A Study on Visco-antalgic Intra-articular Administration in Symptomatic Knee Osteoarthritis

• Sponsor: Bone Therapeutics S.A (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02740231
• Collaborator: (none)
• Enrollment: 173
• Arms: 4
• Actual Duration (Months): 26.8

Study Details

Study Description

Brief Summary

Osteoarthritis (OA) is the most common joint disease affecting millions of people around the world, for which there is unfortunately no cure. Among existing therapies, viscosupplementation, i.e., the injection of hyaluronic acid into the joint, has an established place in the symptomatic treatment of knee OA.

The present Phase IIb/III aiming to assess the safety and efficacy of JTA-004 is organized in two phases. With results obtained in the first phase the best dose of JTA-004 is determined, and the efficacy of the selected dose will then be confirmed in the second phase.

Condition or Disease	Intervention/Treatment	Phase
Knee Osteoarthritis	Drug: JTA-004 intra-articular injection; Device: Reference product intra-articular injection	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 173 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: Double-blind
• Primary Purpose: Treatment
• Official Title: A Two-stage 6-month Multicentre, Randomised, Double-blind, Controlled Study on the Safety and Efficacy Intra-articular Administration of JTA-004 in Patients With Symptomatic Knee Osteoarthritis
• Actual Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Apr 27, 2018
• Actual Study Completion Date: Apr 27, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Reference product Hylan G-F 20	Device: Reference product intra-articular injection; Each patient will undergo a single injection of Reference product into the knee joint
Experimental: JTA-004 50 (2 ml) Sodium hyaluronate, plasma proteins and clonidine	Drug: JTA-004 intra-articular injection; Each patient will undergo a single injection of JTA-004 into the knee joint
Experimental: JTA-004 50 (4 ml) Sodium hyaluronate, plasma proteins and clonidine	Drug: JTA-004 intra-articular injection; Each patient will undergo a single injection of JTA-004 into the knee joint
Experimental: JTA-004 100 (2 ml) Sodium hyaluronate, plasma proteins and clonidine	Drug: JTA-004 intra-articular injection; Each patient will undergo a single injection of JTA-004 into the knee joint

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in WOMAC VA3.1 Pain Subscale Score at Month 6 [Baseline and 6 months]

   The primary endpoint is the Western Ontario McMaster universities (WOMAC®) VA3.1 Pain Subscale (subscale A): the individual changes in WOMAC® VA3.1 Pain Subscale Score between Baseline and Month 6 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms. The WOMAC® Index Pain Subscale (VAS format) was used. The VAS score was determined by measuring in millimetres from the left-hand end of the line to the point that the patient marks (0-100 mm) for 5 questions. Results are summed and normalized on a 100 mm scale: 0 represents no knee pain and 100 extreme knee pain.

Secondary Outcome Measures

1. WOMAC® Pain Subscale at Month 3 [Baseline and 3 months]

   The primary endpoint is the Western Ontario McMaster universities (WOMAC®) VA3.1 Pain Subscale (subscale A): the individual changes in WOMAC® VA3.1 Pain Subscale Score between Baseline and Month 3 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms. The WOMAC® Index Pain Subscale (VAS format) was used. The VAS score was determined by measuring in millimetres from the left-hand end of the line to the point that the patient marks (0-100 mm) for 5 questions. Results are summed and normalized on a 100 mm scale: 0 represents no knee pain and 100 extreme knee pain.

2. WOMAC® Total Score Over Time [Baseline and 2 weeks]

   The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC VA3.1 Total Score between Baseline and 2 weeks were calculated and compared by Mixed-Effect Model for Repeated Measurements, adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity and osteonecrosis symptoms. The Total score (VAS format) was determined by measuring in millimetres from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of k

3. WOMAC® Total Score Over Time [Baseline and 3 months]

   The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC VA3.1 Total Score between Baseline and Month 3 were calculated and compared by Mixed-Effect Model for Repeated Measurements, adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms. The Total score (VAS format) was determined by measuring in millimetres from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of knee disease severity.

4. WOMAC® Total Score Over Time [Baseline and 6 months]

   The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC VA3.1 Total Score between Baseline and Month 6 were calculated and compared by Mixed-Effect Model for Repeated Measurements, adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms.The Total score (VAS format) was determined by measuring in millimetres from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of knee disease severity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ambulatory

• Diagnosed with primary knee osteoarthritis, fulfilling the following American College of Rheumatology (ACR) criteria at the target knee:

• Pain ≥ 40 mm on a 0-100 mm VAS during the 3 days preceding the date of the screening visit

• Morning stiffness not exceeding 30 minutes

• Kellgren-Lawrence grade II or III

• Insufficient / failed response to analgesic and / or NSAIDs

• No physical therapy of the knee, and knee braces for the entire duration of study

• Ability to provide a written, dated, and signed informed consent prior to any study related procedure, and to understand and comply with study requirements

Exclusion Criteria:

Current symptoms and/or signs related to the disease under study:

• Isolated symptomatic femoropatellar OA of the target knee

• History of trauma or surgery or arthroscopy at the target knee within 6 months before inclusion

• Concomitant inflammatory disease or other condition affecting the joints (e.g., rheumatoid arthritis, septic arthritis, inflammatory joint disease, metabolic bone disease, psoriasis, gout, microcrystalline arthropathies/chondrocalcinosis, Paget's disease)

• Any musculoskeletal condition (such as hip osteoarthritis, amputation, neurologic disorder) that would impede measurement of efficacy at target knee

• Target knee prosthesis planned within 12 months after the Screening Visit

Current or previous diagnoses, signs and/or symptoms:

• Uncontrolled diabetes mellitus, end-stage hepatic or renal disease

• Current (or within the last 5 years prior to entering the study) history of solid or haematological neoplasia or bone marrow transplantation (except for basal cell carcinoma and completely excised squamous cell carcinoma)

• Other severe acute or chronic medical or psychiatric conditions or pre-dispositions or laboratory abnormalities, as judged by the Investigator

• Current or past history of coagulation disorders, as judged by the Investigator

• Hypersensitivity to any components of HA-based injection products

• History of hypersensitivity to human biological material including blood and blood derived products, potential excipients and residues from manufacturing process documented clinically or by laboratory tests

• Hypersensitivity to avian proteins

• Life expectancy less than 6 months

Current or previous treatment:

• Participation in another clinical study within 6 months prior to Screening

• Patients previously treated with JTA-004

• Treatment:

• Within 6 months prior to Screening: intra-articular hyaluronic acid injection at the target knee

• Within 2 months prior to Screening: intra-articular glucocorticoids at the target knee

• Current chemo-, radio- or immuno-cancer-therapy or immunosuppressive therapy

• Current anti-hypertensive medication the effects of which are known to be potentiated by a single dose of clonidine

• Current (or within 6 months prior to Screening) illicit drug abuse

Safety aspects concerning female subjects of childbearing potential:

• Females who are pregnant, lactating or woman with childbearing potential (last menstrual bleeding less than 12 months ago) unwilling to use medically acceptable contraception, or women with childbearing potential unwilling to perform a pregnancy test before administration of study treatment.

Other exclusion criteria:

• Body Mass Index (BMI) of 35 kg/m2 or greater

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Bone Therapeutics S.A

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 10, 2017

More Information

Publications

None provided.

• Responsible Party: Bone Therapeutics S.A
• ClinicalTrials.gov Identifier: NCT02740231
• Other Study ID Numbers: JTA-KOA1
• First Posted: Apr 15, 2016
• Last Update Posted: Dec 6, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bone Therapeutics S.A: viscosupplement; osteoarthritis; knee; intra-articular injection; arthritis; degenerative
• Additional relevant MeSH terms: Osteoarthritis; Osteoarthritis, Knee

Study Results

Participant Flow

Pre-assignment Detail	From the patients enrolled in the study at Visit #1 (screening visit), 173 patients were randomized just before Visit #2 (within 6 weeks after confirmation of eligibility). During visit #2, a total of 164 patients were treated (41 subject in each treatment group) and included in the FAS. 9 randomized patients were not treated.

