Priapism
Conditions
Keywords
Priapism, sickle cell disease, SCD, crizanlizumab, P-selectin, SEG101, monoclonal antibody, prolonged erection, painful erection
Brief summary
The goal of the study was to evaluate the efficacy and safety of crizanlizumab in sickle cell disease (SCD) patients with priapism.
Detailed description
Before participating in this study, information to determine key eligibility criteria was collected as a part of a 14-week Pre-Screening period. The study included a 12-week Screening period and a 52-week (1 year) Treatment period. Eligible participants received crizanlizumab 5 mg/kg by intravenous infusion (IV). Study treatment was received at clinic visits on Week 1 Day 1, Week 3 Day 1, and then on Day 1 of every 4-week cycle. Efficacy assessments included evaluation of priapic and vaso-occlusive (VOC) events. Safety assessments included laboratory tests, electrocardiograms (ECGs), vital signs and physical examinations. Participants had a safety follow-up for up to 15 weeks after the last dose.
Interventions
DRUGCrizanlizumab
Crizanlizumab is a concentrate for solution for infusion, IV use. Supplied in single use 10 mL vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Male patients aged 12 years and above * Confirmed diagnosis of SCD by hemoglobin electrophoresis or high-performance liquid chromatography. All SCD genotypes were eligible (HbSS, HbSβ0, HbSC, HbSβ+, and others) * Experienced 4 or more priapic events (unwanted erection lasting at least 60 minutes) over the 14 weeks preceding study participation * Experienced at least 3 priapic events (unwanted erection lasting at least 60 minutes) during the 12-week Screening period with at least 1 event occurring within 4 weeks prior to the first treatment * If receiving hydroxyurea/hydroxycarbamide or L-glutamine or erythropoietin stimulating agent or voxelotor, must have been receiving the drug for at least 14 weeks prior to screening and planned to continue taking the drug at the same dose and schedule during the trial * If receiving prophylactic treatment for priapism, must have been receiving the drug for at least 14 weeks prior to screening and planned to continue taking the drug at the same dose and schedule during the trial * Written informed consent (or assent/parental consent for minor participants) prior to any screening procedures
Exclusion criteria
* Had penile prosthetic implants or shunts or any other surgical procedure on the penis performed within 12 months prior to consenting was not allowed * Took drugs/medications that may induce priapism over the 14 weeks preceding study entry * Received leuprolide acetate (Lupron) or any other gonadotropin releasing hormone receptor agonist agent within 3 months before pre-screening * Had an erection lasting more than 12 hours over the 14 weeks preceding study entry * Had an erection lasting more than 12 hours during the 12 weeks of the Screening period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Priapic Events From Baseline to 26 Weeks | Baseline up to 26 weeks | A priapic event was defined as an unwanted or painful penile erection lasting at least 60 minutes. Priapic events were self-reported via an electronic reporting system, and data was collected throughout the study period. Number of priapic events was summarized at Baseline (adjusted for 26 weeks) and by 26 weeks, and percent reduction from adjusted Baseline by 26 weeks was summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Priapic Events | Baseline up to 26 and 52 weeks | A priapic event was defined as an unwanted or painful penile erection lasting at least 60 minutes. Priapic events were self-reported via an electronic reporting system, and data was collected throughout the study period. The annualized rate of events was defined as the total number of events for a participant occurring from the date of initial infusion to the last contact date of the Treatment Phase of the study x 365.25 divided by the number of days during that same time period. The calculation accounted for early dropouts or lost to follow-up by extrapolating the priapism events rate of every participant to 1 year. |
| Number of Acute Priapic Events From Baseline to 26 and 52 Weeks | Baseline up to 26 and 52 weeks | An acute priapic event was defined as an unwanted, painful erection that lasted more than 4 hours and required a visit to the emergency room. |
| Annualized Rate of Uncomplicated Vaso-occlusive Crises (VOCs) | Baseline up to 26 and 52 weeks | An uncomplicated VOC event was defined as an acute event of pain with no known cause for pain other than a VOC event; and requiring treatment with a parenteral or oral opioids or other parenteral analgesic; but was NOT classified as an acute chest syndrome, hepatic sequestration, splenic sequestration or priapism. Events included both healthcare and self-reported events. The annualized rate of events was defined as the total number of events for a participant occurring from the date of initial infusion to the last contact date of the Treatment Phase of the study x 365.25 divided by the number of days during that same time period. The calculation accounted for early dropouts or lost to follow-up by extrapolating the priapism events rate of every participant to 1 year. |
| Annualized Rate of Complicated VOCs | Baseline up to 26 and 52 weeks | Complicated VOCs were defined as acute chest syndrome, hepatic sequestration, splenic sequestration, and acute priapism recorded by healthcare visit. The annualized rate of events was defined as the total number of events for a participant occurring from the date of initial infusion to the last contact date of the Treatment Phase of the study x 365.25 divided by the number of days during that same time period. The calculation accounted for early dropouts or lost to follow-up by extrapolating the priapism events rate of every participant to 1 year. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Crizanlizumab 5 mg/kg Participants received 5 mg/kg by IV infusion on Week 1 Day 1, Week 3 Day 1, and on Day 1 of every 4-week cycle until Week 51. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Crizanlizumab 5 mg/kg |
|---|---|
| Age, Continuous | 31.5 years STANDARD_DEVIATION 10.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 36 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 36 |
| other Total, other adverse events | 26 / 36 |
| serious Total, serious adverse events | 7 / 36 |
Outcome results
Primary
Percent Change in Priapic Events From Baseline to 26 Weeks
A priapic event was defined as an unwanted or painful penile erection lasting at least 60 minutes. Priapic events were self-reported via an electronic reporting system, and data was collected throughout the study period. Number of priapic events was summarized at Baseline (adjusted for 26 weeks) and by 26 weeks, and percent reduction from adjusted Baseline by 26 weeks was summarized.
Time frame: Baseline up to 26 weeks
Population: The full analysis set (FAS) included all enrolled participants to whom the study treatment was assigned regardless of whether or not they received at least one dose of study treatment or had at least one post-baseline assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Crizanlizumab 5 mg/kg | Percent Change in Priapic Events From Baseline to 26 Weeks | -61.3 Percent change from baseline |
p-value: 0.067695% CI: [23.5, 65.36]Wilcoxon Sign Rank Test
Secondary
Annualized Rate of Complicated VOCs
Complicated VOCs were defined as acute chest syndrome, hepatic sequestration, splenic sequestration, and acute priapism recorded by healthcare visit. The annualized rate of events was defined as the total number of events for a participant occurring from the date of initial infusion to the last contact date of the Treatment Phase of the study x 365.25 divided by the number of days during that same time period. The calculation accounted for early dropouts or lost to follow-up by extrapolating the priapism events rate of every participant to 1 year.
Time frame: Baseline up to 26 and 52 weeks
Population: The FAS included all enrolled participants to whom the study treatment was assigned regardless of whether or not they received at least one dose of study treatment or had at least one post-baseline assessment. Only participants who had complicated VOC events within the specified time frame were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab 5 mg/kg | Annualized Rate of Complicated VOCs | Annualized rate of complicated VOCs by 26 weeks | 1.9 Events per year |
| Crizanlizumab 5 mg/kg | Annualized Rate of Complicated VOCs | Annualized rate of complicated VOCs by 52 weeks | 1.4 Events per year |
Secondary
Annualized Rate of Priapic Events
A priapic event was defined as an unwanted or painful penile erection lasting at least 60 minutes. Priapic events were self-reported via an electronic reporting system, and data was collected throughout the study period. The annualized rate of events was defined as the total number of events for a participant occurring from the date of initial infusion to the last contact date of the Treatment Phase of the study x 365.25 divided by the number of days during that same time period. The calculation accounted for early dropouts or lost to follow-up by extrapolating the priapism events rate of every participant to 1 year.
Time frame: Baseline up to 26 and 52 weeks
Population: The FAS included all enrolled participants to whom the study treatment was assigned regardless of whether or not they received at least one dose of study treatment or had at least one post-baseline assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab 5 mg/kg | Annualized Rate of Priapic Events | Annualized rate of priapic events by 26 weeks | 31.1 Events per year |
| Crizanlizumab 5 mg/kg | Annualized Rate of Priapic Events | Annualized rate of priapic events by 52 weeks | 25.6 Events per year |
Secondary
Annualized Rate of Uncomplicated Vaso-occlusive Crises (VOCs)
An uncomplicated VOC event was defined as an acute event of pain with no known cause for pain other than a VOC event; and requiring treatment with a parenteral or oral opioids or other parenteral analgesic; but was NOT classified as an acute chest syndrome, hepatic sequestration, splenic sequestration or priapism. Events included both healthcare and self-reported events. The annualized rate of events was defined as the total number of events for a participant occurring from the date of initial infusion to the last contact date of the Treatment Phase of the study x 365.25 divided by the number of days during that same time period. The calculation accounted for early dropouts or lost to follow-up by extrapolating the priapism events rate of every participant to 1 year.
