BRIGHT AML1019: A Study Evaluating Intensive Chemotherapy With or Without Glasdegib or Azacitidine With or Without Glasdegib In Patients With Previously Untreated Acute Myeloid Leukemia

Sponsor
Pfizer (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03416179
Collaborator
(none)
730
Enrollment
149
Locations
4
Arms
55.8
Anticipated Duration (Months)
4.9
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (Non-intensive AML population).

Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).

Condition or DiseaseIntervention/TreatmentPhase
Phase 3

Detailed Description

Two separate registration trials conducted under one protocol number are proposed to adequately and independently evaluate the addition of glasdegib in intensive and non-intensive chemotherapy populations. Each study will have an experimental treatment arm and a placebo arm. Endpoints are the same for each study except where specifically indicated.

Assignment to the Intensive Study or the Non-Intensive Study will be made by the Investigator based on the 2017 European LeukemiaNet (ELN) recommendations.

Study B1371019 is a randomized (1:1), double-blind, multi-center, placebo controlled study of chemotherapy in combination with glasdegib versus chemotherapy in combination with placebo in adult patients with previously untreated AML.

Glasdegib is being studied in combination with azacitidine for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) who are not candidates for intensive induction chemotherapy (Non-intensive AML population).

Glasdegib is being studied in combination with cytarabine and daunorubicin for the treatment of adult patients with previously untreated acute myeloid leukemia (Intensive AML population).

Study Design

Study Type:
Interventional
Actual Enrollment :
730 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Randomized, double-blind, multi-center, placebo controlled study.Randomized, double-blind, multi-center, placebo controlled study.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Double blind study.
Primary Purpose:
Treatment
Official Title:
A RANDOMIZED (1:1), DOUBLE-BLIND, MULTI-CENTER, PLACEBO CONTROLLED STUDY EVALUATING INTENSIVE CHEMOTHERAPY WITH OR WITHOUT GLASDEGIB (PF-04449913) OR AZACITIDINE (AZA) WITH OR WITHOUT GLASDEGIB IN PATIENTS WITH PREVIOUSLY UNTREATED ACUTE MYELOID LEUKEMIA
Actual Study Start Date :
Apr 20, 2018
Actual Primary Completion Date :
Jun 5, 2020
Anticipated Study Completion Date :
Dec 13, 2022

Arms and Interventions

ArmIntervention/Treatment
Experimental: Arm A (Intensive Study)

Glasdegib + '7+3' Induction(s)

Drug: glasdegib
Daily Glasdegib (100 mg, PO), beginning on Day 1 and is to continue up to 2 years post randomization. Following consolidation therapy, glasdegib or placebo will be administered daily for up to 2 years after randomization or until they have minimal residual disease (MRD) negative disease, whichever comes first. Daily Glasdegib (100 mg, PO) or matching placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy.
Other Names:
  • PF-04449913
  • Drug: daunorubicin + cytarabine
    '7+3' (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days). If a second induction is needed, Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days ('5+2') or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days ('7+3');

    Drug: cytarabine
    Consolidation with single agent cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 BID on Days 1, 3, and 5, every 28 days for up to 4 cycles or alternative single agent cytarabine consolidation schedules may be used per local prescribing information.

    Procedure: HSCT
    If required, and done per standard of care post Induction(s).

    Placebo Comparator: Arm B (Intensive Study)

    Placebo + '7+3' Induction(s)

    Drug: daunorubicin + cytarabine
    '7+3' (cytarabine 100 mg/m2, IV for 7 days by continuous infusion and daunorubicin 60 mg/m2 for 3 days). If a second induction is needed, Investigators may choose either a 5 day cytarabine continuous infusion plus daunorubicin for 2 days ('5+2') or a 7 day cytarabine continuous infusion plus daunorubicin for 3 days ('7+3');

    Drug: Placebo
    Matching placebo (PO) given on Day 1 and is to continue up to 2 years post randomization. Following consolidation therapy, placebo will be administered daily for up to 2 years after randomization or until they have MRD negative disease, whichever comes first. Daily placebo will continue throughout Induction(s) and Consolidation therapies regardless of dose modifications/delays in the chemotherapy.

    Drug: cytarabine
    Consolidation with single agent cytarabine 3 g/m2 IV for adults <60 years and 1 g/m2 for adults 60 years over 3 BID on Days 1, 3, and 5, every 28 days for up to 4 cycles or alternative single agent cytarabine consolidation schedules may be used per local prescribing information.

    Procedure: HSCT
    If required, and done per standard of care post Induction(s).

    Experimental: Arm A (Non-intensive study)

    Glasdegib + azacitidine

    Drug: azacitidine
    Azacitidine (75 mg/m2, SC or IV) daily for 7 days, in 28 day cycles for as long as they do not meet the criteria for disease progression, unacceptable toxicity, consent withdrawal, or death.

    Drug: glasdegib
    Glasdegib 100 mg PO QD is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays/modifications in the chemotherapy treatment. Subjects will continue glasdegib until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.

    Placebo Comparator: Arm B (Non-intensive study)

    Placebo + azacitidine

    Drug: azacitidine
    Azacitidine (75 mg/m2, SC or IV) daily for 7 days, in 28 day cycles for as long as they do not meet the criteria for disease progression, unacceptable toxicity, consent withdrawal, or death.

    Drug: Placebo
    Matching placebo (PO) is to be administered by mouth daily beginning on Day 1 of chemotherapy and will continue if subjects demonstrate reasonable evidence of clinical benefit and do not meet the criteria for progression regardless of any delays/modifications in the chemotherapy treatment. Subjects will continue placebo until disease progression, unacceptable toxicity, consent withdrawal, or death, whichever comes first.

    Outcome Measures

    Primary Outcome Measures

    1. Intensive Study: Overall Survival (OS) [Baseline up to 25 months]

      OS is defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were to be censored at the date of last contact.

    2. Non-intensive Study: Overall Survival (OS) [Baseline up to 25 months]

      OS is defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were to be censored at the date of last contact.

    Secondary Outcome Measures

    1. Intensive Study: Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (DASI-AML/MDS) Questionnaire [Baseline up to 5 years]

    2. Non-intensive Study: Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (DASI-AML/MDS) Questionnaire [Baseline up to 5 years]

    3. Intensive Study: Percentage of Participants With Complete Remission With Negative Minimal Residual Disease (CRMRD-neg) [Baseline up to 5 years]

    4. Non-intensive Study: Percentage of Participants With Complete Remission With Negative Minimal Residual Disease (CRMRD-neg) [Baseline up to 5 years]

    5. Intensive Study: Percentage of Participants With Complete Remission (CR) Including Complete Remission With Negative Minimal Residual Disease (CRMRD-neg) [Baseline up to 5 years]

    6. Non-intensive Study: Percentage of Participants With Complete Remission (CR) Including Complete Remission With Negative Minimal Residual Disease (CRMRD-neg) [Baseline up to 5 years]

    7. Intensive Study: Percentage of Participants With Complete Remission With Incomplete Hematologic Recovery (CRi) [Baseline up to 5 years]

    8. Non-intensive Study: Percentage of Participants With Complete Remission With Incomplete Hematologic Recovery (CRi) [Baseline up to 5 years]

    9. Intensive Study: Percentage of Participants With Morphologic Leukemia-free State (MLFS) [Baseline up to 5 years]

    10. Non-intensive Study: Percentage of Participants With Morphologic Leukemia-free State (MLFS) [Baseline up to 5 years]

    11. Intensive Study: Percentage of Participants With Partial Remission (PR) [Baseline up to 5 years]

    12. Non-intensive Study: Percentage of Participants With Partial Remission (PR) [Baseline up to 5 years]

    13. Non-intensive Study: Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) [Baseline up to 5 years]

    14. Intensive Study: Duration of Response [Baseline up to 5 years]

    15. Non-intensive Study: Duration of Response [Baseline up to 5 years]

    16. Non-intensive Study: Time to Response [Baseline up to 5 years]

    17. Intensive Study: Event-free Survival [Baseline up to 5 years]

    18. Non-intensive Study: Event-free Survival [Baseline up to 5 years]

    19. Intensive Study: MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Score [Baseline up to 5 years]

    20. Non-intensive Study: MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Score [Baseline up to 5 years]

    21. Intensive Study: EuroQoL 5 Dimension Questionnaire 5-Level Version (EQ-5D-5L) Score [Baseline up to 5 years]

    22. Non-intensive Study: EuroQoL 5 Dimension Questionnaire 5-Level Version (EQ-5D-5L) Score [Baseline up to 5 years]

    23. Intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS) [Baseline up to 5 years]

    24. Non-intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS) [Baseline up to 5 years]

    25. Intensive Study: Participants Global Impression of Symptoms (PGIS) [Baseline up to 5 years]

    26. Non-intensive Study: Participants Global Impression of Symptoms (PGIS) [Baseline up to 5 years]

    27. Intensive Study: Participants Global Impression of Change (PGIC) [Baseline up to 5 years]

    28. Non-intensive Study: Participants Global Impression of Change (PGIC) [Baseline up to 5 years]

    29. Intensive Study: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 [Baseline up to 5 years]

    30. Non-intensive Study: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 [Baseline up to 5 years]

    31. Intensive Study: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 [Baseline up to 5 years]

    32. Non-intensive Study: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03 [Baseline up to 5 years]

    33. Intensive Study: Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE v.4.03 [Baseline up to 5 years]

    34. Non-intensive Study: Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE v.4.03 [Baseline up to 5 years]

    35. Intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib [1 and 4 hour post dose on Day 1 in first induction therapy; pre-dose, 1, and 4 hours post dose on day 1 in consolidation phase cycles 1 and 2]

    36. Non-intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib [Pre-dose, 1 and 4 hour post dose on Day 1 and 15 of cycle 1; pre-dose, 1 and 4 hour post dose on day 1 of cycle 2 and 3]

    37. Intensive Study: QTc Interval [Baseline up to 5 years]

    38. Non-intensive Study: QTc Interval [Baseline up to 5 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the Intensive and Non Intensive study (unless where indicated):

    1. Subjects with untreated AML according to the World Health Organization (WHO) 2016
    Classification2, including those with:
    • AML arising from MDS or another antecedent hematologic disease (AHD).

