Phase 3 Randomized Double-Blind Placebo-Controlled Study of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex Membranoproliferative Glomerulonephritis
- Trial ID
- 2024-514130-20-00
- Protocol
- APL2-C3G-310
- Sponsor
- Apellis Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of twice-weekly subcutaneous doses of pegcetacoplan compared with placebo in patients with primary **complement 3 glomerulopathy (C3G)** or **immune complex membranoproliferative glomerulonephritis (IC-MPGN)**, focusing on the reduction of **proteinuria**. This is clinically relevant as proteinuria is a key indicator of kidney damage and its reduction could signify improved renal function and disease management in these conditions.
Secondary objectives include: - Assessing the effect of pegcetacoplan on estimated glomerular filtration rate (**eGFR**), which is crucial for evaluating kidney function over time. - Evaluating the impact of pegcetacoplan on additional disease-related parameters specific to C3G/IC-MPGN, providing a broader understanding of its therapeutic potential. - Assessing the safety profile of pegcetacoplan over a 52-week treatment period, ensuring the treatment's risk-benefit ratio is favorable for long-term use.
Participants
The clinical trial involves a total of **57 participants** diagnosed with **complement 3 glomerulopathy (C3G)** or **immune complex membranoproliferative glomerulonephritis (IC-MPGN)**. The study population includes both male and female subjects, with an age range starting from 12 years, provided they weigh at least 30 kg, to adults. Participants are required to have a stable regimen for C3G/IC-MPGN treatment and must have received specific vaccinations as per ACIP recommendations. The trial population was selected based on the presence of active renal disease and a diagnosis of primary C3G or IC-MPGN, with or without previous renal transplant. Participants must demonstrate a certain level of proteinuria and meet specific renal biopsy criteria. Lifestyle considerations include the ability to self-administer the study medication or have a caregiver who can do so. The trial includes a vulnerable population, ensuring that all participants or their legal representatives provide informed consent. The study does not specify any particular dietary or physical activity requirements.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, placebo-controlled, double-blind, multicenter study designed to evaluate the efficacy and safety of **pegcetacoplan** in patients with **complement 3 glomerulopathy (C3G)** or **immune complex membranoproliferative glomerulonephritis (IC-MPGN)**. The primary objective is to assess the efficacy of twice-weekly subcutaneous doses of pegcetacoplan compared to placebo, focusing on the reduction of proteinuria. The trial is expected to last until February 28, 2025, with recruitment having started on April 13, 2022. Participants will be involved for a maximum treatment period of 52 weeks.
The study includes several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the screening visit, eligibility criteria are assessed, including age, diagnosis, and evidence of active renal disease. Participants must have a stable treatment regimen for C3G/IC-MPGN and meet specific renal function criteria. Follow-up visits will monitor the primary and secondary endpoints, such as changes in proteinuria and renal function. The end-of-study visit will evaluate the overall outcomes and safety of the treatment.
Participants are expected to adhere to the study protocol, including the administration of pegcetacoplan or placebo via a subcutaneous infusion using an ambulatory syringe infusion system. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The primary efficacy endpoint is the log-transformed ratio of urine protein-to-creatinine ratio (uPCR) at week 26 compared to baseline. Secondary endpoints include the proportion of participants achieving a composite renal endpoint, changes in renal biopsy scores, and improvements in serum markers and quality of life scores.
Treatment
The clinical trial involves the administration of **ASPAVELI 1 080 mg solution for infusion**, which contains the active substance **pegcetacoplan**. This investigational medicinal product is formulated as a solution for infusion and is administered via **subcutaneous use**. The dosing regimen consists of twice-weekly subcutaneous infusions, with a maximum daily dose of 1080 mg and a total maximum dose of 112,320 mg over the treatment period. The administration of ASPAVELI is facilitated by an ambulatory syringe infusion system, specifically the Crono Super PID Infusion Pump, which is CE marked. The trial aims to evaluate the efficacy and safety of pegcetacoplan in patients with C3 Glomerulopathy or Immune-Complex Membranoproliferative Glomerulonephritis, focusing on the reduction of proteinuria as a primary endpoint.
