E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Sickle Cell Disease with Vaso-Occlusive Crisis |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040644 |
E.1.2 | Term | Sickle cell disease |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002077 |
E.1.2 | Term | Anaemia sickle cell |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To confirm and establish appropriate dosing of crizanlizumab in patients ages 6 months to <18
years at the time of study entry (Part A and B)
- To evaluate the safety of crizanlizumab in patients ages 6 months to <18 years at the time of study entry (Parts A and B) |
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E.2.2 | Secondary objectives of the trial |
- To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
- To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
- To characterize long-term PK and PD of crizanlizumab in patients ages 6 months to <18 years at the time of study entry |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Male or female patients aged 2 to <18 years (Group 3 will be expanded to allow enrolment of patients aged 6 to <24 months (and at least 6 kg) in Part B once the appropriate dose is confirmed in 2 to <6 year old patients)
•Confirmed diagnosis of sickle cell disease (SCD) (e.g. any genotype including HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia, and others) by hemoglobin electrophoresis or high performance liquid chromatography (HPLC) performed locally.
•Experienced at least 1 VOC within the preceding 12 months, as determined by medical history. Prior VOC must have resolved at least 7 days prior to the first dose in the study and should include all the following:
1.the occurrence of appropriate symptoms (see VOC definition in protocol Section 7.2.1.1)
2.either a visit to a medical facility or healthcare professional,
3.receipt of oral/parenteral opioid or other non-opioid parenteral analgesia.
•If receiving HU/HC or erythropoietin stimulating agent, must have been receiving the drug for at least 6 months prior to Screening and plan to continue taking at the same dose and schedule during the trial. Dose alterations of HU/HC during Part A are not allowed, and if this occurs, the patient will enter directly to the Part B.
•Received standard age-appropriate care for SCD, including penicillin prophylaxis, pneumococcal immunization, and parental education
•Transcranial Doppler (TCD) considered low risk within the past 6 months (for 2 to 16 years).
Other inclusion criteria as per protocol may apply |
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E.4 | Principal exclusion criteria |
•History of stem cell transplant.
•Received any blood products within 30 days of Day 1 dosing.
•Participating and maintaining in a chronic transfusion program (preplanned series of transfusions for prophylactic purposes).
•Patients with bleeding disorders
•Planning on undergoing an exchange transfusion during the duration of the study. Patients requiring episodic transfusion in response to worsened anemia or VOC are permitted.
•Contraindication or hypersensitivity to any drug from similar class as study drug or to any excipients of the study drug formulation.
•Planning to initiate or terminate HU/HC while on study, other than for safety reasons
•Significant active infection or immune deficiency (including chronic use of immunosuppressive drugs) in the opinion of the investigator.
Other exclusion criteria as per protocol may apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
1.PK (AUCd15) after 1st dose
Confirm appropriate dosing of crizanlizumab in patients aged 2 to < 18 years (Parts A)
2.PD (AUCd15) after 1st dose
Confirm appropriate dosing of crizanlizumab in patients aged 2 to < 18 years (Parts A)
3.PK (AUCtau) after 5th dose
Confirm appropriate dosing of Crizanlizumab in patients aged 2 to < 18 years old
4.PD (AUCtau) after 5th dose
Confirm appropriate dosing of Crizanlizumab in patients aged 2 to < 18 years old
5.PK (Cmax) after 1st dose and 5th dose
Confirm appropriate dosing of crizanlizumab in patients aged 2 to < 18 years (Parts A)
6.PK pre-dose concentrations
Confirm appropriate dosing of crizanlizumab in patients aged 6 months to less than 24 months of age (Part B)
7.Frequency of any adverse events (AEs) as a measure of safety and tolerability
Safety of crizanlizumab in patients aged 6 months to < 18 years (Parts A and B)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Day 15
2. Day 15
3. Week 15
4. Week 15
5. Week 1 and Week 15
6. Week 3 and Week 19
7. 6 months, 2 years |
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E.5.2 | Secondary end point(s) |
1.Number of Vaso Occusive Crisis (VOC) events leading to healthcare visit in clinic/ER/hospital
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
2.Number of Vaso Occusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient)
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
3.Number of each subcategory of VOC event (uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism)
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
4.Number of hospitalizations and ER visits (both overall and VOC-related)
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
5.Number of days of ER/hospitalization (both overall and VOC-related)
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
6.Number of dactylitis events
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
7.Number, seriousness, severity, and causality assessments of treatement emergent adverse events and other data as considered appropiate.
To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
8.Absolute change from baseline in hemoglobin
To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
9.Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab
To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
10.Electrocardiogram (ECGs) at relevant PK time points
To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
11.Growth and sexual maturation assessments (Tanner stage)
To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
12.PK pre-dose concentrations prior to each study drug dose.
Characterize long-term PK and PD of crizanlizumab in patients aged 6 months to >18 years
13.PD pre-dose concentrations prior to each study drug dose.
Characterize long-term PK and PD of crizanlizumab in patients aged 6 months to >18 years
14.Percentage P-selectin inhibition prior to dosing
Characterize long-term PK and PD of crizanlizumab in patients aged 6 months to >18 years
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 6 months, 2 years
2. 6 months, 2 years
3. 6 months, 2 years
4. 6 months, 2 years
5. 6 months, 2 years
6. 6 months, 2 years
7. 6 months, 2 years
8. 6 months, 2 years
9. Week 1, Week 3, Week 15, Week 27 and End of Treatment (EOT)
10. Screening, Week 7, Week 11, week 15, week 27 and Week 51
11. Screening, Week 51 and End of Treatment (EOT)
12. Week 1, Week 3, Week 7, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51
13. Week 1, Week 3, Week 7, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51
14. Week 3, Week 15, Week 27 and Week 51 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Brazil |
Canada |
Colombia |
France |
Germany |
India |
Italy |
Lebanon |
Oman |
Spain |
Switzerland |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study will occur when all the patients have either completed or discontinued the
study treatment and/or the 105-days follow-up period. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 11 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |