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| Name | Class |
|---|---|
| California Institute for Regenerative Medicine (CIRM) | OTHER |
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This study will evaluate the safety and tolerability of KA34 when administered via intra-articular injection to subjects with osteoarthritis of the knee.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| KA34 Active Drug | Experimental | KA34 active drug in the dose range of 50 - 400 ug per knee |
|
| Placebo | Placebo Comparator | Placebo is the formulation for KA34. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| KA34 | Drug | 50 µg - 400 µg intra-articular injection (single or multiple doses) |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Day 1 up to Day 29 |
| 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. | Day 1 up to Day 180 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline and Day 8 |
| MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Martin Lotz, MD | Calibr, a division of Scripps Research | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Diablo Clinical Research | Walnut Creek | California | 94598 | United States | ||
| Clinical Research of West Florida |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo (SAD) | Subjects randomized to Cohorts 1 - 4 in the SAD part of the study received single intra-articular (IA) injections of matching placebo in the affected knee and were followed up until Day 29. |
| FG001 | Cohort 1: KA34 50 µg (SAD) | Subjects received a single IA injection of 50 micrograms (µg) KA34 in the affected knee and were followed up until Day 29. |
| FG002 | 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. |
| FG003 | 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. |
| FG004 | 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. |
| FG005 | 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. |
| FG006 | 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. |
| FG007 | 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. |
| FG008 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
The safety analysis set consisted of all subjects who received at least 1 dose of investigational product (IP) and were analyzed according to treatment received.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Cohort 1: KA34 50 µg (SAD) |
| 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 | 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Count of Participants | Participants | Day 1 up to Day 29 |
|
TEAEs were collected from time of first administration of IP (Day 1) up to 30 days after the last administration of IP (approximately 1 month for the SAD cohorts and approximately 6 months for the MAD cohorts).
TEAEs are presented for the safety analysis set which consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received.
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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 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Orthostatic hypotension | Vascular disorders | MedDRA (21.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Injection site erythema | General disorders | MedDRA (21.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Calibr, a Division of Scripps Research | (858) 242 1000 | KA34ph1@scripps.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 2, 2020 | Oct 6, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 15, 2020 | Oct 6, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D020370 | Osteoarthritis, Knee |
| D010003 | Osteoarthritis |
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| ID | Term |
|---|---|
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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| Placebo | Drug | 50 µg - 400 µg intra-articular injection (single or multiple doses) |
|
The mean changes from baseline at Day 180 in hemoglobin levels for subjects in the MAD part of the study are presented. |
| Baseline and Day 180 |
| 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. | Baseline and Day 8 |
| 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. | Baseline and Day 180 |
| 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. | Baseline and Day 8 |
| 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. | Baseline and Day 180 |
| 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). | Baseline and Day 8 |
| 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. | Baseline and Day 180 |
| 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. | Baseline and Day 8 |
| 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. | Baseline and Day 180 |
| 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. | Baseline and Day 8 |
| 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. | Baseline and Day 180 |
| 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. | Baseline up to Day 29 |
| 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. | Baseline up to Day 180 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 |
| 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. | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
| Clearwater |
| Florida |
| 33765 |
| United States |
| Bioclinica Research | Orlando | Florida | 32806 | United States |
| Altoona Center for Clinical Research | Duncansville | Pennsylvania | 16635 | United States |
Subjects received a single IA injection of 50 µg KA34 in the affected knee and were followed up until Day 29.
| BG002 | 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. |
| BG003 | 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. |
| BG004 | 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. |
| BG005 | 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. |
| BG006 | 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. |
| BG007 | 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. |
| BG008 | 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. |
| BG009 | Total | Total of all reporting groups |
| Participants |
| No |
|
| Sex: Female, Male | Count of Participants | Participants | No |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants | No |
|
| Race (NIH/OMB) | Count of Participants | Participants | No |
|
| Region of Enrollment | Number | participants |
|
| Grade of Osteoarthritis (Kellgren and Lawrence radiological classification system) | Grade 0: No radiographic features of OA present; Grade 1: Doubtful joint space narrowing (JSN) + possible osteophytic lipping; Grade 2: Definite osteophytes + possible JSN on anteroposterior weight-bearing radiograph; Grade 3: Multiple osteophytes, definite JSN, sclerosis, possible bony deformity; Grade 4: Large osteophytes, marked JSN, severe sclerosis + definite bony deformity; | Count of Participants | Participants | No |
|
| OG001 | 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. |
| OG002 | 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. |
| OG003 | 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. |
| OG004 | 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. |
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Count of Participants | Participants | Day 1 up to Day 180 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | grams/deciliter (g/dL) | Baseline and Day 8 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | g/dL | Baseline and Day 180 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | volume % of red blood cells (RBCs) | Baseline and Day 8 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | volume % of RBCs | Baseline and Day 180 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | milligrams/dL (mg/dL) | Baseline and Day 8 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | mg/dL | Baseline and Day 180 |
|
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| 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). | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | Units/Liter (U/L) | Baseline and Day 8 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | U/L | Baseline and Day 180 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | millimeters mercury (mmHg) | Baseline and Day 8 |
|
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| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | mmHg | Baseline and Day 180 |
|
|
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| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | milliseconds (msec) | Baseline and Day 8 |
|
|
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| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Mean | Standard Deviation | msec | Baseline and Day 180 |
|
|
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| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Count of Participants | Participants | Baseline up to Day 29 |
|
