IV C1 Esterase Inhibitor for Hereditary Angioedema

Recruiting at 13 trial locations

Overseen By Patrick M Murphy

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Octapharma

Must not be taking: Androgens, Monoclonal antibodies

Disqualifiers: Pregnancy, B-cell malignancy, Thromboembolic events, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: Single administration per attack

124 Participants Needed

Trial Summary

What is the purpose of this trial?

Prospective, multicenter, randomized, double-blind, parallel group, placebo- controlled, efficacy and safety phase 3 study of an intravenous human plasma- derived C1 esterase inhibitor (C1-INH) concentrate in participants with congenital C1-INH deficiency for the treatment and pre-procedure prevention of acute hereditary angioedema attacks

Will I have to stop taking my current medications?

The trial requires participants to stop certain medications before starting the study. You must not take specific blood products, hormone therapies, and some pain medications for a period ranging from 7 to 14 days before the trial. Please check with the study team for details on your specific medications.

What data supports the effectiveness of the drug C1 Esterase Inhibitor for treating hereditary angioedema?

Research shows that C1 esterase inhibitor (C1-INH) is effective for managing hereditary angioedema (HAE) attacks, with studies indicating it is the treatment of choice for acute attacks and effective for long-term prevention. Early treatment with C1-INH is thought to improve outcomes, and subcutaneous C1-INH has been proven effective in preventing HAE attacks. ^{1 2 3 4 5}

Is C1 Esterase Inhibitor safe for humans?

C1 Esterase Inhibitor, used under various names like Berinert and Haegarda, has been shown to be generally safe for treating hereditary angioedema, with rare reports of blood clotting issues usually linked to incorrect use or high doses. ^{4 6 7 8 9}

What makes the drug OCTA-C1-INH unique for treating hereditary angioedema?

OCTA-C1-INH is a new, stable, virus-inactivated, and nanofiltrated concentrate of C1 esterase inhibitor derived from human plasma, which makes it unique compared to other treatments for hereditary angioedema. ^{2 3 4 10 11}

Eligibility Criteria

This trial is for individuals with a confirmed diagnosis of Hereditary Angioedema (HAE) types I or II. Participants must have had multiple HAE attacks in recent months and have specific levels of C1-INH activity and C4 antigen. They should agree to follow study procedures, use certain contraceptives if applicable, and be at least 18 years old for phase one or at least 2 years old for phase two.

Inclusion Criteria

I have been diagnosed with HAE type I or II.

I am willing and able to follow all study rules and attend all appointments.

I've had 3 or more severe HAE attacks in the last 3 months, or if I'm between 2-12 years old, at least 1 in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either OCTA-C1-INH or placebo injection after the first qualifying attack for the treatment and pre-procedure prevention of acute hereditary angioedema attacks

Single administration per attack

1 visit (in-person) per attack

Follow-up

Participants are monitored for symptom relief and response to treatment after injection

4 hours post-injection

Continuous monitoring for 4 hours

Long-term follow-up

Participants are monitored for long-term safety and effectiveness

4 weeks

Treatment Details

Interventions

• OCTA-C1-INH

Trial Overview The trial is testing an intravenous treatment called OCTA-C1-INH against a placebo to see if it's effective and safe in treating acute hereditary angioedema attacks. It's a phase 3 study where participants are randomly assigned to receive either the real medication or a placebo in different groups without knowing which they're getting.

Participant Groups

Group I: OCTA-C1-INH Experimental Treatment 1 Intervention

OCTA-C1-INH injection, 20IU/kg BW after first qualifying attack. Treatment to be administered to blinded as well as open-label subjects.

Group II: Placebo Placebo Group 1 Intervention

0.1 mL/kg BW 0.9% sodium chloride solution injection after first qualifying attack. Only blinded subjects to receive.

