Relative Bioavailability Study of Leniolisib Phosphate in Various Dosages in Healthy Volunteers with Activated Phosphoinositide 3-Kinase Delta Syndrome
- Trial ID
- 2023-508880-61-00
- Protocol
- LE 1102
- Sponsor
- Pharming Technologies B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **relative bioavailability** (relBA) of various dosages and formulations of **leniolisib** in healthy volunteers. Specifically, the study aims to compare the relBA of 10 mg, 30 mg, 40 mg, and 50 mg leniolisib film-coated tablets, as well as 30 mg film-coated granules, against a 70 mg leniolisib film-coated tablet, all administered as a single dose. This evaluation is clinically relevant as it provides insights into the pharmacokinetic profile of leniolisib, which is crucial for optimizing dosing regimens in the treatment of **Activated Phosphoinositide 3-Kinase Delta Syndrome**. Additionally, the study seeks to evaluate the tolerability of leniolisib following the administration of all six single-dose treatments.
Participants
The clinical trial involves participants diagnosed with **Activated Phosphoinositide 3-Kinase Delta Syndrome**. The study population includes both male and female subjects aged between 18 and 60 years. Participants are required to be in good general health, as determined by medical history, physical examination, vital sign measurements, and laboratory safety tests. The trial does not include a vulnerable population. Participants must have a body mass index (BMI) between 18.5 and 30.0 kg/m². Lifestyle considerations include being non-smokers or having quit smoking more than three months prior to the study, and the ability to abstain from alcohol, methylxanthine-containing beverages or food, and grapefruit products for specified periods before and during the trial. The sponsor has not provided information regarding the total number of participants. Key inclusion criteria include being of nonchildbearing potential for female subjects and adherence to specific contraceptive measures for fertile male subjects. Participants must also be willing to comply with all study-related procedures and restrictions. The selection process for the trial population is not detailed by the sponsor.
Plans and Procedures
The clinical trial is designed to evaluate the **relative bioavailability** of various dosages of leniolisib, a small molecule oral inhibitor of p110δ, in healthy volunteers. This study is a randomized, controlled, six-way crossover trial, which is double-blind to ensure unbiased results. The trial will compare the bioavailability of 10 mg, 30 mg, 40 mg, and 50 mg film-coated tablets, as well as 30 mg film-coated granules, against a 70 mg film-coated tablet, all administered as a single dose. The primary objective is to determine the dose-normalized maximum observed drug concentration (Cmax) and the area under the concentration versus time curve (AUC) for each formulation. Secondary endpoints include the incidence of treatment-emergent adverse events (TEAEs) across the different formulations.
The trial is expected to commence on February 1, 2024, and conclude by July 31, 2024. Participants will be involved in the study for the duration of the trial, with specific visits scheduled for screening, treatment administration, and follow-up assessments. The initial screening visit will confirm eligibility based on criteria such as age, health status, and lifestyle factors. Participants will then undergo multiple treatment periods, each separated by a washout phase to prevent carryover effects. The end-of-study visit will involve final assessments to ensure participant safety and collect any remaining data.
Participant involvement is expected to last throughout the trial duration, with conditions for early termination including non-compliance with study protocols, adverse reactions, or withdrawal of consent. The study is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and are aware of their rights to withdraw at any time. The trial aims to provide valuable data on the pharmacokinetics and safety profile of leniolisib, contributing to the understanding of its therapeutic potential for conditions such as **Activated Phosphoinositide 3-Kinase Delta Syndrome**.
Treatment
The clinical trial involves the administration of **CDZ173/Leniolisib**, a small molecule oral inhibitor of p110δ, in various pharmaceutical forms and dosages. The active substance in all formulations is **leniolisib phosphate**, a chemically synthesized compound. The trial aims to determine the relative bioavailability of different dosages and forms of leniolisib in healthy volunteers.
The experimental medication is provided in several forms, including film-coated tablets and film-coated granules in single-dose containers. The film-coated tablets are available in dosages of 10 mg, 30 mg, 40 mg, 50 mg, and 70 mg. The 10 mg, 30 mg, and 40 mg tablets are pediatric formulations, while the 50 mg and 70 mg tablets are not. The film-coated granules are provided in a 15 mg single-dose container, also designed as a pediatric formulation. All forms of the medication are administered orally as a single dose.
There are no non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, used in this study. The focus is solely on evaluating the relative bioavailability and tolerability of the different leniolisib formulations. Participant compliance is monitored through the administration of single doses under controlled conditions, ensuring accurate assessment of the pharmacokinetic parameters.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **relative bioavailability** (relBA) of various dosages of leniolisib film-coated tablets and granules. The primary endpoints for efficacy assessment include the ratio of geometric least square means between the five test formulations and the reference formulation for dose-normalized maximum observed drug concentration (Cmax), dose-normalized area under the concentration versus time curve (AUC) from time zero to the last time point with a measurable concentration (AUC0-tlast), and dose-normalized AUC from time zero to infinity (AUC0-∞). These parameters will be measured to determine the pharmacokinetic profile of leniolisib in healthy volunteers.
Secondary endpoints will focus on the incidence of treatment-emergent adverse events (TEAEs) to compare the safety profile of the five test formulations against the reference formulation. The trial is designed to evaluate these parameters following the administration of single doses of leniolisib, with the aim of determining the tolerability of the drug across different formulations. The study will involve a six-way relative bioavailability comparison, ensuring a comprehensive assessment of the drug's pharmacokinetic and safety profiles.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female between 18 and 60 years of age (both inclusive) at the screening visit; female subjects must be of nonchildbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year postmenopausal [amenorrhea duration of 12 consecutive months]) and have a negative serum pregnancy test at screening and a negative urine pregnancy test at (each) admission to the clinical research center.
- Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to screening and each admission to the clinical research center;
- Ability and willingness to abstain from methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, energy drinks) and grapefruit (juice) from 48 hours (2 days) prior to screening and each admission to the clinical research center;
- Subject understands the study procedures and agrees to participate in the study by giving written informed consent.
- Body mass index (BMI) between 18.5 and 30.0 kg/m2 (both inclusive);
- Subject is judged to be in good health based on medical history, physical examination, vital sign measurements (pulse rate between 50 and 90 bpm), and laboratory safety tests performed at the screening visit and prior to administration of the initial dose of study drug;
- For this study, a fertile male subject must be abstinent, or must agree to use a condom together with a highly effective method of contraception by the female partner of childbearing potential, when sexually active from first admission to the clinical research center until 3 months (90 days) after the last dose. Highly effective methods of contraception to be used by female partners are the following: - Hormonal contraception that inhibits ovulation: combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, or transdermal) or progestogen-only hormonal contraception (oral, injectables or implants) - Intrauterine device or intrauterine hormone-releasing system - Bilateral tubal occlusion of the female partner performed at least 3 months prior to the Screening Visit Notes: Sperm donation is not allowed from first admission to the clinical research center until 3 months (90 days) after the last dose. Subjects who practice true abstinence, because of the subject’s lifestyle choice (i.e., the subject should not become abstinent just for the purpose of study participation), are exempt from contraceptive requirements. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. If a subject who is abstinent at the time of signing the informed consent form (ICF) becomes sexually active, they must agree to use contraception as described. Not required of contraception are: - Female who is premenarchal - Female who is postmenopausal, defined as having 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or having had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment, is she considered not of child-bearing potential.
- No clinically significant abnormality on 12-lead electrocardiogram (ECG) performed at screening;
- Willing to comply with all study related procedures and restrictions;
- Subject is a non -smoker or previous smoker who stopped smoking more than 3 months ago;
- All prescribed medication must have been stopped at least 30 days prior to admission in treatment period 1 to the clinical research center;
- All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (e.g., St. John’s wort) must have been stopped at least 14 days prior to admission in treatment period 1 to the clinical research center. An exception is made for paracetamol, which is allowed up to admission to the clinical research center;
- No abnormal liver function tests defined as the following: a) Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 1.1 x upper limit of normal (ULN); b) Total bilirubin ≤1.5 × ULN; subjects with a history of Gilbert’s syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is not greater than 0.5 mg/dL.
Exclusion Criteria
- Employee of the contract research organization (CRO) or the Sponsor;
- History of known sensitivity or intolerability to leniolisib or to any related compound or excipients in the formulations, or history of significant multiple and/or severe allergies (including latex allergy) or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food;
- History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, neoplastic or genitourinary abnormalities or diseases;
- Subject has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the subject by their participation in the study;
- Any surgical (e.g., gastrectomy, bariatric surgery, small bowel or large bowel resection) or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of any drug;
- Subject is mentally or legally incapacitated, has significant emotional problems at the time of screening visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder over the last year;
- Subject is unable to refrain from or anticipates the use of any medication throughout the study;
- Subject consumes excessive amounts of alcohol, defined as greater than 12 g (females) and 24 g (males) alcohol per day, which is equivalent to 7 (females) and 14 (males) glasses of alcoholic beverages per week (1 glass is approximately equivalent to: beer (284 mL), wine (125 mL), or distilled spirits (25 mL);
- Subject is currently a regular user (including “recreational use”) of any illicit drugs or has a history of drug (including alcohol) abuse within the past year;
- Subject has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 3 months prior to the screening visit;
- Exposure to any investigational drug within 90 days of the screening visit;
- Participation in more than 4 other clinical studies in the 12 months prior to (the first) drug administration in the current study;
- Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies (HCVab), or human immunodeficiency virus (HIV) 1 and 2 antibodies;
- Unsuitable veins for blood sampling;
- Significant and/or acute illness within 5 days prior to drug administration that may impact safety assessments, in the opinion of the Investigator;
- There is any concern by the investigator regarding the safe participation of the subject in the study or for any other reason, the investigator considers the subject inappropriate for participation in the study;
- Any vaccination within 14 days prior to first dosing or scheduled before the follow-up.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Feb 2024 | 18 |
Sites & Investigators
Research 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 |
|---|---|---|---|---|---|---|
CDZ173/Leniolisib | Test | FILM COATED TABLET | ORAL | — | — | PRD9615551 |
CDZ173/Leniolisib | Test | FILM COATED TABLET | ORAL | — | — | PRD9615550 |
CDZ173/Leniolisib | Test | FILM COATED TABLET | ORAL | — | — | PRD9615553 |
CDZ173/Leniolisib | Test | FILM-COATED GRANULES IN SINGLE-DOSE CONTAINER | ORAL | — | — | PRD10234061 |
CDZ173/Leniolisib | Test | FILM COATED TABLET | ORAL | — | — | PRD10916973 |
CDZ173/Leniolisib | Test | FILM COATED TABLET | ORAL | — | — | PRD10917159 |