Acute Alcoholic Hepatitis, Acute Liver Failure, Acute on Chronic Hepatic Failure, Liver Cirrhosis
Conditions
Keywords
Liver Failure, Cirrhosis, Alcoholic Hepatitis
Brief summary
The study will evaluate the pharmacokinetics, pharmacodynamics, safety and preliminary efficacy of IDN-6556 in subjects with cirrhosis of the liver who are hospitalized for more than 24 hours due to acute deterioration of liver function.
Interventions
DRUGIDN-6556
OTHERPlacebo
Sponsors
Conatus Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects of minimum adult legal age (according to local laws for signing the informed consent document), able to provide written informed consent, and understand and comply with the requirements of the study * Subjects with a clinical, radiological and/or histological diagnosis of cirrhosis * Subjects having not required hospital admission within 4 weeks of screening for a complication of cirrhosis * Subjects with an acute deterioration of liver function * Subjects who meet one of the following criteria: 1. Subjects with renal failure (defined as creatinine ≥ 2.0 to ≤ 3.4 mg/dL) 2. Subjects with other single organ failure with i. Renal impairment (defined as an increase in creatinine of \> 0.3 mg/dL from either an established prior Baseline level or if applicable, upon admission to hospital if prior level is unavailable; for inclusion, the creatinine level must be raised above normal levels), and/or ii. Hepatic encephalopathy grade I or II 3. Subjects with two organ failures * If a subject received steroids for alcohol-induced acute liver failure, he/she must be unresponsive to steroid therapy. Responsiveness is based on investigator discretion. * Willingness to utilize two reliable forms of contraception (for both males and females of childbearing potential) from screening to one month after the last dose of study drug
Exclusion criteria
* Known infection with HIV * Subjects with cirrhosis who develop decompensation at any time in the postoperative period following partial hepatectomy * Subjects with evidence of uncontrolled infection defined as persistent bacterial culture positivity despite adequate antibiotic therapy * Subjects with clinical evidence of disseminated intravascular coagulation * Subjects with chronic and/or pre-existing kidney disease defined as eGFR (estimated glomerular filtration rate) of less than 30 mL/min for 3 months or longer * Subjects who are hypotensive (defined as mean arterial pressure \<70 mmHg) or require the use of inotropic support * Subjects with evidence of significant and/or uncontrolled bleeding * Subjects requiring mechanical ventilation * Subjects with active or history of malignancies other than hepatocellular carcinoma (HCC) within Milan criteria or curatively treated skin cancer (basal cell or squamous cell carcinomas), unless adequately treated or in complete remission for five or more years * Subjects previously exposed to IDN-6556 * History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of \> 480 milliseconds (msec)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) | 28 days | Primary endpoints for AUC\_0-8, AUC\_0 last, AUC\_0-inf on Day 1 and Day 4 for the active treatment arms were analyzed. |
| Cmax | 28 Days | Primary endpoints forCmax on Day 1 and Day 4 for the active treatment arms were analyzed. |
| Tmax & t1/2 Parameters | 28 Days | Primary endpoints for tmax & t1/2 on Day 1 and Day 4 for the active treatment arms were analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Levels of CK18/M30 | Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28 | Caspase-cleaved cytokeratin serum levels (CK18/M30) |
| Levels of CK18/M65 | Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28 | Caspase full-length cytokeratin serum levels CK18/M65 |
| Levels of Caspase 3/7 RLU | Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28 | Concentration of Caspase 3/7 Relative Light Units |
Countries
United Kingdom, United States
Participant flow
Recruitment details
In total, 33 subjects were screened at 14 sites, and 23 subjects were randomized to one of the 4 treatment arms.
Pre-assignment details
23 subjects were randomized but 21 subjects received treatment. 1 subject lost due to death and 1 subject lost due to withdrew of consent. 7 subject of 21 completed the treatment phase (Day 28). 4 of 3 completed the two follow-up phone calls made at Months 3 and 6. 14 subjects discontinued the study early.
Participants by arm
| Arm | Count |
|---|---|
| IDN-6556 5 mg Dosed twice daily
IDN-6556 | 5 |
| IDN-6556 25 mg Dosed twice daily
IDN-6556 | 7 |
| IDN-6556 50 mg Dosed twice daily
IDN-6556 | 5 |
| Placebo Dosed twice daily
Placebo | 4 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 1 |
| Overall Study | Death | 1 | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 0 | 2 | 0 |
| Overall Study | Patient lost to FU due to death | 2 | 0 | 0 | 0 |
| Overall Study | Patients unable to swallow | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | IDN-6556 5 mg | IDN-6556 25 mg | IDN-6556 50 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 7 Participants | 4 Participants | 4 Participants | 20 Participants |
| Age, Continuous | 49.0 years | 50.0 years | 61.0 years | 53.5 years | 50.0 years |
| Region of Enrollment United Kingdom | 5 participants | 5 participants | 4 participants | 2 participants | 16 participants |
| Region of Enrollment United States | 0 participants | 2 participants | 1 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 3 Participants | 2 Participants | 13 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 5 | 7 / 7 | 4 / 5 | 3 / 4 |
| serious Total, serious adverse events | 3 / 5 | 6 / 7 | 3 / 5 | 2 / 4 |
Outcome results
Primary
Area Under the Curve (AUC)
Primary endpoints for AUC\_0-8, AUC\_0 last, AUC\_0-inf on Day 1 and Day 4 for the active treatment arms were analyzed.
Time frame: 28 days
Population: AUC\_0-last: The number of participants analyzed in the 25mg arm was 7 at Day 1 AUC\_0-inf: The number of participants analyzed in the 5mg arm was 2 at Day 1 and 0 at Day 4, in the 25mg arm was 5 at Day 1 and 2 at Day 4, in the 50mg arm was 2 at Day 1 and 3 at Day 4.~Values listed as 0 were non-estimable values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| IDN-6556 5 mg | Area Under the Curve (AUC) | Day 1 AUC 0-8 | 275 h*ng/mL | Geometric Coefficient of Variation 40 |
| IDN-6556 5 mg | Area Under the Curve (AUC) | Day 4 AUC 0-8 | 224.3 h*ng/mL | Geometric Coefficient of Variation 36.9 |
| IDN-6556 5 mg | Area Under the Curve (AUC) | Day 1 AUC 0-last | 275 h*ng/mL | Geometric Coefficient of Variation 40 |
| IDN-6556 5 mg | Area Under the Curve (AUC) | Day 4 AUC 0-last | 224.3 h*ng/mL | Geometric Coefficient of Variation 36.9 |
| IDN-6556 5 mg | Area Under the Curve (AUC) | Day 1 AUC 0-inf | 0 h*ng/mL | Geometric Coefficient of Variation 0 |
| IDN-6556 5 mg | Area Under the Curve (AUC) | Day 4 AUC 0-inf | 0 h*ng/mL | Geometric Coefficient of Variation 0 |
| IDN-6556 25 mg | Area Under the Curve (AUC) | Day 4 AUC 0-inf | 0 h*ng/mL | Geometric Coefficient of Variation 0 |
| IDN-6556 25 mg | Area Under the Curve (AUC) | Day 1 AUC 0-8 | 1165 h*ng/mL | Geometric Coefficient of Variation 45.3 |
| IDN-6556 25 mg | Area Under the Curve (AUC) | Day 4 AUC 0-last | 1818 h*ng/mL | Geometric Coefficient of Variation 27.8 |
| IDN-6556 25 mg | Area Under the Curve (AUC) | Day 1 AUC 0-inf | 1462 h*ng/mL | Geometric Coefficient of Variation 30.3 |
| IDN-6556 25 mg | Area Under the Curve (AUC) | Day 4 AUC 0-8 | 1767 h*ng/mL | Geometric Coefficient of Variation 31.4 |
| IDN-6556 25 mg | Area Under the Curve (AUC) | Day 1 AUC 0-last | 1295 h*ng/mL | Geometric Coefficient of Variation 33.4 |
| IDN-6556 50 mg | Area Under the Curve (AUC) | Day 4 AUC 0-8 | 2148 h*ng/mL | Geometric Coefficient of Variation 227.9 |
| IDN-6556 50 mg | Area Under the Curve (AUC) | Day 1 AUC 0-last | 2997 h*ng/mL | Geometric Coefficient of Variation 103.8 |
| IDN-6556 50 mg | Area Under the Curve (AUC) | Day 4 AUC 0-inf | 3447 h*ng/mL | Geometric Coefficient of Variation 188.2 |
| IDN-6556 50 mg | Area Under the Curve (AUC) | Day 4 AUC 0-last | 2294 h*ng/mL | Geometric Coefficient of Variation 257.9 |
| IDN-6556 50 mg | Area Under the Curve (AUC) | Day 1 AUC 0-8 | 2397 h*ng/mL | Geometric Coefficient of Variation 99.3 |
| IDN-6556 50 mg | Area Under the Curve (AUC) | Day 1 AUC 0-inf | 0 h*ng/mL | Geometric Coefficient of Variation 0 |
Primary
Cmax
Primary endpoints forCmax on Day 1 and Day 4 for the active treatment arms were analyzed.
Time frame: 28 Days
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| IDN-6556 5 mg | Cmax | Day 1 Cmax | 84.4 (ng/mL) | Geometric Coefficient of Variation 43.9 |
| IDN-6556 5 mg | Cmax | Day 4 Cmax | 38.0 (ng/mL) | Geometric Coefficient of Variation 33.9 |
| IDN-6556 25 mg | Cmax | Day 1 Cmax | 329.8 (ng/mL) | Geometric Coefficient of Variation 48.3 |
| IDN-6556 25 mg | Cmax | Day 4 Cmax | 586.5 (ng/mL) | Geometric Coefficient of Variation 33.7 |
| IDN-6556 50 mg | Cmax | Day 1 Cmax | 696.1 (ng/mL) | Geometric Coefficient of Variation 117.4 |
| IDN-6556 50 mg | Cmax | Day 4 Cmax | 594.1 (ng/mL) | Geometric Coefficient of Variation 161.3 |
Primary
Tmax & t1/2 Parameters
Primary endpoints for tmax & t1/2 on Day 1 and Day 4 for the active treatment arms were analyzed.
Time frame: 28 Days
Population: t1/2 number of participants analyzed at Day 1 in the 5mg arm was 2 and 1 at Day 4, in the 25mg arm was 5 at Day 1 and 2 at Day 4, in the 50mg arm was 2 at Day 1 and 3 at Day 4.~Values listed as 0 were non-estimable values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IDN-6556 5 mg | Tmax & t1/2 Parameters | Day 1 t1/2 | 0 (h) | Standard Deviation 0 |
| IDN-6556 5 mg | Tmax & t1/2 Parameters | Day 4 t1/2 | 0 (h) | Standard Deviation 0 |
| IDN-6556 5 mg | Tmax & t1/2 Parameters | Day 4 tmax | 3.8 (h) | Standard Deviation 3.4 |
| IDN-6556 5 mg | Tmax & t1/2 Parameters | Day 1 tmax | 3.0 (h) | Standard Deviation 1.3 |
| IDN-6556 25 mg | Tmax & t1/2 Parameters | Day 1 tmax | 2.9 (h) | Standard Deviation 1.5 |
| IDN-6556 25 mg | Tmax & t1/2 Parameters | Day 4 tmax | 2.7 (h) | Standard Deviation 1.8 |
| IDN-6556 25 mg | Tmax & t1/2 Parameters | Day 4 t1/2 | 0 (h) | Standard Deviation 0 |
| IDN-6556 25 mg | Tmax & t1/2 Parameters | Day 1 t1/2 | 2.2 (h) | Standard Deviation 0.7 |
| IDN-6556 50 mg | Tmax & t1/2 Parameters | Day 4 t1/2 | 3.4 (h) | Standard Deviation 2.7 |
| IDN-6556 50 mg | Tmax & t1/2 Parameters | Day 1 tmax | 3.6 (h) | Standard Deviation 3 |
| IDN-6556 50 mg | Tmax & t1/2 Parameters | Day 4 tmax | 3.5 (h) | Standard Deviation 2.8 |
| IDN-6556 50 mg | Tmax & t1/2 Parameters | Day 1 t1/2 | 0 (h) | Standard Deviation 0 |
Secondary
Levels of Caspase 3/7 RLU
Concentration of Caspase 3/7 Relative Light Units
Time frame: Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28
Population: Number of subjects analyzed varied by time point; Day2: 5 and 25 arms are 4 and 6; Day4: 25 and placebo arms are 6 and 2; Day7: 25 arm is 6; Day14: 5, 25, 50, and placebo arms are 2, 5, 3, and 2; Day21: 5, 25, 50, and placebo arms are 2, 3, 2, and 2; Day28: 5, 25, 50, and placebo arms are 0, 3, 2, and 2; 0 are non-estimable values
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IDN-6556 5 mg | Levels of Caspase 3/7 RLU | Baseline | 4418 RLU |
| IDN-6556 5 mg | Levels of Caspase 3/7 RLU | Day 21 | 2914 RLU |
| IDN-6556 5 mg | Levels of Caspase 3/7 RLU | Day 14 | 2265 RLU |
| IDN-6556 5 mg | Levels of Caspase 3/7 RLU | Day 2 | 2893 RLU |
| IDN-6556 5 mg | Levels of Caspase 3/7 RLU | Day 28 | 0 RLU |
| IDN-6556 5 mg | Levels of Caspase 3/7 RLU | Day 4 | 3147 RLU |
| IDN-6556 5 mg | Levels of Caspase 3/7 RLU | Day 7 | 4081 RLU |
| IDN-6556 25 mg | Levels of Caspase 3/7 RLU | Day 21 | 636 RLU |
| IDN-6556 25 mg | Levels of Caspase 3/7 RLU | Day 7 | 1271 RLU |
| IDN-6556 25 mg | Levels of Caspase 3/7 RLU | Day 4 | 1136 RLU |
| IDN-6556 25 mg | Levels of Caspase 3/7 RLU | Day 14 | 1180 RLU |
| IDN-6556 25 mg | Levels of Caspase 3/7 RLU | Day 28 | 1208 RLU |
| IDN-6556 25 mg | Levels of Caspase 3/7 RLU | Day 2 | 1487 RLU |
| IDN-6556 25 mg | Levels of Caspase 3/7 RLU | Baseline | 3967 RLU |
| IDN-6556 50 mg | Levels of Caspase 3/7 RLU | Day 7 | 958 RLU |
| IDN-6556 50 mg | Levels of Caspase 3/7 RLU | Baseline | 4304 RLU |
| IDN-6556 50 mg | Levels of Caspase 3/7 RLU | Day 2 | 974 RLU |
| IDN-6556 50 mg | Levels of Caspase 3/7 RLU | Day 4 | 1204 RLU |
| IDN-6556 50 mg | Levels of Caspase 3/7 RLU | Day 14 | 835 RLU |
| IDN-6556 50 mg | Levels of Caspase 3/7 RLU | Day 21 | 962 RLU |
| IDN-6556 50 mg | Levels of Caspase 3/7 RLU | Day 28 | 963 RLU |
| Placebo | Levels of Caspase 3/7 RLU | Day 4 | 5853 RLU |
| Placebo | Levels of Caspase 3/7 RLU | Day 28 | 1894 RLU |
| Placebo | Levels of Caspase 3/7 RLU | Day 21 | 1590 RLU |
| Placebo | Levels of Caspase 3/7 RLU | Day 2 | 3989 RLU |
| Placebo | Levels of Caspase 3/7 RLU | Baseline | 4074 RLU |
| Placebo | Levels of Caspase 3/7 RLU | Day 14 | 1869 RLU |
| Placebo | Levels of Caspase 3/7 RLU | Day 7 | 3917 RLU |
Secondary
Levels of CK18/M30
Caspase-cleaved cytokeratin serum levels (CK18/M30)
Time frame: Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28
Population: Number of subjects analyzed varied by time point; Day2: 5 and 25 arms are 4 and 6; Day4: 25 and placebo arms are 6 and 2; Day7: 25 arm is 6; Day14: 5, 25, 50, and placebo arms are 2, 5, 3, and 2; Day21: 5, 25, 50, and placebo arms are 2, 3, 2, and 2; Day28: 5, 25, 50, and placebo arms are 0, 3, 2, and 2; 0 are non-estimable values
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IDN-6556 5 mg | Levels of CK18/M30 | Baseline | 703 U/L |
| IDN-6556 5 mg | Levels of CK18/M30 | Day 21 | 850 U/L |
| IDN-6556 5 mg | Levels of CK18/M30 | Day 14 | 1307 U/L |
| IDN-6556 5 mg | Levels of CK18/M30 | Day 2 | 465 U/L |
| IDN-6556 5 mg | Levels of CK18/M30 | Day 28 | 0 U/L |
| IDN-6556 5 mg | Levels of CK18/M30 | Day 4 | 717 U/L |
| IDN-6556 5 mg | Levels of CK18/M30 | Day 7 | 562 U/L |
| IDN-6556 25 mg | Levels of CK18/M30 | Day 21 | 770 U/L |
| IDN-6556 25 mg | Levels of CK18/M30 | Day 7 | 1226 U/L |
| IDN-6556 25 mg | Levels of CK18/M30 | Day 4 | 847 U/L |
| IDN-6556 25 mg | Levels of CK18/M30 | Day 14 | 1149 U/L |
| IDN-6556 25 mg | Levels of CK18/M30 | Day 28 | 808 U/L |
| IDN-6556 25 mg | Levels of CK18/M30 | Day 2 | 616 U/L |
| IDN-6556 25 mg | Levels of CK18/M30 | Baseline | 1392 U/L |
| IDN-6556 50 mg | Levels of CK18/M30 | Day 7 | 319 U/L |
| IDN-6556 50 mg | Levels of CK18/M30 | Baseline | 919 U/L |
| IDN-6556 50 mg | Levels of CK18/M30 | Day 2 | 348 U/L |
| IDN-6556 50 mg | Levels of CK18/M30 | Day 4 | 362 U/L |
| IDN-6556 50 mg | Levels of CK18/M30 | Day 14 | 577 U/L |
| IDN-6556 50 mg | Levels of CK18/M30 | Day 21 | 551 U/L |
| IDN-6556 50 mg | Levels of CK18/M30 | Day 28 | 533 U/L |
| Placebo | Levels of CK18/M30 | Day 4 | 634 U/L |
| Placebo | Levels of CK18/M30 | Day 28 | 553 U/L |
| Placebo | Levels of CK18/M30 | Day 21 | 626 U/L |
| Placebo | Levels of CK18/M30 | Day 2 | 425 U/L |
| Placebo | Levels of CK18/M30 | Baseline | 455 U/L |
| Placebo | Levels of CK18/M30 | Day 14 | 843 U/L |
| Placebo | Levels of CK18/M30 | Day 7 | 466 U/L |
Secondary
Levels of CK18/M65
Caspase full-length cytokeratin serum levels CK18/M65
Time frame: Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28
Population: Number of subjects analyzed varied by time point; Day2: 5 and 25 arms are 4 and 6; Day4: 25 and placebo arms are 6 and 2; Day7: 25 arm is 6; Day14: 5, 25, 50, and placebo arms are 2, 5, 3, and 2; Day21: 5, 25, 50, and placebo arms are 2, 3, 2, and 2; Day28: 5, 25, 50, and placebo arms are 0, 3, 2, and 2; 0 are non-estimable values
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IDN-6556 5 mg | Levels of CK18/M65 | Baseline | 1345 U/L |
| IDN-6556 5 mg | Levels of CK18/M65 | Day 21 | 3809 U/L |
| IDN-6556 5 mg | Levels of CK18/M65 | Day 14 | 1961 U/L |
| IDN-6556 5 mg | Levels of CK18/M65 | Day 2 | 1058 U/L |
| IDN-6556 5 mg | Levels of CK18/M65 | Day 28 | 0 U/L |
| IDN-6556 5 mg | Levels of CK18/M65 | Day 4 | 1237 U/L |
| IDN-6556 5 mg | Levels of CK18/M65 | Day 7 | 1364 U/L |
| IDN-6556 25 mg | Levels of CK18/M65 | Day 21 | 2039 U/L |
| IDN-6556 25 mg | Levels of CK18/M65 | Day 7 | 2601 U/L |
| IDN-6556 25 mg | Levels of CK18/M65 | Day 4 | 2257 U/L |
| IDN-6556 25 mg | Levels of CK18/M65 | Day 14 | 3067 U/L |
| IDN-6556 25 mg | Levels of CK18/M65 | Day 28 | 1825 U/L |
| IDN-6556 25 mg | Levels of CK18/M65 | Day 2 | 2116 U/L |
| IDN-6556 25 mg | Levels of CK18/M65 | Baseline | 2819 U/L |
| IDN-6556 50 mg | Levels of CK18/M65 | Day 7 | 1997 U/L |
| IDN-6556 50 mg | Levels of CK18/M65 | Baseline | 1946 U/L |
| IDN-6556 50 mg | Levels of CK18/M65 | Day 2 | 1287 U/L |
| IDN-6556 50 mg | Levels of CK18/M65 | Day 4 | 1436 U/L |
| IDN-6556 50 mg | Levels of CK18/M65 | Day 14 | 1286 U/L |
| IDN-6556 50 mg | Levels of CK18/M65 | Day 21 | 2500 U/L |
| IDN-6556 50 mg | Levels of CK18/M65 | Day 28 | 2119 U/L |
| Placebo | Levels of CK18/M65 | Day 4 | 990 U/L |
| Placebo | Levels of CK18/M65 | Day 28 | 1027 U/L |
| Placebo | Levels of CK18/M65 | Day 21 | 1125 U/L |
| Placebo | Levels of CK18/M65 | Day 2 | 1195 U/L |
| Placebo | Levels of CK18/M65 | Baseline | 1324 U/L |
| Placebo | Levels of CK18/M65 | Day 14 | 1310 U/L |
| Placebo | Levels of CK18/M65 | Day 7 | 1086 U/L |