| 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 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011762 |
| E.1.2 | Term | Cystic fibrosis |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 |
PART A
SAD Cohorts:
· Evaluate the safety and tolerability of a single dose of PTI-428
MAD Cohorts:
Stable ORKAMBI® Cohort:
· Evaluate the safety and tolerability of multiple doses of PTI-428 in combination with ORKAMBI
PTI-428 Monotherapy Cohorts:
· Evaluate the safety and tolerability of multiple daily doses of PTI-428
PART B/C:
Stable ORKAMBI Cohorts:
· Evaluate the safety and tolerability of multiple doses of PTI-428 in combination with ORKAMBI
ORKAMBI Naïve Cohort:
· Evaluate the safety and tolerability of multiple doses of PTI-428 in combination with ORKAMBI in subjects eligible for ORKAMBI
Stable KALYDECO® Cohort:
· Evaluate the safety and tolerability of multiple doses of PTI-428 in combination with KALYDECO in subjects on stable KALYDECO
PTI-428 Monotherapy Cohort:
· Evaluate the safety and tolerability of multiple doses of PTI-428 in adult CF subjects with pancreatic sufficiency not taking either ORKAMBI or KALYDECO
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| E.2.2 | Secondary objectives of the trial |
Part A
SAD:
· Evaluate the PK profile of a single dose of PTI-428
MAD:
· Evaluate PK profile of multiple once daily doses of PTI-428 (monotherapy) over time
Part A and B Stable ORKAMBI Cohorts:
· Evaluate the PK profile of once daily doses of PTI-428 in combination with ORKAMBI over time
· Evaluate the PK profile of twice daily doses of ORKAMBI in combination with PTI-428 over time
Part C:
ORKAMBI Naive or Stable KALYDECO
· Evaluate PK profile of once daily doses of PTI-428 in combination with ORKAMBI or KALYDECO over time.
· Evaluate PK profile of twice daily doses of ORKAMBI or KALYDECO in combination with PTI-428
PTI-428 Monotherapy Cohort:
· Evaluate PK profile of once daily doses of PTI-428 over time
All Cohorts in Parts B and C:
· Evaluate pulmonary function through FEV1 over time
· Evaluate the treatment effect in sweat chloride over time
· Evaluate change in weight over time
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General study inclusion criteria:
1. Adult males or females age 18 years and older
2. Confirmed diagnosis of CF, defined as:
- A sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis and Clinical findings consistent with CF such as chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities.
(OR)
- 2 CF-causing mutations (all as documented in the subject’s medical record) and Clinical findings consistent with CF such as chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities.
3. FEV1 between 40-90% predicted
4. Pulse Oximetry > 92% at rest
5. Body mass index (BMI) ≥17 kg/m2
6. Subjects of child-bearing potential and who are sexually active must meet the study contraception requirements.
7. Non-smoker and non-tobacco user for a minimum of 30 days prior to screening and for the duration of the study.
8. Subject understands the full nature and purpose of the study, including possible risks and side effects, and is willing and able to comply with all compulsory study procedures and provides informed consent/permission prior to any study procedures being performed.
Stable ORKAMBI® Combination Cohort
- Stable on ORKAMBI® dosing for both label indication and per label dosing for a
minimum of three months at the time of randomization
ORKAMBI® Naïve Combination Cohort
- Eligible to take ORKAMBI® in accordance with the label.
Stable KALYDECO® Combination Cohort
- Stable on KALYDECO® dosing for both label indication and per label dosing for a minimum of three months at the time of randomization.
PTI-428 Monotherapy Cohort
- Pancreatic sufficiency as defined by lack of need for digestive enzymatic supplementation for at least 3 months and historical (within past year) or screening fecal elastase ≥ 200 mcg/g stool.
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| E.4 | Principal exclusion criteria |
1. History or current evidence of any clinically significant cardiac, endocrinologic,
hematologic, hepatobiliary, immunologic, metabolic, urologic, pulmonary (besides
CF), neurologic, dermatologic, psychiatric, renal, or other major disease, as determined
by the Investigator.
2. History of prolonged QT/QTc interval with Fridericia’s correction QTcF > 450 msec
at screening.
3. Abnormal liver function as defined by:
a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) or bilirubin
> 3 x upper limit of the normal range.
4. Abnormal renal function at screening defined as:
a. Creatinine clearance < 60mL/min using the Cockroft-Gault equation.
5. White Blood Cell Count (WBC) < 4,000 cells/mm3.
6. Clinically significant screening results that would exclude subject from the study (e.g., medical histories, physical examination, ECGs, vital signs, pulse oximetry, laboratoryprofiles) as deemed by the investigator.
7. Platelet count < 150,000 cell/mm3.
8. Recent hospitalization or change in CF medication (excluding pancreatic enzymes) within 1 month of Study Day 1.
9. Participation in another clinical trial or treatment with an investigational agent within 30 days or 5 half-lives, whichever is longer, prior to Study Day 1.
10. Participant is currently taking or has taken KALYDECO® or ORKAMBI® within 14 days prior to initial dose of PTI-428 or placebo (unless participating in the Kalydeco / Orkambi stable cohort)
11. Subjects with a body weight > 120 kg at screening.
12. History of cancer within the past five years (excluding cervical CIS with curative therapy for at least one year prior to screening and non-melanoma skin cancer).