|
|
| 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. | The safety analysis set consisted of all subjects who received at least 1 dose of IP and were analyzed according to treatment received. | Posted | Count of Participants | Participants | No | Baseline up to Day 180 |
|
|
|
| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanograms/milliliter (ng/mL) | Pre-dose up to 4 hours post-dose on Day 1 |
|
|
|
| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
|
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|
| 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. | 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. | Posted | Median | Full Range | hours (h) | Pre-dose up to 4 hours post-dose on Day 1 |
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|
| 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. | 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. | Posted | Median | Full Range | h | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
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| 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. | 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. | Posted | Mean | Standard Deviation | ng*h/mL | Pre-dose up to 4 hours post-dose on Day 1 |
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|
| 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. | 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. | Posted | Mean | Standard Deviation | ng*h/mL | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
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| 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. | 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. | Posted | Mean | Standard Deviation | ng*h/mL | Pre-dose up to 4 hours post-dose on Day 1 |
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| 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. | 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. | Posted | Mean | Standard Deviation | ng*h/mL | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
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| 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. | 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. | Posted | Mean | Standard Deviation | h | Pre-dose up to 4 hours post-dose on Day 1 |
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| 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. | 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. | Posted | Mean | Standard Deviation | h | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
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| 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. | 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. | Posted | Mean | Standard Deviation | L/h | Pre-dose up to 4 hours post-dose on Day 1 |
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| 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. | 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. | Posted | Mean | Standard Deviation | L/h | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
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| 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. | 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. | Posted | Mean | Standard Deviation | L | Pre-dose up to 4 hours post-dose on Day 1 |
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| 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. | 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. | Posted | Mean | Standard Deviation | L | Pre-dose up to 4 hours post-dose on Day 1 and pre-dose on Days 8, 15, 22 and 29 |
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|
| 0 |
| 6 |
| 0 |
| 6 |
| 1 |
| 6 |
| EG001 | 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. | 0 | 3 | 0 | 3 | 2 | 3 |
| EG002 | 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. | 0 | 3 | 0 | 3 | 1 | 3 |
| EG003 | 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. | 0 | 6 | 1 | 6 | 4 | 6 |
| EG004 | 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. | 0 | 6 | 0 | 6 | 1 | 6 |
| EG005 | 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. | 0 | 9 | 0 | 9 | 7 | 9 |
| EG006 | 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. | 0 | 9 | 0 | 9 | 3 | 9 |
| EG007 | 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. | 0 | 9 | 0 | 9 | 6 | 9 |
| EG008 | 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. | 0 | 9 | 0 | 9 | 5 | 9 |
| Injection site hypersensitivity | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Peripheral swelling | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Injection site joint discomfort | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Injection site joint pain | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Chills | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Injection site joint inflammation | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Injection site pain | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Injection site inflammation | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Injection site joint swelling | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Injection site nodule | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Injection site swelling | General disorders | MedDRA (21.0) | Systematic Assessment |
|
| Tooth abscess | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
|
| Diverticulitis | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
|
| Rabies | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
|
| Cystitis | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
|
| Viral infection | Infections and infestations | MedDRA (21.0) | Systematic Assessment |
|
| Muscle strain | Injury, poisoning and procedural complications | MedDRA (21.0) | Systematic Assessment |
|
| Post procedural complication | Injury, poisoning and procedural complications | MedDRA (21.0) | Systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA (21.0) | Systematic Assessment |
|
| Skin abrasion | Injury, poisoning and procedural complications | MedDRA (21.0) | Systematic Assessment |
|
| Animal bite | Injury, poisoning and procedural complications | MedDRA (21.0) | Systematic Assessment |
|
| Ligament rupture | Injury, poisoning and procedural complications | MedDRA (21.0) | Systematic Assessment |
|
| Meniscus injury | Injury, poisoning and procedural complications | MedDRA (21.0) | Systematic Assessment |
|
| Joint swelling | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Limb discomfort | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Joint stiffness | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (21.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (21.0) | Systematic Assessment |
|
| Sciatica | Nervous system disorders | MedDRA (21.0) | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA (21.0) | Systematic Assessment |
|
| Tension headache | Nervous system disorders | MedDRA (21.0) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Dermatitis contact | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Rash pruritic | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Skin burning sensation | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Skin ulcer | Skin and subcutaneous tissue disorders | MedDRA (21.0) | Systematic Assessment |
|
| Left ventricular dysfunction | Cardiac disorders | MedDRA (21.0) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (21.0) | Systematic Assessment |
|
| Intestinal mass | Gastrointestinal disorders | MedDRA (21.0) | Systematic Assessment |
|
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA (21.0) | Systematic Assessment |
|
| Type 2 diabetes mellitus | Metabolism and nutrition disorders | MedDRA (21.0) | Systematic Assessment |
|
| Glucose tolerance impaired | Metabolism and nutrition disorders | MedDRA (21.0) | Systematic Assessment |
|
| Vitamin D deficiency | Metabolism and nutrition disorders | MedDRA (21.0) | Systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA (21.0) | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA (21.0) | Systematic Assessment |
|
| Orthostatic hypotension | Vascular disorders | MedDRA (21.0) | Systematic Assessment |
|
Not provided
Not provided
| At least 1 related TEAE |
|
| At least 1 severe TEAE |
|
| At least 1 severe related TEAE |
|
| At least 1 SAE |
|
| TEAE leading to discontinuation |
|
| TEAE leading to death |
|
| TEAE with CTCAE grade >=3 |
|
| Creatinine |
|
| Creatinine |
|
| ALT |
|
| AST |
|
| ALT |
|
| AST |
|
| DBP |
|
| DBP |
|
| Injection site hypersensitvity |
|
| 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 |
|
| Injection site swelling |
|
| 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 |
|
| Injection site swelling |
|