Osteoarthritis, Knee
Conditions
Keywords
Inflammation, Pain, Interleukin, Gene Therapy, plasmid DNA
Brief summary
This is a Phase 2 safety and efficacy study of XT-150 in adult participants experiencing moderate to severe pain due to osteoarthritis of the knee.
Detailed description
In this Phase 2 study, Baseline (Day 0) confirmation of study eligibility will be completed the day before or day of study drug administration. Study drug will be administered by intra-articular (IA) injection into the joint space of the index knee (knee selected for treatment). Up to 270 participants will be randomly enrolled into 1 of 6 treatment sequences (45 participants/ group). Treatment Groups: 1. 0.15 mg/mL XT-150 (1mL), 0.15 mg/mL XT-150 (1mL) 2. 0.15 mg/mL XT-150 (1mL), 0.45 mg/mL XT-150 (1mL) 3. 0.45 mg/mL XT-150 (1mL), 0.15 mg/mL XT-150 (1mL) 4. 0.45 mg/mL XT-150 (1mL), 0.45 mg/mL XT-150 (1mL) 5. Placebo (1mL), 0.15 mg/mL XT-150 (1mL) 6. Placebo (1mL), 0.45 mg/mL XT-150 (1mL) The study will be conducted in 2 stages, A and B. Participants will be randomized at Day 0 to a treatment regimen, one treatment assignment for Stage A and one treatment assignment for Stage B: Stage A (Up to Day 180): Participants will receive placebo, 0.15 mg/mL XT-150 or 0.45 mg/mL XT-150 to the index knee at Day 0. Stage B (Day 180 to Day 360): Participants will have the option to receive a pre-randomized dose (XT-150 0.15 mg/mL or 0.45 mg/mL) to the index knee anytime between Day 180 and Day 330. Final assessments will be 12 months after the first IA dose.
Interventions
BIOLOGICALXT-150
plasmid DNA
DRUGPlacebo
Placebo is a sterile phosphate-buffered saline
Sponsors
Xalud Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Symptomatic disease due to osteoarthritis, defined as a WOMAC Pain score ≥ 8 (worst possible = 20) 2. Focused Analgesia Selection Test will be used to determine whether patients can report pain with sufficient consistency to enter the clinical trial 3. Males and females between 45 and 85 years of age, inclusive 4. Kellgren-Lawrence grading of 2 or 3 within the last 6 months 5. Stable analgesic regimen during the 4 weeks prior to enrollment 6. In the judgment of the Investigator, acceptable general medical condition 7. Life expectancy \>6 months 8. Male and female participants who are heterosexually active and not surgically sterile must agree to use effective contraception, including abstinence, for the duration of the study 9. Have suitable knee joint anatomy for intra-articular injection 10. Willing and able to return for the follow-up (FU) visits 11. Able to read and understand study instructions, and willing and able to comply with all study procedures
Exclusion criteria
1. Hypersensitivity, allergy, or significant reaction to any ingredient of the study drug, including double-stranded DNA, mannose, and sucrose 2. Previously received XT-150 injection(s) 3. Scheduled partial or complete knee replacement within 6 months; participant agrees not to schedule a knee replacement during Stage A of the study 4. History of knee arthroplasty on the Index Knee, i.e., selected for study injection(s) 5. History of rheumatoid arthritis or other inflammatory disease 6. History of immunosuppressive therapy; systemic steroids in the last 3 months 7. Received knee injection with hyaluronic acid or stem-cells in the last 6 months 8. Knee injection of glucocorticoid in the last 3 months 9. Current treatment with systemic immunosuppressive (systemic corticosteroid therapy or other strong immunosuppressant) 10. Currently receiving systemic chemotherapy or radiation therapy for malignancy 11. Clinically significant hepatic disease as indicated by clinical laboratory results ≥3 times the upper limit of normal for any liver function test (e.g., aspartate aminotransferase, alanine aminotransferase) 12. Severe anemia (Grade 3; hemoglobin \<8.0 g/dL, \<4.9 mmol/L, \<80 g/L; transfusion indicated), Grade 1 white cell counts (lymphocytes \<LLN - 800/mm\^3; \<LLN - 0.8 x 109 /L, neutrophils \<LLN - 1500/mm\^3; \<LLN - 1.5 x 109 /L), LLN=Lower Limit Normal Range 13. Positive serology for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus 14. Significant neuropsychiatric conditions; dementia, major depression, or altered mental state that in the opinion of the Investigator will interfere with study participation 15. Current treatment with systemic antibiotics or antivirals (EXCEPTION: topical treatments) 16. Current anticoagulant or anti-platelet treatment (e.g., warfarin, heparins, factor X inhibitors, clopidogrel, prasugrel, ticagrelor, or dipyridamole). Low-dose (≤ 325 mg/day) aspirin is permitted 17. Known or suspected history of active alcohol or intravenous/oral drug abuse within 1 year before the screening visit 18. Use of any investigational drug or device within 3 months before enrollment or current participation in a trial that included intervention with a drug or device; or currently participating in an investigational drug or device study 19. Any condition that, in the opinion of the Investigator, could compromise the safety of the participant, the participant's ability to communicate with the study staff, or the quality of the data
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Day 180 | The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be obtained from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The score for pain category ranges from 0 (no pain) to 20 (maximum pain); higher score indicates worse outcomes. Baseline is defined as the Day 0 value. |
| Stage A: Change From Baseline in WOMAC Pain Score at Day 180 | Day 180 | The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be obtained from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The score for pain category ranges from 0 (no pain) to 20 (maximum pain); higher score indicates worse outcomes. Baseline is defined as the Day 0 value. |
| Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Prior to second dose (Up to Day 180-Day 330) | Adverse events were collected from the time of informed consent through the last study visit on Day 360 (1 year). Treatment Emergent Adverse Events (TEAEs) occurred from the time of study drug treatment on Day 0 through end of study (Day 360) or early termination. This analysis reports any AEs/SAEs that occurred prior to the second dose. |
| Stage B: Number of Participants With AEs and SAEs | Post Second Dose (Day 180-Day 330 through Day 360) | Adverse events were collected from the time of informed consent through the last study visit on Day 360 (1 year). Treatment Emergent Adverse Events occurred from the time of study drug treatment on Day 0 through end of study (Day 360) or early termination. This analysis reports any AEs/SAEs that occurred after the second dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage B: Change From Baseline in WOMAC Pain Score at Day 360 | Day 360 | The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be obtained from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The score for pain category ranges from 0 (no pain) to 20 (maximum pain); higher score indicates worse outcomes. Baseline is defined as the Day 0 value. |
| Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | Up to Day 360 | Presence of Immunoglobulin M (IgM) or Immunoglobulin G (IgG) antibodies against human IL-10 in serum was assessed at Baseline/Day 0 and then post-initial dose on Days 7, 30, 60, 180, and 360. |
| Stage B: Change From Baseline in WOMAC Function Score | At Day 360 | The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score will be obtained from the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The function dimension category asks about the degree of difficulty in doing 17 activities. The score ranges from 0 (normal function) to 170 (severely limited function); higher score indicates worse outcomes. Baseline is defined as the Day 0 value. |
| Stage A: Change From Baseline in Brief Pain Inventory (BPI) of Interference Score | Day 180 | The Brief Pain Inventory (BPI) is a self-administered questionnaire for participants to rate the degree to which their pain interferes with common dimensions of feeling and function. The 7 pain interference items will be rated on 0-10 scale. Total interference score ranges from 0 (does not interfere) to 10 (completely interferes); higher score indicates worse outcomes. |
| Stage A: Change From Baseline in Patients Overall Assessment (POA) | Day 180 | The Patient Overall Assessment (POA) is a self-administered questionnaire that records participants' responses to the question Considering all the ways the OA in your knee affects you, how are you doing today? on a scale of 1 to 5; 1 being very good (asymptomatic and no limitation of normal activities) to 5, very poor (very severe, intolerable symptoms and inability to carry out normal activities). Higher score indicates worse symptoms. |
Countries
Australia, United States
Participant flow
Pre-assignment details
289 participants signed a consent form, but 3 withdrew during the screening period. 286 participants were dosed and that is the number reflected in this section. The data listed here is based on the Safety Population and actual treatment received, not the ITT population. One participant received 0.15mg due to a site error, although they were originally randomized to 0.45mg in Stage A.
Participants by arm
| Arm | Count |
|---|---|
| Stage A: 0.15 mg/mL XT-150, Stage B: 0.15 mg/mL XT-150 Low dose active in Stage A and Stage B
XT-150: plasmid DNA | 49 |
| Stage A: 0.15 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 Low dose active in Stage A, high dose active in Stage B
XT-150: plasmid DNA | 47 |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.15 mg/mL XT-150 High dose active in Stage A, low dose active in Stage B
XT-150: plasmid DNA | 47 |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 High dose active in Stage A and Stage B
XT-150: plasmid DNA | 47 |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 Inactive comparator in Stage A, low dose active in Stage B
XT-150: plasmid DNA
Placebo: Placebo is a sterile phosphate-buffered saline | 48 |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 Inactive comparator in Stage A, high dose active in Stage B
XT-150: plasmid DNA
Placebo: Placebo is a sterile phosphate-buffered saline | 48 |
| Total | 286 |
Baseline characteristics
| Characteristic | Stage A: 0.15 mg/mL XT-150, Stage B: 0.15 mg/mL XT-150 | Stage A: 0.15 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage A: 0.45 mg/mL XT-150, Stage B: 0.15 mg/mL XT-150 | Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.1 years STANDARD_DEVIATION 8.15 | 62.0 years STANDARD_DEVIATION 6.68 | 64.9 years STANDARD_DEVIATION 7.09 | 62.6 years STANDARD_DEVIATION 7.82 | 62.9 years STANDARD_DEVIATION 7.35 | 65.3 years STANDARD_DEVIATION 9.52 | 63.3 years STANDARD_DEVIATION 7.79 |
| Body Mass Index | 32.482 kg/m2 STANDARD_DEVIATION 7.398 | 31.823 kg/m2 STANDARD_DEVIATION 7.087 | 31.101 kg/m2 STANDARD_DEVIATION 7.192 | 33.401 kg/m2 STANDARD_DEVIATION 8.19 | 32.405 kg/m2 STANDARD_DEVIATION 5.234 | 31.659 kg/m2 STANDARD_DEVIATION 7.236 | 32.150 kg/m2 STANDARD_DEVIATION 7.047 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants | 43 Participants | 47 Participants | 47 Participants | 47 Participants | 46 Participants | 272 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 6 Participants | 5 Participants | 5 Participants | 11 Participants | 4 Participants | 41 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 35 Participants | 41 Participants | 39 Participants | 38 Participants | 31 Participants | 39 Participants | 223 Participants |
| Sex: Female, Male Female | 20 Participants | 20 Participants | 22 Participants | 33 Participants | 27 Participants | 33 Participants | 155 Participants |
| Sex: Female, Male Male | 29 Participants | 27 Participants | 25 Participants | 14 Participants | 21 Participants | 15 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 49 | 0 / 47 | 0 / 47 | 0 / 47 | 0 / 48 | 0 / 48 |
| other Total, other adverse events | 15 / 49 | 16 / 47 | 18 / 47 | 24 / 47 | 10 / 48 | 23 / 48 |
| serious Total, serious adverse events | 3 / 49 | 2 / 47 | 3 / 47 | 2 / 47 | 4 / 48 | 3 / 48 |
Outcome results
Primary
Stage A: Change From Baseline in WOMAC Pain Score at Day 180
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be obtained from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The score for pain category ranges from 0 (no pain) to 20 (maximum pain); higher score indicates worse outcomes. Baseline is defined as the Day 0 value.