Arm/Group Title	Reference Product	JTA-004 50 (2 ml)	JTA-004 50 (4 ml)	JTA-004 100 (2 ml)
Arm/Group Description	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint
Period Title: Overall Study
STARTED	41	41	41	41
COMPLETED	39	35	40	33
NOT COMPLETED	2	6	1	8

Baseline Characteristics

Arm/Group Title	Reference Product	JTA-004 50 (2 ml)	JTA-004 50 (4 ml)	JTA-004 100 (2 ml)	Total
Arm/Group Description	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Total of all reporting groups
Overall Participants	41	41	41	41	164
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.8 (7.7)	64.2 (8.0)	62.9 (7.2)	61.7 (7.0)	62.7 (7.5)
Sex: Female, Male (Count of Participants)
Female	30 73.2%	31 75.6%	27 65.9%	24 58.5%	112 68.3%
Male	11 26.8%	10 24.4%	14 34.1%	17 41.5%	52 31.7%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
Belgium	41 100%	41 100%	41 100%	41 100%	164 100%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.5 (4.2)	29.0 (3.9)	28.0 (3.6)	29.6 (3.5)	28.5 (3.9)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in WOMAC VA3.1 Pain Subscale Score at Month 6
Description	The primary endpoint is the Western Ontario McMaster universities (WOMAC®) VA3.1 Pain Subscale (subscale A): the individual changes in WOMAC® VA3.1 Pain Subscale Score between Baseline and Month 6 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms. The WOMAC® Index Pain Subscale (VAS format) was used. The VAS score was determined by measuring in millimetres from the left-hand end of the line to the point that the patient marks (0-100 mm) for 5 questions. Results are summed and normalized on a 100 mm scale: 0 represents no knee pain and 100 extreme knee pain.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

The primary efficacy parameter results were evaluated on JTA-004 100 (2 mL) (the most effective strength) and reference group only. From the 41 patients treated per group, pain subscale evaluation was not performed at 6 months for 6 patients from JTA-004 100 (2 mL) and 2 patients from Reference product group due to patient discontinuation. Statistical analysis was performed on the Full Analysis Set (FAS) (= all randomized and treated patients).

Arm/Group Title	JTA-004 100 (2 mL)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	35	39
Mean (Standard Error) [mm]	-23.6 (4.6)	-14.1 (4.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments	The primary endpoint is the WOMAC® VA3.1 Pain Subscale (subscale A): the individual changes in WOMAC® VA3.1 Pain Subscale Score between Baseline and Month 6 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.141
	Comments	The threshold for statistical significance was p=0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-9.49
	Confidence Interval	(2-Sided) 95%; -22.21 to 3.23
	Parameter Dispersion	Type: Standard Deviation; Value: 6.38
	Estimation Comments	Difference between groups JTA-004 100 (2mL) minus Reference - adjusted mean change

2. Secondary Outcome

Title	WOMAC® Pain Subscale at Month 3
Description	The primary endpoint is the Western Ontario McMaster universities (WOMAC®) VA3.1 Pain Subscale (subscale A): the individual changes in WOMAC® VA3.1 Pain Subscale Score between Baseline and Month 3 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms. The WOMAC® Index Pain Subscale (VAS format) was used. The VAS score was determined by measuring in millimetres from the left-hand end of the line to the point that the patient marks (0-100 mm) for 5 questions. Results are summed and normalized on a 100 mm scale: 0 represents no knee pain and 100 extreme knee pain.
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

The secondary efficacy parameter results were evaluated on JTA-004 100 (2 mL) (the most effective strength) and reference group only. From the 41 patients treated per group, pain subscale evaluation at 3 month was not performed for 6 patients from JTA-004 100 (2 mL) and 1 patients from Reference product group due to patient discontinuation. Statistical analysis was performed on the Full Analysis Set (FAS) (= all randomized and treated patients).

Arm/Group Title	JTA-004 100 (2 mL)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	35	40
Mean (Standard Deviation) [mm]	-26.8 (3.9)	-15.1 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments	The threshold for statistical significance was p=0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-11.63
	Confidence Interval	(2-Sided) 95%; -22.60 to -0.66
	Parameter Dispersion	Type: Standard Deviation; Value: 5.50
	Estimation Comments	Difference between groups JTA-004 100 (2mL) minus Reference

3. Secondary Outcome

Title	WOMAC® Total Score Over Time
Description	The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC VA3.1 Total Score between Baseline and 2 weeks were calculated and compared by Mixed-Effect Model for Repeated Measurements, adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity and osteonecrosis symptoms. The Total score (VAS format) was determined by measuring in millimetres from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of k
Time Frame	Baseline and 2 weeks

Outcome Measure Data

Analysis Population Description

The primary efficacy parameter results were evaluated on JTA-004 100 (2 mL) (the most effective strength) and reference group only. Full Analysis Set (FAS) = all randomized and treated patients

Arm/Group Title	JTA-004 100 (2 mL)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	41	41
Mean (Standard Deviation) [mm]	-21.0 (3.1)	-19.5 (3.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.997
	Comments	The threshold for statistical significance was p=0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-1.48
	Confidence Interval	(2-Sided) 95%; -12.70 to 9.74
	Parameter Dispersion	Type: Standard Deviation; Value: 4.35
	Estimation Comments

4. Secondary Outcome

Title	WOMAC® Total Score Over Time
Description	The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC VA3.1 Total Score between Baseline and Month 3 were calculated and compared by Mixed-Effect Model for Repeated Measurements, adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms. The Total score (VAS format) was determined by measuring in millimetres from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of knee disease severity.
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

The primary efficacy parameter results were evaluated on JTA-004 100 (2 mL) (the most effective strength) and reference group only. From the 41 patients treated per group, total score evaluation was not performed at month 3 for 7 patients from JTA-004 100 (2 mL) group and 1 patient from Reference group due to discontinuation of patients and deviation (at least one subscale of Total score not evaluated) Full Analysis Set (FAS) (= all randomized and treated patients)

Arm/Group Title	JTA-004 100 (2 ml)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	34	40
Mean (Standard Deviation) [mm]	-22.3 (3.8)	-19.4 (3.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.972
	Comments	The threshold for statistical significance was p=0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-2.94
	Confidence Interval	(2-Sided) 95%; -16.52 to 10.65
	Parameter Dispersion	Type: Standard Deviation; Value: 5.3
	Estimation Comments

5. Secondary Outcome

Title	WOMAC® Total Score Over Time
Description	The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC VA3.1 Total Score between Baseline and Month 6 were calculated and compared by Mixed-Effect Model for Repeated Measurements, adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms.The Total score (VAS format) was determined by measuring in millimetres from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of knee disease severity.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

The primary efficacy parameter results were evaluated on JTA-004 100 (2 mL) (the most effective strength) and reference group only. From the 41 patients treated per group, total score evaluation was not performed at month 6 for 6 patients from JTA-004 100 (2 mL) group and 2 patient from Reference group due to discontinuation of patients or deviation (at least one subscale of Total score not evaluated) Full Analysis Set (FAS) (= all randomized and treated patients)

Arm/Group Title	JTA-004 100 (2 ml)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	35	39
Mean (Standard Deviation) [mm]	-23.7 (4.3)	-16.5 (4.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.599
	Comments	The threshold for statistical significance was p=0.05
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-7.17
	Confidence Interval	(2-Sided) 95%; -22.28 to 7.94
	Parameter Dispersion	Type: Standard Deviation; Value: 5.96
	Estimation Comments

6. Post-Hoc Outcome

Title	WOMAC® Total Score Over Time From Pooled JTA-004 Treatment Groups
Description	The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC VA3.1 Total Score between Baseline and Month 3 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity and osteonecrosis symptoms. The Total score (VAS format) was determined by measuring in mm from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of knee disease severity.
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

