| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate renal impairment |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Not possible to specify |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062237 |
| E.1.2 | Term | Renal impairment |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 |
This is a 2 parts study to determine whether LHW090 displays the clinical safety profile to support further development in patients with moderately impaired renal function. Objective of Part 1 of the study : To assess the safety and tolerability of doses of LHW090 in patients with moderate renal impairment to inform design of Part 2.
- Objective of Part 2 of the study : To assess the renal safety of LHW090 in patients with moderate renal impairment |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the pharmacokinetics of LHW090 and its active metabolite, LHV527, in patients with moderate renal impairment. To assess the safety and tolerability of LHW090 relative to placebo in patients with moderate renal impairment |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
MRI substudy
For a subgroup of patients willing to undergo an MRI procedure and enrolled at a participating imaging site in Part 2, baseline assessments may include an assessment of renal perfusion by arterial spin labeling MRI (ASL-MRI) for up to twenty patients. |
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| 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 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/1.73m2 (inclusive) using the 4 variable MDRD Study equation for at least 3 months.
3. 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
4. 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 - 40kg/m2. BMI = Body weight (kg) / [Height (m)]2.
5. Able to communicate well with the investigator, to understand and comply with the requirements of the study. |
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| E.4 | Principal exclusion criteria |
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or until the expected PD effect has returned to baseline, whichever is longer; or longer if required by local regulations.
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
3. History of angioedema, drug-related or otherwise, as reported by the patient.
4. 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).
5. History of a renal transplant.
6. Known current significant left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or significant severe valvular disease on prior or current echocardiogram.
7. A history of clinically significant ECG abnormalities, as determined by the Investigator, or any of the following ECG abnormalities at screening •QTcF > 480 msec
8. Known history or current clinically significant arrhythmias.
9. History within the previous 6 months of myocardial infarction, coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), stroke, transient ischemic attack (TIA) or acute kidney injury.
10. Hemoglobin levels below 9.0 g/dL at screening.
11. A serum potassium ≤ 3.5 mmol/l or ≥ 5.5 mmol/l at screening.
12. A previous history or previously diagnosed kidney disorder, 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 confound the interpretation of the study results. Such kidney disorders may include 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.
13. Donation or loss of 400 mL or more of blood within 8 weeks prior to initial dosing, or longer if required by local regulations.
14. Significant illness which has not resolved within two (2) weeks prior to initial dosing.
15. History of immunodeficiency diseases, including a positive HIV test result.
16. A positive Hepatitis B surface antigen or Hepatitis C test result.
17. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
18. Pregnant or nursing (lactating) women.
19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
20. Sexually active males unwilling to use a condom during intercourse while taking drug and for 2 weeks after stopping study medication. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of the investigational drug via seminal fluid to their sexual partner.
21. 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 occurred in the past 2 years.
22. 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.
Subset of patients in MRI substudy (Part 2), inclusion/exclusion criteria:
1. Patients with contraindications to MRI, including:
Brain aneurysm clip
Implanted neural stimulator
Implanted cardiac pacemaker or defibrillator, or presence of intracardiac wires
Prosthetic heart valves
Cochlear implant
Ocular foreign bodies that might be ferromagnetic (e.g., metal shavings)
Other implanted medical devices (e.g., insulin pumps)
Metal shrapnel or bullets still in the body
Severe claustrophobia
Tattoos (as determined by the Investigator and Imager)
Weight in excess of MRI machine capacity |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Part 1 of the study : Safety endpoints (including adverse events and serious adverse events) will be measured up to and including the EOS; plasma pharmacokinetic parameters, and serum creatinine will be measured
- Part 2: Proportion of patients who develop a renal event as defined by a ≥0.3 mg/dL increase in serum creatinine
from baseline |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part1: safety parameters will be routinely evaluated over the maximum 12 days of treatment as defined in the protocol
Upon completion of at least 10 patients in Part 1 through the end of study visit, an interim analysis of all safety and PK data as applicable will be pursued to confirm dosing with 100 mg or to choose another dose for Part 2.
-Part 2: as defined in the protocol An interim analysis will be conducted after 36 patients in Part 2 (randomized in 3:1 ratio) of the study have received the last treatment and all safety/tolerability data up to and including 24 hours post last dose are available for analysis. |
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| E.5.2 | Secondary end point(s) |
For all parts of the study:
- Plasma pharmacokinetic parameters (Cmax, Tmax, AUC)
- Safety endpoints (including adverse events and serious adverse events) up to and including the EOS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As defined in the protocol on a routine basis over the 12 days max (part 1) and 4 weeks of treatement ( part 2) |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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 | No |
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 |
| Germany |
| Romania |
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
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