Sickle Cell Disease, Vaso-occlusive Crisis, Vaso-occlusive Pain Episode in Sickle Cell Disease
Conditions
Keywords
Re-admission, Acute, blood disorders, hemoglobin, red blood cells, RBCs, sickle-like shape, mutation in hemoglobin gene, sickle-cell trait, sickle-cell crisis, Sickle Cell Disease, SCD, Vaso-occlusive Crisis, VOC, SCA
Brief summary
This Phase 3 study will assess the safety and efficacy of a single dose of inclacumab, a P-selectin inhibitor, for a vaso-occlusive crisis (VOC) after an index VOC in participants with sickle cell disease (SCD). Participants will be randomized to receive either inclacumab or placebo.
Detailed description
The study will include approximately 280 adult and adolescent participants (≥ 12 years of age) with SCD. Eligible participants will be administered inclacumab or placebo intravenous (IV) as a single dose. Participants that complete the study through Day 90 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 an index VOC. The index VOC is any VOC that required admission to a healthcare facility and treatment with parenteral pain medication. An admission for the index VOC includes: 1. A hospital admission, or 2. An admission to an emergency room, observation unit, or infusion center for ≥ 12 hours, or 3. 2 visits to an emergency room, observation unit, or infusion center over a 72-hour period for an acute episode of pain with no other cause other than a vaso- occlusive event that includes the following: * Uncomplicated VOC, * Acute chest syndrome (ACS), * Acute hepatic sequestration, * Acute splenic sequestration, or * Priapism. 2. Participant has a confirmed diagnosis of SCD (any genotype). Documentation of SCD genotype is required and may be based on documented history of laboratory testing or confirmed by laboratory testing at Baseline. 3. Participant is male or female, ≥ 12 years of age at the time of informed consent. 4. Participant has experienced between 2 and 10 VOCs within the 12 months prior to Screening as determined by documented medical history. The index VOC is not to be considered as one of the 2 to 10 events. A prior VOC is defined as an acute episode of pain that: 1. Has no medically determined cause other than a vaso-occlusive event, and 2. Results in a visit to a healthcare facility (hospital, emergency department, urgent care center, outpatient clinic, or infusion center) or results in a remote contact with a healthcare provider; and 3. Requires parenteral narcotic agents, parenteral nonsteroidal anti-inflammatory drugs (NSAIDs), or an increase in treatment with oral narcotics. 5. Participants receiving erythropoiesis-stimulating agents (ESA, e.g., erythropoietin \[EPO\]) must be on a stable dose for at least 90 days prior to Screening and expected to continue with the stabilized regimen throughout the course of the study. 6. Participants receiving hydroxyurea (HU), L-glutamine, or voxelotor (Oxbryta®) must be on a stable dose for at least 30 days prior to Screening 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 Screening. 3. Participant weighs \> 133 kg (292 lbs.). Other protocol-defined Inclusion/Exclusion may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 1 VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 90 Days of Randomization | Within 90 days of randomization (randomization happened on Day 1 [Day 1 to Day 91]) | A VOC was a complication of SCD characterized by vaso-occlusion presenting as recurrent pain episodes. An admission for a VOC 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. An acute episode of pain with no other cause other than a vaso-occlusive event included: uncomplicated VOC, acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism. All on-study VOCs were adjudicated by an independent, blinded VOC Adjudication Committee comprised of experts in SCD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 90 Days of Randomization | Within 90 days of randomization (randomization happened on Day 1 [Day 1 to Day 91]) or censored day, whichever occurred earlier | A VOC was a complication of SCD characterized by vaso-occlusion presenting as recurrent pain episodes. Time to first VOC that required admission to a healthcare facility and treatment with parenteral pain medication within 90 days was defined as the time between randomization date and onset date of first VOC event. For participants who did not experience a protocol-defined VOC within 90 days of randomization, time to first VOC was censored at the end of their time at risk (participant's end of study date or Study Day 91, whichever was earlier). An admission for a VOC 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. All on-study VOCs were adjudicated by an independent, blinded VOC Adjudication Committee comprised of experts in SCD. Kaplan-Meier method used for analysis. |
| Percentage of Participants With at Least 1 VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 30 Days of Randomization | Within 30 days of randomization (randomization happened on Day 1 [Day 1 to Day 31]) | A VOC was a complication of SCD characterized by vaso-occlusion presenting as recurrent pain episodes. An admission for a VOC 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. An acute episode of pain with no other cause other than a vaso-occlusive event included: uncomplicated VOC, acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism. All on-study VOCs were adjudicated by an independent, blinded VOC Adjudication Committee comprised of experts in SCD. |
| Rate of VOCs Leading to a Healthcare Visit That Requires Parenteral Pain Medication or an Increase in Treatment With Oral Narcotics Within 90 Days Following Randomization | Within 90 days of randomization (randomization happened on Day 1 [Day 1 to Day 91]) | VOC leading to a healthcare visit was defined as VOC at (hospital, emergency room, clinic visit, or remote contact with a healthcare provider) that required parenteral pain medication (e.g., parenteral narcotic agents or parenteral nonsteroidal anti-inflammatory drugs \[NSAIDs\]), or an increased treatment with oral narcotics. Complicated VOCs included acute chest syndrome (ACS),hepatic sequestration, splenic sequestration, and priapism. For each participant, the time period at risk for evaluation of VOCs was from date of randomization to the participant's end of study date or study Day 91, whichever was earlier. In this outcome measure adjusted rates of VOCs (percentages) reported were based on estimate from a negative binomial model with the independent variable of treatment group (inclacumab, placebo) and adjusted for baseline hydroxyurea use (yes, no). All on-study VOCs were adjudicated by an independent, blinded VOC Adjudication Committee comprised of experts in SCD. |
Countries
Brazil, Colombia, France, Germany, Italy, Kenya, Lebanon, Nigeria, Oman, Saudi Arabia, Turkey (Türkiye), United Kingdom, United States, Zambia
Participant flow
Recruitment details
In this study, participants with sickle cell disease (SCD), aged greater than or equal to (\>=) 12 years were randomized to receive either inclacumab or placebo for reducing the frequency of re-admissions due to vaso-occlusive crisis (VOC) after an index VOC.
Pre-assignment details
A total of 72 participants were enrolled and randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Inclacumab 30 mg/kg Participants were administered with inclacumab 30 mg/kg IV infusion on Day 1 as a single dose. | 37 |
| Placebo Participants were administered with placebo IV infusion on Day 1 as a single dose. | 35 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Other | 2 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Inclacumab 30 mg/kg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 23.5 Years STANDARD_DEVIATION 6.95 | 24.9 Years STANDARD_DEVIATION 8.34 | 24.2 Years STANDARD_DEVIATION 7.64 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 33 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 22 Participants | 17 Participants | 39 Participants |
| Sex: Female, Male Male | 15 Participants | 18 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 36 | 0 / 33 |
| other Total, other adverse events | 20 / 36 | 11 / 33 |
| serious Total, serious adverse events | 4 / 36 | 1 / 33 |
Outcome results
Primary
Percentage of Participants With at Least 1 VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 90 Days of Randomization
A VOC was a complication of SCD characterized by vaso-occlusion presenting as recurrent pain episodes. An admission for a VOC 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. An acute episode of pain with no other cause other than a vaso-occlusive event included: uncomplicated VOC, acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism. All on-study VOCs were adjudicated by an independent, blinded VOC Adjudication Committee comprised of experts in SCD.
Time frame: Within 90 days of randomization (randomization happened on Day 1 [Day 1 to Day 91])
Population: The intent-to-treat (ITT) population included all randomized participants. Participants without an observed VOC who discontinued the study prior to Day 91 were assumed to have experienced at least one VOC.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Inclacumab 30 mg/kg | Percentage of Participants With at Least 1 VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 90 Days of Randomization | 45.4 Percentage of participants | 95% Confidence Interval 28.7 |
| Placebo | Percentage of Participants With at Least 1 VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 90 Days of Randomization | 37.5 Percentage of participants | 95% Confidence Interval 20.7 |
p-value: 0.630295% CI: [-15.8, 31.7]Exact Cochran-Mantel-Haenszel test
Secondary
Percentage of Participants With at Least 1 VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 30 Days of Randomization
A VOC was a complication of SCD characterized by vaso-occlusion presenting as recurrent pain episodes. An admission for a VOC 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. An acute episode of pain with no other cause other than a vaso-occlusive event included: uncomplicated VOC, acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism. All on-study VOCs were adjudicated by an independent, blinded VOC Adjudication Committee comprised of experts in SCD.
