Hemolysis Related Complications in SCD. A Phase II Study With Voxelotor (HEMOPROVE)

• ClinicalTrials.gov Identifier: NCT05199766
• Recruitment Status: Not yet recruiting
• First Posted: January 20, 2022
• Last Update Posted: January 20, 2022
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborator: Global Blood Therapeutics (GBT)
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Tracking Information

• First Submitted Date: December 6, 2021
• First Posted Date: January 20, 2022
• Last Update Posted Date: January 20, 2022
• Estimated Study Start Date: January 15, 2022
• Estimated Primary Completion Date: January 15, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 5, 2022)

Evaluation of the biological activity of voxelotor on the change of intra vascular hemolysis measured by decrease of plasma hemoglobin. [ Time Frame: Change from Baseline at Week 48 ]

Change of Intravascular hemolysis, as defined by a ≥20% decrease of plasma Hemoglobin (µmol/l)

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: January 5, 2022)

• Intra vascular hemolysis measured by plasma Heme [ Time Frame: Week 0, Week 24, Week 48 ]
  Absolute and relative (%) changes in plasma Hemoglobin (µmol/l) and free plasma Heme (µmol/l)
• Total hemoglobin mass (MHb) [ Time Frame: Week 0, Week 24, Week 48 ]
  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.
• RBCs lifespan [ Time Frame: Week 0, Week 24, Week 48 ]
  RBC lifespan by measurement of alveolar CO (in days).
• Change of blood volumes (plasma volume (PV) and total blood volume (BV)) [ Time Frame: Week 0, Week 24, Week 48 ]
  Blood volumes by CO rebreathing method (Total blood volume (L), Plasma Volume (L) )
• Change of red blood cell mass (RBCM) [ Time Frame: Week 0, Week 24, Week 48 ]
  RBC mass (g)
• Change of Total Mass of Hemoglobin [ Time Frame: Week 0, Week 24, Week 48 ]
  Total Mass of Hemoglobin (g of Hb)
• Change of blood viscosity [ Time Frame: Week 0, Week 24, Week 48 ]
  Blood viscosity (cP)
• Cerebral perfusion [ Time Frame: Week 0, Week 24, Week 48 ]
  Cerebral perfusion measured by MRI
• Change of cerebrovascular vaso-reactivity measured by transcranial Doppler [ Time Frame: Week 0, Week 24, Week 48 ]
  Transcranial Doppler (Breath holding test)
• Change of cerebrovascular vaso-reactivity measured by Near Infra Red Spectroscopy [ Time Frame: Week 0, Week 24, Week 48 ]
  Cerebral vaso-reactivity measured by Near Infra Red Spectroscopy
• Cognitive function (MoCA) [ Time Frame: Week 0, Week 24, Week 48 ]
  Cognitive performance measured by MoCA Improvement in the 6 minutes walk test on : Time spent under Sp02 88 and 90%, Borg Rating of Perceived Exertion (RPE), distance.
• Measurement of renal perfusion and amount of deoxyhemoglobin [ Time Frame: Week 0, Week 24, Week 48 ]
  Amount of deoxyhemoglobin by MRI
• Study of iron deposits in renal cortex [ Time Frame: Week 0, Week 24, Week 48 ]
  Iron deposits in renal cortex measured by MRI
• Measurement of Glomerular filtration rate [ Time Frame: Week 0, Week 24, Week 48 ]
  Estimation of glomerular filtration rate (CKD/EPI equation)
• Ability to decrease or stop erythropoietin in patients under EPO treatment [ Time Frame: From Week 0 to Week48 ]
  Concomitant treatment observation: decrease / interruption of EPO dose
• Incidence of Treatment-Adverse Events VOC, ACS and Priapism [ Time Frame: From Week 0 to Week48 ]
  Presence/Absence of adverse Events VOC, ACS, Priapism

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Hemolysis Related Complications in SCD. A Phase II Study With Voxelotor
• Official Title: HEMolyse and Organ Damage imPROvement in Sickle Cell Disease by VoxElotor. An Open-label One Stage Phase II Design

Brief Summary

Intro:

Sickle cell disease is a genetic disorder caused by a mutation of the β hemoglobin called HbS, which causes red blood cell (RBC) abnormalities responsible for hemolysis, mainly intravascular, leading to chronic anemia. Intravascular hemolysis is responsible for severe inflammation and endothelial dysfunction.

Maintaining hemoglobin in its oxygenated R-conformation is one of the strategies for inhibiting the polymerization of HbS. Previous experimental therapeutic approaches having this effect have been discontinued due to poor pharmaceutical properties or toxicity. Nevertheless, they proved the validity of the concept by demonstrating an increase in oxyhemoglobin and a decrease in biomarkers of hemolysis.

Voxelotor binds to the α chain of globin and maintains Hb in its R conformation, thereby inhibiting the polymerization of HbS while increasing the affinity of Hb for oxygen.

Because of its mechanism of action affecting anemia and hemolysis, Voxelotor is a promising treatment for the prevention and treatment of renal and cerebral arterial disease.

Hypothesis/Objective :

Investigator hypothesis is that the treatment by Voxelotor (GBT440) will improve intra vascular hemolysis and will increase the total mass of hemoglobin with beneficial effects on organ function.

The primary objective of the study is to evaluate the biological activity of Voxelotor on the reduction of intra vascular hemolysis measured by plasma hemoglobin.

The secondary objectives of the study will aim at characterizing the effects of GBT 440 Voxelotor on:

• Intra vascular hemolysis measured by plasma Heme
• Total hemoglobin mass (MHb)
• RBCs lifespan
• Blood volumes (plasma volume (PV), red blood cell mass (RBCM), total blood volume (BV))
• Blood viscosity
• Cerebral perfusion
• Cerebrovascular vaso-reactivity
• Cognitive function (MoCA)
• Six minute walk test
• Renal perfusion and iron deposits in renal cortex
• Measurement of Glomerular filtration rate Estimation of glomerular filtration rate (CKD/EPI equation)
• Urine albumin/creatinine ratio
• Ability to decrease or stop erythropoietin in patients under EPO treatment
• Safety (VOC, ACS, Priapism) and tolerability of voxelotor
• RBC properties

Method:

This is an open-label, single-arm, single-stage phase II trial in patients treated with Voxelotor 1500 mg daily for 48 weeks. Assessments will be done during the study at week 0, week 6, week 12, week 24, week 36 and week 48.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

This is an open-label, single-arm, single-stage phase II trial in patients treated with Voxelotor 1500 mg daily for 48 weeks.

Assessments will be done during the study at week 0, week 6, week 12, week 24, week 36 and week 48.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Sickle Cell Disease

Intervention

Drug: Voxelotor 1500 mg oral per day (GBT440) for 48 weeks in patients with sickle-cell disease

This is an open-label, single-arm, single-stage phase II trial of voxelotor in patients with sickle-cell disease. Voxelotor 500mg tablets. Voxelotor will be administered as 500mg tablets orally once daily. The participant should always take all 3 tablets in a row at the same time each day, unless the study doctor has instructed them to adjust the dose.

Study Arms

Experimental: Voxelotor 1500 mg oral per day (GBT440) for 48 weeks

Voxelotor 1500 mg oral per day (GBT440) for 48 weeks, in case of discontinuation due to patient's wishes and/or adverse event above grade 2 : 1000mg during 14 days then complete discontinuation if no resolution. In case of sudden discontinuation a therapeutic phlebotomy will be authorized.

Intervention: Drug: Voxelotor 1500 mg oral per day (GBT440) for 48 weeks in patients with sickle-cell disease

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: January 5, 2022): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 15, 2024
• Estimated Primary Completion Date: January 15, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• SS or S-β0 major sickle cell syndrome
• Hemoglobin level < 9 g/dL
• Aged 18 years or older
• Stable dose for at least 3 months if treated with HU, EPO, angiotensin-converting enzyme (ACE) or inhibitor/angiotensin receptor blocker (ARB) therapy; at least after 6 months after initiating HU treatment
• Patient with social security
• Female patient must have a negative serum pregnancy test (betaHCG within 72 hours prior to start of treatment) or evidence of post-menopausal status
• 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:

• Patient meeting Hydroxyurea indications of treatment (recurrent painful vaso-occlusive crises, including acute chest syndrome) at screening; Or if HU treatment is indicated at screening but inappropriate (e.g. hematologic toxicity antecedent) or patient refuses HU.
• Patients in chronic transfusion program or transfused < 3 months before enrolment
• Patient with severe organ involvement: hepatic (TP <50%), renal (eGFR<30 ml / ml/1.73m2 according to CKD/EPI or cardiac (LVEF <45%)
• Transplant patients.
• Pregnancy.
• Breast feeding patients
• Homeless patient
• Patient deprived of liberty by judicial or administrative decision or patient under guardianship
• Patient unable to understand the purpose and conditions of the study and unable to give consent
• Chronic use of NSAIDs (more than 10 days by month)
• Auto immune disease or infection not controlled or cancer
• VIH, HBV, HCV current infection
• Prior drug hypersensitivity to Voxelotor or excipients
• Known allergy or hypersensitivity to imaging contrast product
• Ongoing therapeutic study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Gonzalo De Luna, MD; 0149812443 ext +33; gonzalo.deluna@aphp.fr

Contact: Pablo Bartolucci, PUPH; 0149817406 ext +33; pablo.bartolucci@aphp.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT05199766
• Other Study ID Numbers: APHP200750; 2020-005424-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: APHP IS DATA'S OWNER, PLEASE CONTACT BOARD

• Current Responsible Party: Assistance Publique - Hôpitaux de Paris
• Original Responsible Party: Same as current
• Current Study Sponsor: Assistance Publique - Hôpitaux de Paris
• Original Study Sponsor: Same as current
• Collaborators: Global Blood Therapeutics (GBT)

Investigators

• Study Director: Pierre-Andre Natella, PHD; Assistance Publique - Hôpitaux de Paris

• PRS Account: Assistance Publique - Hôpitaux de Paris
• Verification Date: December 2021