A Study of Prasugrel in Pediatric Participants With Sickle Cell Disease (SCD)

A Phase 3, Double-Blind, Randomized, Efficacy and Safety Comparison of Prasugrel and Placebo in Pediatric Patients With Sickle Cell Disease.

The main purpose of the study is to evaluate the efficacy and safety of the study drug known as prasugrel for the reduction of Vaso-Occlusive Crisis events in pediatric participants with sickle cell disease. The study will also investigate reduction in daily pain in children who have sickle cell disease.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Placebo; Drug: Prasugrel

Detailed Description

The submission database was validated for data reported through the data cutoff date for the submission database lock (SDBL). The SDBL data cutoff was 17 July 2015 for all participants except for 2 in the youngest age group, for whom the SDBL data cutoff occurred on 08 August 2015. The data cutoff date for SDBL corresponds to the primary completion date for the study. The SDBL occurred on 31 August 2015.

The study was stopped following SDBL and review of the topline information indicated that the primary and secondary efficacy endpoints were not met. Subsequently, the Sponsor requested that participants discontinue study drug immediately and that discontinuation visits for all active study participants be conducted as soon as feasible.

After the data cutoff date for SDBL, the Sponsor continued to collect safety data through the final participants contact; some additional efficacy data were collected through the final visit. The last patient visit (LPV) occurred on 17 December 2015, which corresponds to the study completion date and led to the planned supplemental database lock (PSDBL) on 22 January 2016. This supplemental data base was originally designed to capture additional blinded and randomized information to enhance safety data for labeling should the study have been positive.

The safety information contained in this record reflects the entire safety information and reflects the information from the supplemental data base lock in January of 2016. The efficacy information contained in this record reflects the information collected through primary completion date in the submission database. Primary analyses of the major efficacy objectives were repeated using the entire double-blind period data from the PSDBL and did not change the original conclusions and were consistent with the results from the original efficacy analyses included in the SDBL.

• Study Type: Interventional
• Enrollment (Actual): 341
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1200
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Montegnee, Belgium, 4420
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Brazil
  • Rio De Janeiro, Brazil, 20211-030
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Egypt
  • Alexandria, Egypt, 21131
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Cairo, Egypt, 11566
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Fayoum, Egypt, 63514
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Ismailia, Egypt
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Mansoura, Egypt, 35516
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Zagazig, Egypt, 44519
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Ghana
  • Agogo, Ghana
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Korle Bu, Ghana
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Italy
  • Genova, Italy, 16128
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Modena, Italy, 40124
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Monza, Italy, 20900
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Padova, Italy, 35138
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Verona, Italy, 37126
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Kenya
  • Busia, Kenya, 40100
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Kisumu, Kenya
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Kombewa, Kenya
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Nairobi, Kenya
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Lebanon
  • Beirut, Lebanon, 5244
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Oman
  • Muscat, Oman, 123
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Saudi Arabia
  • Jeddah, Saudi Arabia, 21859
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• Turkey
  • Balcali Adana, Turkey, 01330
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Mersin, Turkey, 33079
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• United Arab Emirates
  • Abu Dhabi, United Arab Emirates
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• United Kingdom
  • London, United Kingdom, SE1 7EH
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • Manchester, United Kingdom, M13 9WL
    • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • London
    • Tooting, London, United Kingdom, SW17 0QT
      • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
• United States
  • California
    • Oakland, California, United States, 94609
      • Children's Hospital of Oakland
    • Palo Alto, California, United States, 94304
      • Stanford Univ Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20060
      • Howard University Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Savannah, Georgia, United States, 31404
      • Memorial Health University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Childrens Hospital of Michigan
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • New York
    • Bronx, New York, United States, 10467
      • Albert Einstein College Of Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of NC at Chapel Hill School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Childrens Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19134
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19134
      • St Christophers Hospital For Children
    • Pittsburgh, Pennsylvania, United States, 15224
      • Childrens Hospital of Pittsburgh
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St Jude Childrens Research Hospital
  • Washington
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Have SCD [homozygous sickle cell (HbSS) or hemoglobin (HbS) Beta^0 thalassemia]
• Are participants with SCD who have had ≥2 episodes of vaso-occlusive crisis (VOC) in the past year
• Have a body weight ≥19 kilograms (kg) and are ≥2 and <18 years of age, inclusive at the time of screening
• If participants are ≥2 and ≤16 years of age, must have had a transcranial Doppler within the last year

Exclusion Criteria:

• History of: transient ischemic attack (TIA)/ ischemic or hemorrhagic stroke, severe head trauma, intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm
• History of abnormal or conditional [velocity in middle or anterior cerebral, or internal carotid artery ≥170 centimeter per second (cm/sec)] transcranial Doppler within the last year
• History of, or are undergoing treatment with, chronic red blood cell (RBC) transfusion therapy
• Are at an increased risk for bleeding complications
• Are receiving chronic treatment with nonsteroidal anti-inflammatory drug (NSAID)s and cannot be switched to another analgesic

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prasugrel; Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Drug: Prasugrel; Administered orally; Other Names: Effient; LY640315; Efient
Placebo Comparator: Placebo; Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.	Drug: Placebo; Administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Vaso-Occlusive Crisis (VOC) Events Per Participant Per Year (Rate of VOC)	The VOC is a composite endpoint of painful crisis or acute chest syndrome. Events that occurred within 7 days from the prior event onset date were not counted as a new episode. Data collected through the primary completion date reported below.	Randomization through 24 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Monthly Rate of Days With Pain	Monthly rate of days with pain was measured through participant diaries using a modified version of the Faces Pain Scale-Revised (FPS-R). Each day participants selected the face on the scale that reflected their worst pain related to sickle cell disease (SCD) on that day. This pain scale contains six faces corresponding to the pain intensity of 0, 2, 4, 6, 8 or 10, in which 0 denotes no pain and 10 denotes the worst pain possible. Any day the participant selected a face other than face 0 was considered a day with pain. Monthly rate of days with pain was calculated for each participant by summing the number of days reported with any pain divided by the number of non-missing diary entries completed in the month. A month was defined as 4 weeks (28 days).The monthly rate was set to missing if there were more than 14 missing entries for the FPS-R in a specific month. Data collected through the primary completion date are present below.	Randomization through 9 Months
Monthly Mean in Faces Pain Scale-Revised Score	Each day participants selected the face on the FPS-R scale that reflected their worst pain related to sickle cell disease (SCD) on that day. Monthly mean in FPS-R score was calculated for each participant by summing the FPS-R score divided by the number of non-missing diary entries completed in the month. This pain scale contains six faces corresponding to the pain intensity of 0, 2, 4, 6, 8 or 10, in which 0 denotes no pain and 10 denotes the worst pain possible. A month was defined as 4 weeks (28 days). The monthly mean in FPS-R score was set to missing if there were more than 14 missing entries for the FPS-R in a specific month. Data collected through the primary completion date are presented below.	Randomization through 9 Months
Number of Painful Crisis Events Per Participant Per Year (Rate of Painful Crisis)	A painful crisis is defined as an onset of moderate to severe pain that lasts at least 2 hours for which there is no explanation other than vaso-occlusion and which requires therapy with oral or parenteral opioids, ketorolac, or other analgesics prescribed by a health care provider (HCP) in a medical setting such as a hospital, clinic, emergency room visit, or telephone management. The painful crisis that occurred within 7 days from the prior event onset date was not counted as a new episode. Data collected through the primary completion date are presented below.	Randomization through 24 Months
Number of Hospitalizations for VOC Per Participant Per Year (Rate of Hospitalizations)	Hospitalization that occurred within 7 days of the prior event onset date were not counted as a new episode. Data collected through the primary completion date are presented below.	Randomization through 24 Months
Number of Acute Chest Syndrome Per Participant Per Year (Rate of Acute Chest Syndrome)	Acute chest syndrome was defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray. Acute chest syndrome that occurred within 7 days of the prior event onset date was not counted as a new episode. Data collected through the primary completion date are presented below.	Randomization through 24 Months
Number of Red Blood Cell (RBC) Transfusions Due to Sickle Cell Disease (SCD) Per Participant Per Year (Rate of RBC Transfusions)	RBC transfusions that occurred within 7 days of the prior event onset date were not counted as a new episode. Data collected through the primary completion date are presented below.	Randomization through 24 Months
Monthly Rate of Days of Analgesic Use	Monthly rate of days of analgesic use was measured through participant diaries and was calculated for each participant by summing the number of days they reported analgesic use divided by the number of diary entries completed in the month. A month was defined as 4 weeks (28 days). The monthly rate was set to missing if there were more than 14 missing entries for analgesic use in a specific month. Data collected through the primary completion date are presented below.	Randomization through 9 Months
Quarterly Rate of School Absence Due to Sickle Cell Pain	Quarterly rate of school absence due to sickle cell pain was measured through participant diaries and was calculated for each participant by summing the number of days with school absence due to sickle cell pain divided by the number of school dates in the quarter. A quarter was defined as 12 weeks. The quarterly rate was set to missing if there were more than 6 weeks of missing diary entries during a specific quarter. Data collected through the primary completion date are presented below.	Randomization through 9 Months
Time to First Transient Ischemic Attack (TIA)/Ischemic Stroke		Randomization through 24 Months
Number of Days Hospitalized for VOC	The total length of hospitalization in days for VOC was calculated for each participant. Data collected through the primary completion date are presented below.	Randomization through 24 Months
Time From Randomization to First and Second VOC	Data collected through the primary completion date are presented below.	Randomization to First VOC and Second VOC respectively (up to 24 Months)
Percentage of Participants With Hemorrhagic Events Requiring Medical Intervention	Medical intervention was defined as any medical evaluation resulting in therapy or further investigation, as determined by a trained medical professional. Data collected from the first dose of study medication through 10 days after last dose of study medication during the double blind study period are presented below.	First Dose through 24 Months

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Collaborators: Daiichi Sankyo, Inc.

Publications and helpful links

General Publications

• Heeney MM, Hoppe CC, Abboud MR, Inusa B, Kanter J, Ogutu B, Brown PB, Heath LE, Jakubowski JA, Zhou C, Zamoryakhin D, Agbenyega T, Colombatti R, Hassab HM, Nduba VN, Oyieko JN, Robitaille N, Segbefia CI, Rees DC; DOVE Investigators. A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events. N Engl J Med. 2016 Feb 18;374(7):625-35. doi: 10.1056/NEJMoa1512021. Epub 2015 Dec 8.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: February 14, 2013
• First Submitted That Met QC Criteria: February 14, 2013
• First Posted (Estimate): February 18, 2013

Study Record Updates

• Last Update Posted (Actual): September 25, 2019
• Last Update Submitted That Met QC Criteria: September 10, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride
• Other Study ID Numbers: 13038; H7T-MC-TADO (Other Identifier: Eli Lilly and Company); 2012-003837-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• IPD Sharing Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.