Study to Evaluate the Effect of Voxelotor Administered Orally to Patients With Sickle Cell Disease (GBT_HOPE)

This is a randomized, placebo-controlled, double blind, parallel group, multicenter study of participants, age 12 to 65 years, with SCD. The key purpose for the study is to establish efficacy and safety of voxelotor as compared with placebo.

• voxelotor (Drug), also known as GBT440
• Placebo (Other)

Primary outcomes

• Number of Participants With Increase in Hb >1 g/dL From Baseline to Week 24 [Baseline to Week 24]: Number of participants with increase in Hb >1 g/dL from Baseline to Week 24

Secondary outcomes

• Annualized Vaso-Occlusive Crisis (VOC) Incidence Rate [Baseline to Week 72]: Number of Vaso-Occlusive Crisis (VOC) events averaged per year.
• Percentage Change From Baseline in Hemolysis Measures [Baseline to Week 24]: Percentage change from Baseline to week 24 in unconjugated bilirubin
• Percentage Change From Baseline in Hemolysis Measures [Baseline to Week 24]: Percentage change from Baseline to week 24 in the absolute reticulocyte which is used to estimate the degree of effective erythropoiesis. This values is important in Sickle Cell Disease and was reported by the central laboratory.
• Percentage Change From Baseline in Hemolysis Measures [Baseline to Week 24]: Percentage change from Baseline to week 24 in reticulocytes % which is a % of total Red Blood Cells (RBCs).
• Percentage Change From Baseline in Hemolysis Measures [Baseline to Week 24]: Percentage change from Baseline to week 24 in Lactate Dehydrogenase (LDH)

Sex: All, ages: 12 Years to 65 Years

Inclusion Criteria:

1. Male or female study participants with sickle cell disease
2. Participants have had at least 1 episode of vaso-occlusive crisis (VOC) in the past 12 months.
3. Age 12 to 65 years
4. Hemoglobin (Hb) ≥5.5 and ≤10.5 g/dL during screening
5. For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable for at least 3 months prior to signing the ICF.

Exclusion Criteria:

1. More than 10 VOCs within the past 12 months that required a hospital, emergency room or clinic visit
2. Patients who are receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received a RBC transfusion for any reason within 60 days of signing the ICF
3. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days of signing the ICF (i.e., a vaso-occlusive event cannot be within 14 days prior to signing the ICF)
4. Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4 × upper limit of normal
5. Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the central laboratory) <30 mL/min/1.73 m\^2 or on chronic dialysis

Participant flow

Outcome results

• Number of Participants With Increase in Hb >1 g/dL From Baseline to Week 24 (Primary), Count of participants, Participants: Voxelotor 900 mg 30; Voxelotor 1500 mg 46; Placebo 6
• Annualized Vaso-Occlusive Crisis (VOC) Incidence Rate (Secondary), Mean, Events per year: Voxelotor 900 mg 2.4 (1.9 to 3.1); Voxelotor 1500 mg 2.4 (1.8 to 3.1); Placebo 2.8 (2.2 to 3.6)
• Percentage Change From Baseline in Hemolysis Measures (Secondary), Least squares mean, percentage change: Voxelotor 900 mg -20.1 +/- 3.41; Voxelotor 1500 mg -29.1 +/- 3.46; Placebo -2.8 +/- 3.51
• Percentage Change From Baseline in Hemolysis Measures (Secondary), Least squares mean, percentage change: Voxelotor 900 mg 4.7 +/- 5.13; Voxelotor 1500 mg -6.4 +/- 5.17; Placebo 4.7 +/- 5.19
• Percentage Change From Baseline in Hemolysis Measures (Secondary), Least squares mean, Percentage Change: Voxelotor 900 mg -1.4 +/- 4.65; Voxelotor 1500 mg -18.0 +/- 4.70; Placebo 6.8 +/- 4.73
• Percentage Change From Baseline in Hemolysis Measures (Secondary), Least squares mean, Percentage Change: Voxelotor 900 mg 1.6 +/- 3.68; Voxelotor 1500 mg -4.6 +/- 3.69; Placebo 3.0 +/- 3.75

Adverse events

Time frame: 72 Weeks

Serious adverse events by term

13 more terms not shown.

Other adverse events by term

• Results publication: Howard J, Ataga KI, Brown RC, Achebe M, Nduba V, El-Beshlawy A, Hassab H, Agodoa I, Tonda M, Gray S, Lehrer-Graiwer J, Vichinsky E. Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2021 May;8(5):e323-e333. doi: 10.1016/S2352-3026(21)00059-4. Epub 2021 Apr 7. PMID 33838113
• Results publication: Minniti CP, Knight-Madden J, Tonda M, Gray S, Lehrer-Graiwer J, Biemond BJ. The impact of voxelotor treatment on leg ulcers in patients with sickle cell disease. Am J Hematol. 2021 Apr 1;96(4):E126-E128. doi: 10.1002/ajh.26101. Epub 2021 Feb 19. No abstract available. PMID 33476432
• Results publication: Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC, Diuguid DL, Telfer P, Tsitsikas DA, Elghandour A, Gordeuk VR, Kanter J, Abboud MR, Lehrer-Graiwer J, Tonda M, Intondi A, Tong B, Howard J; HOPE Trial Investigators. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8;381(6):509-519. doi: 10.1056/NEJMoa1903212. Epub 2019 Jun 14. PMID 31199090
• Results publication: Metcalf B, Chuang C, Dufu K, Patel MP, Silva-Garcia A, Johnson C, Lu Q, Partridge JR, Patskovska L, Patskovsky Y, Almo SC, Jacobson MP, Hua L, Xu Q, Gwaltney SL 2nd, Yee C, Harris J, Morgan BP, James J, Xu D, Hutchaleelaha A, Paulvannan K, Oksenberg D, Li Z. Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin. ACS Med Chem Lett. 2017 Jan 23;8(3):321-326. doi: 10.1021/acsmedchemlett.6b00491. eCollection 2017 Mar 9. PMID 28337324

• Study Protocol (PDF, 2020-10-27)
• Statistical Analysis Plan (PDF, 2020-10-27)

• Pfizer CT.gov Call Center, Study director, Pfizer