Sickle Cell Disease, Vaso-occlusive Crisis, Vaso-occlusive Pain Episode in Sickle Cell Disease
Conditions
Keywords
blood disorders, hemoglobin, red blood cells, sickle-like shape, mutation in hemoglobin gene, sickle-cell trait, sickle-cell crisis, Sickle Cell Disease, SCD, Vaso-occlusive Crises, VOC, SCA, RBCs
Brief summary
This Phase 3 study will assess the safety and efficacy of inclacumab, a P-selectin inhibitor, in reducing the frequency of vaso-occlusive crises (VOCs) in approximately 240 adult and adolescent participants (≥ 12 years of age) with sickle cell disease (SCD). Participants will be randomized to receive inclacumab or placebo.
Detailed description
Eligible participants will be administered inclacumab or placebo intravenous (IV) every 12 weeks. The total duration of treatment for each participant will be 48 weeks. Participants that complete the study through Week 48 will be provided the opportunity to enroll in an open-label extension (OLE) study.
Interventions
DRUGInclacumab
Inclacumab will be supplied in single use 10 mL vials at a concentration of 50 mg/mL. One vial contains 500 mg of inclacumab. This is a liquid concentrate for IV infusion.
DRUGPlacebo
Placebo will be supplied in single use 10 mL vials containing the same ingredients without the active drug. Placebo will be prepared as a liquid concentrate for IV infusion and administered in the same manner as active study drug
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind study
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant has a confirmed diagnosis of SCD (HbSS, HbSC, HbSB0 thalassemia, or HbSB+ thalassemia genotype). Documentation of SCD genotype is required and may be based on documented history of laboratory testing or confirmed by laboratory testing during Screening. 2. Participant is male or female, ≥ 12 years of age at the time of informed consent. 3. Participant has experienced between 2 and 10 VOCs within the 12 months prior to the Screening Visit as determined by documented medical history. A prior VOC is defined as an acute episode of pain which: * Has no medically determined cause other than a vaso-occlusive event, and * Results in a visit to a medical facility (hospital, emergency department, urgent care center, outpatient clinic, or infusion center) or results in a remote contact with a healthcare provider; and * Requires parenteral narcotic agents, parenteral nonsteroidal anti- inflammatory drugs (NSAIDs), or an increase in treatment with oral narcotics. 4. Participants receiving erythropoiesis-stimulating agents (ESA, e.g., erythropoietin \[EPO\]) must be on a stable dose for at least 90 days prior to the Screening Visit and expected to continue with the stabilized regimen throughout the course of the study. 5. Participants receiving hydroxyurea (HU), L-glutamine, or voxelotor (Oxbryta®) must be on a stable dose for at least 30 days prior to the Screening Visit and expected to continue with the stabilized regimen throughout the course of the study.
Exclusion criteria
1. Participant is receiving regularly scheduled red blood cell (RBC) transfusion therapy (also termed chronic, prophylactic, or preventative transfusion). 2. Participant is taking or has received crizanlizumab (ADAKVEO®) within 90 days prior to the Screening Visit 3. Participant weighs \> 133 kg (292 lbs.). Other protocol-defined Inclusion/Exclusion may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Vaso-occlusive Crises (VOCs) [Adjudicated] Through Week 48 | Randomization (Day 1) up to Week 48 | A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), or resulted in a remote contact with a healthcare provider and required parenteral narcotic agents, parenteral nonsteroidal anti-inflammatory drugs (NSAIDs), or an increase in treatment with oral narcotics. The rate of VOC was defined as number of VOC events per 48 weeks and presented in this outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Second VOC Through Week 48 | Randomization (Day 1) up to Week 48 | A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), or resulted in a remote contact with a healthcare provider and required parenteral narcotic agents, parenteral NSAIDs, or an increase in treatment with oral narcotics. Time to second VOC was the time between randomization date and onset date of second VOC event during 48 weeks. Kaplan-Meier method was used for estimation. |
| Percentage of Participants With no VOCs Through Week 48 | Randomization (Day 1) up to Week 48 | A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), or resulted in a remote contact with a healthcare provider and required parenteral narcotic agents, parenteral NSAIDs, or an increase in treatment with oral narcotics. Participants without an observed VOC who discontinued the study prior to the end of the 48-week treatment period were assumed to had experienced at least one VOC. |
| Time to First VOC Through Week 48 | Randomization (Day 1) up to Week 48 | A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), or resulted in a remote contact with a healthcare provider and required parenteral narcotic agents, parenteral NSAIDs, or an increase in treatment with oral narcotics. Time to first VOC was the time between randomization date and onset date of first VOC event during 48 weeks. Kaplan-Meier method was used for estimation. |
| Rate of Inpatient Hospitalization Days for a VOC Through Week 48 | Randomization (Day 1) up to Week 48 | A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility hospitalization. For each VOC event requiring inpatient hospitalization (regardless of treatment received) during the 48-week, the number of days hospitalized were determined based on the hospital admission and discharge dates. The rate of inpatient hospitalization days was defined as number of inpatient hospitalization days for a VOC per 48 weeks and presented in this outcome measure. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Day 1 up to Week 60 (12 week of follow-up post Week 48) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. A TEAE was defined as an AE with an onset after the initiation of dosing for the first dose of study drug. A serious adverse events (SAE) or serious suspected adverse reaction is an AE or suspected adverse reaction that, at any dose, in the view of the either the investigator or sponsor, results in any of the following outcomes: death, life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization and congenital anomaly/birth defect. AEs included both serious and all non-SAEs. |
| Rate of VOCs Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication [Adjudicated] Through Week 48 | Randomization (Day 1) up to Week 48 | A VOC that required admission to a healthcare facility and treatment with parenteral pain medication where admission included: a hospital admission or an admission to an emergency room, observation unit, or infusion center for \>= 12 hours, or 2 visits to an emergency room, observation unit, or infusion center over a 72-hour period. The rate of VOC was defined as number of VOC events per 48 weeks; rate of VOCs which required admission to a healthcare facility and treatment with parenteral pain medication is presented in this outcome measure. |
Countries
Brazil, Colombia, Egypt, France, Kenya, Lebanon, Nigeria, Oman, Saudi Arabia, Tanzania, Turkey (Türkiye), United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inclacumab Participants with SCD were randomized to receive inclacumab at a dose of 30 mg/kg IV on Day 1 and Q12W on Weeks 12, 24 and 36. Participants were followed up till Week 48 and was part of 48-Week Treatment Period. Participants at Week 48 had a choice to either enter an OLE study (under a separate protocol) to receive inclacumab or were followed up for another 12 weeks i.e. Week 60. | 119 |
| Placebo Participants with SCD were randomized to receive placebo matched to inclacumab IV on Day 1 and Q12W on Weeks 12, 24 and 36. Participants were followed up till Week 48 and was part of 48-Week Treatment Period. Participants at Week 48 had a choice to either enter an OLE study (under a separate protocol) to receive inclacumab or were followed up for another 12 weeks i.e. Week 60. | 122 |
| Total | 241 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other | 3 | 3 |
| Overall Study | Pregnancy | 2 | 3 |
| Overall Study | Withdrawal by Subject | 8 | 6 |
Baseline characteristics
| Characteristic | Inclacumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 25.0 Years STANDARD_DEVIATION 7.14 | 24.8 Years STANDARD_DEVIATION 7.76 | 24.6 Years STANDARD_DEVIATION 8.34 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 37 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 92 Participants | 194 Participants | 102 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 10 Participants | 1 Participants |
| Race/Ethnicity, Customized Race African | 63 Participants | 121 Participants | 58 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Arab | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Black or African American | 16 Participants | 40 Participants | 24 Participants |
| Race/Ethnicity, Customized Race Middle Eastern | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Multiracial | 22 Participants | 47 Participants | 25 Participants |
| Race/Ethnicity, Customized Race Not Reported | 4 Participants | 4 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 7 Participants | 17 Participants | 10 Participants |
| Sex: Female, Male Female | 64 Participants | 127 Participants | 63 Participants |
| Sex: Female, Male Male | 55 Participants | 114 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 118 | 2 / 121 |
| other Total, other adverse events | 83 / 118 | 90 / 121 |
| serious Total, serious adverse events | 23 / 118 | 27 / 121 |
Outcome results
Primary
Rate of Vaso-occlusive Crises (VOCs) [Adjudicated] Through Week 48
A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), or resulted in a remote contact with a healthcare provider and required parenteral narcotic agents, parenteral nonsteroidal anti-inflammatory drugs (NSAIDs), or an increase in treatment with oral narcotics. The rate of VOC was defined as number of VOC events per 48 weeks and presented in this outcome measure.
Time frame: Randomization (Day 1) up to Week 48
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclacumab | Rate of Vaso-occlusive Crises (VOCs) [Adjudicated] Through Week 48 | 1.49 Events per 48 weeks |
| Placebo | Rate of Vaso-occlusive Crises (VOCs) [Adjudicated] Through Week 48 | 1.58 Events per 48 weeks |
Comparison: Adjusted rates are based on estimate from a negative binomial model with the independent variable of treatment group (inclacumab, placebo) and adjusted for baseline hydroxyurea (HU) use (yes, no), number of VOCs in 12 months prior to screening visit (2-4, 5-10), and geographic region (North America, sub-Saharan Africa, Europe/rest of world).p-value: 0.696795% CI: [0.71, 1.25]Negative binomial regression model
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. A TEAE was defined as an AE with an onset after the initiation of dosing for the first dose of study drug. A serious adverse events (SAE) or serious suspected adverse reaction is an AE or suspected adverse reaction that, at any dose, in the view of the either the investigator or sponsor, results in any of the following outcomes: death, life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization and congenital anomaly/birth defect. AEs included both serious and all non-SAEs.
