Sickle Cell Disease
Conditions
Keywords
Sickle cell disease, Young adults, Hestia2, Ticagrelor
Brief summary
The purpose of this study is to determine whether ticagrelor is effective in reducing the number of days of pain, intensity of pain, and reducing the use of analgesics due to sickle cell disease
Detailed description
This is a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, study evaluating 2 doses of ticagrelor in 90 patients aged 18 to 30 years, with sickle cell disease (SCD). Patients will be randomised to double-blind double-dummy treatment period in a 1:1:1 ratio (30 to each treatment group) to receive ticagrelor 10 mg twice daily (bid), or ticagrelor 45 mg bid, or placebo bid to determine the frequency of days with pain using an electronic diary (eDiary) every day. Approximately 180 patients will be enrolled. Patient will be followed for safety assessment during and after 2 weeks of treatment completion. During the 16 week treatment period, patients will complete a daily eDiary concerning daily pain intensity, pain location, use of analgesics and absence from school or work. At the end of the study patients will be asked to rate the change in their sickle cell pain compared to the start of treatment. Platelet aggregation will be measured and reported as P2Y12 reaction units (PRU) pre-dose and 2 hours post-dose at week 4 and week 5 after treatment start. Pharmacokinetic (PK) parameters will be measured at 2 hours post-dose at week 4, and pre-dose and at 2 hours post-dose at week 5. Biomarkers will be assessed pre-dose at week 4, week 5 and week 8. During the study, patients will be evaluated for adverse events (AEs) including bleeding and vaso-occlusive crisis (VOC).
Interventions
DRUGTicagrelor
Two arms: 1) 10 mg ticagrelor + 45 mg ticagrelor placebo or 2) 45 mg ticagrelor + 10 mg ticagrelor placebo. Drugs taken orally, twice a day (morning and evening, at least 12 hours apart) from randomization until the end of treatment.
DRUGPlacebo
10 mg ticagrelor placebo + 45 mg ticagrelor placebo. Drugs taken orally, twice a day (morning and evening at least 12 hours apart) from randomization until the end of treatment
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
* Confirmed medical history or diagnosis of homozygous sickle cell (HbSS) or sickle beta-zero-thalassaemia (HbS/β0) by HPLC * If treated with hydroxyurea, the dose must have been stable for 3 months
Exclusion criteria
* History of transient ischaemic attack or clinically overt cerebrovascular accident * Moderate or severe hepatic impairment * Treatment with chronic red blood cell transfusion therapy * Pre-dominate cause of pain is not sickle cell disease related * Chronic treatment with anticoagulants or antiplatelet drugs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary | Baseline through Week 12 | To investigate the efficacy of 2 different doses of ticagrelor versus placebo in reducing the number of days with pain due to sickle cell disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average of the Daily Worst Pain Values Reported Via eDiary | Baseline through Week 12 | To determine the efficacy of 2 different doses of ticagrelor versus placebo in reducing the intensity of pain due to sickle cell disease. Intensity of pain was recorded on an 11-point scale where 0 represented no pain and 10 represented the worst pain imaginable. |
| Change in Proportion of Days With Analgesic Use Measured by an eDiary | Baseline through Week 12 | To assess the efficacy of 2 different doses of ticagrelor versus placebo in reducing the use of analgesics by patients with sickle cell disease. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients) | Baseline through Week 12 | To assess safety and tolerability of 2 different doses of ticagrelor versus placebo in patients with SCD |
| Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Baseline through Week 12 | To assess safety and tolerability of 2 different doses of ticagrelor versus placebo in patients with SCD |
Countries
Egypt, France, Italy, Kenya, Lebanon, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 26 centers in 8 countries between 09 July 2015 and 16 November 2016.
Pre-assignment details
The study duration was approximately 18 weeks, consisting of a screening period including a 4-week single-blind placebo treatment for baseline assessments, a 12-week double-blind randomised treatment period, and a 2-week follow-up period. A total of 87 patients were randomized
Participants by arm
| Arm | Count |
|---|---|
| PLACEBO 10MG BID + PLACEBO 45MG BID | 30 |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID Note that 1 patient in the Ticagrelor 10mg BID + Placebo 45mg BID group was excluded from the Safety analysis set because they had no post-dose assessments. | 27 |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | 30 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Dev. of Study-Spec. Withdrawal Criteria | 0 | 0 | 1 |
| Overall Study | Did Not Fulfill Randomization Criteria | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 2 |
Baseline characteristics
| Characteristic | PLACEBO 10MG BID + PLACEBO 45MG BID | TICAGRELOR 10MG BID + PLACEBO 45MG BID | TICAGRELOR 45MG BID + PLACEBO 10MG BID | Total |
|---|---|---|---|---|
| Age, Continuous | 21.6 Years STANDARD_DEVIATION 3.42 | 21.9 Years STANDARD_DEVIATION 2.72 | 23.2 Years STANDARD_DEVIATION 3.69 | 22.2 Years STANDARD_DEVIATION 3.35 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 14 Participants | 17 Participants | 46 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 12 Participants | 13 Participants | 40 Participants |
| Sex: Female, Male Female | 16 Participants | 15 Participants | 16 Participants | 47 Participants |
| Sex: Female, Male Male | 14 Participants | 12 Participants | 14 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 30 | 15 / 26 | 20 / 30 |
| serious Total, serious adverse events | 6 / 30 | 6 / 26 | 5 / 30 |
Outcome results
Primary
Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary
To investigate the efficacy of 2 different doses of ticagrelor versus placebo in reducing the number of days with pain due to sickle cell disease.