13. History of organ transplantation.
14. History of alcohol or drug abuse or dependence within 12 months of screening as determined by the Investigator.
15. Positive urine screen for prohibited drugs (cocaine, cannabinoids, nicotine [urine cotinine is the detection mechanism for nicotine], opiates, barbiturates, amphetamines, and benzodiazepines) or positive alcohol testing at screening.
16. Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (HCVAb) at screening.
17. Any sinopulmonary infection or CF exacerbation requiring a change or addition of medication (including antibiotics) within 1 month of Study Day 1 or any other clinically significant infection as determined by the investigator within 1 month of Day 1.
18. Known or suspected hypersensitivity or idiosyncratic reaction to study medication or any components thereof.
19. Has donated blood within 3 months of screening or plans to donate blood within 3 months of study completion.
20. Pregnant or nursing women.
21. Any conditions that, in the opinion of the Investigator, would make the subject unsuitable for enrollment or could interfere with the subject’s participation in or completion of the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A
SAD:
Measured by number of subjects who experience adverse events and potential clinically significant changes in safety labs, electrocardiograms (ECGs), physical examinations, and vital signs. Baseline through Day 7.
MAD:
Measured by number of subjects who experience adverse events and potential clinically significant changes in safety labs, electrocardiograms (ECGs), physical examinations, and vital signs. Baseline through Day 14
Part B and C:
Measured by number of subjects who experience adverse events and potential clinically significant changes in safety labs, electrocardiograms (ECGs), physical examinations, and vital signs. Baseline through Day 35 or 49 (depending on the cohort).
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| E.5.2 | Secondary end point(s) |
Part A
SAD:
- PK
- For plasma PTI-428: PK parameters including, but may not be limited to, t1/2, Tmax, Cmax and AUCt as appropriate
MAD:
Stable ORKAMBI Cohort:
o PK
o For plasma PTI-428: PK parameters including, but may not be limited to, t1/2, Tmax, Cmax and AUCt as appropriate
o For plasma ORKAMBI (ivacaftor and lumacaftor): PK parameters including, but may not be limited to, t1/2, Tmax, Cmax, and AUCt as appropriate
PTI-428 Monotherapy Cohorts:
o PK
o For plasma PTI-428: PK parameters including, but may not be limited to, t1/2, Tmax, Cmax and AUCt as appropriate
Part B
Stable ORKAMBI Cohorts:
o PK:
o For plasma PTI-428: PK parameters including, but may not be limited to, t1/2, Tmax, Cmax and AUCt as appropriate
o For plasma ORKAMBI (ivacaftor and lumacaftor): PK parameters including, but may not be limited to, t1/2, Tmax, Cmax,AUCt as appropriate
• Change in FEV1 over time
• Change in sweat chloride over time
• Change in weight over time
Part C
ORKAMBI Naïve Cohort:
PK:
o For plasma PTI-428: PK parameters including but may not be limited to t1/2, Tmax, Cmax, AUCt as appropriate.
o For plasma ORKAMBI (ivacaftor and lumacaftor): PK parameters including but may not be limited to t1/2, Tmax, Cmax, AUCt as appropriate.
• Change in FEV1 over time
• Change in sweat chloride over time
• Change in weight over time
Stable KALYDECO Cohort:
PK:
o For plasma PTI-428: PK parameters including but may not be limited to t1/2, Tmax, Cmax, AUCt as appropriate.
o For plasma KALYDECO: PK parameters including but may not be limited to t1/2, Tmax, Cmax, AUCt as appropriate.
• Change in FEV1 over time
• Change in sweat chloride over time
• Change in weight over time
PTI-428 Monotherapy Cohort:
o PK:
o For plasma PTI-428: PK parameters including but may not be limited to t1/2, Tmax, Cmax, AUCt as appropriate.
• Change in FEV1 over time
• Change in sweat chloride over time
• Change in weight over time
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A:
SAD:
Pk - Pre-dose, 0,0.25,0.5,0.75,1,1.5,2,3,4,6,8,12,24,36,48,72hrs
MAD:
Pk - Day 1;Pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,6,8,12,24 hrs and pre-dose on Days 3-6, and Day 7 pre-dose and 0.25,0.5,0.75,1,1.5,2,3,4,6,8,12,24 hrs post Day 7 dose.
Part B and C:
Pk - Day -1: pre-dose, 1, 4, 6, 8, and 12 hrs post ORKAMBI Day -1 dose; Day 1 and Day 8 pre-dose, 1, 4, 6, 8, 12, 24 hrs post Day 1/8 dose; Day 28 and 42 pre-dose, 1, 4, 6, 8,12, 24 hrs post Day 28/42 dose (depending on cohort).
For ORKAMBI and KALYDECO Cohorts, each 12 hr post dose sample should be collected prior to the second daily dose of ORKAMBI or KALYDECO (depending on cohort). Each 24 Hrs post dose sample should be collected prior to the following days morning dose of ORKAMBI or KALYDECO /PTI-428/Placebo.
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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 | Yes |
| 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) | 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 |
| Safety, Tolerability and PK study |
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| 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 | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 11 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Italy |
| United Kingdom |
| United States |
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| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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