Site 1404:

What is the problem/background?

Sickle cell disease (SCD) is a disease that can be passed on from both parents to a child. It affects the red blood cells that carry oxygen to the body. Normal red blood cells have a circular shape and are very flexible. For patients with SCD, their red blood cells can look like a sickle or crescent moon and become very stiff. These sickle-shaped red blood cells can get stuck in the blood vessels leading to early destruction of these abnormal red blood cells.

These blocked blood vessels and loss of red blood cells makes it hard for the blood to transport oxygen. The lack of oxygen can cause severe body pains, which is a key symptom of SCD. Before 2017, the only known medication approved for preventing painful episodes and other SCD problems was hydroxyurea. Hydroxyurea works by reducing the number of the sickle red blood cells.

What questions is the study trying to answer?

Crizanlizumab is a new medication that was manufactured to help reduce the frequency of painful crisis and hospitalizations that have a significant impact on the quality of life in patients with sickle cell disease. This study seeks to find whether the 5mg/kg of crizanlizumab works better than the placebo in reducing red blood cells sickling. A placebo is a medication with similar physical characteristics (color, packing) as the crizanlizumab but does not contain any active chemical ingredients that affect the body.

Where is the study taking place, how many people does it involve and how are they selected?

The study will be conducted in many centres across the world including the Kondele Children’s Hospital (KCH) in adolescents aged 12 years and above and adult patients aged 18 years and older. Globally, about 315 patients will be enrolled into the study. At KCH, about 30 patients are expected to be recruited into the study. All patients who fulfil the study enrolment criteria will be included in the research study.

What does the study involve for those who are in it?

For those who enroll in the study several tests will be done to determine their general state of health. Participants will have a two times chance to receive the crizanlizumab or the placebo in the first 52 weeks of the study after which they will all receive crizanlizumab up to the end of the 2 years. Crizanlizumab or placebo will be given as an infusion through the vein once a month for the entire duration of the study. These tests will include taking samples of blood and urine as well as tests to determine how the heart is functioning. In addition, regular medical assessments by the study doctor on the participant’s well-being, quality of life as well as for any side effects of the crizanlizumab will be done.

What are the benefits and risks/costs of the study for those involved?

The use of crizanlizumab may cause headaches, fever and vomiting. However, these last for a short duration and do not need medical treatment. During the process of blood sample collection, the participants may have discomfort due to the needle prick to collect the blood as well as bruising and swelling at the point of the needle prick. The research study will be done at no cost to the participants, and they will be reimbursed for their transport cost to and from the study site.

How will the study benefit society?

By participating in the study, the participants will help contribute to the new information on the dosage and usefulness of crizanlizumab in the management of SCD.

When does the study start and finish?

The study will start as soon as ethical approval is received. Duration of study participation for an individual patient may last up to 2 years and includes the screening period (up to 4 weeks before study treatment), the double-blind treatment period of the study for up to 52 weeks, participation in the open-label extension treatment period for up to week 103 and an End of Study (EOS) visit at 4 weeks after the last dose of study drug.

Trial Design:

This is a Phase III multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of crizanlizumab 5 mg/kg versus placebo, with or without concurrent HU/HC therapy in patients with SCD who experience frequent VOCs (4-12 events in the 12 months prior to the screening visit).

Purpose of the study:

The main purpose of this study is to determine whether crizanlizumab may reduce the number of VOCs when compared to placebo, with or without standard of care medications in adolescent and adult SCD patients with frequent VOCs leading to healthcare visits. The study duration will be approximately 2 years.

Study Rationale:

Crizanlizumab was first approved in the USA (BLA 761128) under the trade name Adakveo® on 15-Nov-2019. This BLA approval was based on the results from the Phase II Study CSEG101A2201 (SUSTAIN), a 52-week, randomized, placebo-controlled study (N=198) of crizanlizumab 2.5 and 5 mg/kg. In Study A2201, a vasoocclusive crises (VOC) was defined as an acute episode of pain with no other cause than a vasoocclusion, which required a visit to a medical facility and treatment with oral or parenteral opioids or parenteral non-steroidal anti-inflammatory drugs (NSAIDs). This included both uncomplicated VOCs as well as complicated VOCs such as acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism. These visits required a visit to a medical facility. An uncomplicated crisis was defined as a VOC that was not classified as acute chest syndrome, hepatic sequestration, splenic sequestration, priapism, and which did not lead to death.

