Leg Ulcers, Sickle Cell Disease
Conditions
Keywords
Sickle Cell Disease, SCD
Brief summary
This study is a Phase 3, multicenter, randomized, placebo-controlled study to evaluate the efficacy of voxelotor and standard of care for the treatment of leg ulcers in participants with sickle cell disease. The study is divided into a 5 study periods: Screening, Run-in, Randomized Treatment, Open-label Treatment, and Follow-up/End of Study (EOS). The study will be conducted in approximately 80 eligible participants at approximately 20 global clinical trial sites.
Interventions
Synthetic small molecule supplied as 500 mg tablets, administered Orally
OTHERPlacebo
Placebo
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Brazil, Kenya, Nigeria
Participant flow
Recruitment details
A total of 88 participants with sickle cell disease (SCD) were enrolled, randomized and treated with study drug for leg ulcers.
Pre-assignment details
Eligible participants were randomized to receive study drug for 12 weeks in DB randomized period.Following this,eligible participants received voxelotor (delayed) for minimum 12 weeks in OL period. Participants were followed up for 4 weeks after last dose of study drug. All participants received the SOC per investigator/protocol for SCD leg ulcers.
Participants by arm
| Arm | Count |
|---|---|
| Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC Participants were randomized to receive voxelotor 1500 mg (3 tablets\*500 mg) orally, OD and SOC for 12 weeks in double blinded randomized treatment period. Eligible participants then in open label treatment period, continued to receive voxelotor 1500 mg (3 tablets\*500 mg) orally OD and SOC for minimum of 12 weeks. | 45 |
| Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC Participants were randomized to receive placebo matched to voxelotor, orally OD and SOC for 12 weeks in double blinded randomized treatment period. Eligible participants then in open label treatment period, received voxelotor 1500 mg (3 tablets\*500 mg) orally OD and SOC for minimum of 12 weeks. | 43 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open Label Treatment Period | Adverse Event | 6 | 4 |
| Open Label Treatment Period | Lost to Follow-up | 1 | 1 |
| Open Label Treatment Period | Other | 1 | 0 |
| Open Label Treatment Period | Physician Decision | 0 | 1 |
| Open Label Treatment Period | Pregnancy | 1 | 0 |
| Open Label Treatment Period | Study terminated by sponsor | 29 | 30 |
| Open Label Treatment Period | Withdrawal by Subject | 0 | 1 |
| Randomized Treatment Period | Adverse Event | 1 | 0 |
| Randomized Treatment Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Total | Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC |
|---|---|---|---|
| Age, Continuous | 25.1 Years STANDARD_DEVIATION 8.53 | 24.64 Years STANDARD_DEVIATION 8.04 | 24.2 Years STANDARD_DEVIATION 7.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 8 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 62 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 18 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 42 Participants | 87 Participants | 45 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 17 Participants | 38 Participants | 21 Participants |
| Sex: Female, Male Male | 26 Participants | 50 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 1 / 45 | 4 / 43 | 6 / 43 |
| other Total, other adverse events | 25 / 43 | 37 / 45 | 36 / 43 | 31 / 43 |
| serious Total, serious adverse events | 14 / 43 | 18 / 45 | 25 / 43 | 30 / 43 |
Outcome results
Primary
Percentage of Participants Who Achieved Resolution of the Target Ulcers by Week 12 in 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.
Time frame: Through Week 12 of randomized treatment period
Population: Intention to treat (ITT) population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Percentage of Participants Who Achieved Resolution of the Target Ulcers by Week 12 in Randomized Treatment Period | 6.7 Percentage of participants |
| Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Percentage of Participants Who Achieved Resolution of the Target Ulcers by Week 12 in Randomized Treatment Period | 7.0 Percentage of participants |
p-value: =195% CI: [-10.9, 10.2]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Total Surface Area of Target Ulcers at Week 12 in 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.
Time frame: Baseline, Week 12 of randomized treatment period
Population: ITT population included all randomized participants. Here, Overall Number of Participants Analyzed signifies the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Change From Baseline in Total Surface Area of Target Ulcers at Week 12 in Randomized Treatment Period | -4.8 cm^2 |
| Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Change From Baseline in Total Surface Area of Target Ulcers at Week 12 in Randomized Treatment Period | 3.4 cm^2 |
Comparison: The mixed model for repeated measures (MMRM) model contained fixed effects for treatment group (categorical variable), visit (ordered categorical variable), and treatment group by visit interaction with additional fixed effects for stratification factors.p-value: =0.029795% CI: [-15.6, -0.8]Mixed Models Analysis
Secondary
Percentage of Participants With New Ulcers by Week 12 in 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.
Time frame: Through Week 12 of randomized treatment period
Population: ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Percentage of Participants With New Ulcers by Week 12 in Randomized Treatment Period | 24.4 Percentage of participants |
| Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Percentage of Participants With New Ulcers by Week 12 in Randomized Treatment Period | 32.6 Percentage of participants |
p-value: =0.345695% CI: [-26.9, 10.7]Cochran-Mantel-Haenszel
Secondary
Time to Resolution of Target Ulcers up to Week 12 in 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. 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.
Time frame: From Day 1 to censoring date before Week 12 or maximum up to Week 12 of randomized treatment period, whichever occurred first
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voxelotor (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Time to Resolution of Target Ulcers up to Week 12 in Randomized Treatment Period | NA Days |
| Placebo (Blinded) + SOC Then Voxelotor (Open Label) + SOC | Time to Resolution of Target Ulcers up to Week 12 in Randomized Treatment Period | NA Days |