Renal Impairment
Conditions
Keywords
Renal Impairment, Renal Disease, Sodium Sulfide
Brief summary
This is a Phase 1 study to assess the pharmacokinetics (PK) of IK-1001 (sodium sulfide) in healthy volunteers as well as in subjects with varying degrees of impaired renal function. A total of 28 subjects will be enrolled into the study over a 6 month period. There will be 4 cohorts. The first cohort will consist of subjects with mild renal impairment, the fourth cohort will be subjects with intermediate renal impairment and the third cohort will be subjects with severe renal impairment and the second cohort will consist of normal healthy subjects. All subjects will receive the study drug for 3 hours as a single intravenous (IV) infusion and will be followed over a 7 day period.
Detailed description
This is a Phase 1 pharmacokinetic study to assess the pharmacokinetics of IK-1001 in healthy volunteers as well as subjects with varying degrees of impaired renal function following a single intravenous infusion. A total of 28 subjects will be enrolled into the study, including 6 normal subjects (Creatinine Clearance (CrCL) \> 80 mL/min), 9 subjects with mild impairment (CrCL ≥ 50 to \< 80 mL/min), 6 subjects with intermediate impairment (≥ 30 to \< 50 mL/min) and 7 subjects with severe impairment (CrCL \< 30 mL/min). Mild, moderate and normal healthy subjects will receive IK-1001 as a single IV infusion for 3 hours at 1.5 mg/kg/hr. Blood, plasma, urine and exhaled air will be collected from each subject over 48 hours and at follow-up visit (Day 7), to evaluate pharmacokinetics of Hydrogen Sulfide (H2S) (exhaled air), IK-1001 (blood) and thiosulfate in plasma and urine. Severe subjects will receive IK-1001 as a single IV infusion for 3 hours at 1.0 mg/kg/hr. For each dosing cohort, the study will consist of a screening visit (Days -28 to -1), a treatment visit (Day 0 (check-in) to Day 3), and a follow-up (exit) visit day 7 (+/- 2 days). Study subjects will be enrolled to one of 4 cohorts and all will receive investigational product at the given dose level. The subjects will be considered to be enrolled in the study at randomization. IK-1001 will be administered by a healthcare professional intravenously over 3 hours using an infusion pump. Dosage of IK-1001 will be administered on actual body weight basis, according to cohort assignment and using the subject's body weight determined on Day -1. After the end of the initial 3-hour study period, subjects will be observed for an additional 45 hour period before discharge from the unit.
Interventions
DRUGSodium Sulfide
Sodium sulfide administered intravenously at 1.5 mg/kg/hr for 3 hours
Sponsors
Mallinckrodt
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
1. For normal subjects arm (CrCL \> 80 ml/min): Healthy male and female subjects age 18 to 70 years of age inclusive. Pregnant women are excluded and women of child-bearing potential must agree to the use of medically reliable contraceptive methods for the duration of the study and for 30 days after study. For renally impaired arm: Male and female - pregnant women are excluded and women of child-bearing potential must agree to the use of medically reliable contraceptive methods for the duration of the study and for 30 days after study. Subjects with mild, moderate and severe renal function aged between 18 to 70 years old 2. Body mass index (BMI) within the range of 18 to 40 kg/m2 3. Electrocardiogram (ECG) recording without clinically relevant abnormalities 4. Having had no febrile or infectious disease for at least seven days prior to dosing of study drug 5. Able to communicate well with the study staff and to understand and comply with the requirements of the study, understand and sign the written informed consent
Exclusion criteria
1. High risk patients who may need an urgent dialysis during clinical conduct portion of the study (from Day -1 until last PK sampling on Day 7) 2. All smokers. 3. More than moderate alcohol consumption (\>35 g ethanol regularly or \> 2 drinks per day ) 4. Any history of alcohol or drug abuse 5. Any active physical or psychiatric disease, acute or chronic 6. Any clinically relevant history of drug hypersensitivity, asthma, urticaria or other severe allergic diathesis 7. Pregnant or nursing women 8. Blood donation within 30 days 9. Participation in any clinical study within 30 days prior to the treatment phase of this study 10. Lab values outside of reference range and clinically relevant liver function tests (AST, ALT, gamma-GT) 11. Positive tests for HIV antibodies, Hepatitis B-virus surface antigen (HBsAg), Anti-Hepatitis C-virus antibodies (Anti-HCV)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Thiosulfate in Plasma | 8 hours after treatment | Total concentration of thiosulfate in plasma was measured through pharmacokinetic blood sampling. |
| Thiosulfate in Urine | 48 hours after treatment | Total concentration of thiosulfate in urine was measure through pharmacokinetic urine collection |
| Sodium Sulfide in Blood | 8 hours after treatment | Total concentration of sodium sulfide in blood was measured through pharmacokinetic blood sampling. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sodium Sulfide - Mild Cohort Mild renal impairment (RI) Cohort administered 1.5 mg/kg/hr infusion of Sodium sulfide intravenously for 3 hours. | 9 |
| Sodium Sulfide - Healthy Cohort Healthy subjects received soduim sufide intravenously at 1.5 mg/kg/hr for 3 hours | 6 |
| Sodium Sulfide - Moderate Cohort Moderate RI cohort received sodium sulfide intravenously at 1.5 mg/kg/hr for 3 hours | 6 |
| Sodium Sulfide - Severe Cohort Severe RI cohort received sodium sulfide intravenously at 1.0 mg/kg/hr for 3 hours | 7 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Sodium Sulfide - Healthy Cohort | Sodium Sulfide - Moderate Cohort | Sodium Sulfide - Mild Cohort | Sodium Sulfide - Severe Cohort | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 9 Participants | 7 Participants | 28 Participants |
| Age, Continuous | 56.1 years STANDARD_DEVIATION 14.69 | 60.6 years STANDARD_DEVIATION 7.91 | 56.3 years STANDARD_DEVIATION 7.41 | 48.9 years STANDARD_DEVIATION 11.96 | 55.3 years STANDARD_DEVIATION 10.82 |
| Region of Enrollment United States | 6 participants | 6 participants | 9 participants | 7 participants | 28 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 14 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants | 2 Participants | 14 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 / 9 | 0 / 6 | 0 / 6 | 0 / 7 |
| other Total, other adverse events | 7 / 9 | 1 / 6 | 5 / 6 | 4 / 7 |
| serious Total, serious adverse events | 0 / 9 | 0 / 6 | 0 / 6 | 0 / 7 |
Outcome results
Primary
Sodium Sulfide in Blood
Total concentration of sodium sulfide in blood was measured through pharmacokinetic blood sampling.
Time frame: 8 hours after treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sodium Sulfide - Mild Cohort | Sodium Sulfide in Blood | 51.2 ng/mL | Standard Deviation 12.23 |
| Sodium Sulfide - Healthy Cohort | Sodium Sulfide in Blood | 49.6 ng/mL | Standard Deviation 14.58 |
| Sodium Sulfide - Moderate Cohort | Sodium Sulfide in Blood | 49.8 ng/mL | Standard Deviation 17.23 |
| Sodium Sulfide - Severe Cohort | Sodium Sulfide in Blood | 42.9 ng/mL | Standard Deviation 5.55 |
Primary
Thiosulfate in Plasma
Total concentration of thiosulfate in plasma was measured through pharmacokinetic blood sampling.
Time frame: 8 hours after treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sodium Sulfide - Mild Cohort | Thiosulfate in Plasma | 120.4 ng/mL | Standard Deviation 57.83 |
| Sodium Sulfide - Healthy Cohort | Thiosulfate in Plasma | 199.6 ng/mL | Standard Deviation 100.74 |
| Sodium Sulfide - Moderate Cohort | Thiosulfate in Plasma | 199.1 ng/mL | Standard Deviation 60.32 |
| Sodium Sulfide - Severe Cohort | Thiosulfate in Plasma | 190.1 ng/mL | Standard Deviation 36.41 |
Primary
Thiosulfate in Urine
Total concentration of thiosulfate in urine was measure through pharmacokinetic urine collection
Time frame: 48 hours after treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sodium Sulfide - Mild Cohort | Thiosulfate in Urine | 1805.5 ng/mL | Standard Deviation 552 |
| Sodium Sulfide - Healthy Cohort | Thiosulfate in Urine | 2137.7 ng/mL | Standard Deviation 688.83 |
| Sodium Sulfide - Moderate Cohort | Thiosulfate in Urine | 1114.3 ng/mL | Standard Deviation 720.79 |
| Sodium Sulfide - Severe Cohort | Thiosulfate in Urine | 603.8 ng/mL | Standard Deviation 433.44 |