Chronic Graft Versus Host Disease
Conditions
Keywords
chronic graft versus host disease, PCYC1140, PCYC1140IM, 1140, Ibrutinib, GVHD, Steroid dependent, refractory, chronic, PCI32765, IMBRUVICA, Pharmacyclics, PCYC, graft versus host disease, immunology, new onset graft versus host disease, INTEGRATE, Corticosteroids, prednisone
Brief summary
To evaluate the safety and efficacy of ibrutinib in combination with prednisone in subjects with newly diagnosed moderate to severe cGVHD.
Interventions
DRUGibrutinib
Ibrutinib capsules administered orally daily
DRUGPlacebo
Placebo capsules administered orally daily
DRUGPrednisone
Prednisone administered daily
Sponsors
Janssen Research & Development, LLC
Pharmacyclics LLC.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * New onset moderate or severe cGVHD as defined by the 2014 National Institutes of Health (NIH) Consensus Development Project Criteria * Need for systemic treatment with corticosteroids for cGVHD * No previous systemic treatment for cGVHD (including extracorporeal photopheresis \[ECP\]) * Participants may be receiving other immunosuppressants for the prophylaxis or treatment of acute GVHD but if the subject is receiving prednisone for prophylaxis or treatment of acute GVHD it must be at or below 0.5 mg/kg/d * Age ≥12 years old * Karnofsky or Lansky (subjects \<16 years) performance status ≥60 Key
Exclusion criteria
* Received any previous systemic treatment for cGVHD with the exception of corticosteroids administered for cGVHD within the 72 hours prior to signing the informed consent form. * Inability to begin a prednisone dose ≥0.5 mg/kg/d for the treatment of cGVHD * Any uncontrolled infection or active infection requiring ongoing systemic treatment * Progressive underlying malignant disease or any post-transplant lymphoproliferative disease * Known bleeding disorders * Active hepatitis C virus (HCV) or hepatitis B virus (HBV)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Analysis: Response Rate at 48 Weeks | 48 weeks (Cumulatively up to 30 March 2020) | Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site. |
| Final Analysis: Response Rate at 48 Weeks | 48 weeks (Cumulatively up to 12 July 2021) | Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | Months 3, 6, 9, 12, 15, 18, 21, 24 (cumulatively up to 30 March 2020) | The cumulative incidence of withdrawal of all immunosuppressants (95% CI) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all immunosuppressants at a given time point. The time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD, sustained for at least 30 days. All immunosuppressants include corticosteroids but they do not include ibrutinib. |
| Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021) | The cumulative incidence of withdrawal of all immunosuppressants (95% CI) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all immunosuppressants at a given time point. The time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD, sustained for at least 30 days. All immunosuppressants include corticosteroids but they do not include ibrutinib. |
| Primary Analysis: Response Rate at 24 Weeks | 24 weeks (Cumulatively up to 30 March 2020) | Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a CR or PR at 24 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site. |
| Final Analysis: Response Rate at 24 Weeks | 24 weeks (Cumulatively up to 12 July 2021) | Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a CR or PR at 24 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site. |
| Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits | Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020) | Clinically meaningful improvement on Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment. The Lee cGVHD Symptom Scale score has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely, with lower values representing a better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores. |
| Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits | Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021) | Clinically meaningful improvement on Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment. The Lee cGVHD Symptom Scale score has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely, with lower values representing a better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores. |
| Primary Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days | 24 weeks (Cumulatively up to 30 March 2020) | — |
| Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 30 March 2020) | The cumulative incidence of withdrawal of all corticosteroids (95% confidence interval \[CI\]) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all corticosteroids at given time point. The time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days. |
| Primary Analysis: Overall Survival (OS) | Median time on study (cumulatively up to 30 March 2020) was 19.8 months and 18.4 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively. | OS was defined as the time of randomization until the time of death due to any cause, in months. |
| Final Analysis: OS | Median time on study (cumulatively up to 12 July 2021) was 33.1 months and 32.5 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively. | OS was defined as the time of randomization until the time of death due to any cause, in months. |
| Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time | Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020) | Response was defined using the NIH Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR was defined as resolution of all manifestations in each organ or site. PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. Duration of response was estimated by Kaplan-Meier methodology. |
| Final Analysis: DOR for Participants Who Had PR or CR at Any Time | Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021) | Response was defined using the NIH Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR was defined as resolution of all manifestations in each organ or site. PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. Duration of response was estimated by Kaplan-Meier methodology. |
| Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 30 March 2020), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months. | AE: any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization \>24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity was graded according to the Common Terminology Criteria for Adverse Events version 4.03 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death). Treatment-related events are those that were possibly related or related to study treatment per investigator's judgment. Treatment emergent AEs (TEAEs) occurred from the first dose of study drug up to 30 days after the last dose of study drug. |
| Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 12 July 2021), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months. | AE: any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization \>24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity was graded according to the Common Terminology Criteria for Adverse Events version 4.03 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death). Treatment-related events are those that were possibly related or related to study treatment per investigator's judgment. Treatment emergent AEs (TEAEs) occurred from the first dose of study drug up to 30 days after the last dose of study drug. |
| Final Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days | 24 weeks (Cumulatively up to 12 July 2021) | — |
| Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021) | The cumulative incidence of withdrawal of all corticosteroids (95% confidence interval \[CI\]) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all corticosteroids at given time point. The time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days. |
Countries
Australia, Austria, Canada, China, Croatia, France, Germany, Hungary, Italy, Japan, Singapore, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
Participants were enrolled at 66 sites overall: 24 sites in North America, and 42 sites in the rest of the world.
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib + Prednisone Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for CYP inhibitors or hepatic dysfunction as applicable.
Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses. | 95 |
| Placebo + Prednisone Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity.
Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses. | 98 |
| Total | 193 |
Baseline characteristics
| Characteristic | Placebo + Prednisone | Total | Ibrutinib + Prednisone |
|---|---|---|---|
| Age, Continuous | 51.1 years STANDARD_DEVIATION 14.99 | 50.6 years STANDARD_DEVIATION 14.71 | 50.0 years STANDARD_DEVIATION 14.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 7 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 156 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 30 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 46 Participants | 27 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 10 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 28 Participants | 12 Participants |
| Race (NIH/OMB) White | 58 Participants | 105 Participants | 47 Participants |
| Sex: Female, Male Female | 33 Participants | 67 Participants | 34 Participants |
| Sex: Female, Male Male | 65 Participants | 126 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 94 | 22 / 96 |
| other Total, other adverse events | 88 / 94 | 92 / 96 |
| serious Total, serious adverse events | 51 / 94 | 49 / 96 |
Outcome results
Primary
Final Analysis: Response Rate at 48 Weeks
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
Time frame: 48 weeks (Cumulatively up to 12 July 2021)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: Response Rate at 48 Weeks | 41.1 percentage of participants |
| Placebo + Prednisone | Final Analysis: Response Rate at 48 Weeks | 36.7 percentage of participants |
p-value: 0.538495% CI: [-0.094, 0.181]Chi-squared
Primary
Primary Analysis: Response Rate at 48 Weeks
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
Time frame: 48 weeks (Cumulatively up to 30 March 2020)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Response Rate at 48 Weeks | 41.1 percentage of participants |
| Placebo + Prednisone | Primary Analysis: Response Rate at 48 Weeks | 36.7 percentage of participants |
p-value: 0.538495% CI: [-0.094, 0.181]Chi-squared
Secondary
Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD
The cumulative incidence of withdrawal of all corticosteroids (95% confidence interval \[CI\]) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all corticosteroids at given time point. The time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days.
Time frame: Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)
Population: Intent to Treat Population: all randomized participants. Participants with withdrawal of all corticosteroids. No participants were on corticosteroids at 21 and 24 Months in the Ibrutinib + Prednisone Arm/Group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 3 Months | 0.042 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 6 Months | 0.218 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 9 Months | 0.318 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 12 Months | 0.406 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 15 Months | 0.439 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 18 Months | 0.450 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 21 Months | 0.495 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 24 Months | 0.495 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 24 Months | 0.391 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 3 Months | 0.021 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 15 Months | 0.359 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 6 Months | 0.219 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 21 Months | 0.391 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 9 Months | 0.326 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 18 Months | 0.369 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 12 Months | 0.359 proportion of participants |
p-value: 0.281Chi-squared
Secondary
Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants
The cumulative incidence of withdrawal of all immunosuppressants (95% CI) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all immunosuppressants at a given time point. The time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD, sustained for at least 30 days. All immunosuppressants include corticosteroids but they do not include ibrutinib.
Time frame: Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)
Population: Intent to Treat Population: all randomized participants. Participants with withdrawal of all immunosuppressants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 3 Months | 0.011 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 6 Months | 0.143 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 9 Months | 0.222 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 12 Months | 0.280 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 15 Months | 0.314 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 18 Months | 0.349 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 21 Months | 0.372 proportion of participants |
| Ibrutinib + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 24 Months | 0.406 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 24 Months | 0.307 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 3 Months | 0.000 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 15 Months | 0.274 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 6 Months | 0.136 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 21 Months | 0.307 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 9 Months | 0.221 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 18 Months | 0.285 proportion of participants |
| Placebo + Prednisone | Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 12 Months | 0.264 proportion of participants |
p-value: 0.216Chi-squared
Secondary
Final Analysis: DOR for Participants Who Had PR or CR at Any Time
Response was defined using the NIH Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR was defined as resolution of all manifestations in each organ or site. PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. Duration of response was estimated by Kaplan-Meier methodology.
Time frame: Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021)
Population: Participants in the Intent-to-Treat Population (all randomized participants) who had response of CR/PR at any time during the study and had not started any subsequent therapy for cGVHD or had evidence of relapse of their underlying disease that was indication for transplant at the time of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: DOR for Participants Who Had PR or CR at Any Time | 19.1 months |
| Placebo + Prednisone | Final Analysis: DOR for Participants Who Had PR or CR at Any Time | 10.2 months |
p-value: 0.100495% CI: [0.482, 1.068]Regression, Cox
Secondary
Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone
AE: any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization \>24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity was graded according to the Common Terminology Criteria for Adverse Events version 4.03 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death). Treatment-related events are those that were possibly related or related to study treatment per investigator's judgment. Treatment emergent AEs (TEAEs) occurred from the first dose of study drug up to 30 days after the last dose of study drug.
Time frame: From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 12 July 2021), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months.
Population: Safety Population: all participants who received at least one dose of either ibrutinib or placebo, analyzed according to the actual treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Corticosteroid-Related TEAE | 72 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to DC of Corticosteroid | 10 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 TEAE | 64 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Treatment Emergent SAE (TESAE) | 49 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 Corticosteroid-Related TEAE | 34 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 TESAE | 46 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 Ibrutinib-/Placebo-Related TEAE | 35 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Treatment-Related TESAE | 29 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to Discontinuation (DC) of Any Treatment | 23 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Ibrutinib/Placebo Treatment-Related TESAE | 26 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Ibrutinib-/Placebo-Related TEAE | 67 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Corticosteroid Treatment-Related TESAE | 26 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to DC of Ibrutinib/Placebo | 22 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Fatal TEAE | 12 Participants |
| Ibrutinib + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE | 93 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Fatal TEAE | 6 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE | 95 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 TEAE | 64 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Ibrutinib-/Placebo-Related TEAE | 57 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 Ibrutinib-/Placebo-Related TEAE | 27 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Corticosteroid-Related TEAE | 76 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 Corticosteroid-Related TEAE | 35 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to Discontinuation (DC) of Any Treatment | 28 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to DC of Ibrutinib/Placebo | 27 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to DC of Corticosteroid | 9 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Treatment Emergent SAE (TESAE) | 47 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 TESAE | 45 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Treatment-Related TESAE | 27 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Ibrutinib/Placebo Treatment-Related TESAE | 18 Participants |
| Placebo + Prednisone | Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Corticosteroid Treatment-Related TESAE | 26 Participants |
Secondary
Final Analysis: OS
OS was defined as the time of randomization until the time of death due to any cause, in months.
Time frame: Median time on study (cumulatively up to 12 July 2021) was 33.1 months and 32.5 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively.
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: OS | NA months |
| Placebo + Prednisone | Final Analysis: OS | NA months |
95% CI: [0.591, 1.904]
Secondary
Final Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days
Time frame: 24 weeks (Cumulatively up to 12 July 2021)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days | 41.1 percentage of participants |
| Placebo + Prednisone | Final Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days | 45.9 percentage of participants |
p-value: 0.495595% CI: [-0.188, 0.091]Chi-squared
Secondary
Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits
Clinically meaningful improvement on Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment. The Lee cGVHD Symptom Scale score has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely, with lower values representing a better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores.
Time frame: Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits | 43.2 percentage of participants |
| Placebo + Prednisone | Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits | 30.6 percentage of participants |
p-value: 0.070895% CI: [-0.01, 0.261]Chi-squared
Secondary
Final Analysis: Response Rate at 24 Weeks
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a CR or PR at 24 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
Time frame: 24 weeks (Cumulatively up to 12 July 2021)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Prednisone | Final Analysis: Response Rate at 24 Weeks | 47.4 percentage of participants |
| Placebo + Prednisone | Final Analysis: Response Rate at 24 Weeks | 54.1 percentage of participants |
p-value: 0.35195% CI: [-0.208, 0.074]Chi-squared
Secondary
Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD
The cumulative incidence of withdrawal of all corticosteroids (95% confidence interval \[CI\]) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all corticosteroids at given time point. The time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days.
Time frame: Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 30 March 2020)
Population: Intent to Treat Population: all randomized participants. Participants with withdrawal of all corticosteroids. No participants were on corticosteroids at 21 and 24 Months in the Ibrutinib + Prednisone Arm/Group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 15 Months | 0.419 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 6 Months | 0.229 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 18 Months | 0.419 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 12 Months | 0.392 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 9 Months | 0.318 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 3 Months | 0.042 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 18 Months | 0.356 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 21 Months | 0.425 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 24 Months | 0.425 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 3 Months | 0.021 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 6 Months | 0.216 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 9 Months | 0.322 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 12 Months | 0.356 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD | 15 Months | 0.356 proportion of participants |
p-value: 0.324Chi-squared
Secondary
Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants
The cumulative incidence of withdrawal of all immunosuppressants (95% CI) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all immunosuppressants at a given time point. The time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD, sustained for at least 30 days. All immunosuppressants include corticosteroids but they do not include ibrutinib.
Time frame: Months 3, 6, 9, 12, 15, 18, 21, 24 (cumulatively up to 30 March 2020)
Population: Intent to Treat Population: all randomized participants. Participants with withdrawal of all immunosuppressants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 3 Months | 0.011 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 6 Months | 0.142 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 9 Months | 0.220 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 12 Months | 0.256 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 15 Months | 0.285 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 18 Months | 0.313 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 21 Months | 0.376 proportion of participants |
| Ibrutinib + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 24 Months | 0.421 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 24 Months | 0.268 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 3 Months | 0.000 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 15 Months | 0.241 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 6 Months | 0.134 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 21 Months | 0.268 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 9 Months | 0.207 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 18 Months | 0.241 proportion of participants |
| Placebo + Prednisone | Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants | 12 Months | 0.241 proportion of participants |
p-value: 0.275Chi-squared
Secondary
Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time
Response was defined using the NIH Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR was defined as resolution of all manifestations in each organ or site. PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. Duration of response was estimated by Kaplan-Meier methodology.
Time frame: Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020)
Population: Participants in the Intent-to-Treat Population (all randomized participants) who had response of CR/PR at any time during the study and had not started any subsequent therapy for cGVHD or had evidence of relapse of their underlying disease that was indication for transplant at the time of response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time | 19.8 months |
| Placebo + Prednisone | Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time | 10.0 months |
p-value: 0.10195% CI: [0.451, 1.076]Regression, Cox
Secondary
Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone
AE: any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization \>24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity was graded according to the Common Terminology Criteria for Adverse Events version 4.03 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death). Treatment-related events are those that were possibly related or related to study treatment per investigator's judgment. Treatment emergent AEs (TEAEs) occurred from the first dose of study drug up to 30 days after the last dose of study drug.
Time frame: From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 30 March 2020), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months.
Population: Safety Population: all participants who received at least one dose of either ibrutinib or placebo, analyzed according to the actual treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to DC of Ibrutinib/Placebo | 21 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Ibrutinib/Placebo Treatment-Related TESAE | 24 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to DC of Corticosteroid | 8 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 Ibrutinib-/Placebo-Related TEAE | 32 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Treatment Emergent SAE (TESAE) | 46 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 TEAE | 60 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 TESAE | 43 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Corticosteroid-Related TEAE | 71 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Treatment-Related TESAE | 27 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE | 93 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 Corticosteroid-Related TEAE | 32 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Corticosteroid Treatment-Related TESAE | 24 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Ibrutinib-/Placebo-Related TEAE | 66 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Fatal TEAE | 10 Participants |
| Ibrutinib + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to Discontinuation (DC) of Any Treatment | 21 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Fatal TEAE | 7 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE | 95 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 TEAE | 64 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Ibrutinib-/Placebo-Related TEAE | 58 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 Ibrutinib-/Placebo-Related TEAE | 28 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Corticosteroid-Related TEAE | 77 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 Corticosteroid-Related TEAE | 36 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to DC of Ibrutinib/Placebo | 23 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to DC of Corticosteroid | 8 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Treatment Emergent SAE (TESAE) | 48 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Grade ≥ 3 TESAE | 46 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Treatment-Related TESAE | 28 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Ibrutinib/Placebo Treatment-Related TESAE | 19 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any Corticosteroid Treatment-Related TESAE | 27 Participants |
| Placebo + Prednisone | Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone | Any TEAE Leading to Discontinuation (DC) of Any Treatment | 24 Participants |
Secondary
Primary Analysis: Overall Survival (OS)
OS was defined as the time of randomization until the time of death due to any cause, in months.
Time frame: Median time on study (cumulatively up to 30 March 2020) was 19.8 months and 18.4 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively.
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Overall Survival (OS) | NA months |
| Placebo + Prednisone | Primary Analysis: Overall Survival (OS) | NA months |
95% CI: [0.507, 1.949]
Secondary
Primary Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days
Time frame: 24 weeks (Cumulatively up to 30 March 2020)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days | 40.0 percentage of participants |
| Placebo + Prednisone | Primary Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days | 45.9 percentage of participants |
p-value: 0.406495% CI: [-0.199, 0.08]Chi-squared
Secondary
Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits
Clinically meaningful improvement on Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment. The Lee cGVHD Symptom Scale score has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely, with lower values representing a better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores.
Time frame: Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits | 38.9 percentage of participants |
| Placebo + Prednisone | Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits | 26.5 percentage of participants |
p-value: 0.065995% CI: [-0.007, 0.256]Chi-squared
Secondary
Primary Analysis: Response Rate at 24 Weeks
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a CR or PR at 24 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
Time frame: 24 weeks (Cumulatively up to 30 March 2020)
Population: Intent to Treat Population: all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib + Prednisone | Primary Analysis: Response Rate at 24 Weeks | 47.4 percentage of participants |
| Placebo + Prednisone | Primary Analysis: Response Rate at 24 Weeks | 54.1 percentage of participants |
p-value: 0.35195% CI: [-0.208, 0.074]Chi-squared