Osteoarthritis, Knee
Conditions
Keywords
AMZ001
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled, parallel group, 4-week trial of a formulation of AMZ001 once or twice daily versus placebo twice daily, including a single-blind treatment group with a commercial gel four times daily.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled, parallel group, 4-week trial of a formulation of AMZ001 once or twice daily versus placebo twice daily, including a single-blind treatment group with a commercial gel four times daily. Participants will be evaluated for osteoarthritis by X-ray images of the knees and one knee will be selected for treatment as the target knee. The study gel will be applied directly to that knee throughout the 4 weeks of the study.
Interventions
Sponsors
Amzell
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
3 treatment arms will be double-blind, the 4th (comparator) will be single-blind
Intervention model description
placebo-controlled, double-blind, randomized, parallel study
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Osteoarthritis of the knee, according the American College of Rheumatology (ACR) clinical and X-ray criteria. 2. Pain score rated on an 11-point numerical rating scale of the target knee of ≥ 20 and ≤ 45 out of 50 in response to the WOMAC pain sub-score (5 questions), at the time of screening, after washout of any pain relief medication. 3. Women of child-bearing potential must use at least an acceptably effective method of contraception from enrollment up to at least 3 months after the study end. 4. Knee pain in the target knee for 14 days of the preceding month (knee pain due to osteoarthritis and not due to another condition such as bursitis, tendinitis, etc.) based on subject report. 5. On stable pain therapy (i.e., at least 3 days per week for the previous month) with an oral or topical NSAID prescribed by physician for 30 days prior to the Screening Visit and/or prescribed over-the-counter. 6. Except for osteoarthritis, in reasonably good health as determined by the Investigator.
Exclusion criteria
1. Known or suspected hypersensitivity to diclofenac, other non-steroidal anti-inflammatory drugs or related substances including aspirin, any of the components in either of the investigation products, or any physical impediment to gel application on the target knee. 2. Injection of corticosteroids or hyaluronic acid in the target knee within 6 months of screening or into any other joint within 30 days of screening. 3. High dose oral/injected corticosteroid treatment of more than 14 days during the past 6 months prior to screening. 4. Major surgery or arthroscopy of the target knee within the previous year prior to screening. 5. Planned surgery of the target knee within the next 3 months. 6. Presence of an additional non-osteoarthritic disease affecting either knee, such as rheumatoid arthritis, psoriasis, gout or pseudo-gout, if there is reason to believe that the disease(s) may significantly interfere with the interpretation of the clinical response to the study drug. 7. Medical history of coronary artery bypass graft surgery. 8. Current cancer or treatment for cancer within the past five years, with the exception of non-melanoma skin cancer, unless affecting the target knee area. 9. Secondary osteoarthritis of the target knee, previous procedures or trauma affecting joint of the target knee. 10. Reported incidence of any of the following diseases: known osteoarthritis of the hip(s) if pain in hip(s) exceeds that of the target knee using the WOMAC Hip Pain subscore, presence of significant back pain, or at least one migraine attack within the past 12 months before screening, as reported by the subject. 11. Body Mass Index \> 45.0 kg/m2. 12. Generalized skin irritation, previous skin reactions upon use of topical NSAIDs, current skin irritation or redness at the planned site of gel application, or significant skin disease including psoriasis, as judged by the investigator. 13. Known presence of a ulcer or any gastrointestinal bleeding within 6 months prior to screening. 14. Use of moderate or higher doses of opioid medication for the treatment of pain within 6 weeks before the screening visit. 15. Use of duloxetine, pregabalin, or gabapentin within 4 weeks before the screening visit. 16. History of alcohol or drug abuse within the past year prior to randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| WOMAC Pain Sub-score | baseline, week 4 | Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain sub-score (questions 1-5; score 0 \[no pain\]-50 \[extreme pain\]) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where higher scores indicate greater pain, stiffness or difficulty in performing daily tasks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| WOMAC Total Score and WOMAC Function and Stiffness | baseline, week 4 | Change from baseline in Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) total score and WOMAC function (degree of difficulty experienced in performing daily activities - 17 questions score 0-170) and stiffness (the degree and timing of joint stiffness - 2 questions score 0-20). The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks. |
| WOMAC Pain Weight-bearing Score and Non-weight-bearing Score | baseline, week 4 | Change from baseline in Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) pain weight-bearing score (questions 1,2, & 5; score 0-30) and non-weight-bearing score (questions 3&4; score 0-20) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks. |
| ICOAP Scores | baseline, week 4 | Change from baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) scores (score 0 \[no pain\]- 4 \[extreme pain\]). ICOAP scores were normalized to a 0-100 point scale, where 0 is no pain and higher scores indicate greater pain. |
| Physical Function | baseline, week 4 | Change in baseline in physical function assessed by the chair-stand test. The test measures the maximum number of chair stand repetitions possible in a 30-second period with out using the arms. Where 0 is no repetition completed and higher numbers corresponds to greater repetitions and physical function. |
| Proportion of Responders as Per OMERACT-OARSI Criteria | week 4 | Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT-OARSI) response involves changes that are deemed to be clinically relevant in three domains: pain, function, and PGA (Patient Global Assessment). For each of these domains, ranges are defined for absolute and percent changes from baseline that correspond to high improvement and moderate improvement. OMERACT-OARSI response is defined as either high improvement in at least 1 of WOMAC pain and function scores OR moderate improvement in at least 2 of WOMAC pain scores, WOMAC function score or Patient Global Assessment (PGA) |
| Total Dose of Rescue Medication | weeks 1 through 4 | Total dose of rescue medication calculated as the average gram use/day, based on pill counts. |
| Time Between Baseline and First Use of Rescue Medication | weeks 1 through 4 | Time between baseline and first use of rescue medication. |
| WOMAC Pain Sub-score (Dose Comparison) | baseline, week 4 | Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain sub-score (questions 1-5; score 0 \[no pain\]-50 \[extreme pain\]) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks. |
| Work Productivity | baseline, week 4 | Change from baseline in work productivity and activity assessed by the Work Productivity and Active Impairment (WPAI scores 0-100% in four different categories: absenteeism, presenteeism, work productivity loss, and activity impairment). Outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity. |
| Change in Quality of Life: EQ5D VAS Score | baseline, week 4 | The EuroQol-5 Domain (EQ-5D) is a standardized generic measure of health-related quality of life. The visual analog scale (VAS) is scored on a 0-100 scale, where 0 is the worst health you can imagine and 100, the best health you can imagine. |
| ICOAP Scores (Dose Comparison) | baseline, week 4 | Change from baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) scores (score 0 \[no pain\]- 4 \[extreme pain\]). ICOAP scores were normalized to a 0-100 point scale, where 0 is no pain and higher scores indicate greater pain. |
| WOMAC Pain Weight-bearing Score and Non-weight-bearing Score (Dose Comparison) | baseline, week 4 | Changes from baseline in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain weight-bearing score (questions 1,2, & 5; score 0-30) and non-weight-bearing score (questions 3&4; score 0-20) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks. |
| Physical Function (Dose Comparison) | baseline, week 4 | Change in baseline assessed by the chair-stand test. The test measures the maximum number of chair stand repetitions possible in a 30-second period with out using the arms. Where 0 is no repetition completed and higher numbers corresponds to greater repetitions and physical function. |
| WOMAC Total Score and WOMAC Function and Stiffness (Dose Comparison) | baseline, week 4 | Change from baseline in Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) total score and WOMAC function (degree of difficulty experienced in performing daily activities - 17 questions score 0-170) and stiffness (the degree and timing of joint stiffness - 2 questions score 0-20). The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks. |
| Impact of Osteoarthritis on Daily Living (PGA Score) | baseline, week 4 | Change from baseline in Impact of OA daily living assessed using Patient Global Assessment (PGA) score. PGA is scored on a 11-point scale from 0 (none) to 10 (extreme), where higher scores represents a higher level of disease activity or worse health. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety Endpoint (Adverse Events) | weeks 1 through 4 | Nature, incidence and severity of AEs. |
| Skin Tolerability Assessment (Skin Reactions) | week 4 | Skin tolerability assessment, incidence of erythema at the application site. Grading scheme from 0-4 (0, normal skin, no erythema; 4, blister formation and/or necrosis). |
Countries
Czechia, Denmark, United States
Participant flow
Recruitment details
Seven trial sites in Denmark (1 site), Czech Republic (3 sites) and the USA (3 sites). Trial initiation: 04-Oct-2018 Trial completion: 09-Jul-2019
Participants by arm
| Arm | Count |
|---|---|
| AMZ001 BID on the target knee
AMZ001 gel twice daily.