OCTA-C1-INH is already approved in United States, European Union for the following indications:

Approved in United States as Berinert for:

• Acute abdominal, facial, or laryngeal hereditary angioedema (HAE) attacks

Approved in United States as Cinryze for:

• Routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE

Approved in United States as Haegarda for:

• Routine prophylaxis to prevent Hereditary Angioedema (HAE) attacks in patients 6 years of age and older

Approved in European Union as C1 Esterase Inhibitor (Human) for:

• Hereditary Angioedema (HAE)

Who Is Running the Clinical Trial?

Octapharma

Lead Sponsor

Trials

86

Recruited

11,300+

Wolfgang Marguerre

Octapharma

Chief Executive Officer since 1983

MBA from INSEAD

Wolfgang Frenzel

Octapharma

Chief Medical Officer since 2010

MD from University of Vienna

Findings from Research

Recombinant human C1-esterase inhibitor (rhC1-INH) effectively manages acute hereditary angioedema (HAE) attacks in adolescents, with symptom relief beginning within 19 to 78.5 minutes after administration, based on a study involving 16 adolescents.

The treatment is well tolerated, showing no severe adverse events or hypersensitivity reactions, and successfully restored functional plasma C1-esterase inhibitor levels to normal in nearly all patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant Human C1-Esterase Inhibitor to Treat Acute Hereditary Angioedema Attacks in Adolescents. Baker, JW., Reshef, A., Moldovan, D., et al.[2018]

Administering C1 esterase inhibitor (C1-INH) concentrate within 6 hours of the onset of a hereditary angioedema (HAE) attack significantly improves the speed of symptom relief and complete resolution compared to treatment after 6 hours, as shown in a post hoc analysis of two studies involving C1-INH.

The analysis indicated that early treatment resulted in a hazard ratio of 3.36 for symptom relief and 4.30 for complete resolution, reinforcing the recommendation for prompt treatment of HAE attacks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks. Craig, TJ., Rojavin, MA., Machnig, T., et al.[2013]

Home therapy with human plasma-derived C1-esterase inhibitor (pC1-INH) significantly reduced the mean annual hospitalization days for pediatric patients with hereditary angioedema (HAE) from 3.8 to 0.11, indicating improved management of acute edema attacks.

The time from the onset of an attack to treatment administration decreased from 67.5 minutes to 15 minutes, and the time to initial symptom relief improved from 60 minutes to 40 minutes, demonstrating the efficacy and safety of pC1-INH in home settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema. Kreuz, W., Rusicke, E., Martinez-Saguer, I., et al.[2017]

In a long-term study involving 126 patients with hereditary angioedema, subcutaneous human C1-esterase inhibitor (C1-INH[SC]) demonstrated a strong safety profile, with low incidence of adverse events and effective prophylaxis against angioedema attacks over an average treatment duration of 1.5 years.

Patients receiving the higher dose of 60 IU/kg experienced a significant reduction in attack rates, with 83% of those treated for over 2 years remaining attack-free, highlighting the efficacy of C1-INH(SC) as a long-term treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks. Craig, T., Zuraw, B., Longhurst, H., et al.[2020]

In a phase III study involving 74 patients with hereditary angioedema (HAE), treatment with recombinant human C1 esterase inhibitor (rhC1INH) did not result in any thrombotic or thromboembolic events, indicating its safety for acute attack management.

Elevated plasma D-dimer levels were observed in 80% of patients during acute HAE attacks, especially in those with submucosal symptoms, but these levels decreased by Day 7 post-treatment, suggesting that rhC1INH effectively manages acute symptoms without increasing the risk of deep vein thrombosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk. Reshef, A., Zanichelli, A., Longhurst, H., et al.[2018]

A registry study involving 135 subjects and 3196 infusions of the C1-inhibitor concentrate Berinert confirmed its extensive safety profile, with only 0.09 adverse events per infusion and minimal related complications.

Only two thromboembolic events were reported, both in patients with existing prothrombotic risk factors, indicating that Berinert is not an independent risk factor for such events when used for treating hereditary angioedema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of C1-esterase inhibitor in acute and prophylactic therapy of hereditary angioedema: findings from the ongoing international Berinert patient registry. Busse, P., Bygum, A., Edelman, J., et al.[2015]

C1-INH administered subcutaneously (C1-INH(SC)) at 60 IU/kg twice weekly significantly reduced the number of hereditary angioedema (HAE) attacks compared to C1-INH given intravenously (C1-INH(IV)) at 1000 U twice weekly, with a difference of 1.3 attacks per month (P=0.034).

The percentage of patients experiencing substantial reductions in monthly HAE attack rates (≥50%, ≥70%, and ≥90%) was significantly higher with C1-INH(SC) compared to C1-INH(IV), indicating that C1-INH(SC) may be a more effective option for routine prevention of HAE attacks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect comparison of intravenous vs. subcutaneous C1-inhibitor placebo-controlled trials for routine prevention of hereditary angioedema attacks. Bernstein, JA., Li, HH., Craig, TJ., et al.[2022]

C1 esterase inhibitor (Berinert®) is effective in treating severe angioedema, not just from hereditary causes but also from angiotensin-converting enzyme inhibitors (ACEIs), as demonstrated in a case study.

The successful treatment of a life-threatening angioedema episode with Berinert® highlights its potential as a therapeutic option for patients experiencing angioedema due to ACEIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal. Lipski, SM., Casimir, G., Vanlommel, M., et al.[2020]

In a study of 28 patients with hereditary angioedema (HAE) with normal C1-INH, Berinert® was found to be effective in treating acute attacks, with 22 out of 38 assessed attacks showing improvement within 60 minutes of treatment.

No severe adverse effects were reported, indicating that Berinert® is a safe treatment option for patients with HAE, including those with F12 gene mutations or unknown origins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hereditary angioedema with normal C1 inhibitor: clinical characteristics and treatment response with plasma-derived human C1 inhibitor concentrate (Berinert®) in a French cohort. Bouillet, L., Boccon-Gibod, I., Gompel, A., et al.[2017]

A retrospective analysis of 97 patients treated with plasma-derived C1-INH (Berinert) for acute hereditary angioedema attacks revealed a mean half-life of 32.7 hours, indicating prolonged therapeutic effects.

The long half-life of pC1-INH concentrate suggests it may offer extended protection against edema attacks, even after symptoms have resolved, compared to other treatments with shorter durations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks. Bernstein, JA., Ritchie, B., Levy, RJ., et al.[2011]

A study involving 20 adults with hereditary angioedema showed that the new C1-INH concentrate has pharmacokinetic parameters similar to existing treatments, indicating it is likely effective for managing the condition.

The new C1-INH demonstrated a favorable safety profile, with no serious adverse events or thromboembolic events reported, suggesting it is well tolerated in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma-derived C1 esterase inhibitor pharmacokinetics and safety in patients with hereditary angioedema. Martinez-Saguer, I., Bork, K., Latysheva, T., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Recombinant Human C1-Esterase Inhibitor to Treat Acute Hereditary Angioedema Attacks in Adolescents. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes with Subcutaneous C1-Inhibitor Replacement Therapy for Prevention of Hereditary Angioedema Attacks. [2020]

5. Denmark pubmed.ncbi.nlm.nih.gov

Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Safety of C1-esterase inhibitor in acute and prophylactic therapy of hereditary angioedema: findings from the ongoing international Berinert patient registry. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Indirect comparison of intravenous vs. subcutaneous C1-inhibitor placebo-controlled trials for routine prevention of hereditary angioedema attacks. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Angiotensin-converting enzyme inhibitors-induced angioedema treated by C1 esterase inhibitor concentrate (Berinert®): about one case and review of the therapeutic arsenal. [2020]

9. France pubmed.ncbi.nlm.nih.gov

Hereditary angioedema with normal C1 inhibitor: clinical characteristics and treatment response with plasma-derived human C1 inhibitor concentrate (Berinert®) in a French cohort. [2017]

10. United States pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of plasma-derived C1 esterase inhibitor concentrate used to treat acute hereditary angioedema attacks. [2011]

11. United States pubmed.ncbi.nlm.nih.gov

Plasma-derived C1 esterase inhibitor pharmacokinetics and safety in patients with hereditary angioedema. [2023]