Resolution of Sickle Cell Leg Ulcers With Voxelotor

• Voxelotor Oral Tablet (Drug): Synthetic small molecule supplied as 500 mg tablets, administered Orally
• Placebo (Other): Placebo

Primary outcomes

• Percentage of Participants Who Achieved Resolution of the Target Ulcers by Week 12 in Randomized Treatment Period [Through Week 12 of randomized treatment period]: An ulcer qualified as a target ulcer, if met the following criteria: a) duration of ulcer was greater than equal to (>=) 2 weeks and less than (<) 6 months at screening; b) healed by <25 percent (%) during the SOC run-in phase prior to randomization; c) size was greater than (>2) square centimeters (cm\^2) at any visit, prior to randomization. Resolution of the target ulcer was defined as skin re-epithelialization confirmed at 2 consecutive study visits, 2 weeks apart during the 12-week randomized treatment period. For participants with more than one target ulcer, all target ulcers must be confirmed resolved in order for the participant to be a responder.

Secondary outcomes

• Time to Resolution of Target Ulcers up to Week 12 in Randomized Treatment Period [From Day 1 to censoring date before Week 12 or maximum up to Week 12 of randomized treatment period, whichever occurred first]: An ulcer qualified as a target ulcer, if met the following criteria: a) duration of ulcer was >=2 weeks and <6 months at screening; b) healed by <25% during the SOC run-in phase prior to randomization; c) size was >2 cm\^2 at any visit, prior to randomization. Resolution of the target ulcer was defined as skin re-epithelialization confirmed at 2 consecutive study visits, 2 weeks apart during the 12-week randomized treatment period. Time to resolution of target ulcers was defined as the first time of the observed ulcer was resolved. For participants with more than one target ulcer, time to resolution of target ulcers was defined as time to the last target ulcer confirmed resolved. For participants who did not have the last target ulcer confirmed resolved by Week 12 or who were discontinued from study, the time to resolution was censored. Median time to event was evaluated using Kaplan-Meier method.
• Change From Baseline in Total Surface Area of Target Ulcers at Week 12 in Randomized Treatment Period [Baseline, Week 12 of randomized treatment period]: An ulcer qualified as a target ulcer, if met the following criteria: a) duration of ulcer was >=2 weeks and <6 months at screening; b) healed by <25% during the SOC run-in phase prior to randomization; c) size was >2 cm\^2 at any visit, prior to randomization.
• Percentage of Participants With New Ulcers by Week 12 in Randomized Treatment Period [Through Week 12 of randomized treatment period]: New ulcers were defined as ulcer(s) that were not captured at visit 1/screening. In this outcome measure, participants with occurrence of new ulcers during 12 weeks of treatment were considered.

Sex: All, ages: 12 Years to any

Inclusion Criteria:

1. Male or female participants with documented diagnosis of SCD (HbSS, HbS/β0 thalassemia)
2. Age 12 years and older
3. At least 1 cutaneous ulcer(s) on the lower extremity (leg, ankle, or dorsum of foot) that meets the following criteria:

   * Duration: ≥ 2 weeks and < 6 months at Screening, and
   * Size: > 2 cm2 prior to randomization
4. Written informed consent (≥ 18 years) or parental/guardian consent and participant assent (≥ 12-17 years) per IEC policy and requirements, consistent with ICH guidelines

Exclusion Criteria:

1. Target ulcer(s) healed by ≥ 25% during the standard of care run-in period prior to randomization
2. Active infection/purulence at ulcer site, or exposed tendon or bone at the ulcer site, based on Investigator's clinical judgment
3. Current osteomyelitis at or near the ulcer site
4. Known vascular abnormalities that would preclude healing in the opinion of the Investigator (eg, pre-existing severe arterial insufficiency in the affected limb)
5. Serum albumin < 2.0 g/dL
6. RBC transfusion within 60 days of initiation of study drug
7. Receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) during the study
8. Planned elective surgery within the next 6 months
9. Anemia due to bone marrow failure (eg, myelodysplasia)
10. Absolute reticulocyte count < 100 × 109/L
11. Screening alanine aminotransferase (ALT) > 4 × upper limit of normal (ULN)
12. Severe renal dysfunction (estimated glomerular filtration rate \[eGFR\] < 30 mL/min/1.73 m2 by Schwartz formula) or is on chronic dialysis
13. Clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy

Other protocol-defined Eligibility Criteria that apply

Participant flow

Outcome results

• Percentage of Participants Who Achieved Resolution of the Target Ulcers by Week 12 in Randomized Treatment Period (Primary), Number, Percentage of participants: Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC 6.7 (1.4 to 18.3); Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC 7.0 (1.5 to 19.1) (p =1.0000)
• Time to Resolution of Target Ulcers up to Week 12 in Randomized Treatment Period (Secondary), Median, Days: Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC NA (NA to NA); Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC NA (NA to NA)
• Change From Baseline in Total Surface Area of Target Ulcers at Week 12 in Randomized Treatment Period (Secondary), Least squares mean, cm^2: Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC -4.8 (-10.0 to 0.4); Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC 3.4 (-1.8 to 8.6) (p =0.0297)
• Percentage of Participants With New Ulcers by Week 12 in Randomized Treatment Period (Secondary), Number, Percentage of participants: Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC 24.4 (12.9 to 39.5); Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC 32.6 (19.1 to 48.5) (p =0.3456)

Adverse events

Time frame: Day 1 of dosing up to 4 weeks post last dose of study drug: maximum up to approximately 16 weeks for double blinded randomized treatment; maximum up to approximately 89.43 weeks for open label treatment

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2023-12-25)
• Statistical Analysis Plan (PDF, 2024-12-17)

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