Time frame: Day 1 up to Week 60 (12 week of follow-up post Week 48)
Population: Safety population included randomized participants who received treatment with study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inclacumab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 87 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 97 Participants |
Secondary
Percentage of Participants With no VOCs Through Week 48
A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), or resulted in a remote contact with a healthcare provider and required parenteral narcotic agents, parenteral NSAIDs, or an increase in treatment with oral narcotics. Participants without an observed VOC who discontinued the study prior to the end of the 48-week treatment period were assumed to had experienced at least one VOC.
Time frame: Randomization (Day 1) up to Week 48
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclacumab | Percentage of Participants With no VOCs Through Week 48 | 36.0 Percentage of participants |
| Placebo | Percentage of Participants With no VOCs Through Week 48 | 25.7 Percentage of participants |
Comparison: Cochran-Mantel-Haenszel (CMH) test stratified by baseline HU use (yes, no), number of VOCs in the 12 months prior to study entry (2-4, 5-10), and geographic region (North America, sub-Saharan Africa, Europe/rest of world).p-value: 0.091295% CI: [-1.6, 22.2]Cochran-Mantel-Haenszel
Secondary
Rate of Inpatient Hospitalization Days for a VOC Through Week 48
A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility hospitalization. For each VOC event requiring inpatient hospitalization (regardless of treatment received) during the 48-week, the number of days hospitalized were determined based on the hospital admission and discharge dates. The rate of inpatient hospitalization days was defined as number of inpatient hospitalization days for a VOC per 48 weeks and presented in this outcome measure.
Time frame: Randomization (Day 1) up to Week 48
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclacumab | Rate of Inpatient Hospitalization Days for a VOC Through Week 48 | 4.96 Hospitalization days per 48 weeks |
| Placebo | Rate of Inpatient Hospitalization Days for a VOC Through Week 48 | 5.37 Hospitalization days per 48 weeks |
Comparison: Adjusted rates are based on estimate from a negative binomial model with the independent variable of treatment group (inclacumab, placebo) and adjusted for baseline HU use (yes, no), number of VOCs in 12 months prior to screening visit (2-4, 5-10), and geographic region (North America, sub-Saharan Africa, Europe/rest of world).p-value: =0.826395% CI: [0.46, 1.87]Negative binomial regression model
Secondary
Rate of VOCs Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication [Adjudicated] Through Week 48
A VOC that required admission to a healthcare facility and treatment with parenteral pain medication where admission included: a hospital admission or an admission to an emergency room, observation unit, or infusion center for \>= 12 hours, or 2 visits to an emergency room, observation unit, or infusion center over a 72-hour period. The rate of VOC was defined as number of VOC events per 48 weeks; rate of VOCs which required admission to a healthcare facility and treatment with parenteral pain medication is presented in this outcome measure.
Time frame: Randomization (Day 1) up to Week 48
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inclacumab | Rate of VOCs Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication [Adjudicated] Through Week 48 | 0.85 Events per 48 weeks |
| Placebo | Rate of VOCs Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication [Adjudicated] Through Week 48 | 0.83 Events per 48 weeks |
Comparison: Adjusted rates are based on estimate from a negative binomial model with the independent variable of treatment group (inclacumab, placebo) and adjusted for baseline HU use (yes, no), number of VOCs in the 12 months prior to screening visit (2-4, 5-10), and geographic region (North America, sub-Saharan Africa, Europe/rest of the world).p-value: 0.924695% CI: [0.71, 1.47]Negative binomial regression model
Secondary
Time to First VOC Through Week 48
A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), or resulted in a remote contact with a healthcare provider and required parenteral narcotic agents, parenteral NSAIDs, or an increase in treatment with oral narcotics. Time to first VOC was the time between randomization date and onset date of first VOC event during 48 weeks. Kaplan-Meier method was used for estimation.
Time frame: Randomization (Day 1) up to Week 48
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Inclacumab | Time to First VOC Through Week 48 | 28.7 Weeks |
| Placebo | Time to First VOC Through Week 48 | 21.6 Weeks |
Comparison: Analysis was stratified by baseline HU use (yes, no), number of VOCs in 12 months prior to screening visit (2-4, 5-10), and geographic region (North America, sub-Saharan Africa, Europe/rest of world).p-value: 0.429895% CI: [0.63, 1.22]Log Rank
Secondary
Time to Second VOC Through Week 48
A VOC was defined as an acute episode of pain that: had no medically determined cause other than a vaso-occlusive event; resulted in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), or resulted in a remote contact with a healthcare provider and required parenteral narcotic agents, parenteral NSAIDs, or an increase in treatment with oral narcotics. Time to second VOC was the time between randomization date and onset date of second VOC event during 48 weeks. Kaplan-Meier method was used for estimation.
Time frame: Randomization (Day 1) up to Week 48
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Inclacumab | Time to Second VOC Through Week 48 | NA Weeks |
| Placebo | Time to Second VOC Through Week 48 | NA Weeks |