| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Not Applicable. This is a PK study (including evaluation of food effect). |
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| E.1.1.1 | Medical condition in easily understood language |
| Not applicable as this is a PK trial |
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| MedDRA Classification |
| 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 |
- To evaluate the pharmacokinetics of two pediatric formulations relative to the Final Market Image formulation of AFQ056 under fasting conditions at a single dose of 50 mg
- To assess the effect of a high fat meal on the relative bioavailability of the two pediatric formulations of AFQ056 at a single dose of 50 mg
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| E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of two pediatric formulations and the FMI formulation of AFQ056 at a single dose of 50 mg
- To evaluate the palatability of the two pediatric formulations of AFQ056
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed.
2. Healthy male and female subjects, aged 18 to 55 years and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram (ECG), and laboratory tests at screening.
3. Vital signs should be within normal ranges as deemed by the Investigator.
The Investigator should be guided by the following ranges (taken in a sitting position).
• Oral body temperature between 35.0-37.5 °C
• Systolic blood pressure, 90-140 mm Hg
• Diastolic blood pressure, 50-90 mm Hg
• Pulse rate, 50-90 bpm
When blood pressure and pulse are taken after at least 3 minutes standing, there should be no more than a 20 mm Hg drop in systolic or 10 mm Hg drop in diastolic blood pressure and increase in heart rate (>20 bpm) (compared to the sitting results) associated with clinical manifestation of postural hypotension. Any subject exhibiting clinical manifestations of postural hypotension should be excluded.
4. Female subjects must be of non-child bearing potential. Women are considered postmenopausal females and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the reproductive status of the women has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. (Surgical sterilization procedures must be supported with clinical documentation made available to sponsor and noted in the Relevant Medical History / Current Medical Conditions section of the CRF). All female subjects must have negative pregnancy results at screening (regardless of reported reproductive status) and the first baseline visit.
5. Subjects must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 to 30 kg/m2.
6. Subjects must be able to communicate well with the investigator, to understand and comply with the requirements of the study.
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| E.4 | Principal exclusion criteria |
1. Participation in any clinical investigation and/or use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations.
2. History of hypersensitivity to AFQ056 or to drugs of similar chemical classes
3. History or presence of clinically significant ECG abnormalities at screening.
The investigator may be guided by the following:
• PR > 220 msec
• QRS complex > 120 msec
• History of Long QT syndrome
• QTcF > 450 msec (males); QTcF > 470 msec (females)
4. History or presence of any clinically significant disease of any major system organ class including (but not limited to) cardiovascular, metabolic, renal, neurological or
psychiatric diseases.
5. History of malignancy of any organ system, treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
6. Pregnant or nursing (=lactating) women.
7. History or presence of suicidal behavior or any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) in the past 6 months or history of suicidality as assessed by the investigator.
8. Smokers (use of tobacco products in the previous 3 months). Smokers will be defined as any subject who reports tobacco use and/or who has a urine cotinine ≥ 500 ng/mL. Urine cotinine levels will be measured during screening for all subjects.
9. Use of any prescription drugs, herbal supplements (e.g. St. John’s wort) or over-thecounter (OTC) medication, within 30 days or 5 half-lives prior to initial dosing, whichever is longer , and/or dietary supplements (vitamins included) within two (2) weeks prior to initial dosing and during the entire study period until completion visit. If needed, (i.e. an incidental and limited need for analgesic treatment) paracetamol is acceptable, but must be documented in the Concomitant medications / Significant non-drug therapies page of the (e)CRF.
10. Donation or loss of 400 mL or more of blood or plasma within eight (8) weeks prior to initial dosing, or longer if required by local regulation.
11. Recent (within the last three [3] years) and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated).
12. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The Investigator should make this determination in consideration of the subject’s medical history and/or clinical or laboratory evidence of any of the following:
• History or presence of inflammatory bowel disease, ulcers, gastrointestinal or rectal
bleeding;
• History or presence of major gastrointestinal tract surgery such as gastrectomy,
gastroenterostomy, or bowel resection;
• History or presence of pancreatic injury or pancreatitis;
• History or presence of liver disease or injury as indicated by abnormal liver function
tests such as SGOT (AST), SGPT (ALT), γ-GT, alkaline phosphatase, or serum
bilirubin. The Investigator should be guided by the following criteria:
a. Any single parameter may not exceed 1.5 x upper limit of normal (ULN). A
single parameter elevated up to and including 1.5 x ULN should be re-checked
once more as soon as possible, and in all cases, at least prior to
enrollment/randomization to rule out lab error.
b. If the total bilirubin concentration is increased above 1.5 x ULN, total bilirubin
should be differentiated into the direct and indirect reacting bilirubin.
Re-check results must be within normal limits or below 1.5x ULN in order for the
subject to be enrolled.
• History or presence of impaired renal function as indicated by clinically significantly
abnormal creatinine or BUN and/or urea values, or abnormal urinary constituents
(e.g., albuminuria).
• Evidence of urinary obstruction or difficulty in voiding at screening.
13. History or presence of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result at screening.
14. History of hepatitis B or C and/or positive Hepatitis B surface antigen (HBsAg) or
Hepatitis C test result at screening.
15. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening or at any baseline assessment
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| AFQ056 Pharmacokinetic assessments. PK parameters for 2 pediatric formulations under fed and fasted conditions |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PK samples will be collected for 48 hours post dose. |
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| E.5.2 | Secondary end point(s) |
| 1) Assess safety and tolerability of a single dose of the pediatric formulations and the final market image. 2) Assess palatability of the pediatric formulations |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1) Safety and tolerability will be monitored continuously. 2) Palatability assesments will be collected within 15 mins post dosing. |
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| PK study (including evaluation of food effect) |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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