Safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) Stu... | NCT02593539

ID	Type	Description	Link
2015-004876-31	EudraCT Number

Label	Type	Description	Intervention Names
Participants recieving nemiralisib	Experimental		Drug: Nemiralisib

Name	Type	Description	Arm Group Labels	Other Names
Nemiralisib	Drug	Participants will be administered nemiralisib	Participants recieving nemiralisib

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Any Serious Adverse Events (SAEs) and Any Non-serious Adverse Events (Non-SAEs)	An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations as judged by physician. Number of participants with any SAE and non-SAEs are presented.	Upto 7.5 months
Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)	SBP and DBP were measured in participants in a semi-supine position after 5 minutes rest. Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. Not applicable (NA) indicates that standard deviation could not be calculated as a single participant was analyzed.	Baseline (Day 1 pre-dose) and at Days 14, 28, 56, 83 and 84
Change From Baseline in Pulse Rate	Pulse rate was measured in participants in a semi-supine position after 5 minutes rest. Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. NA indicates that standard deviation could not be calculated as a single participant was analyzed.	Baseline (Day 1 pre-dose) and at Days 14, 28, 56, 83 and 84
Change From Baseline in Respiratory Rate	Respiratory rate was measured in participants in a semi-supine position after 5 minutes rest. . Baseline value is defined as latest pre-dose (Day 1) assessment with a non-missing value, including those from unscheduled visits. Change from Baseline is defined as post-dose visit value minus Baseline value. NA indicates that standard deviation could not be calculated as a single participant was analyzed.

Secondary Outcomes

Measure	Description	Time Frame
Plasma Concentration Following Administration of NEMI	Blood samples for pharmacokinetic analysis was collected at the indicated time points following administration of NEMI. NA indicates that standard deviation could not be calculated as a single participant was analyzed	Day 1: Pre-dose, 5 minutes, 3 hours and 24 hours post-dose; Days 14 and 83: pre-dose

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male and female subjects aged 18 or older at the time of signing the informed consent.
Patients with a clinical phenotype consistent with APDS, including a history of recurrent (frequency greater than would be expected in an immunocompetent individual) ear, sinus or pulmonary infections, and who have a known type 1 APDS-associated genetic PI3K delta mutation (i.e. E1021K, N334K, E525K and C416R).
Body weight >=45 kilograms (kg) and body mass index (BMI) >=18 kg/square meter (m^2) (inclusive)
Male subject. Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until completion of the follow-up telephone call at 1-2 weeks from last dose. Vasectomy with documentation of azoospermia. Male condom plus partner use of one of the following contraceptive options: 1. Contraceptive subdermal implant 2. Intrauterine device or intrauterine system 3. Combined estrogen and progestogen oral contraceptive, 4. Injectable progestogen 5. Contraceptive vaginal ring 6. Percutaneous contraceptive patches. This is an all inclusive list of those methods that meet the GSK definition of highly effective: having a failure rate of less than 1% per year when used consistently and, correctly and, when applicable, in accordance with the product label. For non-product methods (e.g. male sterility), the investigator determines what is consistent and correct use. The GlaxoSmithKline (GSK) definition is based on the definition provided by International Conference on Harmonisation (ICH).
Female subject. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the following conditions applies: 1. Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] and estradiol levels consistent with menopause). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. 2. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until completion of the follow-up telephone call at 1-2 weeks from last dose.
Capable of giving signed informed consent as described in protocol which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.

Exclusion Criteria:

Alanine aminotransferase (ALT) >2xupper limit normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Current or chronic history of liver disease except where hepatomegaly is identified by their clinician to be secondary to APDS, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Corrected QT interval (QTc) > 450 milliseconds (msec) or QTc > 480 msec in subjects with Bundle Branch Block
A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator, in consultation with the Medical Monitor if required, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
Regular or chronic treatment with strong inhibitors of Cytochrome P450 (CYP) 3A4 and/or CYP2D6 (this includes some anti-epileptic treatments, macrolide antibiotics, oral antifungal treatments and anti-tuberculosis therapy are prohibited from the screening visit until the end of treatment visit. Where clinically appropriate, an alternative drug in the same class (or unrelated class) that is not a strong CYP3A4 and/or CYP2D6 inhibitor can, after signing informed consent, be substituted for the original strong inhibitor of these enzymes
Use of unstable dosing regimen with intravenous (i.v.) immunoglobulin (Ig) /subcutaneous (s.c.) Ig in the last 6 months before screening. Stable maintenance immunoglobulin regimen, as per local practice, such as regular injections with a consistent dosing interval (e.g. monthly) is acceptable.
Previous use of an mechanistic target of rapamycin (mTOR) antagonist (e.g. rapamycin, everolimus) or PI3K delta inhibitor (selective or non-selective PI3K inhibitors).
History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (~240 milliliters [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
History of sensitivity to any of the study medications, or components thereof (including lactose) or a history of drug or other allergy (including a milk protein allergy) that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
History of previous intolerance of the induced sputum procedure.
Bronchoalveolar Lavage (BAL) sub study only: History of bronchospasm in response to the brochoscopy/BAL procedure
Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dose of study medication in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
A positive test for human immunodeficiency virus (HIV) antibody.
Exposure to more than 4 investigational medicinal products within 12 months prior to the first dose of study medication.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Cambridge		CB2 0GG	United Kingdom

ID	Title	Description
FG000	All NEMI	Participants were administered with either NEMI 1000 mcg using DISKUS DPI or NEMI 700 or 500 mcg using ELLIPTA DPI once daily in the morning. NEMI DISKUS and NEMI ELLIPTA were combined as All NEMI treatment group as there was no intent to compare two dose levels or devices.

ID	Title	Description
BG000	All NEMI	Participants were administered with either NEMI 1000 mcg using DISKUS DPI or NEMI 700 or 500 mcg using ELLIPTA DPI once daily in the morning. NEMI DISKUS and NEMI ELLIPTA were combined as All NEMI treatment group as there was no intent to compare two dose levels or devices.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Any Serious Adverse Events (SAEs) and Any Non-serious Adverse Events (Non-SAEs)

An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations as judged by physician. Number of participants with any SAE and non-SAEs are presented.

All Subjects Population consisted of all participants who received at least one dose of the study treatment.

Posted

Count of Participants

Participants

Upto 7.5 months

ID	Title	Description
OG000	All NEMI	Participants were administered with either NEMI 1000 mcg using DISKUS DPI or NEMI 700 or 500 mcg using ELLIPTA DPI once daily in the morning. NEMI DISKUS and NEMI ELLIPTA were combined as All NEMI treatment group as there was no intent to compare two dose levels or devices.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 15, 2018	May 10, 2021	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Jan 8, 2021	May 10, 2021	SAP_001.pdf