Cystic Fibrosis
Conditions
Keywords
Exacerbation, CF, Lung disease, Lung infection, Gram negative, Bacterial Infection, pneumonia, bronchitis
Brief summary
This study investigates the use of cysteamine in the treatment of adults with Cystic Fibrosis who are experiencing an exacerbation of CF-associated lung disease. There are six different potential dosing regimens, including one that is placebo.
Detailed description
This is a multicenter, double-blind, randomized, placebo-controlled, 6-arm study to investigate the optimal dose regimen, efficacy, and safety of cysteamine in the treatment of adult patients with CF who are experiencing an exacerbation of CF-associated lung disease. Patients will be screened for the study and eligible patients will be randomized to receive either cysteamine or placebo as add-on therapy to their standard of care treatment for CF-associated lung disease.
Interventions
DRUGCysteamine
Oral Cysteamine Capsule
DRUGPlacebo Oral Capsule
Placebo Oral Capsule
Sponsors
Agility Clinical, Inc.
PSR Group B.V.
NovaBiotics Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. CF-associated lung disease with documented history of chronic infection with Gram-negative organism(s) 2. Established patient of the Principal Investigator's CF Multi Disciplinary Team (MDT) 3. Age ≥18 years 4. Weight \>40 kg 5. FEV1 \>30% of predicted within the 6 months prior to study exacerbation 6. At the baseline visit: experiencing a new exacerbation of CF-associated lung disease (based on Investigator assessment of ≥4 symptoms present on the Fuchs' criteria) requiring treatment that includes an aminoglycoside antibiotic 7. Females of childbearing potential will be included if they are either sexually inactive (sexually abstinent for 14 days prior to the first study drug dose continuing through 28 days after the last study drug dose, or using one of the following highly effective contraceptive (i.e. results in \<1% failure rate when used consistently and correctly) methods in this trial: 1. intrauterine device (IUD); 2. surgical sterilization of the partner (vasectomy for 6 months minimum); 3. combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal); 4. progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable); 5. intrauterine hormone releasing system (IUS); 6. bilateral tubal occlusion. 8. Females of childbearing potential agree to remain sexually inactive or to keep the same birth control method for at least 28 days following the last dose. 9. A female of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first study drug dose: 1. hysteroscopic sterilization; 2. bilateral tubal ligation or bilateral salpingectomy; 3. hysterectomy; 4. bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to the first study drug dose and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status. 10. A non-vasectomized male subject agrees to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study medication and the female partner agrees to comply with inclusion 7 or 9. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male. 11. If male, agrees not to donate sperm from the first study drug dose until 90 days after dosing. 12. Willing and able to comply with all protocol requirements and procedures, including induction of sputum, if necessary 13. Willing and able to provide signed and dated informed consent
Exclusion criteria
1. Hypersensitive to cysteamine or to any of the excipients 2. Hypersensitive to penicillamine 3. Transplant recipient 4. Participation in any other interventional clinical research study (participation in observational studies is not exclusionary) within 30 days of Baseline (Day 0), and any planned participation in an interventional clinical research study for the duration of this study 5. If female, pregnancy, planned pregnancy, or breast-feeding 6. Any other significant disease/disorder which, in the Investigator's opinion, either puts the patient at risk due to study participation, or may influence the results of the study or the patient's ability to participate in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sputum Bacterial Load | Baseline through Day 21/End of Study | Change from baseline through to Day 21 in log10 cfu/ml transformed total gram negative sputum bacterial load |
| Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Baseline through Day 21/End of Study | Assessed by variables such as adverse events (AEs), laboratory assessments, physical examinations, and vital signs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Neutrophil Elastase Levels | Baseline through Day 21/End of Study | Actual values and change from baseline in neutrophil elastase levels were summarized using descriptive statistics by visit for each treatment group and each TDD group for the ITT Population. |
| Change From Baseline in Sputum IL8 | Baseline through Day 21/End of Study | Sputum IL-8 Levels by Visit - Covariate Adjusted ANCOVA with Observed Data ITT Population |
| Change From Baseline in FEV1 | Baseline through Day 21/End of Study | Change from Baseline in FEV1 Percent Predicted (%) - Covariate Adjusted ANCOVA with Observed Data ITT Population |
| Change From Baseline in BMI | Baseline through Day 21/End of Study | BMI (kg/m\^2) by Visit - ANCOVA with Observed Data ITT Population |
| Change From Baseline in C-Reactive Protein | Baseline through Day 21 | Change from baseline in C-Reactive Protein at visits 7, 14 and 21 |
| Change From Baseline in Blood Leukocyte Count | Baseline through Day 21/End of Study | Blood Leukocyte Count (10\^9 leucocytes/L) by Visit - ANCOVA with Observed Data ITT Population |
| Assessment of Blood Cysteamine Levels | Day 14 | Study Drug Plasma at Day 14 Safety Population |
| Assessment of Sputum Cysteamine Levels | Day 14 | Study Drug Sputum Concentrations at Day 14 Safety Population |
| Change From Baseline in CFRSD-CRISS | Baseline through to Day 21 | Mean Change from Baseline in Cystic Fibrosis Respiratory Symptom Diary (CFRSD)-Chronic Respiratory Infection Symptom Scale (CRISS) CRFSD-CRISS:The CFRSD is a 16-item PROM to evaluate the effect of treatment on the severity of symptoms of acute respiratory infections associated with CF (i.e., CFRSD-CRISS) and to assess the emotional and activity impacts of these symptoms. The overall CRISS score range is 0-100 with 100 being the most severe symptoms.The CFRSD-CRISS is a validated unidimensional scale based on a subset of 8 items from the CFRSD questionnaire that quantifies symptom severity for the previous 24 hours to capture the magnitude of symptoms in stable CF, during medically treated CF exacerbations, and during recover from an exacerbation. The 8 items on the CFRSD-CRISS were scored using a 5-point Likert scale ranging from 0 (no symptom) to 4 (the highest magnitude of severity). So score range of 0-32. |
| Change From Baseline in CFQ-R | Baseline through Day 21/End of Study | The CFQ-R is a disease-specific HRQOL (Health related quality of life) measure containing both generic and CF-specific scales and measures functioning during the previous 2 weeks. Each CFQ-R scale yielded standardized scores ranging from 0 to 100; higher scores indicated better HRQOL |
| Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | changes from baseline at day 7 and day 14 | The Jarad and Sequeiros Symptom Questionnaire (Jarad, 2012) is a simple participant-completed questionnaire that assesses and evaluates change in participant symptoms related to different aspects of respiratory function during a CF exacerbation. The questionnaire consists of 4 questions, each answered on a 4-point scale ranging from 1 (best) to 4 (worst). A range of minimum 4 to maximum16.Jarad and Sequeiros Questionnaire Score - changes from baseline at day 7 and day 14 |
| Change From Baseline in Weight | Baseline through Day 21/End of Study | Weight (kg) by visit - ANCOVA with observed data |
Countries
Italy, United Kingdom, United States
Participant flow
Recruitment details
91 adult CF patients experiencing a pulmonary exacerbation were enrolled across 15 US and EU centres. 89 patients were randomised and 78 completed the 14 day treatment period of the study. First Patient first visit was 12 Jan 2017 and Last Patient last visit was 11 April 2018.
Pre-assignment details
Of the 91 patients enrolled 89 patients met the inclusion criteria and 2 were not eligible: 1 patient had \<4 Fuchs criteria (not considered to be exacerbating) 1 patient had reproductive issues
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patient takes three oral doses of placebo, one in the morning, one at mid-day and one in the evening.
Placebo Oral Capsule: Placebo Oral Capsule | 17 |
| 450mg, Once Per Day Patient takes one oral dose of Cysteamine (450mg) per day, in the morning. The patient takes two oral placebo doses, one at mid-day and one in the evening.
Cysteamine: Oral Cysteamine Capsule
Placebo Oral Capsule: Placebo Oral Capsule | 11 |
| 150mg, Three Times Per Day Patient takes three oral doses of Cysteamine (150mg) per day, one in the morning, one at mid-day and one in the evening.
Cysteamine: Oral Cysteamine Capsule
Placebo Oral Capsule: Placebo Oral Capsule | 15 |
| 450mg, Twice Per Day Patient takes two oral doses of Cysteamine (450mg) per day, one in the morning and one in the evening. The patient takes one oral placebo dose, at mid-day.
Cysteamine: Oral Cysteamine Capsule
Placebo Oral Capsule: Placebo Oral Capsule | 15 |
| 300mg, Three Times Per Day Patient takes three oral doses of Cysteamine (300mg) per day, one in the morning, one at mid-day and one in the evening.
Cysteamine: Oral Cysteamine Capsule
Placebo Oral Capsule: Placebo Oral Capsule | 16 |
| 450mg, Three Times Per Day Patient takes three oral doses of Cysteamine (150mg) per day, one in the morning, one at mid-day and one in the evening.
Cysteamine: Oral Cysteamine Capsule | 15 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 1 | 1 | 1 |
| Overall Study | Consent | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Dosing | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Failure to expectorate sputum | 1 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | No gram negative | 1 | 2 | 1 | 1 | 1 | 1 |
| Overall Study | Patient had no transport | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | 450mg, Once Per Day | 150mg, Three Times Per Day | 450mg, Twice Per Day | 300mg, Three Times Per Day | 450mg, Three Times Per Day |
|---|---|---|---|---|---|---|---|
| Age at CF Diagnosis | 0.9 years STANDARD_DEVIATION 2.41 | 0.9 years STANDARD_DEVIATION 2.41 | 3.9 years STANDARD_DEVIATION 0.24 | 0.3 years STANDARD_DEVIATION 0.49 | 1.6 years STANDARD_DEVIATION 4.93 | 4.8 years STANDARD_DEVIATION 11.45 | 1.8 years STANDARD_DEVIATION 5.63 |
| Age, Continuous | 29.8 years STANDARD_DEVIATION 9.59 | 27.2 years STANDARD_DEVIATION 5.64 | 27.5 years STANDARD_DEVIATION 6.77 | 32.5 years STANDARD_DEVIATION 12.7 | 32.3 years STANDARD_DEVIATION 9.78 | 31.4 years STANDARD_DEVIATION 12 | 27.5 years STANDARD_DEVIATION 7.89 |
| BMI | 20.8 kg/m^2 STANDARD_DEVIATION 2.61 | 20.2 kg/m^2 STANDARD_DEVIATION 2.23 | 20.3 kg/m^2 STANDARD_DEVIATION 3.03 | 20.7 kg/m^2 STANDARD_DEVIATION 2.41 | 21.5 kg/m^2 STANDARD_DEVIATION 2.21 | 20.5 kg/m^2 STANDARD_DEVIATION 3.03 | 21.7 kg/m^2 STANDARD_DEVIATION 2.84 |
| Duration of CF years | 27.85 years STANDARD_DEVIATION 9.97 | 26.36 years STANDARD_DEVIATION 5.69 | 23.7 years STANDARD_DEVIATION 9.26 | 32.45 years STANDARD_DEVIATION 12.44 | 31.11 years STANDARD_DEVIATION 10.92 | 26.76 years STANDARD_DEVIATION 11.69 | 25.88 years STANDARD_DEVIATION 7.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 15 Participants | 10 Participants | 13 Participants | 12 Participants | 15 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants |
| FEV1 Percent predicted (%) | 43.3 litres per second STANDARD_DEVIATION 18.34 | 41.5 litres per second STANDARD_DEVIATION 15.31 | 39.4 litres per second STANDARD_DEVIATION 19.81 | 48.0 litres per second STANDARD_DEVIATION 18.26 | 46.1 litres per second STANDARD_DEVIATION 22.75 | 37.7 litres per second STANDARD_DEVIATION 13.44 | 46.9 litres per second STANDARD_DEVIATION 20.58 |
| Sex: Female, Male Female | 43 Participants | 8 Participants | 6 Participants | 5 Participants | 8 Participants | 8 Participants | 8 Participants |
| Sex: Female, Male Male | 46 Participants | 9 Participants | 5 Participants | 10 Participants | 7 Participants | 8 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 11 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 15 |
| other Total, other adverse events | 9 / 17 | 10 / 11 | 11 / 15 | 12 / 15 | 10 / 16 | 13 / 15 |
| serious Total, serious adverse events | 1 / 17 | 1 / 11 | 2 / 15 | 1 / 15 | 0 / 16 | 1 / 15 |
Outcome results
Primary
Change From Baseline in Sputum Bacterial Load
Change from baseline through to Day 21 in log10 cfu/ml transformed total gram negative sputum bacterial load
Time frame: Baseline through Day 21/End of Study
Population: Intention to treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Sputum Bacterial Load | Day 14 change from baseline | -1.38 log 10 cfu/ml | Standard Deviation 2.291 |
| Placebo | Change From Baseline in Sputum Bacterial Load | Day 7 change from baseline | -2.1 log 10 cfu/ml | Standard Deviation 2.887 |
| Placebo | Change From Baseline in Sputum Bacterial Load | Day 21 change from baseline | -0.18 log 10 cfu/ml | Standard Deviation 1.238 |
| 450mg, Once Per Day | Change From Baseline in Sputum Bacterial Load | Day 14 change from baseline | 0.12 log 10 cfu/ml | Standard Deviation 2.045 |
| 450mg, Once Per Day | Change From Baseline in Sputum Bacterial Load | Day 7 change from baseline | -1.03 log 10 cfu/ml | Standard Deviation 3.124 |
| 450mg, Once Per Day | Change From Baseline in Sputum Bacterial Load | Day 21 change from baseline | -1.22 log 10 cfu/ml | Standard Deviation 2.76 |
| 150mg, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 14 change from baseline | -1.24 log 10 cfu/ml | Standard Deviation 2.686 |
| 150mg, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 7 change from baseline | -1.28 log 10 cfu/ml | Standard Deviation 1.978 |
| 150mg, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 21 change from baseline | -0.26 log 10 cfu/ml | Standard Deviation 1.639 |
| 450mg, Twice Per Day | Change From Baseline in Sputum Bacterial Load | Day 14 change from baseline | -1.32 log 10 cfu/ml | Standard Deviation 2.298 |
| 450mg, Twice Per Day | Change From Baseline in Sputum Bacterial Load | Day 7 change from baseline | -1.7 log 10 cfu/ml | Standard Deviation 2.439 |
| 450mg, Twice Per Day | Change From Baseline in Sputum Bacterial Load | Day 21 change from baseline | -1.04 log 10 cfu/ml | Standard Deviation 2.891 |
| 300mg, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 14 change from baseline | -0.98 log 10 cfu/ml | Standard Deviation 1.894 |
| 300mg, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 7 change from baseline | -1.03 log 10 cfu/ml | Standard Deviation 1.997 |
| 300mg, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 21 change from baseline | -0.87 log 10 cfu/ml | Standard Deviation 1.677 |
| High Dose, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 7 change from baseline | -0.25 log 10 cfu/ml | Standard Deviation 2.228 |
| High Dose, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 21 change from baseline | 0.93 log 10 cfu/ml | Standard Deviation 2.348 |
| High Dose, Three Times Per Day | Change From Baseline in Sputum Bacterial Load | Day 14 change from baseline | 0.33 log 10 cfu/ml | Standard Deviation 2.27 |
Primary
Safety and Tolerability Assessed by the Number of Subjects With Adverse Events
Assessed by variables such as adverse events (AEs), laboratory assessments, physical examinations, and vital signs.
Time frame: Baseline through Day 21/End of Study
Population: Summary of participant reported adverse events (AEs) by study group
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Abdominal pain | 1 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE mild | 7 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of AEs | 30 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Haemoptysis | 2 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of SAEs | 1 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE severe | 0 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Decreased appetite | 0 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE moderate | 2 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Rash | 0 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Oropharyngeal pain | 0 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Insomnia | 0 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Nausea | 0 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | 1 or more AEs | 9 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Arthralgia | 0 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | AEs leading to drug discontinuation | 1 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Vomiting | 0 participants |
| Placebo | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Breath odour | 0 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE severe | 0 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Arthralgia | 1 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Insomnia | 0 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Rash | 0 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | 1 or more AEs | 10 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of AEs | 29 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Abdominal pain | 0 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE mild | 6 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Oropharyngeal pain | 1 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE moderate | 4 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Breath odour | 0 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Haemoptysis | 0 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | AEs leading to drug discontinuation | 1 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of SAEs | 1 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Decreased appetite | 0 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Nausea | 3 participants |
| 450mg, Once Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Vomiting | 2 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of SAEs | 2 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE mild | 5 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | 1 or more AEs | 11 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Rash | 1 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | AEs leading to drug discontinuation | 1 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Arthralgia | 1 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Decreased appetite | 1 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Insomnia | 2 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Abdominal pain | 1 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Vomiting | 2 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Nausea | 5 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE moderate | 6 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Haemoptysis | 1 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Oropharyngeal pain | 1 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of AEs | 40 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE severe | 0 participants |
| 150mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Breath odour | 0 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Rash | 1 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of AEs | 33 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of SAEs | 1 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | 1 or more AEs | 12 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE mild | 6 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE moderate | 5 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE severe | 1 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | AEs leading to drug discontinuation | 1 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Nausea | 3 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Vomiting | 2 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Insomnia | 0 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Arthralgia | 1 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Decreased appetite | 0 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Haemoptysis | 1 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Oropharyngeal pain | 0 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Abdominal pain | 0 participants |
| 450mg, Twice Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Breath odour | 1 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Decreased appetite | 2 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE mild | 4 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Nausea | 5 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Oropharyngeal pain | 1 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Arthralgia | 0 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE severe | 1 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | 1 or more AEs | 10 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | AEs leading to drug discontinuation | 1 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Breath odour | 0 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Abdominal pain | 2 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of AEs | 45 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Haemoptysis | 2 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Insomnia | 1 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Rash | 3 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of SAEs | 0 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE moderate | 5 participants |
| 300mg, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Vomiting | 2 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE mild | 7 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Arthralgia | 1 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | AEs leading to drug discontinuation | 1 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of AEs | 36 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Decreased appetite | 1 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE severe | 0 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Severity of AE moderate | 6 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Haemoptysis | 0 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Nausea | 3 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Breath odour | 2 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Oropharyngeal pain | 1 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | 1 or more AEs | 13 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Number of SAEs | 1 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Abdominal pain | 0 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Insomnia | 2 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Rash | 0 participants |
| High Dose, Three Times Per Day | Safety and Tolerability Assessed by the Number of Subjects With Adverse Events | Vomiting | 1 participants |
Secondary
Assessment of Blood Cysteamine Levels
Study Drug Plasma at Day 14 Safety Population
Time frame: Day 14
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Assessment of Blood Cysteamine Levels | 10.0 ng/ml | Standard Deviation 0 |
| 450mg, Once Per Day | Assessment of Blood Cysteamine Levels | 515.11 ng/ml | Standard Deviation 683.956 |
| 150mg, Three Times Per Day | Assessment of Blood Cysteamine Levels | 102.45 ng/ml | Standard Deviation 144.863 |
| 450mg, Twice Per Day | Assessment of Blood Cysteamine Levels | 347.76 ng/ml | Standard Deviation 507.747 |
| 300mg, Three Times Per Day | Assessment of Blood Cysteamine Levels | 256.85 ng/ml | Standard Deviation 377.262 |
| High Dose, Three Times Per Day | Assessment of Blood Cysteamine Levels | 256.84 ng/ml | Standard Deviation 251.593 |
Secondary
Assessment of Sputum Cysteamine Levels
Study Drug Sputum Concentrations at Day 14 Safety Population
Time frame: Day 14
Population: Safety Population - there are fewer numbers of patients due to the inability of some patients to provide sputum samples
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Assessment of Sputum Cysteamine Levels | 150.0 ng/ml | Standard Deviation 0 |
| 450mg, Once Per Day | Assessment of Sputum Cysteamine Levels | 682.8 ng/ml | Standard Deviation 1009.8 |
| 150mg, Three Times Per Day | Assessment of Sputum Cysteamine Levels | 150.0 ng/ml | Standard Deviation 0 |
| 450mg, Twice Per Day | Assessment of Sputum Cysteamine Levels | 316.4 ng/ml | Standard Deviation 1423.6 |
| 300mg, Three Times Per Day | Assessment of Sputum Cysteamine Levels | 739.7 ng/ml | Standard Deviation 1423.6 |
| High Dose, Three Times Per Day | Assessment of Sputum Cysteamine Levels | 811.1 ng/ml | Standard Deviation 917.49 |
Secondary
Change From Baseline in Blood Leukocyte Count
Blood Leukocyte Count (10\^9 leucocytes/L) by Visit - ANCOVA with Observed Data ITT Population
Time frame: Baseline through Day 21/End of Study
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Blood Leukocyte Count | Day 14 change from baseline | -1.568 10^9 leucocytes/L | Standard Deviation 4.7176 |
| Placebo | Change From Baseline in Blood Leukocyte Count | Day 21 change from baseline | -1.870 10^9 leucocytes/L | Standard Deviation 4.6187 |
| Placebo | Change From Baseline in Blood Leukocyte Count | Day 7 change from baseline | -2.553 10^9 leucocytes/L | Standard Deviation 4.617 |
| 450mg, Once Per Day | Change From Baseline in Blood Leukocyte Count | Day 21 change from baseline | -1.757 10^9 leucocytes/L | Standard Deviation 2.667 |
| 450mg, Once Per Day | Change From Baseline in Blood Leukocyte Count | Day 14 change from baseline | -2.220 10^9 leucocytes/L | Standard Deviation 2.3451 |
| 450mg, Once Per Day | Change From Baseline in Blood Leukocyte Count | Day 7 change from baseline | -1.836 10^9 leucocytes/L | Standard Deviation 2.0566 |
| 150mg, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 14 change from baseline | -2.648 10^9 leucocytes/L | Standard Deviation 3.9122 |
| 150mg, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 7 change from baseline | -2.808 10^9 leucocytes/L | Standard Deviation 3.595 |
| 150mg, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 21 change from baseline | -1.880 10^9 leucocytes/L | Standard Deviation 3.0935 |
| 450mg, Twice Per Day | Change From Baseline in Blood Leukocyte Count | Day 14 change from baseline | -3.419 10^9 leucocytes/L | Standard Deviation 3.5734 |
| 450mg, Twice Per Day | Change From Baseline in Blood Leukocyte Count | Day 7 change from baseline | -2.482 10^9 leucocytes/L | Standard Deviation 3.4502 |
| 450mg, Twice Per Day | Change From Baseline in Blood Leukocyte Count | Day 21 change from baseline | -1.763 10^9 leucocytes/L | Standard Deviation 3.3193 |
| 300mg, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 14 change from baseline | -0.193 10^9 leucocytes/L | Standard Deviation 3.8376 |
| 300mg, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 7 change from baseline | -2.575 10^9 leucocytes/L | Standard Deviation 3.1189 |
| 300mg, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 21 change from baseline | -0.127 10^9 leucocytes/L | Standard Deviation 2.5869 |
| High Dose, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 7 change from baseline | -2.863 10^9 leucocytes/L | Standard Deviation 2.9932 |
| High Dose, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 21 change from baseline | -3.316 10^9 leucocytes/L | Standard Deviation 3.6322 |
| High Dose, Three Times Per Day | Change From Baseline in Blood Leukocyte Count | Day 14 change from baseline | -4.066 10^9 leucocytes/L | Standard Deviation 2.4102 |
Secondary
Change From Baseline in BMI
BMI (kg/m\^2) by Visit - ANCOVA with Observed Data ITT Population
Time frame: Baseline through Day 21/End of Study
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in BMI | BMI Day 14 change from baseline | 0.34 kg/m^2 for BMI | Standard Deviation 0.452 |
| Placebo | Change From Baseline in BMI | BMI Day 7 change from baseline | 0.39 kg/m^2 for BMI | Standard Deviation 0.371 |
| Placebo | Change From Baseline in BMI | BMI Day 21 change from baseline | 0.54 kg/m^2 for BMI | Standard Deviation 0.537 |
| 450mg, Once Per Day | Change From Baseline in BMI | BMI Day 14 change from baseline | 0.64 kg/m^2 for BMI | Standard Deviation 0.505 |
| 450mg, Once Per Day | Change From Baseline in BMI | BMI Day 7 change from baseline | 0.32 kg/m^2 for BMI | Standard Deviation 0.498 |
| 450mg, Once Per Day | Change From Baseline in BMI | BMI Day 21 change from baseline | 0.55 kg/m^2 for BMI | Standard Deviation 0.553 |
| 150mg, Three Times Per Day | Change From Baseline in BMI | BMI Day 14 change from baseline | 0.34 kg/m^2 for BMI | Standard Deviation 0.477 |
| 150mg, Three Times Per Day | Change From Baseline in BMI | BMI Day 7 change from baseline | 0.28 kg/m^2 for BMI | Standard Deviation 0.3 |
| 150mg, Three Times Per Day | Change From Baseline in BMI | BMI Day 21 change from baseline | 0.47 kg/m^2 for BMI | Standard Deviation 0.564 |
| 450mg, Twice Per Day | Change From Baseline in BMI | BMI Day 14 change from baseline | 0.37 kg/m^2 for BMI | Standard Deviation 0.488 |
| 450mg, Twice Per Day | Change From Baseline in BMI | BMI Day 7 change from baseline | 0.24 kg/m^2 for BMI | Standard Deviation 0.428 |
| 450mg, Twice Per Day | Change From Baseline in BMI | BMI Day 21 change from baseline | 0.18 kg/m^2 for BMI | Standard Deviation 0.478 |
| 300mg, Three Times Per Day | Change From Baseline in BMI | BMI Day 14 change from baseline | 0.23 kg/m^2 for BMI | Standard Deviation 0.705 |
| 300mg, Three Times Per Day | Change From Baseline in BMI | BMI Day 7 change from baseline | 0.15 kg/m^2 for BMI | Standard Deviation 0.586 |
| 300mg, Three Times Per Day | Change From Baseline in BMI | BMI Day 21 change from baseline | -0.02 kg/m^2 for BMI | Standard Deviation 0.98 |
| High Dose, Three Times Per Day | Change From Baseline in BMI | BMI Day 7 change from baseline | 0.15 kg/m^2 for BMI | Standard Deviation 0.589 |
| High Dose, Three Times Per Day | Change From Baseline in BMI | BMI Day 21 change from baseline | 0.12 kg/m^2 for BMI | Standard Deviation 0.828 |
| High Dose, Three Times Per Day | Change From Baseline in BMI | BMI Day 14 change from baseline | 0.32 kg/m^2 for BMI | Standard Deviation 0.893 |
Secondary
Change From Baseline in CFQ-R
The CFQ-R is a disease-specific HRQOL (Health related quality of life) measure containing both generic and CF-specific scales and measures functioning during the previous 2 weeks. Each CFQ-R scale yielded standardized scores ranging from 0 to 100; higher scores indicated better HRQOL
Time frame: Baseline through Day 21/End of Study
Population: Change from Baseline to Day 14 in CFQ-R Respiratory Score: ANCOVA with Observed Data ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CFQ-R | Day 14 change from baseline | 22.9 units on a scale | Standard Deviation 21.51 |
| Placebo | Change From Baseline in CFQ-R | Day 21 change from baseline | 24.3 units on a scale | Standard Deviation 19.34 |
| Placebo | Change From Baseline in CFQ-R | Day 7 Change from baseline | 14.7 units on a scale | Standard Deviation 18.21 |
| 450mg, Once Per Day | Change From Baseline in CFQ-R | Day 14 change from baseline | 24.4 units on a scale | Standard Deviation 14.15 |
| 450mg, Once Per Day | Change From Baseline in CFQ-R | Day 21 change from baseline | 30.6 units on a scale | Standard Deviation 17.62 |
| 450mg, Once Per Day | Change From Baseline in CFQ-R | Day 7 Change from baseline | 12.2 units on a scale | Standard Deviation 13.81 |
| 150mg, Three Times Per Day | Change From Baseline in CFQ-R | Day 21 change from baseline | 25.2 units on a scale | Standard Deviation 19.19 |
| 150mg, Three Times Per Day | Change From Baseline in CFQ-R | Day 7 Change from baseline | 12.0 units on a scale | Standard Deviation 16.32 |
| 150mg, Three Times Per Day | Change From Baseline in CFQ-R | Day 14 change from baseline | 19.7 units on a scale | Standard Deviation 16.76 |
| 450mg, Twice Per Day | Change From Baseline in CFQ-R | Day 7 Change from baseline | 12.1 units on a scale | Standard Deviation 14.95 |
| 450mg, Twice Per Day | Change From Baseline in CFQ-R | Day 14 change from baseline | 31.3 units on a scale | Standard Deviation 17.38 |
| 450mg, Twice Per Day | Change From Baseline in CFQ-R | Day 21 change from baseline | 31.3 units on a scale | Standard Deviation 30.08 |
| 300mg, Three Times Per Day | Change From Baseline in CFQ-R | Day 21 change from baseline | 24.8 units on a scale | Standard Deviation 14.85 |
| 300mg, Three Times Per Day | Change From Baseline in CFQ-R | Day 7 Change from baseline | 15.9 units on a scale | Standard Deviation 14.1 |
| 300mg, Three Times Per Day | Change From Baseline in CFQ-R | Day 14 change from baseline | 21.8 units on a scale | Standard Deviation 14.07 |
| High Dose, Three Times Per Day | Change From Baseline in CFQ-R | Day 14 change from baseline | 28.6 units on a scale | Standard Deviation 15.69 |
| High Dose, Three Times Per Day | Change From Baseline in CFQ-R | Day 7 Change from baseline | 19.6 units on a scale | Standard Deviation 16.11 |
| High Dose, Three Times Per Day | Change From Baseline in CFQ-R | Day 21 change from baseline | 37.3 units on a scale | Standard Deviation 23.61 |
Secondary
Change From Baseline in CFRSD-CRISS
Mean Change from Baseline in Cystic Fibrosis Respiratory Symptom Diary (CFRSD)-Chronic Respiratory Infection Symptom Scale (CRISS) CRFSD-CRISS:The CFRSD is a 16-item PROM to evaluate the effect of treatment on the severity of symptoms of acute respiratory infections associated with CF (i.e., CFRSD-CRISS) and to assess the emotional and activity impacts of these symptoms. The overall CRISS score range is 0-100 with 100 being the most severe symptoms.The CFRSD-CRISS is a validated unidimensional scale based on a subset of 8 items from the CFRSD questionnaire that quantifies symptom severity for the previous 24 hours to capture the magnitude of symptoms in stable CF, during medically treated CF exacerbations, and during recover from an exacerbation. The 8 items on the CFRSD-CRISS were scored using a 5-point Likert scale ranging from 0 (no symptom) to 4 (the highest magnitude of severity). So score range of 0-32.
