| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 1 of the study is only conducted in US. Primary objectives are:
- Evaluate the safety and tolerability of a single oral dose and multiple oral doses of PTI-808 in healthy adults.
- Evaluate the PK profile of a single oral dose and multiple oral doses of PTI-808 in healthy adults.
- Evaluate the effect of food on the PK profile of PTI-808 in healthy adults.
Part 2 of the study is only conducted in US. Primary objective is:
Evaluate the safety and tolerability of PTI-808 co-administered with PTI-801 and PTI-428 in healthy adults.
Part 3 of the study will be conducted in EU, US and Canada. Primary objective is: Evaluate the safety and tolerability of PTI-808 coadministered
with PTI-801 and PTI-428 in subjects with cystic fibrosis.
Part 4 of the study will be conducted in EU, US and Canada. Primary objective is: Evaluate the safety and tolerability of PTI-808 coadministered with PTI-801 and PTI-428 in subjects with cystic fibrosis. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1:
Sec. obj.: safety and tolerability of a single oral dose of PTI-808 in healthy adults
PD obj.: effect of PTI-808 on the QT interval
Part 2:
Sec. obj.: PK profile of PTI-808, PTI-801, and PTI-428 when PTI-808 is co-administered with PTI-801 and PTI-428 in healthy adults
Expl. obj.: effect on genes expressed in nasal epithelial cells
Part 3:
Sec. obj.: Please see section 5.1 of the updated protocol
Expl. obj.: sweat chloride concentrations, weight, BMI, blood glucose over time and treatment effect on genes expressed in nasal epithelial cells
Part 4:
Sec. obj.: PK profiles of PTI-808, PTI-801, and PTI-428 when PTI-808 is co-administered with PTI-801 with or without PTI-428 in subjects with cystic fibrosis, pulmonary function (FEV1) and sweat chloride concentration over time
Expl. obj.: weight, BMI, blood glucose, disease-specific health-related quality of life over time and the treatment effect on genes expressed in nasal epithelial cells |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Study part 1 (in US only): A list of inclusion criteria for part 1 of the Study is available in the clinical study protocol number PTI-808-01 version 9.3; dated 22 October 2019 (section 3.4.1).
Study part 2 (in US only): A list of inclusion criteria for part 2 of the Study is available in the clinical study protocol number PTI-808-01 version 9.3; dated 22 October 2019 (section 4.4.1).
Study part 3 (in EU, US and Canada): A list of inclusion criteria for part 3 of the Study is available in the clinical study protocol number PTI-808-01 version 9.3; dated 22 October 2019 (section 5.4.1).
Study part 4 (in EU, US and Canada):
Inclusion criteria are:
1. Understands the full nature and purpose of the study, including possible risks and side effects, is willing and able to comply with all compulsory study procedures, and provides written informed consent/permission prior to any study procedures being performed
2. Adult male or female, ≥18 years of age, at the time of informed consent
3. Confirmed diagnosis of CF as follows:
a. For homozygous subjects: Confirmed diagnosis of CF with the F508del CFTR homozygous genotype on record, along with clinical findings consistent with CF, such as, chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities. The medical monitor's approval is not required for homozygous subjects with a sweat chloride value ≥60 mmol/L at screening or documented in the form of a laboratory report in the subject's medical record. For subjects with a sweat chloride value <60 mmol/L at screening and no documented historical value of ≥60 mmol/L, medical monitor approval is required based on documented evidence of chronic sinopulmonary disease manifested by at least 1 of the following:
- Persistent colonization/infection with typical CF pathogens, including but not limited to, Staphylococcus aureus, Haemophilus influenzae, and/or Pseudomonas aeruginosa
- Chronic cough and sputum production
- Persistent chest radiograph abnormalities (eg, bronchiectasis, atelectasis, infiltrates, hyperinflation)
- Nasal polyps, chronic sinusitis, or radiographic or computed tomographic abnormalities of the paranasal sinuses
b. For heterozygous subjects: Confirmed diagnosis of CF with only one copy of the F508del CFTR mutation on record, along with clinical findings consistent with CF, such as, chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities;
AND
a sweat chloride value of ≥60 mmol/L based on quantitative pilocarpine iontophoresis (as documented in the subject's medical record or as confirmed at the screening visit)
4. Subject must be able to produce a valid sweat sample (quantitysufficient; ie, >15 μL) at the screening visit. If the sweat volume is insufficient then the sweat chloride collection may be repeated once with approval from the medical monitor.
5. Clinically stable CF disease in the opinion of the investigator with no significant changes in health status within 14 days prior to Day 1
6. FEV1 40% to 90%, predicted, inclusive (subjects with FEV1 <40% or >90% predicted at Day -1 must be reviewed with the medical monitor to ensure subject meets criteria to continue in the study)
7. Pulse oximetry >92% at rest
8. BMI ≥16 and <30 kg/m2
9. Subjects of childbearing potential must meet contraception requirements
10. Non-smoker and non-tobacco user for a minimum of 30 days prior to screening, and agrees not to smoke or use tobacco for the duration of the study |
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| E.4 | Principal exclusion criteria |
Study part 1 (in US only): A list of exclusion criteria for part 1 of the Study is available in the clinical study protocol number PTI-808-01 version 9.3; dated 22 October 2019 (section 3.4.2).
Study part 2 (in US only): A list of exclusion criteria for part 2 of the Study is available in the clinical study protocol number PTI-808-01 version 9.3; dated 22 October 2019 (section 4.4.2).
Study part 3 (in EU, US and Canada): A list of exclusion criteria for part 3 of the Study is available in the clinical study protocol number PTI-808-01 version 9.3; dated 22 October 2019 (section 5.4.2).
Study part 4 (in EU, US and Canada):
Exclusion criteria are:
1. History or current evidence of any clinically significant cardiac (eg, heart failure, left ventricular hypertrophy, myocardial infarction, and arrhythmia), endocrinologic, hematologic, hepatobiliary (eg, clinically significant cirrhosis with or without portal hypertension), immunologic, metabolic, urologic, pulmonary (besides CF), neurologic (eg, subarachnoid hemorrhage, intracranial hemorrhage, cerebrovascular accident, intracranial trauma, and autonomic neuropathy), dermatologic, psychiatric, renal, or other major disease, that is unstable or could interfere with the subject's participation in or completion of the study, in the opinion of the investigator (eg, subjects with CFRD can participate in the study if the CFRD is well controlled using a stable medication regimen)
2. Clinically significant screening results that would exclude subject from the study (eg, medical histories, physical exams, ECGs, vital signs, pulse oximetry, laboratory profiles) or any conditions that, would make the subject unsuitable for enrollment or could interfere with the subject's participation in or completion of the study, in the opinion of the investigator. The medical monitor must be contacted for review of any subjects with screening results or conditions that may make them unsuitable for enrollment or could interfere with participation in or completion of the study.
3. Prolonged QTcF >450 msec at screening
4. Abnormal liver function as defined by AST, ALT, gamma-glutamyl transferase (GGT), or alkaline phosphatase ≥3 times or total bilirubin ≥2 times upper limit of the normal range
5. Hemoglobin <10 g/dL
6. Platelet count <150,000 cells/mm3
7. Abnormal renal function at screening defined as creatinine clearance <60 mL/min using the Modified Diet in Renal Disease (MDRD)
8. Hospitalization, sinopulmonary infection, CF exacerbation, or other clinically significant infection or illness (in the opinion of the investigator) requiring an increase or addition of medication, such as antibiotics or corticosteroids, within 28 days of Day 1
9. Lung infection with organisms associated with a more rapid decline in pulmonary status (eg, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For subjects who have had a history of a positive culture in the past, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms:
- The subject has had 2 respiratory tract cultures negative for these organisms within the 12 months before the screening visit, with no subsequent positive cultures.
- These 2 respiratory tract cultures were separated by at least 3 months, and 1 of them was obtained within 6 months before the screening visit.
10. Subject is currently taking or has taken a CFTR modulator within 14 days prior to the screening visit
11. Participation in another clinical trial or treatment with an investigational agent within 30 days or 5 half-lives, whichever is longer, prior to screening. The duration of the elapsed time may be longer if required by local regulations.
12. History of cancer (excluding cervical carcinoma in situ and nonmelanoma skin cancer with curative therapy for at least 5 years prior to screening)
13. History of organ or hematologic transplantation
14. History or current evidence of alcohol or drug abuse or dependence within 12 months of screening, in the opinion of the investigator
15. Positive blood screen for HIV, HBsAg, or HCVAb at screening
16. Initiation of any new chronic therapy (eg, ibuprofen, hypertonic saline, azithromycin, Pulmozyme®, Cayston®, TOBI®) or any change in chronic therapy (excluding pancreatic enzyme replacement therapy) within 28 days prior to Day 1
17. Known or suspected hypersensitivity or idiosyncratic reaction to the study drugs or any components thereof
18. Pregnant or nursing women
19. Special or vulnerable status (eg, institutionalized, or person related to or an employee of the sponsor or investigator) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 (in US only):
Primary safety endpoints for Healthy Volunteer SAD and MAD are:
- Clinical laboratory tests: hematology, chemistry, urinalysis, and coagulation
- 12-lead electrocardiograms (ECGs)
- Physical examinations
- Vital signs
- Adverse events (AEs)
Primary PK endpoints for Healthy Volunteer SAD and MAD are:
- For plasma PTI-808: Parameters include, but not limited to, apparent terminal half-life (t1/2), time to reach maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), AUC(0-24), AUC from time 0 to time of last measurable concentration (AUC0-last), AUC from time 0 to infinity (AUC0-inf), percentage of AUC(0-inf) due to extrapolation from time of last measurable concentration to infinity (AUC%extrap), apparent total clearance (CL/F), apparent volume of distribution (V/F), and terminal elimination rate constant (λz) using non compartmental methods as appropriate
- For urine PTI-808 (Healthy Volunteer MAD only): Parameters include, but are not limited to, cumulative amount of PTI-808 excreted unchanged in urine (Ae) and renal clearance (CLR) as appropriate
Primary PK endpoints for Healthy Volunteer Food Effect are:
- For plasma PT-808 with fasting and after a high fat, high calorie meal: parameters include, but not limited to, t1/2, Tmax, Cmax, AUC(0-24), AUC(0-last), AUC(0-inf), AUC(%extrap), CL/F, V/F, and λz, using noncompartmental methods, as appropriate
Part 2 (in US only):
Safety and tolerability endpoints are :
- Clinical laboratory tests (hematology, serum chemistry, urinalysis, and coagulation), 12-lead ECGs, physical exams, vital signs, and AEs
Part 3 (in EU, US and Canada)
Primary safety and tolerability endpoints are:
- Clinical laboratory tests (hematology, serum chemistry, urinalysis, and coagulation) 12-lead ECGs, physical exams, vital signs, and AEs
Part 4 (in EU, US and Canada)
Primary safety and tolerability endpoints are:
- Clinical laboratory tests (hematology, serum chemistry, urinalysis, and coagulation), 12 lead ECGs, physical exams, vital signs, and AEs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1 (in US only):
- HV SAD (see Table 15-1 in the appendices of the protocol)
- HV MAD (see Table 15-2 in the appendices of the protocol)
- HV Food Effect (see Table 15-3 in appendices of the protocol)
Part 2 (in US only):
- HV Co-Administration (see Table 15-4 in appendices of the protocol)
Part 3 (in EU, US and Canada):
- CF MAD Co-Administration (see Table 15-5 in appendices of the protocol).
Part 4 (in EU, US, Canada):
- CF Cohorts (see Table 15-6 in appendices of the protocol).
- The safety evaluation is performed at Day1, Day 2, Day 7 (± 1 day), Day 14 (± 1 day), Day 21 (± 1 day), Day 28 (-1 day), Day 29 and Day 42 (± 4 days). |
|
| E.5.2 | Secondary end point(s) |
Part 1 (US only):
The secondary safety endpoints for HV Food Effect are:
- Clinical laboratory tests: hematology, chemistry, urinalysis, and coagulation
- 12-lead ECGs
- Physical exams
- Vital signs
- AEs
The Pharmacodynamic endpoint for HV SAD, HV MAD and HV Food Effect is:
- Holter monitoring
Part 2 (in US only):
Endpoints to evaluate PK of PTI-808, PTI-801, and PTI-428 in plasma include, but are not limited to:
- T1/2, Tmax, Cmax, AUC(0-last), and AUC(0-inf) using non-compartmental methods, as appropriate
Exploratory endpoint:
- Change in nasal epithelial mRNA and protein expression
Part 3 (in EU, US and Canada)
Secondary endpoints are:
- For plasma PTI-808, PTI-801, and PTI-428: PK parameters including, but not limited to Tmax, Cmax, and AUC(0-last), as appropriate
- Change in FEV1 over time
Exploratory endpoints are:
- Change in sweat chloride concentrations over time
- Change in weight and BMI over time
- Change in blood glucose over time
- Change in nasal epithelial mRNA and protein expression
Part 4 (in EU, US and Canada)
Secondary endpoints are:
- For plasma PTI-808, PTI-801, and PTI-428: PK parameters including, but not limited to Tmax, Cmax, and AUC(0-last), as appropriate
- Change in FEV1 over time
- Change in sweat chloride concentrations over time
Exploratory endpoints are:
Weight, BMI, blood glucose, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain, and nasal epithelial mRNA and protein expression |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1:
- HV SAD (see Table 15-1 of the protocol)
- HV MAD (see Table 15-2 of the protocol)
- HV Food Effect (see Table 15-3 of the protocol)
Part 2:
- HV Co-Administration (see Table 15-4 of the protocol)
Part 3:
- CF MAD Co-Administration (see Table 15-5 of the protocol).
Part 4:
- CF Cohorts (see Table 15-6 of the protocol).
- Evaluation timepoints are:
- For plasma PTI-808, PTI-801, and PTI-428: PK parameters: day 1, 2, 7, 14, 21, 28, 29
- FEV1 and sweat chloride concentrations over time: day 7, 14, 21, 28 and 42
- Weight and BMI: day 1, 7, 14, 21, 28, 42
- Blood glucose: day 28 and 42
- Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain and in nasal epithelial mRNA and protein expression: day 14, 28 and 42 |
|
| 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 | 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) | 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 of PTI-808 in Healthy Adult Subjects and in Adults with Cystic Fibrosis |
|
| 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 | 8 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of the study is defined as the date of the last study visit for the last subject (which will be their follow-up visit). |
|
| 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 | 24 |
| 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 | 24 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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