Time frame: Baseline up to 26 and 52 weeks
Population: The FAS included all enrolled participants to whom the study treatment was assigned regardless of whether or not they received at least one dose of study treatment or had at least one post-baseline assessment. Only participants who had uncomplicated VOC events within the specified time frame were included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab 5 mg/kg | Annualized Rate of Uncomplicated Vaso-occlusive Crises (VOCs) | Annualized rate of uncomplicated VOCs by 26 weeks | 4.1 Events per year |
| Crizanlizumab 5 mg/kg | Annualized Rate of Uncomplicated Vaso-occlusive Crises (VOCs) | Annualized rate of uncomplicated VOCs by 52 weeks | 2.5 Events per year |
Secondary
Number of Acute Priapic Events From Baseline to 26 and 52 Weeks
An acute priapic event was defined as an unwanted, painful erection that lasted more than 4 hours and required a visit to the emergency room.
Time frame: Baseline up to 26 and 52 weeks
Population: The FAS included all enrolled participants to whom the study treatment was assigned regardless of whether or not they received at least one dose of study treatment or had at least one post-baseline assessment. Only participants with Acute Priapic Events are included in this analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Crizanlizumab 5 mg/kg | Number of Acute Priapic Events From Baseline to 26 and 52 Weeks | Number of acute priapic events at Baseline | 7.0 Number of acute priapic events |
| Crizanlizumab 5 mg/kg | Number of Acute Priapic Events From Baseline to 26 and 52 Weeks | Number of post-baseline acute priapic events by 26 weeks | 1.5 Number of acute priapic events |
| Crizanlizumab 5 mg/kg | Number of Acute Priapic Events From Baseline to 26 and 52 Weeks | Number of post-baseline acute priapic events by 52 weeks | 1.0 Number of acute priapic events |
Post Hoc
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest)
A TEAE was defined as an adverse event starting or worsening after the administration of study medication. TEAEs experienced by participants in association with infusion related reactions were classified as adverse events of special interest (AESIs).
Time frame: Baseline up to 57 weeks
Population: The Safety Analysis Set consisted of all participants who received at least 1 dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | With at least one AESI | 9 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Axillary pain | 1 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Non-cardiac chest pain | 1 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Infusion related reaction | 2 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Arthralgia | 1 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Back pain | 1 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Neck pain | 1 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Headache | 3 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Pruritis | 1 Participants |
| Crizanlizumab 5 mg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Associated With Infusion Related Reactions (Adverse Events of Special Interest) | Rash maculo-papular | 1 Participants |
Post Hoc
Percent Change in Priapic Events From Baseline to 26 Weeks Without the Outlier
A priapic event was defined as an unwanted or painful penile erection lasting at least 60 minutes. Priapic events were self-reported via an electronic reporting system, and data was collected throughout the study period. Number of priapic events was summarized at Baseline (adjusted for 26 weeks) and by 26 weeks, and percent reduction from adjusted Baseline by 26 weeks was summarized. For one participant, the outlier, a large amount of data corresponding to 38 days of screening (45% of the period), was not reported. Additionally, data in the other days of the Screening Period were also not collected. This was a unique occurrence which did not happen with other participants. To understand its impact, the primary endpoint has also been analyzed excluding this outlier in a post-hoc sensitivity analysis.
Time frame: Baseline up to 26 weeks
Population: The FAS included all enrolled participants to whom the study treatment was assigned regardless of whether or not they received at least one dose of study treatment or had at least one post-baseline assessment. Analysis was performed excluding one outlier participant, who had a large amount of data unreported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Crizanlizumab 5 mg/kg | Percent Change in Priapic Events From Baseline to 26 Weeks Without the Outlier | -63.3 Percent change from baseline |
p-value: 0.025995% CI: [27.94, 67.36]Wilcoxon Sign Rank Test