Impaired Renal Function
Conditions
Keywords
Impaired Renal Function, PK
Brief summary
Phase 1 - Pharmacokinetics in Patients with Impaired Renal Function
Detailed description
The study is a two-center, Phase 1, open-label, single-dose, one-period, four-parallel-group, PK study in subjects with various severities of renal dysfunction and healthy volunteers. Subjects will be categorized in 4 groups: Group 1: subjects with mild renal impairment Group 2: subjects with moderate renal impairment Group 3: subjects with severe renal impairment Group 4 (control group): subjects with normal renal function The mild (group 1) and moderate (group 2) patients with renal disease will be dosed first, in a parallel fashion. At this point, interim PK analyses will be performed and a safety committee composed of Sponsor and Contract Research Organization (CRO) members will jointly review the PK data before dosing the patients with severe renal disease (group 3). Control subjects (group 4) will be recruited after the recruitment of groups 1 to 3.
Interventions
DRUGELX-02
ELX-02 is a synthetic, designer eukaryotic ribosomal specific glycoside (ERSG) optimized as a translational read-through drug. All groups will get the same treatment.
Sponsors
Syneos Health
Eloxx Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Subjects will be categorized in 4 groups: Group 1: subjects with mild renal impairment Group 2: subjects with moderate renal impairment Group 3: subjects with severe renal impairment Group 4 (control group): subjects with normal renal function
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male or female, non-smoker and/or light smoker 2. Have a diagnosis of renal impairment that has been stable, without any significant change in overall disease status in the last 3 months prior to screening. 3. Have an estimated glomerular filtration rate (eGFR) expressed in mL/min/1.73 m2 (Modification of Diet in Renal Disease 4-variable \[MDRD4\] equation) at screening within the range of: 1. Group 1 - Mild Group: 60 - 89 mL/min/1.73 m2; 2. Group 2 - Moderate Group: 30 - 59 mL/min/1.73 m2; 3. Group 3 - Severe Group: \< 30 mL/min/1.73 m2 not requiring dialysis. eGFR results that are deemed inconsistent with the usual stage of renal impairment may be repeated. Subjects are categorized into severity group at screening. If the eGFR scores change on Day-1 or other visit due to a non-clinically significant change in clinical status or laboratory result, the subject keeps the original severity group. 4. Subject may have stable treated medical illnesses and underlying diseases producing the renal impairment such as diabetes, hypertension, or cardiovascular disease, providing that, in the opinion of the PI, the disease is stable. 5. Have normal or non-clinically significant findings at physical examination, vital signs and electrocardiogram (ECG) and normal limits or non-clinically significant deviations in clinical laboratory evaluations at screening. 6. Other than renal impairment, have no other conditions which may significantly impact study drug absorption or metabolism. 7. Stable medical regimen, deemed not to interact with study drug PK, for 14 days prior to dosing, except for routine daily management of electrolytes (e.g. potassium), acid-base, or other associated disorders expected in patients with renal impairment. 8. Females of childbearing potential who are sexually active with a non-sterile male partner (sterile male partners are defined as men vasectomized since at least 6 months) must be willing to use acceptable contraceptive method throughout the study and for 30 days after study drug administration. 9. Male subjects who are not vasectomized for at least 6 months, and who are sexually active with a non-sterile female partner (sterile female partners include post-menopausal females and surgically sterile females) must be willing to use acceptable contraceptive method from dosing until at least 90 days after study drug administration. 10. Male subjects (including men who have had vasectomy) with a pregnant partner must agree to use a condom from dosing until at least 90 days after study drug administration. 11. Male subjects must be willing not to donate sperm until 90 days following study drug administration. 12. Able to understand and willing to sign the Informed Consent Form (ICF) and comply with the study restrictions.
