of the subject with their primary physician must be used to determine their suitability and safety for temporary withholding of their diuretics.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Stage 1 : LHW090, Healthy Volunteers
Healthy Volunteers will receive single dose of LHW090 on Day 1.
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1 mg, 12.5 mg, 100 mg capsules
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Experimental: Stage 2: LHW090, Healthy Volunteer
Healthy Volunteers across 7 single ascending dose cohorts will be administered LHW090 or matching placebo day 1
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Matching placebo capsules
1 mg, 12.5 mg, 100 mg capsules
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Experimental: Stage 3: LHW090, Healthy Volunteer
Healthy Volunteers across 6 multiple ascending dose cohorts will be administered LHW090 or matching placebo for 14 days.
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Matching placebo capsules
1 mg, 12.5 mg, 100 mg capsules
|
Experimental: Stage 4: LHW090, Patients
Subjects with Chronic Renal Insufficiency across 3 cohorts will be administered a single dose of LHW090 in Day 1.
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1 mg, 12.5 mg, 100 mg capsules
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of participants (Healthy Volunteers) with reported adverse events receiving single oral dose of LHW090 as assessment of safety and tolerabiility
Time Frame: 6 months
|
In this analysis AE and SAE will be reported
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6 months
|
Number of participants (Healthy Volunteers) with reported adverse events receiving multiple oral dose of LHW090 as assessment of safety and tolerabiility
Time Frame: 6 months
|
In this analysis AE and SAE will be reported
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6 months
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Number of participants (patients) with reported adverse events receiving single oral dose of LHW090 as assessment of safety and tolerabiility
Time Frame: 6 months
|
In this analysis AE and SAE will be reported
|
6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacokinetics of LHW090/LHV527 in plasma: observe maximum plasma concentration following LHW090 at steady state in healthy volunteers and patients
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
In this analysis Cmax will be reported
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
Pharmacokinetics of LHW090/LHV527 in plasma: time to reach the maximum concentration after administration of LHW090 (Tmax)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
In this analysis Tmax will be reported
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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Pharmacokinetics of LHW090/LHV527 in plasma: area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
In this analysis AUClast will be reported
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
Pharmacokinetics of LHW090/LHV527 in plasma: area under the plasma concentration-time curve from time zero to infinity (AUCinf)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
In this analysis AUCinf will be reported
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
Pharmacokinetics of LHW090/LHV527 in plasma: terminal elimination half-life (T1/2)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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In this analysis T1/2 will be reported
|
Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
Pharmacokinetics of LHW090/LHV527 in plasma: accumulation ratio (RACC)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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In this analysis the accumulation ratio will be reported
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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Pharmacokinetics of LHW090/LHV527 in plasma: apparent volume of distribution during the terminal elimination phase following extravascular administration (Vd/F)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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In this analysis apparent volume of distribution during the terminal elimination phase will be reported
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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Pharmacokinetics of LHW090/LHV527 in plasma: apparent system clearance from plasma following intravenous administration of iothalamate (CL/F)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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In this analysis the apparent system clearance from plasma will be reported
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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Pharmacokinetics of LHW090/LHV527 in urine: apparent system clearance from urine from time 0 - 24 hrs following drug administration (Ae0-24)
Time Frame: Stage 1, 2 and 4 :0-4, 4-8, 8-12, 12-24, 24-36, 36-48 and 48 - 72 h post dose in Day 1 and Day 14; Stage 3: 0-4, 4-8, 8-12, and 12-24 h post dose
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In this analysis the apparent system clearance by urine will be reported from 0 - 24 hrs post dose
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Stage 1, 2 and 4 :0-4, 4-8, 8-12, 12-24, 24-36, 36-48 and 48 - 72 h post dose in Day 1 and Day 14; Stage 3: 0-4, 4-8, 8-12, and 12-24 h post dose
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Pharmacokinetics of LHW090/LHV527 in urine: apparent system clearance from urine from time 0 - 72 hrs following drug administration (Ae0-72h)
Time Frame: Stage 1, 2 and 4 :0-4, 4-8, 8-12, 12-24, 24-36, 36-48 and 48 - 72 h post dose in Day 1 and Day 14; Stage 3: 0-4, 4-8, 8-12, and 12-24 h post dose
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In this analysis the apparent system clearance by urine will be reported from 0 - 72 hrs post dose
|
Stage 1, 2 and 4 :0-4, 4-8, 8-12, 12-24, 24-36, 36-48 and 48 - 72 h post dose in Day 1 and Day 14; Stage 3: 0-4, 4-8, 8-12, and 12-24 h post dose
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Pharmacokinetics of LHW090/LHV527 in urine: apparent renal clearance from urine following drug administration (CLr)
Time Frame: Stage 1, 2 and 4 :0-4, 4-8, 8-12, 12-24, 24-36, 36-48 and 48 - 72 h post dose in Day 1 and Day 14; Stage 3: 0-4, 4-8, 8-12, and 12-24 h post dose
|
In this analysis the apparent system clearance by urine will be reported
|
Stage 1, 2 and 4 :0-4, 4-8, 8-12, 12-24, 24-36, 36-48 and 48 - 72 h post dose in Day 1 and Day 14; Stage 3: 0-4, 4-8, 8-12, and 12-24 h post dose
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Pharmacodynamics of LHW090/LHV527 in serum: post treatment peak and mean area under the plasma concentration-time curve from time zero to 24 hour (AUC0-24h/24h) for cyclic guanosine (cGMP)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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In this analysis AUC0-24/24h will be reported for single ascending dose healthy volunteers and CRI subjects
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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Pharmacodynamics of LHW090/LHV527 in serum: post treatment peak and mean area under the plasma concentration-time curve from time zero to 24 hour (AUC0-24h/24h) for atrial natriuretic peptide (ANP)
Time Frame: Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
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In this analysis AUC0-24/24h will be reported for single ascending dose healthy volunteers and CRI subjects
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Within 60 min prior to dosing, post dose: +/- 5 min up to 3 hrs, +/- 10 min from ≥3 hrs to 24hrs, +/- 2 hrs from ≥24 hrs to 72hrs
|
Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- CLHW090X2101
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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