Cystic Fibrosis
Conditions
Brief summary
The goal of this clinical trial is to learn if drug SPL84 is safe for adult patients with cystic fibrosis (CF). It will also learn if the drug works to treat works to treat CF with a specific mutation (3849 +10kb C--\>T). The purpose of this research study is to test the safety and effectiveness of multiple doses of the study drug, SPL84. Researchers will compare drug SPL84 to a placebo (a look-alike substance that contains no drug) to see if drug SPL84 is safe and if it works to treat CF. In cohorts 1-3, SPL84 will be tested as a monotherapy, and in Cohort 4, SPL84 will be tested in participants who are already stable on CFTR modulator therapy. Participants will take drug SPL84 or a placebo by inhalation every week for 9 weeks (cohorts 1-3) or 12 weeks (cohort 4) and visit the clinic approximately weekly for checkups and tests.
Interventions
DRUGSPL84
SPL84 solution for nebulization
OTHERPlacebo
Placebo solution for nebulization
Sponsors
SpliSense Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cohort 1-3: Inclusion Criteria: * Diagnosis of CF and two CF causing mutations; 3849+10 Kb C-\>T mutation on one allele in the CF transmembrane conductance regulator (CFTR) gene (homozygote or compound heterozygote). Source documentation from a certified genetic laboratory is required. * Body mass index (BMI) of ≥ 17 kg/m2. * FEV1 40-90% predicted at screening. * Non-smokers or vapers for at least 180 days (6 months) prior to screening, per participant report.
Exclusion criteria
* Use of Kalydeco, Orkambi, Symdeko/Symkevi or Trikafta/Kaftrio within 30 days of first dose with study intervention. * Use of any investigational drug (other than SPL84) or device within 30 days of first dose with study intervention. * Use of systemic steroids over 3 consecutive months in the last 6 months prior to screening, or use of systemic steroids in the last month prior to screening. Use of inhaled steroids above 1 mg. * Use of CF medications, e.g. inhaled antibiotics, dornase alfa (Pulmozyme), hypertonic saline and physiotherapy should be on stable regimen for the period 28 days prior to screening; those participants taking inhaled antibiotics for prophylaxis must be on a stable regimen of these drugs for at least 90 days prior to first dose with study intervention. * Any acute infection including acute upper respiratory or lower respiratory infections, pulmonary exacerbation, changes in therapy for pulmonary disease, or any non CF-related illness which results in the initiation of any new therapy within 14 days prior to first dose with study intervention. * Hemoptysis of greater than 30 mL within 90 days prior to Day 1, or hospitalization for hemoptysis within 6 months of first dose with study intervention. * Liver disease characterized by clinically significant cirrhosis and/or documented portal hypertension. * History of any organ transplantation. * Documented coronavirus disease (COVID-19) infection within 4 weeks prior to dosing. Cohort 4: Inclusion Criteria: * Diagnosis of CF and two CF causing mutations; 3849+10 Kb C-\>T mutation on one allele in the CF transmembrane conductance regulator (CFTR) gene (homozygote or compound heterozygote). Source documentation from a certified genetic laboratory is required. * Body mass index (BMI) of ≥ 17 kg/m2. * FEV1 40-80% predicted at screening. * Non-smokers or vapers for at least 180 days (6 months) prior to screening, per participant report. * Stable adherence to standard use of Trikafta/Kaftio or Alyftrek for at least 3 months, or Alyftrek for 1 month after switching from Trikafta/Kaftio, according to prescribing information.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of SPL84 as evaluated by number of subjects with at least one treatment-related adverse event (AE) or serious adverse event (SAEs) | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | Incidence, nature, and severity of AEs and SAEs |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal heart rate | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal respiratory rate | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal systolic and diastolic blood pressure | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal oximetry | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal temperature | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal hematology lab test results | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal biochemistry lab test results | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal urinalysis lab test results | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal electrocardiogram (ECG) parameters | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | using an ECG machine that automatically calculates heart rate and measure PR, QRS, QT, and QTc intervals |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal physical examination findings | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | