| Protocol No: | ECCT/23/10/01 | Date of Protocol: | 06-02-2023 |
| Study Title: |
A RANDOMIZED DOUBLE-BLIND PHASE IIA STUDY EVALUATING THE EFFICACY, SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF CROVALIMAB AS ADJUNCT TREATMENT IN PREVENTION OF VASO-OCCLUSIVE EPISODES (VOE) IN SICKLE CELL DISEASE (SCD) (CROSSWALK-c)
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| Study Objectives: |
- Annualized rate of home VOE (defined in Section 4.5.1.5) captured by patient report on a handheld device at home
- Annualized rate of uncomplicated medical facility VOE as defined in Section 4.5.1.2
- Annualized rate of ACS as defined in Section 4.5.1.3
- Annualized rate of days hospitalized for medical facility VOE (defined in Section 4.5.1.1)
- Annualized rate of days hospitalized for treatment of non-VOE complications of SCD (defined in Section 4.5.1.7)
- Change in hematologic measures from baseline to Week 49
- Time to first medical facility VOE from randomization as defined in primary efficacy endpoint (Section 4.5.1.1)
- Change in urinary albumin-creatinine ratio from baseline to Week 49
- Change from baseline to Week 49 in tricuspid regurgitant jet velocity (TRV)
- Proportion of patients with TRV more than 2.5 m/s at Week 49
- Change from baseline to Week 49 in Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults
- Combined rate of VOEs leading to medical facility visit (defined in Section 4.5.1.1) or treated only at home (defined in Section 4.5.1.5)
- Annualized rate of home VOE (defined in Section 4.5.1.5) captured by patient recall at study clinic visits
- Annualized number of RBC transfusions
- Endpoints collected during any medical facility VOE (defined in Section 4.5.1.1) and requiring hospitalization between baseline visit and Week 49:
– Re-admission rate for a subsequent medical facility VOE within 28 days of
discharge
– Duration in days of hospitalization for each medical facility VOE
– Need for RBC transfusion during admission for each medical facility VOE
- Change from baseline to Week 49 in the scores of the following PROs:
- Emotional impact and stiffness impact as assessed by the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) in adults
- Physical functioning as assessed by the PROMIS Physical Function in adults
- Physical functioning as assessed by the Pediatric Quality of Life Inventory (PedsQL) Core in adolescents
- Fatigue as assessed by the PROMIS Pediatric Fatigue in adolescents
- Incidence and severity of adverse events with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events,
Version 5.0 (NCI CTCAE v5.0)
- Change from baseline in targeted vital signs and clinical laboratory test results of clinical significance
- Incidence and severity of injection-site reactions, infusion-related reactions (IRRs), hypersensitivity, and infections (including meningococcal meningitis)
- Serum concentrations of crovalimab over time
- To evaluate potential relationships between drug exposure, pharmacodynamics, efficacy, and safety of crovalimab (in patients randomized to crovalimab)
- Prevalence of ADAs at baseline and incidence of ADAs during the study (patients randomized to crovalimab)
- To evaluate the potential effects of ADA on PD, efficacy, safety, and PK endpoints
- Change over time in PD biomarkers, including CH50 measured by a LIA, total and free C5 concentrations, and sC5b-9 concentration
- Change over time in additional 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 urine and efficacy, safety, PK, immunogenicity, or other biomarker endpoints
- Change in biomarkers collected during hospitalization for medical facility VOE, from baseline to discharge
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| Laymans Summary: | This study is designed to evaluate the efficacy, safety and pharmacokinetics of crovalimab compared with placebo as adjunct therapy in the prevention of VOEs in participants with SCD.
This randomized, multicenter, placebo-controlled, double-blinded Phase IIa study is designed to evaluate the efficacy, safety, and pharmacokinetics of crovalimab compared with placebo as adjunct therapy in the prevention of VOE in patients with SCD. The study will enroll approximately 90 patients at approximately 30 sites globally. The screening period of the study will be up to 28 days in length. Patients who do not meet the criteria for participation in this study (screen failure) may qualify for two rescreening opportunities (for a total of three screenings per patient) at the investigator’s discretion.
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| Abstract of Study: |
PROTOCOL NUMBER: BO42451
STUDY NAME: Crosswalk c
VERSION NUMBER: 2 (Africa)
TEST COMPOUND(S): Crovalimab (RO7112689)
This randomized, multicenter, placebo-controlled, double-blinded Phase IIa study is designed to evaluate the efficacy, safety, and pharmacokinetics of crovalimab compared with placebo as adjunct therapy in the prevention of VOE in patients with SCD. The study will enroll approximately 90 patients at approximately 30 sites globally. The screening period of the study will be up to 28 days in length. Patients who do not meet the criteria for participation in this study (screen failure) may qualify for two rescreening opportunities (for a total of three screenings per patient) at the investigator’s discretion.
Eligible patients will be randomized 1:1 to receive either crovalimab or placebo in addition to their current SCD therapy. Patients in both treatment arms will receive standard treatment for SCD as guided by the treating physician and/or institutional guidelines, including but not limited to treatments currently approved for SCD within each country participating in this study (e.g., hydroxyurea, L-glutamine, crizanlizumab, or voxelotor), pain management treatment (e.g., opioid analgesics, NSAIDs), hydration, oxygen, and other best supportive care (BSC).
Stratification factors at randomization are:
- Number of VOEs in the 12 months prior to enrollment (less than 4 vs. more than or equal to 4 VOEs)
- Use of concurrent SCD-directed therapy in any combination (e.g., hydroxyurea, L-glutamine, crizanlizumab, or voxelotor) (yes vs. no)
The primary analysis will be performed when all patients have either completed 48 weeks of the study treatment (refers to crovalimab or placebo) or have discontinued from the study, whichever occurs first.
An initial crovalimab (or matching placebo) intravenous (IV) loading dose will be administered on Week 1 Day 1 followed by 4 weekly subcutaneous (SC) doses of the study treatment on Week 1 Day 2, then on Weeks 2, 3, and 4. Maintenance dosing will begin at Week 5 and will continue every 4 weeks (Q4W) thereafter, for a total of 48 weeks of treatment. All patients will receive the study treatment according to a weight-based tiered dosing schedule. Study treatment dosing will continue per protocol schedule during any medical facility or home VOE occurring on treatment.
For patients who discontinue from study treatment, a safety follow-up visit will be conducted at 24 weeks after the last dose of study treatment, and a safety follow-up telephone call will be conducted at 46 weeks after the last dose of study treatment.
NUMBER OF PATIENTS
Approximately 90 patients with SCD will be randomized in this study.
END OF STUDY
The end of this study is defined as the date when the last patient, last visit, occurs, which is defined as completion of 48 weeks of the study treatment, followed by the end of safety follow-up period of 46 weeks. The end of the study is expected to occur approximately 2 years after the last patient is enrolled. In addition, the study treatment may be discontinued, the patient may discontinue from the study, or the Sponsor may decide to terminate the study or discontinue a site at any time.
LENGTH OF STUDY
The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 3.5 years.
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