BID: twice a day/twice daily | 121 |
| AMZ001 + Placebo QD on the target knee
AMZ001 gel once daily, Placebo gel once daily.
QD: Every day/daily | 121 |
| Placebo BID on the target knee
Placebo gel twice daily.
BID: 2 times a day/ twice a day | 121 |
| Voltaren 1% QID on the target knee
Voltaren gel 1% applied 4 times a day | 81 |
| Total | 444 |
Baseline characteristics
| Characteristic | Total | AMZ001 BID | AMZ001 + Placebo QD | Placebo BID | Voltaren 1% QID |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 228 Participants | 61 Participants | 66 Participants | 59 Participants | 42 Participants |
| Age, Categorical Between 18 and 65 years | 216 Participants | 60 Participants | 55 Participants | 62 Participants | 39 Participants |
| Baseline WOMAC pain sub-score | 27.5 score on a scale STANDARD_DEVIATION 5.41 | 28.2 score on a scale STANDARD_DEVIATION 6.07 | 27.5 score on a scale STANDARD_DEVIATION 5.24 | 27.1 score on a scale STANDARD_DEVIATION 4.82 | 27.3 score on a scale STANDARD_DEVIATION 5.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 439 Participants | 120 Participants | 121 Participants | 118 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 6 Participants | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 426 Participants | 115 Participants | 119 Participants | 115 Participants | 77 Participants |
| Sex: Female, Male Female | 297 Participants | 83 Participants | 83 Participants | 77 Participants | 54 Participants |
| Sex: Female, Male Male | 147 Participants | 38 Participants | 38 Participants | 44 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 121 | 0 / 121 | 0 / 121 | 0 / 121 |
| other Total, other adverse events | 29 / 121 | 30 / 121 | 52 / 121 | 11 / 81 |
| serious Total, serious adverse events | 0 / 121 | 0 / 121 | 0 / 121 | 0 / 121 |
Outcome results
Primary
WOMAC Pain Sub-score
Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain sub-score (questions 1-5; score 0 \[no pain\]-50 \[extreme pain\]) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where higher scores indicate greater pain, stiffness or difficulty in performing daily tasks.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | WOMAC Pain Sub-score | -26.49 score on a scale |
| AMZ001 + Placebo QD | WOMAC Pain Sub-score | -27.33 score on a scale |
| Placebo BID | WOMAC Pain Sub-score | -22.73 score on a scale |
Secondary
Change in Quality of Life: EQ5D VAS Score
The EuroQol-5 Domain (EQ-5D) is a standardized generic measure of health-related quality of life. The visual analog scale (VAS) is scored on a 0-100 scale, where 0 is the worst health you can imagine and 100, the best health you can imagine.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | Change in Quality of Life: EQ5D VAS Score | 13.04 score on a scale |
| AMZ001 + Placebo QD | Change in Quality of Life: EQ5D VAS Score | 11.76 score on a scale |
| Placebo BID | Change in Quality of Life: EQ5D VAS Score | 8.34 score on a scale |
Secondary
ICOAP Scores
Change from baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) scores (score 0 \[no pain\]- 4 \[extreme pain\]). ICOAP scores were normalized to a 0-100 point scale, where 0 is no pain and higher scores indicate greater pain.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AMZ001 BID | ICOAP Scores | ICOAP constant pain score | -20.82 score on a scale |
| AMZ001 BID | ICOAP Scores | ICOAP total score | -20.62 score on a scale |
| AMZ001 BID | ICOAP Scores | ICOAP intermittent pain score | -20.18 score on a scale |
| AMZ001 + Placebo QD | ICOAP Scores | ICOAP constant pain score | -19.01 score on a scale |
| AMZ001 + Placebo QD | ICOAP Scores | ICOAP total score | -18.87 score on a scale |
| AMZ001 + Placebo QD | ICOAP Scores | ICOAP intermittent pain score | -19.00 score on a scale |
| Placebo BID | ICOAP Scores | ICOAP total score | -17.98 score on a scale |
| Placebo BID | ICOAP Scores | ICOAP intermittent pain score | -17.99 score on a scale |
| Placebo BID | ICOAP Scores | ICOAP constant pain score | -18.37 score on a scale |
Secondary
ICOAP Scores (Dose Comparison)
Change from baseline in Intermittent and Constant Osteoarthritis Pain (ICOAP) scores (score 0 \[no pain\]- 4 \[extreme pain\]). ICOAP scores were normalized to a 0-100 point scale, where 0 is no pain and higher scores indicate greater pain.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | ICOAP Scores (Dose Comparison) | -20.62 score on a scale |
| AMZ001 + Placebo QD | ICOAP Scores (Dose Comparison) | -18.87 score on a scale |
Secondary
Impact of Osteoarthritis on Daily Living (PGA Score)
Change from baseline in Impact of OA daily living assessed using Patient Global Assessment (PGA) score. PGA is scored on a 11-point scale from 0 (none) to 10 (extreme), where higher scores represents a higher level of disease activity or worse health.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | Impact of Osteoarthritis on Daily Living (PGA Score) | -2.29 score on a scale |
| AMZ001 + Placebo QD | Impact of Osteoarthritis on Daily Living (PGA Score) | -2.31 score on a scale |
| Placebo BID | Impact of Osteoarthritis on Daily Living (PGA Score) | -1.68 score on a scale |
Secondary
Physical Function
Change in baseline in physical function assessed by the chair-stand test. The test measures the maximum number of chair stand repetitions possible in a 30-second period with out using the arms. Where 0 is no repetition completed and higher numbers corresponds to greater repetitions and physical function.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | Physical Function | 2.41 repetitions |
| AMZ001 + Placebo QD | Physical Function | 2.30 repetitions |
| Placebo BID | Physical Function | 2.37 repetitions |
Secondary
Physical Function (Dose Comparison)
Change in baseline assessed by the chair-stand test. The test measures the maximum number of chair stand repetitions possible in a 30-second period with out using the arms. Where 0 is no repetition completed and higher numbers corresponds to greater repetitions and physical function.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | Physical Function (Dose Comparison) | 2.41 repetitions |
| AMZ001 + Placebo QD | Physical Function (Dose Comparison) | 2.3 repetitions |
Secondary
Proportion of Responders as Per OMERACT-OARSI Criteria
Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT-OARSI) response involves changes that are deemed to be clinically relevant in three domains: pain, function, and PGA (Patient Global Assessment). For each of these domains, ranges are defined for absolute and percent changes from baseline that correspond to high improvement and moderate improvement. OMERACT-OARSI response is defined as either high improvement in at least 1 of WOMAC pain and function scores OR moderate improvement in at least 2 of WOMAC pain scores, WOMAC function score or Patient Global Assessment (PGA)
Time frame: week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMZ001 BID | Proportion of Responders as Per OMERACT-OARSI Criteria | 0.765 Proportion of responders |
| AMZ001 + Placebo QD | Proportion of Responders as Per OMERACT-OARSI Criteria | 0.826 Proportion of responders |
| Placebo BID | Proportion of Responders as Per OMERACT-OARSI Criteria | 0.725 Proportion of responders |
Secondary
Time Between Baseline and First Use of Rescue Medication
Time between baseline and first use of rescue medication.
Time frame: weeks 1 through 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AMZ001 BID | Time Between Baseline and First Use of Rescue Medication | 17 Days |
| AMZ001 + Placebo QD | Time Between Baseline and First Use of Rescue Medication | 9 Days |
| Placebo BID | Time Between Baseline and First Use of Rescue Medication | 10 Days |
Secondary
Total Dose of Rescue Medication
Total dose of rescue medication calculated as the average gram use/day, based on pill counts.
Time frame: weeks 1 through 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | Total Dose of Rescue Medication | 0.27 gram/day |
| AMZ001 + Placebo QD | Total Dose of Rescue Medication | 0.31 gram/day |
| Placebo BID | Total Dose of Rescue Medication | 0.30 gram/day |
Secondary
WOMAC Pain Sub-score (Dose Comparison)
Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain sub-score (questions 1-5; score 0 \[no pain\]-50 \[extreme pain\]) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | WOMAC Pain Sub-score (Dose Comparison) | -26.49 score on a scale |
| AMZ001 + Placebo QD | WOMAC Pain Sub-score (Dose Comparison) | -27.33 score on a scale |
Secondary
WOMAC Pain Weight-bearing Score and Non-weight-bearing Score
Change from baseline in Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) pain weight-bearing score (questions 1,2, & 5; score 0-30) and non-weight-bearing score (questions 3&4; score 0-20) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AMZ001 BID | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score | Change from baseline WOMAC pain weight bearing | -27.03 score on a scale |
| AMZ001 BID | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score | Change from baseline WOMAC pain non-weight bearing | -25.65 score on a scale |
| AMZ001 + Placebo QD | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score | Change from baseline WOMAC pain weight bearing | -27.68 score on a scale |
| AMZ001 + Placebo QD | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score | Change from baseline WOMAC pain non-weight bearing | -26.89 score on a scale |
| Placebo BID | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score | Change from baseline WOMAC pain weight bearing | -22.65 score on a scale |
| Placebo BID | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score | Change from baseline WOMAC pain non-weight bearing | -22.93 score on a scale |
Secondary
WOMAC Pain Weight-bearing Score and Non-weight-bearing Score (Dose Comparison)
Changes from baseline in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) pain weight-bearing score (questions 1,2, & 5; score 0-30) and non-weight-bearing score (questions 3&4; score 0-20) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AMZ001 BID | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score (Dose Comparison) | Weight-bearing | -27.03 score on a scale |
| AMZ001 BID | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score (Dose Comparison) | Non-weight-bearing | -25.65 score on a scale |
| AMZ001 + Placebo QD | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score (Dose Comparison) | Weight-bearing | -27.68 score on a scale |
| AMZ001 + Placebo QD | WOMAC Pain Weight-bearing Score and Non-weight-bearing Score (Dose Comparison) | Non-weight-bearing | -26.89 score on a scale |
Secondary
WOMAC Total Score and WOMAC Function and Stiffness
Change from baseline in Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) total score and WOMAC function (degree of difficulty experienced in performing daily activities - 17 questions score 0-170) and stiffness (the degree and timing of joint stiffness - 2 questions score 0-20). The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AMZ001 BID | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC function score | -23.43 score on a scale |
| AMZ001 BID | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC total score | -24.15 score on a scale |
| AMZ001 BID | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC stiffness score | -23.17 score on a scale |
| AMZ001 + Placebo QD | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC function score | -22.30 score on a scale |
| AMZ001 + Placebo QD | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC total score | -23.32 score on a scale |
| AMZ001 + Placebo QD | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC stiffness score | -23.35 score on a scale |
| Placebo BID | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC total score | -20.57 score on a scale |
| Placebo BID | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC stiffness score | -20.65 score on a scale |
| Placebo BID | WOMAC Total Score and WOMAC Function and Stiffness | Change from baseline WOMAC function score | -19.94 score on a scale |
Secondary
WOMAC Total Score and WOMAC Function and Stiffness (Dose Comparison)
Change from baseline in Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) total score and WOMAC function (degree of difficulty experienced in performing daily activities - 17 questions score 0-170) and stiffness (the degree and timing of joint stiffness - 2 questions score 0-20). The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AMZ001 BID | WOMAC Total Score and WOMAC Function and Stiffness (Dose Comparison) | Function | -23.43 score on a scale |
| AMZ001 BID | WOMAC Total Score and WOMAC Function and Stiffness (Dose Comparison) | Stiffness | -23.17 score on a scale |
| AMZ001 + Placebo QD | WOMAC Total Score and WOMAC Function and Stiffness (Dose Comparison) | Function | -22.30 score on a scale |
| AMZ001 + Placebo QD | WOMAC Total Score and WOMAC Function and Stiffness (Dose Comparison) | Stiffness | -23.35 score on a scale |
Secondary
Work Productivity
Change from baseline in work productivity and activity assessed by the Work Productivity and Active Impairment (WPAI scores 0-100% in four different categories: absenteeism, presenteeism, work productivity loss, and activity impairment). Outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.
Time frame: baseline, week 4
Population: The mITT (modified Intent to treat; N=120) population set includes subjects with a baseline and at least one post-treatment WOMAC pain sub-score and was used in statistical analysis for primary and secondary endpoint outcome measures.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AMZ001 BID | Work Productivity | WPAI % Time missed | 0.39 percentage of impairment |
| AMZ001 BID | Work Productivity | WPAI % Impairment while working | -13.11 percentage of impairment |
| AMZ001 BID | Work Productivity | WPAI % Overall work impairment | -11.69 percentage of impairment |
| AMZ001 BID | Work Productivity | WPAI % Activity impairment | -17.75 percentage of impairment |
| AMZ001 + Placebo QD | Work Productivity | WPAI % Activity impairment | -20.41 percentage of impairment |
| AMZ001 + Placebo QD | Work Productivity | WPAI % Time missed | -3.10 percentage of impairment |
| AMZ001 + Placebo QD | Work Productivity | WPAI % Overall work impairment | -16.93 percentage of impairment |
| AMZ001 + Placebo QD | Work Productivity | WPAI % Impairment while working | -14.38 percentage of impairment |
| Placebo BID | Work Productivity | WPAI % Activity impairment | -13.03 percentage of impairment |
| Placebo BID | Work Productivity | WPAI % Impairment while working | -5.28 percentage of impairment |
| Placebo BID | Work Productivity | WPAI % Overall work impairment | -6.50 percentage of impairment |
| Placebo BID | Work Productivity | WPAI % Time missed | 1.58 percentage of impairment |
Other Pre-specified
Safety Endpoint (Adverse Events)
Nature, incidence and severity of AEs.
Time frame: weeks 1 through 4
Population: The SAF (Safety Analysis Set; N=121) was used for safety evaluation of adverse events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMZ001 BID | Safety Endpoint (Adverse Events) | Severity Mild | 39 Participants |
| AMZ001 BID | Safety Endpoint (Adverse Events) | Severity Severe | 0 Participants |
| AMZ001 BID | Safety Endpoint (Adverse Events) | SAEs | 0 Participants |
| AMZ001 BID | Safety Endpoint (Adverse Events) | ADR | 29 Participants |
| AMZ001 BID | Safety Endpoint (Adverse Events) | All TEAEs | 51 Participants |
| AMZ001 BID | Safety Endpoint (Adverse Events) | Deaths | 0 Participants |
| AMZ001 BID | Safety Endpoint (Adverse Events) | AEs leading to treatment discontinuation | 3 Participants |
| AMZ001 BID | Safety Endpoint (Adverse Events) | Severity Moderate | 17 Participants |
| AMZ001 + Placebo QD | Safety Endpoint (Adverse Events) | AEs leading to treatment discontinuation | 8 Participants |
| AMZ001 + Placebo QD | Safety Endpoint (Adverse Events) | Severity Mild | 45 Participants |
| AMZ001 + Placebo QD | Safety Endpoint (Adverse Events) | Severity Severe | 0 Participants |
| AMZ001 + Placebo QD | Safety Endpoint (Adverse Events) | Deaths | 0 Participants |
| AMZ001 + Placebo QD | Safety Endpoint (Adverse Events) | All TEAEs | 53 Participants |
| AMZ001 + Placebo QD | Safety Endpoint (Adverse Events) | SAEs | 0 Participants |
| AMZ001 + Placebo QD | Safety Endpoint (Adverse Events) | Severity Moderate | 11 Participants |
| AMZ001 + Placebo QD | Safety Endpoint (Adverse Events) | ADR | 29 Participants |
| Placebo BID | Safety Endpoint (Adverse Events) | AEs leading to treatment discontinuation | 7 Participants |
| Placebo BID | Safety Endpoint (Adverse Events) | ADR | 51 Participants |
| Placebo BID | Safety Endpoint (Adverse Events) | All TEAEs | 75 Participants |
| Placebo BID | Safety Endpoint (Adverse Events) | Deaths | 0 Participants |
| Placebo BID | Safety Endpoint (Adverse Events) | SAEs | 0 Participants |
| Placebo BID | Safety Endpoint (Adverse Events) | Severity Mild | 66 Participants |
| Placebo BID | Safety Endpoint (Adverse Events) | Severity Moderate | 14 Participants |
| Placebo BID | Safety Endpoint (Adverse Events) | Severity Severe | 1 Participants |
| Voltaren 1% QID | Safety Endpoint (Adverse Events) | AEs leading to treatment discontinuation | 5 Participants |
| Voltaren 1% QID | Safety Endpoint (Adverse Events) | SAEs | 0 Participants |
| Voltaren 1% QID | Safety Endpoint (Adverse Events) | Severity Severe | 1 Participants |
| Voltaren 1% QID | Safety Endpoint (Adverse Events) | Severity Moderate | 9 Participants |
| Voltaren 1% QID | Safety Endpoint (Adverse Events) | Deaths | 0 Participants |
| Voltaren 1% QID | Safety Endpoint (Adverse Events) | ADR | 9 Participants |
| Voltaren 1% QID | Safety Endpoint (Adverse Events) | All TEAEs | 26 Participants |
| Voltaren 1% QID | Safety Endpoint (Adverse Events) | Severity Mild | 20 Participants |
Other Pre-specified
Skin Tolerability Assessment (Skin Reactions)
Skin tolerability assessment, incidence of erythema at the application site. Grading scheme from 0-4 (0, normal skin, no erythema; 4, blister formation and/or necrosis).
Time frame: week 4
Population: Nature, incidence and severity of AEs. The SAF (Safety Analysis Set; N=121) was used for safety evaluation of adverse events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMZ001 BID | Skin Tolerability Assessment (Skin Reactions) | Questionable erythema not covering entire app site | 14 Participants |
| AMZ001 BID | Skin Tolerability Assessment (Skin Reactions) | Normal skin; no erythema | 100 Participants |
| AMZ001 BID | Skin Tolerability Assessment (Skin Reactions) | Definite erythema not covering entire app site | 2 Participants |
| AMZ001 BID | Skin Tolerability Assessment (Skin Reactions) | Blister formation and/or necrosis | 0 Participants |
| AMZ001 BID | Skin Tolerability Assessment (Skin Reactions) | Definite erythema and swelling or induration | 0 Participants |
| AMZ001 + Placebo QD | Skin Tolerability Assessment (Skin Reactions) | Definite erythema and swelling or induration | 0 Participants |
| AMZ001 + Placebo QD | Skin Tolerability Assessment (Skin Reactions) | Normal skin; no erythema | 89 Participants |
| AMZ001 + Placebo QD | Skin Tolerability Assessment (Skin Reactions) | Questionable erythema not covering entire app site | 18 Participants |
| AMZ001 + Placebo QD | Skin Tolerability Assessment (Skin Reactions) | Definite erythema not covering entire app site | 2 Participants |