Time frame: Within 30 days of randomization (randomization happened on Day 1 [Day 1 to Day 31])
Population: The ITT population included all randomized participants. Participants without an observed VOC who discontinued the study prior to Day 31 were assumed to have experienced at least one VOC.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Inclacumab 30 mg/kg | Percentage of Participants With at Least 1 VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 30 Days of Randomization | 8.2 Percentage of participants | 95% Confidence Interval 0 |
| Placebo | Percentage of Participants With at Least 1 VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 30 Days of Randomization | 25.0 Percentage of participants | 95% Confidence Interval 9.6 |
p-value: 0.114395% CI: [-34.4, 0.8]Exact Cochran-Mantel-Haenszel test
Secondary
Rate of VOCs Leading to a Healthcare Visit That Requires Parenteral Pain Medication or an Increase in Treatment With Oral Narcotics Within 90 Days Following Randomization
VOC leading to a healthcare visit was defined as VOC at (hospital, emergency room, clinic visit, or remote contact with a healthcare provider) that required parenteral pain medication (e.g., parenteral narcotic agents or parenteral nonsteroidal anti-inflammatory drugs \[NSAIDs\]), or an increased treatment with oral narcotics. Complicated VOCs included acute chest syndrome (ACS),hepatic sequestration, splenic sequestration, and priapism. For each participant, the time period at risk for evaluation of VOCs was from date of randomization to the participant's end of study date or study Day 91, whichever was earlier. In this outcome measure adjusted rates of VOCs (percentages) reported were based on estimate from a negative binomial model with the independent variable of treatment group (inclacumab, placebo) and adjusted for baseline hydroxyurea use (yes, no). All on-study VOCs were adjudicated by an independent, blinded VOC Adjudication Committee comprised of experts in SCD.
Time frame: Within 90 days of randomization (randomization happened on Day 1 [Day 1 to Day 91])
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Inclacumab 30 mg/kg | Rate of VOCs Leading to a Healthcare Visit That Requires Parenteral Pain Medication or an Increase in Treatment With Oral Narcotics Within 90 Days Following Randomization | 0.83 Percentage of VOCs | 95% Confidence Interval 0.57 |
| Placebo | Rate of VOCs Leading to a Healthcare Visit That Requires Parenteral Pain Medication or an Increase in Treatment With Oral Narcotics Within 90 Days Following Randomization | 0.76 Percentage of VOCs | 95% Confidence Interval 0.51 |
p-value: 0.754995% CI: [0.63, 1.89]Negative binomial model
Secondary
Time to First VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 90 Days of Randomization
A VOC was a complication of SCD characterized by vaso-occlusion presenting as recurrent pain episodes. Time to first VOC that required admission to a healthcare facility and treatment with parenteral pain medication within 90 days was defined as the time between randomization date and onset date of first VOC event. For participants who did not experience a protocol-defined VOC within 90 days of randomization, time to first VOC was censored at the end of their time at risk (participant's end of study date or Study Day 91, whichever was earlier). An admission for a VOC 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. All on-study VOCs were adjudicated by an independent, blinded VOC Adjudication Committee comprised of experts in SCD. Kaplan-Meier method used for analysis.
Time frame: Within 90 days of randomization (randomization happened on Day 1 [Day 1 to Day 91]) or censored day, whichever occurred earlier
Population: The ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Inclacumab 30 mg/kg | Time to First VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 90 Days of Randomization | NA Days |
| Placebo | Time to First VOC That Required Admission to a Healthcare Facility and Treatment With Parenteral Pain Medication Within 90 Days of Randomization | NA Days |
p-value: 0.938295% CI: [0.43, 2.16]Stratified log-rank test