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Safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Repeat Doses of Inhaled GSK2269557 in Patients With APDS/PASLI

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ClinicalTrials.gov Identifier: NCT02593539
Recruitment Status : Recruiting
First Posted : November 2, 2015
Last Update Posted : May 18, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
This is a multi-center, non-randomised, open-label, uncontrolled, single group study to investigate the safety and pharmacokinetics (PK) during 84 days repeat dosing treatment with 1000 micrograms (mcg) of inhaled GSK2269557 in addition to standard of care, in subjects with activated phosphoinositide 3-kinase (PI3K) delta syndrome /p110delta-activating mutation causing senescent T Cells, lymphadenopathy and immunodeficiency (APDS/PASLI). To date GSK2269557 has been administered to healthy subjects (smokers and non smokers), subjects with: stable Chronic Obstructive Pulmonary Disease (COPD); subjects experiencing a COPD exacerbation; and subjects with persistent, uncontrolled asthma. As this study is the first administration of GSK2269557 to subjects with APDS, this study will provide safety, tolerability, efficacy and pharmacokinetic data in this patient population. Up to 20 subjects will be enrolled into the study. The total duration of the study is approximately 30 weeks, including pre-screening/screening and follow-up.

Condition or disease Intervention/treatment Phase
Activated PI3K-delta Syndrome Drug: GSK2269557 DPI 500 mcg Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Single Arm Study to Investigate the Safety, Pharmacokinetics and Pharmacodynamics of Repeat Doses of Inhaled GSK2269557 in Patients With APDS/PASLI
Actual Study Start Date : July 22, 2016
Estimated Primary Completion Date : December 11, 2019
Estimated Study Completion Date : December 11, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: GSK2269557 DPI 1000 mcg
Subjects will receive GSK2269557 1000 mcg once daily via dry powder inhaler (DPI) for 84 days
Drug: GSK2269557 DPI 500 mcg
Subjects will receive 2 inhalations of GSK2269557 500 mcg in DPI (total dose: 1000 mcg) to be taken every day before breakfast (with the exception of days when the subjects have a planned visit to the study clinic. On those days, they will be dosed at the clinic). The subject should hold their breath for 10 seconds before exhaling. Inhalations should be taken approximately 30 seconds apart.




Primary Outcome Measures :
  1. Number of subjects with any adverse events (AE) [ Time Frame: Up to 6 months ]
    An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  2. Systolic and diastolic blood pressure as a measure of safety [ Time Frame: Up to 7.5 months ]
    Systolic and diastolic blood pressure will be measured in semi-supine position after 5 minutes rest.

  3. Temperature as a measure of safety [ Time Frame: Up to 7.5 months ]
    Temperature will be measured in semi-supine position after 5 minutes rest.

  4. Pulse rate as a measure of safety [ Time Frame: Up to 7.5 months ]
    Pulse rate will be measured in semi-supine position after 5 minutes rest.

  5. Respiratory rate as a measure of safety [ Time Frame: Up to 7.5 months ]
    Respiratory rate will be measured in semi-supine position after 5 minutes rest.

  6. 12-lead electrocardiogram (ECG) as a measure of safety [ Time Frame: Up to 7.5 months ]
    Single (triplicate at screening) 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.

  7. Composite of hematology parameters as a measure of safety [ Time Frame: Up to 7.5 months ]
    The following hematology parameters will be measured: Platelet Count, red blood cell (RBC) Count, Hemoglobin, Hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), white blood cells (WBC) count, Neutrophils, Lymphocytes, Monocytes, Eosinophils, and Basophils

  8. Composite of clinical chemistry parameters as a measure of safety [ Time Frame: Up to 7.5 months ]
    The following clinical chemistry parameters will be measured: blood urea nitrogen (BUN)/Urea, Creatinine, Glucose, C-reactive protein (CRP), Potassium, Sodium, Calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, Total and direct bilirubin, Total Protein, and Albumin

  9. Composite of urinalysis parameters as a measure of safety [ Time Frame: Up to 7.5 months ]
    Specific gravity, power of hydrogen (pH), glucose, protein, blood and ketones measured by dipstick; and microscopic examination (if blood or protein is abnormal)

  10. Spirometry: Forced expiratory volume in one second (FEV1) [ Time Frame: Up to 7.5 months ]
    FEV1 is the maximal amount of air that can be forcefully exhaled in one second.


Secondary Outcome Measures :
  1. GSK2269557 trough plasma concentration following single and repeated treatment [ Time Frame: Pre-dose, 5 minutes, 3 hours and 24 hours post-dose on Day 1 and pre-dose on Days 2, 14, and 83 and early withdrawal ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02593539


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
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United Kingdom
GSK Investigational Site Recruiting
Cambridge, United Kingdom, CB2 0GG
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02593539     History of Changes
Other Study ID Numbers: 204745
First Posted: November 2, 2015    Key Record Dates
Last Update Posted: May 18, 2018
Last Verified: May 2018

Keywords provided by GlaxoSmithKline:
APDS
Safety
Pharmacokinetics
GSK2269557
PASLI

Additional relevant MeSH terms:
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Immunologic Deficiency Syndromes
Immune System Diseases