A Study of SHP655 (rADAMTS13) in Sickle Cell Disease

Sickle Cell Disease Clinical Trial

— RAISE  

Official title:

A Phase 1 Randomized, Double-blind, Placebo-controlled, Multicenter, Ascending Dose, Safety and PK/PD Study of SHP655 (rADAMTS13) in Sickle Cell Disease at Baseline Health

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03997760
• Other study ID #: SHP655-101
• Status: Completed
• Phase: Phase 1
• Start date: October 21, 2019
• Est. completion date: October 26, 2022

Study information

• Verified date: April 2024
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

TAK-755 (previously known as 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 TAK-755 in SCD participants.

Study participants will receive TAK-755 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: October 26, 2022
• Est. primary completion date: October 26, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age 18 to 65 years at the time of signing the informed consent.

• An understanding, ability, and willingness to fully comply with study procedures and requirements.

• Ability to voluntarily provide written, signed, and dated (personally or via a legally authorized representative) informed consent to participate in the study.

• Male or female with a documented history of HbSS or HbSßo thalassemia (based on clinical record of genetic, electrophoresis, or high-performance liquid chromatography testing).

• Participant currently taking hydroxyurea must be on a stable dosing for 3 months at screening.

Exclusion Criteria:

• The participant was diagnosed with acute VOC in the 21 days before dosing on Day 1.

• 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.

• The participant has a history of acquired or congenital thrombotic thrombocytopenic purpura.

• The participant has serum creatinine level greater than (>) 1.2 milligrams per deciliter (mg/dL).

• 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.

• The participant has a hemoglobin level <5 grams per deciliter (g/dL) at the Screening Visit.

• The participant has a platelet count of <100 000/cubic millimeter (mm^3) at the Screening Visit.

• Signs or symptoms of infection requiring treatment with IV antibiotics during the Screening Period.

• 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.

• 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:

1. Fever with body temperature >39°C (102.2°F)

2. Hypoxia (confirmed by arterial blood gases with partial pressure of arterial oxygen (PaO2) <70 millimeter of mercury [mmHg])

3. Chest pain

4. Suspicious findings on physical examination (tachypnea, intercostal retraction, wheezing, and/or rales)

• 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.

• 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.

• Any history of hemorrhagic stroke or bleeding diathesis.

• 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.

• For participants receiving chronic or long-acting opioids, a change in dose or pain requiring medical attention in the past 14 days before dosing.

• 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.

• 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.

• There is the expectation that the participant will not be able to be followed for the duration of the study.

• 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.

• The participant with active use of illicit drugs (excluding marijuana) and/or alcohol dependence, as determined by the investigator.

• The participant has been administered SHP655 previously.

• Known life-threatening hypersensitivity reaction, including anaphylaxis, to the parent molecule ADAMTS-13, hamster protein, or other constituents of SHP655.

• 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 participant with a hepatitis C antibody and a negative hepatitis C virus ribonucleic acid (RNA) polymerase chain reaction test is not excluded.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• TAK-755
Participants will receive TAK-755 as a single IV infusion at one of the 3 dose levels of 40 IU/kg, 80 IU/kg, or 160 IU/kg.

Other:
• Placebo
Participants will receive placebo matched to TAK-755 of the 3 dose levels of 40 IU/kg, 80 IU/kg, and 160 IU/kg as single IV infusion.

Locations

Country	Name	City	State
United States	University of Colorado Sickle Cell Treatment and Research Center	Aurora	Colorado
United States	Johns Hopkins University School Of Medicine	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Medical University of South Carolina (MUSC)	Charleston	South Carolina
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Illinois	Chicago	Illinois
United States	Ohio State University Medical Center	Columbus	Ohio
United States	Sickle Cell Center	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	East Carolina University	Greenville	North Carolina
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Tennessee -- Memphis	Memphis	Tennessee
United States	Ochsner Health System	New Orleans	Louisiana
United States	VCU Health - Research Parent	Richmond	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Shire	Takeda Development Center Americas, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious (TEAEs)	An adverse event (AE) was 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 (IP) or medicinal product. TEAEs were defined as AEs that started or worsened in severity on or after the infusion of IP. A serious TEAEs was any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product or not and at any dose) which resulted in death, was life-threatening, required inpatient hospitalization, prolongation of hospitalization, was an important medical event. TEAEs included both serious and non-serious AEs.	From date of signing informed consent up to end of study visit (Day 28)
Primary	Number of Participants Who Developed Positive Binding Anti-ADAMTS13 and Inhibitory Anti-ADAMTS13 Antibodies to TAK-755	Measurement of Anti-ADAMTS13 antibodies can be used to assess whether the body's immune system has been stimulated to react to TAK-755. Binding Anti-ADAMTS13 antibodies measure antibodies that are able to bind to ADAMTS13, whether or not the antibodies have an effect on how well ADAMTS13 works. An inhibitory Anti-ADAMTS13 antibody is antibody that both binds to ADAMTS13 and able to affect how well ADAMTS13 works. Binding and Inhibitory anti-ADAMTS13 antibodies were categorized as pre-existing, treatment-induced, and treatment-boosted. Pre-existing: anti-ADAMTS13 antibodies were detected in the baseline sample prior to infusion with TAK-755. Treatment-induced: no anti-ADAMTS13 antibodies were detected in baseline sample but were detected in any sample drawn after TAK-755 infusion. Treatment-boosted: anti-ADAMTS13 antibodies were pre-existing and were detected at any time after TAK-755 infusion at titers that were at least 4 steps higher than the titers detected before TAK-755 infusion.	From date of signing informed consent up to end of study visit (Day 28)
Secondary	Incremental Recovery (IR) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	IR was defined as the ratio of maximum increase in plasma ADAMTS13 antigen or activity level to TAK-755 dose per body weight. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall. Here "IU/mL/IU/kg" refers to "International units per milliliter per international units per kilogram".	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Observed Maximum Concentration (Cmax) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	Cmax was a measure of the maximum amount of drug in the plasma after the dose was given. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Time to Reach Cmax (Tmax) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	Tmax was a measure of the time to reach the maximum concentration in the plasma after the drug dose. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Terminal Half-Life (t1/2) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	t1/2 was the time required for a given drug concentration in the plasma to decrease by 50%. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Mean Residence Time From Zero to Infinite (MRT0-Inf) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	The MRT is the average time that the study product stays in the body (or plasma). The MRT0-Inf is defined as the average time from zero (pre-dose) extrapolated to infinite time (MRT0-inf). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Mean Residence Time From Zero to 72 Hours Post-dose (MRT0-72) of ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	The MRT is the average time that the study product stays in the body (or plasma) and The MRT0-72 is defined as the average time from zero (predose) to 72 hours post-dose (MRT0-72). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, and 72 hours post-dose
Secondary	Area Under the Curve From Zero to Time of Last Quantifiable Concentration (AUC0-Last) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	AUC0-Last was an area under the concentration-time curve from zero (pre-dose) to time of last quantifiable concentration. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Area Under the Curve Time Curve From Zero to 72 Hours Post-dose (AUC0-72) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	AUC0-72 was an area under the concentration-time curve from zero (predose) to 72 hours post-dose (AUC0-72). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, and 72 hours post-dose
Secondary	Area Under the Curve From Zero to Infinite Time (AUC0-Inf) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	AUC0-inf was area under the concentration-time curve from zero (pre-dose) extrapolated to infinite time. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Systemic Clearance (CL) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the plasma Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Volume of Distribution at Steady State (Vss) for ADAMTS13 Activity and ADAMTS13 Antigen of TAK-755	Vss is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by MRT(0-inf)*CL. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the first dose of TAK-755. Baseline-adjusted values were used for this analysis. Baseline-adjusted values at each timepoint were calculated as the measured value minus the pre-infusion (baseline) value and results were summarized overall.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Change From Baseline in Von Willebrand Factor: Antigen (VWF:Ag) at Specified Timepoints	Von Willebrand factor (vWF or VWF) is a protein that is one of several components of the coagulation system that work together to stop bleeding within the body. VWF:Ag measures the level of von Willebrand factor protein in the blood. The change from baseline in VWF:Ag concentration was measured at different time points. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Change from baseline was calculated by subtracting the baseline value from the post-dose value.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Change From Baseline in Von Willebrand Factor:Ristocetin Cofactor Activity (VWF:RCo) At Specified Timepoints	Von Willebrand factor (vWF or VWF) is a protein that is one of several components of the coagulation system that work together, to stop bleeding within the body. VWF:RCo assay is a test that measures the activity of the VWF in a plasma sample in terms of how well it is able to clump platelets together in the presence of the antibiotic ristocetin. Change from baseline in vWF:RCo concentration was measured at different timepoints. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Change from baseline was calculated by subtracting the baseline value from the post-dose value.	Baseline (Pre-dose), 0.25, 1, 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Change From Baseline in Platelet Count at Specified Timepoints	Blood samples were collected to analyze platelet count. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Thechange from baseline was calculated by subtracting the baseline value from the post-dose value.	Baseline (Pre-dose), 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Change From Baseline in Plasma Free Hemoglobin at Specified Timepoints	The plasma free hemoglobin test measures the level of hemoglobin in the plasma (that is, not contained within the red blood cells). Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Change from baseline was calculated by subtracting the baseline value from the post-dose value.	Baseline (Pre-dose), 3, 8, 24, 72, 120, 168, 216, 288, and 648 hours post-dose
Secondary	Change From Baseline in Plasma Thrombospondin Levels at Specified Timepoints	Change from baseline in plasma thrombospondin levels over time was reported. Baseline was defined as the last non-missing measurement obtained prior to the date and time of the dose of IP. Change from baseline was calculated by subtracting the baseline value from the post-dose value.	Baseline (Pre-dose), 3, 8, 24, 72, 120, 168, 288, and 648 hours post-dose

External Links

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