E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Sickle Cell Disease with Vaso-Occlusive Crisis |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040644 |
E.1.2 | Term | Sickle cell disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
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 | 10010331 - Congenital, familial and genetic disorders |
|
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) |
|
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 |
|
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 7 kg) in Part B once the appropriate dose is confirmed in 2 to <6 year old participants)
•Confirmed diagnosis of sickle cell disease (SCD) (e.g. any genotype
including HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia, and
others) by hemoglobin electrophoresis and/or high performance liquid chromatography (HPLC) performed locally. Confirmation of diagnosis by two accepted methods is recommended.
•Experienced at least 1 VOC within the preceding 12 months prior to
screening, as determined by medical history. Prior VOC must have
resolved at least 7 days prior to the first dose in the study and must 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 parenteral NSAIDs.
•If receiving HU/HC, L-glutamine or erythropoietin stimulating agent,
must have been receiving the drug consistently for at least 6 months
prior to Screening and plan to continue taking it at the same dose and
schedule during the trial. Patients who have not been receiving such
drugs must have been off them for at least 6 months prior to screening.
Dose alterations of HU/HC during Part A are not allowed, and if this
occurs, the participant will enter directly to Part B.
•Received standard age-appropriate care for SCD, including penicillin
prophylaxis, pneumococcal immunization, and parental education
• Performance status: Karnofsky ≥ 50% for patients >10 years of age,
and Lansky ≥ 50 for patients ≤ 10 years of age
• Patient must meet the following laboratory values prior to Week 1 Day 1:
Absolute Neutrophil Count ≥1.0 x 109/L
Platelets ≥75 x 109/L
Hemoglobin (Hgb) > 5.5 g/dL
• Patient must have adequate renal and hepatic function as defined:
Estimated Glomerular filtration rate (eGFRe) ≥ 75 mL/min/1.73 m2
using Schwartz formula
Direct (conjugated) bilirubin ≤ 2.0 x ULN
Alanine transaminase (ALT) ≤ 3.0 x ULN
•Transcranial Doppler (TCD) for patients aged 2 to < 16 years at time of screening. with HbSS, HbSβ0-thalassemia, and HbSD disease indicating low risk for stroke (per investigator). Please refer to Section 7.2.2.6 for details.
Other inclusion criteria as per protocol may apply |
|
E.4 | Principal exclusion criteria |
•History of stem cell transplant.
•Received any blood products within 30 days prior to Day 1 dosing.
•Plan to participate in a chronic transfusion program (preplanned series of transfusions for prophylactic purposes) or undergo exchange
transfusions/plasmapheresis during the study. Patients requiring
episodic transfusion (simple or exchange) in response to worsened
anemia or VOC are permitted.
•Patients with bleeding disorders
•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
•Patient with active human immunodeficiency virus (HIV) infection
(detectable viral load)
•Significant active infection or immune deficiency (including chronic use of immunosuppressive drugs) in the opinion of the investigator.
•Patients having taken voxelotor less than 30 days prior to Screening, or planning to take voxelotor while on study are not allowed
Other exclusion criteria as per protocol may apply |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1.PK (AUCd15) after 1st dose
Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A)
2.PD (AUCd15) after 1st dose
Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A)
3.PK (AUCtau) after multiple dose
Confirm appropriate dosing of Crizanlizumab in participants aged 2 to < 18 years old
4.PD (AUCtau) after multiple dose
Confirm appropriate dosing of Crizanlizumab in participants aged 2 to < 18 years old
5.PK (Cmax) after 1st dose and multiple dose
Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A)
6.PK pre-dose concentrations
Confirm appropriate dosing of crizanlizumab in participants 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 participants aged 6 months to < 18 years (Parts A and B)
|
|
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 1 and Week 19
7. 6 months, 2 years |
|
E.5.2 | Secondary end point(s) |
1.Annualized rate VasoOccusive 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 participants at the time of study entry (Parts A and B)
2.Annualized rate 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 participants at the time of study entry (Parts A and B)
3.Annualized rate 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 participants at the time of study entry (Parts A and B)
4.Annualized rate hospitalizations and ER visits (both overall and VOC-related)
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B)
5.Annualized rate days of ER/hospitalization (both overall and VOC-related)
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B)
6.Annualized rate dactylitis events
To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants 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 participants 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 participants 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 participants 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 participants 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 participants 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 participants 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 participants aged 6 months to >18 years
14.Percentage P-selectin inhibition prior to dosing
Characterize long-term PK and PD of crizanlizumab in participants aged 6 months to >18 years
|
|
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 |
|
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
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 |
|
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
|
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. |
|
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 | 0 |
E.8.9.1 | In the Member State concerned days | |
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 |