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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Octapharma Pharmazeutika Produktionsgesellschaft mbH

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

30 Apr 2024 → ongoing

Decision date (initial)

2024-06-27

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Octapharma Pharmazeutika Produktionsges.m.b.H.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Prophylaxis, Safety, Pharmacokinetic

To confirm the superiority of OCTA-C1-INH in comparison to placebo administered in a double-blind manner by IV injection to relieve symptoms of an acute attack in adult and adolescent participants (≥12 to <18 years of age) with HAE.

Secondary objectives 9

1. Further assess the efficacy of OCTA-C1-INH compared to placebo to relieve symptoms of an acute attack within 4 hours
2. Assess efficacy of open-label OCTA-C1-INH to relieve symptoms of first and subsequent laryngeal attacks
3. Assess the efficacy of open-label OCTA-C1-INH to relieve symptoms of first and subsequent attacks in participants <12 years of age
4. Assess the efficacy of OCTA-C1-INH to relieve symptoms of repeated attacks
5. Assess the efficacy and safety of OCTA-C1-INH in pre-procedure prevention (IV injection within 24 hours before a medical, dental, or surgical procedure)
6. Assess the PK characteristics following a slow IV injection of 20 IU of OCTA--C1--INH per kg body weight (BW) in participants ≥2 to <18 years of age with C1-INH deficiency
7. Assess the PK characteristics following an IV injection of 20 IU of OCTA--C1--INH per kg BW in adults with C1-INH deficiency compared to historical control (consistency with CONE-01 study data)
8. Assess the safety of OCTA-C1-INH in participants with an acute HAE attack
9. Assess the quality of life (QoL) after treatment with OCTA-C1-INH compared with baseline

Conditions and MedDRA coding

acute hereditary angioedema attacks

Study design 5 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002818-PIP01-20

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Is at least 18 years of age (applicable for 1st study phase) or is at least 2 years of age (applicable for 2nd study phase)
2. Has confirmed diagnosis of HAE type I or II
3. Has had at least 3 moderate or severe HAE attacks (excluding extremity attacks) in the last 3 months before the Screening Visit. For participants ≥2 and ≤12 years of age, has had at least 1 moderate or severe HAE attack (excluding extremity attacks) in the last 6 months before Screening Visit
4. Has a documented congenital C1-INH functional activity <50% with or without C1-INH deficiency and C4 antigen level below the laboratory reference range
5. Participant or the participant’s legally authorized representative(s) has signed informed consent (as required by local law), with the assent of participants legally capable of providing it, as applicable
6. States willingness to comply with all study procedures and availability for the duration of the study
7. If the participant is of childbearing potential (CBP), has a negative pregnancy test and must have been using a highly effective method of contraception and continue to do so until at least 2 weeks after their last dose (for both blinded and open-label doses of IMP). Not of CBP is defined as surgically sterilized (hysterectomy, bilateral oophorectomy) or who are postmenopausal (defined as women with no menses for 12 months without an alternative medical cause)

Exclusion criteria 10

1. Has a history of clinically relevant antibody development against C1-INH
2. Has a medical history consistent with Type 3 HAE (i.e., onset at age above 40 year, no family history, no known HAE mutation, low C1q level in plasma)
3. Has a history of allergic reaction to C1-INH or other blood/plasma product
4. Has a history of B-cell malignancy that was unresolved in the past 5 years
5. Has a narcotic and/or alcoholic addiction
6. Has participated in any other investigational drug evaluation within 30 days before screening
7. Is pregnant or breastfeeding
8. Has any clinically significant medical or psychiatric condition that, in the investigator’s opinion would interfere with the participant’s ability to participate in the study
9. Has a history of thromboembolic events (TEEs), myocardial infarction, unstable angina pectoris, critical aortic stenosis, cerebrovascular accident, transient ischemic attack, severe peripheral vascular disease, or disseminated intravascular coagulation within one year before screening
10. (applicable until IDMC review of the interim preliminary safety and efficacy data): has clinically significant derangement in measurements of cardiovascular status (i.e. uncontrolled arterial hypertension, cardiac insufficiency New York Heart Association (NYHA) class III-IV), pulmonary status (i.e., COPD GOLD classification 3 and 4, severe asthma) and renal status (i.e., eGFR below 90 ml/min per 1.73 m2)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint of this study is the time to the beginning of unequivocal symptom relief at the defining attack site (site of swelling or pain) in blinded participants. Participants will rate symptom relief for the defining site from the start of the IMP injection every 15 minutes over 4 hours.

Secondary endpoints 26

1. Percentage of participants responding to treatment, defined as beginning of unequivocal symptom relief at the defining site within 4 hours after injection (once per participant after first QAT in the study)
2. Time to the beginning of unequivocal symptom relief at all sites involved within 4 hours after injection
3. Changes in symptom severity at the defining site by visual analog scale (VAS) rating from pre-injection over 4 hours after injection
4. Time to the beginning of unequivocal symptom relief at the defining site in participants receiving open-label treatment within 4 hours after injection
5. Percentage of participants responding to treatment, defined as beginning of unequivocal symptom relief at the defining site within 4 hours after injection
6. Changes in symptom severity at the defining site by VAS rating from pre-injection over 4 hours after injection
7. Time to the beginning of unequivocal symptom relief at all sites involved within 4 hours after injection
8. Time from each open-label injection start to complete resolution of QAT attacks
9. Percentage of repeated attacks per participant with unequivocal symptom relief at the defining site beginning within 4 hours after injection for subsequent attacks
10. Time from each open-label injection start to beginning of unequivocal symptom relief at the defining site for subsequent attacks within 4 hours after injection
11. Time from each open-label injection start to beginning of unequivocal symptom relief at all sites involved for subsequent attacks within 4 hours after injection
12. Time from each open-label injection start to complete resolution of subsequent attacks
13. Changes in symptom severity at the defining site by VAS rating from pre-injection over 4 hours after each IMP injection for repeated attacks
14. Occurrence of HAE attacks within 72 hours after pre-procedure injection
15. Changes in QoL at the end of study compared with baseline
16. Number and severity of adverse events (AEs)
17. Withdrawals due to AEs
18. Number and severity of AEs of special interest (AESIs), which comprise hypersensitivity, transmissible infectious agents, and AEs of the thromboembolic event (TEE) type
19. Changes in physical examination findings at the end of study compared with baseline
20. Changes in vital signs from pre- to post-injection
21. Changes in laboratory parameters from pre- to post-injection
22. Serology testing, blood nuclear antigen tests for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV)-1/2, and parvovirus B19 at the end of study compared with baseline
23. Presence of anti-C1-INH antibodies
24. Number and severity of local injection site reactions AEs
25. Number and severity of AEs reported within 7 days after a pre-procedure injection
26. The PK endpoint (for participants ≥2 to <18 years of age and a subset of 30 adults) is the effect of treatment on C1-INH activity, C1-INH antigen levels, and complement component 4 (C4) antigen levels. The area under the curve (AUC) over 1 week for C1-INH activity, uncorrected and corrected for baseline, will be used as the primary PK endpoints to be matched between adult and pediatric patients

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Octapharma Pharmazeutika Produktionsgesellschaft mbH

Sponsor organisation

Octapharma Pharmazeutika Produktionsgesellschaft mbH

Address

Oberlaaer Strasse 235, Favoriten Favoriten

City

Vienna

Postcode

1100

Country

Austria

Scientific contact point

Organisation

Octapharma Pharmazeutika Produktionsgesellschaft mbH

Contact name

Medical Expert Group

Public contact point

Organisation

Octapharma Pharmazeutika Produktionsgesellschaft mbH

Contact name

Medical Expert Group

Third parties 4

Locations

2 EU/EEA countries · 2 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 49 files

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

Application history

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