A study evaluating the safety, pharmacokinetics, pharmacodynamics, and efficacy of crovalimab for the management of acute uncomplicated vaso-occlusive episodes in participants with sickle cell disease
| ISRCTN | ISRCTN89975936 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN89975936 |
| EudraCT/CTIS number | 2020-004840-27 / 2022-502546-26-00 |
| IRAS number | 1005134 |
| ClinicalTrials.gov number | NCT04912869 |
| Secondary identifying numbers | BO42452, CPMS 46764 |
- Submission date
- 22/02/2022
- Registration date
- 07/07/2022
- Last edited
- 22/10/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Haematological Disorders
Plain English summary of protocol
Background and study aims
Sickle cell disease (SCD) is a genetic disorder leading to red blood cells that distort into a sickled shape, contributing to painful vaso-occlusive episodes (VOEs). The purpose of this clinical trial is to look at the safety and effectiveness of crovalimab, and to understand the way your body processes (pharmacokinetics) and reacts (pharmacodynamics) to crovalimab.
Who can participate?
People aged 12 to 55 years with a confirmed diagnosis of sickle cell anemia (HbSS or HbSβ0)
What does the study involve?
Everyone who joins this clinical trial will receive ONLY one dose of either:
Crovalimab as a single infusion into the vein, OR
Placebo as a single infusion into the vein
The patients will have a 2 in 3 (67%) chance of being in the crovalimab group and a 1 in 3 (33%) chance of being in the placebo group.
During the clinical trial, participants can continue to have standard treatment for the pain attack (crisis) as recommended by the clinical trial doctor.
This is a ‘placebo-controlled’ clinical trial, which means that one of the groups will be given a saline (salt water) infusion with no active ingredients (also known as ‘placebo’). A placebo is used as a control, to make sure any health effects are from the clinical trial treatment rather than
other factors.
Neither the participant nor the site staff can choose or know which group they are in. An exception is made if the clinical trial doctor needs to know which group the participant is in for safety reasons.
While the participant is in the hospital for treatment for the sickle cell pain attack (crisis), they will be seen by the clinical trial doctor.
After being given treatment with crovalimab or a placebo, the participant will have regular tests and check-ups while hospitalised until they are well enough to go home from the hospital (discharged).
Once the participant is discharged from the hospital, they will have 5 telephone check-ups and 2 clinic visits with the clinical trial doctor to check on their health and any side effects they may be having.
The clinical trial will last for a total of 322 days (approximately 10.5 months) after the participant is given clinical trial treatment (crovalimab or placebo).
What are the possible benefits and risks of participating?
As with any study, there are risks (both known and unknown) associated with the drug or procedures used. Before starting the clinical trial, participants will be told about any risks and benefits of taking part in the trial. The participants will also be told what other treatments are available so that they may decide if they still want to take part. Participants health may or may not improve in this study, but the information that is learned may help other people who have a similar medical condition in the future. The potential side effects related to the study drug, based on laboratory studies, knowledge of similar drugs, or studies in other diseases, are listed below:
1. Increased risk of infection, including Neisseria meningitidis infection
2. Allergic reactions
3. Infusion-related reactions
You may also receive antibiotics while taking part in this study. There may be risks to taking antibiotics:
1. Allergic reactions
2. Clostridium difficile infection
3. Development of resistant (unresponsive to treatment) bacteria in the body
It is possible that side effects of crovalimab which are unknown at this time may occur during the study. Any new information that may affect participants' health or which may make the participants want to stop taking part in the study will be shared with them as soon as it becomes available. There may be a risk in exposing an unborn child to crovalimab, and all risks are not known at this time. Participants cannot take part in the study if they are pregnant or become pregnant.
Participants will be fully informed of the potential risks and burdens involved in taking part in this research study in the Participant Information Sheet and will be given opportunities to ask questions prior to consent and during their participation. Participants will be monitored throughout the study in order to minimize risks.
Where is the study run from?
F. Hoffmann-La Roche (Switzerland)
When is the study starting and how long is it expected to run for?
January 2021 to October 2025
Who is funding the study?
F. Hoffmann-La Roche (Switzerland)
Who is the main contact?
Reference Study ID Number: BO42452; https://forpatients.roche.com/, global-roche-genentechtrials@gene.com
Contact information
Public, Scientific, Principal Investigator
Building 1, Grenzacherstrasse 124
Basel
CH-4058
Switzerland
| Phone | +1 888-662-6728 |
|---|---|
| global-roche-genentech-trials@gene.com |
Study information
| Study design | Interventional double-blind randomized parallel group placebo controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | See additional files |
| Scientific title | A phase Ib randomized, placebo-controlled study evaluating the safety, pharmacokinetics, pharmacodynamics, and efficacy of crovalimab for the management of acute uncomplicated vaso-occlusive episodes (VOE) in patients with sickle cell disease (SCD) |
| Study objectives | Current study hypothesis as of 09/02/2023: The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of crovalimab compared with placebo for the management of acute uncomplicated vasoocclusive episodes (VOE) in participants with sickle cell disease (SCD). ____ Previous study hypothesis: Objectives: • To evaluate the safety of crovalimab compared with placebo • To evaluate the pharmacokinetics (PK) of crovalimab • To evaluate the pharmacodynamics (PD) of crovalimab • To evaluate the efficacy of crovalimab compared with placebo • To evaluate the immune response to crovalimab |
| Ethics approval(s) |
Approved 23/05/2022, East of England - Cambridge and Hertfordshire Research Ethics Committee (Equinox House, City link, Nottingham, NG2 4LA, United Kingdom; +44 (0)207 104 8265; cambsandherts.rec@hra.nhs.uk), ref: 22/YH/0061 |
| Health condition(s) or problem(s) studied | Sickle cell disease (SCD); vaso-occlusive episodes in SCD; Pain crisis |
| Intervention | Current interventions as of 09/02/2023: 1. Crovalimab: Participants will receive a single intravenous (IV) infusion of Crovalimab based on body weight. 2. Placebo: Participants will receive a single IV infusion of a matching Placebo. _____ Previous interventions: Patients who meet all eligibility criteria and have consented for participation in the study will be randomized 2:1 to receive either a single intravenous (IV) tiered weight-based dose of crovalimab or placebo. Patients will be randomised via an online platform hosted by Clinphone. A 2-step process for screening procedures is encouraged to preliminarily identify and consent patients for the study prior to VOE presentation, Screen Visit #1 (initial screen) is conducted at an outpatient visit (i.e., when the patient is not experiencing a VOE), where the main Informed Consent Form (ICF) is signed and preliminary eligibility is assessed. During this visit, preliminary screening assessments can be conducted, and a steady state SCD exploratory biomarker sample will be collected (only after consent is received). No additional assessments are required until Screen Visit #2. Eligibility at Screen Visit #1 does not guarantee eligibility at Screen Visit #2. Screen Visit #2 (VOE presentation screen) is then conducted when the patient presents with a VOE to the A/E department. The patient consent from Screen Visit #1 must be confirmed prior to starting study assessments (this confirmation must be documented). Once patient consent is confirmed, all remaining eligibility criteria must be assessed, and all screening assessments will be conducted . Alternatively, if a patient is only first identified for participation in the study at presentation with a VOE, then all consent procedures (main ICF signature) and all screening assessments listed for both Screen Visit #1 and Screen Visit #2 (excluding the steady state SCD exploratory biomarker listed under Screen Visit #1) can be conducted at the same time after the patient presents in A/E. If the patient meets all eligibility criteria then they are randomised and will receive treatment within 12 hours of presenting to A/E. Patients will be admitted to Hospital, Patients will be followed for the duration of the hospitalization until the time of discharge. After discharge, they will continue to be followed during an observational period on Days 14, 28, 46, 64, and 84 after study treatment administration; Days 14, 46, and 64 are telephone follow-ups and Days 28 and 84 are study site visits. The total duration of the study is 12 weeks (84 days) following administration of study treatment. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacokinetic, Pharmacodynamic |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | crovalimab |
| Primary outcome measure | Current primary outcome measure as of 09/02/2023: 1. Percentage of participants with adverse events (AEs), measured from Baseline up to Day 322 2. Percentage of participants with infusion-related reactions and hypersensitivity, measured from Baseline up to Day 84 _____ Previous primary outcome measure: Incidence and severity of adverse events, with severity determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE v5.0) measured at Screening visit 2, during study treatment, within 30 mins post-infusion, 12 hours post-infusion, day 2 - day 14, day of discharge, post-discharge day 28, day 46, day 64, and day 84 |
| Secondary outcome measures | Current secondary outcome measures as of 09/02/2023: 1. Time to improvement of the primary acute uncomplicated VOE, measured from Baseline up to Day 84 2. Total cumulative opioid dose, measured from Baseline up to Day 84 3. Time to discontinuation of all parenteral opioids, measured from Baseline up to Day 84 4. Time to readiness for hospital discharge, measured from Baseline up to Day 84 5. Time to hospital discharge, measured from Baseline up to Day 84 6. Time to a confirmed decrease in pain score of at least 2 points from the maximal pre-dose pain score, measured from Baseline up to Day 84 7. Change in pain score from the maximal pre-dose pain score to the score at hospital discharge, measured from Baseline up to Day 84 8. Percentage of participants who develop acute chest syndrome (ACS), measured from Baseline up to Day 28 9. Percentage of participants requiring intensive care unit (ICU)/critical care admission for SCD-related complications, measured from Baseline up to Day 84 10. Percentage of participants requiring blood transfusion for SCD-related complications, measured from Baseline up to Day 84 11. Readmission rate for a VOE or VOE-related event within 28 days of discharge of the primary VOE, measured from Baseline up to Day 84 12. Serum concentrations of crovalimab over time, measured from Baseline up to Day 84 13. Change in PD Biomarkers including complement activity (CH50)s over time, measured from Baseline up to Day 84 14. Change over time in free C5 concentration, measured from Baseline up to Day 84 15. Change over time in soluble complement 5b 9 (sC5b-9) concentration, measured from Baseline up to Day 84 16. Percentage of participants with anti-drug antibodies to crovalimab, measured from Baseline up to Day 84 _____ Previous secondary outcome measures: Change from baseline in targeted vital signs and clinical laboratory test results : 1. Vital signs (temperature, pulse, and blood pressure) at Screening visit 2, during study treatment, within 30 mins post-infusion, 12 hours post-infusion, day 2 - day 14, day 28, and Day 84 2. Clinical lab tests (Hematology (including reticulocytes), Chemistry (including LDH), Serum PK sample, Serum ADA sample, Plasma and serum PD samples, and Blood sample for clinical genotyping) at screening visit 2, day 2, day6, day 10, day 14, day if discharge, day 28, and day 84 3. Incidence and severity of infusion-related reactions and hypersensitivity, will be measured during the infusion and also post-infusion, depending on the incidence and the severity of the infusion |
| Overall study start date | 09/01/2021 |
| Completion date | 31/10/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 12 Years |
| Upper age limit | 55 Years |
| Sex | Both |
| Target number of participants | 30 |
| Key inclusion criteria | Current inclusion criteria as of 15/10/2024: 1. Age >=12 to =<55 years 2. Body weight >=40 kg 3. Confirmed diagnosis of HbSS (SCD genotype of sickle cell anemia) or HbSβ0 (SCD genotype of sickle cell beta zero thalassemia) 4. Vaccination against Neisseria meningitidis 5. Vaccinations against H. influenzae type B and S. pneumoniae 6. Participants vaccinated against SARS-CoV-2 are eligible, as long as it has been 3 days or more after inoculation with the vaccine. 7. Diagnosis of an acute uncomplicated VOE, that requires admission to a hospital/acute medical facility and treatment with parenteral opioid analgesics 8. Adequate hepatic and renal function 9. Hemoglobin >=5 grams/deciliter (g/dL) 10. Platelet count >=100,000/microliter (µL) 11. Participants receiving SCD-directed therapies must be on a stable dose for >=28 days 12. For female participants of childbearing potential, an agreement to remain abstinent or use contraception for 6 months after the dose of study treatment _____ Previous inclusion criteria as of 09/02/2023: 1. Age >=12 to =<55 years 2. Body weight >=40 kg 3. Confirmed diagnosis of HbSS (SCD genotype of sickle cell anemia) or HbSβ0 (SCD genotype of sickle cell beta zero thalassemia) 4. Vaccination against Neisseria meningitidis 5. Vaccinations against H. influenzae type B and S. pneumoniae 6. Participants vaccinated against SARS-CoV-2 are eligible, as long as it has been 3 days or more after inoculation with the vaccine. 7. Diagnosis of an acute uncomplicated VOE, that requires admission to a hospital/acute medical facility and treatment with parenteral opioid analgesics 8. Adequate hepatic and renal function 9. Hemoglobin >=5 grams/deciliter (g/dL) 10. Platelet count >=100,000/microliter (µL) 11. Participants receiving sickle cell therapies must be on a stable dose for >=28 days 12. For female patients of childbearing potential, an agreement to remain abstinent or use contraception for 6 months after the dose of study treatment _____ Previous inclusion criteria: 1. Signed ICF or Assent Form (as determined by patient’s age and individual site and country standards) 2. Age >=12 to =<55 years 3. Body weight >=40 kg 4. Confirmed diagnosis of HbSS (SCD genotype of sickle cell anemia) or HbSβ0 (SCD genotype of sickle cell beta zero thalassemia) 5. Vaccination against Neisseria meningitidis 6. Vaccinations against H. influenzae type B and S. pneumoniae 7. Diagnosis of an acute uncomplicated VOE, that requires admission to a hospital/acute medical facility and treatment with parenteral opioid analgesics 8. Adequate hepatic and renal function 9. Hemoglobin >=5 g/dL 10. Platelet count >=100,000/µL 11. Patients receiving sickle cell therapies must be on a stable dose for >=28 days 12. For female patients of childbearing potential, an agreement to remain abstinent or use contraception for 6 months after the dose of study treatment |
| Key exclusion criteria | Current exclusion criteria as of 15/10/2024: 1. More than 10 VOEs within the last 12 months prior to presentation, that have required a medical facility visit 2. Pain related to the current VOE ongoing for >36 hours 3. Acute pain related to avascular necrosis, hepatic or splenic sequestration, or priapism 4. Pain atypical of an acute uncomplicated VOE 5. Evidence of or suspicion of ACS 6. Evidence or high suspicion of a severe systemic infection 7. Major surgery and/or hospitalization for any reason within 30 days 8. History of Neisseria meningitidis infection within 6 months prior 9. Known HIV infection with a documented CD4 count <200 cells/µL 10. Transfusion or receipt of blood products within 3 months or current participation in a chronic transfusion protocol 11. Immunized with a live attenuated vaccine within 30 days 12. History of hematopoietic stem cell transplant 13. Known or suspected hereditary complement deficiency 14. Pregnant or breastfeeding, or intending to become pregnant during the study or within 322 days (approximately 10.5 months) after the study drug administration. 15. Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within the prior 28 days or within five half-lives of that investigational product, whichever was greater _____ Previous exclusion criteria as of 09/02/2023: 1. More than 10 VOEs within the last 12 months prior to presentation, that have required a medical facility visit 2. Pain related to the current VOE ongoing for >48 hours 3. Acute pain related to avascular necrosis, hepatic or splenic sequestration, or priapism 4. Pain atypical of an acute uncomplicated VOE 5. Evidence of or suspicion of ACS 6. Evidence or high suspicion of a severe systemic infection 7. Major surgery and/or hospitalization for any reason within 30 days 8. History of Neisseria meningitidis infection within 6 months prior 9. Known HIV infection with a documented CD4 count <200 cells/µL 10. Transfusion or receipt of blood products within 3 months or current participation in a chronic transfusion protocol 11. Immunized with a live attenuated vaccine within 30 days 12. History of hematopoietic stem cell transplant 13. Known or suspected hereditary complement deficiency 14. Pregnant or breastfeeding, or intending to become pregnant during the study or within 322 days (approximately 10.5 months) after the study drug administration. 15. Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within the prior 28 days or within five half-lives of that investigational product, whichever was greater _____ Previous exclusion criteria: 1. More than 10 VOEs within the last 12 months prior to presentation, that have required a medical facility visit 2. Pain related to the current VOE ongoing for >48 hours 3. Acute pain related to avascular necrosis, hepatic or splenic sequestration, or priapism 4. Pain atypical of an acute uncomplicated VOE 5. Evidence of or suspicion of ACS 6. Evidence or high suspicion of a severe systemic infection 7. Major surgery and/or hospitalization for any reason within 30 days 8. History of Neisseria meningitidis infection within 6 months prior 9. Known HIV infection with a documented CD4 count <200 cells/µL 10. Transfusion or receipt of blood products within 3 months or current participation in a chronic transfusion protocol 11. Immunized with a live attenuated vaccine within 30 days 12. History of hematopoietic stem cell transplant 13. Known or suspected hereditary complement deficiency 14. Pregnant or breastfeeding, or intending to become pregnant during the study or within 6 months after the study drug administration 15. Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within the prior 28 days or within five half-lives of that investigational product, whichever was greater |
| Date of first enrolment | 26/03/2022 |
| Date of final enrolment | 31/12/2024 |
Locations
Countries of recruitment
- Brazil
- France
- Italy
- Kenya
- Lebanon
- Netherlands
- South Africa
- Spain
- United Kingdom
- United States of America
Study participating centres
371734
Italy
28009
Spain
41013
Spain
94010
France
34295
France
10029
United States of America
27834
United States of America
41253-190
Brazil
90035-903
Brazil
15090-000
Brazil
London
N19 5NF
United Kingdom
London
NW1 2BU
United Kingdom
50009
Spain
30322
United States of America
1105 AZ
Netherlands
30100
Kenya
00100
Kenya
1003
Lebanon
-
Lebanon
2193
South Africa
Sponsor information
Industry
Grenzacherstrasse 124
Basel
4047
Switzerland
| Phone | +1 888-662-6728 |
|---|---|
| global-roche-genentech-trials@gene.com | |
| Website | https://www.roche.com/about/ |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Hoffman-La Roche, F. Hoffmann-La Roche Ltd.
