E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Intestinal acute graft-versus-host disease (aGvHD) |
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E.1.1.1 | Medical condition in easily understood language |
Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066264 |
E.1.2 | Term | Acute graft versus host disease in intestine |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in subjects who receive allo-HSCT as treatment for a hematologic malignancy or myeloproliferative disorder. |
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E.2.2 | Secondary objectives of the trial |
Safety Objective: To evaluate the safety of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen. Secondary Objectives: • To evaluate the effect of vedolizumab compared to placebo on intestinal aGvHD free, relapse-free (free of underlying malignancy) survival by Day +180. • To evaluate the effect of vedolizumab compared to placebo on Grade C-D aGvHD free (any organ involvement) survival by Day +180. • To evaluate the effect of vedolizumab compared to placebo on (NRM) in subjects by Day +180. • To evaluate the effect of vedolizumab compared to placebo on OS by Day +180. • To evaluate the effect of vedolizumab compared to placebo on Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The subject or, when applicable, the subject’s legally acceptable representative voluntarily signs and dates a written, informed consent form (ICF) and any required privacy authorization before performance of any study-related procedures not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. As applicable, a parent/both parents or legally acceptable representative must provide signature of informed consent, and there must be documentation of age-appropriate assent by the subject. 2. Male or female subjects ≥18 years of age and and, in selected countries (where local requirements permit and based on feasibility), adolescents aged 12 years and greater and weighing ≥30 kg at time of randomization. 3. Subjects must undergo DNA-based HLA matching and be 8 of 8 or 7 of 8 HLA-matched (single allele or antigen mismatch at HLA-A, -B, and -C, and HLA-DRB1 is allowable) unrelated hematopoietic stem cell transplantation (HSCT) from either peripheral blood or bone marrow stem cells for a hematologic malignancy or myeloproliferative disorder. Subjects should follow local practice for additional HLA-match, for example France, 9/10 or 10/10 HLA match. 4. Subjects for whom a myeloablative conditioning or RIC is planned. 5. Allo-HSCT eligible (meeting institutional criteria)-subjects planned medical care should include aGvHD prophylaxis with a combination of CNI (CYS or TAC) and MTX or CNI and MMF. With the exception of ATG (ATG-F or thymoglobulin), all other therapies, approved or investigational, for GvHD prophylaxis are excluded. 6. Status of the primary disease as follows: a. Subjects with acute leukemia or chronic myelogenous leukemia: no circulating blasts and <5% blasts in the bone marrow. b. Subjects with myelodysplasia: no circulating blasts and <10% blasts in the bone marrow. c. Subjects with chronic lymphocytic leukemia or small lymphocytic lymphoma with chemosensitive disease at the time of transplantation (partial or complete response to last salvage therapy). d. Subjects with other nonHodgkin or Hodgkin lymphoma with a response to last salvage therapy or chemo-sensitive disease per institutional standards at the time of transplantation. e. For subjects with myelofibrosis and other myeloproliferative disorders: <5% blasts in the blood and bone marrow. 7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 for subjects aged ≥18 years at randomization or ≥60% using the Karnofsky performance status for adolescent subjects aged ≥16 years at randomization or the Lansky performance status for adolescent subjects aged 12 to <16 years at randomization. 8. Sufficient cognitive ability to reliably complete the PML checklist at baseline. 9. Female subjects who are: • Postmenopausal for at least 1 year before signing of the informed consent, OR • Surgically sterile, OR • If they are aged 12 years and greater and not postmenopausal or surgically sterilized, must use a highly effective method of contraception during the study and through 18 weeks after the last dose of study drug, OR • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) Male subjects, even if surgically sterilized (ie, status postvasectomy), who: • Agree to practice an acceptable effective barrier method of contraception during the entire study treatment period and through 18 weeks after the last dose of study drug, OR • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) 10. Suitable venous access for the study-required blood sampling, including PK sampling.
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E.4 | Principal exclusion criteria |
1. Prior allo-HSCT. 2. Planned umbilical cord blood transplant or planned to receive posttransplant cyclophosphamide, in vivo or ex vivo T-cell depleted hematopoietic stem cells (HSCs) with the exception of ATG (ATG-F or thymoglobulin). 3. Planned allo-HSCT for nonmalignant hematological disorders (eg, aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia or immunodeficiency). 4. Known active cerebral/meningeal disease (including central nervous system involvement of the primary disease), or signs or symptoms of PML, any history of PML, or a positive PML subjective checklist before the administration of study drug on Day -1. 5. Evidence of encephalopathy at screening. 6. History of any major neurological disorder, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease. 7. Prior or current therapy with α4 and/or β7 integrin inhibitors (including, but not limited to natalizumab, etrolizumab, AMG-181), MAdCAM-1-antibodies, anti-CD11a mAb (eg, efalizumab) within 60 days or 5 half-lives, whichever is longer from randomization. 8. Prior known exposure of the transplant recipient to vedolizumab. 9. Any serious medical or psychiatric condition that could, in the investigator or medical monitor’s opinion, potentially interfere with the completion of treatment according to this protocol. 10. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, coagulation, immunological, endocrine/metabolic, neurologic or other medical disorder not related to the subject’s primary disease that, in the opinion of the investigator, would confound the study results or compromise subject safety. 11. Clinically active systemic infection during screening. 12. Clinically active cytomegalovirus (CMV) colitis during screening. 13. Clinically active Clostridium difficile infection or other intestinal pathogen during screening. 14. Active or latent tubercolosis (TB), regardless of treatment history, as evidenced by any of the following: history of TB, OR positive QuantiFERON test, OR T-spot or 2 successive indeterminate QuantiFERON tests, OR T-Spot tests OR a tuberculin skin test reaction ≥10 mm (≥5 mm in subjects receiving the equivalent of >15 mg/day prednisone). 15. Chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive [HBsAg+]) or hepatitis C infection (evident by active viral replication by polymerase chain reaction [PCR] if hepatitis C virus antibody positive). Hepatitis B core antibody (HBcAb) positive (HBcAb+) and negative for hepatitis B surface antigen (HBsAg-) may be enrolled if viral DNA is undetectable. 16. History of human immunodeficiency virus (HIV) positive test. 17. Treatment with anti-T-cells antibody such as alemtuzumab (anti-CD52), excluding ATG (ATG-F or thymoglobulin), within 4 months before the first dose of study drug on Day -1. 18. Treatment with any live vaccinations within 30 days before randomization. 19. If female, the subject is pregnant, lactating or breastfeeding, or intending to become pregnant before, during or within 18 weeks after participating in this study, or intending to donate ova during such time period. 20. Diagnosed or treated for another malignancy within 2 years before the first dose of study drug or previously diagnosed with another malignancy and have any evidence of residual disease. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is intestinal aGvHD-free survival by Day +180 after allo HSCT. Intestinal aGvHD is defined as Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Intestinal aGvHD-free and relapse-free (of the underlying malignancy) survival by Day +180. • Grade C-D aGvHD-free (any organ involvement) survival by Day +180. • NRM by Day +180. • OS by Day +180. • Grade B-D aGvHD-free (any organ involvement) survival by Day +180.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenicity Tolerability |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Norway |
Poland |
Portugal |
Romania |
Russian Federation |
Singapore |
Spain |
Sweden |
Switzerland |
Taiwan |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The final visit (end-of-study) will be performed 12 months after allo-HSCT. Subjects who discontinue study drug treatment will complete an early termination (ET) visit upon discontinuation and a final visit 12 months after allo-HSCT. The global study will end after the last subject has completed the final visit 12 months after allo-HSCT, or the subject has died, withdrawn consent, or been lost to follow-up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 23 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 23 |