Efficacy and Safety of Lanadelumab (SHP643) in Japanese Participants With Hereditary Angioedema (HAE)
Study Details
Study Description
Brief Summary
The purpose of this phase 3, open-label, multi-center study is to evaluate the safety and efficacy of lanadelumab in Japanese participants with HAE Type I or II.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 3 |
Detailed Description
This study will consist of 52-week treatment period and a 4-week follow-up period. 52-week treatment period comprises of a 26-week treatment period A (Day 0 to Day 182) and a 26-week treatment period B (Day 183 to Day 364). Participants who complete treatment period A will immediately continue into treatment period B. After completion of treatment period B participants may roll over into an expanded access study TAK-743-5007. Participants who elect to rollover to Study TAK-743-5007 will complete their end of study (EOS) assessments on Day 378. All other participants will complete their EOS assessments on Day 392.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Lanadelumab Participants will receive 300 milligram (mg) lanadelumab solution once every 2 weeks (q2w) for 26 weeks (treatment period A), followed by treatment period B during which participants may remain on treatment period A regimen or will receive 300 mg lanadelumab solution once every 4 weeks (q4w) for 26 weeks if well tolerated with overall treatment period of 52 weeks. |
Drug: Lanadelumab
Participants receive 300 mg of lanadelumab solution q2w (treatment period A) for 26 weeks and q2w or q4w (treatment period B) for 26 weeks, for overall 52 weeks of treatment period.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Number of Participants Achieving Attack-Free Status for the Efficacy Evaluation Period of Day 0 Through Day 182 [Day 0 through Day 182]
A participant will be considered as attack free during an efficacy evaluation period if the participant has no investigator-confirmed HAE attacks during that efficacy evaluation period. A HAE attack is defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of participants achieving attack-free status for the efficacy evaluation period of day 0 through day 182 will be assessed.
Secondary Outcome Measures
- Number of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks During Each of the Efficacy Evaluation Periods [Day 0 through Day 182, Day 0 through Day 364, Day 70 through Day 182, Day 70 through Day 364]
Efficacy evaluation period will consist of four periods: Day 0 (after study drug administration) through Day 182 (the end of Treatment Period A), Day 0 (after study drug administration) through Day 364 (the end of Treatment Period B), presumed steady-state period from Day 70 through Day 182, presumed steady-state period from Day 70 through Day 364. Number of investigator-confirmed HAE attacks during each of the efficacy evaluation periods will be assessed.
- Number of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment During Each of the Efficacy Evaluation Periods [Day 0 through Day 182, Day 0 through Day 364, Day 70 through Day 182, Day 70 through Day 364]
Number of investigator-confirmed HAE attacks requiring acute treatment during each of the efficacy evaluation periods will be assessed.
- Number of Moderate or Severe Investigator-Confirmed Hereditary Angioedema (HAE) Attacks During Each of the Efficacy Evaluation Periods [Day 0 through Day 182, Day 0 through Day 364, Day 70 through Day 182, Day 70 through Day 364]
Severe attack is defined as grade 3 (some assistance usually required, medical intervention/therapy required, hospitalizations possible), moderate attack is defined as grade 2 (some assistance may be needed, no or minimal medical intervention/therapy required). Number of investigator-confirmed moderate or severe HAE attacks during the each of efficacy evaluation periods will be assessed.
- Number of Participants with Maximum Attack Severity During Each of the Efficacy Evaluation Periods [Day 0 through Day 182, Day 0 through Day 364, Day 70 through Day 182, Day 70 through Day 364]
Number of participants with maximum attack severity during each of the efficacy evaluation periods will be assessed.
- Number of High-Morbidity Investigator-Confirmed Hereditary Angioedema (HAE) Attacks During Each of the Efficacy Evaluation Periods [Day 0 through Day 182, Day 0 through Day 364, Day 70 through Day 182, Day 70 through Day 364]
A high morbidity HAE attack is defined as any attack that has at least 1 of the following characteristics: severe, results in hospitalization (except hospitalization for observation less than (<) 24 hours), hemodynamically significant (systolic blood pressure less than < 90, requires intravenous (IV) hydration, or associated with syncope or near syncope) or laryngeal. Number of high-morbidity investigator-confirmed HAE attacks during each of the efficacy evaluation periods will be assessed.
- Time to First Hereditary Angioedema (HAE) Attack After Day 0 for the Efficacy Evaluation Period of Day 0 Through Day 182 [Day 0 through Day 182]
The time to the first HAE attack (days) after Day 0 for the efficacy evaluation period of Day 0 through Day 182 will be calculated from the date and time of the first dose of lanadelumab for the efficacy evaluation period (Day 0 through Day 182) to the date and time of the first in HAE attack after the first open-label dose for the efficacy evaluation period of Day 0 through Day 182.
- Time to First Hereditary Angioedema (HAE) Attack After Day 0 for the Efficacy Evaluation Period of Day 70 Through Day 182 [Day 70 through Day 182]
The time to the first HAE attack (days) after Day 0 for the efficacy evaluation period of Day 70 through Day 182 will be calculated from the date and time of the first dose of lanadelumab for the efficacy evaluation period (Day 70 through Day 182) to the date and time of the first in HAE attack after the first open-label dose for the efficacy evaluation period of Day 70 through Day 182.
- Number of Participants Achieving at Least 50 %, 70% and 90% Reduction in the Investigator-Confirmed Normalized Number of Attacks (NNA) per 4 Weeks Relative to the Run-in Period Normalized Number of Attacks (NNA) for Each of Efficacy Evaluation Periods [Day 0 through Day 182, Day 0 through Day 364, Day 70 through Day 182, Day 70 through Day 364]
Run in period will be 4 weeks and may be extended up to 8 weeks to determine their baseline attack rate. The normalized number of investigator-confirmed HAE attacks (NNA) during each efficacy evaluation period will be expressed as a monthly (28 days) HAE attack rate. Number of participants achieving at least 50 percent (%), 70% and 90% reduction in the investigator-confirmed NNA per 4 weeks relative to the run-in period normalized NNA for each of the efficacy evaluation period will be assessed.
- Number of Participants Achieving Normalized Number of Attacks (NNA) Less than (<) 1.0 per 4 weeks, Less than (<)0.75 per 4 weeks, Less than (<) 0.50 per 4 weeks, and Less than (<) 0.25 per 4 weeks for Each of the Efficacy Evaluation Periods [Day 0 through Day 182, Day 0 through Day 364, Day 70 through Day 182, Day 70 through Day 364]
The normalized number of investigator-confirmed HAE attacks (NNA) during each efficacy evaluation period will be expressed as a monthly (28 days) HAE attack rate. Number of participants achieving NNA <1.0 per 4 weeks, <0.75 per 4 weeks, <0.50 per 4 weeks, and <0.25 per 4 weeks for each of the efficacy evaluation periods will be assessed.
- Number of Participants Achieving Attack-Free Status for the Efficacy Evaluation Period of Day 0 Through Day 364, Day 70 Through Day 182, and Day 70 Through Day 364 [Day 0 through Day 364, Day 70 through Day 182, and Day 70 through Day 364]
A participant will be considered as attack free during an efficacy evaluation period if the participant has no investigator-confirmed HAE attacks during that efficacy evaluation period. A HAE attack is defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of participants achieving attack-free status for the efficacy evaluation period of day 0 through day 364 will be assessed.
- Number of Participants Achieving Attack-Free Status for Monthly Increments Through Day 364 [Day 0 through Day 364]
A participant will be considered as attack free during an efficacy evaluation period if the participant has no investigator-confirmed HAE attacks during that efficacy evaluation period. A HAE attack is defined as the symptoms or signs consistent with an attack in at least 1 of the following locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). Number of participants achieving attack-free status for the monthly increments of day 0 through day 364 will be assessed
- Number of Participants Achieving Investigator-Confirmed Hereditary Angioedema (HAE) Attack-Free Intervals [Day 0 through Day 182]
A participant is considered as attack free during a time period if the participant has no investigator-confirmed HAE attacks during that time period. Participants who discontinued during a time period are considered as non-responders for that time period. Number of participants achieving investigator-confirmed HAE attack free intervals from day 0 through day 182 will be assessed.
- Percentage of Attack Free Days During Each of the Efficacy Evaluation Periods [Day 0 through Day 182, Day 0 through Day 364, Day 70 through Day 182, Day 70 through Day 364]
An attack-free day is defined as a calendar day with no investigator-confirmed HAE attack. HAE attack free days will be calculated by counting the number of days in the efficacy evaluation period without an HAE attack and dividing by the number of days the participant contributed to the efficacy evaluation period. Percentage of attack free days during each of the efficacy evaluation periods will be assessed.
- Number of Participants with Treatment Emergent Adverse Events (TEAEs) Including Adverse Events of Special Interest (AESI) and Serious Adverse Events (SAEs) [From start of the study up to end of study (EOS) (up to Day 392)]
A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with an investigational product (IP) or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the IP or medicinal product. A SAE is any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product or not and at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, congenital abnormality/birth defect, an important medical event. AESI will include hypersensitivity reactions, events of disordered coagulation such as bleeding AESI, hypercoagulable AESI. Number of participants with TEAEs including AESI and SAE will be assessed.
- Plasma Concentrations of Lanadelumab [Day 0, 56, 98, 140, 182, 266, 350, 364, 378 and 392]
Plasma Concentrations of Lanadelumab will be assessed.
- Angioedema Quality of life (AE-QoL) Questionnaire [Day 0, 56, 98, 140, 182, 266, 350, 364, 378 and 392]
The AE-QoL questionnaire is a self-administered validated instrument to assess health related (HR)QoL among participants with recurrent angioedema (including HAE). The AE-QoL consists of 17 disease-specific quality-of-life items, to produce a total AE-QoL score and 4 domain scores (functioning, fatigue/mood, fear/shame, and nutrition) and each of the 17 items has a five-point response scale ranging from 1 (Never) to 5 (Very Often).
- Plasma Kallikrein (pKal) Activity [Day 0, 56, 98, 140, 182, 266, 350, 364, 378 and 392]
pKal activity will be measured by biomarker cleaved high molecular weight kininogen (cHMWK ) level to assess pharmacodynamics (PD) of lanadelumab.
- Number of Participants With Positive Anti-drug Antibody (ADA) in Plasma [Day 0, 56, 98, 140, 182, 266, 350, 364, 378 and 392]
Number of participants with positive ADA in plasma will be assessed.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese maternal and paternal grandparents.
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The participant is male or female and greater than or equal to (> =) 12 years of age at the time of informed consent.
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Documented diagnosis of HAE (Type I or II) based upon all of the following:
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Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling episodes without accompanying urticaria).
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Diagnostic testing results obtained during screening that confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level less than (<)40 percent (%) of the normal level. Participants with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. With prior sponsor approval, participants may be retested during the run-in period if results are in congruent with clinical history or believed by the investigator to be confounded by recent C1 inhibitor use.
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At least one of the following: age at reported onset of first angioedema symptoms less than or equal to (< or =) 30 years, a family history consistent with HAE Type I or II, or C1q within normal range.
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Attack rate: Participants must experience at least 1 investigator-confirmed HAE attack per 4 weeks during the run-in period to enter the lanadelumab treatment period.
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The participant (or the participants parent/legal authorized representative, if applicable) has provided written informed consent approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC).
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If the participant is an adult, be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed or if the participant is a minor (ie, below the age of majority), have a parent/legally authorized representative who is informed of the nature of the study provide written informed consent (ie, permission) for the minor to participate in the study before any study-specific procedures are performed. Assent will be obtained from minor participants.
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Males, or non pregnant, non lactating females who are fertile and sexually active and who agree to be abstinent or agree to comply with the applicable contraceptive requirements of this protocol for the duration of the study, or females of non child bearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or postmenopausal for at least 12 months.
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Agree to adhere to the protocol-defined schedule of assessments and procedures.
Exclusion Criteria:
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Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1-INH (also known as HAE Type 3), idiopathic angioedema, or recurrent angioedema associated with urticaria.
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Participation in a prior lanadelumab study.
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Dosing with investigational drug or exposure to an investigational device within 4 weeks prior to entering to screening.
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Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systematic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
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Exposure to androgens (eg, danazol, methyltestosterone, testosterone) within 2 weeks prior to entering the run-in period.
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Use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or anti-fibrinolytics) within 2 weeks prior to entering the run in period.
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Use of short-term prophylaxis for HAE 7 days prior to entering the run-in period. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from medically indicated procedures.
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Any of the following liver function abnormalities: alanine aminotransferase (ALT) greater than (>) 3x upper limit of normal, or aspartate aminotransferase (AST) >3x upper limit of normal or bilirubin >2x upper limit of normal (unless the bilirubin is a result of Gilbert's syndrome).
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Pregnancy or breast feeding.
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Participant has any condition that in the opinion of the investigator or sponsor, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (eg, history of substance abuse, or dependence, significant preexisting illnesses or major comorbidity the investigator considers may confound the interpretation of the study results).
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Participant has a known hypersensitivity to the IP or its components.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Toyohashi Municipal Hospital | Toyohashi-shi | Aichi-Ken | Japan | 441-8570 |
| 2 | Asahi General Hospital | Asahi-shi | Chiba-Ken | Japan | 289-2511 |
| 3 | Ogaki Municipal Hospital | Ogaki-shi | Gifu-Ken | Japan | 503-8502 |
| 4 | Hiroshima University Hospital | Hiroshima-shi | Hiroshima-Ken | Japan | 734-8551 |
| 5 | Tomakomai City Hospital | Tomakomai-shi | Hokkaido | Japan | 053-8567 |
| 6 | Kobe University Hospital | Kobe-shi | Hyogo-Ken | Japan | 650-0017 |
| 7 | Tokai University Hospital | Isehara-shi | Kanagawa-Ken | Japan | 259-1193 |
| 8 | Yokohama City University Hospital | Yokohama-shi | Kanagawa-Ken | Japan | 236-0004 |
| 9 | Kyoto University Hospital | Kyoto-shi | Kyoto-Fu | Japan | 606-8507 |
| 10 | Osaka University Hospital | Suita-shi | Osaka-Fu | Japan | 565-0871 |
| 11 | Saiyu Soka Hospital | Soka-shi | Saitama-Ken | Japan | 340-0041 |
| 12 | Shimane University Hospital | Izumo-shi | Shimane-Ken | Japan | 693-8501 |
Sponsors and Collaborators
- Shire
Investigators
- Study Director: Study Director, Shire
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- SHP643-302
- 195014