Time frame: Day 180
Population: The Intent-to-Treat (ITT) Population will comprise all enrolled participants who received the treatment injection, analyzed according to randomized Stage A treatment. The ITT Population will be the primary analysis population for efficacy.~One (1) participant was randomized to 0.45 mg/ml XT-150 but inadvertently received 0.15 mg/ml XT-150 due to site error, explaining the difference between number analyzed in XT-150 groups compared to the overall participant flow.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage A: Change From Baseline in WOMAC Pain Score at Day 180 | -1.77 score on a scale | Standard Error 0.386 |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Change From Baseline in WOMAC Pain Score at Day 180 | -1.95 score on a scale | Standard Error 0.38 |
| Stage A: Placebo | Stage A: Change From Baseline in WOMAC Pain Score at Day 180 | -2.21 score on a scale | Standard Error 0.374 |
p-value: 0.41395% CI: [-0.62, 1.5]Mixed Models Analysis
p-value: 0.62995% CI: [-0.79, 1.31]Mixed Models Analysis
Primary
Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be obtained from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The score for pain category ranges from 0 (no pain) to 20 (maximum pain); higher score indicates worse outcomes. Baseline is defined as the Day 0 value.
Time frame: Day 180
Population: The Intent-to-Treat (ITT) Population will comprise all enrolled participants who received the treatment injection, analyzed according to randomized Stage A treatment. The ITT Population will be the primary analysis population for efficacy.~One (1) participant was randomized to 0.45 mg/ml XT-150 but inadvertently received 0.15 mg/ml XT-150 due to site error, explaining the difference between number analyzed in XT-150 groups compared to the overall participant flow.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Non-responder | 53 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Responder | 26 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Not Analyzed | 16 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Non-responder | 56 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Responder | 28 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Not Analyzed | 11 Participants |
| Stage A: Placebo | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Responder | 38 Participants |
| Stage A: Placebo | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Not Analyzed | 7 Participants |
| Stage A: Placebo | Stage A: Number of Participants Achieving 30% Improvement From Baseline in Western Ontario and McMasters Arthritis Index (WOMAC) Pain Score | Non-responder | 51 Participants |
95% CI: [0.347, 1.237]
95% CI: [0.381, 1.336]
Primary
Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Adverse events were collected from the time of informed consent through the last study visit on Day 360 (1 year). Treatment Emergent Adverse Events (TEAEs) occurred from the time of study drug treatment on Day 0 through end of study (Day 360) or early termination. This analysis reports any AEs/SAEs that occurred prior to the second dose.
Time frame: Prior to second dose (Up to Day 180-Day 330)
Population: The Safety Population will comprise all participants who receive any amount of study drug, analyzed according to treatment actually received.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any TEAEs | Yes | 30 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any TEAEs | No | 66 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related TEAEs | Yes | 4 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related TEAEs | No | 92 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious TEAEs | Yes | 2 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious TEAEs | No | 94 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related Serious TEAEs | Yes | 0 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related Serious TEAEs | No | 96 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related TEAEs | Yes | 0 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related Serious TEAEs | Yes | 0 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related TEAEs | No | 94 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious TEAEs | Yes | 3 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious TEAEs | No | 91 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any TEAEs | Yes | 53 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any TEAEs | No | 41 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related Serious TEAEs | No | 94 Participants |
| Stage A: Placebo | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related TEAEs | Yes | 4 Participants |
| Stage A: Placebo | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any TEAEs | No | 58 Participants |
| Stage A: Placebo | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any TEAEs | Yes | 38 Participants |
| Stage A: Placebo | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related TEAEs | No | 92 Participants |
| Stage A: Placebo | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related Serious TEAEs | Yes | 0 Participants |
| Stage A: Placebo | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious TEAEs | No | 90 Participants |
| Stage A: Placebo | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious TEAEs | Yes | 6 Participants |
| Stage A: Placebo | Stage A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Related Serious TEAEs | No | 96 Participants |
Primary
Stage B: Number of Participants With AEs and SAEs
Adverse events were collected from the time of informed consent through the last study visit on Day 360 (1 year). Treatment Emergent Adverse Events occurred from the time of study drug treatment on Day 0 through end of study (Day 360) or early termination. This analysis reports any AEs/SAEs that occurred after the second dose.
Time frame: Post Second Dose (Day 180-Day 330 through Day 360)
Population: The Safety Population will comprise all participants who receive any amount of study drug, analyzed according to treatment actually received.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | Yes | 0 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | Yes | 2 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | No | 39 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | Yes | 12 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | No | 39 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | No | 27 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | No | 37 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | Yes | 0 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | Yes | 0 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | Yes | 0 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | Yes | 1 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | No | 27 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | No | 41 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | No | 41 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | Yes | 14 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | No | 40 Participants |
| Stage A: Placebo | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | No | 36 Participants |
| Stage A: Placebo | Stage B: Number of Participants With AEs and SAEs | Any TEAE | Yes | 18 Participants |
| Stage A: Placebo | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | No | 37 Participants |
| Stage A: Placebo | Stage B: Number of Participants With AEs and SAEs | Any TEAE | No | 19 Participants |
| Stage A: Placebo | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | Yes | 0 Participants |
| Stage A: Placebo | Stage B: Number of Participants With AEs and SAEs | Related TEAE | Yes | 0 Participants |
| Stage A: Placebo | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | Yes | 1 Participants |
| Stage A: Placebo | Stage B: Number of Participants With AEs and SAEs | Related TEAE | No | 37 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | No | 25 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | Yes | 16 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | Yes | 1 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | No | 40 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | Yes | 1 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | No | 40 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | Yes | 0 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | No | 41 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | No | 43 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | No | 43 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | No | 34 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | Yes | 0 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | No | 43 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | Yes | 0 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | Yes | 9 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | Yes | 0 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | Yes | 1 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | No | 43 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related Serious TEAE | Yes | 0 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Serious TEAE | No | 42 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | No | 25 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Any TEAE | Yes | 18 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | No | 42 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Number of Participants With AEs and SAEs | Related TEAE | Yes | 1 Participants |
Secondary
Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody
Presence of Immunoglobulin M (IgM) or Immunoglobulin G (IgG) antibodies against human IL-10 in serum was assessed at Baseline/Day 0 and then post-initial dose on Days 7, 30, 60, 180, and 360.
Time frame: Up to Day 360
Population: The Safety Population will comprise all participants who receive any amount of study drug, analyzed according to treatment actually received.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | No Anti-IL-10 Antibodies Detected | 49 Participants |
| Stage A: 0.15 mg/ml XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | Anti-IL-10 Antibodies Detected | 0 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | Anti-IL-10 Antibodies Detected | 0 Participants |
| Stage A: 0.45 mg/ml XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | No Anti-IL-10 Antibodies Detected | 47 Participants |
| Stage A: Placebo | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | Anti-IL-10 Antibodies Detected | 0 Participants |
| Stage A: Placebo | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | No Anti-IL-10 Antibodies Detected | 47 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | Anti-IL-10 Antibodies Detected | 0 Participants |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | No Anti-IL-10 Antibodies Detected | 47 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | Anti-IL-10 Antibodies Detected | 0 Participants |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | No Anti-IL-10 Antibodies Detected | 48 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | No Anti-IL-10 Antibodies Detected | 48 Participants |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage A and B: Number of Participants With Presence of Anti-interleukin (IL)-10 Antibody | Anti-IL-10 Antibodies Detected | 0 Participants |
Secondary
Stage A: Change From Baseline in Brief Pain Inventory (BPI) of Interference Score
The Brief Pain Inventory (BPI) is a self-administered questionnaire for participants to rate the degree to which their pain interferes with common dimensions of feeling and function. The 7 pain interference items will be rated on 0-10 scale. Total interference score ranges from 0 (does not interfere) to 10 (completely interferes); higher score indicates worse outcomes.
Time frame: Day 180
Population: The Intent-to-Treat (ITT) Population will comprise all enrolled participants who received the treatment injection, analyzed according to randomized Stage A treatment. The ITT Population will be the primary analysis population for efficacy.~One (1) participant was randomized to 0.45 mg/ml XT-150 but inadvertently received 0.15 mg/ml XT-150 due to site error, explaining the difference between number analyzed in XT-150 groups compared to the overall participant flow.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage A: Change From Baseline in Brief Pain Inventory (BPI) of Interference Score | -0.96 score on a scale | Standard Error 0.263 |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Change From Baseline in Brief Pain Inventory (BPI) of Interference Score | -1.10 score on a scale | Standard Error 0.253 |
| Stage A: Placebo | Stage A: Change From Baseline in Brief Pain Inventory (BPI) of Interference Score | -1.46 score on a scale | Standard Error 0.258 |
p-value: 0.137495% CI: [-0.16, 1.16]Mixed Models Analysis
p-value: 0.280795% CI: [-0.29, 1]Mixed Models Analysis
Secondary
Stage A: Change From Baseline in Patients Overall Assessment (POA)
The Patient Overall Assessment (POA) is a self-administered questionnaire that records participants' responses to the question Considering all the ways the OA in your knee affects you, how are you doing today? on a scale of 1 to 5; 1 being very good (asymptomatic and no limitation of normal activities) to 5, very poor (very severe, intolerable symptoms and inability to carry out normal activities). Higher score indicates worse symptoms.
Time frame: Day 180
Population: The Intent-to-Treat (ITT) Population will comprise all enrolled participants who received the treatment injection, analyzed according to randomized Stage A treatment. The ITT Population will be the primary analysis population for efficacy.~One (1) participant was randomized to 0.45 mg/ml XT-150 but inadvertently received 0.15 mg/ml XT-150 due to site error, explaining the difference between number analyzed in XT-150 groups compared to the overall participant flow.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage A: Change From Baseline in Patients Overall Assessment (POA) | -0.19 score on a scale | Standard Error 0.102 |
| Stage A: 0.45 mg/ml XT-150 | Stage A: Change From Baseline in Patients Overall Assessment (POA) | -0.32 score on a scale | Standard Error 0.1 |
| Stage A: Placebo | Stage A: Change From Baseline in Patients Overall Assessment (POA) | -0.33 score on a scale | Standard Error 0.098 |
p-value: 0.34695% CI: [-0.14, 0.41]Mixed Models Analysis
p-value: 0.96895% CI: [-0.27, 0.28]Mixed Models Analysis
Secondary
Stage B: Change From Baseline in WOMAC Function Score
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score will be obtained from the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The function dimension category asks about the degree of difficulty in doing 17 activities. The score ranges from 0 (normal function) to 170 (severely limited function); higher score indicates worse outcomes. Baseline is defined as the Day 0 value.
Time frame: At Day 360
Population: The Intent-to-Treat (ITT) Population will comprise all enrolled participants who received the treatment injection, analyzed according to randomized Stage A treatment. The ITT Population will be the primary analysis population for efficacy.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage B: Change From Baseline in WOMAC Function Score | -11.23 score on a scale | Standard Error 2.236 |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Change From Baseline in WOMAC Function Score | -11.79 score on a scale | Standard Error 2.292 |
| Stage A: Placebo | Stage B: Change From Baseline in WOMAC Function Score | -12.8 score on a scale | Standard Error 2.33 |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Change From Baseline in WOMAC Function Score | -13.63 score on a scale | Standard Error 2.218 |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Change From Baseline in WOMAC Function Score | -9.44 score on a scale | Standard Error 2.292 |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Change From Baseline in WOMAC Function Score | -8.66 score on a scale | Standard Error 2.164 |
Secondary
Stage B: Change From Baseline in WOMAC Pain Score at Day 360
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be obtained from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The score for pain category ranges from 0 (no pain) to 20 (maximum pain); higher score indicates worse outcomes. Baseline is defined as the Day 0 value.
Time frame: Day 360
Population: The Intent-to-Treat (ITT) Population will comprise all enrolled participants who received the treatment injection, analyzed according to randomized Stage A treatment. The ITT Population will be the primary analysis population for efficacy.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Stage B: Change From Baseline in WOMAC Pain Score at Day 360 | -3.4 score on a scale | Standard Error 0.666 |
| Stage A: 0.45 mg/ml XT-150 | Stage B: Change From Baseline in WOMAC Pain Score at Day 360 | -3.26 score on a scale | Standard Error 0.662 |
| Stage A: Placebo | Stage B: Change From Baseline in WOMAC Pain Score at Day 360 | -3.44 score on a scale | Standard Error 0.682 |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Stage B: Change From Baseline in WOMAC Pain Score at Day 360 | -3.87 score on a scale | Standard Error 0.643 |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Stage B: Change From Baseline in WOMAC Pain Score at Day 360 | -2.9 score on a scale | Standard Error 0.659 |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Stage B: Change From Baseline in WOMAC Pain Score at Day 360 | -2.9 score on a scale | Standard Error 0.639 |
Post Hoc
Post-Hoc WOMAC Function Score Change From Baseline - 2-dose 0.45mg XT-150 vs. Single-dose 0.45mg XT-150 (mITT)
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score will be obtained from the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The function dimension category asks about the degree of difficulty in doing 17 activities. The score ranges from 0 (normal function) to 170 (severely limited function); higher score indicates worse outcomes. Baseline is defined as the Day 0 value. The data reported in this outcome measure is a head-to-head comparison of two doses of 0.45 mg/ml vs. a single dose of 0.45 mg/ml and only includes these 2 treatment sequences whereas outcome measure #13 reports the least squared mean based on data for all 6 treatment sequences.
Time frame: Day 360
Population: The Modified Intent-to-Treat population consists of the ITT population who received at least one treatment injection with a baseline WOMAC Pain score of 9-20 (\>8). This is the target population of interest who may benefit most from the treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Post-Hoc WOMAC Function Score Change From Baseline - 2-dose 0.45mg XT-150 vs. Single-dose 0.45mg XT-150 (mITT) | -15.42 score on a scale | Standard Error 2.887 |
| Stage A: 0.45 mg/ml XT-150 | Post-Hoc WOMAC Function Score Change From Baseline - 2-dose 0.45mg XT-150 vs. Single-dose 0.45mg XT-150 (mITT) | -5.82 score on a scale | Standard Error 3.201 |
Comparison: Outcome measure #11 is an analysis of 2 tx groups (two doses of 0.45 mg/ml vs. a single dose of 0.45 mg/ml), whereas outcome measure #13 is all 6 tx groups. A MMRM model was used. LS Means in an MMRM model are influenced by the overall mean structure and covariance estimation. When fewer treatment groups are included, the model adjusts based on a different subset of data, leading to potential shifts in estimated LS Means due to changes in the reference population/covariance structure.p-value: 0.010195% CI: [-16.85, -2.34]Mixed Models Analysis
Post Hoc
Post-Hoc WOMAC Function Score Change From Baseline - All Dose Regimens (mITT)
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score will be obtained from the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The function dimension category asks about the degree of difficulty in doing 17 activities. The score ranges from 0 (normal function) to 170 (severely limited function); higher score indicates worse outcomes. Baseline is defined as the Day 0 value.
Time frame: Day 360
Population: The Modified Intent-to-Treat population consists of the ITT population who received at least one treatment injection with a baseline WOMAC Pain score of 9-20 (\>8). This is the target population of interest who may benefit most from the treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Post-Hoc WOMAC Function Score Change From Baseline - All Dose Regimens (mITT) | -12.73 score on a scale | Standard Error 2.81 |
| Stage A: 0.45 mg/ml XT-150 | Post-Hoc WOMAC Function Score Change From Baseline - All Dose Regimens (mITT) | -12.42 score on a scale | Standard Error 2.767 |
| Stage A: Placebo | Post-Hoc WOMAC Function Score Change From Baseline - All Dose Regimens (mITT) | -13.95 score on a scale | Standard Error 2.695 |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Post-Hoc WOMAC Function Score Change From Baseline - All Dose Regimens (mITT) | -15.28 score on a scale | Standard Error 2.731 |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Post-Hoc WOMAC Function Score Change From Baseline - All Dose Regimens (mITT) | -9.33 score on a scale | Standard Error 2.848 |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Post-Hoc WOMAC Function Score Change From Baseline - All Dose Regimens (mITT) | -7.03 score on a scale | Standard Error 2.904 |
Post Hoc
Post-Hoc WOMAC Pain Score Change From Baseline - 2-dose 0.45mg XT-150 vs. Single-dose 0.45mg XT-150 (mITT)
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be obtained from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The score for pain category ranges from 0 (no pain) to 20 (maximum pain); higher score indicates worse outcomes. Baseline is defined as the Day 0 value. The data reported in this outcome measure is a head-to-head comparison of two doses of 0.45 mg/ml vs. a single dose of 0.45 mg/ml and only includes these 2 treatment sequences whereas outcome measure #12 reports the least squared mean based on data for all 6 treatment sequences.
Time frame: Day 360
Population: The Modified Intent-to-Treat population consists of the ITT population who received at least one treatment injection with a baseline WOMAC Pain score of 9-20 (\>8). This is the target population of interest who may benefit most from the treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Post-Hoc WOMAC Pain Score Change From Baseline - 2-dose 0.45mg XT-150 vs. Single-dose 0.45mg XT-150 (mITT) | -5.02 score on a scale | Standard Error 0.815 |
| Stage A: 0.45 mg/ml XT-150 | Post-Hoc WOMAC Pain Score Change From Baseline - 2-dose 0.45mg XT-150 vs. Single-dose 0.45mg XT-150 (mITT) | -2.19 score on a scale | Standard Error 0.911 |
Comparison: Outcome measure #10 is an analysis of 2 tx groups (two doses of 0.45 mg/ml vs. a single dose of 0.45 mg/ml), whereas outcome measure #12 is all 6 tx groups. A MMRM model was used. LS Means in an MMRM model are influenced by the overall mean structure and covariance estimation. When fewer treatment groups are included, the model adjusts based on a different subset of data, leading to potential shifts in estimated LS Means due to changes in the reference population/covariance structure.p-value: 0.008195% CI: [-4.91, -0.75]Mixed Models Analysis
Post Hoc
Post-Hoc WOMAC Pain Score Change From Baseline - All Dose Regimens (mITT)
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score will be obtained from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire which is a validated, commonly used instrument to assess the participant's opinion about their knee and associated problems. Each item is answered on a 5-point Likert scale. The score for pain category ranges from 0 (no pain) to 20 (maximum pain); higher score indicates worse outcomes. Baseline is defined as the Day 0 value.
Time frame: Day 360
Population: The Modified Intent-to-Treat population consists of the ITT population who received at least one treatment injection with a baseline WOMAC Pain score of 9-20 (\>8). This is the target population of interest who may benefit most from the treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Stage A: 0.15 mg/ml XT-150 | Post-Hoc WOMAC Pain Score Change From Baseline - All Dose Regimens (mITT) | -3.76 score on a scale | Standard Error 0.835 |
| Stage A: 0.45 mg/ml XT-150 | Post-Hoc WOMAC Pain Score Change From Baseline - All Dose Regimens (mITT) | -3.53 score on a scale | Standard Error 0.8 |
| Stage A: Placebo | Post-Hoc WOMAC Pain Score Change From Baseline - All Dose Regimens (mITT) | -4.07 score on a scale | Standard Error 0.797 |
| Stage A: 0.45 mg/mL XT-150, Stage B: 0.45 mg/mL XT-150 | Post-Hoc WOMAC Pain Score Change From Baseline - All Dose Regimens (mITT) | -4.93 score on a scale | Standard Error 0.789 |
| Stage A: Placebo, Stage B: 0.15 mg/mL XT-150 | Post-Hoc WOMAC Pain Score Change From Baseline - All Dose Regimens (mITT) | -3.03 score on a scale | Standard Error 0.805 |
| Stage A: Placebo, Stage B: 0.45 mg/mL XT-150 | Post-Hoc WOMAC Pain Score Change From Baseline - All Dose Regimens (mITT) | -2.42 score on a scale | Standard Error 0.852 |