E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Activated PI3K Delta Syndrome, a disease which predisposes affected patients to an increased frequency of infections especially of the lungs and ears |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10024970 |
E.1.2 | Term | Respiratory tract infections |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Safety
To assess the safety and tolerability of 84 days repeat dosing of inhaled nemiralisib in patients with APDS |
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E.2.2 | Secondary objectives of the trial |
Pharmacokinetics
To define the plasma pharmacokinetics (PK) of inhaled nemiralisib following repeat dosing in patients with APDS. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Bronchoalveolar lavage (BAL) Sub-Study
Objectives: Pharmacokinetics: To define the lung trough concentration of nemiralisib after repeat dosing
•Trough nemiralisib concentration in lung epithelial lining fluid (ELF) and Bronchoalveolar lavage (BAL) cell pellet at Day 84 visit.
Pharmacodynamics: To understand lung disease biology in patients with APDS and to explore the pharmacodynamic effects of inhaled nemiralisib.
•In BAL cell pellet/ELF when available analysis of:
o Lymphocyte cell subsets
o Exploratory phospho-protein biomarkers (e.g. pAKT)
o Soluble proinflammatory mediators (including IL-8, IL-6, TNFα & MMP9)
o Exploratory mRNA biomarkers
o Proteomic markers
o Antibody levels |
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E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
AGE
1. Male and female subjects aged 18 or older at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. 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 PI3Kdelta mutation (e.g. E1021K, N334K, E525K and C416R) or type 2 APDS-associated mutation
WEIGHT
3. Body weight ≥40 kg and body mass index (BMI) ≥17kg/m2 (inclusive)
SEX
4. 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:
- Non-reproductive potential defined as:
o Pre-menopausal females with one of the following:
– Documented tubal ligation
– Documented hysteroscopic tubal occlusion procedure with followup confirmation of bilateral tubal occlusion
– Hysterectomy
– Documented Bilateral Oophorectomy
o 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 (refer to laboratory reference ranges for confirmatory levels)]. 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.
- 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) (see Appendix 5 of the study protocol) 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.
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
INFORMED CONSENT
5. Capable of giving signed informed consent as described in Section 10.2 of the study protocol which includes compliance with the requirements and restrictions listed in the consent form and in this protocol’.
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E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER
FUNCTION AND QTc INTERVAL)
1. Alanine aminotransferase (ALT) >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
2. 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).
3. QTc > 450 millisecond (msec) or QTc > 480 msec in subjects with Bundle Branch Block
NOTES: The QTc is the QT interval corrected for heart rate (HR) according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machineread or manually over-read.
The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. In other words, several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.
For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used as specified in the Reporting and Analysis Plan (RAP).
4. 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.
CONCOMITANT MEDICATIONS
5. CYTOCHROME P450 3A4:
Strong CYP3A4 substrates:
Strong inhibitors of cytochrome P450 3A4: Currently, only limited in vivo information is available on the in vivo metabolism of nemiralisib; and, the role of
cytochrome P450s (CYPs) in the elimination of nemiralisib is based upon in vitro data. In vitro studies indicate that nemiralisib is predominantly metabolised by CYP3A4 enzymes with minor contributions from CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2J2. Co-administration of nemiralisib with
CYP3A4 inhibitors may result in increased systemic exposure to nemiralisib.
Regular or chronic treatment with medications that are considered strong inhibitors
of CYP3A4 are not permitted:
• Antiretrovirals including protease inhibitors (e.g., indinavir, nelfinavir,ritonavir, saquinavir, atazanavir)
• Oral antifungal treatments such as ketoconazole and itraconazole. Short courses of up to 14 days are allowed for fluconazole and voriconazole,but chronic
administrations are not permitted. It is recommended that amphotericin or posaconazole are used as oral antifungal treatment of choice.
• Antibiotics such as telithromycin and troleandomycin (macrolide). Short courses up to 14 days are allowed for mibefradil (calcium channel blocker), erythromycin
and clarithromycin (including intravenous clarithromycin) but chronic administrations are not permitted. Azithromycin may be used chronically and is
recommended as the macrolide antibiotic of choice.
• Anti-epileptic treatments; and anti-tuberculous therapy.
These medications must all have been stopped at least 14 days prior to first dose of study treatment.
Sensitive narrow therapeutic index CYP3A4 substrates:
Nemiralisib is a time-dependent inhibitor of CYP3A4 and co-administration of CYP3A4 substrates with nemiralisib may result in increased systemic exposure to the CYP3A4 substrate. Regular or chronic treatment with medications that are considered sensitive narrow therapeutic index substrates of CYP3A4 are, therefore,
not permitted:
• Alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine and tacrolimus.
These medications must all have been stopped at least 14 days prior to first dose of study treatment.
- Intravenous and oral theophylline will be allowed according to the approved label/Prescribing Information, since a specific mechanistic model constructed for nemiralisib co-administered with theophylline, suggests a negligible effect of
nemiralisib on theophylline exposure. Monitoring of patients receiving IV theophylline will be required in line with normal practice.
• Use of unstable dosing regimen with i.v. Ig / 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 mTOR antagonist (e.g. rapamycin, everolimus) or PI3K delta inhibitor (selective or non-selective PI3K inhibitors) within 6 weeks prior to first dosing.
Refer remaining Exclusion criteria from points 6 to 15 in the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
–Adverse Events (AE)
–Vital signs
–12-lead electrocardiogram (ECG)
–Clinical laboratory parameters (Haematology, clinical chemistry, urinalysis)
–Spirometry (forced expiratory volume in 1 second (FEV1)1 hr post-dose)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
–Adverse events (AEs): From start of study treatment until 3 month follow-up visit
–Hematology, clinical chemistry, urinalysis: Screening, clinic visit #1, Day -1, Day 14, Day 28, Day 56, Day 83, 3 month follow-up visit
–Vital signs, 12-lead ECG: Screening, clinic visit #1, Day -1, Day 1, Day 14, Day 28, Day 56, Day 83, Day 84, 3 month follow-up visit
–FEV1: Screening, clinic visit #1, Day 1, Day 2, Day 14.
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E.5.2 | Secondary end point(s) |
–nemiralisib trough plasma concentration following single and repeated treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
–Day 1: pre-dose then 5 min, 3 h and 24h post-dose
–Trough concentration Day 2, Day 14, Day 83
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |