A Phase 3, Open-label, Single-arm, Multicenter Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy, Safety, and Immunogenicity of Ravulizumab Administered Intravenously in Pediatric Participants (6 to < 18 years of age) with Generalized Myasthenia Gravis (gMG)
- Trial ID
- 2022-501882-29-00
- Protocol
- ALXN1210-MG-319
- Sponsor
- Alexion Pharmaceuticals Inc.
Trial statistics
Objectives
The primary objective of this study is to characterize the **pharmacokinetics** (PK) and **pharmacodynamics** (PD) of ravulizumab in pediatric participants with Generalized Myasthenia Gravis (gMG). Understanding the PK and PD profiles is crucial for determining the appropriate dosing regimen and ensuring the therapeutic efficacy and safety of ravulizumab in this population.
Secondary objectives include:
- Assessing the efficacy of ravulizumab in pediatric participants with gMG who are either complement inhibitor-naïve/off treatment or complement inhibitor experienced (on treatment).
- Evaluating the effect of ravulizumab on quality of life (QoL) based on patient-reported outcomes in the same participant groups.
- Evaluating the safety of ravulizumab in pediatric participants with gMG.
- Assessing the immunogenicity of ravulizumab in this population.
- Characterizing the long-term effects of ravulizumab on efficacy, health-related QoL, safety, and immunogenicity in pediatric participants with gMG.
Participants
The clinical trial involves a total of **8 participants** diagnosed with **Generalized Myasthenia Gravis (gMG)**. The study population comprises both male and female subjects, aged between **6 to less than 18 years**, with a body weight of at least 10 kg. Participants were selected based on their clinical stability and previous treatment history with eculizumab or ravulizumab, ensuring they have been on a stable dose for a specified duration. The trial includes individuals who have demonstrated improvement in MG signs while on these treatments. Participants are required to have a confirmed diagnosis of gMG through serologic tests and meet specific clinical criteria, such as the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification of Class II to Class IV. Lifestyle considerations include adherence to a stable dosing regimen of immunosuppressive therapies and vaccinations against meningococcal infection, Haemophilus influenzae type b, and Streptococcus pneumoniae, as per national and local guidelines. The trial population is considered vulnerable, necessitating informed consent from legal guardians and assent from the participants themselves, where applicable.
Plans and Procedures
The clinical trial is a **Phase 3**, open-label, single-arm, multicenter study designed to evaluate the pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity of **ravulizumab** administered intravenously in pediatric participants aged 6 to less than 18 years with **Generalized Myasthenia Gravis (gMG)**. The trial is expected to run until July 31, 2028, with recruitment having commenced on June 15, 2023. Participants will be involved in the study for a maximum treatment period of 122 days, with the primary endpoints focusing on the summary statistics of ravulizumab concentrations and serum free C5 from Day 1 predose through Week 18 predose. Secondary endpoints include changes from baseline in various clinical scores and the incidence of adverse events and immunogenicity markers.
The trial involves a sequence of study visits, beginning with an inclusion (screening) visit where eligibility is confirmed based on criteria such as age, body weight, and a confirmed diagnosis of gMG. Participants must have a positive serologic test for anti-AChR antibodies and meet additional clinical criteria. Following the screening, participants will receive the study drug intravenously, with follow-up visits scheduled to monitor drug levels, clinical efficacy, and safety outcomes. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse events.
Participants are expected to adhere to protocol-specified contraception guidance and must have received vaccinations against meningococcal infection, Haemophilus influenzae type b, and Streptococcus pneumoniae according to national guidelines. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant's legal guardian. The study aims to provide comprehensive data on the use of ravulizumab in this pediatric population, contributing to the understanding of its therapeutic potential in managing gMG.
Treatment
The clinical trial involves the administration of **Ultomiris** (ravulizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 300 mg/3 mL and is intended for intravenous administration. The active substance, **ravulizumab**, is a Fc- and CDR-modified humanised monoclonal antibody against C5, classified under the ATC code L04AA43. The maximum daily and total dose permitted in the study is 3600 mg, with a treatment period extending up to 122 days. The pharmaceutical form is a solution for infusion, and the product is manufactured by Alexion Europe SAS. The medication is not a paediatric formulation, and it is not classified as an orphan drug.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity of ravulizumab in pediatric participants aged 6 to less than 18 years with generalized **myasthenia gravis** (gMG). Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. Participants receive the medication intravenously, and the administration is conducted under controlled clinical settings to ensure safety and accuracy in dosing.
Efficacy
Efficacy in this clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoints include summary statistics of **ravulizumab** concentrations and serum free C5 levels, measured from Day 1 predose through Week 18 predose. Secondary endpoints focus on efficacy and quality of life (QoL) measures, such as changes from baseline in the Quantitative Myasthenia Gravis (QMG) total score, Myasthenia Gravis Activities of Daily Living (MG-ADL) total score, and Myasthenia Gravis Composite (MGC) score, all evaluated through Week 18. Additionally, the Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS) will be assessed through Week 18.
Further secondary endpoints include changes from baseline in the Neuro-QoL Pediatric Fatigue score for participants aged 8 years and older, and the PROMIS Parent Proxy – Fatigue score for participants under 8 years of age, both assessed through Week 18. The proportion of participants achieving a ≥5-point reduction in the QMG total score and a ≥3-point reduction in the MG-ADL total score compared to baseline will also be evaluated over time through Week 18. The stability or improvement in QMG and MG-ADL total scores at Week 18 compared to baseline will be determined, with stability defined as a ±5-point change for QMG and a ±3-point change for MG-ADL.
Safety will be monitored by recording the incidence of adverse events (AEs) and serious adverse events (SAEs). Immunogenicity assessments will include the incidence, response categories, and titer of anti-drug antibodies (ADA), as well as the incidence of neutralizing antibodies (NAb) throughout the study. The long-term extension phase will continue to evaluate these estimands and endpoints through the end of the extension period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must be 6 to < 18 years of age at the time of signing the informed consent and body weight ≥ 10 kg.
- Female participants of childbearing potential and male participants must be willing to follow protocol-specified contraception guidance
- Diagnosis of gMG confirmed by a positive serologic test for anti-AChR (Abs) obtained at Screening and/or during Screening Period and at least 1 of the following: a. History of abnormal neuromuscular transmission test demonstrated by single-fiber electromyography or repetitive nerve stimulation, or b. History of positive anticholinesterase test (eg, edrophonium chloride or neostigmine test), or c. Demonstrated improvement in MG signs on oral AChIs, as assessed by the Investigator
- Must have QMG total score as outlined below: a. Complement inhibitor -naïve/off treatment participants 12 to < 18 years of age must have QMG total score ≥ 12 at Screening and on Day 1 b. Complement inhibitor treatment-naïve/off treatment participants 6 to < 12 years of age have no minimum QMG required for inclusion; however, participants must have documented limb weakness in at least 1 limb.
- Myasthenia Gravis Foundation of America (MGFA) Clinical Classification of Class II to Class IV at Screening
- Participants receiving treatment with any of the following must be on a stable dosing regimen of adequate duration prior to Screening and during the Screening Period as follows: a. AZA for ≥ 6 months (180 days) and have been on a stable dose for ≥ 2 months (60 days) prior to Screening b. ISTs (ie, MMF, MTX, CYC, TAC, or CY) for ≥ 3 months (90 days) and have been on a stable dose for ≥ 4 weeks (28 days) prior to Screening c. Chronic IVIg for ≥ 6 months (180 days) and on a stable dose for ≥ 3 months (90 days) prior to Screening, with the frequency and dose expected to remain stable during Screening Period and for at least 18 weeks following the first dose of study intervention (Note: Participants must not have received acute IVIg therapy within 28 days prior to Screening as outlined in Exclusion Criterion 13 of the protocol). d. Oral corticosteroids for ≥ 4 weeks (28 days) prior to Screening e. AChIs for ≥ 2 weeks (14 days) prior to Screening
- To reduce the risk of meningococcal infection (Neisseria meningitidis), all participants must be vaccinated against meningococcal infection from serogroups A, C, Y, W135, and B within 3 years prior to, or at least 14 days prior to Day 1, according to national/local guidelines. Participants who do not meet this requirement will be vaccinated against meningococcal infection according to national/local guidelines and will receive prophylactic antibiotics for at least 2 weeks after meningococcal vaccination if Day 1 occurs < 2 weeks after initial vaccination
- Must have received vaccination against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae according to current national and local vaccination guidelines
- Participant’s legal guardian must be capable of giving written informed consent and the participant must be capable of giving written informed assent (if applicable as determined by the central or local institutional review board [IRB]/independent ethics committee [IEC]) which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- Participants receiving any of the following treatments: a. Currently actively receiving eculizumab (can be in Study ECU-MG-303) or ravulizumab. Patients need to have been receiving the drug for at least 6 months and on a stable dose for ≥ 2 months (60 days) (except for dose increases due to weight change) b. Previously received eculizumab or ravulizumab with a washout period of at least 67 days eculizumab and 308 days for ravulizumab before receiving first dose of study drug. All the participants previously exposed to eculizumab or ravulizumab must have tolerated the treatment well, without side effects that might interfere with participation in the study, pose any added risk to the participant, or confound the assessment of safety or efficacy of the study intervention in the opinion of the Investigator. Furthermore, participants must have demonstrated improvement in MG signs while being treated with eculizumab, as assessed by the Investigator. Participants receiving eculizumab or ravulizumab at the time of screening must be considered clinically stable.
