Ulcerative Colitis
Conditions
Brief summary
The primary objective of this study is to demonstrate the efficacy of tilpisertib (formerly GS-4875) compared with placebo control in achieving clinical remission per modified Mayo Clinic Score (MCS) in adults with moderately to severely active ulcerative colitis (UC).
Interventions
DRUGTilpisertib
Tablets administered orally once daily
DRUGPlacebo
Tablets administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Males, or non-pregnant, non-lactating females, at least 18 years of age based on the date of the screening visit. * UC of at least 3 months duration before randomization confirmed by endoscopy and histology at any time in the past AND a minimum disease extent of 15 centimeter (cm) from the anal verge. Documentation of endoscopy and histology consistent with the diagnosis of UC must be available in the source documents prior to the initiation of screening. * Moderately to severely active UC as determined during screening by a centrally read endoscopy score ≥ 2, a Rectal Bleeding subscore ≥ 1, a Stool Frequency subscore ≥ 1 and Physicians Global Assessment (PGA) of ≥ 2 as defined by the Mayo Clinic Score; total MCS must be between 6 and 12, inclusive. * Previously demonstrated an inadequate response (primary non-response) or loss of response (secondary non-response) to a tumor necrosis factor-alpha (TNFα) inhibitor (ie, infliximab, adalimumab, golimumab, or biosimilars). The induction treatment regimen resulting in inadequate response or loss of response should have been in accordance with local prescribing information/guidelines or as outlined below. * Infliximab: 5 mg/kg at Weeks 0, 2, and 6 * Adalimumab: 160 mg on Day 1 (given in 1 day or split over consecutive days), followed by 80 mg 2 weeks later (Day 15), 40 mg 2 weeks later (Day 29) and every 2 weeks thereafter until Day 57 * Golimumab: 200 mg on Day 1 followed by 100 mg at Week 2 * May be receiving concomitant therapy for UC at the time of enrollment as specified in the protocol, provided the dose prescribed has been stable as indicated prior to randomization. * Meet the following Tuberculosis (TB) screening criteria: * No evidence of active TB, latent TB, or inadequately treated TB as evidenced by 1 of the following: * A negative QuantiFERON test or equivalent assay reported by the central lab at screening or within 90 days prior to randomization date. OR * A history of fully treated active or latent TB according to local standard of care. Investigator must verify adequate previous anti-TB treatment and provide documentation; these individuals do not require QuantiFERON testing and eligibility must be approved by the sponsor prior to enrollment in the study. AND * A chest radiograph (views as per local guidelines with the report or films available for investigator review) taken at screening or within the 4 months prior to randomization without evidence of active or latent TB infection. * Laboratory assessments at screening within the following parameters: * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and total bilirubin ≤ 2 X upper limit of normal (ULN) * Estimated glomerular filtration rate (eGFR) ≥ 60 ml/min (1.0 mL/sec) as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Cystatin C formula as described in protocol. * Hemoglobin ≥ 8 g/dL (≥ 80 g/L) * Absolute neutrophil count (ANC) ≥ 1.5 × 10\^3/μL (≥ 1.5 GI/L) * Platelets ≥ 100 × 10\^3/μL (≥ 100 GI/L) * White blood cells (WBC) ≥ 3 × 10\^3/μL (≥ 3 GI/L) * Absolute lymphocyte count ≥ 0.75 × 10\^3/μL (≥ 0.75 GI/L) Key
Exclusion criteria
* Currently displaying clinical signs of acute severe colitis, fulminant colitis, or toxic megacolon. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Clinical Remission Per Modified Mayo Clinic Score (MCS) at Week 10 | Week 10 | The modified MCS is a scoring system for assessment of ulcerative colitis (UC) activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and physician's global assessment (PGA) (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. Clinical remission per modified MCS is defined as stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1 at Week 10. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved MCS Response at Week 10 | Week 10 | The modified MCS is a scoring system for assessment of UC activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and PGA (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. MCS response is defined as a decrease from baseline of ≥ 3 points and at least 30% in MCS, in addition to a ≥ 1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore ≤ 1 at Week 10. |
| Percentage of Participants Who Achieved MCS Remission at Week 10 | Week 10 | The modified MCS is a scoring system for assessment of UC activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and PGA (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. MCS remission is defined as a MCS score of ≤ 2 and no individual subscore \> 1 at Week 10. |
| Percentage of Participants Who Achieved Endoscopic Response at Week 10 | Week 10 | Endoscopic response was defined as an endoscopic subscore of ≤ 1 at Week 10. Endoscopic subscore is a part of the modified MCS which is a scoring system for assessment of UC activity. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease, 1 = mild disease (erythema, decreased vascular pattern), 2 = moderate disease (marked erythema, lack of vascular pattern, friability, erosions), and 3 = severe disease (spontaneous bleeding, ulceration). |
| Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label phase: First dose date up to 50.7 weeks plus 30 days | Treatment-emergent adverse events (TEAEs) for the Blinded Treatment phase are either defined as AEs with an onset date on or after the Blinded Treatment phase study drug start date and no later than 30 days after permanent discontinuation of the Blinded Treatment phase study drug if no Open-label Treatment phase study drug was taken, or any AEs with an onset date on or after the Blinded Treatment phase study drug start date and before the Open-label Treatment phase study drug start date if Open-label Treatment phase study drug was taken and/or any AEs leading to premature discontinuation of Blinded Treatment phase study drug. TEAEs for the Open-label Treatment phase are either defined as AEs with an onset date on or after the Open-label Treatment phase study drug start date and no later than 30 days after permanent discontinuation of the Open-lab Treatment phase study drug and/or any AEs leading to premature discontinuation of Open-label Treatment phase study drug. |
| Percentage of Participants Who Experienced Laboratory Abnormalities | Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label phase: First dose date up to 50.7 weeks plus 30 days | Treatment-emergent laboratory abnormalities for Blinded Treatment phase are defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of Blinded Treatment phase study drug plus 30 days for participants who permanently discontinued Blinded Treatment phase study drug or before the first dose of Open-label Treatment phase study drug. For the Open-label Treatment phase, treatment-emergent laboratory abnormalities are defined as values that increase at least 1 toxicity grade from Open-label baseline at any postbaseline time point, up to and including the date of last dose of Open-label Treatment phase study drug plus 30 days for participants who permanently discontinued Open-label phase study drug. For maximum postbaseline toxicity grade, the most severe graded abnormality from all tests was counted for each patient. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening. |
| Percentage of Participants Who Achieved Histologic Remission Based Upon the Geboes Scale at Week 10 | Week 10 | Geboes histologic remission was assessed using the Geboes histologic scores to identify histologic changes in ulcerative colitis. Possible scores are Grade 0:Architectural changes(0.0=No abnormality to 0.3=Severe diffuse or multifocal abnormalities); Grade 1:Chronic inflammatory infiltrate(1.0=No increase to 1.3=Marked increase);Grade 2A:Eosinophils in lamina propria(2A.0=No increase to 2A.3-=Marked increase; Grade 2B:Neutrophils in lamina propria(2B.0= No increase to 2B.3=Marked increase);Grade 3:Neutrophils in epithelium (3.0=None to 3.3=\>50% crypts involved);Grade 4:Crypt destruction(4.0=none to 4.3=Unequivocal crypt destruction),and Grade 5:Erosions and ulcerations:(5.0=No erosion, ulceration or granulation to 5.4=Ulcer or granulation tissue). Histologic remission defined as having Grade 0 of ≤ 0.3, Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and Grade 5 of 5.0. Geboes score ranges from 0 to 5.4. Lower values indicate better outcome. |
Countries
Australia, Austria, Canada, France, Germany, Italy, Poland, Switzerland, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Australia, Europe and the United States.
Pre-assignment details
32 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Tilpisertib 300 mg (Blinded Treatment Phase) Tilpisertib 300 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive tilpisertib 300 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase. | 7 |
| Tilpisertib 100 mg (Blinded Treatment Phase) Tilpisertib 100 mg tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive tilpisertib 100 mg tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase. | 6 |
| Placebo (Blinded Treatment Phase) Placebo tablet orally once daily up to Week 10. Participants who achieved clinical response per modified MCS at Week 10, continued to receive placebo tablets orally once daily for a maximum of 50 weeks in the Blinded Treatment phase. | 6 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Blinded Treatment Phase | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Blinded Treatment Phase | Disease worsening | 0 | 0 | 1 | 0 | 0 | 0 |
| Blinded Treatment Phase | Investigator's decision | 0 | 1 | 0 | 0 | 0 | 0 |
| Blinded Treatment Phase | Study terminated by sponsor | 1 | 1 | 1 | 0 | 0 | 0 |
| Blinded Treatment Phase | Withdrew consent | 1 | 0 | 0 | 0 | 0 | 0 |
| Open-label Treatment Phase | Disease worsening | 0 | 0 | 0 | 1 | 0 | 1 |
| Open-label Treatment Phase | Investigator's decision | 0 | 0 | 0 | 1 | 0 | 0 |
| Open-label Treatment Phase | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
| Open-label Treatment Phase | MCS response not achieved at open-label week 10 | 0 | 0 | 0 | 0 | 1 | 0 |
| Open-label Treatment Phase | Withdrew consent | 0 | 0 | 0 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Tilpisertib 100 mg (Blinded Treatment Phase) | Tilpisertib 300 mg (Blinded Treatment Phase) | Total | Placebo (Blinded Treatment Phase) |
|---|---|---|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 22.6 | 51 years STANDARD_DEVIATION 11.8 | 48 years STANDARD_DEVIATION 17.2 | 43 years STANDARD_DEVIATION 18.4 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 4 Participants | 6 Participants | 16 Participants | 6 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 6 Participants | 7 Participants | 16 Participants | 3 Participants |
| Region of Enrollment Australia | 1 Participants | 1 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Austria | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Germany | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Region of Enrollment Switzerland | 1 Participants | 2 Participants | 3 Participants | 0 Participants |
| Region of Enrollment United States | 3 Participants | 3 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 13 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 4 / 7 | 3 / 6 | 2 / 6 | 2 / 4 | 2 / 3 | 2 / 3 |
| serious Total, serious adverse events | 1 / 7 | 0 / 6 | 1 / 6 | 0 / 4 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Percentage of Participants Who Achieved Clinical Remission Per Modified Mayo Clinic Score (MCS) at Week 10
The modified MCS is a scoring system for assessment of ulcerative colitis (UC) activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and physician's global assessment (PGA) (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. Clinical remission per modified MCS is defined as stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1 at Week 10.
Time frame: Week 10
Population: Full analysis set included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved Clinical Remission Per Modified Mayo Clinic Score (MCS) at Week 10 | 0 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved Clinical Remission Per Modified Mayo Clinic Score (MCS) at Week 10 | 0 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Achieved Clinical Remission Per Modified Mayo Clinic Score (MCS) at Week 10 | 0 percentage of participants |
Secondary
Percentage of Participants Who Achieved Endoscopic Response at Week 10
Endoscopic response was defined as an endoscopic subscore of ≤ 1 at Week 10. Endoscopic subscore is a part of the modified MCS which is a scoring system for assessment of UC activity. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease, 1 = mild disease (erythema, decreased vascular pattern), 2 = moderate disease (marked erythema, lack of vascular pattern, friability, erosions), and 3 = severe disease (spontaneous bleeding, ulceration).
Time frame: Week 10
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved Endoscopic Response at Week 10 | 14.3 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved Endoscopic Response at Week 10 | 16.7 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Achieved Endoscopic Response at Week 10 | 0 percentage of participants |
Secondary
Percentage of Participants Who Achieved Histologic Remission Based Upon the Geboes Scale at Week 10
Geboes histologic remission was assessed using the Geboes histologic scores to identify histologic changes in ulcerative colitis. Possible scores are Grade 0:Architectural changes(0.0=No abnormality to 0.3=Severe diffuse or multifocal abnormalities); Grade 1:Chronic inflammatory infiltrate(1.0=No increase to 1.3=Marked increase);Grade 2A:Eosinophils in lamina propria(2A.0=No increase to 2A.3-=Marked increase; Grade 2B:Neutrophils in lamina propria(2B.0= No increase to 2B.3=Marked increase);Grade 3:Neutrophils in epithelium (3.0=None to 3.3=\>50% crypts involved);Grade 4:Crypt destruction(4.0=none to 4.3=Unequivocal crypt destruction),and Grade 5:Erosions and ulcerations:(5.0=No erosion, ulceration or granulation to 5.4=Ulcer or granulation tissue). Histologic remission defined as having Grade 0 of ≤ 0.3, Grade 1 of ≤ 1.1, Grade 2a of ≤ 2A.3, Grade 2b of 2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and Grade 5 of 5.0. Geboes score ranges from 0 to 5.4. Lower values indicate better outcome.
Time frame: Week 10
Population: Participants in the Full Analysis Set with at least 1 histological assessment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved Histologic Remission Based Upon the Geboes Scale at Week 10 | 16.7 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved Histologic Remission Based Upon the Geboes Scale at Week 10 | 16.7 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Achieved Histologic Remission Based Upon the Geboes Scale at Week 10 | 25.0 percentage of participants |
Secondary
Percentage of Participants Who Achieved MCS Remission at Week 10
The modified MCS is a scoring system for assessment of UC activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and PGA (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. MCS remission is defined as a MCS score of ≤ 2 and no individual subscore \> 1 at Week 10.
Time frame: Week 10
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved MCS Remission at Week 10 | 0 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved MCS Remission at Week 10 | 0 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Achieved MCS Remission at Week 10 | 0 percentage of participants |
Secondary
Percentage of Participants Who Achieved MCS Response at Week 10
The modified MCS is a scoring system for assessment of UC activity and is composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease \[spontaneous bleeding, ulceration\]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal), and PGA (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. MCS response is defined as a decrease from baseline of ≥ 3 points and at least 30% in MCS, in addition to a ≥ 1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore ≤ 1 at Week 10.
Time frame: Week 10
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved MCS Response at Week 10 | 28.6 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Achieved MCS Response at Week 10 | 16.7 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Achieved MCS Response at Week 10 | 16.7 percentage of participants |
Secondary
Percentage of Participants Who Experienced Laboratory Abnormalities
Treatment-emergent laboratory abnormalities for Blinded Treatment phase are defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of Blinded Treatment phase study drug plus 30 days for participants who permanently discontinued Blinded Treatment phase study drug or before the first dose of Open-label Treatment phase study drug. For the Open-label Treatment phase, treatment-emergent laboratory abnormalities are defined as values that increase at least 1 toxicity grade from Open-label baseline at any postbaseline time point, up to and including the date of last dose of Open-label Treatment phase study drug plus 30 days for participants who permanently discontinued Open-label phase study drug. For maximum postbaseline toxicity grade, the most severe graded abnormality from all tests was counted for each patient. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening.
Time frame: Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label phase: First dose date up to 50.7 weeks plus 30 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 2 | 28.6 percentage of participants |
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 1 | 42.9 percentage of participants |
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 | 14.3 percentage of participants |
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 | 0 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 2 | 33.3 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 1 | 66.7 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 | 0 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 1 | 16.7 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 2 | 50.0 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 300 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 1 | 25.0 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 300 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 2 | 25.0 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 300 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 | 25.0 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 300 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 100 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 2 | 0 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 100 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 1 | 33.3 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 100 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 | 66.7 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 100 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Tilpisertib 300 mg From Placebo (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 1 | 66.7 percentage of participants |
| Tilpisertib 300 mg From Placebo (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Tilpisertib 300 mg From Placebo (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 3 | 0 percentage of participants |
| Tilpisertib 300 mg From Placebo (Open-label Treatment Phase) | Percentage of Participants Who Experienced Laboratory Abnormalities | Grade 2 | 33.3 percentage of participants |
Secondary
Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
Treatment-emergent adverse events (TEAEs) for the Blinded Treatment phase are either defined as AEs with an onset date on or after the Blinded Treatment phase study drug start date and no later than 30 days after permanent discontinuation of the Blinded Treatment phase study drug if no Open-label Treatment phase study drug was taken, or any AEs with an onset date on or after the Blinded Treatment phase study drug start date and before the Open-label Treatment phase study drug start date if Open-label Treatment phase study drug was taken and/or any AEs leading to premature discontinuation of Blinded Treatment phase study drug. TEAEs for the Open-label Treatment phase are either defined as AEs with an onset date on or after the Open-label Treatment phase study drug start date and no later than 30 days after permanent discontinuation of the Open-lab Treatment phase study drug and/or any AEs leading to premature discontinuation of Open-label Treatment phase study drug.
Time frame: Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label phase: First dose date up to 50.7 weeks plus 30 days
Population: Safety Analysis Set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tilpisertib 300 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 57.1 percentage of participants |
| Tilpisertib 100 mg (Blinded Treatment Phase) | Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 50.0 percentage of participants |
| Placebo (Blinded Treatment Phase) | Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 50.0 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 300 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 50.0 percentage of participants |
| Tilpisertib 300 mg From Tilpisertib 100 mg (Open-label Treatment Phase) | Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 66.7 percentage of participants |
| Tilpisertib 300 mg From Placebo (Open-label Treatment Phase) | Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 66.7 percentage of participants |