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NCT02959944: iNTEGRATE

Ibrutinib in Combination With Corticosteroids vs Placebo in Combination With Corticosteroids in Participants With New Onset Chronic Graft Versus Host Disease (cGVHD)

Completed Phase 3 Results posted Last updated 30 March 2023
What this trial tests

Phase 3 trial testing ibrutinib in Chronic Graft Versus Host Disease in 193 participants. Completed in 12 July 2021.

Timeline
11 May 2017
Primary endpoint
27 March 2020
12 July 2021

Quick facts

Lead sponsorPharmacyclics LLC.
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment193
Start date11 May 2017
Primary completion27 March 2020
Estimated completion12 July 2021
Sites102 locations across France, Italy, Japan, Austria, Taiwan, Germany, Hungary, South Korea

Drugs / interventions tested

Conditions studied

Sponsor

Pharmacyclics LLC. — full company profile →

Who can join

12 and older, any sex, with Chronic Graft Versus Host Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Primary Analysis: Response Rate at 48 Weeks Primary · 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

GroupValue95% CI
Ibrutinib + Prednisone41.1
Placebo + Prednisone36.7
Final Analysis: Response Rate at 48 Weeks Primary · 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

GroupValue95% CI
Ibrutinib + Prednisone41.1
Placebo + Prednisone36.7
Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD Secondary · 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.

3 Months
GroupValue95% CI
Ibrutinib + Prednisone0.0420.014 – 0.097
Placebo + Prednisone0.0210.004 – 0.066
6 Months
GroupValue95% CI
Ibrutinib + Prednisone0.2290.149 – 0.320
Placebo + Prednisone0.2160.140 – 0.304
9 Months
GroupValue95% CI
Ibrutinib + Prednisone0.3180.225 – 0.415
Placebo + Prednisone0.3220.231 – 0.417
12 Months
GroupValue95% CI
Ibrutinib + Prednisone0.3920.290 – 0.492
Placebo + Prednisone0.3560.260 – 0.453
15 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4190.314 – 0.520
Placebo + Prednisone0.3560.260 – 0.453
18 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4190.314 – 0.520
Placebo + Prednisone0.3560.260 – 0.453
21 Months
GroupValue95% CI
Placebo + Prednisone0.4250.299 – 0.545
24 Months
GroupValue95% CI
Placebo + Prednisone0.4250.299 – 0.545
Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD Secondary · 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.

3 Months
GroupValue95% CI
Ibrutinib + Prednisone0.0420.014 – 0.097
Placebo + Prednisone0.0210.004 – 0.066
6 Months
GroupValue95% CI
Ibrutinib + Prednisone0.2180.140 – 0.308
Placebo + Prednisone0.2190.142 – 0.307
9 Months
GroupValue95% CI
Ibrutinib + Prednisone0.3180.225 – 0.414
Placebo + Prednisone0.3260.234 – 0.422
12 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4060.305 – 0.505
Placebo + Prednisone0.3590.263 – 0.455
15 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4390.336 – 0.538
Placebo + Prednisone0.3590.263 – 0.455
18 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4500.346 – 0.549
Placebo + Prednisone0.3690.272 – 0.466
21 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4950.388 – 0.593
Placebo + Prednisone0.3910.292 – 0.489
24 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4950.388 – 0.593
Placebo + Prednisone0.3910.292 – 0.489
Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants Secondary · 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 includ

3 Months
GroupValue95% CI
Ibrutinib + Prednisone0.0110.001 – 0.052
Placebo + Prednisone0.000NA – NA
6 Months
GroupValue95% CI
Ibrutinib + Prednisone0.1420.079 – 0.222
Placebo + Prednisone0.1340.075 – 0.210
9 Months
GroupValue95% CI
Ibrutinib + Prednisone0.2200.141 – 0.310
Placebo + Prednisone0.2070.132 – 0.294
12 Months
GroupValue95% CI
Ibrutinib + Prednisone0.2560.170 – 0.350
Placebo + Prednisone0.2410.160 – 0.331
15 Months
GroupValue95% CI
Ibrutinib + Prednisone0.2850.193 – 0.383
Placebo + Prednisone0.2410.160 – 0.331
18 Months
GroupValue95% CI
Ibrutinib + Prednisone0.3130.210 – 0.422
Placebo + Prednisone0.2410.160 – 0.331
21 Months
GroupValue95% CI
Ibrutinib + Prednisone0.3760.252 – 0.499
Placebo + Prednisone0.2680.174 – 0.370
24 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4210.280 – 0.556
Placebo + Prednisone0.2680.174 – 0.370
Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants Secondary · 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 includ

3 Months
GroupValue95% CI
Ibrutinib + Prednisone0.0110.001 – 0.052
Placebo + Prednisone0.000NA – NA
6 Months
GroupValue95% CI
Ibrutinib + Prednisone0.1430.080 – 0.224
Placebo + Prednisone0.1360.076 – 0.213
9 Months
GroupValue95% CI
Ibrutinib + Prednisone0.2220.142 – 0.313
Placebo + Prednisone0.2210.143 – 0.309
12 Months
GroupValue95% CI
Ibrutinib + Prednisone0.2800.191 – 0.375
Placebo + Prednisone0.2640.179 – 0.356
15 Months
GroupValue95% CI
Ibrutinib + Prednisone0.3140.220 – 0.412
Placebo + Prednisone0.2740.188 – 0.367
18 Months
GroupValue95% CI
Ibrutinib + Prednisone0.3490.251 – 0.448
Placebo + Prednisone0.2850.197 – 0.379
21 Months
GroupValue95% CI
Ibrutinib + Prednisone0.3720.272 – 0.472
Placebo + Prednisone0.3070.216 – 0.402
24 Months
GroupValue95% CI
Ibrutinib + Prednisone0.4060.303 – 0.507
Placebo + Prednisone0.3070.216 – 0.402
Primary Analysis: Response Rate at 24 Weeks Secondary · 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 evaluat

GroupValue95% CI
Ibrutinib + Prednisone47.4
Placebo + Prednisone54.1
Final Analysis: Response Rate at 24 Weeks Secondary · 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 evaluat

GroupValue95% CI
Ibrutinib + Prednisone47.4
Placebo + Prednisone54.1
Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits Secondary · 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

GroupValue95% CI
Ibrutinib + Prednisone38.9
Placebo + Prednisone26.5
Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits Secondary · 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

GroupValue95% CI
Ibrutinib + Prednisone43.2
Placebo + Prednisone30.6
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 Secondary · 24 weeks (Cumulatively up to 30 March 2020)
GroupValue95% CI
Ibrutinib + Prednisone40.0
Placebo + Prednisone45.9
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 Secondary · 24 weeks (Cumulatively up to 12 July 2021)
GroupValue95% CI
Ibrutinib + Prednisone41.1
Placebo + Prednisone45.9

Adverse events — posted to ClinicalTrials.gov

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.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Ibrutinib
Serious: 51/94 (54%)
Deaths: 23/94
Placebo
Serious: 49/96 (51%)
Deaths: 22/96

Serious adverse events (128 terms)

ReactionSystemIbrutinibPlacebo
PNEUMONIAInfections and infestations——
INFLUENZAInfections and infestations——
ACUTE MYELOID LEUKAEMIA RECURRENTNeoplasms benign, malignant and unspecified (incl cysts and polyps)——
PULMONARY EMBOLISMRespiratory, thoracic and mediastinal disorders——
PYREXIAGeneral disorders——
GRAFT VERSUS HOST DISEASEImmune system disorders——
CHRONIC GRAFT VERSUS HOST DISEASEImmune system disorders——
CELLULITISInfections and infestations——
ATRIAL FIBRILLATIONCardiac disorders——
PERICARDIAL EFFUSIONCardiac disorders——
DIARRHOEAGastrointestinal disorders——
GASTROINTESTINAL HAEMORRHAGEGastrointestinal disorders——
DEATHGeneral disorders——
COVID-19Infections and infestations——
PNEUMONIA RESPIRATORY SYNCYTIAL VIRALInfections and infestations——
SEPSISInfections and infestations——
SEPTIC SHOCKInfections and infestations——
HYPERGLYCAEMIAMetabolism and nutrition disorders——
HYPONATRAEMIAMetabolism and nutrition disorders——
STEROID DIABETESMetabolism and nutrition disorders——
LEUKAEMIA RECURRENTNeoplasms benign, malignant and unspecified (incl cysts and polyps)——
SYNCOPENervous system disorders——
ACUTE KIDNEY INJURYRenal and urinary disorders——
HAEMATURIARenal and urinary disorders——
RESPIRATORY FAILURERespiratory, thoracic and mediastinal disorders——
Other adverse events (70 terms — click to expand)

ReactionSystemIbrutinibPlacebo
COUGHRespiratory, thoracic and mediastinal disorders——
INSOMNIAPsychiatric disorders——
OEDEMA PERIPHERALGeneral disorders——
THROMBOCYTOPENIABlood and lymphatic system disorders——
FATIGUEGeneral disorders——
MUSCLE SPASMSMusculoskeletal and connective tissue disorders——
PYREXIAGeneral disorders——
ALANINE AMINOTRANSFERASE INCREASEDInvestigations——
VOMITINGGastrointestinal disorders——
UPPER RESPIRATORY TRACT INFECTIONInfections and infestations——
CONSTIPATIONGastrointestinal disorders——
DIARRHOEAGastrointestinal disorders——
HYPOKALAEMIAMetabolism and nutrition disorders——
DYSPNOEARespiratory, thoracic and mediastinal disorders——
NAUSEAGastrointestinal disorders——
ASPARTATE AMINOTRANSFERASE INCREASEDInvestigations——
HYPERGLYCAEMIAMetabolism and nutrition disorders——
ARTHRALGIAMusculoskeletal and connective tissue disorders——
HEADACHENervous system disorders——
HYPERTENSIONVascular disorders——
ANAEMIABlood and lymphatic system disorders——
BACK PAINMusculoskeletal and connective tissue disorders——
DIZZINESSNervous system disorders——
CONTUSIONInjury, poisoning and procedural complications——
INCREASED TENDENCY TO BRUISEBlood and lymphatic system disorders——
VISION BLURREDEye disorders——
HYPONATRAEMIAMetabolism and nutrition disorders——
HYPOPHOSPHATAEMIAMetabolism and nutrition disorders——
MUSCULAR WEAKNESSMusculoskeletal and connective tissue disorders——
TREMORNervous system disorders——
ABDOMINAL PAINGastrointestinal disorders——
NASOPHARYNGITISInfections and infestations——
HYPERKALAEMIAMetabolism and nutrition disorders——
HYPOMAGNESAEMIAMetabolism and nutrition disorders——
ACUTE KIDNEY INJURYRenal and urinary disorders——
RHINORRHOEARespiratory, thoracic and mediastinal disorders——
CATARACTEye disorders——
DYSPEPSIAGastrointestinal disorders——
BRONCHITISInfections and infestations——
RHINOVIRUS INFECTIONInfections and infestations——

Most-reported serious reactions: PNEUMONIA, INFLUENZA, ACUTE MYELOID LEUKAEMIA RECURRENT, PULMONARY EMBOLISM, PYREXIA, GRAFT VERSUS HOST DISEASE, CHRONIC GRAFT VERSUS HOST DISEASE, CELLULITIS.

Data from ClinicalTrials.gov NCT02959944 adverse events section.

Sponsor's own description

To evaluate the safety and efficacy of ibrutinib in combination with prednisone in subjects with newly diagnosed moderate to severe cGVHD.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy.
    Miklos D, Cutler CS, Arora M, Waller EK, et al · · 2017 · cited 374× · PMID 28924018 · DOI 10.1182/blood-2017-07-793786
  2. Paediatric cardio-oncology: epidemiology, screening, prevention, and treatment.
    Chow EJ, Leger KJ, Bhatt NS, Mulrooney DA, et al · · 2019 · cited 88× · PMID 30768157 · DOI 10.1093/cvr/cvz031
  3. New and emerging therapies for acute and chronic graft <i>versus</i> host disease.
    Hill L, Alousi A, Kebriaei P, Mehta R, et al · · 2018 · cited 81× · PMID 29317998 · DOI 10.1177/2040620717741860
  4. How ibrutinib, a B-cell malignancy drug, became an FDA-approved second-line therapy for steroid-resistant chronic GVHD.
    Jaglowski SM, Blazar BR. · · 2018 · cited 67× · PMID 30108109 · DOI 10.1182/bloodadvances.2018013060
  5. Three US Food and Drug Administration-approved therapies for chronic GVHD.
    Zeiser R, Lee SJ. · · 2022 · cited 57× · PMID 35081254 · DOI 10.1182/blood.2021014448
  6. Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease.
    Martini DJ, Chen YB, DeFilipp Z. · · 2022 · cited 55× · PMID 35443042 · DOI 10.1093/oncolo/oyac076
  7. Bruton's Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives.
    Robak E, Robak T. · · 2022 · cited 45× · PMID 35628931 · DOI 10.3390/jcm11102807
  8. Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study.
    Miklos DB, Abu Zaid M, Cooney JP, Albring JC, et al · · 2023 · cited 43× · PMID 36608310 · DOI 10.1200/jco.22.00509

Verify or expand the search:

Other trials of ibrutinib

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Trials by the same sponsor.

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Data sources for this page

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing