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Open-label prospective non-comparative ascending dose randomized cohort study of single and multiple oral administration of PBTZ169 (capsules 80 mg) in healthy volunteers
Open-label prospective non-comparativerandomized cohort study of safety, tolerability, pharmacokinetics and the effect of food of PBTZ169 in adult healthy volunteers after single and multiple oral administration. Study was conducted in one study center in the Russian Federation. The study included two stages:
Stage 1 - single or double oral administration with dose escalation (fasted/after meal) in 5 cohorts 10 healthy volunteers each plus 5 back-up volunteers;
Stage 2 - multiple oral administration once a day after meal for 14 days in 1 cohort of 10 healthy volunteers.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 (C1A), PBTZ169 | Experimental | Two doses of PBTZ169: 640 mg OD fasted and 640 mg OD after meal. Wash-out period ≥6 days. |
|
| Cohort 1 (C1B), PBTZ169 | Experimental | Two doses of PBTZ169: 640 mg OD after meal and 640 OD mg fasted. Wash-out period ≥6 days. |
|
| Cohort 2 (C2), PBTZ169 | Experimental | Single dose of PBTZ169: 960 mg fasted |
|
| Cohort 3 (C3), PBTZ169 | Experimental | Two doses of PBTZ169: 640 mg twice a day (fasted) with a 12-hour interval; total daily dose - 1280 mg |
|
| Cohort 4 (C4), PBTZ169 | Experimental | Single dose of PBTZ169: 1280 mg fasted |
|
| Cohort 5 (C5), PBTZ169 | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PBTZ169 640 mg OD | Drug | Two administrations once a day with a wash-out period: food effect |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Adverse Events | Safety and tolerability: number of (S)AEs | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
| Number of Subjects With AEs | Safety and tolerability: number of subjects with adverse events | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
| Measure | Description | Time Frame |
|---|---|---|
| CS Changes in Vital Signs | Safety and tolerability:Clinically significant changes in vital signs (blood pressure, HR, body temperature, RR) | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
| ECG Results (Safety and Tolerability) |
Not provided
Inclusion Criteria:
Written informed consent from the volunteer.
Men and women aged 18-45 years, inclusive.
Body mass index of 18.5-30 kg/m2.
Verified "healthy" diagnosis based on physical examination, vital signs, standard laboratory tests (complete blood count and biochemical blood test, urine analysis) and instrumental tests (ECG, fluorography examination or X-ray examination).
Negative results of tests for human immunodeficiency virus (HIV), syphilis, hepatitis B (Hbs Ag) and hepatitis C (antibodies to HCV).
Ability to comply with all the requirements of the protocol in the opinion of the investigator.
Consent of the participant and his/her partner to use reliable contraceptive methods during the study and within 90 days after the end of their participation. A reliable method of contraception is a combination of a male condom with at least one of the following methods:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical hospital at the Yaroslavl station of the Open Joint Stock Company Russian Railways | Yaroslavl | 150030 | Russia |
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Period 1: Single or double dosing (Cohorts 1-4) Period 2: Multiple dosing (Cohort 5)
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1 (C1A), PBTZ169 | Two doses of PBTZ169: 640 mg OD fasted and 640 mg OD after meal. Wash-out period ≥6 days. PBTZ169 640 mg OD: Two administrations once a day with a wash-out period: food effect |
| FG001 | Cohort 1 (C1B), PBTZ169 | Two doses of PBTZ169: 640 mg OD after meal and 640 OD mg fasted. Wash-out period ≥6 days. PBTZ169 640 mg OD: Two administrations once a day with a wash-out period: food effect |
| FG002 | Cohort 2 (C2), PBTZ169 | Single dose of PBTZ169: 960 mg fasted PBTZ169 960 mg SD: Once a day fasted |
| FG003 | Cohort 3 (C3), PBTZ169 | Two doses of PBTZ169: 640 mg twice a day (fasted) with a 12-hour interval; total daily dose - 1280 mg PBTZ169 640 mg BiD: Twice a day fasted; 1 day of administration |
| FG004 | Cohort 4 (C4), PBTZ169 | Single dose of PBTZ169: 1280 mg fasted PBTZ169 1280 mg SD: Once a day fasted |
| FG005 | Cohort 5 (C5), PBTZ169 | Multiple administration of PBTZ169: 1280 mg once a day after meal for 14 days PBTZ169 1280 mg MD: Once a day after meal, 14 doses |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1 (C1A), PBTZ169 | Two doses of PBTZ169: 640 mg OD fasted and 640 mg OD after meal. Wash-out period ≥6 days. PBTZ169 640 mg OD: Two administrations once a day with a wash-out period: food effect |
| BG001 | Cohort 1 (C1B), PBTZ169 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Number of Adverse Events | Safety and tolerability: number of (S)AEs | Safety population | Posted | Number | AEs | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
|
Single and double dosing groups - up to 5 ± 1 days after the last PBTZ169 dose intake (Cohorts 1-4): C1A, C1B - up to Day 12 ± 1 (Day 1 - 1st dosing day) C2, C3, C4 - up to Day 6 ± 1 (Day 1 - dosing day) Multiple dosing group - up to 7 ± 1 days after the last PBTZ169 dose intake (Cohort 5): C5 - up to Day 21±1 (Day 1 - 1st dosing day)
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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 | Cohort 1 (C1A+C1B), PBTZ169 | Two doses of PBTZ169: 640 mg OD fasted/after meal and 640 mg OD after meal/fasted. Wash-out period ≥6 days. PBTZ169 640 mg OD: Two administrations once a day with a wash-out period: food effect |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sinus tachycardia | Cardiac disorders | MedDRA 20.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Viсtoria Shcherbakova | Nearmedic Plus | +7 (495) 741 49 89 | 3869 | Viktoriya.Shcherbakova@nearmedic.ru |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 11, 2018 | Feb 13, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D018088 | Tuberculosis, Multidrug-Resistant |
| D054908 | Extensively Drug-Resistant Tuberculosis |
| ID | Term |
|---|---|
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
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| ID | Term |
|---|---|
| C000592783 | macozinone |
| C494814 | BID protein, human |
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Multiple administration of PBTZ169: 1280 mg once a day after meal for 14 days
|
| PBTZ169 640 mg BiD | Drug | Twice a day fasted; 1 day of administration |
|
|
| PBTZ169 960 mg SD | Drug | Once a day fasted |
|
|
| PBTZ169 1280 mg SD | Drug | Once a day fasted |
|
|
| PBTZ169 1280 mg MD | Drug | Once a day after meal, 14 doses |
|
|
Clinically significant abnormal deviations in ECG findings |
| Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
| Laboratory Examinations Results (Safety and Tolerability) | Complete blood count, biochemical blood test, urine analysis | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
| Results of Physical Examination: CS Deviations | Safety and tolerability: number of physical examinations with CS deviations in results | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
| Peak Plasma Concentration (Сmax) | Сmax of PBTZ169 at the timepoints: C1A, C1B, C2 and C4: point 0 (-5 min to -1 min), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 9:00, 12:00, 24:00, 48:00 and 72:00 (h:min). C3 (two administrations): point 0 (-5 min to -1 min), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 9:00, 12:00 (the point before the second administration from -5 min to -1 min), 12:30, 13:00, 13:30, 14:00, 15:00, 16:00, 18:00, 21:00, 24:00, 48:00 , 72:00 (h:min) after the first administration of the medicinal product. C5 (14 days of intake): 5 minutes before the administration (only until the first dose), 0 min and within 24 h after the administration of the 1st, 7th and last (14th) dose: 0:15, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 (h:min after the administration of a dose of the medicinal product); at 48 h and 72 h points after the last (14th) dose of PBTZ169 | In the dosing interval (up to 72 hours after the last drug administration) |
| Trough Concentration With Repeated Administration (Ctrough) | PBTZ169 concentration before drug intake (Days 2 - 15) | Up to 72 hours after the last drug administration |
| Time to Reach Maximum Concentration (Tmax) | Cohort 3: Tmax relative to the time of administration in any dosage interval | Up to 72 hours after the last drug administration |
| Plasma Half-life Time (T1/2) | Up to 72 hours after the last drug administration |
| Area Under the Concentration-time Curve (AUC0 t) | In the time interval from 0 to time (t) when the last blood sample is collected with a concentration above the limit of quantification. C5: for the data of Day 14 based on measurements within 72 hours after the last dose administration | Up to 72 hours after the last drug administration |
| Area Under the Concentration-time Curve (AUC0-∞) | In the time interval from 0 to infinity | Up to 72 hours after the last drug administration |
