E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Graft Versus Host Disease (cGVHD) |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Graft Versus Host Disease (cGVHD) is a disease observed in transplant recipients. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066261 |
E.1.2 | Term | Chronic graft versus host disease |
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 effect of ENTO on the best overall response rate (BORR) as assessed by the NIH cGVHD Activity Assessment (NCAA) by 24 weeks in the setting of add-on to systemic corticosteroids as part of first-line therapy for cGVHD |
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E.2.2 | Secondary objectives of the trial |
The key secondary objectives are:
- To evaluate the effect of ENTO on the skin domain of the Lee Symptom Scale (LSS) at 24 weeks
- To evaluate the effect of ENTO on the mouth domain of the LSS at 24 weeks
- To evaluate the effect of ENTO on the eyes domain of the LSS at 24 weeks
- To evaluate the effect of ENTO on the total score of the LSS at 24 weeks
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
2) 18-75 years of age, inclusive at Screening
3) Newly diagnosed cGVHD defined by:
a) At least 100 days after receiving any allogeneic hematopoietic stem cell transplant
AND
b) Receiving a new course of systemic corticosteroids (≥ 0.5 mg/kg/day) as first-line cGVHD therapy for at least 1 day
and no more than 21 days prior to first dose of ENTO/Placebo
AND
c) Moderate to severe cGVHD as assessed by NCDSC with at least three organ systems involved OR one organ system with a score of 2 OR lung organ score = 1
4) Subjects who have undergone transplantation for benign indications are eligible for the study. Complete remission is required for subjects who have undergone transplantations for hematologic malignancies.
5) Have either a normal ECG or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the Sponsor
6) A negative serum pregnancy test is required for female subjects (unless permanently sterile or greater than two years post-menopausal)
7) A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant or nursing
b) Of non-childbearing potential (i.e., women who have had a hysterectomy, have had both ovaries removed or medically documented ovarian failure, or are postmenopausal women > 54 years of age with cessation (for more than or equal to 12 months) of previously occurring menses), or
c) Of childbearing potential and agrees to utilize a highly effective protocol-specified contraceptive method or be non-heterosexually active or practice sexual abstinence from Screening throughout the duration of study treatment and for 30 days following the last study drug dose
d) Female subjects who utilize a hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing
8) Male subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception.
9) Both female and male subjects of childbearing potential who are receiving mycophenolate mofetil (MMF) must agree to utilize contraceptive measures in accordance with the current MMF SmPC and the precautions for ENTO outlined in Appendix 8, whichever is stricter. |
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E.4 | Principal exclusion criteria |
1) Inability to begin systemic corticosteroids therapy at a dose of ≥ 0.5 mg/kg/day (or equivalent)
2) Uncontrolled infection within 4 weeks prior to Randomization
3) History of the following therapies in the post-transplant period:
a) B cell depleting biologic agents
b) CD19 CAR-T cells based therapies
c) BTK/SYK/JAK/PI3K inhibitors
d) Phototherapy-unless administered for aGVHD
4) Treatment of cGVHD with anti-thymocyte globulins (ATG), or campath within 60 days of Screening visit unless used for treatment of acute GVHD
5) Severe organ dysfunction manifest during Screening period:
a) Requiring supplemental oxygen at more than 2L/min
b) Uncontrolled arrhythmia or heart failure
c) Creatinine clearance (Cockroft-Gault) < 30 mL/min
6) Known hypersensitivity to the Investigational Medicinal Product (IMP), the metabolites, or formulation excipient.
7) Laboratory abnormalities including:
a) Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen or hepatitis C antibody positive (Subjects with positive HCV antibody and without detectable HCV RNA are permitted to enrol)
b) Aspartate aminotrasferase (AST)/Alanine aminotransferase (ALT) ≥ 2 X upper limit of normal (ULN) unless deemed to be secondary to Liver GVHD
c) Total bilirubin ≥ 2 X ULN unless deemed to be secondary to Liver GVHD
8) Positive serum pregnancy test (for female subjects)
9) Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements
10) Participation in any other clinical trial without prior approval from the sponsor is prohibited while participating in this trial
11) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety
12) Subjects receiving ongoing therapy with any of the medications from the following drug class: mTOR inhibitor, any cell depleting antibody, phototherapy, BTK agents, JAK inhibitors, strong and moderate CYP3A/2C9 inducers, strong CYP2C9 inhibitors, herbal/natural supplements |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is BORR as assessed by the NCAA by 24 weeks in the setting of add-on to systemic corticosteroids as part of first-line therapy for cGVHD |
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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) |
The key secondary endpoints are:
- Change from Baseline in the skin domain of the LSS at 24 weeks
- Change from Baseline in the mouth domain of the LSS at 24 weeks
- Change from Baseline in the eyes domain of the LSS at 24 weeks
- Change from Baseline in the total score of the LSS at 24 weeks
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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 | No |
E.6.3 | Therapy | Yes |
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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 |
Australia |
Canada |
France |
Germany |
Korea, Republic of |
Spain |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 27 |