A post-hoc analysis was conducted comparing pooled JTA-004 treated patients (all strengths) and patients treated with Reference product to complete the study and evaluate the efficacy of JTA-004 product versus Reference. At month 3, on the 41 patients treated per group, 3 patients from JTA 50 (2ml), 7 patients from JTA 100 (2 ml) and 1 patient from Reference were not analysed for total score due to patient discontinuation or deviation (at least one subscale not evaluated)

Arm/Group Title	JTA-004 (All Strenghts)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	113	40
Mean (Standard Deviation) [mm]	-26.3 (2.2)	-19.7 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.126
	Comments	The threshold for statistical significance was p=0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-6.62
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Deviation; Value: 4.3
	Estimation Comments

7. Post-Hoc Outcome

Title	WOMAC® Total Score Over Time From Pooled JTA-004 Treatment Groups
Description	The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC Total Score between Baseline and Month 6 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity and osteonecrosis symptoms. The Total score (VAS format) was determined by measuring in millimetres from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of knee disease severity.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

A comparison of pooled JTA-004 treated patients (all strengths) vs Reference group was conducted to evaluate the efficacy of JTA-004 product versus Reference. At month 6, on the 41 patients treated per group, 5 patients JTA 50(2ml), 1 patient JTA 50 (4ml), 6 patients JTA 100 (2 ml) and 2 patients from Reference were not analysed for total score due to patient discontinuation or deviation (at least one subscale not evaluated) Full Analysis Set (FAS) (= all randomized and treated patients)

Arm/Group Title	JTA-004 (All Strenghts)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	111	39
Mean (Standard Deviation) [mm]	-26.2 (2.4)	-17.3 (4.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments	The threshold for statistical significance was p=0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-8.88
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Deviation; Value: 4.76
	Estimation Comments

8. Post-Hoc Outcome

Title	WOMAC® Pain Subscale Over Time From Pooled JTA-004 Treatment Groups
Description	The primary endpoint is the Western Ontario McMaster universities (WOMAC®) VA3.1 Pain Subscale A: the individual changes in WOMAC® Pain Subscale Score between Baseline and Month 3 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity ans osteonecrosis symptoms. The WOMAC® Index Pain Subscale (VAS format) was used. The VAS score was determined by measuring in millimetres from the left-hand end of the line to the point that the patient marks (0-100 mm) for 5 questions. Results are summed and normalized on a 100 mm scale: 0 represents no knee pain and 100 extreme knee pain.
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

A comparison od pooled JTA-004 treated patients (all strengths) and Reference group was conducted to complete the study and evaluate the efficacy of JTA-004 product versus Reference. On the 41 patients treated per group, 2 patients from JTA 50 (2ml), 6 patients from JTA 100 (2 ml) and 1 patient from Reference were not analysed for total score due to patient discontinuation. Full Analysis Set (FAS) (= all randomized and treated patients)

Arm/Group Title	JTA-004 (All Strenghts)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	115	40
Mean (Standard Deviation) [mm]	-27.2 (2.2)	-16.4 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-10.79
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Deviation; Value: 4.35
	Estimation Comments

9. Post-Hoc Outcome

Title	WOMAC® Pain Subscale Score Over Time From Pooled JTA-004 Treatment Groups
Description	The Western Ontario McMaster universities (WOMAC®) VA3.1 Total Score was used: the individual changes in WOMAC Total Score between Baseline and M6 were calculated and compared by analysis of covariance (ANCOVA), adjusted for baseline value, to the Reference group. Results are expressed as "adjusted mean" based on the model used for group comparison. WOMAC Osteoarthritis Index is a tri-dimensional, self-administered, patient-centred health status questionnaire for knee disease severity and osteonecrosis symptoms. . The Total score (VAS format) was determined by measuring in millimetres from the left hand end of the line to the point that the patient marks (0-100 mm) for the pain (5 questions), stiffness (2 questions), and physical function (17 questions). Results are normalized on a 0-100 mm scale format. A higher score represents a higher degree of knee disease severity.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

