A Phase 3, Open-Label, Single-arm, Multicenter Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Activity, and Safety of Ravulizumab Administered Subcutaneously in Pediatric Participants (2 to < 18 years of age) with Paroxysmal Nocturnal Hemoglobinuria (PNH) or Atypical Hemolytic Uremic Syndrome (aHUS)
- Trial ID
- 2022-502335-19-00
- Protocol
- ALXN1210-PED-316
- Sponsor
- Alexion Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to **characterize the pharmacokinetics (PK) and pharmacodynamics (PD)** of subcutaneously administered ravulizumab in pediatric participants with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** or **Atypical Hemolytic Uremic Syndrome (aHUS)**. Understanding the PK and PD profiles is crucial for optimizing dosing regimens and ensuring therapeutic efficacy and safety in this population.
Secondary objectives include:
- Characterizing the PK and PD of ravulizumab in both cohorts.
- Assessing the efficacy of ravulizumab in the PNH cohort.
- Evaluating the efficacy of ravulizumab in the aHUS cohort.
- Assessing the effect of ravulizumab on health-related quality of life (QoL), including fatigue, based on patient-reported and caregiver-reported outcomes.
- Evaluating the safety profile of ravulizumab in both cohorts.
- Assessing the performance of the ravulizumab on-body delivery system (OBDS) in both cohorts.
- Evaluating the immunogenicity of ravulizumab in both cohorts.
Participants
The clinical trial involves a total of **8 participants** who are pediatric patients diagnosed with **Paroxysmal Nocturnal Hemoglobinuria (PNH)** or **Atypical Hemolytic Uremic Syndrome (aHUS)**. The study population includes both male and female subjects, aged between **2 to less than 18 years**. Participants are required to have a body weight of at least **10 kg** at the time of screening. The trial population was selected based on specific inclusion criteria, including documented diagnosis of PNH or aHUS, and relevant laboratory findings. Participants must have been vaccinated against meningococcal infection, **Streptococcus pneumoniae**, and **Haemophilus influenzae type b** according to national and local guidelines. The trial includes both complement inhibitor treatment-naïve and experienced participants, with the latter having been treated with eculizumab or ravulizumab for at least 90 days prior to screening. The study population is considered vulnerable, and all participants or their legal guardians must provide informed consent or assent as applicable.
Plans and Procedures
The clinical trial is a Phase 3, open-label, single-arm, multicenter study designed to evaluate the pharmacokinetics, pharmacodynamics, activity, and safety of **ravulizumab** administered subcutaneously in pediatric participants aged 2 to less than 18 years with **paroxysmal nocturnal hemoglobinuria** (PNH) or **atypical hemolytic uremic syndrome** (aHUS). The trial will span an estimated duration until October 31, 2027, with recruitment anticipated to commence on August 30, 2024. The study involves a series of structured visits, beginning with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as age, documented diagnosis, and vaccination status. Participants will be required to have received vaccinations against meningococcal infection, Streptococcus pneumoniae, and Haemophilus influenzae type b according to national and local guidelines.
Following the screening, participants will undergo a series of follow-up visits to monitor the primary and secondary endpoints, which include the measurement of ravulizumab concentrations and serum free C5 concentrations at specified intervals, as well as assessments of efficacy, safety, and device performance. The primary endpoints focus on summary statistics of ravulizumab and serum free C5 concentrations at various time points, while secondary endpoints include changes in laboratory parameters, health-related quality of life, and immunogenicity. The study will conclude with an end-of-study visit to evaluate the overall outcomes and any adverse events experienced by the participants.
Participant involvement is expected to last up to 52 weeks, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or the occurrence of adverse events that necessitate discontinuation. The trial is not categorized as low intervention and is conducted under the sponsorship of Alexion Pharmaceuticals, Inc. and Alexion Europe SAS. The study aims to provide comprehensive data on the use of ravulizumab in the specified pediatric population, contributing to the understanding of its pharmacological profile and therapeutic potential in treating PNH and aHUS.
Treatment
The clinical trial involves the administration of **Ravulizumab**, a **solution for injection** developed by Alexion Pharmaceuticals, Inc. This experimental medication is administered subcutaneously with a maximum daily dose of 150 mg. The treatment period extends up to 52 weeks. Ravulizumab is a protein-based therapeutic, specifically a Fc- and CDR-modified humanised monoclonal antibody against C5, and is not formulated for pediatric use. The administration of this medication is monitored to ensure compliance with the dosing schedule.
Another formulation of **Ravulizumab** used in the trial is marketed under the name Ultomiris 300 mg/3 mL concentrate for solution for infusion, produced by Alexion Europe SAS. This formulation is administered intravenously with a maximum daily dose of 2700 mg. The treatment duration is also up to 52 weeks. This concentrate is prepared for infusion and is not a pediatric formulation. The administration process is carefully monitored to ensure adherence to the prescribed dosing regimen.
The trial also utilizes a drug-device combination product, the Ravulizumab OBDS, which includes a prefilled cartridge containing Ravulizumab for subcutaneous administration. This device is a compact, sterile, single-use, disposable, electro-mechanical device with a 29-gauge integrated needle, designed to be used with a prefilled stoppered cartridge. The maximum daily dose for this formulation is 490 mg, with a treatment period of up to 52 weeks. The device is investigational and does not have a CE mark. Compliance with the administration protocol is closely monitored throughout the trial.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. The focus remains on evaluating the pharmacokinetics, pharmacodynamics, activity, and safety of Ravulizumab in pediatric participants with Paroxysmal Nocturnal Hemoglobinuria (PNH) or Atypical Hemolytic Uremic Syndrome (aHUS).
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include summary statistics of **ravulizumab** concentrations and serum free C5 concentrations at specified timepoints: Day 1 postdose, Day 15 predose, Day 15 postdose, and Day 71 predose. Secondary endpoints will evaluate pharmacokinetics (PK) and pharmacodynamics (PD) across both cohorts, with serum **ravulizumab** concentrations monitored over time through Week 52. Additionally, changes from baseline in free serum C5 concentrations will be measured over the same period.
For the Paroxysmal Nocturnal Hemoglobinuria (PNH) cohort, efficacy will be further assessed by the percentage change from baseline in lactate dehydrogenase (LDH) levels at Week 10 and Week 52, incidence of breakthrough hemolysis (BTH), achievement of transfusion avoidance, and stabilized hemoglobin levels. Changes in PNH red blood cell (RBC) clone size at Week 52 will also be evaluated. In the Atypical Hemolytic Uremic Syndrome (aHUS) cohort, dialysis requirement status, changes in estimated glomerular filtration rate (eGFR), serum creatinine, and hematologic parameters such as platelets, LDH, and hemoglobin will be observed through Week 10 and Week 52.
Health-related quality of life (QoL) will be measured using patient-reported outcomes, specifically changes from baseline in fatigue as assessed by the Pediatric FACIT-Fatigue scale for participants aged 8 years and older, and the PedsQL 4.0 Generic Core Scale, both evaluated at Week 10 and Week 52. Safety assessments will include the incidence of adverse events (AEs) and serious adverse events (SAEs), as well as adverse device effects (ADEs) in participants treated with **ravulizumab** subcutaneously via an on-body injector (OBI). Device performance will be monitored through reported outcomes of attempted full-dose administration and any device deficiencies or complaints. Immunogenicity will be assessed by monitoring anti-drug antibody (ADA) incidence, response categories, and titer throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Must be 2 to < 18 years of age at the time of informed consent
- Male or female
- Female participants of childbearing potential and male participants must be willing to follow protocol-specified contraception guidance
- Body weight ≥ 10 kg at Screening
- To reduce the risk of meningococcal infection (N 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 2 weeks prior to Day 1, according to national/local guidelines. Participants who do not meet this requirement must be vaccinated against meningococcal infection according to national/local guidelines and receive prophylactic antibiotics for at least 2 weeks after meningococcal vaccination if Day 1 occurs < 2 weeks after initial vaccination.
- Must have received vaccination for Streptococcus pneumoniae according to national and local vaccination schedule guidelines
- Must have received vaccination for Haemophilus influenzae type b according to national and local vaccination schedule guidelines
- Complement inhibitor-experienced participants must have been treated with eculizumab or ravulizumab according to the labeled dosing recommendation for at least 90 days prior to Screening with no missed doses within 2 months prior to study entry and no more than 2 doses outside of the visit window.
- Participant’s legal guardian/legally authorized representative 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 (Section 10.1.3).
- Inclusion Criteria Specific for PNH Cohort: 10. Documented diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation (Borowitz, 2010) of red blood cells (RBCs) and white blood cells (WBCs), with granulocyte or monocyte clone size of ≥ 5%
- Complement inhibitor treatment-naïve participants must have the presence of 1 or more of the following PNH-related signs or symptoms within 3 months of Screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia, history of a MAVE (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cell transfusion due to PNH.
- LDH values at Screening as follows: a. Complement inhibitor treatment-naïve participants must have LDH ≥ 1.5 × ULN analyzed by the central laboratory b. Eculizumab- or ravulizumab-experienced participants must have LDH ≤ 1.5 × ULN (sample must be obtained within 1 day prior to the scheduled eculizumab/ ravulizumab dosing day [ie, at trough eculizumab/ravulizumab level] and analyzed by the central laboratory)
- Inclusion Criteria Specific for aHUS Cohort: Complement inhibitor treatment-naïve participants must have evidence of TMA, including thrombocytopenia, evidence of hemolysis, and kidney injury, based on the following laboratory findings: a. Platelet count < 150000/μL during the Screening Period or within 28 days prior to the start of the Screening Period, and b. LDH ≥ 1.5 × ULN for age and sex during the Screening Period or within 28 days prior to the start of the Screening Period, and c. Hemoglobin ≤ lower limit of normal (LLN) for age and sex during the Screening Period or within 28 days prior to the start of the Screening Period, and d. Serum creatinine level ≥ 97.5th percentile for age at Screening (participants who require dialysis for acute kidney injury are also eligible regardless of serum creatinine level)
- Eculizumab- or ravulizumab-experienced participants must have confirmed diagnosis of aHUS including all of the following laboratory findings documented by local laboratories at the time of the TMA event: a. Increase in LDH > ULN, and b. Increase in serum creatinine > ULN, and c. Decrease in platelets < LLN
- Eculizumab- or ravulizumab-experienced participants must have clinical evidence of response to eculizumab or ravulizumab indicated by stable TMA parameters (via central laboratory results) at Screening, including: a. LDH < 1.5 × ULN, and b. Platelet count ≥ 150000/μL, and c. Estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73m2 using the Schwartz formula
- Among participants with a kidney transplant: a. Known history of aHUS prior to current kidney transplant, or b. No known history of aHUS, and persistent evidence of TMA at least 4 days after modifying the immunosuppressive regimen (eg, suspending or reducing the dose) of calcineurin inhibitor ([CNI]; eg, cyclosporine, tacrolimus) or mammalian target of rapamycin inhibitor ([mTORi]; eg, sirolimus, everolimus)
- Among participants with onset of TMA postpartum, persistent evidence of TMA for > 3 days after the day of childbirth.
Exclusion Criteria
- History of bone marrow transplantation
- History of N meningitidis infection
- History of unexplained infections
- Active systemic bacterial, viral, or fungal infection within 14 days prior to study intervention administration on Day 1
- Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study intervention administration on Day 1
- Known history or positive serology of hepatitis B or C viral infection
- Known human immunodeficiency virus (HIV) infection (known history or evidenced by HIV type 1 or type 2 [HIV-1, HIV-2] antibody
- History of malignancy within 5 years of Screening with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence
- History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease (eg, active hepatitis) that, in the opinion of the Investigator or Alexion, precludes the participant’s participation in an investigational clinical study
- Unstable medical conditions (eg, myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 6 months of Day 1, coexisting chronic anemia unrelated to PNH) that would make participants unlikely to tolerate the requirements of the protocol
- 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
- Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to the start of the Screening Period
- History of hypersensitivity reactions to: a. Commonly used antibacterial agents, including beta-lactams, penicillin, aminopenicillins, fluoroquinolones (specifically including ciprofloxacin), cephalosporins, and carbapenems, which in the opinion of the Investigator would make it ifficult to properly provide either empiric antibiotic therapy or treat an active infection b. Any ingredient contained in the study intervention, including hypersensitivity to murine proteins
- Concomitant use of anticoagulants is prohibited if not on a stable regimen for at least 2 weeks prior to study entry
- Participation in another experimental therapy or investigational device study within 4 weeks before initiation of study intervention on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater (except for participation in observational studies [eg, PNH Registry])
- Received any other experimental C5 antagonist at any time
- Pregnant, breastfeeding, or intending to conceive during the course of the study
- Inability for participant/caregiver to complete the requirements for SC self-administration
- Inability to travel to the clinic for specified visits during the Primary Evaluation Period or fulfil the logistic requirements of study intervention administration
- Exclusion Criteria Specific for PNH Cohort: More than 1 LDH value > 2 × ULN within the 3 months prior to study entry (eculizumab-experienced participants or ravulizumab-experienced participants only)
- MAVE in the 6 months prior to study entry (eculizumab-experienced participants or ravulizumab-experienced participants only)
- Platelet count < 30,000/mm3 (30 × 109/L) at Screening
- Absolute neutrophil count < 500/μL (0.5 × 109/L) at Screening
- Exclusion Criteria Specific for aHUS Cohort: Hemolytic uremic syndrome related to known genetic defects of cobalamin C metabolism
- Identified drug exposure-related HUS
- Any known abnormal TMA parameters within 90 days prior to screening (ie, LDH ≥ 1.5 × ULN, or platelet count < 150,000/μL, or eGFR ≤ 30 mL/min/1.73m2 using the Schwartz formula) (eculizumab-experienced participants or ravulizumab-experienced participants only)
- Known familial or acquired ADAMTS13 (“a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13”) deficiency (activity < 5%)
- Known Shiga toxin-related hemolytic uremic syndrome (ST-HUS) as demonstrated by a positive test for Shiga toxin or culture of Shiga toxin producing bacteria
- Positive direct Coombs test which in the judgment of the Investigator is indicative of a clinically significant immune-mediated hemolysis not due to TMA
- Participants with a confirmed diagnosis of ongoing sepsis defined as positive blood cultures within 7 days prior to the start of screening and untreated with antibiotics
- Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator, confounded an accurate diagnosis of aHUS or impeded the ability to manage the aHUS disease
- Heart, lung, small bowel, pancreas, or liver transplant
- Among participants with a kidney transplant, acute kidney dysfunction within 4 weeks of transplant consistent with the diagnosis of acute cell-mediated or antibody-mediated rejection according to Banff 2013 criteria
- Among participants without a kidney transplant, history of kidney disease other than aHUS, such as: a. Known kidney biopsy finding suggestive of underlying disease other than aHUS b. Known kidney ultrasound finding consistent with an alternative diagnosis to aHUS (eg, small kidneys for age) c. Known family history and/or genetic diagnosis of noncomplement-mediated genetic renal disease (eg, focal segmental glomerulosclerosis)
- Known systemic sclerosis (scleroderma), systemic lupus erythematosus or antiphospholipid antibody positivity or syndrome
- Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for end-stage kidney disease)
- Received chronic IV immunoglobulin within 8 weeks prior to the start of Screening, unless for unrelated medical condition (eg, hypogammaglobinemia); or chronic rituximab therapy within 12 weeks prior to the start of Screening
- Received other immunosuppressive therapies such as steroids, mTORi (eg, sirolimus, everolimus), CNI (eg, cyclosporine or tacrolimus) unless: a. Part of an established post-transplant antirejection regimen, or b. Participant had confirmed anti-complement factor antibodies requiring immunosuppressive therapy, or c. Steroids were being used for a condition other than aHUS (eg, asthma)
- Use of tranexamic acid within 7 days prior to Screening
- For complement inhibitor treatment-naïve participants, received plasma exchange/plasma infusion, for 28 days or longer, prior to the start of the Screening Period for the current TMA
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 30 Aug 2024 | 6 |
 Spain | Not Recruiting | 30 Aug 2024 | 8 |
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 |
|---|---|---|---|---|---|---|
Ravulizumab | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | 150 | 52 | PRD10214990 |
Ultomiris 300 mg/3 mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 2700 | 52 | PRD8534323 |
Ravulizumab | Test | SOLUTION FOR INJECTION | SOLUTION FOR INJECTION | 490 | 52 | PRD10152375 |