Multicenter, Prospective, Open-label, Randomized, Crossover Study to Evaluate Pharmacokinetics (PK), Safety, and Tolerability of TAK-881 in Primary Immunodeficiency Diseases (PIDD)
- Trial ID
- 2022-502095-23-01
- Protocol
- TAK-881-3001
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **pharmacokinetics** (PK) comparability of TAK-881 and HYQVIA at steady-state following subcutaneous administration in subjects aged 16 years and older with Primary Immunodeficiency Diseases (PIDD). This is clinically relevant as it aims to establish the equivalence in drug absorption and distribution, which is crucial for ensuring therapeutic efficacy and safety in this patient population.
Secondary objectives include:
- Assessing infections in all subjects.
- Evaluating healthcare resource utilization for subjects using TAK-881/HYQVIA.
- Evaluating PK, safety, tolerability, and immunogenicity of TAK-881 in subjects aged 16 years and older with PIDD.
- Characterizing the PK of TAK-881 between subjects aged 16 years and those aged 2 to less than 16 years with PIDD.
- Assessing IgG trough levels and evaluating safety, tolerability, and immunogenicity of TAK-881 in pediatric subjects aged 2 to less than 16 years with PIDD.
- Evaluating infusion parameters at full dose for both TAK-881 and HYQVIA in all subjects.
Participants
The clinical trial involves a total of **23 participants** diagnosed with **Primary Immunodeficiency Diseases** (PIDD). The study population includes both male and female subjects, with an age range starting from 2 years to individuals aged 16 years and older. Participants were selected based on a documented diagnosis of a form of primary humoral immunodeficiency that necessitates IgG replacement therapy. The trial includes individuals who have been on a stable dose of regular treatment with any IGIV, HYQVIA, or cIGSC for at least 12 weeks prior to screening. Participants are required to have a serum trough level of IgG greater than 5 g/L at specified time points. The study also considers lifestyle factors such as the stability of IgG treatment intervals and requires female participants of childbearing potential to present a negative pregnancy test and agree to use effective contraception. The trial population includes vulnerable groups, ensuring that all participants or their legally designated representatives have provided informed consent and are willing to comply with study requirements.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, crossover study to evaluate the pharmacokinetics, safety, and tolerability of TAK-881 in individuals with **Primary Immunodeficiency Diseases** (PIDD). The trial aims to demonstrate pharmacokinetic comparability between TAK-881 and HYQVIA at steady-state following subcutaneous administration in subjects aged 16 years and older. The study is expected to span approximately two years, with an estimated recruitment start date in August 2024 and an anticipated completion by September 2026.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a documented diagnosis of primary humoral immunodeficiency and stable prior treatment with immunoglobulin therapies. Following successful screening, participants will be randomized to receive either TAK-881 or HYQVIA, with crossover to the alternate treatment after a defined period. The trial includes multiple follow-up visits to monitor safety, efficacy, and pharmacokinetic parameters, with blood samples collected for analysis. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected and reviewed.
The expected duration of participant involvement is approximately 27 weeks, during which they will receive regular infusions and attend scheduled visits. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The primary endpoint focuses on the area under the curve (AUC) of total IgG levels, while secondary endpoints assess infection rates, health resource utilization, and additional pharmacokinetic and safety measures. The study employs a comprehensive set of devices, including syringes, infusion pumps, and catheters, all of which are CE-marked to ensure compliance with regulatory standards.
Treatment
The clinical trial involves the administration of **TAK-881**, an experimental medication formulated as a **solution for infusion**. This investigational product contains **human normal immunoglobulin** and **hyaluronidase (human recombinant)** as active substances. The pharmaceutical form is a solution intended for **subcutaneous** administration. The dosing regimen allows for a maximum daily dose of 120 grams and a total maximum dose of 1080 grams over a treatment period of 27 weeks. The administration is facilitated using devices such as syringes, infusion pumps, and subcutaneous access catheters, all of which are CE marked. Participant compliance is monitored through scheduled visits and assessments.
The comparator treatment in this study is **HyQvia**, a commercially available product also formulated as a **solution for infusion** for **subcutaneous** use. HyQvia contains **human normal immunoglobulin** as its active substance. The dosing schedule for HyQvia mirrors that of TAK-881, with a maximum daily dose of 120 grams and a total maximum dose of 1080 grams over the same treatment period. The administration of HyQvia is supported by similar medical devices, ensuring consistency in the method of delivery between the experimental and comparator treatments. Compliance with the dosing regimen is similarly monitored through regular clinical evaluations.
Efficacy
Efficacy in this clinical trial will be assessed using several endpoints. The primary endpoint is the area under the curve (AUC0-τ,ss) based on total **IgG** levels, which will be used to evaluate the pharmacokinetic comparability of TAK-881 and HYQVIA at steady-state after subcutaneous administration in subjects with Primary Immunodeficiency Diseases (PIDD). Secondary efficacy endpoints include the annualized rate of all infections, annualized rate of acute serious bacterial infections (ASBIs), annualized rate of episodes of fever, time to first ASBI, and duration of infections. Additionally, health resource utilization will be measured by tracking days not able to attend school, work, or perform normal activities due to infections or their treatment, days on antibiotics, number of hospitalizations and their indications, and number of acute physician visits due to infections or other illnesses.
Pharmacokinetic endpoints will also be evaluated, including parameters such as Cmax, Tmax, t1/2, CL/F, Vz/F, and AUC0-τ,ss/week based on total **IgG** levels. Trough levels of total **IgG**, **IgG** subclasses, and antigen-specific **IgG** antibodies (for subjects aged 16 years and older) will be assessed. Safety endpoints will include the occurrence of treatment-emergent adverse events (TEAEs), tolerability issues such as infusion withdrawals, interruptions, and rate reductions due to TAK-881-related TEAEs, and immunogenicity, defined by the occurrence of positive binding and neutralizing antibodies to rHuPH20. Infusion-related endpoints will be monitored, including the number of infusions per month, number of infusion sites per month and per infusion, duration of infusions, monthly infusion time, maximum infusion rate per site, and infusion volume per site.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject must have a documented diagnosis of a form of primary humoral immunodeficiency involving a defect in antibody formation and requiring IgG replacement, as defined according to the International Union of Immunological Societies (IUIS) Committee (Bousfiha et al., 2020, Tangye et al., 2021).
- Subject is 2 years to <16 years at the time of signing the ICF for the single-arm treatment part of the study OR 16 years or older at the time of signing the ICF for the crossover part of the study.
- Subject has received a stable dose of regular treatment with any IGIV OR HYQVIA with a treatment interval of every 21 or 28 days OR any cIGSC with a treatment interval of every 7 or 14 days over a period of at least 12 weeks prior to screening at a minimum prestudy IgG dose equivalent to 0.3 g/kg BW/4 weeks and a maximum dose equivalent to 1 g/kg BW/4 weeks. Over that period, the subject should have been on the same product of IGIV, HYQVIA, or cIGSC. A stable dose is defined as one that deviates less than ±25% from the mean dose for all IgG infusions within this 12-week period prior to screening. Variations in the treatment interval of up to ±5 days for subjects with a 28-day treatment interval and of up to ±3 days for subjects with a 7, 14, or 21-day treatment interval are acceptable up to the first IP infusion.
- Subject has a serum trough level of IgG >5 g/L at the following time points: a. At screening (sample taken prior to prestudy IgG infusion after signing the ICF) and b. Within 12 weeks prior to screening.
- If female of childbearing potential, subject presents with a negative pregnancy test and agrees to employ a highly effective form of contraception for the duration of the study.
- Subject or, in the case of minors, legally designated representative(s) is/are willing and able to comply with the requirements of the protocol, including PK blood sampling, for the duration of the study.
- The subject or, in the case of minors, legally designated representative(s) is/are willing and able to understand and fully comply with study procedures and requirements, in the opinion of the investigator.