A comparison of pooled JTA-004 treated patients (all strengths) and Reference was conducted to evaluate the efficacy of JTA-004 product versus Reference. On the 41 patients treated per group, 5 patients from JTA 50 (2ml), 1 patient from JTA 50 (4ml), 6 patients from JTA 100 (2 ml) and 2 patients from Reference were not analysed for total score due to patient discontinuation Full Analysis Set (FAS) (= all randomized and treated patients)

Arm/Group Title	JTA-004 (All Strenghts)	Reference Product
Arm/Group Description	JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint
Measure Participants	111	39
Mean (Standard Deviation) [mm]	-26.1 (2.4)	-15.6 (4.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	JTA-004 100 (2 mL), Reference Product
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	The threshold for statistical significance was p=0.05
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-10.57
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Deviation; Value: 4.81
	Estimation Comments

Adverse Events

Time Frame	6 months post injection
Adverse Event Reporting Description	No death was reported during the study
Arm/Group Title	Reference Product		JTA-004 50 (2 ml)		JTA-004 50 (4 ml)		JTA-004 100 (2 ml)
Arm/Group Description	Reference product intra-articular injection: Each patient will undergo a single injection of Reference product into the knee joint		JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint		JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint		JTA-004 intra-articular injection: Each patient will undergo a single injection of JTA-004 into the knee joint
All Cause Mortality
	Reference Product		JTA-004 50 (2 ml)		JTA-004 50 (4 ml)		JTA-004 100 (2 ml)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/41 (0%)		0/41 (0%)		0/41 (0%)
Serious Adverse Events
	Reference Product		JTA-004 50 (2 ml)		JTA-004 50 (4 ml)		JTA-004 100 (2 ml)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/41 (4.9%)		4/41 (9.8%)		1/41 (2.4%)		2/41 (4.9%)
Gastrointestinal disorders
Barett's oesophagus	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Diaorrhea	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Hernia eventration	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Infections and infestations
Osteomyelitis acute	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Osteomyelitis chronic	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	2
Pneumonia	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Injury, poisoning and procedural complications
Alcohol poisoning	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/41 (2.4%)	1	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Back pain	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of lung	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Reproductive system and breast disorders
Rectocele	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Reference Product		JTA-004 50 (2 ml)		JTA-004 50 (4 ml)		JTA-004 100 (2 ml)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/41 (26.8%)		3/41 (7.3%)		12/41 (29.3%)		8/41 (19.5%)
Cardiac disorders
Supraventricular Extrasystoles	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Tachycardia	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Ear and labyrinth disorders
Vertigo	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
Gastrointestinal disorders
Abdominal Pain	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Diarrhoea	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Melaena	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
General disorders
Injection Site Pain	2/41 (4.9%)	2	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Fatigue	1/41 (2.4%)	1	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Application Site Oedema	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Conditions aggravated	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Influenza Like Illness	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Thirst	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Infections and infestations
Osteomyelitis Acute	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Osteomyelitis Chronic	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	2
Injury, poisoning and procedural complications
Procedural hypotension	0/41 (0%)	0	0/41 (0%)	0	3/41 (7.3%)	3	0/41 (0%)	0
Delayed Recovery from Anesthesia	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Procedural Pain	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
Investigations
Blood and Creatine Phosphokinase Increased	2/41 (4.9%)	2	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
Amylase Increased	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Blood Pressure Decreased	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Blood Triglycerides Increased	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/41 (7.3%)	4	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Osteoarthritis	1/41 (2.4%)	1	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Joint Stiffness	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Pain in Extremity	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Plantar Fasciitis	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
Tendonitis	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Nervous system disorders
Headache	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
Psychiatric disorders
Major Depression	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0
Skin and subcutaneous tissue disorders
Eczema	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Erythema	0/41 (0%)	0	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1
Hyperkeratosis	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Skin Irritation	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Skin Lesion	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0
Surgical and medical procedures
Joint Injection	1/41 (2.4%)	1	1/41 (2.4%)	1	0/41 (0%)	0	0/41 (0%)	0
Vascular disorders
Hypotension	0/41 (0%)	0	0/41 (0%)	0	1/41 (2.4%)	1	0/41 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.