The study also includes a **placebo** group, where participants receive a placebo solution for ASPAVELI 1 080 mg solution for infusion. The placebo is administered in the same pharmaceutical form and via the same route as the experimental medication, ensuring the double-blind nature of the trial. The placebo serves as a comparator to assess the true efficacy of pegcetacoplan by providing a baseline for evaluating changes in proteinuria and other clinical outcomes. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol and to maintain the integrity of the trial results.
Efficacy
The efficacy of pegcetacoplan in the clinical trial will be assessed primarily through the evaluation of **proteinuria** reduction. The primary efficacy endpoint is defined as the log-transformed ratio of urine protein-to-creatinine ratio (uPCR) at week 26 compared to baseline. This measurement will provide a quantitative assessment of the treatment's impact on proteinuria levels in patients with primary C3 Glomerulopathy (C3G) or Immune-Complex Membranoproliferative Glomerulonephritis (IC-MPGN).
Secondary efficacy endpoints include several parameters: the proportion of participants achieving a composite renal endpoint, which involves a stable or improved estimated glomerular filtration rate (eGFR) and a ≥50% reduction in uPCR compared to baseline; the proportion of participants with a ≥50% reduction in uPCR; changes in the activity score of the C3G histologic index for those with evaluable renal biopsies; and decreases in C3c staining on renal biopsy. Additional secondary endpoints involve changes from baseline in eGFR, the proportion of participants achieving proteinuria <1 g/day, normalization of serum albumin levels for those below the lower limit of normal (LLN) at baseline, and normalization of serum C3 levels for those below the LLN at baseline. Patient-reported outcomes will also be assessed through changes in the FACIT-Fatigue Scale score and the KDQOL score.
The efficacy assessments will be conducted at specified timepoints, with the primary endpoint evaluated at week 26. The trial will utilize validated laboratory tests and scales to ensure accurate and reliable data collection. The use of an ambulatory syringe infusion system, specifically the Crono Super PID Infusion Pump, will facilitate the administration of pegcetacoplan as a subcutaneous infusion, ensuring consistent dosing throughout the study period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Aged at least 18 years; where approved, adolescents (aged 12-17 years) weighing at least 30 kg may also be enrolled.
- A diagnosis of primary C3G or IC-MPGN (with or without previous renal transplant).
- Evidence of active renal disease, based on one or more of the following: a. In adults or adolescents with a baseline renal biopsy (either one collected during screening or a historic biopsy collected within 28 weeks prior to randomization), at least 2+ C3c staining on the baseline renal biopsy b. In adolescents not providing a baseline renal biopsy, at least one of the following: − Plasma sC5b-9 level above the upper limit of normal during screening − Serum C3 below the lower limit of normal (LLN) during screening − Presence of an active urine sediment during screening, as evidenced by hematuria with at least 5 red blood cells per high-power field and/or red blood cell casts on routine local or central microscopic analysis of urine − Presence of C3 nephritic factor within 6 months of screening, based on central laboratory results or medical history
- No more than 50% global glomerulosclerosis or interstitial fibrosis on the baseline biopsy for adult participants or adolescent participants providing a baseline biopsy.
- At least 1 g/day of proteinuria on a screening 24-hour urine collection and a uPCR of at least 1000 mg/g in at least 2 FMU samples collected during screening.
- eGFR ≥30 mL/min/1.73 m2 calculated by the CKD-EPI creatinine equation for adults or the Bedside Schwartz equation for adolescents.
- Stable regimen for C3G/IC-MPGN treatment, as described below: a. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and/or sodium-glucose cotransporter-2 inhibitor therapy that is stable and optimized, in the opinion of the investigator, for at least 12 weeks prior to randomization b. Stable doses of other medications that can affect proteinuria (eg, steroids, mycophenolate mofetil, and/or other allowed immunosuppressants that the participant is receiving for treatment of C3G or IC-MPGN) for at least 12 weeks prior to randomization. c. If a participant is on prednisone (or other systemic corticosteroid) for C3G or IC-MPGN treatment, the dosage is stable and no higher than 20 mg/day (or equivalent dosage of a corticosteroid other than prednisone) for at least 12 weeks prior to randomization.
- Have received vaccinations against S pneumoniae, N meningitidis (types A, C, W, Y, and B), and H influenzae (type B) as per ACIP recommendations for adults or children with complement deficiencies. Vaccination series should be initiated at least 14 days prior to randomization. Vaccination is mandatory unless documented evidence exists that participants are nonresponders to vaccination.
- Female participants of childbearing potential, defined as any women who have experienced menarche and who are not permanently sterile or postmenopausal, must have negative blood pregnancy tests at screening (and negative urine pregnancy tests on day 1) and must agree to use protocol-defined methods of contraception from screening through at least 90 days after receiving the last dose of pegcetacoplan.
- Male participants must agree to use protocol-defined methods of contraception and agree to refrain from donating semen from screening through at least 90 days after receiving the last dose of pegcetacoplan.
- Participants above the legal age of consent, in accordance with local regulations, must be willing and able to provide informed consent. The legally authorized representative of participants under the legal age of consent must be willing and able to provide informed consent; where appropriate, participants under the legal age of consent must also give their assent to participation in the study.
- Willing and able to self-administer pegcetacoplan or have an identified caregiver who can perform the administration.
Exclusion Criteria
- Previous exposure to pegcetacoplan.
- Evidence of improving renal disease in the 8 weeks prior to screening or during the screening period according to available data; improving renal disease is defined as >30% increase in eGFR or >50% decrease in proteinuria.
- From a renal transplant participant, evidence of rejection that requires treatment in the baseline renal biopsy collected during screening.
- C3G/IC-MPGN secondary to another condition (eg, infection, malignancy, monoclonal gammopathy, a systemic autoimmune disease such as systemic lupus erythematosus, chronic antibody-mediated rejection, or a medication), in the opinion of the investigator.
- Current or prior diagnosis of HIV, hepatitis B, or hepatitis C infection or positive serology during screening that is indicative of infection with any of these viruses.
- Body weight greater than 100 kg at screening.
- Hypersensitivity to pegcetacoplan or to any of the excipients.
- History of meningococcal disease.
- Malignancy, except for the following: a. Cured basal or squamous cell skin cancer b. Curatively treated in situ disease c. Malignancy-free and off treatment for ≥5 years
- Severe infection (eg, requiring IV antibiotic therapy) within 14 days prior to the first dose of pegcetacoplan.
- An absolute neutrophil count <1000 cells/mm3 at screening.
- Significant other renal disease that would, in the opinion of the investigator, confound interpretation of study results.
- Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedure within 30 days or 5 half-lives from the last dose of investigational agent (whichever is longer) prior to screening period.
- Use of rituximab, belimumab, or any approved or investigational anticomplement therapy other than pegcetacoplan within 5 half-lives of that product prior to the screening period.
- Female participants who are pregnant or who are currently breastfeeding and are unwilling to discontinue for the duration of the study and for at least 90 days after the final dose of study drug.
- Inability to cooperate or any condition that, in the opinion of the investigator, creates an undue risk for the participant by participating in the study or is likely to confound interpretation of the study results.
- Evidence of ongoing drug or alcohol abuse or dependence, in the opinion of the investigator.
- Presence or suspicion of severe infection during the screening period (including but not limited to recurrent or chronic infections) that, in the opinion of the investigator, may place the participant at unacceptable risk by study participation.
- Known or suspected hereditary fructose intolerance.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 13 Apr 2022 | 2 |
 Germany | Not Recruiting | 13 Apr 2022 | 6 |
 Italy | Not Recruiting | 13 Apr 2022 | 6 |
 The Netherlands | Not Recruiting | 13 Apr 2022 | — |
| Netherlands | — | — | 5 |
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 |
|---|---|---|---|---|---|---|
Placebo for ASPAVELI 1 080 mg solution for infusion | Placebo | N/A | — | — | — | N/A |
ASPAVELI 1 080 mg solution for infusion | Test | SOLUTION FOR INFUSION | SUBCUTANEOUS USE | 1080 | 52 | PRD9373388 |