Time frame: Baseline through Week 12
Population: The Efficacy analysis set included all randomized patients with at least 1 eDiary record post dose. Patients were analyzed according to their randomized IP.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO 10MG BID + PLACEBO 45MG BID | Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary | -0.1802 Proportion of days with pain | 90% Confidence Interval 0.05453 |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary | -0.1352 Proportion of days with pain | 90% Confidence Interval 0.05287 |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary | -0.1001 Proportion of days with pain | 90% Confidence Interval 0.05233 |
90% CI: [-0.061, 0.151]Mixed Models Analysis
90% CI: [-0.023, 0.1832]Mixed Models Analysis
Secondary
Average of the Daily Worst Pain Values Reported Via eDiary
To determine the efficacy of 2 different doses of ticagrelor versus placebo in reducing the intensity of pain due to sickle cell disease. Intensity of pain was recorded on an 11-point scale where 0 represented no pain and 10 represented the worst pain imaginable.
Time frame: Baseline through Week 12
Population: The Efficacy analysis set included all randomized patients with at least 1 eDiary record post dose. Patients were analyzed according to their randomized IP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO 10MG BID + PLACEBO 45MG BID | Average of the Daily Worst Pain Values Reported Via eDiary | 1.02 Average daily worst pain rating | Standard Deviation 1.106 |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Average of the Daily Worst Pain Values Reported Via eDiary | 1.15 Average daily worst pain rating | Standard Deviation 1.547 |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Average of the Daily Worst Pain Values Reported Via eDiary | 1.74 Average daily worst pain rating | Standard Deviation 2.277 |
Secondary
Change in Proportion of Days With Analgesic Use Measured by an eDiary
To assess the efficacy of 2 different doses of ticagrelor versus placebo in reducing the use of analgesics by patients with sickle cell disease.
Time frame: Baseline through Week 12
Population: The Efficacy analysis set included all randomized patients with at least 1 eDiary record post dose. Patients were analyzed according to their randomized IP.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO 10MG BID + PLACEBO 45MG BID | Change in Proportion of Days With Analgesic Use Measured by an eDiary | -0.1991 Proportion of days with analgesic use | 90% Confidence Interval 0.08763 |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Change in Proportion of Days With Analgesic Use Measured by an eDiary | -0.0799 Proportion of days with analgesic use | 90% Confidence Interval 0.0854 |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Change in Proportion of Days With Analgesic Use Measured by an eDiary | -0.1016 Proportion of days with analgesic use | 90% Confidence Interval 0.08664 |
90% CI: [0.035, 0.2035]Mixed Models Analysis
90% CI: [0.0155, 0.1795]Mixed Models Analysis
Other Pre-specified
Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events)
To assess safety and tolerability of 2 different doses of ticagrelor versus placebo in patients with SCD
Time frame: Baseline through Week 12
Population: The Safety analysis set included all patients who received at least 1 single dose of randomised IP, ticagrelor or placebo, and for whom any post-dose data were available. Patients were analysed according to the actual treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PLACEBO 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Total number of bleeding events | 2 Number of events |
| PLACEBO 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Maximum severity of bleeding event: Minor | 0 Number of events |
| PLACEBO 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Max sever. of bleed event: Clin-relevant nonmajor | 2 Number of events |
| PLACEBO 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Maximum severity of bleeding event: Major | 0 Number of events |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Maximum severity of bleeding event: Major | 0 Number of events |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Total number of bleeding events | 2 Number of events |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Max sever. of bleed event: Clin-relevant nonmajor | 1 Number of events |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Maximum severity of bleeding event: Minor | 1 Number of events |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Maximum severity of bleeding event: Major | 0 Number of events |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Maximum severity of bleeding event: Minor | 0 Number of events |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Max sever. of bleed event: Clin-relevant nonmajor | 2 Number of events |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) | Total number of bleeding events | 2 Number of events |
Other Pre-specified
Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients)
To assess safety and tolerability of 2 different doses of ticagrelor versus placebo in patients with SCD
Time frame: Baseline through Week 12
Population: The Safety analysis set included all patients who received at least 1 single dose of randomised IP, ticagrelor or placebo, and for whom any post-dose data were available. Patients were analysed according to the actual treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PLACEBO 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients) | Patients with any bleeding events | 2 Number of patients |
| PLACEBO 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients) | Pts w/ any bleeding event requiring intervention | 2 Number of patients |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients) | Patients with any bleeding events | 2 Number of patients |
| TICAGRELOR 10MG BID + PLACEBO 45MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients) | Pts w/ any bleeding event requiring intervention | 1 Number of patients |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients) | Patients with any bleeding events | 2 Number of patients |
| TICAGRELOR 45MG BID + PLACEBO 10MG BID | Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients) | Pts w/ any bleeding event requiring intervention | 2 Number of patients |