Osteoarthritis, Knee
Conditions
Keywords
Osteoarthritis, Arthritis, Joint Disease, Osteoarthritis, Knee
Brief summary
This study will evaluate the safety and tolerability of KA34 when administered via intra-articular injection to subjects with osteoarthritis of the knee.
Detailed description
This is a randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of KA34 when administered via intra-articular injection to subjects with osteoarthritis of the knee. OA patients are randomized to receive either placebo or KA34 active drug in the range of 50-400 ug by intra-articular injection. The first portion of the study is with single ascending doses, the second portion of the study is with multiple ascending doses.
Interventions
DRUGKA34
50 µg - 400 µg intra-articular injection (single or multiple doses)
DRUGPlacebo
50 µg - 400 µg intra-articular injection (single or multiple doses)
Sponsors
California Institute for Regenerative Medicine (CIRM)
Calibr, a division of Scripps Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of localized osteoarthritis of the knee * Males willing to use contraception and females who are no longer able to bear children
Exclusion criteria
* Body Mass Index (BMI) \> 40 * Grade 0, 3 or 4 osteoarthritis on the Kellgren and Lawrence classification system * Injury to the knee or other joint within the last 12 months * Receipt of any investigational product or experimental therapeutic procedure within the last 12 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | Day 1 up to Day 29 | TEAEs were collected from time of first administration of IP (Day 1) until 28 days after the last administration of IP. The severity of TEAEs was classified by the investigator as mild, moderate or severe and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The investigator also assessed relatedness of TEAEs. The number of subjects who experienced any TEAEs, serious TEAEs (SAE), related TEAEs and TEAEs with CTCAE Grade ≥ 3 are presented. |
| MAD Part: Number of Subjects Who Experienced TEAEs | Day 1 up to Day 180 | TEAEs were collected from time of first administration of IP (Day 1) until 30 days after the last administration of IP. The severity of TEAEs was classified by the investigator as mild, moderate or severe and graded using the CTCAE version 5.0. The investigator also assessed relatedness of TEAEs. The number of subjects who experienced any TEAEs, SAEs, related TEAEs and TEAEs with CTCAE Grade ≥ 3 are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 | Baseline and Day 180 | The mean changes from baseline at Day 180 in hemoglobin levels for subjects in the MAD part of the study are presented. |
| SAD Part: Mean Change From Baseline in Hematocrit at Day 8 | Baseline and Day 8 | The mean changes from baseline at Day 8 in hematocrit levels for subjects in the SAD part of the study are presented. |
| SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Baseline and Day 8 | The mean changes from baseline at Day 8 in total bilirubin and creatinine for subjects in the SAD part of the study are presented. |
| MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Baseline and Day 180 | The mean changes from baseline at Day 180 in total bilirubin and creatinine for subjects in the MAD part of the study are presented. |
| SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | Baseline and Day 8 | The mean changes from baseline at Day 8 in the following liver enzyme levels are presented for subjects in the SAD part of the study: alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). |
| MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | Baseline and Day 180 | The mean changes from baseline at Day 180 in the following liver enzyme levels are presented for subjects in the MAD part of the study: ALP, ALT and AST. |
| SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | Baseline and Day 8 | The mean changes from baseline at Day 8 in systolic blood pressure (SBP) and diastolic blood pressure (DBP) for subjects in the SAD part of the study are presented. |
| MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | Baseline and Day 180 | The mean changes from baseline at Day 180 in SBP and DBP for subjects in the MAD part of the study are presented. |
| SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 | Baseline and Day 8 | The mean changes from baseline at Day 8 in the electrocardiogram (ECG) parameter QTcF interval for subjects in the SAD part of the study are presented. |
| MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180 | Baseline and Day 180 | The mean changes from baseline at Day 180 in the ECG parameter QTcF interval for subjects in the MAD part of the study are presented. |
| SAD Part: Number of Subjects With Injection Site TEAEs | Baseline up to Day 29 | Physical examinations were conducted by a physician or another medically-qualified individual and findings were noted at the injection site during the study. The number of subjects with injection site TEAEs, including the following, are presented: Injection site erythema, Injection site hypersensitivity, Injection site inflammation, Injection site joint discomfort, Injection site joint inflammation, Injection site joint pain, Injection site joint swelling, Injection site nodule, Injection site pain and Injection site swelling. |
| MAD Part: Number of Subjects With Injection Site TEAEs | Baseline up to Day 180 | Physical examinations were conducted by a physician or another medically-qualified individual and findings were noted at the injection site during the study. The number of subjects with injection site TEAEs, including the following, are presented: Injection site erythema, Injection site hypersensitivity, Injection site inflammation, Injection site joint discomfort, Injection site joint inflammation, Injection site joint pain, Injection site joint swelling, Injection site nodule, Injection site pain and Injection site swelling. |
| SAD Part: Mean Maximum Plasma Concentration (Cmax) | Pre-dose up to 4 hours post-dose on Day 1 | All Pharmacokinetic (PK) samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Cmax values were obtained directly from the observed concentration versus time data, and the geometric mean Cmax values for subjects who received KA34 in the SAD part of the study are presented. |
| MAD Part: Mean Change From Baseline in Hematocrit at Day 180 | Baseline and Day 180 | The mean changes from baseline at Day 180 in hematocrit levels for subjects in the MAD part of the study are presented. |
| SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax) | Pre-dose up to 4 hours post-dose on Day 1 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Tmax was obtained directly from the observed concentration versus time data and the median Tmax values for subjects who received KA34 in the SAD part of the study are presented. |
| MAD Part: Median Tmax | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Tmax was obtained directly from the observed concentration versus time data and the median Tmax values for subjects who received KA34 in the MAD part of the study are presented. |
| SAD Part: Mean Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-t]) | Pre-dose up to 4 hours post-dose on Day 1 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-t) was calculated by linear up/log down trapezoidal summation, and the mean AUC(0-t) values for subjects who received KA34 in the SAD part of the study are presented. |
| MAD Part: Mean AUC(0-t) | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-t) was calculated by linear up/log down trapezoidal summation, and the mean AUC(0-t) values for subjects who received KA34 in the MAD part of the study are presented. |
| SAD Part: Mean Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | Pre-dose up to 4 hours post-dose on Day 1 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-inf) was calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable concentration (Clast) divided by the elimation rate constant (λz), i.e. AUC(0-t) + Clast/λz. The mean AUC(0-inf) values for subjects who received KA34 in the SAD part of the study are presented. |
| MAD Part: Mean AUC(0-inf) | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-inf) was calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable concentration (Clast) divided by the elimation rate constant (λz), i.e. AUC(0-t) + Clast/λz. The mean AUC(0-inf) values are presented for subjects who received KA34 in the MAD part of the study. |
| SAD Part: Mean Apparent Terminal Half-life (t1/2) | Pre-dose up to 4 hours post-dose on Day 1 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. t1/2 was determined as the natural log of λz, i.e. as ln2/λz. Mean t1/2 values for subjects who received KA34 in the SAD part of the study are presented. |
| MAD Part: Mean t1/2 | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. t1/2 was determined as the natural log of λz, i.e. as ln2/λz. Mean t1/2 values for subjects who received KA34 in the MAD part of the study are presented. |
| SAD Part: Mean Apparent Clearance (CL/F) | Pre-dose up to 4 hours post-dose on Day 1 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. The CL/F after extravascular dosing was calculated as dose divided by AUC(0-inf), and is presented for subjects who received KA34 in the SAD part of the study. |
| MAD Part: Mean CL/F | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. The CL/F after extravascular dosing was calculated as dose divided by AUC(0-inf), and is presented for subjects who received KA34 in the MAD part of the study. |
| SAD Part: Mean Apparent Volume of Distribution (Vz/F) | Pre-dose up to 4 hours post-dose on Day 1 | The Vz/F was calculated as dose divided by (λz\*AUC\[0-inf\]), and the mean Vz/F values for subjects who received KA34 in the SAD part of the study are presented. |
| MAD Part: Mean Vz/F | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 | The Vz/F was calculated as dose divided by (λz\*AUC\[0-inf\]), and the mean Vz/F values for subjects who received KA34 in the MAD part of the study are presented. |
| MAD Part: Mean Cmax | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 | All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Cmax values were obtained directly from the observed concentration versus time data, and the geometric mean Cmax values for subjects who received KA34 in the MAD part of the study are presented. |
| SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 | Baseline and Day 8 | The mean changes from baseline at Day 8 in hemoglobin levels for subjects in the SAD part of the study are presented. |
Countries
United States
Participant flow
Recruitment details
A total of 60 subjects were randomized to 1 of 7 cohorts to receive KA34 or placebo. In the single-ascending dose (SAD) part, 24 subjects were randomized to receive a single dose of KA34 or placebo in 1 of 4 cohorts. After a thorough review of the Day 29 safety data from the SAD cohorts by the blinded Data Safety Monitoring Board, 36 subjects were randomized in the multiple-ascending dose (MAD) part of the study to receive 4 weekly doses of KA34 or placebo in 1 of 3 cohorts.
Pre-assignment details
Subjects with a diagnosis of osteoarthritis (OA) of the knee as per the clinical and radiographic criteria of the American College of Rheumatology and joint pain with a visual analog scale score of ≥ 40 millimeters (mm) on a 100 mm scale on the index knee, determined by the Investigator at Screening were eligible to join the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (SAD) Subjects randomized to Cohorts 1 - 4 in the SAD part of the study received single IA injections of matching placebo in the affected knee and were followed up until Day 29. | 6 |
| Cohort 1: KA34 50 µg (SAD) Subjects received a single IA injection of 50 µg KA34 in the affected knee and were followed up until Day 29. | 3 |
| Cohort 2: KA34 100 µg (SAD) Subjects received a single IA injection of 100 µg KA34 in the affected knee and were followed up until Day 29. | 3 |
| Cohort 3: KA34 200 µg (SAD) Subjects received a single IA injection of 200 µg KA34 in the affected knee and were followed up until Day 29. | 6 |
| Cohort 4: KA34 400 µg (SAD) Subjects received a single IA injection of 400 µg KA34 in the affected knee and were followed up until Day 29. | 6 |
| Placebo (MAD) Subjects randomized to Cohorts 5 - 7 in the MAD part of the study received weekly IA injections of matching placebo in the affected knee for 4 weeks and were followed up until Day 180. | 9 |
| Cohort 5: KA34 100 µg (MAD) Subjects received IA injections of 100 µg KA34 in the affected knee once weekly for 4 weeks and were followed up until Day 180. | 9 |
| Cohort 6: KA34 200 µg (MAD) Subjects received IA injections of 200 µg KA34 in the affected knee once weekly for 4 weeks and were followed up until Day 180. | 9 |
| Cohort 7: KA34 400 µg (MAD) Subjects received IA injections of 400 µg KA34 in the affected knee once weekly for 4 weeks and were followed up until Day 180. | 9 |
| Total | 60 |
Baseline characteristics
| Characteristic | Total | Placebo (SAD) | Cohort 1: KA34 50 µg (SAD) | Cohort 2: KA34 100 µg (SAD) | Cohort 3: KA34 200 µg (SAD) | Cohort 4: KA34 400 µg (SAD) | Placebo (MAD) | Cohort 5: KA34 100 µg (MAD) | Cohort 6: KA34 200 µg (MAD) | Cohort 7: KA34 400 µg (MAD) |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 4 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 4 Participants | 3 Participants | 2 Participants | 5 Participants | 3 Participants | 6 Participants | 5 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants | 6 Participants | 3 Participants | 3 Participants | 6 Participants | 6 Participants | 9 Participants | 7 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Grade of Osteoarthritis (Kellgren and Lawrence radiological classification system) Grade 0 | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Grade of Osteoarthritis (Kellgren and Lawrence radiological classification system) Grade 1 | 31 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants | 4 Participants | 4 Participants | 6 Participants | 3 Participants | 7 Participants |
| Grade of Osteoarthritis (Kellgren and Lawrence radiological classification system) Grade 2 | 27 Participants | 4 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 5 Participants | 3 Participants | 6 Participants | 2 Participants |
| Grade of Osteoarthritis (Kellgren and Lawrence radiological classification system) Grade 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Grade of Osteoarthritis (Kellgren and Lawrence radiological classification system) Grade 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 46 Participants | 6 Participants | 3 Participants | 1 Participants | 4 Participants | 4 Participants | 5 Participants | 8 Participants | 6 Participants | 9 Participants |
| Region of Enrollment United States | 60 participants | 6 participants | 3 participants | 3 participants | 6 participants | 6 participants | 9 participants | 9 participants | 9 participants | 9 participants |
| Sex: Female, Male Female | 33 Participants | 5 Participants | 1 Participants | 2 Participants | 4 Participants | 4 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 27 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants | 4 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 1 / 6 | 2 / 3 | 1 / 3 | 4 / 6 | 1 / 6 | 7 / 9 | 3 / 9 | 6 / 9 | 5 / 9 |
| serious Total, serious adverse events | 0 / 6 | 0 / 3 | 0 / 3 | 1 / 6 | 0 / 6 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
MAD Part: Number of Subjects Who Experienced TEAEs
TEAEs were collected from time of first administration of IP (Day 1) until 30 days after the last administration of IP. The severity of TEAEs was classified by the investigator as mild, moderate or severe and graded using the CTCAE version 5.0. The investigator also assessed relatedness of TEAEs. The number of subjects who experienced any TEAEs, SAEs, related TEAEs and TEAEs with CTCAE Grade ≥ 3 are presented.
