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 compare the efficacy of 7.5 mg/kg of
crizanlizumab versus placebo on the annualized rate of VOC leading to healthcare visit, in addition to standard of care
- To compare the efficacy of 5.0 mg/kg of
crizanlizumab versus placebo on the annualized rate of VOC leading to healthcare visit, in addition to standard of care |
|
E.2.2 | Secondary objectives of the trial |
Key secondary:
- Compare the efficacy of 7.5 mg/kg vs placebo on the annualized rate of all VOCs (managed at home + leading to healthcare visit)
- Compare the efficacy of 5.0 mg/kg vs placebo on the annualized rate of all VOC (managed at home + leading to healthcare visit)
-Assess the time to first and second VOC leading to healthcare visit in
each group
- Assess the annualized rate of VOCs managed at home in each group
- Assess the duration of VOCs leading to healthcare visit in each group
- Assess rate of participants free from VOC leading to healthcare visit in
each group
- Healthcare resource utilization (visits to clinic, Emergency room (ER)
and hospitalizations) in each group vs placebo
- Assess SCD-related renal damage in each group
- Characterize PK profile of SEG101 at 5.0 and 7.5 mg/kg
- Characterize PD (P-selectin inhibition) of SEG101 at 5.0 and 7.5 mg/kg
- Assess efficacy, safety and immunogenicity of SEG101 over study
period (treatment of 5y+105d follow-up) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained prior
to any screening procedures
2. Male or female patients aged 12 years and older on the day of signing informed consent. Adolescent include patients aged 12 to 17 years old and adults ≥ 18 years
3. Confirmed diagnosis of SCD by hemoglobin
electrophoresis or high performance liquid
chromatography (HPLC) [performed locally]. All SCD
genotypes are eligible, genotyping is not required for study entry
4a. Experienced at least 2 VOCs leading to healthcare visit within the 12
months prior to screening visit as determined by medical history. Prior
VOC leading to healthcare visit must resolve at least 7 days prior to
Week 1 Day 1 and must include:
a. Pain crisis defined as an acute onset of pain for
which there is no other medically determined
explanation other than vaso- occlusion -
b. a visit to a medical facility and/or healthcare
professional,
c. and receipt of oral/parenteral opioids or parenteral nonsteroidal anti-inflammatory drug (NSAID) analgesics
Acute chest syndrome (ACS), priapism, and hepatic or splenic
sequestration will be considered VOC in this study
5. If receiving HU/HC or L-glutamine (local HA approved medicinal
product), must have been receiving the drug for at least 6 months and at a stable dose for at least 3 months prior to Screening visit and plan to continue taking at the same dose and schedule until the participant has reached one year of study treatment
6. Patients must meet the following central laboratory values prior to
Week 1 Day 1. In case of re-sampling needed, local laboratory values are allowed. Refer to Section 8.4.1 for further details:
• Absolute Neutrophil Count ≥1.0 x 109/L
• Platelet count ≥75 x 109/L
• Hemoglobin: for adults (Hb) ≥4.0 g/dL and for
adolescents (Hb) ≥5.5 g/dL
• Glomerular filtration rate ≥ 45 mL/min/1.73 m2
using CKD-EPI formula in adults, and Shwartz formula in adolescents
• Direct (conjugated) bilirubin < 2.0 x ULN
• Alanine transaminase (ALT) < 3.0 x ULN
7. ECOG performance status ≤2.0 for adults and
Karnofsky ≥ 50% for adolescents |
|
E.4 | Principal exclusion criteria |
1. History of stem cell transplant.
2. Participating in a chronic transfusion program
(pre-planned series of transfusions for prophylactic
purposes) and/or planning on undergoing an
exchange transfusion during the duration of the study; episodic transfusion in response to worsened anemia or VOC is permitted.
3. Contraindication or hypersensitivity to any drug or
metabolites from similar class as study drug or to any excipients of the study drug formulation. History of severe hypersensitivity reaction to other monoclonal antibodies, which in the opinion of the investigator may pose an increased risk of serious infusion reaction.
4. Received active treatment on another
investigational trial within 30 days (or 5 half-lives of
that agent, whichever is greater) prior to Screening
visit or plans to participate in another investigational
drug trial.
5. Women of child-bearing potential, defined as all
women physiologically capable of becoming pregnant unless they are using highly effective methods of contraception during dosing and for 15 weeks after stopping treatment.
6. Concurrent severe and/or uncontrolled medical
conditions which, in the opinion of the Investigator,
could cause unacceptable safety risks or compromise participation in the study.
7. History or current diagnosis of ECG abnormalities
indicating significant risk of safety such as:
• Concomitant clinically significant cardiac
arrhythmias (e.g ventricular tachycardia), and clinically significant second or third degree AV block without a pacemaker
• History of familial long QT syndrome or know
family history of Torsades de Pointes
8. Not able to understand and to comply with study
intructions and requirements. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Annualized rate of VOC events leading to healthcare visit in each treatment group over the first year post-randomization |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
for key secondary:
- Annualized rate of all VOCs leading to healthcare
visit and treated at home (based on documentation by health care provider following contact with participant) over the first year post randomization
- The time to first and second VOC calculated
respectively as the time from date of randomization until the first and the second VOC leading to healthcare visit over the first year post randomization
- Annualized rate of VOCs managed at home over the first year post
randomization
- Duration of VOCs leading to healthcare visit over the first year post
randomization
- Number and percentage of participants free from
VOCs leading to healthcare visit in each group
over the first year post randomization
- Annualized rate of visits to clinic, Emergency room
(ER) and hospitalizations, both overall and VOCrelated over the first year post randomization
- Evolution of albuminuria and ACR over the first
year post randomization
- PK parameters after the first and fifth dose (e.g.,
AUC, Cmax, Tmax, half-life)
- PD parameter (P-selectin inhibition) after the first
and fifth dose
- Annualized rate of VOCs leading to healthcare visit
-Annualized rate of all VOCs leading to healthcare visit and treated at
home
Annualized rate of VOCs managed at home
Number, seriousness, severity, and causality
assessments of treatment-emergent adverse
events, including infections (serious, non-serious
and opportunistic infections) and other safety data
as considered appropriate
Absolute change from baseline in hemoglobin
Growth and sexual maturity assessment in
adolescents (Tanner stage)
Immunogenicity: measurement of anti-drug
antibodies (ADA) to crizanlizumab |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 year
- 1 year
-1 year
- 5 years
- 5 years
- 5 years
- 5 years
- 5 years
- 5 years
- 5 years
-5 years |
|
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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
healthcare resource utilization |
|
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
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 | 30 |
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 |
Colombia |
Egypt |
Ghana |
Oman |
Panama |
United Arab Emirates |
Belgium |
Brazil |
Canada |
Finland |
France |
Germany |
Greece |
India |
Italy |
Jordan |
Kenya |
Lebanon |
Netherlands |
Saudi Arabia |
South Africa |
Spain |
Turkey |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 8 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 8 |