    • AML after previous cytotoxic therapy or radiation (secondary AML).

    1. 18 years of age (In Japan, 20 years of age).

    2. Adequate Organ Function as defined by the following:

    • Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) 3 x upper limit of normal (ULN), excluding subjects with liver function abnormalities due to underlying malignancy.

    • Total serum bilirubin 2 x ULN (except subjects with documented Gilbert's syndrome).

    • Estimated creatinine clearance 30 mL/min as calculated using the standard method for the institution.

    1. QTc interval 470 msec using the Fridericia correction (QTcF).

    2. All anti cancer treatments (unless specified) should be discontinued 2 weeks from study entry, for example: targeted chemotherapy, radiotherapy, investigational agents, hormones, anagrelide or cytokines.

    • For control of rapidly progressing leukemia, all trans retinoic acid (ATRA), hydroxyurea, and/or leukopheresis may be used before and for up to 1 week after the first dose of glasdegib.
    1. Serum or urine pregnancy test (for female subjects of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (hCG) negative at screening.

    2. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use at least one highly effective method of contraception throughout the study and for 180 days after the last dose of azacitidine, cytarabine, or daunorubicin; and the last dose of glasdegib or placebo, whichever occurs later.

    3. Female subjects of non childbearing potential must meet at least 1 of the following criteria:

    4. Have undergone a documented hysterectomy and/or bilateral oophorectomy;

    5. Have medically confirmed ovarian failure; or

    6. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state.

    All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.

    1. Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision.

    2. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.

    3. Subjects who are willing and able to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures (including bone marrow [BM] assessments).

    Exclusion Criteria:

    Subjects with any of the following characteristics/conditions will not be included in the study:

    1. Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016 classification).

    2. AML with BCR ABL1 or t(9;22)(q34;q11.2) as a sole abnormality.

    • Complex genetics may include t(9;22) cytogenetic translocation.
    1. Subjects with known active CNS leukemia.

    2. Participation in other clinical studies involving other investigational drug(s) (Phases 1 4) within 4 weeks prior study entry and/or during study participation.

    3. Subjects known to be refractory to platelet or packed red cell transfusions per Institutional Guidelines, or a patient who refuses blood product support.

    4. Subjects with another active malignancy on treatment with the exception of basal cell carcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior or concurrent malignancies will be considered on a case by case basis.

    5. Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, symptomatic arrhythmias (including sustained ventricular tachyarrhythmia), right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms.

    6. Subjects with an active, life threatening or clinically significant uncontrolled systemic infection not related to AML.

    7. Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the Intensive Chemotherapy Study only.

    8. Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for the Intensive Chemotherapy Study only.

    9. Known malabsorption syndrome or other condition that may significantly impair absorption of study medication in the investigator's judgment (eg, gastrectomy, lap band, Crohn's disease) and inability or unwillingness to swallow tablets or capsules.

    10. Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers.

    11. Concurrent administration of herbal preparations.

    12. Major surgery or radiation within 4 weeks of starting study treatment.

    13. Documented or suspected hypersensitivity to any one of the following:

    • For subjects assigned to intensive chemotherapy, documented or suspected hypersensitivity to cytarabine (not including drug fever or exanthema, including known cerebellar side effects) or daunorubicin.

    • For subjects assigned to non intensive chemotherapy, documented or suspected hypersensitivity to azacitidine or mannitol.

