A Phase 2 interventional study of AZD9567 and Prednisolone in Rheumatoid Arthritis, sponsored by AstraZeneca. Completed at 5 sites in 2 countries. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2020-10-05.
Sponsored by AstraZeneca · Phase 2, Interventional, and Treatment
This is a phase 2a study to be run in 2-3 countries in European Union involving 5-6 sites. It will enroll approximately 80 patients to ensure 40 randomized with active rheumatoid arthritis. The treatment period is 2 weeks and total study duration per patient is approximately 1 month. The study drugs are AZD9567 40 mg (an oral SGRM) and the comparator is prednisolone 20mg. The primary endpoint is DAS28 including evaluation of 28 joints and C-reactive protein. Safety parameters will also be evaluated and a biomarker program is included for future research.
This randomized double blind with double dummy technique phase 2a study will be run in 2-3 EU countries, most likely Sweden, Denmark and The Netherlands involving 5-6 sites. It is estimated that 80-100 patients have to be enrolled to ensure the randomization target of 40. The study population is patients with rheumatoid arthritis on stable treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs) with an active flare. It is a two-arm parallel study and the randomization ratio is 1:1 to the two weeks of once daily treatment of 40 mg of AZD9567 and 20 mg prednisolone.
The primary objective is to assess the efficacy of AZD9567 40 mg, compared to prednisolone 20 mg in patients with active rheumatoid arthritis in spite of stable treatment with conventional and/or s.c/i.v. biological DMARDs and the primary variable is change from baseline in 28 joint Disease Activity Score using CRP (DAS28 - CRP). As secondary variables swollen and tenderness of 66-68 joints and safety variables are also included. For exploratively purposes there is also a biomarker program, collecting blood samples for future research.
Exclusion Criteria:
oral suspension of 40 mg AZD9567 once daily (OD) for two weeks
Drug: AZD9567
oral OD treatment of 20 mg prednisolone administered as capsules
Drug: Prednisolone
oral OD SGRM administered as suspension
oral capsules of 20 mg prednisolone administered OD for two weeks
Least Square (LS) Mean Change From Baseline in 28 Joint Disease Activity Score Using C-Reactive Protein (DAS28-CRP) at Day 15
The DAS28-CRP is a measure of disease activity in RA. The score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment (PGA) of health (ranging from very well to very poor). The DAS28-CRP was derived as follows: 0.56 x √\[tender joint count 28 (TJC28)\] + 0.28 x √\[swollen joint count 28 (SJC28)\] + 0.014 x global health (GH) + 0.36 x Ln(CRP+1) + 0.96 to produce the overall DAS28-CRP score on a scale ranged from 0-10 with higher score indicating worse RA symptoms. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline (Day 1) and Day 15
Percentage of Participants Achieving American College of Rheumatology (ACR) 20, ACR50 and ACR70 Responses
The ACR20, ACR50 or ACR70 was achieved if there was at least a 20%, 50% or 70% improvement from baseline in swollen joint count 66 (SJC66) and tender joint count 68 (TJC68) and 3 or more of the 5 following assessments: participant's assessment of pain, GH, physician's global assessment of disease activity, participant's assessment of physical function and CRP. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Day 15
LS Mean Change From Baseline in SJC66 Score at Day 15
A total of 66 joints (33 left, 33 right) were evaluated for swelling. The swollen joint count represents the number of joints in which there was synovial fluid and or soft tissue swelling, but not if bony overgrowth was found. A swollen joint was scored as 0 (absent) and 1 (present) for each joint. The SJC66 was calculated as sum of swollen joints with present status on electronic case report form (eCRF). The swollen joint count ranged from 0-66 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
LS Mean Change From Baseline in TJC68 Score at Day 15
A total of 68 joints (34 left, 34 right) were evaluated for tenderness. The tender joint count represents the number of joints in which pain was reported. A tender joint was scored as 0 (absent) and 1 (present) for each joint. The TJC68 was calculated as sum of tender joints with present status on eCRF. The tender joint count ranged from 0-68 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
LS Mean Change From Baseline in TJC28 Score at Day 15
TJC28 was evaluated as one of the components that comprised the DAS28-score. A total of 28 joints (14 left, 14 right) were evaluated for tenderness as obtained from the joint count right or left eCRF. The tender joint count represents the number of joints in which pain was reported. A tender joint was scored as 0 (absent) and 1 (present) for each joint. The TJC28 was calculated as sum of tender joints with present status on eCRF. The tender joint count ranged from 0-28 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
LS Mean Change From Baseline in SJC28 Score at Day 15
SJC28 was evaluated as one of the components that comprised the DAS28-score. A total of 28 joints (14 left, 14 right) were evaluated for swelling as obtained from the joint count right or left eCRF. The swollen joint count represents the number of joints in which there was synovial fluid and or soft tissue swelling, but not if bony overgrowth was found. A swollen joint was scored as 0 (absent) and 1 (present) for each joint. The SJC28 was calculated as sum of swollen joints with present status on eCRF. The swollen joint count ranged from 0-28 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
LS Mean Change From Baseline in GH Score at Day 15
GH was evaluated as one of the components that comprised the DAS28-score. Participant's GH was measured using PGA of disease activity by means of the visual analogue scale (VAS). The PGA VAS consists of a 100 millimeter (mm) long scale ranging from 0 (very well) to 100 (very poor). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
LS Mean Change From Baseline in CRP at Day 15
CRP was evaluated as one of the components that comprised the DAS28-score. The CRP was collected at the local laboratory during screening and central laboratory on Days 1, 8, 15 and 28. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
LS Mean Change From Baseline in Participant's Assessment of Pain Score at Day 15
Participant's assessment of pain score was evaluated as one of the components that comprised the ACR. Participant's assessment of pain score was assessed from the amount of pain due to RA on a VAS ranging from 0 (no pain) to 100 (extreme pain). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
LS Mean Change From Baseline in Physician's Global Assessment of Disease Activity Score at Day 15
Physician's global assessment of disease activity score was evaluated as one of the components that comprised the ACR. The physician's global assessment of disease activity was measured on a VAS ranging from 0 (very well) to 100 (very poor). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
LS Mean Change From Baseline in Participant's Assessment of Physical Function Score at Day 15
Participant's assessment of physical function score was evaluated as one of the components that comprised the ACR. The participant's assessment of physical function across 8 functional areas was measured by health assessment questionnaire. The total score ranging from 0 (no difficulty) to 24 (inability to perform tasks). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
Time frame: Baseline and Day 15
Area Under the Plasma Concentration-Time Curve Until the Last Quantifiable Concentration (AUClast) of AZD9567
The AUClast was determined using non-compartmental method and calculated using the linear trapezoidal rule when concentrations were increased and the logarithmic trapezoidal rule when concentrations were decreased.
Time frame: Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hour postdose on Day 15.
Area Under the Concentration-Time Curve From Time Zero to 6 Hours After Dose (AUC0-6) of AZD9567
The AUC0-6 was determined using non-compartmental method and calculated using the linear trapezoidal rule when concentrations were increased and the logarithmic trapezoidal rule when concentrations were decreased.
Time frame: Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hour postdose on Day 15.
Maximum Observed Plasma Concentration (Cmax) of AZD9567
The Cmax of AZD9567 was determined using non-compartmental method.
Time frame: Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hour postdose on Day 15.
Time to Reach Maximum Plasma Concentration (Tmax) of AZD9567
The tmax of AZD9567 was determined using non-compartmental method.
Time frame: Predose and 0.25, 0.5, 1, 1.5, 2, 3, 4 and 6 hour postdose on Day 15.
Last Plasma Concentration Measured Before the Last Dose (Ctrough) of AZD9567
The Ctrough of AZD9567 was determined using non-compartmental method before the last dose on Day 15.
Time frame: Predose on Day 15
This was a Phase 2a study conducted in participants with active rheumatoid arthritis (RA) in spite of stable treatment with conventional disease-modifying anti-rheumatic drugs at 5 investigational sites across Sweden and The Netherlands between 18 January 2018 and 12 November 2019.
| Milestone | AZD9567 | Prednisolone |
|---|---|---|
| Started | 11 | 10 |
| Completed | 11 | 10 |
| Not completed | 0 | 0 |
The DAS28-CRP is a measure of disease activity in RA. The score includes the number of tender and swollen joints (out of 28), CRP level (a measure of inflammation in the blood), and the patient's global assessment (PGA) of health (ranging from very well to very poor). The DAS28-CRP was derived as follows: 0.56 x √\[tender joint count 28 (TJC28)\] + 0.28 x √\[swollen joint count 28 (SJC28)\] + 0.014 x global health (GH) + 0.36 x Ln(CRP+1) + 0.96 to produce the overall DAS28-CRP score on a scale ranged from 0-10 with higher score indicating worse RA symptoms. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| Least Square (LS) Mean Change From Baseline in 28 Joint Disease Activity Score Using C-Reactive Protein (DAS28-CRP) at Day 15 | -1.931 ± 0.3460 | -2.403 ± 0.3373 |
The ACR20, ACR50 or ACR70 was achieved if there was at least a 20%, 50% or 70% improvement from baseline in swollen joint count 66 (SJC66) and tender joint count 68 (TJC68) and 3 or more of the 5 following assessments: participant's assessment of pain, GH, physician's global assessment of disease activity, participant's assessment of physical function and CRP. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| percentage of participants | AZD9567 | Prednisolone |
|---|---|---|
| ACR20 | 63.6 | 70.0 |
| ACR50 | 36.4 | 70.0 |
| ACR70 | 18.2 | 50.0 |
A total of 66 joints (33 left, 33 right) were evaluated for swelling. The swollen joint count represents the number of joints in which there was synovial fluid and or soft tissue swelling, but not if bony overgrowth was found. A swollen joint was scored as 0 (absent) and 1 (present) for each joint. The SJC66 was calculated as sum of swollen joints with present status on electronic case report form (eCRF). The swollen joint count ranged from 0-66 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in SJC66 Score at Day 15 | -6.24 ± 0.894 | -6.66 ± 0.860 |
A total of 68 joints (34 left, 34 right) were evaluated for tenderness. The tender joint count represents the number of joints in which pain was reported. A tender joint was scored as 0 (absent) and 1 (present) for each joint. The TJC68 was calculated as sum of tender joints with present status on eCRF. The tender joint count ranged from 0-68 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in TJC68 Score at Day 15 | -9.02 ± 2.463 | -7.90 ± 2.362 |
TJC28 was evaluated as one of the components that comprised the DAS28-score. A total of 28 joints (14 left, 14 right) were evaluated for tenderness as obtained from the joint count right or left eCRF. The tender joint count represents the number of joints in which pain was reported. A tender joint was scored as 0 (absent) and 1 (present) for each joint. The TJC28 was calculated as sum of tender joints with present status on eCRF. The tender joint count ranged from 0-28 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in TJC28 Score at Day 15 | -6.12 ± 1.251 | -6.07 ± 1.208 |
SJC28 was evaluated as one of the components that comprised the DAS28-score. A total of 28 joints (14 left, 14 right) were evaluated for swelling as obtained from the joint count right or left eCRF. The swollen joint count represents the number of joints in which there was synovial fluid and or soft tissue swelling, but not if bony overgrowth was found. A swollen joint was scored as 0 (absent) and 1 (present) for each joint. The SJC28 was calculated as sum of swollen joints with present status on eCRF. The swollen joint count ranged from 0-28 with higher score indicating disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in SJC28 Score at Day 15 | -5.14 ± 0.653 | -5.40 ± 0.628 |
GH was evaluated as one of the components that comprised the DAS28-score. Participant's GH was measured using PGA of disease activity by means of the visual analogue scale (VAS). The PGA VAS consists of a 100 millimeter (mm) long scale ranging from 0 (very well) to 100 (very poor). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in GH Score at Day 15 | -27.7 ± 7.26 | -37.4 ± 7.11 |
CRP was evaluated as one of the components that comprised the DAS28-score. The CRP was collected at the local laboratory during screening and central laboratory on Days 1, 8, 15 and 28. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| mg per liter (L) | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in CRP at Day 15 | -10.830 ± 2.4207 | -15.586 ± 2.5245 |
Participant's assessment of pain score was evaluated as one of the components that comprised the ACR. Participant's assessment of pain score was assessed from the amount of pain due to RA on a VAS ranging from 0 (no pain) to 100 (extreme pain). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in Participant's Assessment of Pain Score at Day 15 | -27.3 ± 8.17 | -43.4 ± 7.71 |
Physician's global assessment of disease activity score was evaluated as one of the components that comprised the ACR. The physician's global assessment of disease activity was measured on a VAS ranging from 0 (very well) to 100 (very poor). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in Physician's Global Assessment of Disease Activity Score at Day 15 | -37.0 ± 4.38 | -40.9 ± 4.30 |
Participant's assessment of physical function score was evaluated as one of the components that comprised the ACR. The participant's assessment of physical function across 8 functional areas was measured by health assessment questionnaire. The total score ranging from 0 (no difficulty) to 24 (inability to perform tasks). Higher score indicated greater disease severity. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) prior to the first dose of study treatment.
| score on a scale | AZD9567 | Prednisolone |
|---|---|---|
| LS Mean Change From Baseline in Participant's Assessment of Physical Function Score at Day 15 | -0.441 ± 0.1758 | -0.571 ± 0.1712 |
The AUClast was determined using non-compartmental method and calculated using the linear trapezoidal rule when concentrations were increased and the logarithmic trapezoidal rule when concentrations were decreased.
| hour*nanomole per L (h*nmol/L) | AZD9567 |
|---|---|
| Area Under the Plasma Concentration-Time Curve Until the Last Quantifiable Concentration (AUClast) of AZD9567 | 17800 ± 35.02 |
The AUC0-6 was determined using non-compartmental method and calculated using the linear trapezoidal rule when concentrations were increased and the logarithmic trapezoidal rule when concentrations were decreased.
| h*nmol/L | AZD9567 |
|---|---|
| Area Under the Concentration-Time Curve From Time Zero to 6 Hours After Dose (AUC0-6) of AZD9567 | 17740 ± 35.34 |
The Cmax of AZD9567 was determined using non-compartmental method.
| nmol/L | AZD9567 |
|---|---|
| Maximum Observed Plasma Concentration (Cmax) of AZD9567 | 4468 ± 26.89 |
The tmax of AZD9567 was determined using non-compartmental method.
| hour | AZD9567 |
|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) of AZD9567 | 0.67 (0.33 to 1.03) |
The Ctrough of AZD9567 was determined using non-compartmental method before the last dose on Day 15.
| nmol/L | AZD9567 |
|---|---|
| Last Plasma Concentration Measured Before the Last Dose (Ctrough) of AZD9567 | NA ± 95.67 |
Collected over From first administration of study treatment (Day 1) up to 2 weeks after last administration of study treatment, approximately 28 days.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| AZD9567 | 0/11 (0%) | 1/11 (9.1%) | 10/11 (90.9%) |
| Prednisolone | 0/10 (0%) | 0/10 (0%) | 9/10 (90%) |
| Event | AZD9567 | Prednisolone |
|---|---|---|
| Depression suicidalPsychiatric disorders | 1/11 | 0/10 |
| Event | AZD9567 | Prednisolone |
|---|---|---|
| FatigueGeneral disorders | 3/11 | 0/10 |
| Hot flushVascular disorders | 3/11 | 0/10 |
| Eye painEye disorders | 2/11 | 0/10 |
| Abdominal pain upperGastrointestinal disorders | 2/11 | 0/10 |
| Dry mouthGastrointestinal disorders | 2/11 | 0/10 |
| HeadacheNervous system disorders | 2/11 | 1/10 |
| InsomniaPsychiatric disorders | 2/11 | 0/10 |
| CoughRespiratory, thoracic and mediastinal disorders | 2/11 | 1/10 |
| Periorbital swellingEye disorders | 0/11 | 1/10 |
| Oral discomfortGastrointestinal disorders | 0/11 | 1/10 |
The Full analysis set (FAS) included all participants who were randomized and received at least 1 dose of study treatment.
| Age, Continuous(years) | AZD9567 | Prednisolone | Total |
|---|---|---|---|
| Mean | 64.5 ± 8.41 | 55.5 ± 13.58 | 60.2 ± 11.82 |
| Sex: Female, Male(Participants) | AZD9567 | Prednisolone | Total |
|---|---|---|---|
| Female | 8 | 5 | 13 |
| Male | 3 | 5 | 8 |
| Ethnicity (NIH/OMB)(Participants) | AZD9567 | Prednisolone | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 |
| Not Hispanic or Latino | 11 | 10 | 21 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | AZD9567 | Prednisolone | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 11 | 10 | 21 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
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