RAISE: A Study of SHP655 (rADAMTS13) in Sickle Cell Disease
Study Details
Study Description
Brief Summary
SHP655 is a medicine used to treat sickle cell disease (SCD). The main aim of the study is to measure the safety and tolerability of SHP655 in SCD participants.
Study participants will receive SHP655 or placebo on Day 1. Their SCD will be treated by their doctor according to their doctor's usual clinical practice.
During the study, participants will be asked to follow-up on 13 days following SHP655 or placebo administration for safety assessment. Maximum duration of participation is expected to be about 2 months
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: SHP655 Participants with baseline SCD will receive a single intravenous (IV) infusion at one of the 3 dose levels of 40, 80 and 160 International units per kilogram (IU/kg) in a dose escalation manner for 14 days. |
Drug: SHP655
Participants will receive SHP655 as a single IV infusion at one of the 3 dose levels of 40 IU/kg, 80 IU/kg, or 160 IU/kg.
Other Names:
|
| Placebo Comparator: Placebo Participants will receive placebo matched to SHP655 of the 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg as single IV infusion for 14 days. |
Other: Placebo
Participants will receive placebo matched to SHP655 of the 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg as single IV infusion.
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From date of signing informed consent up to study completion (up to Day 31)]
An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this investigational product or medicinal product. An AE can therefore be any unfavorable and unintended sign (including a clinically significant laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not causality is suspected (ICH Guidance E2A 1995). A serious adverse event (SAE) is any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product or not and at any dose) which results in death, is life-threatening, requires inpatient hospitalization, prolongation of hospitalization, is an important medical event. Number of participants with AEs and SAEs will be assessed.
- Number of Participants With Binding and Inhibitory Antibodies to SHP655 [From start of study treatment up to study completion (up to Day 31)]
The number of participants will be summarized by dose for binding and inhibitory antibodies to SHP655 and will be reported as AEs. The study completion date is defined as the date on which the last participant in the study completes the final assessments.
Secondary Outcome Measures
- Incremental Recovery (IR) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
IR will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Observed Maximum Concentration (Cmax) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
Cmax will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Time to Reach Cmax (tmax) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
Tmax will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Terminal Half-Life (t1/2) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
Terminal half-life (t1/2) will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Mean Residence Time From Zero to Infinite (MRT0-Inf) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
MRT0-inf will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Mean Residence Time From Zero to 72 hours Post-dose (MRT0-72) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, and 72 hours post-dose]
MRT0-72 will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Area Under the Curve (AUC) From Zero to Time of Last Quantifiable Concentration (AUC0-Last) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
AUC0-last will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Area Under the Curve Time Curve (AUC) From Zero to 72 hours Post-dose (AUC0-72) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, and 72 hours post-dose]
AUC0-72 will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Area Under the Curve (AUC) From Zero to Infinite Time (AUC0-Inf) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
AUC0-inf will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Systemic Clearance (CL) of ADAMTS13 Activity and ADAMTS13 Antigen [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
Systemic clearance (CL) will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Volume of Distribution at Steady State (Vss) of ADAMTS13 Activity and ADAMTS13 Antigen. [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
Vss will be estimated for ADAMTS13 activity and ADAMTS13 antigen (ADAMTS13Ag) following SHP655 infusion.
- Von Willebrand Factor:antigen (VWF:Ag) [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
Plasma VWF:Ag a PD variable will be observed to evaluate the effect of SHP655 on VWF.
- Von Willebrand Factor:Ristocetin cofactor activity (VWF:RCo) [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
Plasma VWF:RCo a PD variable will be observed to evaluate the effect of SHP655 on VWF.
- Change From Baseline in Platelet Count up to Day 31 [Baseline up to Day 31]
Change from baseline in platelet count up to Day 31 will be assessed.
- Plasma Free Hemoglobin [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
The correlation of plasma free hemoglobin on SHP655 activity and VWF will be assessed.
- Plasma Thrombospondin Levels [Pre-dose, 15 minutes, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 744 hours post-dose]
The correlation of plasma free thrombospondin levels on SHP655 activity and VWF will be assessed.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age 18 to 65 years at the time of signing the informed consent.
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An understanding, ability, and willingness to fully comply with study procedures and requirements.
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Ability to voluntarily provide written, signed, and dated (personally or via a legally authorized representative) informed consent to participate in the study.
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Male or female with a documented history of HbSS or HbSβo thalassemia (based on clinical record of genetic, electrophoresis, or high-performance liquid chromatography testing).
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Participant currently taking hydroxyurea must be on a stable dosing for 3 months at screening.
Exclusion Criteria:
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The participant was diagnosed with acute VOC in the 21 days before dosing on Day 1.
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The participant has undergone blood transfusion within the last 30 days or blood transfusion on greater than or equal to (>=) 2 occasions in the last 90 days, at Screening Visit.
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The participant has a history of acquired or congenital thrombotic thrombocytopenic purpura.
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The participant has serum creatinine level greater than (>) 1.2 milligrams per deciliter (mg/dL).
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The participant has alanine transaminase >3* upper limit of normal (based on clinical laboratory normal range), direct bilirubin level >2 mg/dL, or indirect bilirubin level
5 mg/dL at the Screening Visit.
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The participant has a hemoglobin level <5 grams per deciliter (g/dL) at the Screening Visit.
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The participant has a platelet count of <100 000/cubic millimeter (mm^3) at the Screening Visit.
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Signs or symptoms of infection requiring treatment with IV antibiotics during the Screening Period.
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The participant has fever with body temperature of >=38.5 degree Celsius (ºC) (101.3 degree Fahrenheit [ºF]) at the Screening Visit or before dosing on Day 1.
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The participant has Acute Chest Syndrome (ACS), diagnosed or strongly suspected, as evidenced by a new infiltrate on chest radiograph, and one or more of the following criteria:
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Fever with body temperature >39°C (102.2°F)
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Hypoxia (confirmed by arterial blood gases with partial pressure of arterial oxygen (PaO2) <70 millimeter of mercury [mmHg])
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Chest pain
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Suspicious findings on physical examination (tachypnea, intercostal retraction, wheezing, and/or rales)
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The participant has recently (within the past 28 days, from Screening Visit) undergone major surgery, requires hospitalization, documented serious bacterial infection requiring antibiotic treatment, or significant bleeding.
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The participant has had a recent (within the past 90 days, from Screening Visit) episode of stroke, transient ischemic attack, symptomatic pulmonary hypertension, or seizure.
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Any history of hemorrhagic stroke or bleeding diathesis.
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The participant has received any of the following protocol-restricted medicines: a) systemic steroid therapy within 48 hours before dosing, or there is the expectation that such therapy may be given during the study (inhaled or topical steroids are allowed); b) Anticoagulant or antiplatelet therapy within the past 3 weeks before dosing; c) crizanlizumab within the past 30 days before dosing; d) voxelotor within the past 14 days before dosing.
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For participants receiving chronic or long-acting opioids, a change in dose or pain requiring medical attention in the past 14 days before dosing.
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The participant has a medical or psychiatric condition that, in the opinion of the investigator, may pose a risk to the participant for participation or interfere with the conduct or results of the study.
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The participant has received or plans to receive any other investigational agent within the 4 weeks prior to the study screening visit or during the course of the study.
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There is the expectation that the participant will not be able to be followed for the duration of the study.
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The participant is pregnant or lactating or a female of childbearing potential or male unable or unwilling to comply with birth control methods or abstinence until the end of study visit.
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The participant with active use of illicit drugs (excluding marijuana) and/or alcohol dependence, as determined by the investigator.
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The participant has been administered SHP655 previously.
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Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule ADAMTS-13, hamster protein, or other constituents of SHP655.
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The participant has a positive test result for hepatitis B surface antigen, or hepatitis C antibody, or human immunodeficiency virus (HIV) antigen/antibody, at the Screening Visit. However, a subject with a hepatitis C antibody and a negative hepatitis C virus ribonucleic acid (RNA) polymerase chain reaction test is not excluded.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Alabama at Birmingham | Birmingham | Alabama | United States | 35233 |
| 2 | Arkansas Children's Hospital | Little Rock | Arkansas | United States | 77202 |
| 3 | University of Colorado Sickle Cell Treatment and Research Center | Aurora | Colorado | United States | 80045 |
| 4 | Sickle Cell Center | Denver | Colorado | United States | 80262 |
| 5 | University of Illinois | Chicago | Illinois | United States | 60612-4325 |
| 6 | University Medical Center New Orleans | New Orleans | Louisiana | United States | 70112 |
| 7 | Ochsner Health System | New Orleans | Louisiana | United States | 70121 |
| 8 | Johns Hopkins University School Of Medicine | Baltimore | Maryland | United States | 21218 |
| 9 | Duke University Medical Center | Durham | North Carolina | United States | 27705 |
| 10 | East Carolina University | Greenville | North Carolina | United States | 27858 |
| 11 | Ohio State University Medical Center | Columbus | Ohio | United States | 43210 |
| 12 | Medical University of South Carolina (MUSC) | Charleston | South Carolina | United States | 29425 |
| 13 | University of Tennessee -- Memphis | Memphis | Tennessee | United States | 38163-2116 |
| 14 | VCU Health - Research Parent | Richmond | Virginia | United States | 23298 |
Sponsors and Collaborators
- Shire
- Takeda Development Center Americas, Inc.
Investigators
- Study Director: Study Director, Takeda
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- SHP655-101