Exclusion Criteria
- Clinical features that, in the opinion of the Investigator, are consistent with MG crisis/exacerbation or Clinical Deterioration during the Screening Period or within: a. ≤ 28 days prior to Screening for complement inhibitor-naïve/off treatment participants b. ≤ 6 months prior to Screening for complement inhibitor experienced (on treatment) participants
- Active systemic bacterial, viral, or fungal infection within 14 days prior to Day 1
- Presence of fever ≥ 38°C (100.4°F) within 7 days prior to Day 1
- Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to the start of the Screening Period
- For participants who are not receiving a stable maintenance dose of IVIg, as described in the Inclusion Criteria, use of IVIg (eg, as acute therapy) within 4 weeks prior to first dose of study intervention
- Use of PE/PP within ≤ 28 days prior to Day 1
- Use of rituximab within ≤ 6 months (180 days) prior to Day 1
- Prior use of any experimental C5 antagonist (other than eculizumab or ravulizumab) at any time
- Participation in another investigational drug or investigational device study (other than Study ECU-MG-303) within 5 half-lives of that investigational product (if known) or within 30 days before initiation of the first dose of study intervention, whichever is longer
- Pregnant, breastfeeding, or intending to conceive during the course of the study
- Parent or legal guardian is an employee or directly related to an employee of Alexion or the institution/investigational site
- Any untreated thymic malignancy, carcinoma, or thymoma. Participants with a history of treated thymic malignancy or carcinoma are eligible for enrollment if they meet the following conditions: a. Treatment completed > 5 years prior to the Screening Visit b. No recurrence within the 5 years prior to the Screening Visit c. No radiological indication of recurrence in a computed tomography (CT) or magnetic resonance imaging (MRI) scan, including administration of IV contrast, performed within 6 months of randomization (Day 1) Participants with a history of treated benign thymoma [≤ Stage II, according to the Masaoka Staging System are eligible if they meet the following conditions: d. Histopathological or equivalent records confirming the diagnosis of benign thymoma e. Treatment completed > 6 months prior to the Screening Visit f. No known recurrence within the 6 months prior to the Screening Visit g. No radiological indication of recurrence in a CT or MRI scan, including administration of IV contrast, performed within 6 months of randomization (Day 1) h. If adequate records confirming the diagnosis of benign thymoma are not available, the participant must satisfy the eligibility criteria for thymic malignancy or carcinoma stated above
- History of thymectomy, thymomectomy, or any thymic surgery within the 6 months prior to Screening
- History of hypersensitivity to any ingredient contained in the study intervention, including hypersensitivity to murine proteins
- History of N meningitidis infection
- Known to be human immunodeficiency virus (HIV) positive
- Known medical or psychological condition(s) or risk factor that, in the opinion of the Investigator, might interfere with the participant’s full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study
- History of hospitalization for ≥ 24 hours, for any reason, within the 4 weeks (28 days) prior to Screening
- History of unexplained infections
- Previously received human neonatal Fc receptor inhibitor < 5 half-lives before Day 1
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 15 Jun 2023 | 1 |
 Italy | Recruiting | 15 Jun 2023 | 1 |
 The Netherlands | Not Recruiting | 15 Jun 2023 | — |
 Spain | Not Recruiting | 15 Jun 2023 | 1 |
| Netherlands | — | — | 1 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ultomiris 300 mg/3 mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 3600 | 122 | PRD8534323 |