Rheumatoid Arthritis
Conditions
Brief summary
This is a multicenter, two-part, randomized, double-blind, placebo-kontrolled, 4-week study with repeated doses of AP1189. The study population will consist of newly diagnosed subjects with severe active Rheumatoid Arthritis, defined with a Clinical Disease Activity score (CDAI) \> 22, who are to start up-titration with methotrexate.
Detailed description
A multicenter, two-part, randomized, double-blind, placebo-kontrolled, 4-week study with repeated doses of AP1189. The study population will consist of newly diagnosed subjects with severe active Rheumatoid Arthritis, defined with a Clinical Disease Activity score (CDAI) \> 22, who are to start up-titration with methotrexate. The study will be conducted in two parts separated by an interim analysis. Part 1: The subjects will be randomized in a 1:1:1 ratio into: . * AP1189 dose 50 mg * AP1189 dose 100 mg * placebo INTERIM ANALYSIS Part 2: All subjects will be randomized into either design 1, 2 or 3 based on data from the interim analysis. * Design 1: AP1189 dose 50 mg or placebo in a 2:1 ratio * Design 2: AP1189 dose 100 mg or placebo in a 2:1 ratio * Design 3: Continue with the same doses as in Part 1 The purpose of this study is to determine the safety and efficacy of 2 doses of AP1189 compared with placebo after 4 weeks of treatment.
Interventions
DRUG50 mg AP1189
50 mg AP1189 powder in bottle
DRUGAP1189
100 mg AP1189 powder in bottle
DRUGPlacebo
Placebo powder in bottle
Sponsors
SynAct Pharma Aps
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Multicenter, two-part, randomized, double-blind, placebo-controlled 4-week study with repeated doses of AP1189
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent has been obtained prior to initiating any study specific procedures * Male and female subjects, 18 to 85 years of age * Confirmed diagnosis of RA (Rheumatoid Arthritis) according to the 2010 American College of Rheumatology (ACR)/EULAR RA classification criteria * Polyarthritis with joint swelling and tenderness of a minimum of three joints out of 68 joints tested * Candidate for Methotrexate treatment * Is about to begin treatment with MTX (Methotrexate) * Tested positive for anti-CCP (Anti-cyclic citrullinated peptide) or RF (Rheumatoid Factor) * Severe active RA (Clinical Disease Activity Index (CDAI)) \> 22) at screening and baseline * Negative QFG-IT (QuantiFERON-in-Tube test) * Subjects should be able to complete the PRO (Patient Reported Outcome) questionnaires * Females of child-bearing potential may only participate if using reliable means of contraception or are post-menopausal. Surgically sterilized women at least 6 months prior to screening * Females of childbearing potential must have a negative pregnancy test at screening and baseline
Exclusion criteria
* Participation in any other study involving investigational drug(s) within 4 weeks prior to study entry * Major surgery within 8 weeks prior to screening or planned surgery within 1 month following randomization * Rheumatic autoimmune disease other than RA, including SLE (systemic Lupus Erythematosus), MCTD (Mixed Connective Tissue Disease), scleroderma, polymyositis, or significant systemic involvement secondary to RA. Sjögren syndrome with RA is allowable * Functional class IV as defined by the ACR Criteria for Classification of Functional Status in RA or wheelchair/bedbound * Prior history of or current inflammatory joint disease other than RA * Subjects with fibromyalgia * Initiation or change in dose for NSAIDs within 2 weeks prior to dosing with the IMP (Investigational Medicinal Product) * Corticosteroids are prohibited within 2 weeks prior to screening (and during the entire treatment period and until the final visit * Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disease * Have prior renal transplant, current renal dialysis or severe renal insufficiency (determined by a derived glomerular filtration rate (GFR) using Cockcroft Gault Formula of ≤30 mL/min/1,73 m2 calculated by the local lab) * Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids * Evidence of active malignant disease * Pregnant women or nursing mothers * History of alcohol, drug, or chemical abuse within the 6 months prior to screening * Neuropathies or other painful conditions that might interfere with pain evaluation * Body weight of \>150 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Disease Activity Index (CDAI) | 4 weeks | The change in CDAI from severe (CDAI \> 22) to moderate (CDAI \<= 22) after 4 weeks treatment compared to baseline. CDAI is calculated as a sum of: * SJC (28): Number of Swollen 28-Joint Count (shoulders, elbows, wrists, MCPs, PIPs including thumb IP, knees); * TJC (28): Number of Tender 28-Joint Count (shoulders, elbows, wrists, MCPs, PIPs including thumb IP, knees) * PGA: Patient Global Disease Activity (patient's