Time frame: Baseline through to Day 21
Population: Mean Change from Baseline in CRFSD-CRISS - Linear MMRM Model with Observed Data (ITT Population)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in CFRSD-CRISS | Day 14 change from baseline | -16.3 units on a scale | Standard Deviation 15 |
| Placebo | Change From Baseline in CFRSD-CRISS | Day 21 change from baseline | -18.3 units on a scale | Standard Deviation 11.7 |
| Placebo | Change From Baseline in CFRSD-CRISS | Day 7 change from baseline | -16.4 units on a scale | Standard Deviation 8.31 |
| 450mg, Once Per Day | Change From Baseline in CFRSD-CRISS | Day 14 change from baseline | -24.3 units on a scale | Standard Deviation 16.35 |
| 450mg, Once Per Day | Change From Baseline in CFRSD-CRISS | Day 21 change from baseline | -23.2 units on a scale | Standard Deviation 13.36 |
| 450mg, Once Per Day | Change From Baseline in CFRSD-CRISS | Day 7 change from baseline | -18.1 units on a scale | Standard Deviation 10.19 |
| 150mg, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 21 change from baseline | -15.8 units on a scale | Standard Deviation 11.68 |
| 150mg, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 7 change from baseline | -11.9 units on a scale | Standard Deviation 7.98 |
| 150mg, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 14 change from baseline | -15.5 units on a scale | Standard Deviation 12.48 |
| 450mg, Twice Per Day | Change From Baseline in CFRSD-CRISS | Day 7 change from baseline | -19.1 units on a scale | Standard Deviation 10.65 |
| 450mg, Twice Per Day | Change From Baseline in CFRSD-CRISS | Day 14 change from baseline | -28.1 units on a scale | Standard Deviation 16.88 |
| 450mg, Twice Per Day | Change From Baseline in CFRSD-CRISS | Day 21 change from baseline | -19.9 units on a scale | Standard Deviation 19.23 |
| 300mg, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 21 change from baseline | -12.9 units on a scale | Standard Deviation 6.37 |
| 300mg, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 7 change from baseline | -10.5 units on a scale | Standard Deviation 5.91 |
| 300mg, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 14 change from baseline | -14.8 units on a scale | Standard Deviation 8.53 |
| High Dose, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 14 change from baseline | -23.9 units on a scale | Standard Deviation 16.41 |
| High Dose, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 7 change from baseline | -17.8 units on a scale | Standard Deviation 12.67 |
| High Dose, Three Times Per Day | Change From Baseline in CFRSD-CRISS | Day 21 change from baseline | 22.0 units on a scale | Standard Deviation 17.71 |
Secondary
Change From Baseline in C-Reactive Protein
Change from baseline in C-Reactive Protein at visits 7, 14 and 21
Time frame: Baseline through Day 21
Population: CRP by visit ANCOVA with observed data ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in C-Reactive Protein | Day 14 change from baseline | -75.671 nmol/L | Standard Deviation 331.222 |
| Placebo | Change From Baseline in C-Reactive Protein | Day 7 change from baseline | -182.828 nmol/L | Standard Deviation 188.1222 |
| Placebo | Change From Baseline in C-Reactive Protein | Day 21 change from baseline | -44.341 nmol/L | Standard Deviation 296.4493 |
| 450mg, Once Per Day | Change From Baseline in C-Reactive Protein | Day 14 change from baseline | -312.435 nmol/L | Standard Deviation 323.8782 |
| 450mg, Once Per Day | Change From Baseline in C-Reactive Protein | Day 7 change from baseline | -285.006 nmol/L | Standard Deviation 295.0114 |
| 450mg, Once Per Day | Change From Baseline in C-Reactive Protein | Day 21 change from baseline | -237.062 nmol/L | Standard Deviation 378.4493 |
| 150mg, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 14 change from baseline | -216.105 nmol/L | Standard Deviation 617.1174 |
| 150mg, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 7 change from baseline | -229.821 nmol/L | Standard Deviation 590.1267 |
| 150mg, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 21 change from baseline | -116.442 nmol/L | Standard Deviation 730.9709 |
| 450mg, Twice Per Day | Change From Baseline in C-Reactive Protein | Day 14 change from baseline | -215.242 nmol/L | Standard Deviation 225.7293 |
| 450mg, Twice Per Day | Change From Baseline in C-Reactive Protein | Day 7 change from baseline | -318.933 nmol/L | Standard Deviation 344.9138 |
| 450mg, Twice Per Day | Change From Baseline in C-Reactive Protein | Day 21 change from baseline | -198.759 nmol/L | Standard Deviation 235.0256 |
| 300mg, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 14 change from baseline | -111.272 nmol/L | Standard Deviation 124.8394 |
| 300mg, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 7 change from baseline | -120.193 nmol/L | Standard Deviation 200.2307 |
| 300mg, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 21 change from baseline | -23.421 nmol/L | Standard Deviation 157.4203 |
| High Dose, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 7 change from baseline | -281.752 nmol/L | Standard Deviation 293.2595 |
| High Dose, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 21 change from baseline | -225.787 nmol/L | Standard Deviation 543.107 |
| High Dose, Three Times Per Day | Change From Baseline in C-Reactive Protein | Day 14 change from baseline | -294.13 nmol/L | Standard Deviation 509.9255 |
Secondary
Change From Baseline in FEV1
Change from Baseline in FEV1 Percent Predicted (%) - Covariate Adjusted ANCOVA with Observed Data ITT Population
Time frame: Baseline through Day 21/End of Study
Population: Change from Baseline in FEV1 Percent Predicted (%) - Covariate Adjusted ANCOVA with Observed Data ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in FEV1 | Day 14 change from baseline | 9.2 percentage of predicted | Standard Deviation 14.03 |
| Placebo | Change From Baseline in FEV1 | Day 7 change from baseline | 7.9 percentage of predicted | Standard Deviation 13.67 |
| Placebo | Change From Baseline in FEV1 | Day 21 change from baseline | 9.5 percentage of predicted | Standard Deviation 13.5 |
| 450mg, Once Per Day | Change From Baseline in FEV1 | Day 14 change from baseline | 4.0 percentage of predicted | Standard Deviation 5.14 |
| 450mg, Once Per Day | Change From Baseline in FEV1 | Day 7 change from baseline | 4.4 percentage of predicted | Standard Deviation 5.52 |
| 450mg, Once Per Day | Change From Baseline in FEV1 | Day 21 change from baseline | 4.7 percentage of predicted | Standard Deviation 5.03 |
| 150mg, Three Times Per Day | Change From Baseline in FEV1 | Day 14 change from baseline | 8.9 percentage of predicted | Standard Deviation 10.87 |
| 150mg, Three Times Per Day | Change From Baseline in FEV1 | Day 7 change from baseline | 6.9 percentage of predicted | Standard Deviation 8.85 |
| 150mg, Three Times Per Day | Change From Baseline in FEV1 | Day 21 change from baseline | 6.5 percentage of predicted | Standard Deviation 7.25 |
| 450mg, Twice Per Day | Change From Baseline in FEV1 | Day 14 change from baseline | 13.6 percentage of predicted | Standard Deviation 10.83 |
| 450mg, Twice Per Day | Change From Baseline in FEV1 | Day 7 change from baseline | 11.8 percentage of predicted | Standard Deviation 9.96 |
| 450mg, Twice Per Day | Change From Baseline in FEV1 | Day 21 change from baseline | 8.9 percentage of predicted | Standard Deviation 10.66 |
| 300mg, Three Times Per Day | Change From Baseline in FEV1 | Day 14 change from baseline | 5.3 percentage of predicted | Standard Deviation 6.65 |
| 300mg, Three Times Per Day | Change From Baseline in FEV1 | Day 7 change from baseline | 4.9 percentage of predicted | Standard Deviation 5.48 |
| 300mg, Three Times Per Day | Change From Baseline in FEV1 | Day 21 change from baseline | 6.4 percentage of predicted | Standard Deviation 8.18 |
| High Dose, Three Times Per Day | Change From Baseline in FEV1 | Day 7 change from baseline | 3.7 percentage of predicted | Standard Deviation 8.65 |
| High Dose, Three Times Per Day | Change From Baseline in FEV1 | Day 21 change from baseline | 6.3 percentage of predicted | Standard Deviation 11.34 |
| High Dose, Three Times Per Day | Change From Baseline in FEV1 | Day 14 change from baseline | 7.5 percentage of predicted | Standard Deviation 7.07 |
Secondary
Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire
The Jarad and Sequeiros Symptom Questionnaire (Jarad, 2012) is a simple participant-completed questionnaire that assesses and evaluates change in participant symptoms related to different aspects of respiratory function during a CF exacerbation. The questionnaire consists of 4 questions, each answered on a 4-point scale ranging from 1 (best) to 4 (worst). A range of minimum 4 to maximum16.Jarad and Sequeiros Questionnaire Score - changes from baseline at day 7 and day 14
Time frame: changes from baseline at day 7 and day 14
Population: ITT Linear MMRM Model with Observed Data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 7 | -2.6 units on a scale | Standard Deviation 1.97 |
| Placebo | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 14 | -3.2 units on a scale | Standard Deviation 2.9 |
| 450mg, Once Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 7 | -1.9 units on a scale | Standard Deviation 2.38 |
| 450mg, Once Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 14 | -2.9 units on a scale | Standard Deviation 2.6 |
| 150mg, Three Times Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 7 | -1.4 units on a scale | Standard Deviation 1.85 |
| 150mg, Three Times Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 14 | -2.0 units on a scale | Standard Deviation 2.48 |
| 450mg, Twice Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 7 | -3.3 units on a scale | Standard Deviation 2.35 |
| 450mg, Twice Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 14 | -4.3 units on a scale | Standard Deviation 2.16 |
| 300mg, Three Times Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 7 | -2.4 units on a scale | Standard Deviation 2.21 |
| 300mg, Three Times Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 14 | -3.1 units on a scale | Standard Deviation 2.63 |
| High Dose, Three Times Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 7 | -3.1 units on a scale | Standard Deviation 3.33 |
| High Dose, Three Times Per Day | Change From Baseline in Jarad and Sequeiros Symptom Score Questionnaire | change from baseline to day 14 | -4.2 units on a scale | Standard Deviation 3.19 |
Secondary
Change From Baseline in Neutrophil Elastase Levels
Actual values and change from baseline in neutrophil elastase levels were summarized using descriptive statistics by visit for each treatment group and each TDD group for the ITT Population.
Time frame: Baseline through Day 21/End of Study
Population: Neutrophil Elastase Levels by Visit - Covariate Adjusted ANCOVA with Observed Data ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Neutrophil Elastase Levels | Day 14 change from baseline | -3706 ng/mL | Standard Deviation 42879 |
| Placebo | Change From Baseline in Neutrophil Elastase Levels | Day 7 change from baseline | -4659 ng/mL | Standard Deviation 38335 |
| Placebo | Change From Baseline in Neutrophil Elastase Levels | Day 21 change from baseline | -1000 ng/mL | Standard Deviation 59856 |
| 450mg, Once Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 14 change from baseline | -380 ng/mL | Standard Deviation 157122 |
| 450mg, Once Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 7 change from baseline | 23431 ng/mL | Standard Deviation 53111 |
| 450mg, Once Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 21 change from baseline | 4853 ng/mL | Standard Deviation 18616 |
| 150mg, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 14 change from baseline | -7208 ng/mL | Standard Deviation 19210 |
| 150mg, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 21 change from baseline | 171 ng/mL | Standard Deviation 19229 |
| 150mg, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 7 change from baseline | 704 ng/mL | Standard Deviation 36395 |
| 450mg, Twice Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 14 change from baseline | -12014 ng/mL | Standard Deviation 23269 |
| 450mg, Twice Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 7 change from baseline | -19623 ng/mL | Standard Deviation 35548 |
| 450mg, Twice Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 21 change from baseline | -21002 ng/mL | Standard Deviation 2472 |
| 300mg, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 14 change from baseline | -14083 ng/mL | Standard Deviation 41215 |
| 300mg, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 7 change from baseline | -15769 ng/mL | Standard Deviation 40899 |
| 300mg, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 21 change from baseline | -14591 ng/mL | Standard Deviation 39179 |
| High Dose, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 7 change from baseline | 5135 ng/mL | Standard Deviation 27791 |
| High Dose, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 21 change from baseline | -2558 ng/mL | Standard Deviation 20068 |
| High Dose, Three Times Per Day | Change From Baseline in Neutrophil Elastase Levels | Day 14 change from baseline | 14660 ng/mL | Standard Deviation 35539 |
Secondary
Change From Baseline in Sputum IL8
Sputum IL-8 Levels by Visit - Covariate Adjusted ANCOVA with Observed Data ITT Population
Time frame: Baseline through Day 21/End of Study
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Sputum IL8 | Day 14 Change from baseline | -28856 pg/mL | Standard Deviation 39456 |
| Placebo | Change From Baseline in Sputum IL8 | Day 7 change from baseline | -26088 pg/mL | Standard Deviation 55506 |
| Placebo | Change From Baseline in Sputum IL8 | Day 21 change from baseline | 9576 pg/mL | Standard Deviation 66157 |
| 450mg, Once Per Day | Change From Baseline in Sputum IL8 | Day 14 Change from baseline | -26528 pg/mL | Standard Deviation 46737 |
| 450mg, Once Per Day | Change From Baseline in Sputum IL8 | Day 7 change from baseline | -17864 pg/mL | Standard Deviation 33785 |
| 450mg, Once Per Day | Change From Baseline in Sputum IL8 | Day 21 change from baseline | -16043 pg/mL | Standard Deviation 34551 |
| 150mg, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 14 Change from baseline | -33653 pg/mL | Standard Deviation 55302 |
| 150mg, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 7 change from baseline | -5511 pg/mL | Standard Deviation 46204 |
| 150mg, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 21 change from baseline | -19778 pg/mL | Standard Deviation 49306 |
| 450mg, Twice Per Day | Change From Baseline in Sputum IL8 | Day 14 Change from baseline | 3167 pg/mL | Standard Deviation 28204 |
| 450mg, Twice Per Day | Change From Baseline in Sputum IL8 | Day 7 change from baseline | 111574 pg/mL | Standard Deviation 70338 |
| 450mg, Twice Per Day | Change From Baseline in Sputum IL8 | Day 21 change from baseline | 2831 pg/mL | Standard Deviation 23050 |
| 300mg, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 14 Change from baseline | -6136 pg/mL | Standard Deviation 53611 |
| 300mg, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 7 change from baseline | -2663 pg/mL | Standard Deviation 41802 |
| 300mg, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 21 change from baseline | 631 pg/mL | Standard Deviation 32350 |
| High Dose, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 7 change from baseline | -25785 pg/mL | Standard Deviation 53721 |
| High Dose, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 21 change from baseline | -10671 pg/mL | Standard Deviation 65656 |
| High Dose, Three Times Per Day | Change From Baseline in Sputum IL8 | Day 14 Change from baseline | 221 pg/mL | Standard Deviation 30639 |
Secondary
Change From Baseline in Weight
Weight (kg) by visit - ANCOVA with observed data
Time frame: Baseline through Day 21/End of Study
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Weight | Day 14 | 0.85 kg | Standard Deviation 1.355 |
| Placebo | Change From Baseline in Weight | Day 7 | 0.96 kg | Standard Deviation 1.084 |
| Placebo | Change From Baseline in Weight | Day 21 | 1.37 kg | Standard Deviation 1.486 |
| 450mg, Once Per Day | Change From Baseline in Weight | Day 14 | 1.71 kg | Standard Deviation 1.27 |
| 450mg, Once Per Day | Change From Baseline in Weight | Day 7 | 0.83 kg | Standard Deviation 1.241 |
| 450mg, Once Per Day | Change From Baseline in Weight | Day 21 | 1.50 kg | Standard Deviation 1.639 |
| 150mg, Three Times Per Day | Change From Baseline in Weight | Day 14 | 0.96 kg | Standard Deviation 1.368 |
| 150mg, Three Times Per Day | Change From Baseline in Weight | Day 7 | 0.79 kg | Standard Deviation 1.145 |
| 150mg, Three Times Per Day | Change From Baseline in Weight | Day 21 | 1.30 kg | Standard Deviation 1.503 |
| 450mg, Twice Per Day | Change From Baseline in Weight | Day 14 | 1.04 kg | Standard Deviation 1.445 |
| 450mg, Twice Per Day | Change From Baseline in Weight | Day 7 | 0.67 kg | Standard Deviation 1.182 |
| 450mg, Twice Per Day | Change From Baseline in Weight | Day 21 | 0.52 kg | Standard Deviation 1.295 |
| 300mg, Three Times Per Day | Change From Baseline in Weight | Day 14 | 0.55 kg | Standard Deviation 1.872 |
| 300mg, Three Times Per Day | Change From Baseline in Weight | Day 7 | 0.25 kg | Standard Deviation 1.547 |
| 300mg, Three Times Per Day | Change From Baseline in Weight | Day 21 | -0.28 kg | Standard Deviation 2.728 |
| High Dose, Three Times Per Day | Change From Baseline in Weight | Day 7 | 0.36 kg | Standard Deviation 1.74 |
| High Dose, Three Times Per Day | Change From Baseline in Weight | Day 21 | 0.34 kg | Standard Deviation 2.477 |
| High Dose, Three Times Per Day | Change From Baseline in Weight | Day 14 | 0.89 kg | Standard Deviation 2.621 |