- The subject or, in the case of minors, legally designated representative(s) has/have provided informed consent/assent, if applicable, (that is, in writing, documented via a signed and dated ICF and/or eConsent, if available), and any required privacy authorization prior to the initiation of any study procedures.
Exclusion Criteria
- Subject has a known history of a positive result or is positive at screening for one or more of the following: hepatitis B surface antigen (HBsAg), polymerase chain reaction (PCR) for hepatitis C virus (HCV), PCR for human immunodeficiency virus (HIV) Type 1/2. Cured subjects with a history of hepatitis C infection who have a negative PCR test at screening are eligible.
- Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent): a. Persistent alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2.5× the upper limit of normal (ULN) for the testing laboratory. b. Persistent severe neutropenia (defined as an absolute neutrophil count [ANC] ≤500/mm3).
- Known history of chronic kidney disease, or estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m2 at screening.
- Subject has anemia that would preclude phlebotomy for laboratory studies, according to standard practice at the site, at the discretion of the investigator.
- Subject has a known history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IV immunoglobulin, SC immunoglobulin, and/or immune serum globulin infusions.
- Subjects with a known systemic hypersensitivity to any of the excipients of TAK 881/HYQVIA in accordance with the IB/package insert/Summary of Product Characteristics (SmPC).
- Known substance or prescription drug abuse within 12 months of screening.
- Subject has immunoglobulin A (IgA) deficiency (IgA less than 0.07 g/L) associated with known anti-IgA antibodies and a history of hypersensitivity.
- Subject has a known systemic hypersensitivity to hyaluronidase or rHuPH20.
- Subject has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening.
- Subject has a bleeding disorder or a platelet count less than 20,000/µL, or, in the opinion of the investigator, would be at significant risk of increased bleeding or bruising as a result of IGSC therapy.
- Treatment with immunosuppressants including chemotherapeutic agents, immunomodulators, and long-term systemic corticosteroid (defined as a daily dose of >1 mg of prednisone equivalent/kg/day for >30 days) within 12 weeks prior to screening. Short or intermittent courses (≤10 days) of corticosteroids are allowed.
- Live-attenuated viral vaccination within 12 weeks prior to screening.
- History or current diagnosis of thrombotic episodes; venous thrombus that occurred in association with a medical device >2 years prior to screening are allowed.
- Subject has severe dermatitis that would preclude adequate sites for safe product administration in the opinion of the investigator.
- Subject has a medical condition, laboratory finding, or physical examination finding that precludes participation, or with clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may interfere with successful completion of the study or place the subject at undue medical risk.
- Subject has participated in another clinical study involving an investigational product (IP) or investigational device within 30 days prior to screening.
- Subject is scheduled to participate in another clinical study involving an IP (except for subjects scheduled to enroll in a long-term follow-up study with TAK-881) or investigational device during the course of this study.
- Subject is a family member or employee of the investigator or the investigator’s site staff.
- If female, subject is pregnant or lactating at the time of screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 30 Aug 2024 | 4 |
 Denmark | Not Recruiting | 30 Aug 2024 | 2 |
 Germany | Not Recruiting | 30 Aug 2024 | 3 |
 Greece | Not Recruiting | 30 Aug 2024 | 1 |
 The Netherlands | Not Recruiting | 30 Aug 2024 | — |
 Poland | Not Recruiting | 30 Aug 2024 | 8 |
 Slovakia | Not Recruiting | 30 Aug 2024 | 3 |
 Spain | Not Recruiting | 30 Aug 2024 | 3 |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
HyQvia 100 mg/ml solution for infusion for subcutaneous use | Comparator | SOLUTION FOR INFUSION FOR SUBCUTANEOUS USE | SUBCUTANEOUS | 120 | 27 | PRD3237752 |
HyQvia 100 mg/ml solution for infusion for subcutaneous use | Comparator | SOLUTION FOR INFUSION FOR SUBCUTANEOUS USE | SUBCUTANEOUS | 120 | 27 | PRD3237754 |
TAK-881 | Test | SOLUTION FOR INFUSION | SUBCUTANEOUS | 120 | 27 | PRD10021986 |