A study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of crovalimab as an adjunct treatment in the prevention of vaso-occlusive episodes in sickle cell disease
| ISRCTN | ISRCTN14514128 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN14514128 |
| EudraCT/CTIS number | 2020-004839-25 |
| IRAS number | 1005491 |
| Secondary identifying numbers | BO42451, IRAS 1005491, CPMS 52468 |
- Submission date
- 20/05/2022
- Registration date
- 02/08/2022
- Last edited
- 04/12/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Haematological Disorders
Plain English summary of protocol
Background and study aims
Sickle cell disease (SDC) is a disorder of the structure of haemoglobin found in red blood cells and is a serious lifelong condition. Although treatment and survival of SCD have improved, there is still a need to improve treatments for people living with SCD, particularly in the chronic setting. Crovalimab is a new experimental drug which may help to decrease inflammation and destruction of red blood cells and may improve episodes of pain attack (crisis). The aim of this study is to compare the effects, good and bad, of crovalimab versus placebo (dummy drug).
Who can participate?
Patients aged between 12- 55 years old with SCD experiencing a pain attack
What does the study involve?
Participants will receive either crovalimab or placebo. A placebo looks like a drug but has no active ingredient. The treatment group is decided by chance using a computer program. Neither the participant nor the study staff can choose or know which treatment group is allocated.
The study has three stages:
1. Screening: to see if the patient is eligible for the study
2. Treatment: with crovalimab or placebo, initially given as an infusion into the vein, then as an injection in the skin over a period of 48 weeks
3. Follow-up period of 24 weeks to check on the participant’s response and their health
The total time in the study will be about 1 year and 6 months, which includes the screening, treatment and follow-up visits.
What are the possible benefits and risks of participating?
There are risks, discomforts, and inconveniences associated with any research study. It is possible that these general risks could be increased by the addition of test medications. Some of the general risks may be potentially life-threatening and may not have been previously reported. Some of these procedures take place more often than they would if patients were not taking part in this study. Taking blood samples may cause bruising and discomfort and a risk of infection or blood clots at the site of the blood collection. If patients have a central line, this may be used for blood samples. There is always a risk of infection at the site where the line is fitted. Crovalimab will be given in a clinic with emergency equipment and staff who are trained to monitor for and respond to any potential medical emergencies. Side effects can be referred to in the main PIS ICF due to the character count limit. Treatment with crovalimab may increase the risk of infection by the bacteria Neisseria meningitidis (also known as a meningococcal infection). Meningococcal infections can be life-threatening, especially if not treated early. To reduce the risk of meningococcal infections, all patients in the study need to be vaccinated against Neisseria meningitidis. There may be a risk of infusion-related reactions with intravenous crovalimab administration This may occur during, shortly after, or within 24 hours of receiving crovalimab. To reduce any risk participants will be observed for 1 hour after the infusion is complete. During the study, crovalimab will also be given by an injection under the skin (called subcutaneous administration). There is a possible risk of injection-site reactions. To help reduce any risk participants will be observed for at least 1 hour after the first three injections under the skin. Participants may be required to receive antibiotics to prevent infections, depending on which antibiotic they receive, they may experience side effects associated with antibiotic therapy. There could be an allergic reaction, which can range from a mild rash to severe life-threatening anaphylaxis. There could be a risk of developing Clostridium difficile infection, which is a gastrointestinal infection characterised by abdominal pain, diarrhoea, and fever, which in some cases is difficult to treat and, in rare cases, could be fatal. The use of antibiotics could cause the development of resistant (unresponsive to treatment) bacteria in the body. This could lead to an infection, which may be difficult to treat and, in rare cases, could be fatal. 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. Patients cannot take part in the study if they are pregnant or become pregnant. Patients will be informed of all of the above risks in the Patient Information Sheet and will be asked to notify their study doctor or study staff should they experience any side effects during the study. Patients will be monitored throughout the study in order to minimise 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?
February 2021 to May 2025
Who is funding the study?
F. Hoffmann-La Roche (Switzerland)
Who is the main contact?