| Area Under the Concentration-time Curve (AUC0-24) | C5 (multiple administration once a day for 14 days): AUC0-24 was calculated based on measurements within 24 hours after PBTZ169 intake | In the dosing interval (up to 24 hours after drug administration) |
| Total Clearance (Clt/F) | Up to 72 hours after the last drug administration |
| Volume of Distribution (Vd/F) | Up to 72 hours after the last drug administration |
| Elimination Constant Kel | Up to 72 hours after the last drug administration |
| Relative Bioavailability | f=AUC0-∞(T)/AUC0-∞(R); f'=AUC0-t(T)/AUC0-t(R) Test (T) - PBTZ169 640 mg after meals, reference (R) - PBTZ169 640 mg fasted | Up to 72 hours after the last drug administration |
| Relative Degree of Absorption | f"=Cmax(T)/Cmax(R). Test (T) - PBTZ169 640 mg after meals, reference (R) - PBTZ169 640 mg fasted | Up to 72 hours after the last drug administration |
| Number of Subjects With CS Changes in Vital Signs | Safety and tolerability: No. of sbjs with clinically significant changes in vital signs (blood pressure, HR, body temperature, RR) | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
Two doses of PBTZ169: 640 mg OD after meal and 640 OD mg fasted. Wash-out period ≥6 days. PBTZ169 640 mg OD: Two administrations once a day with a wash-out period: food effect |
| BG002 | Cohort 2 (C2), PBTZ169 | Single dose of PBTZ169: 960 mg fasted PBTZ169 960 mg SD: Once a day fasted |
| BG003 | Cohort 3 (C3), PBTZ169 | Two doses of PBTZ169: 640 mg twice a day (fasted) with a 12-hour interval; total daily dose - 1280 mg PBTZ169 640 mg BiD: Twice a day fasted; 1 day of administration |
| BG004 | Cohort 4 (C4), PBTZ169 | Single dose of PBTZ169: 1280 mg fasted PBTZ169 1280 mg SD: Once a day fasted |
| BG005 | Cohort 5 (C5), PBTZ169 | Multiple administration of PBTZ169: 1280 mg once a day after meal for 14 days PBTZ169 1280 mg MD: Once a day after meal, 14 doses |
| BG006 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG002 |
| Cohort 3 (C3), PBTZ169 |
Two doses of PBTZ169: 640 mg twice a day (fasted) with a 12-hour interval; total daily dose - 1280 mg PBTZ169 640 mg BiD: Twice a day fasted; 1 day of administration |
| OG003 | Cohort 4 (C4), PBTZ169 | Single dose of PBTZ169: 1280 mg fasted PBTZ169 1280 mg SD: Once a day fasted |
| OG004 | Cohort 5 (C5), PBTZ169 | Multiple administration of PBTZ169: 1280 mg once a day after meal for 14 days PBTZ169 1280 mg MD: Once a day after meal, 14 doses |
|
|
| Primary | Number of Subjects With AEs | Safety and tolerability: number of subjects with adverse events | Safety population | Posted | Number | participants | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
|
|
|
| Secondary | CS Changes in Vital Signs | Safety and tolerability:Clinically significant changes in vital signs (blood pressure, HR, body temperature, RR) | Safety population | Posted | Number | No of cases of CS changes in vital signs | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
|
|
|
| Secondary | ECG Results (Safety and Tolerability) | Clinically significant abnormal deviations in ECG findings | Safety population | Posted | Number | participants | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
|
|
|
| Secondary | Laboratory Examinations Results (Safety and Tolerability) | Complete blood count, biochemical blood test, urine analysis | Posted | Number | participants | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
|
|
|
| Secondary | Results of Physical Examination: CS Deviations | Safety and tolerability: number of physical examinations with CS deviations in results | Safety population | Posted | Number | CS physical examination deviations | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
|
|
|
| Secondary | Peak Plasma Concentration (Сmax) | Сmax of PBTZ169 at the timepoints: C1A, C1B, C2 and C4: point 0 (-5 min to -1 min), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 9:00, 12:00, 24:00, 48:00 and 72:00 (h:min). C3 (two administrations): point 0 (-5 min to -1 min), 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 9:00, 12:00 (the point before the second administration from -5 min to -1 min), 12:30, 13:00, 13:30, 14:00, 15:00, 16:00, 18:00, 21:00, 24:00, 48:00 , 72:00 (h:min) after the first administration of the medicinal product. C5 (14 days of intake): 5 minutes before the administration (only until the first dose), 0 min and within 24 h after the administration of the 1st, 7th and last (14th) dose: 0:15, 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00, 24:00 (h:min after the administration of a dose of the medicinal product); at 48 h and 72 h points after the last (14th) dose of PBTZ169 | C1-4 - Single or double dose administration, C5 - Multiple administration for 14 days | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/ml | In the dosing interval (up to 72 hours after the last drug administration) |
|
|
|
| Secondary | Trough Concentration With Repeated Administration (Ctrough) | PBTZ169 concentration before drug intake (Days 2 - 15) | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/ml | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Time to Reach Maximum Concentration (Tmax) | Cohort 3: Tmax relative to the time of administration in any dosage interval | C1-4 - Single or double dose administration, C5 - Multiple administration for 14 days | Posted | Mean | Standard Deviation | h | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Plasma Half-life Time (T1/2) | C1-4 - Single or double dose administration, C5 - Multiple administration for 14 days | Posted | Mean | Standard Deviation | h | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Area Under the Concentration-time Curve (AUC0 t) | In the time interval from 0 to time (t) when the last blood sample is collected with a concentration above the limit of quantification. C5: for the data of Day 14 based on measurements within 72 hours after the last dose administration | C1-4 - Single or double dose administration, C5 - Multiple administration for 14 days | Posted | Mean | Standard Deviation | ng*h/ml | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Area Under the Concentration-time Curve (AUC0-∞) | In the time interval from 0 to infinity | C1-4 - Single or double dose administration, C5 - Multiple administration for 14 days | Posted | Mean | Standard Deviation | ng*h/ml | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Area Under the Concentration-time Curve (AUC0-24) | C5 (multiple administration once a day for 14 days): AUC0-24 was calculated based on measurements within 24 hours after PBTZ169 intake | C5 (multiple administration for 14 days) - AUC0-τ within 72 hours after the last (14th) dose administration | Posted | Mean | Standard Deviation | ng/ml*h | In the dosing interval (up to 24 hours after drug administration) |
|
|
|
| Secondary | Total Clearance (Clt/F) | C1-4 - Single or double dose administration, C5 - Multiple administration for 14 days | Posted | Mean | Standard Deviation | l/h | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Volume of Distribution (Vd/F) | C1-4 - Single or double dose administration, C5 - Multiple administration for 14 days | Posted | Mean | Standard Deviation | l | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Elimination Constant Kel | C1-4 - Single or double dose administration, C5 - Multiple administration for 14 days | Posted | Mean | Standard Deviation | 1/h | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Relative Bioavailability | f=AUC0-∞(T)/AUC0-∞(R); f'=AUC0-t(T)/AUC0-t(R) Test (T) - PBTZ169 640 mg after meals, reference (R) - PBTZ169 640 mg fasted | Posted | Geometric Mean | 90% Confidence Interval | % of T/R geometric mean ratio | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Relative Degree of Absorption | f"=Cmax(T)/Cmax(R). Test (T) - PBTZ169 640 mg after meals, reference (R) - PBTZ169 640 mg fasted | Posted | Geometric Mean | 90% Confidence Interval | geometric mean ratio, % | Up to 72 hours after the last drug administration |
|
|
|
| Secondary | Number of Subjects With CS Changes in Vital Signs | Safety and tolerability: No. of sbjs with clinically significant changes in vital signs (blood pressure, HR, body temperature, RR) | Safety population | Posted | Number | participants | Up to last visit time point: C2, C3, C4 up to Day 7; C1 up to Day 13; C5 up to Day 21 after first drug intake |
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 6 |
| 20 |
| EG001 | Cohort 2 (C2), PBTZ169 | Single dose of PBTZ169: 960 mg fasted PBTZ169 960 mg SD: Once a day fasted | 0 | 10 | 0 | 10 | 3 | 10 |
| EG002 | Cohort 3 (C3), PBTZ169 | Two doses of PBTZ169: 640 mg twice a day (fasted) with a 12-hour interval; total daily dose - 1280 mg PBTZ169 640 mg BiD: Twice a day fasted; 1 day of administration | 0 | 10 | 0 | 10 | 5 | 10 |
| EG003 | Cohort 4 (C4), PBTZ169 | Single dose of PBTZ169: 1280 mg fasted PBTZ169 1280 mg SD: Once a day fasted | 0 | 10 | 0 | 10 | 1 | 10 |
| EG004 | Cohort 5 (C5), PBTZ169 | Multiple administration of PBTZ169: 1280 mg once a day after meal for 14 days PBTZ169 1280 mg MD: Once a day after meal, 14 doses | 0 | 10 | 0 | 10 | 5 | 10 |
| Defect conduction intraventricular | Cardiac disorders | MedDRA 20.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Blood glucose increased | Investigations | MedDRA 20.0 | Systematic Assessment |
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| Electrocardiogram abnormal | Investigations | MedDRA 20.0 | Systematic Assessment |
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| Electrocardiogram repolarisation abnormality | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Hypercreatininaemia | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
Not provided
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| Number of sbjs with drug-related AEs |
|
| CS changes in HH: Sinus tachycardia |
|
| CS Changes in Temperature |
|
| CS Changes in RR |
|
| Sinus tachycardia |
|
| Electrocardiogram abnormal |
|
| Defect conduction intraventricular |
|
| CS Hypercreatininaemia |
|
| CS Anaemia |
|
| CS Haemoglobin decreased |
|
| CS Thrombocytosis |
|
|
| 0.25 h |
|
|
| 0.5 h |
|
|
| 1 h |
|
|
| 1.5 h |
|
|
| 2 h |
|
|
| 3 h |
|
|
| 4 h |
|
|
| 6 h |
|
|
| 8 h |
|
|
| 9 h |
|
|
| 10 h |
|
|
| 12 h |
|
|
| 12.5 h |
|
|
| 13 h |
|
|
| 13.5 h |
|
|
| 14 h |
|
|
| 15 h |
|
|
| 16 h |
|
|
| 18 h |
|
|
| 21 h |
|
|
| 24 h |
|
|
| 48 h |
|
|
| 72 h |
|
|
| Day 7, before dosing |
|
|
| Day 7, 0.25 h |
|
|
| Day 7, 0.5 h |
|
|
| Day 7, 1 h |
|
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| Day 7, 1.5 h |
|
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| Day 7, 2 h |
|
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| Day 7, 3 h |
|
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| Day 7, 4 h |
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| Day 7, 6 h |
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| Day 7, 8 h |
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| Day 7, 10 h |
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| Day 7, 12 h |
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| Day 7, 24 h |
|
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| Day 14, befor dosing |
|
|
| Day 14, 0.25 h |
|
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| Day 14, 0.5 h |
|
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| Day 14, 1 h |
|
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| Day 14, 1.5 h |
|
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| Day 14, 2 h |
|
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| Day 14, 3 h |
|
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| Day 14, 4 h |
|
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| Day 14, 6 h |
|
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| Day 14, 8 h |
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| Day 14, 10 h |
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| Day 14, 12 h |
|
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| Day 14, 24 h |
|
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| Day 14, 48 h |
|
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| Day 14, 72 h |
|
|
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| Day 5 |
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| Day 6 |
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| Day 7 |
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| Day 8 |
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| Day 9 |
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| Day 10 |
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| Day 11 |
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| Day 12 |
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| Day 13 |
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| Day 14 |
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| Day 15 |
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| Day 7 |
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| Day 14 |
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| Day 7 |
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| Day 14 |
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| Day 14 |
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| Day 7 |
|
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| Day 14 |
|
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| Title | Measurements |
|---|---|
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|
| Day 7 |
|
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| Day 14 |
|
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| Day 7 |
|
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| Day 14 |
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| Day 7 |
|
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| Day 14 |
|
|
| CS Sinus tachycardia |
|
| CS Temperature changes |
|
| CS RR changes |
|