Eculizumab in hypertensive emergency-associated hemolytic uremic syndrome: a randomized multicenter controlled trial (HYPERSHU)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

13 Feb 2024 → ongoing

Decision date (initial)

2024-11-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS - French Ministry of Health

External identifiers

EU CT number

2024-516402-32-00

EudraCT number

2022-002329-84

ClinicalTrials.gov

NCT05726916

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To demonstrate the efficacy of early Eculizumab administration added on standard of care BP control on dialysis-dependence at month 6 in HEaHUS patients with severely impaired initial renal function.

Secondary objectives 9

1. To evaluate the role of complement biomarkers in predicting therapeutic response
2. To evaluate the frequency of complement genetic rare variants in this population
3. To evaluate the efficacy of early eculizumab administration added on standard of care BP control on 3-month (W13) and 12 months renal replacement therapy risk
4. To evaluate the frequency of severe infections in both groups
5. To evaluate the time to resolution of hemolysis and acute dialysis
6. To evaluate the frequency of histological lesions and their prognosis (if kidney biopsy is performed)
7. To evaluate the medico-economic impact of Eculizumab
8. Objective of the first ancillary study: A first ancillary study will include a pangenomic analysis aimed at identifying new genetic variants associated with HE-aHUS. This ancillary study will be based on the residual genetic samples already scheduled in the biocollection. This ancillary study will be coordinated by Pr L. Mesnard (Nephrology Department, Tenon Hospital, Paris) and performed according to an already available funding
9. Objective of any other potential ancillary study: biological collection For any other ancillary study: residual samples will be stored for a biological collection to identify new potential genetic and pathophysiological determinants of HE-aHUS (Department of Immunobiology, HEGP, Dr Frémeaux-Bacchi).

Conditions and MedDRA coding

Adult patients with aHUS associated with HE and severe kidney involvement (needing dialysis or serum creatinine ≥ 354μM)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age ≥ 18 years
2. Hospitalization forHE-aHUS within prior 10 days: o Presume acute renal failure (renal replacement therapy or serum creatinine ≥ 354μM). o Mechanical hemolysis including: anemia, and: thrombopenia, or low haptoglobin (1,5UNL), or presence of schistocytes or histological lesions of thrombotic microangiopathy o Severe hypertension with systolic blood pressure >180mmHg and/or diastolic blood pressure>110mmHg o Target organ damage, including neurological involvement (notably hypertensive encephalopathy, headache, confusion, nausea, posterior reversible encephalopathy syndrome), or cardiovascular involvement (notably acute left ventricular failure, acute pulmonary edema, acute cardiac ischemia, chest pain, dyspnea, palpitations), or ophtalmological involvement (notably ischemic retinopathy or blurred vision)
3. For women of childbearing potential: Effective contraception during the study and for at least 5 months after the last dose of treatment with eculizumab
4. Subject affiliated to a social security regimen
5. Subject having signed written informed consent

Exclusion criteria 18

1. Atrophic kidneys with maximum length<8cm on recent (<1 month) renal ultrasound, CT scan, or renal MRI
2. High clinical suspicion of Complement-mediated aHUS (including familial history of aHUS)
3. High clinical suspicion of typical HUS (including Shiga Toxin-producing E. Coli infection) or Thrombotic thrombocytopenic purpura
4. High clinical suspicion of secondary HUS related to autoimmune disease (including lupus, scleroderma, antiphospholipid syndrome, ANCA vasculitis), or C3 glomerulopathy.
5. High clinical suspicion of recent constituted hemorrhagic or ischemic stroke justifying specific blood pressure targets
6. ADAMTS 13<10%, HIV or HCV infection, positivity of 2 markers among: anticardiolipin IgG/antiBeta2 GP1 IgG/lupus anticoagulant, positivity of ANCA (ELISA PR3 or MPO)
7. Active infection
8. Subjects with unresolved Neisseria meningitidis infection
9. Subjects refusing Neisseria meningitidis vaccination or refusing antibioprophylaxis with oracillin (In case of penicillin allergy, antibioprophylaxis with macrolide couldbeproposed according to ANSM recommendations (azithromycin or roxithromycin))
10. Contra-indication to eculizumab or renin angiotensin system blockers
11. Solid organ or haematopoietic transplant
12. History (<1year) of active cancer or exposition to drugs associated with aHUS (< 3 months)
13. Severe cognitive or psychiatric disorders, patients unable to give an informed consent
14. Positive SARS-CoV2 PCR or antigenic test
15. Pregnant or breastfeeding woman or ineffective contraception
16. Persons deprived of their liberty by judicial or administrative decision
17. Persons under legal protection (guardianship, curatorship)
18. Participation in another interventional study involving human participants or being in the exclusion period at the end of a previous study involving human participants

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Response to therapy, defined by the absence of any of the following events: i) at 6-month follow-up: persistent renal replacement therapy, eGFR<15ml/mn/1,73m2, or patient death; ii) at W2 : persistent hemolysis despite well conducted antihypertensive therapy. Any Eculizumab rescue in the control group will be considered as a failure.

Secondary endpoints 8

1. Prognosis role of repeat complement biomarkers (W1, W4, W13)
2. Frequency of Complement genetic rare variants
3. Renal replacement therapy rates at months 3 and 12 follow-up
4. Frequency of severe infections (defined by the need for hospitalization)
5. Time to resolution of haemolysis
6. Time to resolution of renal replacement therapy
7. Frequency and prognostic role of kidney lesions (glomerular and arteriolar microthromboses), glomerulosclerosis and kidney fibrosis if kidney biopsy is performed
8. Costs relating to renal replacement therapy (or lack of), Eculizumab and other antihypertensive treatments, hospitalizations

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Dr El Karoui Khalil

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Dr El Karoui Khalil

Locations

1 EU/EEA country · 16 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

Documents 8 files

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

Application history

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