E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Symptoms or signs such as swelling or pain at any location. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019860 |
E.1.2 | Term | Hereditary angioedema |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of 1000 U and 2000 U doses of CINRYZE with rHuPH20 administered by SC injection to prevent angiodema attacks.
To assess the safety and tolerability of CINRYZE with rHuPH20 administered by SC injection. |
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E.2.2 | Secondary objectives of the trial |
To determine the optimal dose of CINRYZE with rHuPH20 administered by SC injection for prevention of angioedema attacks based upon benefit-risk assessment.
To further characterize the PK/PD of CINRYZE with rHuPH20 administered by SC injection.
To assess the immunogenicity of CINRYZE with rHuPH20 following SC administration.
To assess subject acceptance of SC administration of CINRYZE with rHuPH20 for prevention of angioedema attacks.
To evaluate subject experience with self administration of SC CINRYZE with rHuPH20.
To assess health status (quality of life) of this patient population.
To perform a longitudinal analysis of treatment-emergent anti-rHuPH20 antibody titers after completion of dosing with rHuPH20.
To further characterize treatment-emergent anti-rHuPH20 binding antibodies in applicable subjects. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Be ≥12 years of age.
2. Have a confirmed diagnosis of HAE with a history of at least one of the
following:
• C1 INH antigen level below normal
• Functional C1 INH level below normal
3. If currently receiving prophylactic IV CINRYZE therapy (i.e., 1000 U every 3 or 4 days or up to 2000 U per week) or other C1 INH therapy, have:
• during the 3 consecutive months prior to randomization, an angioedema attack rate of ≤1.0 moderate or severe attack per month (average).
NOTE: if the duration of prophylactic therapy is <3 months, but at least 1 month, the subject should satisfy this attack rate (i.e., ≤1.0 moderate or severe attack per month [average]) for the timeframe that the subject has actually received prophylactic therapy.
AND
• during the 3 consecutive months prior to starting prophylactic therapy, a history of at least 2.0 moderate or severe angioedema attacks per month (average).
NOTE: the attack rate may be estimated based on subject recall.
4. If not on prophylactic C1 INH therapy, have a history of at least 2.0 moderate or severe angioedema attacks per month (average) during the 3 consecutive months prior to randomization.
NOTE: the attack rate may be estimated based on subject recall.
5. Agree to avoid his/her known HAE triggers during the study to the best of his/her ability.
6. Agree to adhere to the protocol-defined schedule of assessments and procedures.
7. If female, be post-menopausal (cessation of menses greater than or equal to 1 year), surgically sterile, or following an acceptable non-hormonal method of birth control such as intrauterine device or barrier control for at least 1 complete menstrual cycle before the screening visit and agree to continue
use through the 30-day post-treatment visit, or using hormonal birth control products for at least 3 months prior to the first dose of study drug in Treatment Period 1 and agree to continue use through the 30-day post-treatment visit.
8. If male, be surgically sterile or agree to follow an acceptable method of birth control (e.g., barrier control) from the screening visit through 2 months after the last dose of study drug.
9. If an adult (≥18 years of age), be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
OR
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of the study provide written informed consent for the child to participate in the study before any study-specific procedures are performed (with assent from the child when appropriate). Alternatively, certain sites/IRAs may permit adolescents who are <18 years of age to be informed of the nature of the study and provide written informed consent without consent from a parent(s)/legal guardian.
To be eligibile for the post treatment follow-up, subjects must:
1. Be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
2. Have anti-rHuPH20 binding antibody titers detected post-baseline at a titer > 1:20. |
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E.4 | Principal exclusion criteria |
1. Have received any C1 INH therapy or any blood products for treatment or prevention of an angioedema attack within 7 days prior to the first dose of study drug in Treatment Period 1.
2. Be receiving prophylactic IV CINRYZE that exceeds the approved dosing regimen of 1000 U every 3 or 4 days (maximum weekly dose of 2000 U).
3. Have had angioedema attack signs or symptoms within 2 days prior to the first dose of study drug in Treatment Period 1.
4. Have received any androgen therapy (e.g., danazol, oxandrolone, stanozolol, testosterone) within 7 days prior to the first dose of study drug in Treatment Period 1.
5. If female, have started taking or changed the dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progestin containing products) within 3 months prior to the first dose of study drug in Treatment Period 1.
6. Have a history of hypercoagulability (abnormal blood clotting).
7. Have a diagnosis of acquired angioedema or known to have C1 INH antibodies.
8. Have a history of allergic reaction to C1 INH products, including CINRYZE (or any components of CINRYZE), or other blood products.
9. Have a known allergy to hyaluronidase or any other ingredient in the study formulation.
10. Be pregnant or breastfeeding.
11. Have received an investigational study drug within 30 days prior to the first dose of study drug in Treatment Period 1.
12. Have, as determined by the Investigator and/or the Sponsor’s medical monitor, any surgical or medical condition that could interfere with the administration of study drug or interpretation of study results. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the number of angioedema attacks recorded during each treatment period, normalized for the number of days the subject participated in that period. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of the treatment period. |
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E.5.2 | Secondary end point(s) |
•Cumulative Attack-Severity. This score is the sum of the maximum symptom severity recorded for each angioedema attack in a treatment period.
• Cumulative Daily-Severity. This score is the sum of the severity scores recorded for every day of reported symptoms in a treatment period.
• Time (measured in days from the first dose of study drug in a treatment period) to the first angioedema attack reported in that treatment period.
• Effects of C1 INH and C4 levels on clinical outcome (frequency, severity or anatomic location of attack) during each treatment period.
• Number of angioedema attacks requiring acute treatment during each treatment
period. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of the treatment period. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Different dose of the same product. |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |