A Study Evaluating The Safety, Pharmacokinetics, and Efficacy Of Crovalimab Versus Eculizumab In Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Complement Inhibitors (COMMODORE 1)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

17 Mar 2021 → ongoing

Decision date (initial)

2024-06-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche AG

External identifiers

EU CT number

2023-506526-37-00

EudraCT number

2020-000597-26

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic, Others

To evaluate the safety and tolerability of crovalimab compared with eculizumab

Secondary objectives 4

1. To characterize the crovalimab, eculizumab, and ravulizumab pharmacokinetics profile
2. To evaluate the immune response to crovalimab
3. To identify and/or evaluate biomarkers that can potentially provide evidence of crovalimab, eculizumab, and ravulizumab activity
4. To evaluate the efficacy of crovalimab compared with eculizumab

Conditions and MedDRA coding

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002709-PIP01-19

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. General Inclusion Criteria (All Patients) Body weight >= 40 kg at screening (pediatric patients with body weight <40 kg)
2. General Inclusion Criteria (All Patients) Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry evaluation of WBCs
3. General Inclusion Criteria (All Patients) Platelet count >= 30,000/mm3 at screening without transfusion support within 7 days of lab testing
4. For Patients in Randomized Arms (Arm A and B) Age >= 18 years Documented treatment with eculizumab according to the approved dosing recommended for PNH and completion of a minimum of 24 weeks of treatment prior to Day 1
5. For Patients in Randomized Arms (Arm A and B) Lactate dehydrogenase (LDH) <= 1.5 × ULN at screening
6. For Patients in Non-Randomized Arm (Arm C) - Age ≥2 to <18 years with a body weight ≥ 5 kg, currently treated with eculizumab OR - Currently treated with ravulizumab OR - Currently treated with eculizumab at higher-than-approved doses OR - Patients with known C5 polymorphism and poorly controlled hemolysis by eculizumab or ravulizumab - For adult patients currently treated with approved doses of eculizumab Note: In France and Czech Republic patients under 18 years of age are not eligible to participate in the study.

Exclusion criteria 6

1. Major Adverse Vascular Event within 6 months prior to first drug administration (Day 1)
2. History of allogeneic bone marrow transplantation
3. Neisseria meningitidis infection within 6 months prior to screening and up to first study drug administration
4. History of myelodysplastic syndrome with Revised International Prognostic Scoring System (IPSS-R) prognostic risk categories of intermediate, high and very high
5. Pregnant or breastfeeding, or intending to become pregnant during the study or within 46 weeks (approximately 10.5 months) after the final dose of crovalimab, or 3 months after the final dose of eculizumab (or longer if required by the local product label) Note: In France and Czech republic female patients of childbearing potential are not eligible to participate in the study.
6. Concurrent disease, treatment, procedure, or surgery or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose any additional risk for the patient, or would, in the opinion of the Investigator, preclude the patient’s safe participation in and completion of the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. 1. Incidence and severity of adverse events
2. 2. Change from baseline in targeted vital signs
3. 3. Change from baseline in targeted clinical laboratory test results
4. 4. Incidence and severity of injection-site reactions, infusion-related reactions, hypersensitivity, and infections
5. 5. Incidence of adverse events leading to study drug discontinuation
6. 6. Incidence and severity of clinical manifestations of drug-target-drug complex formation in patients who switched to crovalimab treatment from eculizumab or ravulizumab treatment

Secondary endpoints 20

1. 1. Serum concentration of crovalimab or eculizumab
2. 2. Serum concentration of ravulizumab
3. 3. Prevalence and incidence of anti-drug antibodies (ADAs) to crovalimab
4. 4. Change over time in pharmacodynamic biomarkers
5. 5. Change over time in free C5 concentration in crovalimab-treated patients
6. 6. Observed value and absolute change in parameters reflecting hemolysis
7. 7. Percent change from baseline in LDH levels averaged over Weeks 21, 23, and 25 based on central laboratory LDH measurements
8. 8. Proportion of patients who achieve TA from baseline through Week 25 (after 24 weeks on treatment)
9. 9. Proportion of patients with BTH from baseline through Week 25
10. 10. Proportion of patients with stabilization of hemoglobin from baseline through Week 25
11. 11. Proportion of patients with central LDH ≤ 1.5 X ULN from baseline through Week 25
12. 12. Proportion of patients with central LDH ≤ 1 X ULN from baseline through Week 25
13. 13. Total number of units (based on local equivalent) of pRBCs transfused per patient by Week 25
14. 14. Proportion of patients who have experienced a MAVE from baseline through Week 25
15. 15. Proportion of patients who reach or maintain a hemoglobin level of at least 10 g/dL, without subsequent decrease below 9 g/dL, in the absence of a transfusion
16. 16. Mean change from baseline to Week 25 in fatigue, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue] (for adults aged ≥ 18 years)
17. 17. Mean change from baseline to Week 25 in Physical Functioning, Role Functioning, and Global Health Status (GHS)/Quality of Life (QoL) scales of the EORTC QLQ-C30, and select disease-related symptoms (abdominal pain, headaches, dyspnea, dysphagia, chest pain, and erectile dysfunction) of the EORTC Item Library (for patients aged ≥ 18 years)
18. 18. Mean change from baseline to Week 25 in Pediatric Quality of Life Inventory™ (PedsQL™) Multidimensional Fatigue Scale (MFS), and the Physical Functioning scale of the PedsQL Core (for patients aged 8-17 years)
19. 19. Proportion of patients with preference for crovalimab after switching from eculizumab or ravulizumab at Week 17 (Arms A and C), as assessed through use of a Patient Preference Questionnaire developed by the Sponsor (for patients aged ≥ 12 years)
20. 20. Mean treatment satisfaction with crovalimab or eculizumab at Week 25, as assessed by the Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) (for patients aged ≥ 18 years)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information System - TISL

Third parties 14

Locations

13 EU/EEA countries · 36 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 151 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications