Sickle Cell Anemia
Conditions
Keywords
Sickle Cell Disease, Sickle Cell Anemia, Adult
Brief summary
The purpose of this trial is to assess the safety of Prasugrel in adult patients with sickle cell disease (SCD) by monitoring the rate and severity of hemorrhagic events requiring medical intervention compared to placebo for 30 days.
Interventions
DRUGPrasugrel
Administered orally, once daily for 30 days.
DRUGPlacebo
Administered orally, once daily for 30 days.
Sponsors
Daiichi Sankyo
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Adults with Sickle Cell Disease (SCD). * Are greater than or equal to 50 kilograms (kg) at time of screening. * Are not currently being treated with an investigational drug (use of hydroxyurea, which is not an investigational drug, is permitted under this protocol if the patient has been on a stable dose for at least 30 days prior to randomization and has no signs of hematological toxicity at screening. * Agree to use a reliable method of birth control during the study or are women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause.
Exclusion criteria
* Acute painful crisis (requiring medical attention) within 30 days prior to screening. * Have a concomitant medical illness (for example, terminal malignancy) that, in the opinion of the investigator, is associated with reduced survival over the expected treatment period (approximately 30 days). * Severe hepatic dysfunction (cirrhosis, portal hypertension, or aspartate aminotransferase (AST) greater than or equal to 3x upper limit of normal \[ULN\]). * Renal dysfunction requiring chronic dialysis. * Contraindication for antiplatelet therapy. * History of intolerance or allergy to approved thienopyridines. * Have signs or symptoms of an infection. * Hypertension (systolic blood pressure \>180 millimeters of mercury (mm Hg) or diastolic blood pressure \>110 mm Hg) at the time of screening or randomization. * Hematocrit \<18%. * Any history of bleeding diathesis, bleeding requiring in-hospital treatment, or papillary necrosis. * Active internal bleeding. * History of spontaneous gastrointestinal (GI) bleeding requiring in-hospital treatment. * Gross hematuria. Microhematuria, common in SCD patients, is not a contraindication. * Platelet count \<100,000 per cubic millimeter. * Any history of intraocular hemorrhage. * Prior history of transient ischemic attack (TIA), ischemic stroke, hemorrhagic stroke, or other intracranial hemorrhage. * Known history of intracranial neoplasm, arteriovenous malformation, or aneurysm. * Have clinical findings, in the judgment of the investigator, associated with an increased risk of bleeding. * Have an international normalized ratio (INR) of greater than 1.5 at screening. * Have had recent surgery (within 30 days prior to screening) or are scheduled to undergo surgery within the next 60 days. * History of menorrhagia requiring medical intervention.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hemorrhagic Events Requiring Medical Intervention During the Treatment Duration | Baseline through 30 days | A hemorrhagic event requiring medical intervention. Medical intervention was defined as any medical attention resulting in therapy or further investigation during the 30-day treatment duration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Days With Pain Related to Sickle Cell Disease (SCD) During the Treatment Duration | Baseline through 30 days | Participants recorded the intensity of pain due to SCD each day in the daily pain diaries. A scale of 0 to 9 was used, with 0 indicating no pain, and 9 indicating unbearable pain. A response range of 1 to 9 indicated the participant experienced pain due to SCD, whereas a response of 0 indicated participant did not experience pain due to SCD. The percentage of days with pain (pain rate) was calculated as follows: Pain rate = 100\*(Total number of days with pain/number of daily pain diaries completed). Number of daily pain diaries completed was number of nonmissing pain intensity responses. |
| Percentage of Participants With Pain Events Related to Sickle Cell Disease (SCD) Requiring Medical Attention During the Treatment Duration | Baseline through 30 days | Pain requiring medical attention was defined 2 ways: (1) if the participant attended an unplanned doctor's appointment or clinic visit, visited the emergency room, or was admitted to hospital due to sickle cell pain, or (2) if the participant experienced a vaso-occlusive crisis (VOC), acute chest syndrome, or hepatic sequestration at least once during the treatment period. |
