A Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of KA34 in Subjects With Knee Osteoarthritis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Dose Escalation Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of KA34 Administered Via Intra-Articular Injection in Subjects With Osteoarthritis of the Knee

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: KA34
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KA34 Active Drug<br>KA34 active drug in the dose range of 50 - 400 ug per knee | Drug: KA34<br>* 50 µg - 400 µg intra-articular injection (single or multiple doses)<br>* Other names: KA-34;|
| Placebo Comparator: Placebo<br>Placebo is the formulation for KA34. | Drug: Placebo<br>* 50 µg - 400 µg intra-articular injection (single or multiple doses)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteoarthritis, Arthritis, Joint Disease, Osteoarthritis, Knee