| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild asthma with allergen challenge |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003561 |
| E.1.2 | Term | Asthma, unspecified |
| E.1.2 | System Organ Class | 100000004855 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Examine the effects of multi-dose regimens of different dose strengths of IPI-145 on lung function in asthmatic subjects following allergen challenge |
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| E.2.2 | Secondary objectives of the trial |
• Examine the effects of multi-dose regimens of different dose strengths of IPI-145 on airway hyperresponsiveness (AHR) in mild asthmatic subjects following allergen challenge
• Investigate the safety profile of IPI 145 in mild asthmatic subjects
• Characterize the pharmacokinetic (PK) profile of IPI-145 in mild asthmatic subjects
• Exploratory objectives:
- Examine PI3K pathway and inflammation biomarkers in serum for pharmacodynamic (PD) and predictive diagnostic relationships to IPI-145 clinical activity
- Examine the effects of multi-dose regimens of different dose strengths of IPI-145 on indices of inflammation and PI3K pathway activity in mild asthmatic subjects following allergen challenge using induced sputum (Cohorts 1 and 2 only) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female adults between 18 and 60 years of age
2. Body Mass Index (BMI) between 18 and 29.9 kg/m² at Screening
3. Written informed consent obtained from the subject prior to any study Screening procedures
4. Previously documented diagnosis of asthma for at least 6 months prior to Screening or a history of at least 6 months of episodic symptoms of airflow obstruction such as wheezing and/or chest tightness with other significant lung diseases ruled out (e.g., chronic obstructive pulmonary disease [COPD])
5. Forced expiratory volume in one second (FEV1) ≥70% of predicted value at Screening (based on American Thoracic Society [ATS]/ European Respiratory Society [ERS] standards
6. A positive skin prick test to test allergen [defined as the indurations of skin test wheal ≥2 mm larger in diameter than diameter of control wheal
7. Early-phase asthmatic response (EAR) of at least 20% and a late-phase asthmatic response (LAR) of at least 15% to inhaled allergen challenge [response defined as a decrease from pre-challenge in FEV1 on 2 consecutive occasions within 0 to <3 hours of last allergen challenge administered for EAR and within 3 to 10 hours for LAR]
8. a. Sexually active women, unless surgically sterile (confirmed by documentation) or at least 2 year post-menopausal (confirmed by FSH blood level at Screening), must have a negative serum pregnancy test result at Screening and agree to use two effective methods of contraception from the signing of informed consent through 21 days after the last dose of study drug
b. Sexually active men, unless surgically sterile, must agree to use an effective method of birth control from the signing of informed consent through 21 days after the last dose of study drug
9. Subject has the willingness and ability to complete all the study requirements, instructions, or study related restrictions through the final Safety Follow-up Phone Screen 21 days after last dose of study drug
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| E.4 | Principal exclusion criteria |
1. Any prior treatment with a phosphoinositide-3-kinase (PI3K) inhibitor other than IPI-145 in a previous clinical study
2. History of allergy or reaction to any component of the study drug formulation, such as excipients in the study drug capsule
3. Acute asthma exacerbations leading to hospitalization, emergency room visit, or unscheduled health care provider visit, within 6 weeks prior to Screening or any previous history of intubation or admission to an intensive care unit for asthma
4. Use of any medication for the treatment of asthma other than a short-acting β2 agonist (as needed) within the 4 weeks prior to Screening and no significant changes in short-acting β2 agonist use over the 6 weeks prior to Screening
5. Use if anti-IgE therapy (omalizumab) within 12 weeks prior to Screening
6. Currently receiving a cholinesterase inhibitor medication (including, but not limited to, donepezil, galantamine, rivastigmine, physostigmine, pyridostigmine, neostigmine, or edrophonium)
7. Currently receiving or expected to receive an acid-reducing agent including, but not limited to, proton pump inhibitors, H2-receptor blockers, and/or chronic antacid therapy
8. Upper or lower respiratory tract infections or acute illnesses or evidence of on-going clinically significant infection within the 4 weeks prior to Screening
