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The purpose of this study is to evaluate the exposure of rifabutin (RIB) when administered with atazanavir and ritonavir (ATV/RTV)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| A | Active Comparator |
| |
| B | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rifabutin | Drug | Capsule, Oral, 150 mg, once daily, 11 Days |
| |
| Rifabutin + Atazanavir + Ritonavir |
| Measure | Description | Time Frame |
|---|---|---|
| Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (RIB) | AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150mg once daily (QD); AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7. | Pre-dose (0 hours [h]) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Maximum Plasma Concentration (Cmax) of RIB | Cmax was derived from plasma concentration versus time for RIB and was recorded directly from experimental observations for each treatment period. | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Minimum Plasma Concentration (Cmin) of RIB | Cmin was derived from plasma concentration versus time for RIB. | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| AUC24avg for 25-O-Desacetyl-RIB | AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150 mg QD; AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7 | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Measure | Description | Time Frame |
|---|---|---|
| Cmax of ATV | Cmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Cmin of ATV |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bristol-Myers Squibb | Bristol-Myers Squibb | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Bristol-Myers Squibb Clinical Pharmacology Unit | Hamilton | New Jersey | 08690 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21712242 | Derived | Zhang J, Zhu L, Stonier M, Coumbis J, Xu X, Wu Y, Arikan D, Farajallah A, Bertz R. Determination of rifabutin dosing regimen when administered in combination with ritonavir-boosted atazanavir. J Antimicrob Chemother. 2011 Sep;66(9):2075-82. doi: 10.1093/jac/dkr266. Epub 2011 Jun 28. |
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Of 85 enrolled participants, 52 participants did not receive the study drug (49 did not meet the study criteria and 3 were not needed as study was fully enrolled).
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| ID | Title | Description |
|---|---|---|
| FG000 | RIB 150 mg Once Daily (QD) | Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study. |
| FG001 | ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | RIB 150 mg Once Daily (QD) | Participants were administered an oral dose of rifabutin (RIB) 150 mg QD on Days 1 to 10. RIB was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Average Area Under the Plasma Concentration-time Curve for 24 Hours (AUC24avg) for Rifabutin (RIB) | AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150mg once daily (QD); AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7. | All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | nanograms*hour /milliliters (ng*h/mL) | Pre-dose (0 hours [h]) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | ATV/RTV 300/100mg+RIB 150mg |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| NEUTROPHIL COUNT DECREASED | Investigations | MedDRA 11.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| PALPITATIONS | Cardiac disorders | MedDRA 11.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| BMS Study Director | Bristol-Myers Squibb | ClinicalTrials@bms.com |
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| ID | Term |
|---|---|
| D017828 | Rifabutin |
| D000069446 | Atazanavir Sulfate |
| D019438 | Ritonavir |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Drug |
Capsules, Oral, 18 Days Rifabutin (150 mg, 2x/wk) Atazanavir (300 mg, once daily) Ritonavir (100 mg, once daily) |
|
|
| Cmax of 25-O-Desacetylrifabutin (25-O-Desacetyl-RIB) | Cmax was derived from the plasma concentration versus time for 25-O-Desacetyl-RIB (a metabolite of RIB) and was recorded directly from experimental observations for each treatment period. | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Cmin of 25-O-Desacetyl-RIB | Cmin was derived from plasma concentration versus time for 25-O-Desacetyl-RIB. | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Total Area Under the Plasma Concentration-time Curve (AUCtot) | AUCtot represents the total free RIB plus 25-O-Desacetyl-RIB output. It is calculated as: AUCtot (micromolar[µM]*h) = AUC24avg(RIB)(ng*h/mL)/847.016 (g/mole) + AUC24avg(25-O-Desacetyl-RIB)(ng*h/mL)/804.979(g/mole). The 300 mg RIB arm represents an extrapolation from the 150 mg RIB group. | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
Cmin was derived from the plasma concentration versus time for ATV. |
| Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| AUC(TAU) for ATV | AUC(TAU) was derived from the plasma concentration versus time for ATV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV | Tmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Terminal Elimination Half-life (T-half) of ATV | T-half was obtained directly from the concentration-time data. T-half following doses administered for treatment ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Cmax of RTV | Cmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Cmin of RTV | Cmin was derived from the plasma concentration versus time for RTV. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| AUC(TAU) for RTV | AUC(TAU) was derived from the plasma concentration versus time for RTV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Tmax of RTV | Tmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| T-half of RTV | T-half was obtained directly from the concentration-time data. | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
| Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | AEs were defined as new, untoward medical occurrences/worsening of pre-existing medical condition, whether drug-related or not. SAEs were defined as any AE that: resulted in death; was life threatening; resulted in a persistent or significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; was a cancer; or was an overdose. Discontinuation from the study was due either to an AE or was conducted at the investigator's discretion. | From Day 1 to 30 days after the last dose of study drug. |
| Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin/hematocrit: <0.85 x pre-treatment (pre-Rx) value. Platelet count: <0.85 x lower limit of normal (LLN) (or, if pre-Rx value <LLN, then <0.85 x pre-Rx value) or >1.5 x upper limit of normal (ULN). Leukocytes: <0.9 x LLN or >1.2 x ULN (or, if pre-Rx value <LLN, then <0.85 x pre-Rx or >ULN. If pre-Rx value >ULN, then >1.15 x pre-Rx or \ | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
| Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Neutrophils+bands (absolute): <=1.50 x 10^3 cells/microliter (uL). Lymphocytes (absolute): <0.75 x 10^3 cells/uL or >7.50 x 10^3 cells/uL. Monocytes (absolute): >2.00 x 10^3 cells/uL. Basophils (absolute): >0.40 x 10^3 cells/uL. Eosinophils (absolute): >0.75 x 10^3 cells/uL. | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
| Number of Participants With MAs in Serum Chemistry: Alkaline Phosphatase (ALP),Aspartate Aminotransferase (AST),Alanine Aminotransferase (ALT),Bilirubin (Total),Bilirubin (Direct),Blood Urea Nitrogen (BUN),Creatinine,Sodium (Serum),Potassium (Serum) | MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP, AST, ALT:>1.25xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Bilirubin (total), bilirubin (direct), BUN:>1.1xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Creatinine:>1.33xpre-Rx. Sodium (serum):<0.95xLLN or >1.05xULN (if pre-Rx <LLN, then <0.95xpre-Rx or >ULN. If pre-Rx >ULN, then >1.05xpre-Rx or <LLN). Potassium (serum):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or \ | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
| Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Chloride (serum), calcium (total), protein (total):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN). Bicarbonate:<0.8xLLN or >1.2xULN (if pre-Rx value <LLN, then <0.8xpre-Rx value or >ULN. If pre-Rx >ULN, then >1.2xpre-Rx value or <ULN). Phosphorous (inorganic):<0.85xLLN or >1.25xULN (if pre-Rx <ULN, then <0.85xpre-Rx or <ULN. If pre-Rx >ULN, then >1.25x re-Rx or \ | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
| Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Glucose (fasting serum): <0.8 x LLN or >1.5 ULN (if pre-Rx <LLN, then <0.8 x pre-Rx or >ULN. If pre-Rx >ULN, then >2.0 x pre-Rx or <LLN. Albumin: <0.9 x LLN (if pre-Rx <LLN, then <0.9 x pre-Rx). Creatine kinase: >1.5 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx). Uric acid: >1.2 x ULN (if pre-Rx >ULN, then >1.25 x pre-Rx). LDH: >1.25 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx). | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
| Number of Participants With MAs in Urinalysis | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs. Protein, glucose and blood: >=2+ (or, if pre-treatment value >=1+, then >= 2 x pre-treatment value). | Pre-dose on Day -1, Day 7 and discharge. |
| Number of Participants With Identified Electrocardiogram (ECG) Abnormalities | ECG abnormalities were defined as findings that are clinically meaningful as judged by the investigator. A 12-lead ECG was recorded at least 5 minutes after the participant had been lying down and all ECG recordings were evaluated by the investigator. Abnormalities, if present at any study time point, were listed. | Pre-dose on Day -1 and study discharge. |
| Number of Participants With Clinically Significant Vital Signs or Physical Examination Findings | Vital signs assessments and physical examination were conducted throughout the study. Vital signs assessments included body temperature, respiratory rate, blood pressure (systolic and diastolic), and heart rate. Physical examination included a neurological examination (if ocular signs or symptoms occurred, a reflex to slit lamp exam was performed by an ophthalmologist). The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs or physical examination were clinically meaningful. | Vital signs:screening, prior to dosing on Day 1, Day 7, study discharge. Physical examination:screening, Day -1, Day 7, study discharge |
| ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly |
Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Age, Customized | Number | participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Other race comprises American Indian/Alaskan | Number | participants |
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| Body Mass Index (BMI) | BMI is defined as the individual's body weight divided by the square of his or her height. | Mean | Standard Deviation | kg/m^2 |
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| Height Continuous | Mean | Standard Deviation | cm |
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| Weight Continuous | Mean | Standard Deviation | kg |
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| OG001 | ATV/RTV 300/100 mg QD+RIB 150 mg Twice Weekly | Participants were administered an oral dose of atazanavir/ritonavir (ATV/RTV) 300/100 mg QD on Days 1 to 17 and an oral dose of RIB 150 mg twice weekly on Days 1, 4, 8, 11 and 15. Study treatment was given in the morning within 5 minutes of completing a light meal. Participants were admitted to the clinical facility the evening prior to dosing (Day -1) and remained confined for the duration of the study. |
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| Primary | Maximum Plasma Concentration (Cmax) of RIB | Cmax was derived from plasma concentration versus time for RIB and was recorded directly from experimental observations for each treatment period. | All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng/mL | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Primary | Minimum Plasma Concentration (Cmin) of RIB | Cmin was derived from plasma concentration versus time for RIB. | All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng/mL | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Cmax of ATV | Cmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period. | All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng/mL | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Cmin of ATV | Cmin was derived from the plasma concentration versus time for ATV. | All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng/mL | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | AUC(TAU) for ATV | AUC(TAU) was derived from the plasma concentration versus time for ATV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm. | All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng*h/mL | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV | Tmax was derived from the plasma concentration versus time for ATV and was recorded directly from experimental observations for each treatment period. | All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis. | Posted | Median | Full Range | Hour | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Terminal Elimination Half-life (T-half) of ATV | T-half was obtained directly from the concentration-time data. T-half following doses administered for treatment ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly. | All treated participants who received all doses of ATV as specified per protocol, and were evaluable for analysis. | Posted | Mean | Standard Deviation | Hour | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Cmax of RTV | Cmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period. | All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng/mL | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Cmin of RTV | Cmin was derived from the plasma concentration versus time for RTV. | All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng/mL | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | AUC(TAU) for RTV | AUC(TAU) was derived from the plasma concentration versus time for RTV, and was calculated by linear and log-linear trapezoidal summations using a mixed log-linear algorithm. | All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng*h/mL | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Tmax of RTV | Tmax was derived from the plasma concentration versus time for RTV and was recorded directly from experimental observations for each treatment period. | All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis. | Posted | Median | Full Range | Hour | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | T-half of RTV | T-half was obtained directly from the concentration-time data. | All treated participants who received all doses of RTV as specified per protocol, and were evaluable for analysis. | Posted | Mean | Standard Deviation | Hour | Pre-dose (0h) on Days 4, 8, 11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation. | AEs were defined as new, untoward medical occurrences/worsening of pre-existing medical condition, whether drug-related or not. SAEs were defined as any AE that: resulted in death; was life threatening; resulted in a persistent or significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; was a cancer; or was an overdose. Discontinuation from the study was due either to an AE or was conducted at the investigator's discretion. | All treated participants. | Posted | Number | Participants | From Day 1 to 30 days after the last dose of study drug. |
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| Secondary | Number of Participants With Marked Abnormalities (MAs) in Hematology: Hemoglobin, Hematocrit, Platelet Count and Leukocytes | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Hemoglobin/hematocrit: <0.85 x pre-treatment (pre-Rx) value. Platelet count: <0.85 x lower limit of normal (LLN) (or, if pre-Rx value <LLN, then <0.85 x pre-Rx value) or >1.5 x upper limit of normal (ULN). Leukocytes: <0.9 x LLN or >1.2 x ULN (or, if pre-Rx value <LLN, then <0.85 x pre-Rx or >ULN. If pre-Rx value >ULN, then >1.15 x pre-Rx or \ | All treated participants. If a value had "not evaluable" in the dataset, then these participants were not counted (hemoglobin and hematocrit). | Posted | Number | Participants | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
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| Secondary | Number of Participants With MAs in Hematology: Neutrophils + Bands (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Basophils (Absolute) and Eosinophils (Absolute) | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following hematology MA definitions specify the criteria for the data presented. Neutrophils+bands (absolute): <=1.50 x 10^3 cells/microliter (uL). Lymphocytes (absolute): <0.75 x 10^3 cells/uL or >7.50 x 10^3 cells/uL. Monocytes (absolute): >2.00 x 10^3 cells/uL. Basophils (absolute): >0.40 x 10^3 cells/uL. Eosinophils (absolute): >0.75 x 10^3 cells/uL. | All treated participants. If a value had "not evaluable" in the dataset, then these participants were not counted(neutrophils + bands [absolute], monocytes [absolute], basophils [absolute] and eosinophils [absolute]). | Posted | Number | Participants | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
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| Primary | AUC24avg for 25-O-Desacetyl-RIB | AUC24avg is AUC(0-24 hour) following dosing on Day 10 for RIB 150 mg QD; AUC24avg is the area under the plasma concentration-time curve in 1 dosing interval (AUC[TAU]) divided by the number of days over the sampling duration for ATV/RTV 300/100 mg QD+RIB 150 mg twice weekly, i.e. AUC(TAU)/7 | All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng*h/mL | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Primary | Cmax of 25-O-Desacetylrifabutin (25-O-Desacetyl-RIB) | Cmax was derived from the plasma concentration versus time for 25-O-Desacetyl-RIB (a metabolite of RIB) and was recorded directly from experimental observations for each treatment period. | All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng/mL | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Primary | Cmin of 25-O-Desacetyl-RIB | Cmin was derived from plasma concentration versus time for 25-O-Desacetyl-RIB. | All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. | Posted | Geometric Mean | Full Range | ng/mL | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Primary | Total Area Under the Plasma Concentration-time Curve (AUCtot) | AUCtot represents the total free RIB plus 25-O-Desacetyl-RIB output. It is calculated as: AUCtot (micromolar[µM]*h) = AUC24avg(RIB)(ng*h/mL)/847.016 (g/mole) + AUC24avg(25-O-Desacetyl-RIB)(ng*h/mL)/804.979(g/mole). The 300 mg RIB arm represents an extrapolation from the 150 mg RIB group. | All treated participants who received all doses of RIB as specified per protocol, and were evaluable for analysis. The RIB 300 mg arm represents an extrapolation of the RIB 150 mg arm and as such, does not have a value for "Number of Participants Analyzed". AUCtot for RIB 300 mg QD was calculated as 2 × AUCtot for RIB 150 mg QD. | Posted | Geometric Mean | Full Range | µM*h | Pre-dose (0h) on Days 6, 8, 10, and 11, and post-dose (1h,2h,3h,4h,6h,8h,12h) on Day 10 for RIB 150 mg QD; and pre-dose (0h) on Days 4, 8,11 to 18 and post-dose (1h,2h,3h,4h,6h,8h,12h) on Days 11 and 15 for ATV/RTV + RIB. |
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| Secondary | Number of Participants With MAs in Serum Chemistry: Alkaline Phosphatase (ALP),Aspartate Aminotransferase (AST),Alanine Aminotransferase (ALT),Bilirubin (Total),Bilirubin (Direct),Blood Urea Nitrogen (BUN),Creatinine,Sodium (Serum),Potassium (Serum) | MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. ALP, AST, ALT:>1.25xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Bilirubin (total), bilirubin (direct), BUN:>1.1xULN (if pre-Rx >ULN, then >1.25xpre-Rx). Creatinine:>1.33xpre-Rx. Sodium (serum):<0.95xLLN or >1.05xULN (if pre-Rx <LLN, then <0.95xpre-Rx or >ULN. If pre-Rx >ULN, then >1.05xpre-Rx or <LLN). Potassium (serum):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or \ | All treated participants. If a value had "not evaluable" in the dataset, then these participants were not counted (ALP, AST, ALT, bilirubin [total], bilirubin [direct], BUN and creatinine). | Posted | Number | Participants | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
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| Secondary | Number of Participants With MAs in Serum Chemistry: Chloride (Serum), Calcium (Total), Protein (Total), Bicarbonate, Phosphorous (Inorganic) | MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Chloride (serum), calcium (total), protein (total):<0.9xLLN or >1.1xULN (if pre-Rx <LLN, then <0.9xpre-Rx or >ULN. If pre-Rx >ULN, then >1.1xpre-Rx or <LLN). Bicarbonate:<0.8xLLN or >1.2xULN (if pre-Rx value <LLN, then <0.8xpre-Rx value or >ULN. If pre-Rx >ULN, then >1.2xpre-Rx value or <ULN). Phosphorous (inorganic):<0.85xLLN or >1.25xULN (if pre-Rx <ULN, then <0.85xpre-Rx or <ULN. If pre-Rx >ULN, then >1.25x re-Rx or \ | All treated participants. | Posted | Number | Participants | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
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| Secondary | Number of Participants With MAs in Serum Chemistry: Glucose (Fasting Serum), Albumin, Creatine Kinase, Uric Acid, Lactate Dehydrogenase (LDH) | MAs=laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following serum chemistry MA definitions specify MA criteria. Glucose (fasting serum): <0.8 x LLN or >1.5 ULN (if pre-Rx <LLN, then <0.8 x pre-Rx or >ULN. If pre-Rx >ULN, then >2.0 x pre-Rx or <LLN. Albumin: <0.9 x LLN (if pre-Rx <LLN, then <0.9 x pre-Rx). Creatine kinase: >1.5 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx). Uric acid: >1.2 x ULN (if pre-Rx >ULN, then >1.25 x pre-Rx). LDH: >1.25 x ULN (if pre-Rx >ULN, then >1.5 x pre-Rx). | All treated participants. If a value had "not evaluable" in the dataset, then these participants were not counted(albumin, creatine kinase, uric acid and LDH). | Posted | Number | Participants | Pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14, 20 and 26 for RIB 150 mg QD; and pre-dose on Day -1 and post-dose on Days 3, 7, 11, 14 and 18 for ATV/RTV 300/100 mg QD + RIB 150 mg twice weekly. |
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| Secondary | Number of Participants With MAs in Urinalysis | MAs are laboratory measurements marked as abnormal, per pre-defined study criteria, at any study time point. The following definitions specify the criteria for MAs. Protein, glucose and blood: >=2+ (or, if pre-treatment value >=1+, then >= 2 x pre-treatment value). | All participants who received the study drug on Day 1 were included in the analysis. If a value had "not evaluable" in the dataset, then these participants were not counted (for all parameters: protein, glucose and blood). | Posted | Number | Participants | Pre-dose on Day -1, Day 7 and discharge. |
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| Secondary | Number of Participants With Identified Electrocardiogram (ECG) Abnormalities | ECG abnormalities were defined as findings that are clinically meaningful as judged by the investigator. A 12-lead ECG was recorded at least 5 minutes after the participant had been lying down and all ECG recordings were evaluated by the investigator. Abnormalities, if present at any study time point, were listed. | All participants who received the study drug on Day 1 were included in the analysis. | Posted | Number | Participants | Pre-dose on Day -1 and study discharge. |
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| Secondary | Number of Participants With Clinically Significant Vital Signs or Physical Examination Findings | Vital signs assessments and physical examination were conducted throughout the study. Vital signs assessments included body temperature, respiratory rate, blood pressure (systolic and diastolic), and heart rate. Physical examination included a neurological examination (if ocular signs or symptoms occurred, a reflex to slit lamp exam was performed by an ophthalmologist). The investigator used his/her clinical judgment to decide whether or not abnormalities in vital signs or physical examination were clinically meaningful. | All treated participants. | Posted | Number | Participants | Vital signs:screening, prior to dosing on Day 1, Day 7, study discharge. Physical examination:screening, Day -1, Day 7, study discharge |
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| 2 |
| 18 |
| 13 |
| 18 |
| EG001 | RIB 150mg | 0 | 15 | 5 | 15 |
| VENTRICULAR EXTRASYSTOLES | Cardiac disorders | MedDRA 11.0 | Systematic Assessment |
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| EYE PAIN | Eye disorders | MedDRA 11.0 | Systematic Assessment |
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| EYE PRURITUS | Eye disorders | MedDRA 11.0 | Systematic Assessment |
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| ABDOMINAL DISTENSION | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| ABDOMINAL PAIN | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| ABDOMINAL PAIN UPPER | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| DIARRHOEA | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| DRY MOUTH | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| FREQUENT BOWEL MOVEMENTS | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| GINGIVAL PAIN | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| LIP SWELLING | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| MOUTH ULCERATION | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| NAUSEA | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| SWOLLEN TONGUE | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| VOMITING | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
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| CHEST DISCOMFORT | General disorders | MedDRA 11.0 | Systematic Assessment |
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| CHEST PAIN | General disorders | MedDRA 11.0 | Systematic Assessment |
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| CHILLS | General disorders | MedDRA 11.0 | Systematic Assessment |
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| FATIGUE | General disorders | MedDRA 11.0 | Systematic Assessment |
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| FEELING COLD | General disorders | MedDRA 11.0 | Systematic Assessment |
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| PAIN | General disorders | MedDRA 11.0 | Systematic Assessment |
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| PYREXIA | General disorders | MedDRA 11.0 | Systematic Assessment |
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| JAUNDICE | Hepatobiliary disorders | MedDRA 11.0 | Systematic Assessment |
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| CELLULITIS | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
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| NEUTROPHIL COUNT DECREASED | Investigations | MedDRA 11.0 | Systematic Assessment |
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| PAIN IN JAW | Musculoskeletal and connective tissue disorders | MedDRA 11.0 | Systematic Assessment |
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| DIZZINESS | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
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| HEADACHE | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
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| HYPOAESTHESIA | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
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| SLEEP DISORDER | Psychiatric disorders | MedDRA 11.0 | Systematic Assessment |
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| POLLAKIURIA | Renal and urinary disorders | MedDRA 11.0 | Systematic Assessment |
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| CHOKING SENSATION | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
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| COUGH | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
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| NASAL CONGESTION | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
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| PHARYNGEAL OEDEMA | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
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| PHARYNGOLARYNGEAL PAIN | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
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| THROAT IRRITATION | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
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| THROAT TIGHTNESS | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
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| ERYTHEMA | Skin and subcutaneous tissue disorders | MedDRA 11.0 | Systematic Assessment |
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| RASH | Skin and subcutaneous tissue disorders | MedDRA 11.0 | Systematic Assessment |
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| FLUSHING | Vascular disorders | MedDRA 11.0 | Systematic Assessment |
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| HOT FLUSH | Vascular disorders | MedDRA 11.0 | Systematic Assessment |
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Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D009842 | Oligopeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
| AEs |
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| AE leading to discontinuation |
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| Discontinuation due to investigator discretion |
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| Platelet count |
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| Monocytes (absolute) |
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| Basophils (absolute) |
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| ALT |
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| Bilirubin (direct) |
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| Creatinine |
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| Sodium (serum) |
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| Bicarbonate |
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| LDH |
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| Blood |
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