HEMolyse and Organ damage imPROvement in sickle cell disease by VoxElotor

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] - Hemic and Lymphatic Diseases [C15]

Trial duration

24 Mar 2022 → 4 Dec 2024

Decision date (initial)

2024-08-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Pfizer

External identifiers

EU CT number

2024-513096-41-00

EudraCT number

2020-005424-11

ClinicalTrials.gov

NCT05199766

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To evaluate the biological activity of Voxelotor on the reduction of intra vascular hemolysis measured by plasma hemoglobin

Secondary objectives 16

1. To characterize the effects of Voxelotor on Intra vascular hemolysis measured by plasma Heme
2. To characterize the effects of Voxelotor on Total hemoglobin mass (MHb)
3. To characterize the effects of Voxelotor on RBCs lifespan
4. To characterize the effects of Voxelotor on Blood volumes (plasma volume (PV), red blood cell mass (RBCM), total blood volume (BV))
5. To characterize the effects of Voxelotor on Blood viscosity
6. To characterize the effects of Voxelotor on Cerebral perfusion
7. To characterize the effects of Voxelotor on Cerebrovascular vaso-reactivity
8. To characterize the effects of Voxelotor on Cognitive function (MoCA)
9. To characterize the effects of Voxelotor on Renal perfusion and iron deposits in renal cortex
10. To characterize the effects of Voxelotor on Measurement of Glomerular filtration rate
11. To characterize the effects of Voxelotor on Estimation of glomerular filtration rate (CKD/EPI equation)
12. To characterize the effects of Voxelotor on Urine albumin/creatinine ratio
13. To characterize the effects of Voxelotor on Ability to decrease or stop erythropoietin in patients under EPO treatment
14. To characterize the effects of Voxelotor on Safety (VOC, ACS, Priapism) and tolerability of voxelotor
15. To characterize the effects of Voxelotor on RBC properties
16. To characterize the effects of Voxelotor on Evaluation of integrative cardiovascular, hemodynamic, respiratory and metabolic variables during exercise

Conditions and MedDRA coding

sickle cell disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. SS or S-β0 major sickle cell syndrome
2. Hemoglobin level < 9 g/dL
3. Aged 18 years or older
4. Stable dose for at least 3 months if treated with HU, EPO, angiotensin-converting enzyme (ACE), inhibitor/angiotensin receptor blocker (ARB), glutamine or crizanlizumab therapy; at least after 6 months after initiating HU treatment
5. Patient with social security
6. Female patient must have a negative serum pregnancy test (betaHCGat inclusion W0-V1D1) or evidence of post-menopausal status
7. Effective methods of birth control (e.g., condom, spermicidal gel, oral contraceptive, indwelling intrauterine device, hormonal implant/patch, injections, approved cervical ring) or abstinence from screening through 4 weeks after last Voxelotor dose.

Exclusion criteria 15

1. Patients in chronic transfusion program or transfused < 3 months before enrolment
2. If patient does not have any of the following treatments (HU, Crizanlizumab) he will then be excluded if: Patient meets, at screening, Hydroxyurea/ Crizanlizumab indications of treatment (recurrent painful vaso-occlusive crises, including acute chest syndrome), even if these treatments are inappropriate (e.g. hematologic toxicity antecedent) or if the patient refuses these treatments
3. Patient with severe organ involvement: hepatic (TP <50%), renal (eGFR<30 ml / ml/1.73m2 according to CKD/EPI or cardiac (LVEF <45%)
4. Transplant patients.
5. Pregnancy
6. Breast feeding patients
7. Homeless patient
8. Patient deprived of liberty by judicial or administrative decision or patient under guardianship
9. Patient unable to understand the purpose and conditions of the study and unable to give consent
10. Chronic use of NSAIDs (more than 10 days by month)
11. Auto immune disease or infection not controlled or cancer
12. VIH, HBV, HCV current infection
13. Prior drug hypersensitivity to Voxelotor or excipients
14. Known allergy or hypersensitivity to imaging contrast product
15. Ongoing therapeutic study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Improvement of Intravascular hemolysis, as defined by a ≥20% decrease of plasma Hemoglobin (µmol/l) between W0 and W48 weeks

Secondary endpoints 16

1. Evolution between W0 and W48 weeks in intravascular hemolysis, as measured by absolute and relative (%) changes from baseline in plasma Hemoglobin (µmol/l) and free plasma Heme (µmol/l)
2. Measurement of total hemoglobin mass based on the CO rebreathing technique (g of Hb / kg), or a stable evolution (i.e. decrease ≤ 10%) in patients initially under EPO therapy and who decreased or discontinued EPO during the study period.
3. RBC lifespan by measurement of alveolar CO (in days)
4. Blood volumes by CO rebreathing method (Total Mass of Hemoglobin (g of Hb), Total blood volume (L), RBC mass (g), Plasma Volume (L) )
5. Blood viscosity
6. Cerebral perfusion measured by MRI
7. Cerebral vaso-reactivity measured by transcranial Doppler (Breath holding test) and Near Infra Red Spectroscopy
8. Cognitive performance measured by MoCA
9. Improvement in the 6 minutes walk test on : Time spent under Sp02 88 and 90%, Borg Rating of Perceived Exertion (RPE), distance.
10. Renal perfusion and amount of deoxyhemoglobin by MRI and Iron deposits in renal cortex by MRI
11. Glomerular Filtration Rate measurements, urine concentration capacity (fasting urinary osmolarity)
12. urine albumin/creatinine ratio
13. Concomitant treatment observation: decrease / interruption of EPO dose
14. Safety;(VOC, ACS, Priapism) presence/absence of each signs
15. RBC properties: density, hemoglobin affinity , viscosity, deformability, senescence parameters, HbF/cell measure
16. Blood lactate concentration during stress test (submaximal cardiopulmonary exercise test) and echocardiography during submaximal cardiopulmonary exercise test, at rest, ∼2 mmol.L-1 (LT1), ∼4 mmol.L-1 and during the recovery phase to evaluate parameters of left ventricular (LV) contractility, cardiac output and diastolic function

Investigational products

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

Test 1

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

Gonzalo De Luna

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Gonzalo De Luna

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

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

Documents 16 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