    1. Known active drug or alcohol abuse.

    2. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

    3. Pregnant females or breastfeeding female subjects.

    4. Known recent or active suicidal ideation or behavior.

    5. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1UCLA Department of MedicineLos AngelesCaliforniaUnited States90095
    2UCLA Drug Information/Investigational DrugsLos AngelesCaliforniaUnited States90095
    3UCLA Hematology/Oncology ClinicLos AngelesCaliforniaUnited States90095
    4UCLA Ronald Reagan Medical CenterLos AngelesCaliforniaUnited States90095
    5UC Irvine Health - Chao Family Comprehensive Cancer CenterOrangeCaliforniaUnited States92868-3201
    6UCSF Helen Diller Family Comprehensive Cancer CenterSan FranciscoCaliforniaUnited States94143
    7University of California, San FranciscoSan FranciscoCaliforniaUnited States94143
    8UCLA Hematology/Oncology - Westlake VillageWestlake VillageCaliforniaUnited States91361
    9Augusta University Medical CenterAugustaGeorgiaUnited States30912
    10Georgia Cancer Center at Augusta UniversityAugustaGeorgiaUnited States30912
    11Tufts Medical Center Investigational Drug PharmacyBostonMassachusettsUnited States02111
    12Tufts Medical CenterBostonMassachusettsUnited States02111
    13Massachusetts General HospitalBostonMassachusettsUnited States02114
    14Beth Israel Deaconess Medical CenterBostonMassachusettsUnited States02215
    15MidAmerica Division, Inc., c/o Research Medical CenterKansas CityMissouriUnited States64132
    16Northwell Health/Monter Cancer CenterLake SuccessNew YorkUnited States11042
    17North Shore University HospitalManhassetNew YorkUnited States11030
    18Long Island Jewish Medical CenterNew Hyde ParkNew YorkUnited States11040
    19University of Rochester Medical CenterRochesterNew YorkUnited States14642
    20University Hospitals Cleveland Medical CenterClevelandOhioUnited States44106
    21Cleveland Clinic FoundationClevelandOhioUnited States44195
    22OHSU Center for Health and HealingPortlandOregonUnited States97239
    23Oregon Health & Science UniversityPortlandOregonUnited States97239
    24Centennial Medical CenterNashvilleTennesseeUnited States37203
    25TriStar Bone Marrow TransplantNashvilleTennesseeUnited States37203
    26Baylor University Medical CenterDallasTexasUnited States75246
    27Blood Cancer and Stem Cell Transplant ClinicSan AntonioTexasUnited States78229
    28Methodist Healthcare System of San AntonioSan AntonioTexasUnited States78229
    29Swedish Cancer InstituteSeattleWashingtonUnited States98104
    30Swedish Medical CenterSeattleWashingtonUnited States98122
    31St Vincent's Hospital SydneyDarlinghurstNew South WalesAustralia2010
    32St George HospitalKogarahNew South WalesAustralia2217
    33Royal Adelaide HospitalAdelaideSouth AustraliaAustralia5000
    34Landeskrankenhaus Salzburg, Universitatsklinik fur Innere Medizin III der PMUSalzburgAustria5020
    35Uniklinikum Salzburg, Landeskrankenhaus SalzburgSalzburgAustria5020
    36Krankenhaus Hietzing mit Neurologischem Zentrum RosenhugelWienAustria1130
    37AZ Sint-Jan Brugge-Oostende avBruggeBelgiumB-8000
    38Universitaire Ziekenhuizen Brussel (UZ Brussel)BrusselsBelgiumB-1090
    39Universitaire Ziekenhuizen BrusselBrusselsBelgiumB-1090
    40Universitaire Ziekenhuizen LeuvenLeuvenBelgiumB-3000
    41Health Sciences CentreWinnipegManitobaCanadaR3A 1R9
    42CancerCare ManitobaWinnipegManitobaCanadaR3E 0V9
    43Sunnybrook Research InstituteTorontoOntarioCanadaM4N 3M5
    44Princess Margaret Cancer CentreTorontoOntarioCanadaM5G 2M9
    45CIUSSS de l'Est-de-l'Ile-de- Montréal - Hôpital Maisonneuve-RosemontMontrealQuebecCanadaH1T 2M4
    46Royal University HospitalSaskatoonSaskatchewanCanadaS7N 0W8
    47Saskatoon Cancer CentreSaskatoonSaskatchewanCanadaS7N 4H4
    48The First Affiliated Hospital of USTC, Anhui Provincial HospitalHefeiAnhuiChina230001
    49Anhui Provincial HospitalHefeiAnhuiChina230071
    50Fujian Medical University Union HospitalFuzhouFujianChina350001
    51Guangdong Provincial People's HospitalGuangzhouGuangdongChina510080
    52Guangdong Second Provincial General HospitalGuangzhouGuangdongChina510317
    53Hebei Yanda Lu Daopei HospitalLangfangHebeiChina065201
    54Henan Provincial People's Hospital/Hematology DepartmentZhengzhouHenanChina450003
    55Henan Cancer HospitalZhengzhouHenanChina450008
    56Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology/Cancer CenterWuhanHubeiChina430030
    57West China Hospital, Sichuan UniversityChengduSichuanChina610041
    58Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical SciencesTianjinTianjinChina300020
    59The First Affiliated Hospital College of Medicine, Zhejiang UniversityHangzhouZhejiangChina310003
    60Ruijin Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina200025
    61Interni hematologicka a onkologicka klinika, Fakultni nemocnice BrnoBrnoCzechia625 00
    62Nemocnicni lekarnaBrnoCzechia625 00
    63Ustavni lekarnaOstrava - PorubaCzechia708 52
    64Klinika hematoonkologieOstrava-PorubaCzechia708 52
    65Interní hematologická klinika, Fakultni nemocnice Královské VinohradyPraha 10Czechia100 34
    66Ústavni lékárnaPraha 10Czechia100 34
    67CHU Henri MondorCréteilFrance94010
    68CHU de NantesNantes cedex 1France44093
    69CHU de Nantes Hotel DieuNantes cedexFrance44093
    70Hopital Saint LouisParisFrance75010
    71Centre Hospitalier Lyon Sud - Service d'HematologiePierre-Benite cedexFrance69495
    72Institut Gustave RoussyVillejuif cedexFrance94805
    73Klinikum der Universitaet MuenchenMunichBavariaGermany81377
    74Philipps-Universitaet MarburgMarburgHesseGermany35032
    75Universitätsklinikum KölnKoelnNorth Rhine WestphaliaGermany50937
    76Universitaetsklinikum MuensterMuensterNorth Rhine-westphaliaGermany48149
    77Universitaetsklinikum Hamburg-EppendorfHamburgGermany20246
    78Medizinische Hochschule HannoverHannoverGermany30625
    79Debreceni Egyetem Klinikai Kozpont Belgyogyaszati Klinika, Hematologia TanszekDebrecenHungary4032
    80Debreceni Egyetem Klinikai Kozpont Belgyogyaszati KlinikaDebrecenHungary4032
    81Petz Aladár Megyei Oktató Kórház, II. Belgyógyászat- Hematológiai OsztályGyőrHungary9024
    82Somogy Megyei Kaposi Mor Oktato KorhazKaposvarHungary7400
    83Szabolcs-Szatmar Bereg Megyei Korhazak es Egyetemi Oktatokorhaz, Josa Andras Korhaz, HematologiaNyiregyhazaHungary4400
    84Szabolcs-Szatmar Bereg Megyei Korhazak es Egyetemi Oktatokorhaz, Josa Andras Korhaz,NyiregyhazaHungary4400
    85Rambam Health Care CampusHaifaIsrael3109601
    86Shaare Zedek Medical CenterJerusalemIsrael9103102
    87Hadassah Medical Center (Ein Kerem)JerusalemIsrael91120
    88Hemato-oncology ambulatory ServicePetah TikvaIsrael4941492
    89Rabin Medical Center, Beilinson HospitalPetah TikvaIsrael4941492
    90AOU Ospedali Riuniti Umberto I, G.M. Lancisi, G. Salesi, Clinica Di EmatologiaTorrette Di AnconaAnconaItaly60126
    91SOD Farmacia-Dipt dei servizi -AOU Ospedali Riuniti Umberto I, G.M. Lancisi, G. SalesiTorette Di AnconaANItaly60126
    92A.O.U. di Ferrara- Arcispedale Sant'Anna,Cona, FerraraFEItaly44124
    93AO Ospedali Riuniti Marche Nord - Presidio Ospedaliero San Salvatore di Pesaro -PesaroPUItaly61122
    94Azienda Ospedaliera Universitaria Senese.SienaSIItaly53100
    95Azienda Ospedaliero Universitaria di Bologna Policlinico S.Orsola MalpighiBolognaItaly40138
    96Azienda Ospedaliera Universitaria SeneseSienaItaly53100
    97Japanese Red Cross Nagoya Daini HospitalNagoyaAichiJapan466-8650
    98University of Fukui HospitalYoshida-gunFukuiJapan910-1193
    99Gunma University HospitalMaebashiGunmaJapan371-8511
    100Kobe University HospitalKobe-shiHyogoJapan650-0017
    101Yokohama City University Medical CenterYokohamaKanagawaJapan232-0024
    102Tohoku University HospitalSendaiMiyagiJapan980-8574
    103Osaka City University HospitalOsaka-CityOsakaJapan545-8586
    104Kindai University HospitalOsaka-SayamaOsakaJapan589-8511
    105Shizuoka Cancer CenterSunto-gunShizuokaJapan411-8777
    106National Hospital Organization Disaster Medical CenterTachikawaTokyoJapan190-0014
    107Akita University HospitalAkitaJapan010-8543
    108Kyushu University HospitalFukuokaJapan812-8582
    109National Hospital Organization Kumamoto Medical CenterKumamotoJapan860-0008
    110Nagasaki University HospitalNagasakiJapan852-8501
    111Tokyo Medical University HospitalTokyoJapan160-0023
    112Chonbuk National University HospitalJeonju-siJeollabuk-doKorea, Republic of54907
    113Inje University Busan Paik HospitalBusanKorea, Republic of47392
    114Keimyung University Dongsan HospitalDaeguKorea, Republic of42601
    115Gachon University Gil Medical CenterIncheonKorea, Republic of21565
    116Seoul National University HospitalSeoulKorea, Republic of03080
    117Clinical Trial Center, Severance Hospital, Yonsei University Health SystemSeoulKorea, Republic of03722
    118Severance Hospital, Yonsei University Health SystemSeoulKorea, Republic of03722
    119Samsung Medical CenterSeoulKorea, Republic of06351
    120The Catholic University of Korea Seoul St. Mary's HospitalSeoulKorea, Republic of06591
    121Instituto Nacional de CancerologíaMéxicoMÉXMexico14080
    122Hospital Universitario "Dr. Jose Eleuterio Gonzalez"MonterreyNuevo LEONMexico64460
    123Klinika Hematologii i Transplantologii Uniwersyteckie Centrum KliniczneGdanskPoland80-214
    124WWCOiT im. M. Kopernika w LodziLodzPoland93-513
    125Institutul Oncologic 'Prof. Dr. Ion Chiricuta'Cluj-NapocaClujRomania400124
    126Spitalul Clinic Municipal Filantropia Craiova, Sectia Clinica HematologieCraiovaDoljRomania200136
    127Sp. Clinic de Urgenta Militar Central Dr. Carol DavilaBucharestRomania010825
    128Spitalul Clinic Coltea, Clinica de HematologieBucurestiRomania030171
    129State Budgetary Healthcare Institution of MoscowMoscowRussian Federation129301
    130SBHI NNR NN RCH n. a. N.A. SemashkoNizhniy NovgorodRussian Federation603126
    131State Budgetary Institution of Ryazan Region 'Regional Clinical Hospital' (SBI RR RCH)RyazanRussian Federation390039
    132V.A Almazov NMRCSaint PetersburgRussian Federation197341
    133Hospital del MarBarcelonaSpain08003
    134Hospital de la Santa Creu i Sant PauBarcelonaSpain08025
    135Hospital Universitario Arnau de VilanovaLleidaSpain25198
    136Hospital General Universitario Gregorio MaranonMadridSpain28007
    137Hospital Universitario Ramon y CajalMadridSpain28034
    138Hospital Universitario Virgen del RocioSevillaSpain41013
    139Hospital Universitari i Politecnic La FeValenciaSpain46026
    140Universitetssjukhuset OrebroOrebroSweden701 85
    141Karolinska Universitetssjukhuset HuddingeStockholmSweden141 86
    142National Cheng Kung University HospitalTainanTaiwan704
    143National Taiwan University HospitalTaipeiTaiwan100
    144Taipei Veterans General HospitalTaipeiTaiwan11217
    145Koo Foundation Sun Yat-Sen Cancer CenterTaipeiTaiwan112
    146Chang Gung Memorial Hospital-Linkou BranchTaoyuan CityTaiwan333
    147The Royal Marsden NHS Foundation TrustSuttonSurreyUnited KingdomSM2 5PT
    148University Hospitals Birmingham NHS Foundation TrustBirminghamWEST MidlandsUnited KingdomB15 2TH
    149Imperial College Healthcare NHS TrustLondonUnited KingdomW12 0HS

    Sponsors and Collaborators

    • Pfizer

    Investigators

    • Study Director: Pfizer CT.gov Call Center, Pfizer

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Pfizer
    ClinicalTrials.gov Identifier:
    NCT03416179
    Other Study ID Numbers:
    • B1371019
    • 2017-002822-19
    • BRIGHT
    • BRIGHT AML1019
    First Posted:
    Jan 31, 2018
    Last Update Posted:
    Nov 23, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Pfizer
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment DetailsThis study evaluated glasdegib in intensive and non-intensive chemotherapy populations. Intensive study: Glasdegib was studied in combination with cytarabine and daunorubicin for the treatment of adult participants with previously untreated acute myeloid leukemia (AML). Non-intensive study: Glasdegib was studied in combination with azacitidine for the treatment of adult participants with previously untreated AML who were not candidates for intensive induction chemotherapy.
    Pre-assignment DetailResults are reported at primary completion date and data has been reported only for primary outcome measures. Data for secondary outcome measures would be posted at secondary completion date. Inadvertently 1 participant was enrolled twice into the study resulting in enrollment number as 730. However, a total of 729 participants were randomized and received treatment in the study.
    Arm/Group TitleIntensive Study: Glasdegib + Cytarabine + DaunorubicinIntensive Study: Placebo + Cytarabine + DaunorubicinNon-intensive Study: Glasdegib + AzacitidineNon-intensive Study: Placebo + Azacitidine
    Arm/Group DescriptionParticipants received first induction therapy (28 days) (backbone chemotherapy+experimental therapy). Backbone chemotherapy: Cytarabine 100 milligram per square meter (mg/m^2) daily by intravenous (IV) infusion for 7 days along with daunorubicin 60 mg/m^2 daily IV for 3 days. Depending upon bone marrow blast or investigator judgement participants had second induction i.e. received either same backbone therapy or cytarabine 100 mg/m^2 IV daily for 5 days and daunorubicin 60 mg/m^2 IV daily for 2 days. Participants with less than (<) 5% bone marrow blasts entered into consolation phase- treated with either or both of following: 1) cytarabine 1 to 3 gram per square meter (gm/m^2) IV for adults greater than or equals to (>=) 60 to <60 years twice daily on Days 1, 3, and 5 for 4 cycle (each cycle 28 day) or cytarabine per local prescribing information. 2) Received hematopoietic stem cell transplantation (HSCT) per local standard of care. Experimental Therapy: Participants were to receive Glasdegib 100 milligram (mg) tablet orally (PO) once daily (QD) from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive complete remission (CR) minimal residual disease (MRD)-negative central laboratory results, whichever came first. Participants were to be followed up for first 2 years from last dose and were to had long term survival follow-up for up to 5 years from randomization of last participant or until death/consent withdrawal.Participants received first induction therapy (28 days) (backbone chemotherapy+experimental therapy). Backbone chemotherapy: Cytarabine 100 mg/m^2 daily by IV infusion for 7 days along with daunorubicin 60 mg/m^2 daily IV for 3 days. Depending upon bone marrow blast or investigator judgement participants had second induction i.e. received either same backbone therapy or cytarabine 100 mg/m^2 IV daily for 5 days and daunorubicin 60 mg/m^2 IV daily for 2 days. Participants with <5% bone marrow blasts entered into consolation phase- treated with either or both of following: 1) cytarabine 1 to 3 gram/m^2 IV for adults >=60 to <60 years twice daily on Days 1, 3, and 5 for 4 cycle (each cycle 28 day) or cytarabine per local prescribing information. 2) Received HSCT per local standard of care. Experimental Therapy: Participants were to receive Glasdegib 100 mg matching placebo tablet PO QD from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive CR MRD-negative central laboratory results, whichever came first. Participants were to be followed up for first 2 years from last dose and were to had long term survival follow-up for up to 5 years from randomization of last participant or until death/consent withdrawal.Participants received chemotherapy with azacitidine 75 mg/m^2 subcutaneous (SC) injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, participant refusal or death, whichever occurred first. Participants also were to receive glasdegib 100 mg PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible participants underwent HSCT per local standard of care and were to receive glasdegib up to 2 years following randomization unless 2 consecutive negative MRD assessments. Participants were to be followed up for first 2 years from last dose of drug and were to had long term follow-up for survival for up to 5 years from randomization of last participant in study, or until death, or consent withdrawal.Participants received chemotherapy with azacitidine 75 mg/m^2 SC injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, participants refusal or death, whichever occurred first. Participants also received glasdegib 100 mg tablet matching placebo PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible participants underwent HSCT per local standard of care and were to receive glasdegib matching placebo up to 2 years following randomization unless 2 consecutive negative MRD assessments. Participants were to be followed up for first 2 years from last dose of drug and were to had long term follow-up for survival for up to 5 years from randomization of last participant in study, or until death, or consent withdrawal.
    Period Title: Overall Study
    STARTED201203163162
    COMPLETED0000
    NOT COMPLETED201203163162

    Baseline Characteristics

    Arm/Group TitleIntensive Study: Glasdegib + Cytarabine + DaunorubicinIntensive Study: Placebo + Cytarabine + DaunorubicinNon-intensive Study: Glasdegib + AzacitidineNon-intensive Study: Placebo + AzacitidineTotal
    Arm/Group DescriptionParticipants received first induction therapy (28 days) (backbone chemotherapy+experimental therapy). Backbone chemotherapy: Cytarabine 100 milligram per square meter (mg/m^2) daily by intravenous (IV) infusion for 7 days along with daunorubicin 60 mg/m^2 daily IV for 3 days. Depending upon bone marrow blast or investigator judgement participants had second induction i.e. received either same backbone therapy or cytarabine 100 mg/m^2 IV daily for 5 days and daunorubicin 60 mg/m^2 IV daily for 2 days. Participants with less than (<) 5% bone marrow blasts entered into consolation phase- treated with either or both of following: 1) cytarabine 1 to 3 gram per square meter (gm/m^2) IV for adults greater than or equals to (>=) 60 to <60 years twice daily on Days 1, 3, and 5 for 4 cycle (each cycle 28 day) or cytarabine per local prescribing information. 2) Received hematopoietic stem cell transplantation (HSCT) per local standard of care. Experimental Therapy: Participants were to receive Glasdegib 100 milligram (mg) tablet orally (PO) once daily (QD) from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive complete remission (CR) minimal residual disease (MRD)-negative central laboratory results, whichever came first. Participants were to be followed up for first 2 years from last dose and were to had long term survival follow-up for up to 5 years from randomization of last participant or until death/consent withdrawal.Participants received first induction therapy (28 days) (backbone chemotherapy+experimental therapy). Backbone chemotherapy: Cytarabine 100 mg/m^2 daily by IV infusion for 7 days along with daunorubicin 60 mg/m^2 daily IV for 3 days. Depending upon bone marrow blast or investigator judgement participants had second induction i.e. received either same backbone therapy or cytarabine 100 mg/m^2 IV daily for 5 days and daunorubicin 60 mg/m^2 IV daily for 2 days. Participants with <5% bone marrow blasts entered into consolation phase- treated with either or both of following: 1) cytarabine 1 to 3 gram/m^2 IV for adults >=60 to <60 years twice daily on Days 1, 3, and 5 for 4 cycle (each cycle 28 day) or cytarabine per local prescribing information. 2) Received HSCT per local standard of care. Experimental Therapy: Participants were to receive Glasdegib 100 mg matching placebo tablet PO QD from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive CR MRD-negative central laboratory results, whichever came first. Participants were to be followed up for first 2 years from last dose and were to had long term survival follow-up for up to 5 years from randomization of last participant or until death/consent withdrawal.Participants received chemotherapy with azacitidine 75 mg/m^2 subcutaneous (SC) injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, participant refusal or death, whichever occurred first. Participants also were to receive glasdegib 100 mg PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible participants underwent HSCT per local standard of care and were to receive glasdegib up to 2 years following randomization unless 2 consecutive negative MRD assessments. Participants were to be followed up for first 2 years from last dose of drug and were to had long term follow-up for survival for up to 5 years from randomization of last participant in study, or until death, or consent withdrawal.Participants received chemotherapy with azacitidine 75 mg/m^2 SC injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, participants refusal or death, whichever occurred first. Participants also received glasdegib 100 mg tablet matching placebo PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible participants underwent HSCT per local standard of care and were to receive glasdegib matching placebo up to 2 years following randomization unless 2 consecutive negative MRD assessments. Participants were to be followed up for first 2 years from last dose of drug and were to had long term follow-up for survival for up to 5 years from randomization of last participant in study, or until death, or consent withdrawal.Total of all reporting groups
    Overall Participants201203163162729
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    56.55
    (12.60)
    55.38
    (13.61)
    73.19
    (7.17)
    73.14
    (6.82)
    63.63
    (13.79)
    Sex: Female, Male (Count of Participants)
    Female
    71
    35.3%
    97
    47.8%
    97
    59.5%
    89
    54.9%
    354
    48.6%
    Male
    130
    64.7%
    106
    52.2%
    66
    40.5%
    73
    45.1%
    375
    51.4%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    19
    9.5%
    12
    5.9%
    12
    7.4%
    16
    9.9%
    59
    8.1%
    Not Hispanic or Latino
    166
    82.6%
    171
    84.2%
    140
    85.9%
    139
    85.8%
    616
    84.5%
    Unknown or Not Reported
    16
    8%
    20
    9.9%
    11
    6.7%
    7
    4.3%
    54
    7.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    0.5%
    0
    0%
    0
    0%
    0
    0%
    1
    0.1%
    Asian
    66
    32.8%
    57
    28.1%
    51
    31.3%
    44
    27.2%
    218
    29.9%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    3
    1.5%
    3
    1.5%
    1
    0.6%
    7
    4.3%
    14
    1.9%
    White
    110
    54.7%
    123
    60.6%
    97
    59.5%
    99
    61.1%
    429
    58.8%
    More than one race
    1
    0.5%
    0
    0%
    0
    0%
    0
    0%
    1
    0.1%
    Unknown or Not Reported
    20
    10%
    20
    9.9%
    14
    8.6%
    12
    7.4%
    66
    9.1%

    Outcome Measures

    1. Primary Outcome
    TitleIntensive Study: Overall Survival (OS)
    DescriptionOS is defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were to be censored at the date of last contact.
    Time FrameBaseline up to 25 months

    Outcome Measure Data

    Analysis Population Description
    FA set included all randomized participants.
    Arm/Group TitleIntensive Study: Glasdegib + Cytarabine + DaunorubicinIntensive Study: Placebo + Cytarabine + Daunorubicin
    Arm/Group DescriptionParticipants received first induction therapy (28 days) (backbone chemotherapy+experimental therapy). Backbone chemotherapy: Cytarabine 100 milligram per square meter (mg/m^2) daily by intravenous (IV) infusion for 7 days along with daunorubicin 60 mg/m^2 daily IV for 3 days. Depending upon bone marrow blast or investigator judgement participants had second induction i.e. received either same backbone therapy or cytarabine 100 mg/m^2 IV daily for 5 days and daunorubicin 60 mg/m^2 IV daily for 2 days. Participants with less than (<) 5% bone marrow blasts entered into consolation phase- treated with either or both of following: 1) cytarabine 1 to 3 gram per square meter (gm/m^2) IV for adults greater than or equals to (>=) 60 to <60 years twice daily on Days 1, 3, and 5 for 4 cycle (each cycle 28 day) or cytarabine per local prescribing information. 2) Received hematopoietic stem cell transplantation (HSCT) per local standard of care. Experimental Therapy: Participants were to receive Glasdegib 100 milligram (mg) tablet orally (PO) once daily (QD) from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive complete remission (CR) minimal residual disease (MRD)-negative central laboratory results, whichever came first. Participants were to be followed up for first 2 years from last dose and were to had long term survival follow-up for up to 5 years from randomization of last participant or until death/consent withdrawal.Participants received first induction therapy (28 days) (backbone chemotherapy+experimental therapy). Backbone chemotherapy: Cytarabine 100 mg/m^2 daily by IV infusion for 7 days along with daunorubicin 60 mg/m^2 daily IV for 3 days. Depending upon bone marrow blast or investigator judgement participants had second induction i.e. received either same backbone therapy or cytarabine 100 mg/m^2 IV daily for 5 days and daunorubicin 60 mg/m^2 IV daily for 2 days. Participants with <5% bone marrow blasts entered into consolation phase- treated with either or both of following: 1) cytarabine 1 to 3 gram/m^2 IV for adults >=60 to <60 years twice daily on Days 1, 3, and 5 for 4 cycle (each cycle 28 day) or cytarabine per local prescribing information. 2) Received HSCT per local standard of care. Experimental Therapy: Participants were to receive Glasdegib 100 mg matching placebo tablet PO QD from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive CR MRD-negative central laboratory results, whichever came first. Participants were to be followed up for first 2 years from last dose and were to had long term survival follow-up for up to 5 years from randomization of last participant or until death/consent withdrawal.
    Measure Participants201203
    Median (95% Confidence Interval) [months]
    17.3
    20.4
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Intensive Study: Glasdegib + Cytarabine + Daunorubicin, Intensive Study: Placebo + Cytarabine + Daunorubicin
    Comments Hazard ratio based on Cox proportional hazards model; under proportional hazards, hazard ratio less than (<) 1 indicated a reduction in hazard rate in favor of Glasdegib 100 mg PO + Cytarabine 100 mg/m^2 IV + Daunorubicin 60 mg/m^2 compared to Placebo + Cytarabine 100 mg/m^2 IV + Daunorubicin 60 mg/m^2.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.6579
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value1.08
    Confidence Interval (2-Sided) 95%
    0.755 to 1.532
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    TitleNon-intensive Study: Overall Survival (OS)
    DescriptionOS is defined as the time from the date of randomization to the date of death due to any cause. Participants last known to be alive were to be censored at the date of last contact.
    Time FrameBaseline up to 25 months

    Outcome Measure Data

    Analysis Population Description
    FA set included all randomized participants.
    Arm/Group TitleNon-intensive Study: Glasdegib + AzacitidineNon-intensive Study: Placebo + Azacitidine
    Arm/Group DescriptionParticipants received chemotherapy with azacitidine 75 mg/m^2 subcutaneous (SC) injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, participant refusal or death, whichever occurred first. Participants also were to receive glasdegib 100 mg PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible participants underwent HSCT per local standard of care and were to receive glasdegib up to 2 years following randomization unless 2 consecutive negative MRD assessments. Participants were to be followed up for first 2 years from last dose of drug and were to had long term follow-up for survival for up to 5 years from randomization of last participant in study, or until death, or consent withdrawal.Participants received chemotherapy with azacitidine 75 mg/m^2 SC injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, participants refusal or death, whichever occurred first. Participants also received glasdegib 100 mg tablet matching placebo PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible participants underwent HSCT per local standard of care and were to receive glasdegib matching placebo up to 2 years following randomization unless 2 consecutive negative MRD assessments. Participants were to be followed up for first 2 years from last dose of drug and were to had long term follow-up for survival for up to 5 years from randomization of last participant in study, or until death, or consent withdrawal.
    Measure Participants163162
    Median (95% Confidence Interval) [months]
    10.3
    10.6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Intensive Study: Glasdegib + Cytarabine + Daunorubicin, Intensive Study: Placebo + Cytarabine + Daunorubicin
    Comments Hazard ratio based on Cox proportional hazards model; under proportional hazards, hazard ratio < 1 indicated a reduction in hazard rate in favor of Glasdegib 100 mg PO QD + Azacitidine compared to Placebo + Azacitidine
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.5955
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value1.04
    Confidence Interval (2-Sided) 95%
    0.775 to 1.388
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    TitleIntensive Study: Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (DASI-AML/MDS) Questionnaire
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Secondary Outcome
    TitleNon-intensive Study: Fatigue Score Measured by the MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (DASI-AML/MDS) Questionnaire
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Secondary Outcome
    TitleIntensive Study: Percentage of Participants With Complete Remission With Negative Minimal Residual Disease (CRMRD-neg)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Secondary Outcome
    TitleNon-intensive Study: Percentage of Participants With Complete Remission With Negative Minimal Residual Disease (CRMRD-neg)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Secondary Outcome
    TitleIntensive Study: Percentage of Participants With Complete Remission (CR) Including Complete Remission With Negative Minimal Residual Disease (CRMRD-neg)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Secondary Outcome
    TitleNon-intensive Study: Percentage of Participants With Complete Remission (CR) Including Complete Remission With Negative Minimal Residual Disease (CRMRD-neg)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Secondary Outcome
    TitleIntensive Study: Percentage of Participants With Complete Remission With Incomplete Hematologic Recovery (CRi)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    TitleNon-intensive Study: Percentage of Participants With Complete Remission With Incomplete Hematologic Recovery (CRi)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Secondary Outcome
    TitleIntensive Study: Percentage of Participants With Morphologic Leukemia-free State (MLFS)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Secondary Outcome
    TitleNon-intensive Study: Percentage of Participants With Morphologic Leukemia-free State (MLFS)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    13. Secondary Outcome
    TitleIntensive Study: Percentage of Participants With Partial Remission (PR)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    14. Secondary Outcome
    TitleNon-intensive Study: Percentage of Participants With Partial Remission (PR)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    15. Secondary Outcome
    TitleNon-intensive Study: Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    16. Secondary Outcome
    TitleIntensive Study: Duration of Response
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    17. Secondary Outcome
    TitleNon-intensive Study: Duration of Response
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    18. Secondary Outcome
    TitleNon-intensive Study: Time to Response
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    19. Secondary Outcome
    TitleIntensive Study: Event-free Survival
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    20. Secondary Outcome
    TitleNon-intensive Study: Event-free Survival
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    21. Secondary Outcome
    TitleIntensive Study: MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Score
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    22. Secondary Outcome
    TitleNon-intensive Study: MD Anderson Symptom Inventory -Acute Myelogenous Leukemia/Myelodysplastic Syndrome (MDASI-AML/MDS) Score
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    23. Secondary Outcome
    TitleIntensive Study: EuroQoL 5 Dimension Questionnaire 5-Level Version (EQ-5D-5L) Score
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    24. Secondary Outcome
    TitleNon-intensive Study: EuroQoL 5 Dimension Questionnaire 5-Level Version (EQ-5D-5L) Score
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    25. Secondary Outcome
    TitleIntensive Study: EuroQoL Visual Analogue Scale (EQ-VAS)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    26. Secondary Outcome
    TitleNon-intensive Study: EuroQoL Visual Analogue Scale (EQ-VAS)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    27. Secondary Outcome
    TitleIntensive Study: Participants Global Impression of Symptoms (PGIS)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    28. Secondary Outcome
    TitleNon-intensive Study: Participants Global Impression of Symptoms (PGIS)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    29. Secondary Outcome
    TitleIntensive Study: Participants Global Impression of Change (PGIC)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    30. Secondary Outcome
    TitleNon-intensive Study: Participants Global Impression of Change (PGIC)
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    31. Secondary Outcome
    TitleIntensive Study: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    32. Secondary Outcome
    TitleNon-intensive Study: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    33. Secondary Outcome
    TitleIntensive Study: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    34. Secondary Outcome
    TitleNon-intensive Study: Number of Participants With Treatment Related Adverse Events (AEs) and Serious Adverse Events (SAEs) Graded by NCI CTCAE v.4.03
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    35. Secondary Outcome
    TitleIntensive Study: Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE v.4.03
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    36. Secondary Outcome
    TitleNon-intensive Study: Number of Participants With Laboratory Abnormalities Graded by NCI CTCAE v.4.03
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    37. Secondary Outcome
    TitleIntensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib
    Description
    Time Frame1 and 4 hour post dose on Day 1 in first induction therapy; pre-dose, 1, and 4 hours post dose on day 1 in consolidation phase cycles 1 and 2

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    38. Secondary Outcome
    TitleNon-intensive Study: Plasma Trough Concentration (Ctrough) of Glasdegib
    Description
    Time FramePre-dose, 1 and 4 hour post dose on Day 1 and 15 of cycle 1; pre-dose, 1 and 4 hour post dose on day 1 of cycle 2 and 3