- Location
- Switzerland
Results and Publications
| Intention to publish date | 31/10/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Published as a supplement to the results publication |
| Publication and dissemination plan | Current publication and dissemination plan as of 09/02/2023: Planned publication in a high-impact peer-reviewed journal ____ Previous publication and dissemination plan: Internal report Conference presentation Submission to regulatory authorities Other Roche has a Data Sharing Policy, which allows participants to request and receive global clinical study reports (CSRs) and other summary reports. Roche provides details of all its clinical trials on public websites: http://www.ClinicalTrials.gov https://www.clinicaltrialsregister.eu These websites can also be found via www.roche-trials.com Links to these websites are provided to participants in the Participant Information Sheets. |
| IPD sharing plan | All data generated or analysed during this study will be included in the subsequent results publication |
Editorial Notes
22/10/2024: Study contact was amended.
15/10/2024: The following changes were made to the trial record:
1. A second EudraCT/CTIS number was added.
2. The ethics approval was added.
3. The overall end date was changed from 14/07/2025 to 31/10/2025.
4. The inclusion criteria were changed.
5. The exclusion criteria were changed.
6. The recruitment start date was changed from 26/03/2021 to 26/03/2022.
7. The recruitment end date was changed from 29/04/2024 to 31/12/2024.
8. The countries of recruitment Kenya, Lebanon, Netherlands, South Africa, United Kingdom were added.
9. The study participating centres Amsterdam UMC Location VUMC, International Cancer Institute (ICI), Gertrude’s Children’s Hospital, American University of Beirut - Medical Center, Hopital Nini, Charlotte Maxeke Johannesburg Hospital; Haemophilia Comprehensive Care Center were added.
10. The plain English summary was updated to reflect these changes.
11. The intention to publish date was changed from 14/07/2026 to 31/10/2026.
12. The contact was updated.
04/12/2023: Study website added.
30/06/2023: The scientific contact was changed.
27/06/2023: The following changes were made to the trial record:
1. The scientific contact was changed.
2. The recruitment end date was changed from 08/06/2023 to 29/04/2024.
3. The study participating centres The Whittington Hospital, Uni. College London Hospital, Hospital Universitario Miguel Servet; Servicio Hematologia, Children's Healthcare of Atlanta were added.
09/02/2023: The following changes were made to the trial record:
1. The contacts were changed.
2. The sponsor details were changed.
3. The study hypothesis was changed.
4. The condition was changed from "Sickle cell disease is an inherited red blood cell disorder that affects hemoglobin and leads to painful episodes (also known as vaso-occlusive episodes [VOE])" to "Sickle cell disease (SCD); vaso-occlusive episodes in SCD; Pain crisis".
5. The interventions were changed.
6. The primary outcome measure was changed.
7. The secondary outcome measures were changed.
8. The overall start date was changed from 16/02/2022 to 09/01/2021.
9. The overall end date was changed from 01/01/2024 to 14/07/2025.
10. The inclusion criteria were changed.
11. The exclusion criteria were changed.
12. The recruitment start date was changed from 11/06/2021 to 26/03/2021.
13. The country of recruitment 'United Kingdom' was removed and United States of America' was added.
14. The trial participating centres 'University College London Hospitals NHS Foundation Trust and The Whittington Hospital' were removed and 'Azienda Ospedaliera di Verona-Policlinico G.B. Rossi; Medicina Interna, Hospital General Univ. Gregorio Maranon, Hospital Universitario Virgen del Rocio; Servicio de Hematologia, CHU Henri Mondor; Service de médecine internet, Hôpital Saint Eloi; Service de Médecine internet, Icahn School of Medicine at Mount Sinai, East Carolina University; Brody School of Medicine, Hospital Sao Rafael – HSR, Hospital das Clinicas – UFRGS, Hospital de Base de Sao Jose do Rio Preto were added.
15. The plain English summary was updated to reflect these changes.
16. The publication and dissemination plan was changed.
17. The intention to publish date was changed from 01/01/2025 to 14/07/2026.
23/09/2022: The protocol and participant information sheet were removed from the trial record.
20/09/2022: The following changes were made to the trial record:
1. Uploaded protocol (not peer-reviewed) as an additional file.
2. The participant information sheet was uploaded as an additional file.
3. The participant level data statement was added.
16/09/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 16/09/2022.
04/08/2022: Internal review.
22/02/2022: Trial's existence confirmed by NHS HRA.
