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

• ClinicalTrials.gov Identifier: NCT03133676
• Recruitment Status: Completed
• First Posted: April 28, 2017
• Results First Posted: May 17, 2021
• Last Update Posted: December 27, 2022
• Sponsor: Calibr, a division of Scripps Research
• Collaborator: California Institute for Regenerative Medicine (CIRM)
• Information provided by (Responsible Party): Calibr, a division of Scripps Research

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Osteoarthritis, Knee	Drug: KA34; Drug: Placebo	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 2, 2018
• Actual Primary Completion Date: April 28, 2020
• Actual Study Completion Date: April 28, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: KA34 Active Drug; KA34 active drug in the dose range of 50 - 400 ug per knee	Drug: KA34; 50 µg - 400 µg intra-articular injection (single or multiple doses); Other Name: KA-34
Placebo Comparator: Placebo; Placebo is the formulation for KA34.	Drug: Placebo; 50 µg - 400 µg intra-articular injection (single or multiple doses)

Outcome Measures

Primary Outcome Measures :

1. SAD Part: Number of Subjects Who Experienced Treatment Emergent Adverse Events (TEAEs) [ Time Frame: 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.

2. MAD Part: Number of Subjects Who Experienced TEAEs [ Time Frame: 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 Outcome Measures :

1. SAD Part: Mean Change From Baseline in Hemoglobin at Day 8 [ Time Frame: 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.
2. MAD Part: Mean Change From Baseline in Hemoglobin at Day 180 [ Time Frame: 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.
3. SAD Part: Mean Change From Baseline in Hematocrit at Day 8 [ Time Frame: 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.
4. MAD Part: Mean Change From Baseline in Hematocrit at Day 180 [ Time Frame: 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.
5. SAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 8 [ Time Frame: 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.
6. MAD Part: Mean Change From Baseline in Total Bilirubin and Creatinine at Day 180 [ Time Frame: 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.
7. SAD Part: Mean Change From Baseline in Liver Enzymes at Day 8 [ Time Frame: 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).
8. MAD Part: Mean Change From Baseline in Liver Enzymes at Day 180 [ Time Frame: 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.
9. SAD Part: Mean Change From Baseline in Systolic and Diastolic Blood Pressure at Day 8 [ Time Frame: 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.
10. MAD Part: Mean Change From Baseline in SBP and DBP at Day 180 [ Time Frame: 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.
11. SAD Part: Mean Change From Baseline in the QTcF Interval at Day 8 [ Time Frame: 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.
12. MAD Part: Mean Change From Baseline in the QTcF Interval at Day 180 [ Time Frame: 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.
13. SAD Part: Number of Subjects With Injection Site TEAEs [ Time Frame: 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.
14. MAD Part: Number of Subjects With Injection Site TEAEs [ Time Frame: 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.
15. SAD Part: Mean Maximum Plasma Concentration (Cmax) [ Time Frame: 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.
16. MAD Part: Mean Cmax [ Time Frame: 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.
17. SAD Part: Median Time to Maximum Observed Plasma Concentration (Tmax) [ Time Frame: 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.
18. MAD Part: Median Tmax [ Time Frame: 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.
19. SAD Part: Mean Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-t]) [ Time Frame: 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.
20. MAD Part: Mean AUC(0-t) [ Time Frame: 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.
21. SAD Part: Mean Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) [ Time Frame: 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.
22. MAD Part: Mean AUC(0-inf) [ Time Frame: 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.
23. SAD Part: Mean Apparent Terminal Half-life (t1/2) [ Time Frame: 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.
24. MAD Part: Mean t1/2 [ Time Frame: 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.
25. SAD Part: Mean Apparent Clearance (CL/F) [ Time Frame: 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.
26. MAD Part: Mean CL/F [ Time Frame: 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.
27. SAD Part: Mean Apparent Volume of Distribution (Vz/F) [ Time Frame: 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.
28. MAD Part: Mean Vz/F [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Gender Based Eligibility: Yes
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Diablo Clinical Research

Walnut Creek, California, United States, 94598

United States, Florida

Clinical Research of West Florida

Clearwater, Florida, United States, 33765

Bioclinica Research

Orlando, Florida, United States, 32806

United States, Pennsylvania

Altoona Center for Clinical Research

Duncansville, Pennsylvania, United States, 16635

Sponsors and Collaborators

Calibr, a division of Scripps Research

California Institute for Regenerative Medicine (CIRM)

Investigators

• Study Director: Martin Lotz, MD; Calibr, a division of Scripps Research

  Study Documents (Full-Text)

Documents provided by Calibr, a division of Scripps Research:

Study Protocol  [PDF] April 2, 2020

Statistical Analysis Plan  [PDF] May 15, 2020

More Information

• Responsible Party: Calibr, a division of Scripps Research
• ClinicalTrials.gov Identifier: NCT03133676
• Other Study ID Numbers: CBR-KA34-3001
• First Posted: April 28, 2017
• Results First Posted: May 17, 2021
• Last Update Posted: December 27, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Calibr, a division of Scripps Research:

Osteoarthritis; Arthritis; Joint Disease; Osteoarthritis, Knee

Additional relevant MeSH terms:

Osteoarthritis; Osteoarthritis, Knee; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases