A Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors

Phase 3Active Not RecruitingNCT04434092

Hoffmann-La Roche210 enrolled

Overview

A study designed to evaluate the non-inferiority of crovalimab compared with eculizumab in participants with PNH who have not been previously treated with complement inhibitor therapy.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

210

Conditions

Paroxysmal Nocturnal Hemoglobinuria

Interventions

CrovalimabDRUG

Dosing depends on body weight. Participants will be dosed as follows: * 5 kg to \< 12 kg: 100 mg IV on Week 1 Day 1 (W1D1); 85 mg SC on Week 1 Day 2 (W1D2) and Q2W from Week 3 until end of study * 12 kg to \< 20 kg: 200 mg IV on W1D1; 85 mg SC on W1D2, Weeks 2, 3 and 4; 170 mg SC, Q2W from Week 5 until end of study * 20 kg to \< 30 kg: 300 mg IV on W1D1; 85 mg SC on W1D2, Weeks 2, 3 and 4; 340 mg SC, Q4W from Week 5 until end of study * 30 kg to \< 40 kg: 400 mg IV on W1D1; 170 mg SC on W1D2, Weeks 2, 3 and 4; 510 mg SC, Q4W from Week 5 until end of study * 40 kg to \< 100 kg: 1000 mg IV on W1D1; 340 mg SC W1D2, Weeks 2, 3 and 4; 680 mg SC, Q4W from Week 5 until end of study * 100 kg: 1500 mg IV on W1D1; 340 mg SC W1D2, Weeks 2, 3 and 4; 1020 mg SC, Q4W from Week 5 until end of study.

EculizumabDRUG

Eculizumab will be administered as specified in the respective arm.

Eligibility

Sex: ALLMin age: 2 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Body weight ≥ 40 kg at screening (pediatric participants with body weight \< 40 kg) * Willingness and ability to comply with all study visits and procedures * Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry * LDH level ≥ 2x ULN at screening (as per local assessment) * Vaccination against Neisseria meningitidis serotypes A, C, W, and Y\< 3 years prior to initiation of study treatment; or, if not previously done, vaccination administered no later than one week after the first drug administration * Women of childbearing potential: agreement to remain abstinent or use contraception during the treatment period and for 10.5 months after the final dose of crovalimab or for 3 months after the final dose of eculizumab (or longer if required by the local product label) Exclusion Criteria: * Current or previous treatment with a complement inhibitor * History of allogeneic bone marrow transplantation * History of Neisseria meningitidis infection within 6 months prior to screening and up to first study drug administration * History of myelodysplastic syndrome with Revised International Prognostic Scoring System (IPSS-R) prognostic risk categories of intermediate, high and very high * Pregnant or breastfeeding, or intending to become pregnant during the study, within 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) * Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within 28 days of screening or within 5 half-lives of that investigational product, whichever is greater * 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 participant, or would, in the opinion of the Investigator, preclude the participant's safe participation in and completion of the study * Splenectomy \< 6 months before screening * Positive for Active Hepatitis B and C infection (HBV/HCV) * History of or ongoing cryoglobulinemia at screening

Locations (63)

Outcomes

Primary Outcomes

Percentage of Participants With Transfusion Avoidance (TA)

TA is defined as participants who are packed red blood cell (pRBC) transfusion-free and do not require transfusion per protocol-specified guidelines. 95% Confidence Interval (CI) for percentage of participants with TA was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to have had a transfusion. Percentages are rounded off to the nearest single decimal.

Time frame: Baseline to Week 25

Percentage of Participants With Hemolysis Control Measured by LDH

A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by LDH ≤1.5 x upper limit of normal (ULN)) from Week 5 to Week 25 taking account of the intra-patient and inter-patient correlation between LDH control statuses across visits. Percentages are rounded off to the nearest single decimal.

Time frame: Week 5 to Week 25

Secondary Outcomes

Percentage of Participants With Breakthrough Hemolysis (BTH)

BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath \[dyspnea\], anemia \[hemoglobin \< 10 grams per deciliter (g/dL)\], major adverse vascular event \[MAVE, including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2xULN after a prior LDH reduction to ≤1.5xULN from the start of study treatment. 95% CI for percentage of participants with BTH was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to have experienced a BTH event. Percentages are rounded off to the nearest single decimal.

Time frame: Baseline to Week 25

Percentage of Participants With Stabilization of Hemoglobin

Stabilized hemoglobin is defined as avoidance of a \>= 2 g/dL decrease in hemoglobin level from baseline, in the absence of transfusion. 95% CI for percentage of participants with stabilized hemoglobin was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to not have had hemoglobin stabilization. Percentages are rounded off to the nearest single decimal.

Data from ClinicalTrials.gov

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Organizacion Medica de Investigacion (OMI)

Ciudad Autonoma Buenos Aires, Argentina

Centro Integrado de Oncologia de Curitiba

Curitiba, Paraná, Brazil

*X*CEPHO - Centro de Estudos e Pesquisas em Hematologia e Oncologia

Santo André, São Paulo, Brazil

Beneficencia Portuguesa de Sao Paulo

São Paulo, Brazil

Peking Union Medical College Hospital

Beijing, China

Nanfang Hospital, Southern Medical University

Guangzhou, China

The First Affiliated Hospital, Zhejiang University

Hangzhou, China

Jiangsu Province Hospital

Nanjing, China

Affiliated Hospital of Nantong University

Nantong, China

Huashan Hospital, Fudan University

Shanghai, China

...and 53 more locations

Time frame: Baseline to Week 25

Change From Baseline in Fatigue Assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale

Fatigue was assessed using FACIT-F scale. FACIT-F is a self-assessment questionnaire with a 7-day recall period and 13 items evaluating fatigue and its impact on daily life activities. Items are scored on a response scale that ranges from 0 ("not at all") to 4 ("very much so"). Relevant items are reverse scored, and all the items are summed to create a total score range from 0 to 52, with 0 being the worst possible score and 52 being the best possible score. A higher score indicates low fatigue severity. A positive mean change indicates improvement. FACIT-F was assessed in adult participants only.

Time frame: Baseline to Week 25

Percentage of Participants With Adverse Events (AEs)

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs are reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.

Time frame: Up to 6 years

Percentage of Participants With Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (Including Meningococcal Meningitis)

An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Injection-site reactions or infusion-related reaction are AEs related to the injection site that occur during or within 24 hours after study drug administration that are judged to be related to the study drug injection.

Time frame: Up to 6 years

Percentage of Participants With AEs Leading to Study Drug Discontinuation

Time frame: Up to 6 years

Percentage of Participants With Clinical Manifestations of Drug-Target-Drug Complex (DTDC) Formation Amongst Participants Who Switched to Crovalimab Treatment From Eculizumab Treatment

Time frame: Up to 6 years

Serum Concentrations of Crovalimab And Eculizumab Over Time

Time frame: Up to 6 years

Percentage of Participants With Anti-Crovalimab Antibodies

Time frame: Up to 6 years

Change in Pharmacodynamic (PD) Biomarkers Including Complement Activity (CH50) Over Time

Time frame: Up to 6 years

Change Over Time in Free C5 Concentration in Crovalimab-Treated Participants

Time frame: Up to 6 years

Observed Value in Reticulocyte Count (Count/Milliliters [mL])

Time frame: Up to 6 years

Observed Value in Haptoglobin (Milligrams Per Deciliter [mg/dL])

Time frame: Up to 6 years

Change From Baseline in Absolute Reticulocyte Count

Time frame: Baseline, Day 1 Week 1, Week 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25

Change From Baseline in Free Hemoglobin

Time frame: Baseline, Week 2, 3, 4, 5, 9, 13, 17, 21, and 25

Change From Baseline in Haptoglobin

Time frame: Baseline, Week 2, 3, 4, 5, 9, 13, 15, 17, 21, and 25