Time frame: Day 1 up to Day 180
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 SAE | 0 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 TEAE | 7 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE with CTCAE grade >=3 | 1 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 severe TEAE | 1 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE leading to discontinuation | 0 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 related TEAE | 4 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE leading to death | 0 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 severe related TEAE | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 related TEAE | 1 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE with CTCAE grade >=3 | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE leading to discontinuation | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 SAE | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 severe related TEAE | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE leading to death | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 severe TEAE | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 TEAE | 3 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 SAE | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 TEAE | 6 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 related TEAE | 1 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 severe TEAE | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 severe related TEAE | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE leading to discontinuation | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE leading to death | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE with CTCAE grade >=3 | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 severe TEAE | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 related TEAE | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE with CTCAE grade >=3 | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE leading to death | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 TEAE | 5 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 severe related TEAE | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | At least 1 SAE | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects Who Experienced TEAEs | TEAE leading to discontinuation | 0 Participants |
Primary
SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs)
TEAEs were collected from time of first administration of IP (Day 1) until 28 days after the last administration of IP. The severity of TEAEs was classified by the investigator as mild, moderate or severe and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The investigator also assessed relatedness of TEAEs. The number of subjects who experienced any TEAEs, serious TEAEs (SAE), related TEAEs and TEAEs with CTCAE Grade ≥ 3 are presented.
Time frame: Day 1 up to Day 29
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 TEAE | 1 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 related TEAE | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe TEAE | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe related TEAE | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 SAE | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE with CTCAE grade >=3 | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe TEAE | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 TEAE | 2 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe related TEAE | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 related TEAE | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE with CTCAE grade >=3 | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 SAE | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE with CTCAE grade >=3 | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe related TEAE | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe TEAE | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 related TEAE | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 TEAE | 1 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 SAE | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 related TEAE | 2 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe TEAE | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe related TEAE | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 SAE | 1 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE with CTCAE grade >=3 | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 TEAE | 4 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe related TEAE | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE with CTCAE grade >=3 | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 severe TEAE | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 TEAE | 1 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 related TEAE | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) | At least 1 SAE | 0 Participants |
Secondary
MAD Part: Mean AUC(0-inf)
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-inf) was calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable concentration (Clast) divided by the elimation rate constant (λz), i.e. AUC(0-t) + Clast/λz. The mean AUC(0-inf) values are presented for subjects who received KA34 in the MAD part of the study.
Time frame: Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations. Mean data is presented for subjects with data available for the parameter estimation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean AUC(0-inf) | 5.041 ng*h/mL | Standard Deviation 1.556 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean AUC(0-inf) | 7.370 ng*h/mL | Standard Deviation 1.44 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean AUC(0-inf) | 21.22 ng*h/mL | Standard Deviation 11.05 |
Secondary
MAD Part: Mean AUC(0-t)
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-t) was calculated by linear up/log down trapezoidal summation, and the mean AUC(0-t) values for subjects who received KA34 in the MAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean AUC(0-t) | 4.578 ng*h/mL | Standard Deviation 1.312 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean AUC(0-t) | 7.077 ng*h/mL | Standard Deviation 1.333 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean AUC(0-t) | 19.53 ng*h/mL | Standard Deviation 9.554 |
Secondary
MAD Part: Mean Change From Baseline in Hematocrit at Day 180
The mean changes from baseline at Day 180 in hematocrit levels for subjects in the MAD part of the study are presented.
Time frame: Baseline and Day 180
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean Change From Baseline in Hematocrit at Day 180 | 42.68 volume % of RBCs | Standard Deviation 4.59 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in Hematocrit at Day 180 | 41.33 volume % of RBCs | Standard Deviation 4.77 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in Hematocrit at Day 180 | 42.12 volume % of RBCs | Standard Deviation 2.02 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in Hematocrit at Day 180 | 44.54 volume % of RBCs | Standard Deviation 2.35 |
Secondary
MAD Part: Mean Change From Baseline in Hemoglobin at Day 180
The mean changes from baseline at Day 180 in hemoglobin levels for subjects in the MAD part of the study are presented.
