Ulcerative Colitis
Conditions
Keywords
tralokinumab, inflammatory bowel disease, moderate to severe ulcerative colitis
Brief summary
The study is designed to evaluate the clinical efficacy and safety of tralokinumab as compared to placebo. Investigational product will be administered as subcutaneous injection. All patients will continue background therapy for ulcerative colitis as per local standards of care in addition to investigational product.
Detailed description
A phase IIa, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study to evaluate the efficacy and safety of tralokinumab (CAT-354), a recombinant human monoclonal antibody directed against interleukin-13 (IL-13), as add-on therapy, on clinical response in patients with active, moderate-to-severe, ulcerative colitis
Interventions
DRUGtralokinumab
2 sc injections of every 2 weeks for 12 weeks.
DRUGplacebo
2 sc injections of every 2 weeks for 12 weeks.
Sponsors
MedImmune Ltd
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed ulcerative colitis at least 90 days prior randomisation. * Men or women age 18 - 75 years. * Non-hospitalized patients with moderate-severe ulcerative colitis treated with stable background UC therapy (e.g. containing 5-aminosalicylates, and/or low dose of glucocorticosteroids, and/or purine analogue) prior to randomization. * Females of childbearing potential who are sexually active with a nonsterilized male partner must use highly effective contraception from Day1. * Nonsterilized males or sterilized males who are ≤1 year post-vasectomy who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception.
Exclusion criteria
* Pregnant or breastfeeding women. * History of colostomy. * Current diagnosis of indeterminate colitis, Crohn's disease, ischemic colitis, fulminant colitis and/or toxic megacolon and patients with ulcerative colitis limited to the rectum (ulcerative proctitis). * Hepatitis B, C or HIV. * History of cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response at Week 8 Based on Mayo Score | Eight week treatment period | Clinical response was measured as a decrease in Mayo score of ≥3 points from baseline, decrease in the total Mayo score from baseline ≥30 percentage and a decrease in the sub score for rectal bleeding ≥1 or absolute sub score for rectal bleeding of 0 or 1 point. Mayo score is sum of four sub-scores: stool frequency, rectal bleeding, endoscopy findings and the physician's global assessment. The total Mayo score ranges from 0-12, with higher scores indicating a more severe disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mucosal Healing at Week 8 Based on Mayo Score | Eight week treatment period | Improvement of the endoscopy sub score (from the Mayo score) from 3 or 2 to 0 or 1 point, or from 1 to 0 points. |
| Clinical Remission at Week 8 Based on Mayo Score | Eight week treatment period | Participants were classified as in remission if Mayo score of ≤2 with no individual sub score exceeding 1 point. Mayo score is sum of four sub-scores: stool frequency, rectal bleeding, endoscopy findings and the physician's global assessment. The total Mayo score ranges from 0-12, with higher scores indicating a more severe disease. |
| Change From Baseline in Partial Mayo Score | From baseline to Week 4, 8, 12, 16, 20, and 24. | The partial Mayo score is the sum of the three sub-score areas: stool frequency, rectal bleeding, and the physician's global assessment.The partial Mayo score ranges from 0-9, with higher scores indicating a more severe disease. Change from baseline: Mayo score at each post-baseline timepoint (week 4, 8, 12, 16, 20, and 24) minus the Mayo score at baseline. |
| Change From Baseline in Modified Riley Score | Eight week treatment period | Modified Riley score is biopsy grade which range from 0-5; where 0: Normal mucosa, 1: Infiltration of lymphocytes and plasma cells in the lamina propria, 2: Infiltration of neutrophils and eosinophils in the lamina propria, 3: Infiltration of neutrophils in the epithelium, 4: Crypt destruction, 5: Erosion and/or ulceration. |
| Change in Mayo Score From Baseline to Week 8 | Eight week treatment period | Mayo score is sum of four sub-scores: stool frequency, rectal bleeding, endoscopy findings and the physician's global assessment. The total Mayo score ranges from 0-12, with higher scores indicating a more severe disease. Change from baseline: Mayo score at week 8 minus the Mayo score at baseline. |
| Change From Baseline in Albumin | From baseline to Week 4, 8, 12, 16, 20, and 24. | — |
| Change From Baseline in Calprotectin | From baseline to Week 4, 8, 12, 16, 20, and 24. | — |
| Serum Concentration of Tralokinumab | Pre-dose sampling at baseline, Week 4, 8, 12, 16, 20, and 24. | — |
| Immunogenicity | Pre-dose sampling at baseline, Week 8, 12, 16, and 24. | Incidence of anti-drug antibodies (ADA) to tralokinumab in serum. |
| Change From Baseline in C - Reactive Protein | From baseline to Week 4, 8, 12, 16, 20, and 24. | — |
Countries
Czechia, France, Germany, Italy, Poland, United Kingdom
Participant flow
Recruitment details
147/111 patients were enrolled/randomized from 31 centres in 6 European countries. The first patient was enrolled on 26 March 2012, and the last patient completed the study on 24 June 2013.
Pre-assignment details
Participants were enrolled for a period of 3 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Tralokinumab Tralokinumab 300 mg was administered during study as two subcutaneous 150 mg injections every 2 weeks for 12 weeks starting from Visit 2. | 56 |
| Placebo Placebo was administered during study as two subcutaneous injections every 2 weeks for 12 weeks starting from Visit 2. | 55 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Medical decision due to lack of efficacy | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 13 |
Baseline characteristics
| Characteristic | Tralokinumab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 42.2 Years STANDARD_DEVIATION 11.54 | 40.8 Years STANDARD_DEVIATION 13.26 | 41.5 Years STANDARD_DEVIATION 12.39 |
| Duration of disease | 9.22 Years STANDARD_DEVIATION 8.523 | 7.78 Years STANDARD_DEVIATION 8.664 | 8.51 Years STANDARD_DEVIATION 8.585 |
| Glucocorticosteroid-refractory status No | 53 Participants | 46 Participants | 99 Participants |
| Glucocorticosteroid-refractory status Unknown | 0 Participants | 1 Participants | 1 Participants |
| Glucocorticosteroid-refractory status Yes | 3 Participants | 8 Participants | 11 Participants |
| Mayo score at baseline | 8.36 Scores on scale | 8.33 Scores on scale | 8.34 Scores on scale |
| Partial Mayo score at baseline | 5.91 Scores on scale | 5.85 Scores on scale | 5.88 Scores on scale |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian (Other than Chinese And Japanese) | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Applicable | 35 Participants | 40 Participants | 75 Participants |
| Race/Ethnicity, Customized Other | 17 Participants | 13 Participants | 30 Participants |
| Race/Ethnicity, Customized White | 54 Participants | 54 Participants | 108 Participants |
| Sex: Female, Male Female | 29 Participants | 29 Participants | 58 Participants |
| Sex: Female, Male Male | 27 Participants | 26 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 35 / 55 | 36 / 55 |
| serious Total, serious adverse events | 6 / 55 | 7 / 55 |
Outcome results
Primary
Clinical Response at Week 8 Based on Mayo Score
Clinical response was measured as a decrease in Mayo score of ≥3 points from baseline, decrease in the total Mayo score from baseline ≥30 percentage and a decrease in the sub score for rectal bleeding ≥1 or absolute sub score for rectal bleeding of 0 or 1 point. Mayo score is sum of four sub-scores: stool frequency, rectal bleeding, endoscopy findings and the physician's global assessment. The total Mayo score ranges from 0-12, with higher scores indicating a more severe disease.
Time frame: Eight week treatment period
Population: The full analysis set consist of all randomised participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tralokinumab | Clinical Response at Week 8 Based on Mayo Score | 37.5 Percentage of responders |
| Placebo | Clinical Response at Week 8 Based on Mayo Score | 32.7 Percentage of responders |
Comparison: The null hypothesis is that the proportion of participants responding on tralokinumab is less than or equal to the proportion of participants responding on placebo.p-value: 0.406295% CI: [-13, 22.5]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Albumin
Time frame: From baseline to Week 4, 8, 12, 16, 20, and 24.
Population: The full analysis set consist of all randomised participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tralokinumab | Change From Baseline in Albumin | Week 4 | 0.0 g/L | Full Range 0.31 |
| Tralokinumab | Change From Baseline in Albumin | Week 8 | 0.8 g/L | Full Range 0.29 |
| Tralokinumab | Change From Baseline in Albumin | Week 12 | 0.3 g/L | Full Range 0.34 |
| Tralokinumab | Change From Baseline in Albumin | Week 16 | 0.5 g/L | Full Range 0.34 |
| Tralokinumab | Change From Baseline in Albumin | Week 20 | 1.1 g/L | Full Range 0.33 |
| Tralokinumab | Change From Baseline in Albumin | Week 24 | 1.2 g/L | Full Range 0.35 |
| Placebo | Change From Baseline in Albumin | Week 20 | 0.1 g/L | Full Range 0.37 |
| Placebo | Change From Baseline in Albumin | Week 4 | -0.7 g/L | Full Range 0.31 |
| Placebo | Change From Baseline in Albumin | Week 16 | 0.4 g/L | Full Range 0.37 |
| Placebo | Change From Baseline in Albumin | Week 8 | -0.2 g/L | Full Range 0.3 |
| Placebo | Change From Baseline in Albumin | Week 24 | 0.2 g/L | Full Range 0.38 |
| Placebo | Change From Baseline in Albumin | Week 12 | -0.4 g/L | Full Range 0.36 |
Secondary
Change From Baseline in Calprotectin
Time frame: From baseline to Week 4, 8, 12, 16, 20, and 24.
Population: The full analysis set consist of all randomised participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tralokinumab | Change From Baseline in Calprotectin | Week 16 | -75.10 ug/g | Full Range 0.34 |
| Tralokinumab | Change From Baseline in Calprotectin | Week 20 | 32.55 ug/g | Full Range 0.33 |
| Tralokinumab | Change From Baseline in Calprotectin | Week 24 | -136.78 ug/g | Full Range 0.35 |
| Tralokinumab | Change From Baseline in Calprotectin | Week 4 | 69.45 ug/g | Full Range 0.31 |
| Tralokinumab | Change From Baseline in Calprotectin | Week 8 | 86.47 ug/g | Full Range 0.29 |
| Tralokinumab | Change From Baseline in Calprotectin | Week 12 | -39.19 ug/g | Full Range 0.34 |
| Placebo | Change From Baseline in Calprotectin | Week 8 | -250.52 ug/g | Full Range 0.3 |
| Placebo | Change From Baseline in Calprotectin | Week 16 | -338.76 ug/g | Full Range 0.37 |
| Placebo | Change From Baseline in Calprotectin | Week 4 | 198.80 ug/g | Full Range 0.31 |
| Placebo | Change From Baseline in Calprotectin | Week 20 | -402.81 ug/g | Full Range 0.37 |
| Placebo | Change From Baseline in Calprotectin | Week 12 | 50.31 ug/g | Full Range 0.36 |
| Placebo | Change From Baseline in Calprotectin | Week 24 | -267.58 ug/g | Full Range 0.38 |
Secondary
Change From Baseline in C - Reactive Protein
Time frame: From baseline to Week 4, 8, 12, 16, 20, and 24.
Population: The full analysis set consist of all randomised participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tralokinumab | Change From Baseline in C - Reactive Protein | Week 24 | -2.754 mg/L | Full Range 0.35 |
| Tralokinumab | Change From Baseline in C - Reactive Protein | Week 4 | -2.755 mg/L | Full Range 0.31 |
| Tralokinumab | Change From Baseline in C - Reactive Protein | Week 8 | -1.089 mg/L | Full Range 0.29 |
| Tralokinumab | Change From Baseline in C - Reactive Protein | Week 12 | -2.795 mg/L | Full Range 0.34 |
| Tralokinumab | Change From Baseline in C - Reactive Protein | Week 16 | -3.490 mg/L | Full Range 0.34 |
| Tralokinumab | Change From Baseline in C - Reactive Protein | Week 20 | -4.094 mg/L | Full Range 0.33 |
| Placebo | Change From Baseline in C - Reactive Protein | Week 16 | 0.638 mg/L | Full Range 0.37 |
| Placebo | Change From Baseline in C - Reactive Protein | Week 24 | -1.915 mg/L | Full Range 0.38 |
| Placebo | Change From Baseline in C - Reactive Protein | Week 12 | -1.974 mg/L | Full Range 0.36 |
| Placebo | Change From Baseline in C - Reactive Protein | Week 4 | 0.510 mg/L | Full Range 0.31 |
| Placebo | Change From Baseline in C - Reactive Protein | Week 20 | -1.467 mg/L | Full Range 0.37 |
| Placebo | Change From Baseline in C - Reactive Protein | Week 8 | 0.637 mg/L | Full Range 0.3 |
Secondary
Change From Baseline in Modified Riley Score
Modified Riley score is biopsy grade which range from 0-5; where 0: Normal mucosa, 1: Infiltration of lymphocytes and plasma cells in the lamina propria, 2: Infiltration of neutrophils and eosinophils in the lamina propria, 3: Infiltration of neutrophils in the epithelium, 4: Crypt destruction, 5: Erosion and/or ulceration.
Time frame: Eight week treatment period
Population: The full analysis set consist of all randomised participants however the numbers for the endpoints mentioned for this secondary outcome are lower due to missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tralokinumab | Change From Baseline in Modified Riley Score | -0.49 Grade on scale | Standard Error 0.23 |
| Placebo | Change From Baseline in Modified Riley Score | -0.74 Grade on scale | Standard Error 0.24 |
p-value: 0.44995% CI: [-0.41, 0.91]ANCOVA
Secondary
Change From Baseline in Partial Mayo Score
The partial Mayo score is the sum of the three sub-score areas: stool frequency, rectal bleeding, and the physician's global assessment.The partial Mayo score ranges from 0-9, with higher scores indicating a more severe disease. Change from baseline: Mayo score at each post-baseline timepoint (week 4, 8, 12, 16, 20, and 24) minus the Mayo score at baseline.
Time frame: From baseline to Week 4, 8, 12, 16, 20, and 24.
Population: The full analysis set consist of all randomised participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tralokinumab | Change From Baseline in Partial Mayo Score | Week 16 | -2.6 Score on scale | Full Range 0.34 |
| Tralokinumab | Change From Baseline in Partial Mayo Score | Week 4 | -1.8 Score on scale | Full Range 0.31 |
| Tralokinumab | Change From Baseline in Partial Mayo Score | Week 8 | -2.4 Score on scale | Full Range 0.29 |
| Tralokinumab | Change From Baseline in Partial Mayo Score | Week 12 | -2.7 Score on scale | Full Range 0.34 |
| Tralokinumab | Change From Baseline in Partial Mayo Score | Week 20 | -3.0 Score on scale | Full Range 0.33 |
| Tralokinumab | Change From Baseline in Partial Mayo Score | Week 24 | -3.0 Score on scale | Full Range 0.35 |
| Placebo | Change From Baseline in Partial Mayo Score | Week 20 | -3.6 Score on scale | Full Range 0.37 |
| Placebo | Change From Baseline in Partial Mayo Score | Week 16 | -3.3 Score on scale | Full Range 0.37 |
| Placebo | Change From Baseline in Partial Mayo Score | Week 12 | -2.6 Score on scale | Full Range 0.36 |
| Placebo | Change From Baseline in Partial Mayo Score | Week 4 | -0.8 Score on scale | Full Range 0.31 |
| Placebo | Change From Baseline in Partial Mayo Score | Week 24 | -3.6 Score on scale | Full Range 0.38 |
| Placebo | Change From Baseline in Partial Mayo Score | Week 8 | -1.7 Score on scale | Full Range 0.3 |
Secondary
Change in Mayo Score From Baseline to Week 8
Mayo score is sum of four sub-scores: stool frequency, rectal bleeding, endoscopy findings and the physician's global assessment. The total Mayo score ranges from 0-12, with higher scores indicating a more severe disease. Change from baseline: Mayo score at week 8 minus the Mayo score at baseline.
Time frame: Eight week treatment period
Population: The full analysis set consist of all randomised participants however the numbers for the endpoints mentioned for this secondary outcome are lower due to missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tralokinumab | Change in Mayo Score From Baseline to Week 8 | -2.41 Score on scale | Standard Error 0.58 |
| Placebo | Change in Mayo Score From Baseline to Week 8 | -1.92 Score on scale | Standard Error 0.56 |
p-value: 0.393795% CI: [-1.63, 0.65]ANCOVA
Secondary
Clinical Remission at Week 8 Based on Mayo Score
Participants were classified as in remission if Mayo score of ≤2 with no individual sub score exceeding 1 point. Mayo score is sum of four sub-scores: stool frequency, rectal bleeding, endoscopy findings and the physician's global assessment. The total Mayo score ranges from 0-12, with higher scores indicating a more severe disease.
Time frame: Eight week treatment period
Population: The full analysis set consist of all randomised participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tralokinumab | Clinical Remission at Week 8 Based on Mayo Score | 17.9 Percentage of participants |
| Placebo | Clinical Remission at Week 8 Based on Mayo Score | 5.5 Percentage of participants |
p-value: 0.032695% CI: [0.7, 24.1]Cochran-Mantel-Haenszel
Secondary
Immunogenicity
Incidence of anti-drug antibodies (ADA) to tralokinumab in serum.
Time frame: Pre-dose sampling at baseline, Week 8, 12, 16, and 24.
Population: The safety analysis set consist of all randomised participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Tralokinumab | Immunogenicity | Week 12 | 0 participants | 0.34 |
| Tralokinumab | Immunogenicity | Week 8 | 0 participants | 0.29 |
| Tralokinumab | Immunogenicity | Week 16 | 0 participants | 0.34 |
| Tralokinumab | Immunogenicity | Week 24 | 0 participants | 0.33 |
| Tralokinumab | Immunogenicity | pre-dose at baseline | 0 participants | 0.31 |
| Placebo | Immunogenicity | Week 24 | 0 participants | — |
| Placebo | Immunogenicity | pre-dose at baseline | 1 participants | — |
| Placebo | Immunogenicity | Week 8 | 1 participants | — |
| Placebo | Immunogenicity | Week 12 | 1 participants | — |
| Placebo | Immunogenicity | Week 16 | 1 participants | — |
Secondary
Mucosal Healing at Week 8 Based on Mayo Score
Improvement of the endoscopy sub score (from the Mayo score) from 3 or 2 to 0 or 1 point, or from 1 to 0 points.
Time frame: Eight week treatment period
Population: The full analysis set consist of all randomised participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tralokinumab | Mucosal Healing at Week 8 Based on Mayo Score | 32.1 Percentage of participants |
| Placebo | Mucosal Healing at Week 8 Based on Mayo Score | 20.0 Percentage of participants |
p-value: 0.104395% CI: [-4, 28.3]Cochran-Mantel-Haenszel
Secondary
Serum Concentration of Tralokinumab
Time frame: Pre-dose sampling at baseline, Week 4, 8, 12, 16, 20, and 24.
Population: The safety analysis set consist of all randomised participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tralokinumab | Serum Concentration of Tralokinumab | Week 8 | 50.2 ug/ml | Full Range 0.34 |
| Tralokinumab | Serum Concentration of Tralokinumab | Week 16 | 27.2 ug/ml | Full Range 0.33 |
| Tralokinumab | Serum Concentration of Tralokinumab | Week 4 | 37.9 ug/ml | Full Range 0.29 |
| Tralokinumab | Serum Concentration of Tralokinumab | Week 20 | 9.32 ug/ml | Full Range 0.35 |
| Tralokinumab | Serum Concentration of Tralokinumab | Week 12 | 48.2 ug/ml | Full Range 0.34 |
| Tralokinumab | Serum Concentration of Tralokinumab | Week 24 | 3.66 ug/ml | — |
| Tralokinumab | Serum Concentration of Tralokinumab | pre-dose at baseline | 0.00 ug/ml | Full Range 0.31 |
| Placebo | Serum Concentration of Tralokinumab | Week 24 | NA ug/ml | — |
| Placebo | Serum Concentration of Tralokinumab | pre-dose at baseline | NA ug/ml | — |
| Placebo | Serum Concentration of Tralokinumab | Week 4 | NA ug/ml | — |
| Placebo | Serum Concentration of Tralokinumab | Week 8 | NA ug/ml | — |
| Placebo | Serum Concentration of Tralokinumab | Week 12 | NA ug/ml | — |
| Placebo | Serum Concentration of Tralokinumab | Week 16 | NA ug/ml | — |
| Placebo | Serum Concentration of Tralokinumab | Week 20 | NA ug/ml | — |