| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute graft versus host disease (aGVHD) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 | 10075160 |
| E.1.2 | Term | Graft versus host disease in gastrointestinal tract |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10075161 |
| E.1.2 | Term | Graft versus host disease in GI tract |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 |
|
| 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 | 10066260 |
| E.1.2 | Term | Acute graft versus host disease |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 assess safety and tolerability of apraglutide in subjects with SR lower GI-aGVHD Grade II to IV Mount Sinai aGVHD International Consortium (MAGIC) who are treated with SS and RUX
|
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
• The overall response rate (PR and CR) at Day:
- 56 on the lower GI tract MAGIC score in subjects with SR lower GI-aGVHD Grade II - IV MAGIC that are treated with apraglutide, SS, and RUX compared to SS and RUX alone (BAT)
- 14, 28, 91, 119, 147, and 182 on the lower GI-tract MAGIC score
- 14, 28, 56, 91, 119, 147, and 182 on the total MAGIC score
• The rate of durable overall response rate from Day 28 to Day 56
• duration of response from Day 56 on the total MAGIC score
To assess:
- the individual durations of lower GI response (as per MAGIC score) in all subjects and in subjects re-treated with apraglutide because of a GI-aGVHD-flare
- the time to partial lower and complete lower GI-aGVHD response as defined by MAGIC score
- best overall response, FFS, NRM, OS, incidence of MR, failure of the transplantation (graft), cumulative SS and RUX doses used, incidence of infections and sepsis and effect of the two dose ranges on safety/tolerability and efficacy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent for this trial prior to any trial specific assessment. A signed assent form will also be required for all subjects under the age of 18 years
2. Male or female subjects aged 12 years or above at the time of consent and who weigh a minimum of 40.0kg. Only subjects of 18 years and above will be included in Germany and France
3. Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non-myeloablative, myeloablative, and reduced intensity conditioning are eligible
4. Evident myeloid and platelet engraftment (confirmed prior to trial medication start):
a) Absolute neutrophil count >1000/mm3
and
b) Platelets ≥20,000/mm3
Use of growth factor supplementation (granulocyte-colony stimulating factor and granulocyte-macrophage-colony stimulating factor) and transfusion support is allowed
5. Clinical diagnosis of lower GI-aGVHD, MAGIC Stage 1–4 prior to randomization. Suitable diagnostic procedures should be implemented to exclude alternative reasons for diarrhea; these include (but not limited to) fecal cultures and lower gut biopsy with histological
assessment for infectious diseases
6. Clinically confirmed SR lower GI-aGVHD defined as subjects administered SS, given alone, or combined with CNIs and either:
a) Disease progression based on organ assessment after 3 days of treatment with MP ≥ 2 mg/kg/day ([or prednisone dose ≥ 2.5 mg/kg/day] or equivalent) ± CNIs
or
b) Did not improve after 7 days of treatment with systemic MP ≥ 2 mg/kg/day ([or prednisone dose ≥ 2.5 mg/kg/day] or equivalent)
or
c) Progressed to a new organ after treatment with systemic MP ≥ 2 mg/kg/day ([or prednisone dose ≥ 2.5 mg/kg/day] or equivalent) for skin and upper GI-aGVHD,
or
d) Recurred during or after a steroid taper, Initial dose of SS should be ≥ 2 mg/kg/day ([or prednisone dose ≥ 2.5 mg/kg/day] or equivalent)
7. Treatment with SS plus RUX (RUX started concomitantly to apraglutide or a maximum of 72 hours before apraglutide initiation) .
8. Women of childbearing potential must agree to use a highly effective method of contraception and refrain from donating eggs during the trial and for 4 weeks after the EOT visit. Effective methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner. In Germany,
oral methods of hormonal contraception are to be combined with
another accepted method of contraception.
To be considered sterilized or infertile, females must have undergone surgical sterilization (bilateral tubectomy, hysterectomy, or bilateral ovariectomy) or be post-menopausal (defined as at least 12 months amenorrhea without an alternative medical cause, may be confirmed with follicle-stimulating hormone test in case of doubt). Women who do not engage in heterosexual intercourse will be allowed to join the trial without contraception following a thorough discussion with the Investigator to determine if this is feasible for the subject. The following methods are not considered acceptable methods of contraception: calendar, ovulation, symptothermal, post-ovulation methods, withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method
9. Male subjects with a female partner of childbearing potential must commit to practice methods of contraception and abstain from sperm donation during the trial and for 2 weeks after the EOT visit.