Time frame: Baseline and Day 180
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 | 0.36 g/dL | Standard Deviation 1.21 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 | -0.60 g/dL | Standard Deviation 1.01 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 | -0.48 g/dL | Standard Deviation 1.29 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 | -0.07 g/dL | Standard Deviation 0.19 |
Secondary
MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180
The mean changes from baseline at Day 180 in the following liver enzyme levels are presented for subjects in the MAD part of the study: ALP, ALT and AST.
Time frame: Baseline and Day 180
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | ALP | -3.4 U/L | Standard Deviation 8.8 |
| Placebo (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | AST | 0.7 U/L | Standard Deviation 3.2 |
| Placebo (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | ALT | 2.1 U/L | Standard Deviation 3.9 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | ALP | -0.2 U/L | Standard Deviation 11.6 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | AST | -4.1 U/L | Standard Deviation 12.8 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | ALT | -6.6 U/L | Standard Deviation 21.1 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | ALT | -3.8 U/L | Standard Deviation 8.3 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | ALP | -10.2 U/L | Standard Deviation 13.8 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | AST | -1.1 U/L | Standard Deviation 5.8 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | ALP | 1.1 U/L | Standard Deviation 7.6 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | AST | -0.7 U/L | Standard Deviation 3.1 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 | ALT | 0.3 U/L | Standard Deviation 3.3 |
Secondary
MAD Part: Mean Change From Baseline in SBP and DBP at Day 180
The mean changes from baseline at Day 180 in SBP and DBP for subjects in the MAD part of the study are presented.
Time frame: Baseline and Day 180
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | SBP | 7.7 mmHg | Standard Deviation 13.3 |
| Placebo (SAD) | MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | DBP | 6.6 mmHg | Standard Deviation 10.3 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | DBP | 1.7 mmHg | Standard Deviation 8.5 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | SBP | 8.9 mmHg | Standard Deviation 8.5 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | SBP | -2.1 mmHg | Standard Deviation 15.3 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | DBP | -3.0 mmHg | Standard Deviation 11.3 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | SBP | -0.3 mmHg | Standard Deviation 20.4 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 | DBP | 4.6 mmHg | Standard Deviation 9.4 |
Secondary
MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180
The mean changes from baseline at Day 180 in the ECG parameter QTcF interval for subjects in the MAD part of the study are presented.
Time frame: Baseline and Day 180
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180 | 3.9 msec | Standard Deviation 13.5 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180 | 1.9 msec | Standard Deviation 10.1 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180 | -3.6 msec | Standard Deviation 14.7 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180 | 3.4 msec | Standard Deviation 24 |
Secondary
MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180
The mean changes from baseline at Day 180 in total bilirubin and creatinine for subjects in the MAD part of the study are presented.
Time frame: Baseline and Day 180
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Total bilirubin | 0.067 mg/dL | Standard Deviation 0.1 |
| Placebo (SAD) | MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Creatinine | -0.038 mg/dL | Standard Deviation 0.1 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Creatinine | -0.006 mg/dL | Standard Deviation 0.099 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Total bilirubin | -0.051 mg/dL | Standard Deviation 0.153 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Total bilirubin | -0.017 mg/dL | Standard Deviation 0.112 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Creatinine | 0.054 mg/dL | Standard Deviation 0.112 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Total bilirubin | -0.043 mg/dL | Standard Deviation 0.264 |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 | Creatinine | 0.030 mg/dL | Standard Deviation 0.077 |
Secondary
MAD Part: Mean CL/F
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. The CL/F after extravascular dosing was calculated as dose divided by AUC(0-inf), and is presented for subjects who received KA34 in the MAD part of the study.
Time frame: Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations. Mean data is presented for subjects with data available for the parameter estimation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean CL/F | 21.43 L/h | Standard Deviation 6.182 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean CL/F | 28.11 L/h | Standard Deviation 5.695 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean CL/F | 23.85 L/h | Standard Deviation 11.95 |
Secondary
MAD Part: Mean Cmax
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Cmax values were obtained directly from the observed concentration versus time data, and the geometric mean Cmax values for subjects who received KA34 in the MAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean Cmax | 2.536 ng/mL | Geometric Coefficient of Variation 33.7 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Cmax | 4.807 ng/mL | Geometric Coefficient of Variation 26.7 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Cmax | 10.67 ng/mL | Geometric Coefficient of Variation 40.3 |
Secondary
MAD Part: Mean t1/2
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. t1/2 was determined as the natural log of λz, i.e. as ln2/λz. Mean t1/2 values for subjects who received KA34 in the MAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean t1/2 | 1.072 h | Standard Deviation 0.2567 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean t1/2 | 0.9997 h | Standard Deviation 0.2991 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean t1/2 | 0.9286 h | Standard Deviation 0.3044 |
Secondary
MAD Part: Mean Vz/F
The Vz/F was calculated as dose divided by (λz\*AUC\[0-inf\]), and the mean Vz/F values for subjects who received KA34 in the MAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations. Mean data is presented for subjects with data available for the parameter estimation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Mean Vz/F | 32.51 L | Standard Deviation 10.19 |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Mean Vz/F | 37.98 L | Standard Deviation 13.46 |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Mean Vz/F | 30.00 L | Standard Deviation 13.38 |
Secondary
MAD Part: Median Tmax
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Tmax was obtained directly from the observed concentration versus time data and the median Tmax values for subjects who received KA34 in the MAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo (SAD) | MAD Part: Median Tmax | 0.50 h |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Median Tmax | 0.30 h |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Median Tmax | 0.50 h |
Secondary
MAD Part: Number of Subjects With Injection Site TEAEs
Physical examinations were conducted by a physician or another medically-qualified individual and findings were noted at the injection site during the study. The number of subjects with injection site TEAEs, including the following, are presented: Injection site erythema, Injection site hypersensitivity, Injection site inflammation, Injection site joint discomfort, Injection site joint inflammation, Injection site joint pain, Injection site joint swelling, Injection site nodule, Injection site pain and Injection site swelling.
Time frame: Baseline up to Day 180
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 1 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 1 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 0 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 2 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 1 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 2 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitivity | 0 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 1 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 0 Participants |
| Placebo (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 1 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitivity | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 1 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 1 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitivity | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 1 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 2 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 1 Participants |
| Cohort 2: KA34 100 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 1 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitivity | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 1 Participants |
| Cohort 3: KA34 200 µg (SAD) | MAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 0 Participants |
Secondary
SAD Part: Mean Apparent Clearance (CL/F)
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. The CL/F after extravascular dosing was calculated as dose divided by AUC(0-inf), and is presented for subjects who received KA34 in the SAD part of the study.
Time frame: Pre-dose up to 4 hours post-dose on Day 1
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations. Mean data is presented for subjects with data available for the parameter estimation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Apparent Clearance (CL/F) | 31.70 L/h | Standard Deviation 4.667 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Apparent Clearance (CL/F) | 25.10 L/h | Standard Deviation 18.24 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Apparent Clearance (CL/F) | 19.22 L/h | Standard Deviation 5.466 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Apparent Clearance (CL/F) | 23.92 L/h | Standard Deviation 5.157 |
Secondary
SAD Part: Mean Apparent Terminal Half-life (t1/2)
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. t1/2 was determined as the natural log of λz, i.e. as ln2/λz. Mean t1/2 values for subjects who received KA34 in the SAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Apparent Terminal Half-life (t1/2) | 1.253 h | Standard Deviation 0.7117 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Apparent Terminal Half-life (t1/2) | 1.420 h | Standard Deviation 0.7072 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Apparent Terminal Half-life (t1/2) | 1.145 h | Standard Deviation 0.1666 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Apparent Terminal Half-life (t1/2) | 1.222 h | Standard Deviation 0.4439 |
Secondary
SAD Part: Mean Apparent Volume of Distribution (Vz/F)
The Vz/F was calculated as dose divided by (λz\*AUC\[0-inf\]), and the mean Vz/F values for subjects who received KA34 in the SAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations. Mean data is presented for subjects with data available for the parameter estimation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Apparent Volume of Distribution (Vz/F) | 38.25 L | Standard Deviation 0.495 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Apparent Volume of Distribution (Vz/F) | 34.30 L | Standard Deviation 19.66 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Apparent Volume of Distribution (Vz/F) | 31.47 L | Standard Deviation 9.479 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Apparent Volume of Distribution (Vz/F) | 35.56 L | Standard Deviation 4.706 |
Secondary
SAD Part: Mean Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf])
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-inf) was calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable concentration (Clast) divided by the elimation rate constant (λz), i.e. AUC(0-t) + Clast/λz. The mean AUC(0-inf) values for subjects who received KA34 in the SAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations. Mean data is presented for subjects with data available for the parameter estimation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | 1.595 ng*h/mL | Standard Deviation 0.2333 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | 5.425 ng*h/mL | Standard Deviation 3.953 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | 11.09 ng*h/mL | Standard Deviation 2.94 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) | 17.34 ng*h/mL | Standard Deviation 3.626 |
Secondary
SAD Part: Mean Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-t])
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. AUC(0-t) was calculated by linear up/log down trapezoidal summation, and the mean AUC(0-t) values for subjects who received KA34 in the SAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-t]) | 1.430 ng*h/mL | Standard Deviation 0.2128 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-t]) | 4.473 ng*h/mL | Standard Deviation 2.555 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-t]) | 9.933 ng*h/mL | Standard Deviation 2.382 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-t]) | 15.73 ng*h/mL | Standard Deviation 2.515 |
Secondary
SAD Part: Mean Change From Baseline in Hematocrit at Day 8
The mean changes from baseline at Day 8 in hematocrit levels for subjects in the SAD part of the study are presented.
Time frame: Baseline and Day 8
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Hematocrit at Day 8 | -0.20 volume % of red blood cells (RBCs) | Standard Deviation 1.61 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Hematocrit at Day 8 | 2.40 volume % of red blood cells (RBCs) | Standard Deviation 6.67 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Hematocrit at Day 8 | -0.37 volume % of red blood cells (RBCs) | Standard Deviation 2.7 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Hematocrit at Day 8 | 0.12 volume % of red blood cells (RBCs) | Standard Deviation 1.33 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Hematocrit at Day 8 | -0.97 volume % of red blood cells (RBCs) | Standard Deviation 1.58 |
Secondary
SAD Part: Mean Change From Baseline in Hemoglobin at Day 8
The mean changes from baseline at Day 8 in hemoglobin levels for subjects in the SAD part of the study are presented.
Time frame: Baseline and Day 8
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 | -0.12 grams/deciliter (g/dL) | Standard Deviation 0.58 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 | 0.77 grams/deciliter (g/dL) | Standard Deviation 2.12 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 | -0.07 grams/deciliter (g/dL) | Standard Deviation 0.81 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 | 0.08 grams/deciliter (g/dL) | Standard Deviation 0.48 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 | -0.32 grams/deciliter (g/dL) | Standard Deviation 0.5 |
Secondary
SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8
The mean changes from baseline at Day 8 in the following liver enzyme levels are presented for subjects in the SAD part of the study: alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
Time frame: Baseline and Day 8
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALP | 0.0 Units/Liter (U/L) | Standard Deviation 3.8 |
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | AST | -0.2 Units/Liter (U/L) | Standard Deviation 3 |
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALT | 0.8 Units/Liter (U/L) | Standard Deviation 4.5 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALT | 3.7 Units/Liter (U/L) | Standard Deviation 7.5 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALP | -7.7 Units/Liter (U/L) | Standard Deviation 14.2 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | AST | 6.0 Units/Liter (U/L) | Standard Deviation 10.1 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALT | -0.3 Units/Liter (U/L) | Standard Deviation 1.5 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALP | 3.7 Units/Liter (U/L) | Standard Deviation 7 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | AST | -2.7 Units/Liter (U/L) | Standard Deviation 1.5 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALP | 0.0 Units/Liter (U/L) | Standard Deviation 4.5 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | AST | -1.0 Units/Liter (U/L) | Standard Deviation 2.5 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALT | -1.3 Units/Liter (U/L) | Standard Deviation 3.1 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALT | -2.2 Units/Liter (U/L) | Standard Deviation 4.3 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | ALP | 4.0 Units/Liter (U/L) | Standard Deviation 11.7 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 | AST | -1.2 Units/Liter (U/L) | Standard Deviation 3.5 |
Secondary
SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8
The mean changes from baseline at Day 8 in systolic blood pressure (SBP) and diastolic blood pressure (DBP) for subjects in the SAD part of the study are presented.
Time frame: Baseline and Day 8
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | SBP | -7.3 millimeters mercury (mmHg) | Standard Deviation 18.2 |
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | DBP | -2.0 millimeters mercury (mmHg) | Standard Deviation 8.3 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | SBP | 6.0 millimeters mercury (mmHg) | Standard Deviation 12.2 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | DBP | 0.3 millimeters mercury (mmHg) | Standard Deviation 10.6 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | SBP | -11.3 millimeters mercury (mmHg) | Standard Deviation 6.7 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | DBP | -8.3 millimeters mercury (mmHg) | Standard Deviation 9 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | DBP | 4.2 millimeters mercury (mmHg) | Standard Deviation 9.2 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | SBP | 7.8 millimeters mercury (mmHg) | Standard Deviation 10.9 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | SBP | 3.7 millimeters mercury (mmHg) | Standard Deviation 8.8 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 | DBP | 9.0 millimeters mercury (mmHg) | Standard Deviation 9.5 |
Secondary
SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8
The mean changes from baseline at Day 8 in the electrocardiogram (ECG) parameter QTcF interval for subjects in the SAD part of the study are presented.
Time frame: Baseline and Day 8
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 | 2.3 milliseconds (msec) | Standard Deviation 14.3 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 | 11.7 milliseconds (msec) | Standard Deviation 6.8 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 | -3.7 milliseconds (msec) | Standard Deviation 14.8 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 | -10.7 milliseconds (msec) | Standard Deviation 25.3 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 | 3.5 milliseconds (msec) | Standard Deviation 32.4 |
Secondary
SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8
The mean changes from baseline at Day 8 in total bilirubin and creatinine for subjects in the SAD part of the study are presented.
Time frame: Baseline and Day 8
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Total bilirubin | 0.023 milligrams/dL (mg/dL) | Standard Deviation 0.416 |
| Placebo (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Creatinine | -0.038 milligrams/dL (mg/dL) | Standard Deviation 0.059 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Total bilirubin | 0.053 milligrams/dL (mg/dL) | Standard Deviation 0.137 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Creatinine | 0.100 milligrams/dL (mg/dL) | Standard Deviation 0.2 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Total bilirubin | -0.033 milligrams/dL (mg/dL) | Standard Deviation 0.058 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Creatinine | -0.063 milligrams/dL (mg/dL) | Standard Deviation 0.012 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Creatinine | -0.032 milligrams/dL (mg/dL) | Standard Deviation 0.041 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Total bilirubin | 0.100 milligrams/dL (mg/dL) | Standard Deviation 0.179 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Total bilirubin | 0.037 milligrams/dL (mg/dL) | Standard Deviation 0.102 |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 | Creatinine | -0.117 milligrams/dL (mg/dL) | Standard Deviation 0.215 |
Secondary
SAD Part: Mean Maximum Plasma Concentration (Cmax)
All Pharmacokinetic (PK) samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Cmax values were obtained directly from the observed concentration versus time data, and the geometric mean Cmax values for subjects who received KA34 in the SAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Mean Maximum Plasma Concentration (Cmax) | 0.8528 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 43.6 |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Mean Maximum Plasma Concentration (Cmax) | 2.757 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 29.9 |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Mean Maximum Plasma Concentration (Cmax) | 5.732 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 18.7 |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Mean Maximum Plasma Concentration (Cmax) | 9.435 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 41.4 |
Secondary
SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax)
All PK samples were analyzed by liquid chromatography with tandem mass spectrometry, using a validated, sensitive, specific method. Tmax was obtained directly from the observed concentration versus time data and the median Tmax values for subjects who received KA34 in the SAD part of the study are presented.
Time frame: Pre-dose up to 4 hours post-dose on Day 1
Population: The PK analysis set consisted of all subjects who received KA34 and had at least 1 measured concentration at a scheduled PK time point after start of dosing without protocol violations or events with potential to affect the PK concentrations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo (SAD) | SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax) | 0.25 hours (h) |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax) | 0.50 hours (h) |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax) | 0.38 hours (h) |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax) | 0.30 hours (h) |
Secondary
SAD Part: Number of Subjects With Injection Site TEAEs
Physical examinations were conducted by a physician or another medically-qualified individual and findings were noted at the injection site during the study. The number of subjects with injection site TEAEs, including the following, are presented: Injection site erythema, Injection site hypersensitivity, Injection site inflammation, Injection site joint discomfort, Injection site joint inflammation, Injection site joint pain, Injection site joint swelling, Injection site nodule, Injection site pain and Injection site swelling.
Time frame: Baseline up to Day 29
Population: The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitvity | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 0 Participants |
| Placebo (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitvity | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 0 Participants |
| Cohort 1: KA34 50 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitvity | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 0 Participants |
| Cohort 2: KA34 100 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitvity | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 1 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 0 Participants |
| Cohort 3: KA34 200 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint discomfort | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site pain | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint inflammation | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint pain | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site swelling | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site joint swelling | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site erythema | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site nodule | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site inflammation | 0 Participants |
| Cohort 4: KA34 400 µg (SAD) | SAD Part: Number of Subjects With Injection Site TEAEs | Injection site hypersensitvity | 1 Participants |