| AMZ001 + Placebo QD | Skin Tolerability Assessment (Skin Reactions) | Blister formation and/or necrosis | 0 Participants |
| Placebo BID | Skin Tolerability Assessment (Skin Reactions) | Blister formation and/or necrosis | 0 Participants |
| Placebo BID | Skin Tolerability Assessment (Skin Reactions) | Definite erythema not covering entire app site | 10 Participants |
| Placebo BID | Skin Tolerability Assessment (Skin Reactions) | Definite erythema and swelling or induration | 0 Participants |
| Placebo BID | Skin Tolerability Assessment (Skin Reactions) | Normal skin; no erythema | 79 Participants |
| Placebo BID | Skin Tolerability Assessment (Skin Reactions) | Questionable erythema not covering entire app site | 20 Participants |
| Voltaren 1% QID | Skin Tolerability Assessment (Skin Reactions) | Definite erythema and swelling or induration | 0 Participants |
| Voltaren 1% QID | Skin Tolerability Assessment (Skin Reactions) | Questionable erythema not covering entire app site | 3 Participants |
| Voltaren 1% QID | Skin Tolerability Assessment (Skin Reactions) | Definite erythema not covering entire app site | 0 Participants |
| Voltaren 1% QID | Skin Tolerability Assessment (Skin Reactions) | Normal skin; no erythema | 68 Participants |
| Voltaren 1% QID | Skin Tolerability Assessment (Skin Reactions) | Blister formation and/or necrosis | 1 Participants |
Post Hoc
WOMAC Pain Sub-score (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline)
Change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain sub-score (questions 1-5; score 0 \[no pain\]-50 \[extreme pain\]) on target knee. The WOMAC scores were normalized to a 0-100 point scale for data analysis. The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks.
Time frame: baseline, week 4
Population: Post-hoc statistical analyses were performed for the comparison of each of the AMZ001 regimens vs placebo and between the two AMZ001 regimens. Sub-group of subjects meeting the WOMAC pain sub-score inclusion criterion at both screening and baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AMZ001 BID | WOMAC Pain Sub-score (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | -28.54 score on a scale |
| AMZ001 + Placebo QD | WOMAC Pain Sub-score (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | -29.02 score on a scale |
| Placebo BID | WOMAC Pain Sub-score (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | -23.18 score on a scale |
Post Hoc
WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline)
Change from baseline in Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) total score and WOMAC function (degree of difficulty experienced in performing daily activities - 17 questions score 0-170) and stiffness (the degree and timing of joint stiffness - 2 questions score 0-20) . The WOMAC scores were normalized to a 0-100 point scale for data analysis, where 0 is no pain and higher scores indicate greater pain, stiffness or difficulty in performing daily tasks.
Time frame: baseline, week 4
Population: Post-hoc statistical analyses were performed for the comparison of each of the AMZ001 regimens vs placebo and between the two AMZ001 regimens. Sub-group of subjects meeting the WOMAC pain sub-score inclusion criterion at both screening and baseline.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| AMZ001 BID | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC function score | -24.69 score on a scale |
| AMZ001 BID | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC total score | -25.54 score on a scale |
| AMZ001 BID | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC stiffness score | -24.08 score on a scale |
| AMZ001 + Placebo QD | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC function score | -22.84 score on a scale |
| AMZ001 + Placebo QD | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC total score | -24.03 score on a scale |
| AMZ001 + Placebo QD | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC stiffness score | -23.57 score on a scale |
| Placebo BID | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC total score | -20.61 score on a scale |
| Placebo BID | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC stiffness score | -20.33 score on a scale |
| Placebo BID | WOMAC Total Score and WOMAC Function and Stiffness (Subgroup With WOMAC Normalized Pain Sub-score ≥40 at Baseline) | Change from baseline WOMAC function score | -19.84 score on a scale |