| Percentage of Participants With Hemorrhagic Treatment-Emergent Adverse Events (TEAEs) During the Treatment Duration | Baseline through 30 days | TEAEs were defined as AEs that occurred or worsened after receiving the study drug. |
| Intensity of Pain Related to Sickle Cell Disease (SCD) During the Treatment Duration | Baseline through 30 days | Participants recorded intensity of pain due to SCD each day in daily pain diaries using a pain scale. A scale of 0 to 9 was used, with 0=no pain and 9=unbearable pain. A response range of 1 to 9 indicated participant experienced pain due to SCD, whereas a response of 0 indicated participant did not experience pain due to SCD. Pain intensity was the average of a participant's pain ratings. Average pain intensity=(Sum of all nonmissing pain intensity responses/number of daily pain diaries completed). Number of daily pain diaries completed is number of nonmissing pain intensity responses. |
| P2Y12 Reaction Units (PRU) as Measured by Accumetrics VerifyNow® P2Y12 (VN P2Y12) at 30 Days | 30 days | PRU represents the rate and extent of adenosine (ADP)-stimulated platelet aggregation. The VN P2Y12 assay is a point-of-care device that measures platelet aggregation with single-use, disposable cartridges. A low PRU reflects stronger inhibition of P2Y12, whereas a high PRU reflects weaker inhibition of P2Y12. The Least Squares Mean values were calculated from a mixed-effects model repeated measures analysis with baseline measurement, stratification variable sickle cell genotype, treatment, time, and time\*treatment interaction as fixed effects, and participant as a random effect in the model. |
| Platelet Reactivity Index (PRI) Measured by Vasodilator-Associated Stimulated Phosphoprotein (VASP) at 30 Days | 30 days | PRI was calculated by VASP phosphorylation assay using flow cytometry. The PRI indicates the level of P2Y12 inhibition. A low PRI reflects strong inhibition of P2Y12, whereas a high PRI reflects weak/absent inhibition of P2Y12. The Least Squares (LS) Mean values were calculated from a mixed-effects model repeated measures (MMRM) analysis with baseline measurement, stratification variable sickle cell genotype, treatment, time, and time\*treatment interaction as fixed effects, and participant as a random effect in the model. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo orally, once daily for 30 days. | 21 |
| 5 mg Prasugrel Participants received 5 mg of prasugrel orally, once daily for 30 days. | 41 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 1 |
| Overall Study | Screen Failure | 0 | 1 | 0 |
| Overall Study | Sponsor Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | 5 mg Prasugrel | Total |
|---|---|---|---|
| Age Continuous | 31.52 years STANDARD_DEVIATION 8.2 | 32.88 years STANDARD_DEVIATION 8.6 | 32.42 years STANDARD_DEVIATION 8.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 40 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 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 | 21 Participants | 40 Participants | 61 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 | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Canada | 3 participants | 8 participants | 11 participants |
| Region of Enrollment United States | 18 participants | 33 participants | 51 participants |
| Sex: Female, Male Female | 9 Participants | 21 Participants | 30 Participants |
| Sex: Female, Male Male | 12 Participants | 20 Participants | 32 Participants |
| Sickle-Cell Genotype Hb SC genotype | 5 participants | 10 participants | 15 participants |
| Sickle-Cell Genotype Hb S ß0 thalassemia genotype | 1 participants | 2 participants | 3 participants |
| Sickle-Cell Genotype Hb S ß+ thalassemia genotype | 2 participants | 4 participants | 6 participants |
| Sickle-Cell Genotype Hemoglobin SS (Hb SS) genotype | 13 participants | 24 participants | 37 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 19 | 33 / 41 |
| serious Total, serious adverse events | 4 / 19 | 8 / 41 |
Outcome results
Primary
Percentage of Participants With Hemorrhagic Events Requiring Medical Intervention During the Treatment Duration
A hemorrhagic event requiring medical intervention. Medical intervention was defined as any medical attention resulting in therapy or further investigation during the 30-day treatment duration.
Time frame: Baseline through 30 days
Population: Safety population: All randomized participants who took at least 1 dose of study medication. Participants were analyzed according to the treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Hemorrhagic Events Requiring Medical Intervention During the Treatment Duration | 0 percentage of participants |
| 5 mg Prasugrel | Percentage of Participants With Hemorrhagic Events Requiring Medical Intervention During the Treatment Duration | 0 percentage of participants |
Secondary
Intensity of Pain Related to Sickle Cell Disease (SCD) During the Treatment Duration
Participants recorded intensity of pain due to SCD each day in daily pain diaries using a pain scale. A scale of 0 to 9 was used, with 0=no pain and 9=unbearable pain. A response range of 1 to 9 indicated participant experienced pain due to SCD, whereas a response of 0 indicated participant did not experience pain due to SCD. Pain intensity was the average of a participant's pain ratings. Average pain intensity=(Sum of all nonmissing pain intensity responses/number of daily pain diaries completed). Number of daily pain diaries completed is number of nonmissing pain intensity responses.
Time frame: Baseline through 30 days
Population: Intent to treat (ITT) population consisted of all randomized participants. Participants were analyzed according to the treatment they were randomized to. The analysis was performed in the ITT population who had recorded the pain intensity in at least 1 daily pain diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Intensity of Pain Related to Sickle Cell Disease (SCD) During the Treatment Duration | 2.72 units on a scale | Standard Deviation 2.33 |
| 5 mg Prasugrel | Intensity of Pain Related to Sickle Cell Disease (SCD) During the Treatment Duration | 1.56 units on a scale | Standard Deviation 1.98 |
p-value: 0.244ANCOVA
Secondary
P2Y12 Reaction Units (PRU) as Measured by Accumetrics VerifyNow® P2Y12 (VN P2Y12) at 30 Days
PRU represents the rate and extent of adenosine (ADP)-stimulated platelet aggregation. The VN P2Y12 assay is a point-of-care device that measures platelet aggregation with single-use, disposable cartridges. A low PRU reflects stronger inhibition of P2Y12, whereas a high PRU reflects weaker inhibition of P2Y12. The Least Squares Mean values were calculated from a mixed-effects model repeated measures analysis with baseline measurement, stratification variable sickle cell genotype, treatment, time, and time\*treatment interaction as fixed effects, and participant as a random effect in the model.
Time frame: 30 days
Population: Safety population: All randomized participants who took at least 1 dose of study medication. Participants were analyzed according to the treatment they actually received. The analysis was performed in the safety population who had both baseline and 30-day PRU measurements and a non-missing genotype.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | P2Y12 Reaction Units (PRU) as Measured by Accumetrics VerifyNow® P2Y12 (VN P2Y12) at 30 Days | 336.8 P2Y12 Reaction Units (PRU) | Standard Error 16.8 |
| 5 mg Prasugrel | P2Y12 Reaction Units (PRU) as Measured by Accumetrics VerifyNow® P2Y12 (VN P2Y12) at 30 Days | 208.5 P2Y12 Reaction Units (PRU) | Standard Error 11.9 |
p-value: <0.001Mixed Models Analysis
Secondary
Percentage of Days With Pain Related to Sickle Cell Disease (SCD) During the Treatment Duration
Participants recorded the intensity of pain due to SCD each day in the daily pain diaries. A scale of 0 to 9 was used, with 0 indicating no pain, and 9 indicating unbearable pain. A response range of 1 to 9 indicated the participant experienced pain due to SCD, whereas a response of 0 indicated participant did not experience pain due to SCD. The percentage of days with pain (pain rate) was calculated as follows: Pain rate = 100\*(Total number of days with pain/number of daily pain diaries completed). Number of daily pain diaries completed was number of nonmissing pain intensity responses.
Time frame: Baseline through 30 days
Population: Intent to treat (ITT) population consisted of all randomized participants. Participants were analyzed according to the treatment they were randomized to. The analysis was performed in the ITT population who recorded pain intensity in at least 1 daily pain diary.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Days With Pain Related to Sickle Cell Disease (SCD) During the Treatment Duration | 63.57 percentage of days | Standard Deviation 41.8 |
| 5 mg Prasugrel | Percentage of Days With Pain Related to Sickle Cell Disease (SCD) During the Treatment Duration | 39.04 percentage of days | Standard Deviation 42.2 |
p-value: 0.304ANCOVA
Secondary
Percentage of Participants With Hemorrhagic Treatment-Emergent Adverse Events (TEAEs) During the Treatment Duration
TEAEs were defined as AEs that occurred or worsened after receiving the study drug.
Time frame: Baseline through 30 days
Population: Safety population: All randomized participants who took at least 1 dose of study medication. Participants were analyzed according to the treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Hemorrhagic Treatment-Emergent Adverse Events (TEAEs) During the Treatment Duration | 5.3 percentage of participants |
| 5 mg Prasugrel | Percentage of Participants With Hemorrhagic Treatment-Emergent Adverse Events (TEAEs) During the Treatment Duration | 19.5 percentage of participants |
Secondary
Percentage of Participants With Pain Events Related to Sickle Cell Disease (SCD) Requiring Medical Attention During the Treatment Duration
Pain requiring medical attention was defined 2 ways: (1) if the participant attended an unplanned doctor's appointment or clinic visit, visited the emergency room, or was admitted to hospital due to sickle cell pain, or (2) if the participant experienced a vaso-occlusive crisis (VOC), acute chest syndrome, or hepatic sequestration at least once during the treatment period.
Time frame: Baseline through 30 days
Population: Intent to treat (ITT) population consisted of all randomized participants. Participants were analyzed according to the treatment they were randomized to. The analysis was performed in the ITT population who completed at least 1 page of the daily pain diary or with pain endpoint case report form (CRF) data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Pain Events Related to Sickle Cell Disease (SCD) Requiring Medical Attention During the Treatment Duration | 36.8 percentage of participants |
| 5 mg Prasugrel | Percentage of Participants With Pain Events Related to Sickle Cell Disease (SCD) Requiring Medical Attention During the Treatment Duration | 22.5 percentage of participants |
Secondary
Platelet Reactivity Index (PRI) Measured by Vasodilator-Associated Stimulated Phosphoprotein (VASP) at 30 Days
PRI was calculated by VASP phosphorylation assay using flow cytometry. The PRI indicates the level of P2Y12 inhibition. A low PRI reflects strong inhibition of P2Y12, whereas a high PRI reflects weak/absent inhibition of P2Y12. The Least Squares (LS) Mean values were calculated from a mixed-effects model repeated measures (MMRM) analysis with baseline measurement, stratification variable sickle cell genotype, treatment, time, and time\*treatment interaction as fixed effects, and participant as a random effect in the model.
Time frame: 30 days
Population: All randomized participants who took at least 1 dose of study medication. Participants were analyzed according to the treatment they actually received. The analysis was performed in the safety population who had both baseline and 30-day PRI measurements and a non-missing genotype.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Platelet Reactivity Index (PRI) Measured by Vasodilator-Associated Stimulated Phosphoprotein (VASP) at 30 Days | 74.843 percentage of PRI | Standard Error 4.993 |
| 5 mg Prasugrel | Platelet Reactivity Index (PRI) Measured by Vasodilator-Associated Stimulated Phosphoprotein (VASP) at 30 Days | 50.792 percentage of PRI | Standard Error 3.36 |
p-value: <0.001Mixed Models Analysis