Back to results

A Study of Lanadelumab to Prevent Hereditary Angioedema (HAE) Attacks in Children (SPRING)

Primary Purpose

Hereditary Angioedema

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Lanadelumab

About this trial

This is an interventional prevention trial for Hereditary Angioedema focused on measuring Lanadelumab

Eligibility Criteria

2 Years - 11 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Be a child (male or female) 2 to lesser than (<) 12 years of age at the time of screening.
Documented diagnosis of HAE (Type I or II) based upon both of the following:
1. Documented clinical history consistent with HAE (SC or mucosal, nonpruritic swelling episodes without accompanying urticarial).
2. Diagnostic testing results obtained during screening from a sponsor- approved central laboratory that confirm C1-INH functional level < 40 percent (%) of the normal level. Participants with functional C1 esterase inhibitor (C1-INH) level 40-50% of the normal level may be enrolled if they also have a complement4 (C4) level below the normal range. With prior sponsor approval, participants may be retested during the baseline observation period if results are incongruent with clinical history or believed by the investigator to be confounded by recent complement1 (C1) inhibitor use.
A historical baseline HAE attack rate of at least 1 attack per 3 months. Note: In addition, participants who experience greater than or equal to (>=)1.0 angioedema attacks per three months during the 12-week baseline observation period and who remain eligible per the inclusion criteria will enter the lanadelumab treatment period.
Agree to adhere to the protocol-defined schedule of treatments, assessments, and procedures.
Have a parent(s)/legal guardian who is informed of the nature of the study and can 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).
Females of childbearing potential must agree to be abstinent or agree to comply with the applicable contraceptive requirements of this protocol through the duration of the study from screening through 70 days after the final study visit.

Exclusion Criteria:

Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1-INH, idiopathic angioedema, or recurrent angioedema associated with urticaria.
Dosing with an investigational drug or exposure to an investigational device within 4 weeks prior to screening.
Be pregnant or breastfeeding.
Have initiated androgen treatment (eg, stanozolol, danazol, oxandrolone, methyltestosterone, and testosterone) within 2 weeks prior to entering the observation period.
Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
Have any active infectious illness or fever defined as an oral temperature greater than (>) 38 degree celsius (°C) (100.4 fahrenheit [°F]), tympanic > 38.5°C (101.3°F) , axillary > 38°C (100.4°F), or rectal/core > 38.5°C (101.3°F) within 24 hours prior to the first dose of study drug in treatment period A.
Have any HAE attack that is not resolved prior to the first dose of study drug in treatment period A.
Have any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3*upper limit of normal (ULN), or aspartate aminotransferase (AST) > 3*ULN, or total bilirubin > 2*ULN (unless the bilirubin elevation is a result of Gilbert's syndrome).
Have any condition (any surgical or medical condition) that, in the opinion of the investigator or sponsor, may compromise their safety or compliance, preclude the successful conduct of the study, or interfere with interpretation of the results (eg, significant pre-existing illness or other major comorbidity that the investigator considers may confound the interpretation of study results).
Participant has a known hypersensitivity to the investigational product or its components.

Sites / Locations

AIRE Medical of Los Angeles
Allergy & Asthma Clinical Research
IMMUNOe Research Centers
Institute Asthma and Allergy
Washington University School of Medicine
Hudson-Essex Allergy
Icahn School of Medicine at Mount Sinai
Clinical Research Center of Charlotte
Bernstein Clinical Research Center
Toledo Institute of Clinical Research Asthma & Allergy Center
AARA Research Center
Yang Medicine
Charité - Universitätsmedizin Berlin.
Klinikum der Johann-Wolfgang Goethe-Universitat.
Hämophilie Zentrum Rhein Main GmbH
Semmelweis Egyetem.
Hospital Universitario La Paz. Paseo de la Castellana

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Lanadelumab 150 mg: Age 2 to <6 Years

Lanadelumab 150 mg: Age 6 to <12 Years

Arm Description

Participants aged 2 to <6 years received lanadelumab subcutaneous (SC) injection at a dose of 150 milligrams (mg) for every 4 weeks (q4wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B).

Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator's discretion and sponsor's medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.Participants aged 6 to <12 years received lanadelumab SC injection at a dose of 150 mg for every 2 weeks (q2wks) over 52-week Treatment Period (26-week Treatment Period A and 26-week Treatment Period B). Participants could switch to a dosing regimen of 150 mg q4wks in Treatment Period B at the investigator's discretion and sponsor's medical monitor approval, if they were well controlled (e.g., attack free) for 26 weeks with lanadelumab treatment in this study.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this investigational product 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 which results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, results in a congenital abnormality/birth defect, is an important medical event. Adverse events of special interest for this study are hypersensitivity reactions and disordered coagulation (hypercoagulability events and bleeding events).

Number of Participants With Clinically Significant Laboratory Assessment Abnormalities

Laboratory values (chemistry, hematology, and coagulation) were to be considered clinically significant based on investigator's discretion.

Number of Participants With Clinically Significant Vital Signs Measurements

Vital signs included blood pressure, heart rate, body temperature, and respiratory rate.

Plasma Concentrations of Lanadelumab Over The Treatment Period

The plasma concentration of lanadelumab over treatment period was assessed.

Maximum Observed Concentration at Steady State (Cmax,ss) of Lanadelumab in Plasma

Average Concentration Over Dosing Interval at Steady State (Cavg,ss) of Lanadelumab in Plasma

Minimum Concentration at Steady State (Cmin,ss) of Lanadelumab in Plasma

Time to Reach Maximum Observed Concentration (Cmax) [Tmax] of Lanadelumab in Plasma

Area Under the Concentration-Time Curve Over the Dosing Interval at Steady State (AUCtau,ss) of Lanadelumab in Plasma

Terminal Half-life (t1/2) of Lanadelumab in Plasma

Apparent Clearance (CL/F) of Lanadelumab

Apparent Volume of Distribution (V/F) of Lanadelumab

Secondary Outcome Measures

Normalized Number of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks During Overall Treatment Period

Normalized number of investigator-confirmed HAE attacks during overall period are expressed as a monthly HAE attack rate. Investigator-confirmed HAE attack rate was calculated for each participant as number of investigator-confirmed HAE attacks occurring during given study period divided by the number of days the participant contributed to the period multiplied by 28 days. A HAE attack is defined as the symptoms or signs consistent with an attack in >=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).

Normalized Number of Investigator-Confirmed HAE Attacks For Each Efficacy Evaluation Period Other Than the Overall Treatment Period

Normalized number of investigator-confirmed HAE attacks during each efficacy evaluation period other than overall treatment period are expressed as a monthly HAE attack rate. Investigator-confirmed HAE attack rate was calculated for each participant as number of investigator-confirmed HAE attacks occurring during given study period divided by number of days participant contributed to period multiplied by 28 days. A HAE attack is defined as symptoms or signs consistent with an attack in at least 1 of following locations: peripheral angioedema (cutaneous swelling involving an extremity, 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).

Time to the First Investigator-Confirmed HAE Attack for Each Evaluation Period

Time to first investigator-confirmed HAE attack (days) for each efficacy evaluation period was calculated from date and time of first dose of lanadelumab for that efficacy evaluation period to date and time of first investigator-confirmed HAE attack after first open-label dose for that efficacy evaluation period. A HAE attack is defined as symptoms or signs consistent with an attack in >=1 of following locations: peripheral angioedema (cutaneous swelling involving an extremity, 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 tongue, palate, uvula, or larynx). Kaplan-Meier Method was used for analysis.

Normalized Number of HAE Attacks Requiring Acute Treatment for Each Efficacy Evaluation Period

The normalized number of investigator-confirmed HAE attacks requiring acute treatment during each efficacy evaluation period are expressed as a monthly HAE attack rate. The investigator-confirmed HAE attack rate was calculated for each participant as the number of investigator-confirmed HAE attacks occurring during the given study period divided by the number of days the participant contributed to the period multiplied by 28 days. 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).

Normalized Number of Moderate or Severe Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period

The normalized number of moderate or severe investigator-confirmed HAE attacks requiring acute treatment during each efficacy evaluation period are expressed as a monthly HAE attack rate. The investigator-confirmed HAE attack rate was calculated for each participant as the number of investigator-confirmed HAE attacks occurring during the given study period divided by the number of days the participant contributed to the period multiplied by 28 days. 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).

Normalized Number of High Morbidity Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period

The normalized number of high morbidity investigator-confirmed HAE attacks requiring acute treatment during each efficacy evaluation period are expressed as a monthly HAE attack rate. The investigator-confirmed HAE attack rate was calculated for each participant as the number of investigator-confirmed HAE attacks occurring during the given study period divided by the number of days the participant contributed to the period multiplied by 28 days. 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 With Characteristics of Investigator-Confirmed HAE Attacks for Each Efficacy Evaluation Period

Characteristics of investigator-confirmed HAE attacks for each efficacy evaluation period included duration, severity, attack location, and rescue medication use. 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). Only categories with data are reported.

Number of Participants With HAE Attack-Free Status for Each 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).

Plasma Kallikrein (pKal) Activity

pKal activity was measured by biomarker cleaved high molecular weight kininogen (cHMWK) level to assess pharmacodynamics of lanadelumab.

Number of Participants With Immunogenicity Status as Positive or Negative

Immunogenicity was measured based on the presence or absence of neutralizing or non-neutralizing Anti-drug Antibody (ADA) in plasma.

Full Information

NCT ID

NCT04070326

First Posted

August 26, 2019

Last Updated

April 29, 2022

Sponsor

Shire

1. Study Identification

Unique Protocol Identification Number

NCT04070326

Brief Title

A Study of Lanadelumab to Prevent Hereditary Angioedema (HAE) Attacks in Children

Acronym

SPRING

Official Title

SPRING STUDY: An Open-Label, Multicenter, Phase 3 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Lanadelumab for Prevention Against Acute Attacks of Hereditary Angioedema (HAE) in Pediatric Subjects 2 to <12 Years of Age

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Completed

Study Start Date

August 19, 2019 (Actual)

Primary Completion Date

October 30, 2021 (Actual)

Study Completion Date

October 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Shire

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The main aims of this study are to learn how lanadelumab moves through a child's body and if the children have any medical problems from lanadelumab. Other aims are to learn if prophylactic treatment with lanadelumab reduces the number and severity of HAE attacks in children, how lanadelumab affects the child's body, and if the children develop antibodies to lanadelumab. The study doctors will treat acute HAE attacks according to their standard practice. Participants will receive lanadelumab for up to 52 weeks. When they start treatment, participants will visit their clinic every week for the first 4 weeks. Then, they will visit their clinic every 4 weeks during treatment.

Detailed Description

This study will consists of 52-week treatment period and a 2 or 4-weeks follow-up period (depending on the treatment schedule). 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hereditary Angioedema

Keywords

Lanadelumab

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Lanadelumab 150 mg: Age 2 to <6 Years

Arm Type

Experimental

Arm Description

Arm Title

Lanadelumab 150 mg: Age 6 to <12 Years

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Lanadelumab

Other Intervention Name(s)

TAK-743, DX-2930, SHP643

Intervention Description

Participants will receive 150 mg dose of lanadelumab every 2 or 4 weeks, depending on the participants age, over the 52-week treatment period.

Primary Outcome Measure Information:

Title

Number of Participants With Adverse Events Including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

Description

Time Frame

Up to approximately 115 weeks

Title

Number of Participants With Clinically Significant Laboratory Assessment Abnormalities

Description

Laboratory values (chemistry, hematology, and coagulation) were to be considered clinically significant based on investigator's discretion.

Time Frame

Up to approximately 115 weeks

Title

Number of Participants With Clinically Significant Vital Signs Measurements

Description

Vital signs included blood pressure, heart rate, body temperature, and respiratory rate.

Time Frame

Up to approximately 115 weeks

Title

Plasma Concentrations of Lanadelumab Over The Treatment Period

Description

The plasma concentration of lanadelumab over treatment period was assessed.

Time Frame

Day 0 (Pre-dose), Day 4, 14, 28, 56, 84, 112, 140, 168, 182 196, 252, 308, 364 and 392

Title

Maximum Observed Concentration at Steady State (Cmax,ss) of Lanadelumab in Plasma

Time Frame