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    39. Secondary Outcome
    TitleIntensive Study: QTc Interval
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    40. Secondary Outcome
    TitleNon-intensive Study: QTc Interval
    Description
    Time FrameBaseline up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time FrameBaseline up to 28 days from last dose of study drug (up to 25 months)
    Adverse Event Reporting Description Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis (SA) set included all subjects who received at least one dose of study drug.
    Arm/Group TitleIntensive Study: Glasdegib + Cytarabine + DaunorubicinIntensive Study: Placebo + Cytarabine + DaunorubicinNon-intensive Study: Glasdegib + AzacitidineNon-intensive Study: Placebo + Azacitidine
    Arm/Group DescriptionParticipants received first induction therapy (28 days) (backbone chemotherapy+experimental therapy). Backbone chemotherapy: Cytarabine 100 milligram per square meter (mg/m^2) daily by intravenous (IV) infusion for 7 days along with daunorubicin 60 mg/m^2 daily IV for 3 days. Depending upon bone marrow blast or investigator judgement participants had second induction i.e. received either same backbone therapy or cytarabine 100 mg/m^2 IV daily for 5 days and daunorubicin 60 mg/m^2 IV daily for 2 days. Participants with less than (<) 5% bone marrow blasts entered into consolation phase- treated with either or both of following: 1) cytarabine 1 to 3 gram per square meter (gm/m^2) IV for adults greater than or equals to (>=) 60 to <60 years twice daily on Days 1, 3, and 5 for 4 cycle (each cycle 28 day) or cytarabine per local prescribing information. 2) Received hematopoietic stem cell transplantation (HSCT) per local standard of care. Experimental Therapy: Participants were to receive Glasdegib 100 milligram (mg) tablet orally (PO) once daily (QD) from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive complete remission (CR) minimal residual disease (MRD)-negative central laboratory results, whichever came first. Participants were to be followed up for first 2 years from last dose and were to had long term survival follow-up for up to 5 years from randomization of last participant or until death/consent withdrawal.Participants received first induction therapy (28 days) (backbone chemotherapy+experimental therapy). Backbone chemotherapy: Cytarabine 100 mg/m^2 daily by IV infusion for 7 days along with daunorubicin 60 mg/m^2 daily IV for 3 days. Depending upon bone marrow blast or investigator judgement participants had second induction i.e. received either same backbone therapy or cytarabine 100 mg/m^2 IV daily for 5 days and daunorubicin 60 mg/m^2 IV daily for 2 days. Participants with <5% bone marrow blasts entered into consolation phase- treated with either or both of following: 1) cytarabine 1 to 3 gram/m^2 IV for adults >=60 to <60 years twice daily on Days 1, 3, and 5 for 4 cycle (each cycle 28 day) or cytarabine per local prescribing information. 2) Received HSCT per local standard of care. Experimental Therapy: Participants were to receive Glasdegib 100 mg matching placebo tablet PO QD from Day 1 of chemotherapy up to 28 days in both induction and up to 2 years post randomization or until 2 consecutive CR MRD-negative central laboratory results, whichever came first. Participants were to be followed up for first 2 years from last dose and were to had long term survival follow-up for up to 5 years from randomization of last participant or until death/consent withdrawal.Participants received chemotherapy with azacitidine 75 mg/m^2 subcutaneous (SC) injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, participant refusal or death, whichever occurred first. Participants also were to receive glasdegib 100 mg PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible participants underwent HSCT per local standard of care and were to receive glasdegib up to 2 years following randomization unless 2 consecutive negative MRD assessments. Participants were to be followed up for first 2 years from last dose of drug and were to had long term follow-up for survival for up to 5 years from randomization of last participant in study, or until death, or consent withdrawal.Participants received chemotherapy with azacitidine 75 mg/m^2 SC injection or IV infusion from Day 1 up to Day 7 of each cycle (28 day) and continued for at least 6 cycles or until unacceptable toxicity, participants refusal or death, whichever occurred first. Participants also received glasdegib 100 mg tablet matching placebo PO QD from Day 1 of chemotherapy until clinical benefit or disease progression, unacceptable toxicity, consent withdrawal, or death, whichever occurred first. Eligible participants underwent HSCT per local standard of care and were to receive glasdegib matching placebo up to 2 years following randomization unless 2 consecutive negative MRD assessments. Participants were to be followed up for first 2 years from last dose of drug and were to had long term follow-up for survival for up to 5 years from randomization of last participant in study, or until death, or consent withdrawal.
    All Cause Mortality
    Intensive Study: Glasdegib + Cytarabine + DaunorubicinIntensive Study: Placebo + Cytarabine + DaunorubicinNon-intensive Study: Glasdegib + AzacitidineNon-intensive Study: Placebo + Azacitidine
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total67/198 (33.8%) 60/201 (29.9%) 96/162 (59.3%) 88/160 (55%)
    Serious Adverse Events
    Intensive Study: Glasdegib + Cytarabine + DaunorubicinIntensive Study: Placebo + Cytarabine + DaunorubicinNon-intensive Study: Glasdegib + AzacitidineNon-intensive Study: Placebo + Azacitidine
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total85/198 (42.9%) 91/201 (45.3%) 110/162 (67.9%) 118/160 (73.8%)
    Blood and lymphatic system disorders
    Anaemia2/198 (1%) 1/201 (0.5%) 5/162 (3.1%) 2/160 (1.3%)
    Febrile neutropenia18/198 (9.1%) 17/201 (8.5%) 24/162 (14.8%) 18/160 (11.3%)
    Neutropenia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Thrombocytopenia1/198 (0.5%) 3/201 (1.5%) 2/162 (1.2%) 1/160 (0.6%)
    Leukocytosis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Splenic necrosis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Cardiac disorders
    Atrial fibrillation3/198 (1.5%) 1/201 (0.5%) 1/162 (0.6%) 1/160 (0.6%)
    Cardiac arrest1/198 (0.5%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Cardiac failure0/198 (0%) 1/201 (0.5%) 0/162 (0%) 2/160 (1.3%)
    Cardiac failure acute1/198 (0.5%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Myocarditis1/198 (0.5%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Acute myocardial infarction1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Cardiac failure congestive0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Cardiomyopathy0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Intracardiac mass0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Left ventricular dysfunction0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Myocardial infarction0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Myocardial ischaemia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Atrial flutter0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Bradycardia0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Cardiorenal syndrome0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Ventricular fibrillation0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Eye disorders
    Vision blurred0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Gastrointestinal disorders
    Colitis0/198 (0%) 1/201 (0.5%) 4/162 (2.5%) 1/160 (0.6%)
    Constipation1/198 (0.5%) 0/201 (0%) 2/162 (1.2%) 0/160 (0%)
    Diarrhoea1/198 (0.5%) 0/201 (0%) 3/162 (1.9%) 2/160 (1.3%)
    Diverticulum intestinal haemorrhagic0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Gastrointestinal haemorrhage3/198 (1.5%) 0/201 (0%) 2/162 (1.2%) 1/160 (0.6%)
    Haematemesis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Intestinal haemorrhage0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Large intestine perforation0/198 (0%) 1/201 (0.5%) 1/162 (0.6%) 0/160 (0%)
    Lower gastrointestinal haemorrhage1/198 (0.5%) 1/201 (0.5%) 1/162 (0.6%) 0/160 (0%)
    Neutropenic colitis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Rectal haemorrhage0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Upper gastrointestinal haemorrhage2/198 (1%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Anal fistula1/198 (0.5%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Enteritis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Enterocolitis1/198 (0.5%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Gastric ulcer1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Intussusception1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Proctalgia1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Small intestinal haemorrhage1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Abdominal pain0/198 (0%) 0/201 (0%) 2/162 (1.2%) 0/160 (0%)
    Abdominal distension0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Anal fissure0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Intra-abdominal haematoma0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Mechanical ileus0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Nausea0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Pancreatitis0/198 (0%) 0/201 (0%) 2/162 (1.2%) 0/160 (0%)
    Stomatitis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Vomiting0/198 (0%) 0/201 (0%) 1/162 (0.6%) 2/160 (1.3%)
    Gastritis0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Gastrointestinal perforation0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Glossitis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Haemorrhoidal haemorrhage0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Haemorrhoids thrombosed0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Ileus0/198 (0%) 0/201 (0%) 2/162 (1.2%) 0/160 (0%)
    Inguinal hernia0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    General disorders
    Disease progression2/198 (1%) 4/201 (2%) 14/162 (8.6%) 22/160 (13.8%)
    Multiple organ dysfunction syndrome0/198 (0%) 1/201 (0.5%) 2/162 (1.2%) 0/160 (0%)
    Pyrexia4/198 (2%) 6/201 (3%) 9/162 (5.6%) 11/160 (6.9%)
    Chills0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Malaise1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Mucosal inflammation0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Non-cardiac chest pain1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Asthenia0/198 (0%) 0/201 (0%) 0/162 (0%) 2/160 (1.3%)
    Death0/198 (0%) 0/201 (0%) 4/162 (2.5%) 2/160 (1.3%)
    Sudden death0/198 (0%) 0/201 (0%) 1/162 (0.6%) 1/160 (0.6%)
    Fatigue0/198 (0%) 0/201 (0%) 1/162 (0.6%) 1/160 (0.6%)
    General physical health deterioration0/198 (0%) 0/201 (0%) 0/162 (0%) 3/160 (1.9%)
    Soft tissue inflammation0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Hepatobiliary disorders
    Cholecystitis acute0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Hyperbilirubinaemia2/198 (1%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Cholecystitis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Cholelithiasis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Drug-induced liver injury0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Hepatitis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Bile duct stone0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Cholangitis acute0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Immune system disorders
    Graft versus host disease0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Graft versus host disease in gastrointestinal tract1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Graft versus host disease in skin1/198 (0.5%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Hypersensitivity0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Cytokine release syndrome0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Infections and infestations
    Arthritis infective1/198 (0.5%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Bacteraemia4/198 (2%) 2/201 (1%) 3/162 (1.9%) 4/160 (2.5%)
    Bronchopulmonary aspergillosis1/198 (0.5%) 1/201 (0.5%) 1/162 (0.6%) 0/160 (0%)
    Cellulitis1/198 (0.5%) 0/201 (0%) 2/162 (1.2%) 7/160 (4.4%)
    Clostridium difficile colitis1/198 (0.5%) 1/201 (0.5%) 1/162 (0.6%) 0/160 (0%)
    Enterobacter bacteraemia0/198 (0%) 1/201 (0.5%) 1/162 (0.6%) 0/160 (0%)
    Escherichia bacteraemia1/198 (0.5%) 1/201 (0.5%) 1/162 (0.6%) 1/160 (0.6%)
    Infection3/198 (1.5%) 0/201 (0%) 1/162 (0.6%) 5/160 (3.1%)
    Neutropenic sepsis1/198 (0.5%) 2/201 (1%) 3/162 (1.9%) 5/160 (3.1%)
    Perirectal abscess0/198 (0%) 1/201 (0.5%) 1/162 (0.6%) 0/160 (0%)
    Pneumonia15/198 (7.6%) 11/201 (5.5%) 26/162 (16%) 35/160 (21.9%)
    Pneumonia fungal2/198 (1%) 2/201 (1%) 2/162 (1.2%) 0/160 (0%)
    Pseudomembranous colitis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Sepsis15/198 (7.6%) 13/201 (6.5%) 13/162 (8%) 9/160 (5.6%)
    Septic shock2/198 (1%) 4/201 (2%) 4/162 (2.5%) 5/160 (3.1%)
    Soft tissue infection1/198 (0.5%) 0/201 (0%) 0/162 (0%) 3/160 (1.9%)
    Upper respiratory tract infection1/198 (0.5%) 0/201 (0%) 2/162 (1.2%) 0/160 (0%)
    Urinary tract infection0/198 (0%) 1/201 (0.5%) 9/162 (5.6%) 4/160 (2.5%)
    Anorectal infection0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Atypical pneumonia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Bacterial sepsis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Brain abscess0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Candida pneumonia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Clostridial sepsis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Clostridium bacteraemia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Clostridium colitis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Device related bacteraemia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Diarrhoea infectious0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Disseminated varicella zoster virus infection0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Enterococcal bacteraemia2/198 (1%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Escherichia sepsis1/198 (0.5%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Febrile infection0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Fungal infection1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Fungal sepsis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Groin abscess1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Herpes ophthalmic1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Herpes zoster0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Peritonitis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Pseudomonal bacteraemia3/198 (1.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Pseudomonal sepsis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Pulmonary tuberculosis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Streptococcal sepsis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Urethritis1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Abscess0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Anal abscess0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Bronchitis0/198 (0%) 0/201 (0%) 1/162 (0.6%) 1/160 (0.6%)
    COVID-190/198 (0%) 0/201 (0%) 0/162 (0%) 2/160 (1.3%)
    COVID-19 pneumonia0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Candida sepsis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Catheter site infection0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Device related infection0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Diverticulitis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Herpes dermatitis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Infected skin ulcer0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Influenza0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Klebsiella bacteraemia0/198 (0%) 0/201 (0%) 0/162 (0%) 2/160 (1.3%)
    Liver abscess0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Lower respiratory tract infection0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Lower respiratory tract infection bacterial0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Otitis media acute0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Periodontitis0/198 (0%) 0/201 (0%) 0/162 (0%) 2/160 (1.3%)
    Pharyngitis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Pneumonia staphylococcal0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Post procedural infection0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Pyelonephritis acute0/198 (0%) 0/201 (0%) 1/162 (0.6%) 2/160 (1.3%)
    Rectal abscess0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Skin infection0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Staphylococcal sepsis0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Subdiaphragmatic abscess0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Suspected COVID-190/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Systemic infection0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Systemic mycosis0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Wound infection0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Oral infection0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Injury, poisoning and procedural complications
    Fall1/198 (0.5%) 0/201 (0%) 0/162 (0%) 2/160 (1.3%)
    Spinal fracture0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Splenic rupture0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Femoral neck fracture0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Hip fracture0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Lumbar vertebral fracture0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Post procedural complication0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Subdural haematoma0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Subdural haemorrhage0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Tooth fracture0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Transfusion reaction0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Investigations
    Blood creatinine increased0/198 (0%) 1/201 (0.5%) 1/162 (0.6%) 2/160 (1.3%)
    Electrocardiogram QT prolonged13/198 (6.6%) 8/201 (4%) 5/162 (3.1%) 3/160 (1.9%)
    Platelet count decreased1/198 (0.5%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Alanine aminotransferase increased1/198 (0.5%) 2/201 (1%) 0/162 (0%) 0/160 (0%)
    Aspartate aminotransferase increased1/198 (0.5%) 2/201 (1%) 0/162 (0%) 0/160 (0%)
    Blood alkaline phosphatase increased1/198 (0.5%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Blood bilirubin increased2/198 (1%) 3/201 (1.5%) 0/162 (0%) 0/160 (0%)
    Blood lactate dehydrogenase increased0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Gamma-glutamyltransferase increased0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Neutrophil count decreased0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    C-reactive protein increased0/198 (0%) 0/201 (0%) 0/162 (0%) 2/160 (1.3%)
    Creatinine renal clearance decreased0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Electroencephalogram abnormal0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    SARS-CoV-2 test positive0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Weight decreased0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Metabolism and nutrition disorders
    Decreased appetite0/198 (0%) 1/201 (0.5%) 3/162 (1.9%) 1/160 (0.6%)
    Hyperglycaemia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Hypokalaemia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Failure to thrive0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Hyperkalaemia0/198 (0%) 0/201 (0%) 0/162 (0%) 3/160 (1.9%)
    Hyperuricaemia0/198 (0%) 0/201 (0%) 2/162 (1.2%) 0/160 (0%)
    Hyponatraemia0/198 (0%) 0/201 (0%) 2/162 (1.2%) 1/160 (0.6%)
    Hypophosphataemia0/198 (0%) 0/201 (0%) 1/162 (0.6%) 1/160 (0.6%)
    Musculoskeletal and connective tissue disorders
    Myalgia0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Back pain0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Osteoarthritis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Soft tissue necrosis0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Synovitis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Differentiation syndrome0/198 (0%) 0/201 (0%) 0/162 (0%) 2/160 (1.3%)
    Gastrointestinal neoplasm0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Neoplasm progression0/198 (0%) 0/201 (0%) 0/162 (0%) 2/160 (1.3%)
    Neoplasm prostate0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Nervous system disorders
    Epilepsy0/198 (0%) 1/201 (0.5%) 1/162 (0.6%) 0/160 (0%)
    Haemorrhage intracranial2/198 (1%) 2/201 (1%) 1/162 (0.6%) 1/160 (0.6%)
    Syncope1/198 (0.5%) 0/201 (0%) 1/162 (0.6%) 1/160 (0.6%)
    Carotid artery stenosis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Cerebral haemorrhage1/198 (0.5%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Seizure0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Central nervous system lesion0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Cerebral infarction0/198 (0%) 0/201 (0%) 2/162 (1.2%) 2/160 (1.3%)
    Cerebrovascular accident0/198 (0%) 0/201 (0%) 1/162 (0.6%) 1/160 (0.6%)
    Encephalopathy0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Intracranial aneurysm0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Metabolic encephalopathy0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Partial seizures0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Somnolence0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Psychiatric disorders
    Confusional state0/198 (0%) 1/201 (0.5%) 1/162 (0.6%) 0/160 (0%)
    Adjustment disorder with depressed mood1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Hallucination0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Renal and urinary disorders
    Acute kidney injury2/198 (1%) 3/201 (1.5%) 1/162 (0.6%) 1/160 (0.6%)
    Chronic kidney disease0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Haematuria0/198 (0%) 0/201 (0%) 2/162 (1.2%) 1/160 (0.6%)
    Renal failure0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Urinary retention0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea0/198 (0%) 1/201 (0.5%) 3/162 (1.9%) 1/160 (0.6%)
    Epistaxis2/198 (1%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Respiratory failure1/198 (0.5%) 4/201 (2%) 1/162 (0.6%) 1/160 (0.6%)
    Acute respiratory distress syndrome1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Acute respiratory failure1/198 (0.5%) 3/201 (1.5%) 0/162 (0%) 0/160 (0%)
    Hypoxia1/198 (0.5%) 2/201 (1%) 0/162 (0%) 0/160 (0%)
    Lung infiltration0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Pulmonary alveolar haemorrhage0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Pulmonary haemorrhage1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Oropharyngeal pain0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Pneumonia aspiration0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Pneumonitis0/198 (0%) 0/201 (0%) 0/162 (0%) 3/160 (1.9%)
    Pneumothorax0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Pulmonary oedema0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Skin and subcutaneous tissue disorders
    Erythema1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Rash1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Rash maculo-papular0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Dermatitis exfoliative generalised0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Drug eruption0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Vascular disorders
    Deep vein thrombosis0/198 (0%) 1/201 (0.5%) 0/162 (0%) 1/160 (0.6%)
    Hypotension1/198 (0.5%) 1/201 (0.5%) 1/162 (0.6%) 1/160 (0.6%)
    Embolism0/198 (0%) 1/201 (0.5%) 0/162 (0%) 0/160 (0%)
    Orthostatic hypotension1/198 (0.5%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Aneurysm ruptured0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Axillary vein thrombosis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Circulatory collapse0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Hypovolaemic shock0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Peripheral ischaemia0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Thrombophlebitis superficial0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Thrombosis0/198 (0%) 0/201 (0%) 0/162 (0%) 1/160 (0.6%)
    Venous thrombosis0/198 (0%) 0/201 (0%) 1/162 (0.6%) 0/160 (0%)
    Other (Not Including Serious) Adverse Events
    Intensive Study: Glasdegib + Cytarabine + DaunorubicinIntensive Study: Placebo + Cytarabine + DaunorubicinNon-intensive Study: Glasdegib + AzacitidineNon-intensive Study: Placebo + Azacitidine
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total194/198 (98%) 195/201 (97%) 153/162 (94.4%) 149/160 (93.1%)
    Blood and lymphatic system disorders
    Anaemia101/198 (51%) 97/201 (48.3%) 73/162 (45.1%) 70/160 (43.8%)
    Febrile neutropenia97/198 (49%) 96/201 (47.8%) 22/162 (13.6%) 20/160 (12.5%)
    Leukopenia10/198 (5.1%) 13/201 (6.5%) 11/162 (6.8%) 4/160 (2.5%)
    Neutropenia41/198 (20.7%) 43/201 (21.4%) 35/162 (21.6%) 30/160 (18.8%)
    Thrombocytopenia52/198 (26.3%) 52/201 (25.9%) 37/162 (22.8%) 32/160 (20%)
    Cardiac disorders
    Sinus tachycardia11/198 (5.6%) 7/201 (3.5%) 0/162 (0%) 0/160 (0%)
    Gastrointestinal disorders
    Abdominal pain31/198 (15.7%) 29/201 (14.4%) 12/162 (7.4%) 10/160 (6.3%)
    Constipation71/198 (35.9%) 61/201 (30.3%) 58/162 (35.8%) 50/160 (31.3%)
    Diarrhoea96/198 (48.5%) 88/201 (43.8%) 36/162 (22.2%) 31/160 (19.4%)
    Haemorrhoids13/198 (6.6%) 19/201 (9.5%) 8/162 (4.9%) 10/160 (6.3%)
    Nausea110/198 (55.6%) 106/201 (52.7%) 55/162 (34%) 44/160 (27.5%)
    Vomiting57/198 (28.8%) 40/201 (19.9%) 35/162 (21.6%) 32/160 (20%)
    Abdominal pain upper12/198 (6.1%) 9/201 (4.5%) 0/162 (0%) 0/160 (0%)
    Dyspepsia12/198 (6.1%) 5/201 (2.5%) 0/162 (0%) 0/160 (0%)
    Proctalgia14/198 (7.1%) 6/201 (3%) 0/162 (0%) 0/160 (0%)
    Stomatitis29/198 (14.6%) 41/201 (20.4%) 0/162 (0%) 0/160 (0%)
    General disorders
    Asthenia15/198 (7.6%) 11/201 (5.5%) 15/162 (9.3%) 18/160 (11.3%)
    Fatigue31/198 (15.7%) 32/201 (15.9%) 13/162 (8%) 23/160 (14.4%)
    Oedema peripheral25/198 (12.6%) 32/201 (15.9%) 11/162 (6.8%) 18/160 (11.3%)
    Pyrexia84/198 (42.4%) 84/201 (41.8%) 41/162 (25.3%) 39/160 (24.4%)
    Chills20/198 (10.1%) 11/201 (5.5%) 0/162 (0%) 0/160 (0%)
    Mucosal inflammation12/198 (6.1%) 7/201 (3.5%) 0/162 (0%) 0/160 (0%)
    Non-cardiac chest pain13/198 (6.6%) 8/201 (4%) 0/162 (0%) 0/160 (0%)
    Oedema9/198 (4.5%) 19/201 (9.5%) 0/162 (0%) 0/160 (0%)
    Injection site reaction0/198 (0%) 0/201 (0%) 11/162 (6.8%) 7/160 (4.4%)
    Hepatobiliary disorders
    Hyperbilirubinaemia0/198 (0%) 0/201 (0%) 11/162 (6.8%) 0/160 (0%)
    Infections and infestations
    Pneumonia32/198 (16.2%) 33/201 (16.4%) 19/162 (11.7%) 15/160 (9.4%)
    Upper respiratory tract infection9/198 (4.5%) 11/201 (5.5%) 12/162 (7.4%) 11/160 (6.9%)
    Urinary tract infection5/198 (2.5%) 11/201 (5.5%) 16/162 (9.9%) 9/160 (5.6%)
    Bacteraemia16/198 (8.1%) 11/201 (5.5%) 0/162 (0%) 0/160 (0%)
    Injury, poisoning and procedural complications
    Fall0/198 (0%) 0/201 (0%) 10/162 (6.2%) 10/160 (6.3%)
    Investigations
    Alanine aminotransferase increased39/198 (19.7%) 53/201 (26.4%) 13/162 (8%) 11/160 (6.9%)
    Aspartate aminotransferase increased30/198 (15.2%) 41/201 (20.4%) 10/162 (6.2%) 9/160 (5.6%)
    Blood creatinine increased18/198 (9.1%) 13/201 (6.5%) 20/162 (12.3%) 13/160 (8.1%)
    Electrocardiogram QT prolonged21/198 (10.6%) 20/201 (10%) 20/162 (12.3%) 19/160 (11.9%)
    Gamma-glutamyltransferase increased12/198 (6.1%) 22/201 (10.9%) 10/162 (6.2%) 8/160 (5%)
    Neutrophil count decreased56/198 (28.3%) 49/201 (24.4%) 22/162 (13.6%) 22/160 (13.8%)
    Platelet count decreased77/198 (38.9%) 73/201 (36.3%) 30/162 (18.5%) 26/160 (16.3%)
    Weight decreased21/198 (10.6%) 22/201 (10.9%) 34/162 (21%) 19/160 (11.9%)
    White blood cell count decreased63/198 (31.8%) 53/201 (26.4%) 17/162 (10.5%) 18/160 (11.3%)
    Blood alkaline phosphatase increased14/198 (7.1%) 13/201 (6.5%) 0/162 (0%) 0/160 (0%)
    Blood bilirubin increased25/198 (12.6%) 13/201 (6.5%) 0/162 (0%) 0/160 (0%)
    Lymphocyte count decreased19/198 (9.6%) 21/201 (10.4%) 0/162 (0%) 0/160 (0%)
    C-reactive protein increased0/198 (0%) 0/201 (0%) 7/162 (4.3%) 9/160 (5.6%)
    Metabolism and nutrition disorders
    Decreased appetite52/198 (26.3%) 41/201 (20.4%) 45/162 (27.8%) 21/160 (13.1%)
    Hyperglycaemia10/198 (5.1%) 10/201 (5%) 5/162 (3.1%) 9/160 (5.6%)
    Hypoalbuminaemia32/198 (16.2%) 30/201 (14.9%) 11/162 (6.8%) 13/160 (8.1%)
    Hypocalcaemia25/198 (12.6%) 17/201 (8.5%) 10/162 (6.2%) 13/160 (8.1%)
    Hypokalaemia76/198 (38.4%) 83/201 (41.3%) 35/162 (21.6%) 22/160 (13.8%)
    Hypomagnesaemia29/198 (14.6%) 24/201 (11.9%) 11/162 (6.8%) 5/160 (3.1%)
    Hyponatraemia24/198 (12.1%) 15/201 (7.5%) 16/162 (9.9%) 9/160 (5.6%)
    Hypophosphataemia42/198 (21.2%) 44/201 (21.9%) 10/162 (6.2%) 15/160 (9.4%)
    Hyperuricaemia13/198 (6.6%) 9/201 (4.5%) 0/162 (0%) 0/160 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia17/198 (8.6%) 14/201 (7%) 11/162 (6.8%) 11/160 (6.9%)
    Back pain22/198 (11.1%) 17/201 (8.5%) 7/162 (4.3%) 12/160 (7.5%)
    Muscle spasms20/198 (10.1%) 3/201 (1.5%) 28/162 (17.3%) 4/160 (2.5%)
    Myalgia15/198 (7.6%) 11/201 (5.5%) 0/162 (0%) 0/160 (0%)
    Nervous system disorders
    Dizziness23/198 (11.6%) 18/201 (9%) 9/162 (5.6%) 14/160 (8.8%)
    Dysgeusia39/198 (19.7%) 20/201 (10%) 37/162 (22.8%) 8/160 (5%)
    Headache39/198 (19.7%) 47/201 (23.4%) 4/162 (2.5%) 9/160 (5.6%)
    Paraesthesia11/198 (5.6%) 0/201 (0%) 0/162 (0%) 0/160 (0%)
    Psychiatric disorders
    Insomnia27/198 (13.6%) 30/201 (14.9%) 12/162 (7.4%) 8/160 (5%)
    Respiratory, thoracic and mediastinal disorders
    Cough23/198 (11.6%) 23/201 (11.4%) 10/162 (6.2%) 20/160 (12.5%)
    Dyspnoea15/198 (7.6%) 23/201 (11.4%) 11/162 (6.8%) 18/160 (11.3%)
    Epistaxis19/198 (9.6%) 20/201 (10%) 8/162 (4.9%) 10/160 (6.3%)
    Oropharyngeal pain19/198 (9.6%) 19/201 (9.5%) 0/162 (0%) 0/160 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia22/198 (11.1%) 26/201 (12.9%) 20/162 (12.3%) 3/160 (1.9%)
    Pruritus12/198 (6.1%) 11/201 (5.5%) 8/162 (4.9%) 9/160 (5.6%)
    Rash46/198 (23.2%) 51/201 (25.4%) 10/162 (6.2%) 13/160 (8.1%)
    Dry skin13/198 (6.6%) 10/201 (5%) 0/162 (0%) 0/160 (0%)
    Petechiae8/198 (4%) 11/201 (5.5%) 0/162 (0%) 0/160 (0%)
    Rash maculo-papular21/198 (10.6%) 21/201 (10.4%) 0/162 (0%) 0/160 (0%)
    Vascular disorders
    Hypertension10/198 (5.1%) 25/201 (12.4%) 0/162 (0%) 0/160 (0%)
    Hypotension18/198 (9.1%) 17/201 (8.5%) 0/162 (0%) 0/160 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

    Results Point of Contact

    Name/TitlePfizer ClinicalTrials.gov Call Center
    OrganizationPfizer Inc.
    Phone1-800-718-1021
    EmailClinicalTrials.gov_Inquiries@pfizer.com
    Responsible Party:
    Pfizer
    ClinicalTrials.gov Identifier:
    NCT03416179
    Other Study ID Numbers:
    • B1371019
    • 2017-002822-19
    • BRIGHT
    • BRIGHT AML1019
    First Posted:
    Jan 31, 2018
    Last Update Posted:
    Nov 23, 2021
    Last Verified:
    Nov 1, 2021