Ulcerative Colitis
Conditions
Keywords
Colitis, Ulcer, Moderately active ulcerative colitis, Chronic inflammatory bowel disease, Inflammatory Bowel Diseases, Digestive System Diseases
Brief summary
The primary objective of this study was to evaluate the effect of GLPG3970 compared to placebo on the signs and symptoms of Ulcerative Colitis (UC) in participants with moderately to severely active UC.
Interventions
DRUGGLPG3970
GLPG3970 powder and solvent for oral solution reconstituted prior to use.
DRUGPlacebo
Placebo powder and solvent for oral solution reconstituted prior to use.
Sponsors
Galapagos NV
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 64 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Documented diagnosis of UC of ≥3 months. The criteria for documentation of UC diagnosis based on endoscopy will be medical record documentation, and/or a colonoscopy report dated ≥3 months before screening, which shows features consistent with UC. 2. Treatment-experienced participants with moderately to severely active disease, who have either previously demonstrated inadequate clinical response, loss of response, or intolerance to at least 1 course of standard-of-care (SoC) therapy for UC (i.e. steroids \[oral or parenteral, including but not limited to prednisone, prednisolone, budesonide\], 5-aminosalicylate \[5- ASA\] derivatives \[including but not limited to mesalamine, sulfasalazine\], anti-metabolites \[including but not limited to azathioprine, 6 mercaptopurine, methotrexate\], anti-tumor necrosis factor \[TNF\] agents, anti-integrins, Janus kinase \[JAK\] inhibitors), as confirmed by the investigator. 3. Moderately to severely active UC as determined at screening by: 1. Centrally-read endoscopic evidence of disease activity (MCS- endoscopy subscore \[ES\] ≥2 OR ulcerative colitis endoscopic index of severity \[UCEIS\] ≥4) with a minimum disease extent of 15 cm from anal verge; AND 2. MCS stool frequency (SF) subscore ≥1; AND 3. MCS rectal bleeding (RB) subscore ≥1. 4. Participants currently receiving the following SoC therapies for UC are eligible providing they have been on a stable dose for the designated period of time and are anticipated to be stable throughout the study: 1. oral corticosteroids (prednisone ≤20 mg/day or equivalent or budesonide ≤3 mg/day) stable dose for at least 2 weeks prior to first investigational product (IP) dosing. 2. oral 5-ASA compounds (mesalamine ≤4 grams \[g\]/day or sulfasalazine ≤4 g/day) stable dose for at least 4 weeks prior to first IP dosing. 3. oral thiopurines (azathioprine ≤2.5 mg/kg/day and 6-mercaptopurine 1.5 mg/kilograms \[kg\]/day) stable dose for at least 12 weeks prior to first IP dosing, or methotrexate ≤20 mg/week, stable dose for at least 12 weeks prior to first IP dosing. Key
Exclusion criteria
1. Diagnosis of Crohn's disease, indeterminate colitis, ischemic colitis, fulminant colitis, or toxic megacolon. 2. Prior surgical intervention for UC (e.g. colectomy, partial colectomy, ileostomy or colostomy) or likely requirement for surgery for UC, during the study. 3. History or evidence of incompletely resected colonic mucosal dysplasia. 4. Exhibit acute severe UC per the following criteria: 1. bloody diarrhea ≥6/day AND 2. any of the following signs of systemic toxicity: Body temperature (oral or tympanic) ≥37.8 degrees celsius (°C) OR Resting pulse (after 5 min seated position) \>90 beats per min OR hemoglobin \<105 g/L, OR erythrocyte sedimentation rate \>30 millimeters per hour (mm/h); OR C-reactive protein (CRP) \>30 mg/L. 5. Screening stool sample positive for ova and/or parasites, Clostridium difficile toxin, Escherichia coli, Salmonella species (spp), Shigella spp, Campylobacter spp or Yersinia spp. 6. Participant testing positive at screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as detected by real time polymerase chain reaction (RT-PCR), participants presenting any signs or symptoms as detected at baseline following careful physical examination (e.g. cough, fever, headaches, fatigue, dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, others) or reporting any signs and symptoms for the preceding 2 weeks, or participants who have been exposed to individuals with confirmed or suspected diagnosis of SARS-CoV-2 within 2 weeks prior to baseline. In addition, any other locally applicable standard diagnostic criteria may also apply to rule out SARS-CoV-2 infection. Note: Other protocol-defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total MCS at Week 6 | Baseline and Week 6 | The MCS is the primary tool for assessing ulcerative colitis activity. Total MCS is the sum of 4 subscores (i.e., stool frequency, rectal bleeding, endoscopic findings, and a physician's global assessment); each rated on a scale from 0 (normal) to 3 (severe). The total MCS value ranges from 0 to 12, with higher scores indicating more severe disease. Missing data were imputed using Rubin's multiple imputation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | First dose date up to 14 days after the last dose of study drug (up to 57 days) | Treatment-Emergent Adverse Events (TEAEs) were defined as * Any adverse event (AE) with an onset date on or after the IP start date and no later than 14 days after last dose of IP, or worsening of any AE on or after the IP start date. * Improvement or no change of any ongoing AEs on or after the IP start date are not considered treatment-emergent. If an AE was ongoing at the time of first IP intake and if there was no change or an improvement in its toxicity grade or its seriousness status, this AE was not considered as treatment-emergent. Serious TEAE was defined as a TEAE that * Resulted in death and was life-threatening; * Required in-patient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly / birth defect; * Was medically significant. |
| Plasma Concentration (Ctrough) of GLPG3970 | Day 15: pre-dose; Day 29: pre-dose; Day 43: pre-dose | Ctrough was defined as plasma concentration level at the end of the dosing interval. |
Countries
Georgia, Moldova, Poland, Ukraine
Participant flow
Recruitment details
Study was conducted across 4 countries (Georgia, the Republic of Moldova, Poland, and Ukraine).
Pre-assignment details
A total of 65 participants were screened, out of which 31 were randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| GLPG3970 Participants received 400 mg GLPG3970 oral solution, QD for a period of 6 weeks. | 21 |
| Placebo Participants received GLPG3970 matching placebo oral solution, QD for a period of 6 weeks. | 10 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
Baseline characteristics
| Characteristic | GLPG3970 | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 39.7 years STANDARD_DEVIATION 10.9 | 39.1 years STANDARD_DEVIATION 9.5 | 37.8 years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 31 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 31 Participants | 10 Participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 1 Participants |
| Sex: Female, Male Male | 16 Participants | 25 Participants | 9 Participants |
| Total Mayo Clinical Score (MCS) | 8.5 units on a scale STANDARD_DEVIATION 1.2 | 8.4 units on a scale STANDARD_DEVIATION 1.2 | 8.2 units on a scale STANDARD_DEVIATION 1.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 10 |
| other Total, other adverse events | 11 / 21 | 3 / 10 |
| serious Total, serious adverse events | 0 / 21 | 0 / 10 |
Outcome results
Primary
Change From Baseline in Total MCS at Week 6
The MCS is the primary tool for assessing ulcerative colitis activity. Total MCS is the sum of 4 subscores (i.e., stool frequency, rectal bleeding, endoscopic findings, and a physician's global assessment); each rated on a scale from 0 (normal) to 3 (severe). The total MCS value ranges from 0 to 12, with higher scores indicating more severe disease. Missing data were imputed using Rubin's multiple imputation.
Time frame: Baseline and Week 6
Population: Full analysis set consisted of all randomized participants who received at least 1 dose of IP. Participants with available data at specified timepoint were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GLPG3970 | Change From Baseline in Total MCS at Week 6 | -2.6 units on a scale | Standard Error 0.57 |
| Placebo | Change From Baseline in Total MCS at Week 6 | -2.6 units on a scale | Standard Error 0.85 |
Comparison: An analysis of covariance (ANCOVA) was used with a multiple imputation method to handle missing values, with treatment as fixed effect and baseline score as covariate.p-value: 0.98190% CI: [-1.7, 1.7]ANCOVA
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Treatment-Emergent Adverse Events (TEAEs) were defined as * Any adverse event (AE) with an onset date on or after the IP start date and no later than 14 days after last dose of IP, or worsening of any AE on or after the IP start date. * Improvement or no change of any ongoing AEs on or after the IP start date are not considered treatment-emergent. If an AE was ongoing at the time of first IP intake and if there was no change or an improvement in its toxicity grade or its seriousness status, this AE was not considered as treatment-emergent. Serious TEAE was defined as a TEAE that * Resulted in death and was life-threatening; * Required in-patient hospitalization or prolongation of existing hospitalization; * Resulted in persistent or significant disability/incapacity; * Was a congenital anomaly / birth defect; * Was medically significant.
Time frame: First dose date up to 14 days after the last dose of study drug (up to 57 days)
Population: Participants in the safety analysis set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GLPG3970 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs | 11 participants |
| GLPG3970 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 4 participants |
| GLPG3970 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 participants |
| GLPG3970 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to study drug discontinuation | 1 participants |
| GLPG3970 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to study drug discontinuation | 0 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs | 3 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 1 participants |
Secondary
Plasma Concentration (Ctrough) of GLPG3970
Ctrough was defined as plasma concentration level at the end of the dosing interval.
Time frame: Day 15: pre-dose; Day 29: pre-dose; Day 43: pre-dose
Population: Pharmacokinetic analysis set consisted of all participants who received at least 1 dose of IP with available plasma concentration data. Participants with available plasma concentration at specified time point were included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GLPG3970 | Plasma Concentration (Ctrough) of GLPG3970 | Day 15: Pre-dose | 73.2 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 145 |
| GLPG3970 | Plasma Concentration (Ctrough) of GLPG3970 | Day 29: Pre-dose | 55.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 65.3 |
| GLPG3970 | Plasma Concentration (Ctrough) of GLPG3970 | Day 43: Pre-dose | 84.9 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 107 |