Dr Ramneet Jagdev, welwyn.uk_ethics@roche.com
Contact information
Scientific
None available
None available
None available
United States of America
| Phone | +1 888-662-6728 (U.S. and Canada) |
|---|---|
| global-roche-genentech-trials@gene.com |
Study information
| Study design | Double-blind randomized placebo-controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A randomized double-blind Phase IIa study evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of crovalimab as an adjunct treatment in the prevention of vaso-occlusive episodes in sickle cell disease |
| Study acronym | BO42451 |
| Study objectives | 1. To evaluate the efficacy of crovalimab compared with placebo 2. To evaluate the efficacy of crovalimab compared with placebo 3. To evaluate the safety and tolerability of crovalimab compared with placebo 4. To evaluate the pharmacokinetics of crovalimab 5. To evaluate the immune response to crovalimab |
| Ethics approval(s) | Approved 23/05/2022, East of England - Cambridgeshire and Hertfordshire Research Ethics Committee (Equinox House, City link, Nottingham, NG2 4LA, UK; +44 (0)2071048096, +44 (0)207 104 8102, +44 (0)207 104 8265; cambsandherts.rec@hra.nhs.uk), ref: 22/EE/0139 |
| Health condition(s) or problem(s) studied | Sickle cell disease (SCD); vaso-occlusive episodes in SCD |
| Intervention | Eligible patients will be randomized 1:1 to receive either crovalimab or placebo in addition to their current SCD therapy. Randomisation is via the IXRS system. Patients in both treatment arms will receive standard treatment for SCD as guided by the treating physician and/or institutional guidelines, including but not limited to treatments currently approved for SCD within each country participating in this study (e.g., hydroxyurea, L-glutamine, crizanlizumab, or voxelotor), pain management treatment (e.g., opioid analgesics, nonsteroidal anti-inflammatory drugs [NSAIDs]), hydration, oxygen, and other BSC. Stratification factors at randomization are: 1. Number of vasoocclusive pain events (VOEs) in the 12 months prior to enrollment (4 vs 4 VOEs) 2. Use of concurrent SCD-directed therapy in any combination (e.g., hydroxyurea, L-glutamine, crizanlizumab, or voxelotor) (yes vs no) An initial crovalimab (or matching placebo) intravenous (IV) loading dose will be administered on Week 1 Day 1 followed by 4 once-weekly subcutaneous (SC) doses of the study treatment (refers to crovalimab or placebo) on Week 1 Day 2, then on Weeks 2, 3, and 4. Maintenance dosing will begin at Week 5 and will continue Q4W thereafter, for a total of 48 weeks of treatment. All patients will receive the study treatment according to a weight-based tiered dosing schedule. Study treatment dosing will continue per protocol schedule during any medical facility or home VOE occurring on treatment. For patients who discontinue the study treatment, a safety follow-up visit will be conducted at 24 weeks after the last dose of the study treatment. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Crovalimab |
| Primary outcome measure | Current primary outcome measures as of 07/03/2023: Annualized rate of medical facility VOEs (AVR) measured using data recorded in the electronic case report forms (eCRFs) from Baseline to Week 49 Previous primary outcome measures: Annualized rate of medical facility VOEs (AVR) up to 48 weeks. A medical facility VOE is defined as: 1. An uncomplicated medical facility VOE (defined as an acute episode of pain lasting at least 2 hours and occurring at least 3 days after return to the patient’s chronic baseline pain levels, with no other medically determined cause other than a VOE that requires a medical facility visit and treatment with oral or parenteral opioids, parenteral nonsteroidal anti-inflammatory drugs [NSAIDs], or ketamine), OR 2. Acute chest syndrome (ACS), hepatic or splenic sequestration, or priapism requiring a visit to a medical facility. Patients complete an e-diary and an HVQ sickle cell pain crisis questionnaire which will be reviewed and analysed by clinical scientists |
| Secondary outcome measures | Current secondary outcome measures as of 07/03/2023: All outcomes will be measured from data recorded in the electronic case report forms (eCRFs) unless otherwise stated: 1. Annualized rate of home VOEs from Baseline to Week 49 2. Annualized rate of uncomplicated medical facility VOEs from Baseline up to Week 49 3. Annualized rate of acute chest syndrome (ACS) from Baseline up to Week 49 4. Annualized rate of days hospitalized for medical facility VOE from Baseline up to Week 49 5. Annualized rate of days hospitalized for treatment of Non-VOE complications of SCD from Baseline up to Week 49 6. Time to first medical facility VOE from randomization from Baseline up to Week 49 7. Change in urinary albumin-creatinine ratio from Baseline up to Week 49 8. Change in tricuspid regurgitant jet velocity (TRV) from Baseline to Week 49 9. Percentage of participants with TRV >2.5 m/s at Week 49 10. Change in Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue Score in adults from Baseline to Week 49 11. Percentage of participants with adverse events (AEs) up to 91 weeks 12. Serum concentrations of crovalimab over time from Baseline up to Week 49 13. Percentage of participants with anti-drug antibodies to crovalimab in serum from Baseline up to Week 49 Previous secondary outcome measures: 1. Annualized rate of home VOE captured on the patient's handheld device provided and questionnaires at baseline to Week 49 2. Annualized rate of uncomplicated medical facility VOE captured in the patients notes at baseline to Week 49 3. Annualized rate of acute chest syndrome (ACS) captured in the patients notes at baseline to Week 49 4. Annualized rate of days hospitalized for medical facility VOE captured in the patients notes at baseline to Week 49 5. Annualized rate of days hospitalized for treatment of non-VOE complications of SCD captured in the patients notes at baseline to Week 49 6. Hematologic measures measured using routine safety bloods from baseline to Week 49 7. Time to first medical facility VOE captured in the patients notes from randomization up to Week 49 8. Urinary albumin-creatinine ratio measured using review of routine safety bloods from baseline to Week 49 9. Tricuspid regurgitant jet velocity (TRV) measured using echocardiogram at baseline to Week 49 10. Proportion of patients with TRV >2.5 m/s measured using echocardiogram at Week 49 11. Fatigue measured using the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults at baseline to Week 49 |
| Overall study start date | 12/02/2021 |
| Completion date | 31/05/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 12 Years |
| Upper age limit | 55 Years |
| Sex | Both |
| Target number of participants | 90 |
| Key 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. Male or female with confirmed diagnosis of HbSS (SCD genotype of sickle cell anemia) or HbSβ0 (SCD genotype of sickle cell beta zero thalassemia) 5. Two or more (≥2) to ≤10 documented VOEs in the 12 months prior to randomization 6. If receiving concurrent SCD-directed therapy, the patient must have been on a stable dose for a minimum of 3 months prior to study enrollment. There should be no plans to modify the patients’ dosing throughout the study duration, other than for safety reasons. 7. If receiving erythropoietin, the patient must have been prescribed this medication for the preceding 3 months and be dose-stabilized for at least 3 months prior to study enrollment 8. Vaccination against N. meningitides, vaccinations against H. influenza type B and S. pneumonia 9. Patients who have been vaccinated (partially or in full) against SARS-CoV-2 with a locally approved vaccine are eligible to be enrolled in the study, 3 days or longer after inoculation 10. Adequate hepatic and renal function 11. For women of childbearing potential, agreement to remain abstinent or use contraception during the treatment period and for 6 months after the final dose of study treatment |
| Key exclusion criteria | 1. History of hematopoietic stem cell transplant 2. Participating in a chronic transfusion program and/or planning on undergoing an exchange transfusion during the duration of the study 3. History of hypersensitivity, allergic, or anaphylactic reactions to any ingredient contained in the study treatment 4. Received active treatment on another investigational trial within 28 days (or within five half-lives of that agent, whichever is greater) prior to screening visit, or plans to participate in another investigational drug trial 5. Hemoglobin <6 g/dl 6. Known or suspected hereditary complement deficiency 7. Active systemic bacterial, viral, or fungal infection within 14 days before first drug administration 8. Presence of fever (≥38 degrees Celsius) within 7 days before the first drug administration 9. Immunized with a live attenuated vaccine within 1 month before first drug administration 10. Pregnant or breastfeeding, or intending to become pregnant during the study or within 6 months after the final dose of study treatment 11. Known HIV infection with documented CD4 count <200 cells/microliter within 24 weeks prior to screening 12 History of N. meningitidis infection within the prior 6 months |
| Date of first enrolment | 08/12/2021 |
| Date of final enrolment | 31/07/2023 |
Locations
Countries of recruitment
- Brazil
- England
- France
- Italy
- Spain
- Türkiye
- United Kingdom
Study participating centres
Harrow
HA1 3UJ
United Kingdom
London
NW1 2PQ
United Kingdom
Hammersmith
London
W12 0HS
United Kingdom
Porto Alegre
90035-903
Brazil
Botucatu
18618-970
Brazil
Salvador
41253-190
Brazil
Rio de Janeiro
20211-030
Brazil
São Paulo
01232-010
Brazil
Sao Jose do Rio Preto
15090-000
Brazil
Ribeirao Preto
14051-140
Brazil
São Paulo
01321-00
Brazil
Créteil
94010
France
Montpellier
34295
France
Verona
37134
Italy
Genova
16128
Italy
Napoli
80138
Italy
Madrid
28007
Spain
Sevilla
41013
Spain
Zaragoza
50009
Spain
Adana
01130
Türkiye
Adana
1330
Türkiye
Hatay
31040
Türkiye
Mersin
33110
Türkiye
North Carolina
27834
United States of America
New York
10029
United States of America
Mississippi
39110
United States of America
Sponsor information
Industry
Grenzacherstrasse 124
Basel
4070
Switzerland
| Phone | +44 (0)1707 366000 |
|---|---|
| global.roche-genentech-trials@roche.com |
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 | 31/05/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer-reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on website 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 and https://www.clinicaltrialsregister.eu. These websites can also be found via https://www.roche-trials.com. Links to these websites are provided to participants in the Participant Information Sheets. |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
04/12/2023: Study website added.
06/07/2023: The trial participating centres were added: Hospital das Clinicas - UFRGS, UNESP - Faculdade de Medicina da Universidade Estadual Paulista - Campus Botucatu, Hospital Sao Rafael - HSR, HEMORIO, Hospital Samaritano, Hospital de Base de Sao Jose do Rio Preto, Hospital das Clínicas Faculdades Médicas de Ribeirão Preto, Beneficencia Portuguesa de Sao Paulo, CHU Henri Mondor; Service de médecine interne, Hôpital Saint Eloi; Service de Médecine interne, Azienda Ospedaliera di Verona-Policlinico G.B. Rossi; Medicina Interna, Ospedale Galliera; S.S.D. Ematologia, Università degli Studi della Campania Luigi Vanvitelli; UOC Ematologia ed oncologia pediatrica, Hospital General Univ. Gregorio Maranon, Hospital Universitario Virgen del Rocio; Servicio de Hematologia, Hospital Universitario Miguel Servet; Servicio Hematologia, Adana Acibadem Hospital; Pediatric Hematology, Cukurova University Medical Faculty Balcali Hospital, Mustafa Kemal University Medical Faculty; Infection, Mersin Universitesi Tip Fakultesi Hastanesi; Tibbi Onkoloji Birimi, East Carolina University; Brody School of Medicine, Icahn School of Medicine, and Mississippi Center for Advanced Medicine.
07/03/2023: The following updates have been made:
1. The primary scientific contact was changed and the principal investigator and scientific contacts removed.
2. The primary outcome measure has been changed.
3. The secondary outcome measure has been changed.
16/07/2022: ISRCTN received notification of combined HRA/MHRA approval for this trial on 16/07/2022
05/09/2022: Internal review.
20/05/2022: Trial's existence confirmed by the HRA.