Nevertheless, if their partners are women of childbearing potential, they must agree to practice contraception and use a highly effective method of contraception during the trial and for 4 weeks after the EOT visit.
Such methods include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal
contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion |
|
| E.4 | Principal exclusion criteria |
1. Treatment with any systemic GVHD therapy (other than SS and RUX) including methotrexate and mycophenolate mofetil at the time of randomization/Day 0. Graft versus host disease prophylaxis (ciclosporin A, tacrolimus, sirolimus, everolimus, or anti-thymocyte globulin) is allowed.
2. Concomitant treatment with Janus kinase inhibitor therapy other than RUX at the time of randomization
3. Failed alloSCT due to relapse of underlying malignant disease
4. Presence of SR GI-aGVHD occurring after donor lymphocyte infusion for pre-emptive treatment of malignancy recurrence
5. Ongoing participation in an interventional trial or administration of any investigational drug in less than its five half-lives prior to randomization/Day 0. Participation in observational or interventional trials involving supportive care such as probiotics or antiemetics, graft manipulation or transplant procedures, new combinations or new dosing of approved therapies for conditioning, prophylaxis, pre- or post-alloSCT and treatment of the underlying malignant disease are allowed after consultation with the Sponsor
6. Known or suspected hypersensitivity to GLP-1 or GLP-2 analogs or apraglutide excipients
7. Any use of enteral glutamine or growth factors such as native GLP-2, GLP-1, GLP-2 and GLP-1 analogs or known ADA within 6 months prior to randomization/Day 0
8. Inability to understand or unwillingness to adhere to the trial visit schedules and other protocol requirements, including subjects not willing to comply owing to drug/alcohol abuse or any condition that would interfere with full participation in the trial, including administration of trial medication and attending required trial visits; pose a significant risk to the subject; or interfere with interpretation of trial data
9. Less than 2 weeks anticipated survival at screening
10. Evidence of chronic renal disease as demonstrated by inadequate renal function, which is defined as estimated glomerular filtration rate (eGFR) <20 mL/min/1.73m2 (using the Chronic Kidney Disease Epidemiology [CKD-EPI] formula) and is confirmed within 48 hours prior to randomization/Day 0)
11. Presence of decompensated liver cirrhosis Child Pugh Classes B and C
12. Clinically significant or uncontrolled cardiac disease including acute myocardial infarction within 6 months prior to randomization/Day 0, uncontrolled hypertension, congestive heart failure New York Heart Association Class III or IV
13. Requirement for vasopressor or inotropic support within 30 days prior to randomization/Day 0
14. Presence of uncontrolled cholestatic disorders or unresolved sinusoidal obstructive syndrome/veno-occlusive disease of the liver (defined as persistent bilirubin abnormalities not attributable to aGVHD and ongoing organ dysfunction)
15. Presence of relapsed primary malignancy or treatment for relapse after alloSCT
16. Requirement for unplanned immune suppression withdrawal as treatment of early malignancy relapse or low donor chimerism. Unclear remission states will be discussed with the Sponsor
17. Presence of newly diagnosed malignancies at screening or prior to randomization/Day 0
18. History of chronic gall bladder or bile duct inflammation or biliary obstruction unless a cholecystectomy was performed before screening
19. Presence or history of GI tumors (including the hepatobiliary system and pancreas) within the last five years before randomization; presence of colonic polyps that are not removed
20. Subjects that present or have a history of familial adenomatous polyposis
21. Presence of an active clinically uncontrolled infection or evidence of active tuberculosis (clinical diagnosis per local practice). Cytomegalovirus reactivation is permitted as long as no evidence of pulmonary disease is present.
22. Central venous catheter sepsis requiring systemic antibiotics within the previous 7 days prior to randomization/Day 0
23. Known cGVHD
24. Known active GI inflammation not related to GI-aGVHD (e.g., active inflammatory bowel disease such as Crohn’s and ulcerative colitis)
25. History of progressive multifocal leuko-encephalopathy
26. Known pregnant or nursing (lactating) women
27. Known major abdominal surgery in the last 6 months prior to randomization/Day 0 (surgical feeding tube placement or other minimally invasive surgery is allowed)
28. History of clinically significant intestinal adhesions increasing the risk of GI obstruction or GI contrast examination findings suggesting subacute intestinal obstruction or stricture within 6 months prior to randomization/Day 0
29. Liver enzymes meeting any of the following criteria within 48 hours prior to trial medication start:
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 x upper limit of normal (ULN),
b. Alanine aminotransferase or AST >5 x ULN AND international normalized ratio >3 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Adverse events (AEs; System Organ Class [SOC], frequency and severity).
2. Incidence of AEs of special interest (AESIs) related to apraglutide: (injection site reactions, gastrointestinal obstructions, gallbladder, biliary and pancreatic disease, fluid overload, colorectal polyps, new malignancies, systemic hypersensitivity).
3. Occurrence of clinically significant changes from baseline in clinical chemistry (including liver function tests), hematology, hemostasis, and urinalysis.
4. Occurrence of clinically significant changes from baseline in vital signs (blood pressure, heart rate).
5. Occurrence of clinically significant changes from baseline in electrocardiogram (ECG) measurements (intervals and rhythm).
6. Occurrence and titer of anti-drug antibodies (ADAs). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| All primary endpoints (safety endpoints): From baseline until last visit of each patient. |
|
| E.5.2 | Secondary end point(s) |
1. Overall response rate (PR and CR) at Day 56 on the lower GI tract MAGIC score
2. Overall response rate (PR and CR) at Days 14, 28, 91, 119, 147, and 182 on the lower GI tract MAGIC score
3. Overall response rate (PR and CR) at Days 14, 28, 56, 91, 119, 147, and 182 by organ system (skin, lower and upper GI tract and liver) on the total MAGIC score
4. Proportion of all subjects who achieve a CR or PR at Day 28 and maintain a CR or PR at Day 56
5. Duration of response from Day 56 (median and range) on the total MAGIC score where duration of response is defined as the interval from the Day 56 response (PR and CR) to death or new systemic therapy for aGVHD (including an increase in steroids >2 mg/kg/day methylprednisolone [MP] equivalent), whichever occurs first, with at least 182 days of follow-up
6. Duration of response from Day 28 (median and range) on the total MAGIC score where duration of response is defined as the interval from the Day 28 response (PR and CR) to death or new systemic therapy for aGVHD (including an increase in steroids >2 mg/kg/day MP equivalent), whichever occurs first, with at least 182 days of follow-up
7. Individual duration of lower GI response (according to the MAGIC score) counted from the first response to return to baseline or worse
8. Individual duration of lower GI response (according to the MAGIC score) in subjects that were re-treated with apraglutide because of a lower GI-aGVHD flare, counted from the first response after apraglutide restart to return to baseline or worse
9. Time to partial lower GI-aGVHD response (median and range) as defined by the MAGIC score
10. Time to complete lower GI-aGVHD response (median and range) as defined by the MAGIC score
11. Best overall response defined as overall response (PR or CR) at any time point up to and including Day 91 and before the start of additional systemic therapy for lower GI-aGVHD
12. Failure free survival up to 2 years post-first dose of apraglutide
13. Non relapse mortality up to 2 years post-first dose of apraglutide
14. Incidence of malignancy relapse up to 2 years post-first dose of apraglutide
15. Overall survival up to 2 years post-first dose of apraglutide
16. Graft failure up to 2 years post-first dose of apraglutide
17. Incidence of lower GI-aGVHD flare up to Day 182 after first apraglutide dose following earlier cessation due to complete lower GI-aGVHD response
18. Cumulative SS and RUX doses from start of the RUX treatment up to Day 91 after the first dose of apraglutide
19. Incidence of infections and sepsis from baseline up to Day 91 after first dose of apraglutide
20. Effect of the two dose groups on safety/tolerability and efficacy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Day 56
2. Days 14, 28, 91, 119, 147&182
3. Days 14, 28, 56, 91, 119, 147&182
4. Days 28 & 56
5. From Day 56 to death or new systemic therapy for aGVHD (with at least 182 days of follow-up)
6. From Day 28 to death or new systemic therapy for aGVHD (with at least 182 days of follow-up)
7,8,9 & 10. At any point
11. Any point up to Day 91 and before the start of additional systemic therapy for lower GI-GVHD
12-16. Up to 2 years post-first dose of apraglutide
17. At any point up to Day 182 after first apraglutide dose following earlier cessation due to complete lower GI-GVHD response
18. From start of the RUX treatment up to Day 91 after the first dose of apraglutide
19. From baseline up to Day 91 after first dose of apraglutide
20. From baseline until last visit of each subject |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Portugal |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of the trial is defined as the last subject’s last visit. |
|
| 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 | 0 |
| 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 | 0 |
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