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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alexion Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

3 Nov 2023 → ongoing

Decision date (initial)

2023-06-22

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Alexion Pharmaceuticals, Inc.

External identifiers

EU CT number

2022-501882-29-00

ClinicalTrials.gov

NCT05644561

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Safety, Others, Pharmacokinetic

To characterize the PK and PD of treatment with ravulizumab in pediatric participants with gMG

Secondary objectives 7

1. Efficacy and QoL: To assess the efficacy of treatment with ravulizumab in pediatric participants with gMG who are complement inhibitor-naïve/off treatment or who are complement inhibitor experienced (on treatment).
2. To assess the effect of treatment with ravulizumab on QoL based on patient reported outcomes in pediatric participants with gMG who are complement inhibitor-naïve/off treatment or who are complement inhibitor experienced (on treatment).
3. To assess the efficacy of treatment with ravulizumab in pediatric participants with gMG who are complement inhibitor-naïve/off treatment.
4. To assess the efficacy of treatment with ravulizumab in pediatric participants with gMG who are complement inhibitor experienced (on treatment)
5. Safety: To evaluate safety of ravulizumab in pediatric participants with gMG
6. Immunogenicity: To assess immunogenicity of ravulizumab in pediatric participants with gMG
7. Long-term Extension: To characterize the long-term effect of ravulizumab on efficacy, health-related QoL, safety, and immunogenicity in pediatric participants with gMG

Conditions and MedDRA coding

Generalized Myasthenia Gravis (gMG)

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001943-PIP03-20

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Must be 6 to < 18 years of age at the time of signing the informed consent and body weight ≥ 10 kg.
2. 10. Female participants of childbearing potential and male participants must be willing to follow protocol-specified contraception guidance
3. 2. 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
4. 3. 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.
5. 4. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification of Class II to Class IV at Screening
6. 6. 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
7. 7. 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
8. 8. Must have received vaccination against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae according to current national and local vaccination guidelines
9. 9. 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.
10. 5. 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 20

1. 1. 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
2. 10. Active systemic bacterial, viral, or fungal infection within 14 days prior to Day 1
3. 11. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to Day 1
4. 12. Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to the start of the Screening Period
5. 13. 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
6. 14. Use of PE/PP within ≤ 28 days prior to Day 1
7. 15. Use of rituximab within ≤ 6 months (180 days) prior to Day 1
8. 16. Prior use of any experimental C5 antagonist (other than eculizumab or ravulizumab) at any time
9. 18. 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
10. 19. Pregnant, breastfeeding, or intending to conceive during the course of the study
11. 20. Parent or legal guardian is an employee or directly related to an employee of Alexion or the institution/investigational site
12. 2. 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
13. 3. History of thymectomy, thymomectomy, or any thymic surgery within the 6 months prior to Screening
14. 4. History of hypersensitivity to any ingredient contained in the study intervention, including hypersensitivity to murine proteins
15. 5. History of N meningitidis infection
16. 6. Known to be human immunodeficiency virus (HIV) positive
17. 7. 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
18. 8. History of hospitalization for ≥ 24 hours, for any reason, within the 4 weeks (28 days) prior to Screening
19. 9. History of unexplained infections
20. 17. Previously received human neonatal Fc receptor inhibitor < 5 half-lives before Day 1

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Summary statistics of ravulizumab concentrations at Day 1 predose through Week 18 predose
2. Summary statistics of serum free C5 at Day 1 predose through Week 18 predose

Secondary endpoints 13

1. Efficacy and QoL: Change from baseline in QMG total score through Week 18
2. Change from baseline in MG-ADL total score through Week 18
3. Change from baseline in MGC score through Week 18
4. MGFA-PIS through Week 18
5. Change from baseline in Neuro-QoL Pediatric Fatigue score through Week 18 (participants ≥ 8 years of age only)
6. Change from baseline in PROMIS Parent Proxy – Fatigue score through Week 18 (participants < 8 years of age only)
7. Proportion of participants with ≥ 5-point reduction compared to baseline in the QMG total score over time through Week 18
8. Proportion of participants with ≥ 3-point reduction compared to baseline in the MG-ADL total score over time through Week 18
9. Proportion of participants that improve or remain stable in QMG total score at Week 18 compared to baseline (stable defined as ± 5-point change from baseline)
10. Proportion of participants that improve or remain stable in MG-ADL total score at Week 18 compared to baseline (stable defined as ± 3-point change from baseline)
11. Safety: Incidence of AEs and SAEs
12. Immunogenicity: ADA incidence, response categories, and titer, as well as NAb incidence, for the duration of the study.
13. Long-term Extension: Estimands and endpoints described above will be evaluated through the end of the Extension Period

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alexion Pharmaceuticals Inc.

Sponsor organisation

Alexion Pharmaceuticals Inc.

Address

121 Seaport Boulevard

City

Boston

Postcode

02210-2050

Country

United States

Scientific contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Public contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Third parties 1

Locations

4 EU/EEA countries · 8 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 87 files

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

Application history

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