self-assessment of overall RA disease activity on a scale 0-100, where 100 is maximal activity) * IGA: Physician's Global Disease Activity (evaluator's assessment of the subject's overall RA disease activity on a scale 0-100, where 100 is maximal activity) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ACR (American College of Rheumatology) Response | 4 weeks | Proportion of subjects achieving a response assessed by ACR20. The ACR response rate ACR20 is defined as ≥20% improvement in swollen and tender joint counts (SJC/TJC) and 3 of the following 5 assessments: Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, Patient's Assessment of Pain, Health Assessment Questionnaire - Disability Index or C-Reactive Protein. Proportion in the context of this protocol refers to number of participants. |
Countries
Denmark, Norway
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 50 mg AP1189 50 mg AP1189. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension, i e. the powder will be added 50 ml water.
50 mg AP1189: 50 mg AP1189 powder in bottle | 35 |
| 100 mg AP1189 100 mg AP1189. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension, i e. the powder will be added 50 ml water.
AP1189: 100 mg AP1189 powder in bottle | 36 |
| Placebo Placebo. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension i e. the powder will be added 50 ml water.
Placebo: Placebo powder in bottle | 34 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | 50 mg AP1189 | 100 mg AP1189 | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 10 Participants | 9 Participants | 29 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 26 Participants | 25 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 36 Participants | 32 Participants | 103 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Bulgaria | 9 participants | 12 participants | 10 participants | 31 participants |
| Region of Enrollment Denmark | 13 participants | 15 participants | 15 participants | 43 participants |
| Region of Enrollment Moldova | 8 participants | 6 participants | 7 participants | 21 participants |
| Region of Enrollment Norway | 2 participants | 0 participants | 1 participants | 3 participants |
| Region of Enrollment Sweden | 3 participants | 3 participants | 1 participants | 7 participants |
| Sex: Female, Male Female | 27 Participants | 28 Participants | 27 Participants | 82 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 7 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 36 | 0 / 34 |
| other Total, other adverse events | 14 / 35 | 16 / 36 | 12 / 34 |
| serious Total, serious adverse events | 0 / 35 | 0 / 36 | 0 / 34 |
Outcome results
Primary
Change in Clinical Disease Activity Index (CDAI)
The change in CDAI from severe (CDAI \> 22) to moderate (CDAI \<= 22) after 4 weeks treatment compared to baseline. CDAI is calculated as a sum of: * SJC (28): Number of Swollen 28-Joint Count (shoulders, elbows, wrists, MCPs, PIPs including thumb IP, knees); * TJC (28): Number of Tender 28-Joint Count (shoulders, elbows, wrists, MCPs, PIPs including thumb IP, knees) * PGA: Patient Global Disease Activity (patient's self-assessment of overall RA disease activity on a scale 0-100, where 100 is maximal activity) * IGA: Physician's Global Disease Activity (evaluator's assessment of the subject's overall RA disease activity on a scale 0-100, where 100 is maximal activity)
Time frame: 4 weeks
Population: The number of participants analyzed differs from the overall number of participants. Participants that received rescue medication during the treatment period was excluded from the analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg AP1189 | Change in Clinical Disease Activity Index (CDAI) | 18 Participants |
| 100 mg AP1189 | Change in Clinical Disease Activity Index (CDAI) | 17 Participants |
| Placebo | Change in Clinical Disease Activity Index (CDAI) | 12 Participants |
Primary
Change in Clinical Disease Activity Index (CDAI)
The change in CDAI after 4 weeks treatment compared to baseline. CDAI is calculated as a sum of: * SJC (28): Number of Swollen 28-Joint Count (shoulders, elbows, wrists, MCPs, PIPs including thumb IP, knees); * TJC (28): Number of Tender 28-Joint Count (shoulders, elbows, wrists, MCPs, PIPs including thumb IP, knees) * PGA: Patient Global Disease Activity (patient's self-assessment of overall RA disease activity on a scale 0-100, where 100 is maximal activity) * IGA: Physician's Global Disease Activity (evaluator's assessment of the subject's overall RA disease activity on a scale 0-100, where 100 is maximal activity). The CDAI score range is from 0 - 76, whereas a score of: ≤2.8 means Remission \>2.8 and ≤10 means Low Disease Activity \>10 and ≤22 means Moderate Disease Activity \>22 means High Disease Activity For the purpose of this study, a decrease in CDAI (improvement) is reported as - xx.xx).
Time frame: 4 weeks
Population: The number of participants analyzed differs from the overall number of participants. Participants that received rescue medication during the treatment period was excluded from the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 50 mg AP1189 | Change in Clinical Disease Activity Index (CDAI) | -11.97 Calculated score | Standard Deviation 8.74 |
| 100 mg AP1189 | Change in Clinical Disease Activity Index (CDAI) | -15.52 Calculated score | Standard Deviation 12.7 |
| Placebo | Change in Clinical Disease Activity Index (CDAI) | -9.33 Calculated score | Standard Deviation 10.58 |
Secondary
ACR (American College of Rheumatology) Response
Proportion of subjects achieving a response assessed by ACR20. The ACR response rate ACR20 is defined as ≥20% improvement in swollen and tender joint counts (SJC/TJC) and 3 of the following 5 assessments: Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, Patient's Assessment of Pain, Health Assessment Questionnaire - Disability Index or C-Reactive Protein. Proportion in the context of this protocol refers to number of participants.
Time frame: 4 weeks
Population: The number of participants analyzed differs from the overall number of participants. Participants that received rescue medication during the treatment period was excluded from the analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg AP1189 | ACR (American College of Rheumatology) Response | 11 Participants |
| 100 mg AP1189 | ACR (American College of Rheumatology) Response | 20 Participants |
| Placebo | ACR (American College of Rheumatology) Response | 10 Participants |
Secondary
ACR (American College of Rheumatology) Response
Proportion of subjects achieving a response assessed by ACR50. The ACR response rate ACR50 is defined as ≥50% improvement in swollen and tender joint counts (SJC/TJC) and 3 of the following 5 assessments: Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, Patient's Assessment of Pain, Health Assessment Questionnaire - Disability Index or C-Reactive Protein. Proportion in the context of this protocol refers to number of participants.
Time frame: 4 weeks
Population: The number of participants analyzed differs from the overall number of participants. Participants that received rescue medication during the treatment period was excluded from the analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg AP1189 | ACR (American College of Rheumatology) Response | 2 Participants |
| 100 mg AP1189 | ACR (American College of Rheumatology) Response | 8 Participants |
| Placebo | ACR (American College of Rheumatology) Response | 4 Participants |
Secondary
ACR (American College of Rheumatology) Response
Proportion of subjects achieving a response assessed by ACR70. The ACR response rate ACR70 is defined as ≥70% improvement in swollen and tender joint counts (SJC/TJC) and 3 of the following 5 assessments: Patient's Global Assessment of Disease Activity, Physician's Global Assessment of Disease Activity, Patient's Assessment of Pain, Health Assessment Questionnaire - Disability Index or C-Reactive Protein. Proportion in the context of this protocol refers to number of participants.
Time frame: 4 weeks
Population: The number of participants analyzed differs from the overall number of participants. Participants that received rescue medication during the treatment period was excluded from the analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg AP1189 | ACR (American College of Rheumatology) Response | 0 Participants |
| 100 mg AP1189 | ACR (American College of Rheumatology) Response | 4 Participants |
| Placebo | ACR (American College of Rheumatology) Response | 1 Participants |