Efficacy and Safety of apraglutide in steroid refractory gastrointestinal acute graft versus host disease.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

VectivBio AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

1 Jun 2022 → 18 Dec 2024

Decision date (initial)

2024-05-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

VectivBio AG

External identifiers

EU CT number

2023-507960-38-00

EudraCT number

2021-004588-29

WHO UTN

U1111-1298-7410

ClinicalTrials.gov

NCT05415410

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Therapy, Safety, Others

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.

Secondary objectives 16

1. 1. The overall response rate (PR and CR) at Day: - 56 on the lower GI tract MAGIC score in subjects with SR lower GIaGVHD 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.
2. 2. The rate of durable overall response rate from Day 28 to Day 56.
3. 3. Duration of response from Day 56 on the total MAGIC score.
4. 4. To assess the individual durations of lower GI response (according to the MAGIC score).
5. 5. To assess the individual durations of lower GI response (according to the MAGIC score) in subjects that were re-treated with apraglutide because of a lower GI-aGVHD flare.
6. 6. To assess the time to partial lower GI-aGVHD response as defined by the MAGIC score.
7. 7. To assess the time to complete lower GI-aGVHD response as defined by the MAGIC score.
8. 8. To assess best overall response.
9. 9. Assessment of failure-free survival (FFS1).
10. 10. To assess NRM2.
11. 11. To assess overall survival (OS3).
12. 12. To assess the incidence of malignancy relapse.
13. 13.To assess failure of the transplantation (graft failure5).
14. 14. To assess cumulative SS and RUX doses used.
15. 15. To assess the incidence of infections and sepsis.
16. 16. To assess the effect of the two dose ranges on safety, tolerability, and efficacy.

Conditions and MedDRA coding

Acute graft versus host disease (aGVHD)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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. 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. 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. 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. 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. 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/day6 ([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 should be ≥2 mg/kg/day systemic MP ([or prednisone dose ≥2.5 mg/kg/day] or equivalent)
7. 7. Treatment with SS plus RUX (RUX started concomitantly to apraglutide or a maximum of 72 hours before apraglutide initiation)
8. 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 contraceptive 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. 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

Exclusion criteria 29

1. 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. 18. History of chronic gall bladder or bile duct inflammation or biliary obstruction unless a cholecystectomy was performed before screening.
3. 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.
4. 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)
5. 20. Subjects that present or have a history of familial adenomatous polyposis.
6. 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.
7. 22. Central venous catheter sepsis requiring systemic antibiotics within the previous 7 days prior to randomization/Day 0.
8. 11. Presence of decompensated liver cirrhosis Child Pugh Classes B and C.
9. 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
10. 13. Requirement for vasopressor or inotropic support within 30 days prior to randomization/Day 0.
11. 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)
12. 3. Failed alloSCT due to relapse of underlying malignant disease.
13. 15. Presence of relapsed primary malignancy or treatment for relapse after alloSCT.
14. 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
15. 2. Concomitant treatment with Janus kinase inhibitor therapy other than RUX at the time of randomization.
16. 23. Known cGVHD.
17. 24. Known active GI inflammation not related to GI-aGVHD (e.g., active inflammatory bowel disease such as Crohn's and ulcerative colitis)
18. 25. History of progressive multifocal leuko-encephalopathy.
19. 26. Known pregnant or nursing (lactating) women.
20. 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)
21. 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
22. 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
23. 4. Presence of SR GI-aGVHD occurring after donor lymphocyte infusion for pre-emptive treatment of malignancy recurrence
24. 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
25. 6. Known or suspected hypersensitivity to GLP-1 or GLP-2 analogs or apraglutide excipients.
26. 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
27. 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
28. 17. Presence of newly diagnosed malignancies at screening or prior to randomization/Day 0.
29. 9. Less than 2 weeks anticipated survival at screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. 1. Adverse events (AEs; System Organ Class [SOC], frequency and severity).
2. 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. 3. Occurrence of clinically significant changes from baseline in clinical chemistry (including liver function tests), hematology, hemostasis, and urinalysis
4. 4. Occurrence of clinically significant changes from baseline in vital signs (blood pressure, heart rate).
5. 5. Occurrence of clinically significant changes from baseline in electrocardiogram (ECG) measurements (intervals and rhythm).
6. 6. Occurrence and titer of anti-drug antibodies (ADAs).

Secondary endpoints 20

1. 1. Overall response rate (PR and CR) at Day 56 on the lower GI tract MAGIC score.
2. 2. Overall response rate (PR and CR) at Days 14, 28, 91, 119, 147, and 182 on the lower GI tract MAGIC score.
3. 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. 4. Proportion of all subjects who achieve a CR or PR at Day 28 and maintain a CR or PR at Day 56.
5. 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. 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. 7. Individual duration of lower GI response (according to the MAGIC score) counted from the first response to return to baseline or worse.
8. 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. 9. Time to partial lower GI-aGVHD response (median and range) as defined by the MAGIC score.
10. 10. Time to complete lower GI-aGVHD response (median and range) as defined by the MAGIC score.
11. 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. 12. Failure free survival up to 2 years post-first dose of apraglutide.
13. 13. Non relapse mortality up to 2 years post-first dose of apraglutide.
14. 14. Incidence of malignancy relapse up to 2 years post-first dose of apraglutide.
15. 15. Overall survival up to 2 years post-first dose of apraglutide.
16. 16. Graft failure up to 2 years post-first dose of apraglutide.
17. 17. Incidence of lower GI-aGVHD flare up to Day 182 after first apraglutide dose following earlier cessation due to complete lower GIaGVHD response.
18. 18. Cumulative SS and RUX doses from start of the RUX treatment up to Day 91 after the first dose of apraglutide.
19. 19. Incidence of infections and sepsis from baseline up to Day 91 after first dose of apraglutide.
20. 20. Effect of the two dose groups on safety/tolerability and efficacy.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

VectivBio AG

Sponsor organisation

VectivBio AG

Address

Aeschenvorstadt 36

City

Basel

Postcode

4051

Country

Switzerland

Scientific contact point

Organisation

VectivBio AG

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

VectivBio AG

Contact name

Clinical Trial Information Desk

Third parties 12

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications