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A Study to Assess the Effect of Ticagrelor in Reducing the Number of Days With Pain in Patients With Sickle Cell Disease (Hestia2)

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ClinicalTrials.gov Identifier: NCT02482298
Recruitment Status : Completed
First Posted : June 26, 2015
Results First Posted : December 14, 2017
Last Update Posted : December 14, 2017
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Prevention
Condition: Sickle Cell Disease
Interventions: Drug: Ticagrelor
Drug: Placebo

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted at 26 centers in 8 countries between 09 July 2015 and 16 November 2016.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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

Reporting Groups
  Description
PLACEBO 10MG BID + PLACEBO 45MG BID No text entered.
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.
TICAGRELOR 45MG BID + PLACEBO 10MG BID No text entered.

Participant Flow:   Overall Study
    PLACEBO 10MG BID + PLACEBO 45MG BID   TICAGRELOR 10MG BID + PLACEBO 45MG BID   TICAGRELOR 45MG BID + PLACEBO 10MG BID
STARTED   30   27   30 
COMPLETED   28   24   27 
NOT COMPLETED   2   3   3 
Withdrawal by Subject                2                1                2 
Did Not Fulfill Randomization Criteria                0                1                0 
Dev. of Study-Spec. Withdrawal Criteria                0                0                1 
Lost to Follow-up                0                1                0 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
PLACEBO 10MG BID + PLACEBO 45MG BID No text entered.
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.
TICAGRELOR 45MG BID + PLACEBO 10MG BID No text entered.
Total Total of all reporting groups

Baseline Measures
   PLACEBO 10MG BID + PLACEBO 45MG BID   TICAGRELOR 10MG BID + PLACEBO 45MG BID   TICAGRELOR 45MG BID + PLACEBO 10MG BID   Total 
Overall Participants Analyzed 
[Units: Participants]
 30   27   30   87 
Age 
[Units: Years]
Mean (Standard Deviation)
 21.6  (3.42)   21.9  (2.72)   23.2  (3.69)   22.2  (3.35) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
       
Female      16  53.3%      15  55.6%      16  53.3%      47  54.0% 
Male      14  46.7%      12  44.4%      14  46.7%      40  46.0% 
Race/Ethnicity, Customized 
[Units: Participants]
       
Black Or African American   15   14   17   46 
Other   0   1   0   1 
White   15   12   13   40 


  Outcome Measures

1.  Primary:   Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary   [ Time Frame: Baseline through Week 12 ]

Measure Type Primary
Measure Title Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary
Measure Description 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 Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Efficacy analysis set included all randomized patients with at least 1 eDiary record post dose. Patients were analyzed according to their randomized IP.

Reporting Groups
  Description
PLACEBO 10MG BID + PLACEBO 45MG BID No text entered.
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.
TICAGRELOR 45MG BID + PLACEBO 10MG BID No text entered.

Measured Values
   PLACEBO 10MG BID + PLACEBO 45MG BID   TICAGRELOR 10MG BID + PLACEBO 45MG BID   TICAGRELOR 45MG BID + PLACEBO 10MG BID 
Participants Analyzed   30   27   30 
Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary 
[Units: Proportion of days with pain]
Least Squares Mean (90% Confidence Interval)
 -0.1802 
 (-0.2673 to -0.0931) 
 -0.1352 
 (-0.2260 to -0.0444) 
 -0.1001 
 (-0.1881 to -0.0121) 


Statistical Analysis 1 for Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary
Groups [1] PLACEBO 10MG BID + PLACEBO 45MG BID vs. TICAGRELOR 10MG BID + PLACEBO 45MG BID
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Mixed Models Analysis
Mean Difference (Final Values) [4] 0.0450
90% Confidence Interval -0.0610 to 0.1510
Standard Error of the Mean (0.06367)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Change in Proportion of Days With Pain Due to Sickle Cell Disease as Measured by an eDiary
Groups [1] PLACEBO 10MG BID + PLACEBO 45MG BID vs. TICAGRELOR 45MG BID + PLACEBO 10MG BID
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Mixed Models Analysis
Mean Difference (Final Values) [4] 0.0801
90% Confidence Interval -0.0230 to 0.1832
Standard Error of the Mean (0.06192)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Average of the Daily Worst Pain Values Reported Via eDiary   [ Time Frame: Baseline through Week 12 ]

Measure Type Secondary
Measure Title Average of the Daily Worst Pain Values Reported Via eDiary
Measure Description 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 Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Efficacy analysis set included all randomized patients with at least 1 eDiary record post dose. Patients were analyzed according to their randomized IP.

Reporting Groups
  Description
PLACEBO 10MG BID + PLACEBO 45MG BID No text entered.
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.
TICAGRELOR 45MG BID + PLACEBO 10MG BID No text entered.

Measured Values
   PLACEBO 10MG BID + PLACEBO 45MG BID   TICAGRELOR 10MG BID + PLACEBO 45MG BID   TICAGRELOR 45MG BID + PLACEBO 10MG BID 
Participants Analyzed   30   27   30 
Average of the Daily Worst Pain Values Reported Via eDiary 
[Units: Average daily worst pain rating]
Mean (Standard Deviation)
 1.02  (1.106)   1.15  (1.547)   1.74  (2.277) 

No statistical analysis provided for Average of the Daily Worst Pain Values Reported Via eDiary



3.  Secondary:   Change in Proportion of Days With Analgesic Use Measured by an eDiary   [ Time Frame: Baseline through Week 12 ]

Measure Type Secondary
Measure Title Change in Proportion of Days With Analgesic Use Measured by an eDiary
Measure Description 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 Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Efficacy analysis set included all randomized patients with at least 1 eDiary record post dose. Patients were analyzed according to their randomized IP.

Reporting Groups
  Description
PLACEBO 10MG BID + PLACEBO 45MG BID No text entered.
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.
TICAGRELOR 45MG BID + PLACEBO 10MG BID No text entered.

Measured Values
   PLACEBO 10MG BID + PLACEBO 45MG BID   TICAGRELOR 10MG BID + PLACEBO 45MG BID   TICAGRELOR 45MG BID + PLACEBO 10MG BID 
Participants Analyzed   30   27   30 
Change in Proportion of Days With Analgesic Use Measured by an eDiary 
[Units: Proportion of days with analgesic use]
Least Squares Mean (90% Confidence Interval)
 -0.1991 
 (-0.2753 to -0.1230) 
 -0.0799 
 (-0.1590 to -0.0008) 
 -0.1016 
 (-0.1782 to -0.0250) 


Statistical Analysis 1 for Change in Proportion of Days With Analgesic Use Measured by an eDiary
Groups [1] PLACEBO 10MG BID + PLACEBO 45MG BID vs. TICAGRELOR 10MG BID + PLACEBO 45MG BID
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Mixed Models Analysis
Mean Difference (Final Values) [4] 0.1192
90% Confidence Interval 0.0350 to 0.2035
Standard Error of the Mean (0.05059)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Change in Proportion of Days With Analgesic Use Measured by an eDiary
Groups [1] PLACEBO 10MG BID + PLACEBO 45MG BID vs. TICAGRELOR 45MG BID + PLACEBO 10MG BID
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Mixed Models Analysis
Mean Difference (Final Values) [4] 0.0975
90% Confidence Interval 0.0155 to 0.1795
Standard Error of the Mean (0.04923)
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



4.  Other Pre-specified:   Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients)   [ Time Frame: Baseline through Week 12 ]

Measure Type Other Pre-specified
Measure Title Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients)
Measure Description To assess safety and tolerability of 2 different doses of ticagrelor versus placebo in patients with SCD
Time Frame Baseline through Week 12  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
PLACEBO 10MG BID + PLACEBO 45MG BID No text entered.
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.
TICAGRELOR 45MG BID + PLACEBO 10MG BID No text entered.

Measured Values
   PLACEBO 10MG BID + PLACEBO 45MG BID   TICAGRELOR 10MG BID + PLACEBO 45MG BID   TICAGRELOR 45MG BID + PLACEBO 10MG BID 
Participants Analyzed   30   26   30 
Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients) 
[Units: Number of patients]
     
Patients with any bleeding events   2   2   2 
Pts w/ any bleeding event requiring intervention   2   1   2 

No statistical analysis provided for Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Patients)



5.  Other Pre-specified:   Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events)   [ Time Frame: Baseline through Week 12 ]

Measure Type Other Pre-specified
Measure Title Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events)
Measure Description To assess safety and tolerability of 2 different doses of ticagrelor versus placebo in patients with SCD
Time Frame Baseline through Week 12  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
PLACEBO 10MG BID + PLACEBO 45MG BID No text entered.
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.
TICAGRELOR 45MG BID + PLACEBO 10MG BID No text entered.

Measured Values
   PLACEBO 10MG BID + PLACEBO 45MG BID   TICAGRELOR 10MG BID + PLACEBO 45MG BID   TICAGRELOR 45MG BID + PLACEBO 10MG BID 
Participants Analyzed   30   26   30 
Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events) 
[Units: Number of events]
     
Total number of bleeding events   2   2   2 
Maximum severity of bleeding event: Minor   0   1   0 
Max sever. of bleed event: Clin-relevant nonmajor   2   1   2 
Maximum severity of bleeding event: Major   0   0   0 

No statistical analysis provided for Number of Major Bleeding or Clinically Relevant Non-major Bleeding Events (Events)




  Serious Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
PLACEBO 10MG BID + PLACEBO 45MG BID No text entered.
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.
TICAGRELOR 45MG BID + PLACEBO 10MG BID No text entered.

Serious Adverse Events
    PLACEBO 10MG BID + PLACEBO 45MG BID   TICAGRELOR 10MG BID + PLACEBO 45MG BID   TICAGRELOR 45MG BID + PLACEBO 10MG BID
Total, Serious Adverse Events       
# participants affected / at risk   6/30 (20.00%)   6/26 (23.08%)   5/30 (16.67%) 
Blood and lymphatic system disorders       
Reticulocytopenia † 1       
# participants affected / at risk   0/30 (0.00%)   0/26 (0.00%)   1/30 (3.33%) 
# events   0   0   1 
Sickle cell anaemia with crisis † 1       
# participants affected / at risk   3/30 (10.00%)   5/26 (19.23%)   3/30 (10.00%) 
# events   7   6   3 
General disorders       
Local swelling † 1       
# participants affected / at risk   1/30 (3.33%)   0/26 (0.00%)   0/30 (0.00%) 
# events   1   0   0 
Hepatobiliary disorders       
Hepatic ischaemia † 1       
# participants affected / at risk   1/30 (3.33%)   0/26 (0.00%)   0/30 (0.00%) 
# events   1   0   0 
Infections and infestations       
Cellulitis † 1       
# participants affected / at risk   1/30 (3.33%)   0/26 (0.00%)   0/30 (0.00%) 
# events   1   0   0 
Gastroenteritis † 1       
# participants affected / at risk   2/30 (6.67%)   0/26 (0.00%)   1/30 (3.33%) 
# events   2   0   1 
Lower respiratory tract infection † 1       
# participants affected / at risk   0/30 (0.00%)   1/26 (3.85%)   0/30 (0.00%) 
# events   0   1   0 
Injury, poisoning and procedural complications       
Face injury † 1       
# participants affected / at risk   1/30 (3.33%)   0/26 (0.00%)   0/30 (0.00%) 
# events   1   0   0 
Musculoskeletal and connective tissue disorders       
Arthralgia † 1       
# participants affected / at risk   0/30 (0.00%)   1/26 (3.85%)   0/30 (0.00%) 
# events   0   2   0 
Back pain † 1       
# participants affected / at risk   1/30 (3.33%)   0/26 (0.00%)   0/30 (0.00%) 
# events   1   0   0 
Musculoskeletal chest pain † 1       
# participants affected / at risk   1/30 (3.33%)   0/26 (0.00%)   0/30 (0.00%) 
# events   1   0   0 
Nervous system disorders       
Headache † 1       
# participants affected / at risk   0/30 (0.00%)   1/26 (3.85%)   0/30 (0.00%) 
# events   0   1   0 
Respiratory, thoracic and mediastinal disorders       
Acute chest syndrome † 1       
# participants affected / at risk   0/30 (0.00%)   1/26 (3.85%)   1/30 (3.33%) 
# events   0   1   1 
Vascular disorders       
Vascular occlusion † 1       
# participants affected / at risk   1/30 (3.33%)   0/26 (0.00%)   0/30 (0.00%) 
# events   1   0   0 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 19.0




  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Brilinta Global Clinical Leader
Organization: AstraZeneca
phone: +46 31 776 10 00



Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02482298     History of Changes
Other Study ID Numbers: D5136C00008
First Submitted: June 17, 2015
First Posted: June 26, 2015
Results First Submitted: September 21, 2017
Results First Posted: December 14, 2017
Last Update Posted: December 14, 2017