Treatment with crizanlizumab 5 mg/kg in Study A2201 resulted in a median annual rate of VOCs leading to a healthcare visit that was 45.3% lower than the median annual rate with placebo, which was statistically significant (p=0.010). The median annual rate of uncomplicated crises and median number of days hospitalized were 62.9% and 41.8% lower than in the placebo group, respectively. These constitute meaningful reductions in the frequency of VOCs and hospitalizations that can be expected to have a significant impact on quality of life (QoL), morbidity and mortality in patients with SCD.

Study CSEG101A2301 is an ongoing Phase III, multicenter, randomized, double-blind study to assess efficacy and safety of two doses of crizanlizumab (5 mg/kg and 7.5 mg/kg) versus placebo, with or without hydroxyurea/ hydroxycarbamide therapy (HU/HC), in adolescent and adult patients with SCD. VOC was defined the same way as previously noted in the SUSTAIN trial.

In Dec-2022, the results of the primary analysis of Study CSEG101A2301 did not show evidence of superiority of either dose of crizanlizumab (5 mg/kg or 7.5 mg/kg) over placebo on the primary or key secondary endpoints and therefore are not consistent with the results from Study CSEG101A2201.

While the endpoint of VOC leading to a healthcare visit reflects a key aim of treatment in SCD, i.e., prevention/reduction of VOCs, it is important to note that it is dependent on patients making the decision to go or not go to the hospital. The different results in Study CSEG101A2301 compared with Study CSEG101A2201 could be due to various factors/differences between the studies, including but not limited to:

• The impact of the COVID-19 global pandemic, which may have caused a masking effect/reduction in reporting of VOCs as well as a potential reduction in triggers for VOCs in Study CSEG101A2301.
• Differences in the geographic location of participating patients, thereby factoring in the differences in healthcare utilization: patients were located primarily in the USA in Study CSEG101A2201 vs. globally dispersed in Study CSEG101A2301.

Thus, while the initial randomized, placebo-controlled trial (Study CSEG101A2201), the open label studies (Study SEG101A2202, Study SEG101B2201 and Study SEG101AUS05) and real-world data (MAP data and registries) have all demonstrated clinical benefit with crizanlizumab, the second, randomized, placebo-controlled Study CSEG101A2301 did not.

The current study (Study CSEG101A2303; hereafter referred to as Study A2303), a randomized, placebo-controlled Phase III study, was developed to overcome the uncertainties raised by the conflicting results of Studies CSEG101A2301 and CSEG101A2201. The purpose of this study is to compare the efficacy of crizanlizumab (5 mg/kg) versus placebo, with or without HU/HC in adolescent and adult SCD patients with frequent VOCs (4 to 12 per year) that are Health care practitioner-managed (including VOCs leading to management at a health care facility or those managed via remote consultation).

Data from this study will be used to evaluate the effect of crizanlizumab versus placebo, with or without concurrent HU/HC therapy, on VOC rate in SCD patients aged 12 years and older who experience frequent VOCs.

Study Population:

The study will include participants aged 12 years and older with confirmed diagnosis of SCD (all genotypes are eligible) who have experienced at least 4-12 VOCs that are HCP-managed (including VOCs leading to management at a health care facility or those managed via remote consultation) within the 12 months prior to the screening visit. Participants may receive HU/HC as a standard of care.

This study plans to enroll 315 participants. Participants will be randomized in a 2:1 ratio to the crizanlizumab 5 mg/kg or placebo treatment arm (see Section 9.9 of the Protocol v00 for more details on sample size determination).