9. Heart attack or stroke within the past 3 months, uncontrolled hypertension (systolic BP >200 or diastolic BP >100 mmHg), known aortic aneurysm, or any other cardiac condition in which induced bronchospasm may precipitate excessive cardiovascular stress, as judged by the Investigator
10. If undergoing concomitant allergy vaccination therapy (desensitization immunotherapy), <3 months of stable maintenance doses prior to the Baseline allergen challenge; any allergy concomitant vaccination therapy leading to desensitization to any of the allergens used in the allergen challenge
11. Participation in another clinical study within 30 days prior to study Screening or until completion of the final Safety Follow-up Visit
12. Blood donation (≥500 mL) within 3 months before Screening
13. Any history of treatment with a leukocyte-depleting agent (eg, rituximab, alemtuzumab)
14. Positive laboratory test result for hepatitis B or C or HIV-1 or HIV-2 at Screening
15. A positive screen result for active or latent tuberculosis (verified by either PPD skin test or QuantiFERON-TB blood test at Screening)
16. History of significant systemic disease (e.g., cancer, coronary artery disease, seizure disorder) as judged by the Investigator
17. Currently pregnant or lactating
18. Smoking within 6 months prior to Screening or a smoking history of ≥10 pack-years
19. A positive screen for drug and/or alcohol abuse at Screening or reported use of illegal drugs or history of abuse of prescription drugs or alcohol within 1 year before Screening
20. Planned elective surgery from the time of Screening through the final Safety Follow-up Visit
21. Clinically significant abnormalities on safety laboratory tests, 12-lead ECG, vital signs, or physical examination or medical history at Screening, based on the medical judgment of the Investigator; specific safety laboratory values for exclusion include:
• Serum creatinine ≥2.0 mg/dL (177 μmol/L)
• ALT, AST, or total bilirubin >1.5 x ULN (if the subject has Gilbert’s disease, a total bilirubin value above 1.5 x ULN is acceptable if allowed by the Sponsor’s medical monitor)
• Hemoglobin <9 g/dL, WBC <3.0 x 10^9/L, absolute neutrophil count <1.2 x 10^9/L, or platelets <100×10^9/L
22. Vulnerable subjects (i.e., those subjects imprisoned or lawfully kept in an institution)
23. Subject is an employee or direct relative of an employee of the contract research organization (CRO) or Infinity Pharmaceuticals Inc. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Maximal decrease from pre-allergen challenge in forced expiratory volume in one second (FEV1) following allergen challenge (including early asthmatic response [EAR] and late asthmatic response [LAR])
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Lung function, inflammatory indices, and other efficacy endpoints will be assessed before and after each allergen challenge of each treatment period
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| E.5.2 | Secondary end point(s) |
• Area under the curve (AUC) of FEV1 following allergen challenge
• White blood cell (WBC) count and differential cell count in induced sputum specimen obtained after allergen challenge
• Levels of cytokines and inflammatory mediators in induced sputum specimen obtained after allergen challenge
• Provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20) following allergen challenge
• Concentration of inhaled nitric oxide (NO) after allergen challenge
• Change in C-reactive Protein (CRP) levels from Screening and/or Day 1 of each treatment period over the course of the study
• Adverse events (AEs) and safety laboratory findings.
• PK Parameters including maximum concentration (Cmax), AUC, terminal elimination half-life (T1/2), time to maximum concentration (Tmax)
• Exploratory endpoints:
- Changes in PI3K pathway and inflammation biomarkers in serum (all Cohorts), plasma (Cohorts 1 and 2 only), and sputum (Cohort 2 only)
- White blood cell (WBC) count and differential cell count in induced sputum specimen obtained after allergen challenge (Cohorts 1 and 2 only) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
On the morning of Day 14 of both TP 1 (TP 1 Day 14) and TP 2 (TP 2 Day 14) subjects will be admitted to the clinic prior to taking their morning dose. At this visit, subjects will undergo an allergen challenge; spirometry and other efficacy endpoints will be assessed, and serial blood samples will be collected for PK. Subjects will be confined overnight for safety observation. On Day 15 additional efficacy endpoints will be evaluated in both treatment periods
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 | 1 |
| 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 | 1 |
| 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 |
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