Pharmacy and Poisons Board: Applications

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Protocol No:

ECCT/23/09/02

Date of Protocol:

06-02-2023

Study Title:	A PHASE IB, RANDOMIZED, PLACEBO-CONTROLLED STUDY EVALUATING THE SAFETY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF CROVALIMAB FOR THE MANAGEMENT OF ACUTE UNCOMPLICATED VASO‑OCCLUSIVE EPISODES (VOE) IN PATIENTS WITH SICKLE CELL DISEASE (SCD)
Study Objectives:	This study will evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of crovalimab compared with placebo for the management of acute uncomplicated VOE in patients with SCD. The safety objective for this study is to evaluate the safety of crovalimab compared with placebo on the basis of the following endpoints: - Incidence and severity of adverse events, with severity determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE v5.0) - Change from baseline in targeted vital signs and clinical laboratory test results - Incidence and severity of infusion-related reactions and hypersensitivity The PK objective for this study is to characterize the crovalimab PK profile on the basis of the following endpoints: - Serum concentrations of crovalimab over time - Relationships between drug exposure and pharmacodynamics, efficacy or safety endpoints of crovalimab (patients randomized to crovalimab) The PD objective for this study is to evaluate PD biomarkers that can provide evidence of crovalimab activity, on the basis of the following endpoints: - Change over time in PD biomarkers, including total complement activity (CH50) measured by a LIA, total and free complement component 5 (C5) concentration, and sC5b-9 concentration The efficacy objective for this study is to characterize the efficacy of crovalimab compared with placebo on the basis of the following endpoints: Time to improvement of the primary acute uncomplicated VOE (for definition, see Section 2.4.1) from baseline, defined as the first achieved from the following criteria: - Confirmed decrease in pain score of at least 2 points from the maximal pre-dose pain score, that is sustained in at least two pain assessments conducted a minimum of 6 hours apart from each other (as measured with the Numerical Rating Scale [NRS] on a 010 scale) AND transition to oral pain medications for a minimum of 6 hours after the completion of the last dose of parenteral opioids, OR - Readiness for hospital discharge (as defined by the patient’s assessment that pain can be managed at home AND agreement from investigator), OR - Hospital discharge Total cumulative opioid dose (parenteral and oral) in morphine equivalents per kilogram units (MEU/kg) from baseline to the time of acute uncomplicated VOE improvement Time to discontinuation of all parenteral opioids from baseline (defined as time from baseline to the completion of the last dose of parenteral opioids) Time to readiness for hospital discharge from baseline Time to hospital discharge from baseline Time to a confirmed decrease in pain score of at least 2 points from the maximal pre-dose pain score, that is sustained in at least two assessments conducted a minimum of 6 hours apart from each other, as measured with the NRS on a 010 scale Change in pain score from the maximal pre-dose pain score to the score at hospital discharge, as measured with the NRS on a 010 scale Proportion of patients who develop ACS from baseline to Day 28 Proportion of patients requiring intensive care unit (ICU)/critical care admission for SCD-related complications from baseline to the time of hospital discharge Proportion of patients requiring blood transfusion for SCD-related complications from baseline to the time of hospital discharge Readmission rate for a VOE or VOE-related event within 28 days of discharge of the primary acute uncomplicated VOE The immunogenicity objective for this study is to evaluate the immune response to crovalimab on the basis of the following endpoints: - Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study (patients randomized to crovalimab) - Potential effects of ADAs on efficacy, safety, or PK endpoints The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that are predictive of response to crovalimab (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), are associated with resistance to crovalimab, are associated with susceptibility to developing adverse events or can lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), or can increase the knowledge and understanding of disease biology and drug safety, on the basis of the following endpoints: - Observed value and change over time in exploratory biomarkers including but not limited to markers of hemolysis, immune cell activation, inflammation, endothelial/vascular damage, and end-organ injury - Relationship between biomarkers in blood and efficacy, safety, pharmacokinetics, immunogenicity, or other biomarker endpoints
Laymans Summary:	This randomized, multicenter, placebo-controlled, double-blinded Phase Ib study is designed to evaluate the safety (primary study objective), pharmacokinetics, pharmacodynamics, and efficacy of crovalimab compared with placebo for the management of an acute uncomplicated VOE in adult and adolescent patients with SCD. This study will enroll approximately 30 patients (at approximately 10-15 sites globally), aged 12-55 years old and more than or equal to 40 kg, with SCD genotype of HbSS or HbS beta zero thalassemia, presenting to the ER/ED or acute medical facility with an acute uncomplicated VOE (as defined in Section 2.4.1 of the protocol). Patients who present with acute complications such as ACS, priapism, hepatic or splenic sequestration etc., or present with pain atypical of or unrelated to an acute uncomplicated VOE will be excluded at screening. Complications of the VOE that develop after study treatment administration and during hospitalization will be documented. Patients who develop complications after screening, but before study treatment administration, may no longer be eligible.
Abstract of Study:	PROTOCOL NUMBER: BO42452 STUDY NAME: Crosswalk A VERSION NUMBER: 3 (Africa) TEST COMPOUND(S): Crovalimab (RO7112689) This randomized, multicenter, placebo-controlled, double-blinded Phase Ib study is designed to evaluate the safety (primary study objective), pharmacokinetics, pharmacodynamics, and efficacy of crovalimab compared with placebo for the management of an acute uncomplicated VOE in adult and adolescent patients with SCD. This study will enroll approximately 30 patients (at approximately 10-15 sites globally), aged 12-55 years old and more than or equal to 40 kg, with SCD genotype of sickle cell anemia (HbSS) or SCD genotype of sickle cell beta zero thalassemia, presenting to the emergency room/emergency department (ER/ED) or acute medical facility with an acute uncomplicated VOE, defined as an acute episode of pain with no other medically determined cause, that requires admission to a hospital/acute medical facility and treatment with parenteral opioid analgesics. A 2-step process for screening procedures is encouraged to preliminarily identify and consent patients for the study prior to VOE presentation: Screen Visit #1 (initial screen) is conducted at an outpatient visit (i.e., when the patient is not experiencing a VOE), where the main Informed Consent Form (ICF) is signed, and preliminary eligibility is assessed. During this visit, preliminary screening assessments can be conducted, and a steady state SCD exploratory biomarker sample will be collected (only after consent is received). Eligibility at Screen Visit #1 does not guarantee eligibility at Screen Visit #2. Screen Visit #2 (VOE presentation screen) is then conducted when the patient presents with a VOE to the ER/ED or acute medical facility. The patient consent from Screen Visit #1 must be confirmed prior to starting study assessments (this confirmation must be documented). Once patient consent is confirmed all remaining eligibility criteria must be assessed, and all screening assessments will be conducted. NUMBER OF PATIENTS Approximately 30 patients (20 on crovalimab and 10 on placebo). END OF STUDY The end of this study is defined as the date when the last patient’s last visit occurs, or the date at which the last data point is received from the last patient on study, whichever occurs later. The end of the study is expected to occur approximately 322 days or approximately 10.5 months after the last patient is enrolled. LENGTH OF STUDY Assuming an enrollment period of approximately 2 years, the total length of the study, from screening of the first patient in the ER/ED or acute medical facility to the end of the study, is expected to be approximately 3 years.