Exclusion criteria
1. Unstable renal function or acute exacerbation of renal disease within 14 days of study drug administration, as indicated by recent history or worsening of clinical and/or laboratory signs of renal impairment. 2. Has a functioning renal transplant. 3. Major illness or surgery within 4 weeks prior to dosing. 4. Clinically significant unstable medical condition or history of any illness that may increase the risk associated with study participation or investigational drug administration or may interfere with the interpretation of study results and would make the subject inappropriate for entry into this study. 5. Positive test for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at screening. 6. History of allergic reactions, hypersensitivity or toxic reactions to aminoglycosides. 7. History of anaphylaxis. 8. Supine 12-lead ECG abnormalities at screening considered clinically significant. 9. Clinically significant vital sign abnormalities at screening. 10. History of significant drug or alcohol abuse within six months prior to screening. 11. Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days (or 5 half-lives, whichever is longer) prior to dosing, administration of a biological product in the context of a clinical research study within 90 days prior to dosing, or concomitant participation in an investigational study involving no drug or device administration. 12. Positive urine drug screen or alcohol test at screening. 13. Female subject with positive pregnancy test at screening. 14. Breast-feeding or pregnant subject within 6 months prior to study drug administration. 15. Use of any drugs known as strong inducer or inhibitor of hepatic drug metabolism within 30 days prior to study drug administration. 16. Use of medication other than stable medications approved by the PI and topical products without significant systemic absorption. 17. Use of prohibited medications as directed in the protocol. 18. Donation of plasma within 7 days prior to dosing. Donation or loss of blood within 30 days prior to the first dosing. 19. Any reason which, in the opinion of the PI, would prevent the subject from participating in the study. 20. Inability to be venipunctured and/or tolerate catheter venous access. 21. Presence of mitochondrial mutation(s) making the subject susceptible to aminoglycoside toxicity. 22. Presence of signs of dehydration, recent history of neuromuscular blockade or clinically significant history of vestibular impairment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters- Plasma AUC0-24 | 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, and 24 hours after dosing | Area under the curve (AUC0-24) of ELX-02 plasma concentration following a single subcutaneous (SC) dose |
| Pharmacokinetic Parameters- Plasma Cmax | 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 36, 48, 72, and 168 (Day 8) hours after dosing | Peak Plasma Concentration (Cmax) of ELX-02 following a single subcutaneous (SC) dose in subjects with normal renal function, mild, moderate, or severe renal impairment |
| AUC0-inf | 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 36, 48, 72, and 168 (Day 8) hours after dosing | Area under the curve (AUC0-inf) of ELX-02 plasma concentration following a single subcutaneous (SC) dose |
| Pharmacokinetic Parameters - Plasma Tmax | 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, and 24 hours after dosing. | Time to maximum concentration (Tmax) of ELX-02 plasma concentration following a single subcutaneous (SC) dose |
| Urine Pharmacokinetics Parameter - Ae0-t | Pre-dose (first void in the morning of Day 1), 0-3, 3-6, 6-9, 9-12, 12-18, 18-24, 24-36, 36-48, and 48-72 hours post-dose | Cumulative amount of unchanged drug excreted into urine (Ae0-t) of ELX-02 following a single subcutaneous (SC) dose |
| Urine Pharmacokinetic Parameter - Rmax | Pre-dose (first void in the morning of Day 1), 0-3, 3-6, 6-9, 9-12, 12-18, 18-24, 24-36, 36-48, and 48-72 hours post-dose | Maximum rate of urinary extraction (Rmax) of ELX-02 following a single subcutaneous (SC) dose |
| Number of Patients Reporting Treatment-Emergent Adverse Events (TEAEs) [Safety] | 1-8 days | TEAEs are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the study treatment |
Countries
United States
Participant flow
Recruitment details
All subjects were treated at medical clinics. Groups 1-2 Screening start: January 4, 2019 Screening end: 8 April 2019 Group 3 Screening start: 9 May 2019 Screening end: 17 June 2019 Group 4 Screening start: 26 June 2019 Screening end: 30 June 2019
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Mild Renal Impairment eGFR 60 to 89 mL/min/1.73 m\^2 | 6 |
| Group 2 Moderate Renal Impairment eGFR 30 to 59 mL/min/1.73 m\^2 | 6 |
| Group 3 Severe Renal Impairment eGFR \<30 mL/min/1.73 m\^2, Not Requiring Dialysis | 6 |
| Group 4 Healthy Volunteers eGFR \>=90 mL/min/1.73 m\^2 | 6 |
| Total | 24 |
Baseline characteristics
| Characteristic | Group 1 | Group 2 | Group 3 | Group 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 66.8 years STANDARD_DEVIATION 5.9 | 65.0 years STANDARD_DEVIATION 10.4 | 61.8 years STANDARD_DEVIATION 8.2 | 57.7 years STANDARD_DEVIATION 2.1 | 62.8 years STANDARD_DEVIATION 7.7 |
| eGFR | 74.72 mL/min/1.73 m2 STANDARD_DEVIATION 9.25 | 40.07 mL/min/1.73 m2 STANDARD_DEVIATION 4.54 | 16.92 mL/min/1.73 m2 STANDARD_DEVIATION 9.77 | 100.25 mL/min/1.73 m2 STANDARD_DEVIATION 15.65 | 57.99 mL/min/1.73 m2 STANDARD_DEVIATION 34.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 6 Participants | 6 Participants | 5 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 6 participants | 6 participants | 6 participants | 6 participants | 24 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 1 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 5 Participants | 4 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 0 / 6 | 0 / 6 | 1 / 6 | 5 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
AUC0-inf
Area under the curve (AUC0-inf) of ELX-02 plasma concentration following a single subcutaneous (SC) dose
Time frame: 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 36, 48, 72, and 168 (Day 8) hours after dosing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Renal Impairment | AUC0-inf | 16997.41 h*ng/mL | Standard Deviation 1776.84 |
| Moderate Renal Impairment | AUC0-inf | 35179.57 h*ng/mL | Standard Deviation 9198.37 |
| Severe Renal Impairment | AUC0-inf | 110925.53 h*ng/mL | Standard Deviation 49098.37 |
| Healthy Volunteers | AUC0-inf | 15214.30 h*ng/mL | Standard Deviation 2913.01 |
Primary
Number of Patients Reporting Treatment-Emergent Adverse Events (TEAEs) [Safety]
TEAEs are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the study treatment
Time frame: 1-8 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mild Renal Impairment | Number of Patients Reporting Treatment-Emergent Adverse Events (TEAEs) [Safety] | 0 participants |
| Moderate Renal Impairment | Number of Patients Reporting Treatment-Emergent Adverse Events (TEAEs) [Safety] | 0 participants |
| Severe Renal Impairment | Number of Patients Reporting Treatment-Emergent Adverse Events (TEAEs) [Safety] | 2 participants |
| Healthy Volunteers | Number of Patients Reporting Treatment-Emergent Adverse Events (TEAEs) [Safety] | 9 participants |
Primary
Pharmacokinetic Parameters- Plasma AUC0-24
Area under the curve (AUC0-24) of ELX-02 plasma concentration following a single subcutaneous (SC) dose
Time frame: 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, and 24 hours after dosing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Renal Impairment | Pharmacokinetic Parameters- Plasma AUC0-24 | 16877.94 ng*h/mL | Standard Deviation 1714.57 |
| Moderate Renal Impairment | Pharmacokinetic Parameters- Plasma AUC0-24 | 32787.41 ng*h/mL | Standard Deviation 7410.46 |
| Severe Renal Impairment | Pharmacokinetic Parameters- Plasma AUC0-24 | 64895.29 ng*h/mL | Standard Deviation 16967.68 |
| Healthy Volunteers | Pharmacokinetic Parameters- Plasma AUC0-24 | 15506.68 ng*h/mL | Standard Deviation 3444.66 |
Primary
Pharmacokinetic Parameters- Plasma Cmax
Peak Plasma Concentration (Cmax) of ELX-02 following a single subcutaneous (SC) dose in subjects with normal renal function, mild, moderate, or severe renal impairment
Time frame: 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, 24, 36, 48, 72, and 168 (Day 8) hours after dosing
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Renal Impairment | Pharmacokinetic Parameters- Plasma Cmax | 2993.33 ng/mL | Standard Deviation 280.33 |
| Moderate Renal Impairment | Pharmacokinetic Parameters- Plasma Cmax | 3688.33 ng/mL | Standard Deviation 525.56 |
| Severe Renal Impairment | Pharmacokinetic Parameters- Plasma Cmax | 4273.33 ng/mL | Standard Deviation 947.49 |
| Healthy Volunteers | Pharmacokinetic Parameters- Plasma Cmax | 2995.00 ng/mL | Standard Deviation 568.99 |
Primary
Pharmacokinetic Parameters - Plasma Tmax
Time to maximum concentration (Tmax) of ELX-02 plasma concentration following a single subcutaneous (SC) dose
Time frame: 0.25, 0.5, 0.75, 1, 2, 4, 6, 12, and 24 hours after dosing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mild Renal Impairment | Pharmacokinetic Parameters - Plasma Tmax | 1.00 hour |
| Moderate Renal Impairment | Pharmacokinetic Parameters - Plasma Tmax | 1.00 hour |
| Severe Renal Impairment | Pharmacokinetic Parameters - Plasma Tmax | 2.00 hour |
| Healthy Volunteers | Pharmacokinetic Parameters - Plasma Tmax | 1.50 hour |
Primary
Urine Pharmacokinetic Parameter - Rmax
Maximum rate of urinary extraction (Rmax) of ELX-02 following a single subcutaneous (SC) dose
Time frame: Pre-dose (first void in the morning of Day 1), 0-3, 3-6, 6-9, 9-12, 12-18, 18-24, 24-36, 36-48, and 48-72 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Renal Impairment | Urine Pharmacokinetic Parameter - Rmax | 9.18 mg/h | Standard Deviation 2.91 |
| Moderate Renal Impairment | Urine Pharmacokinetic Parameter - Rmax | 8.06 mg/h | Standard Deviation 5.91 |
| Severe Renal Impairment | Urine Pharmacokinetic Parameter - Rmax | 3.11 mg/h | Standard Deviation 1.81 |
| Healthy Volunteers | Urine Pharmacokinetic Parameter - Rmax | 12.09 mg/h | Standard Deviation 2.82 |
Primary
Urine Pharmacokinetics Parameter - Ae0-t
Cumulative amount of unchanged drug excreted into urine (Ae0-t) of ELX-02 following a single subcutaneous (SC) dose
Time frame: Pre-dose (first void in the morning of Day 1), 0-3, 3-6, 6-9, 9-12, 12-18, 18-24, 24-36, 36-48, and 48-72 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Renal Impairment | Urine Pharmacokinetics Parameter - Ae0-t | 61.50 mg | Standard Deviation 19.37 |
| Moderate Renal Impairment | Urine Pharmacokinetics Parameter - Ae0-t | 72.10 mg | Standard Deviation 26.45 |
| Severe Renal Impairment | Urine Pharmacokinetics Parameter - Ae0-t | 54.86 mg | Standard Deviation 8.74 |
| Healthy Volunteers | Urine Pharmacokinetics Parameter - Ae0-t | 69.22 mg | Standard Deviation 17.7 |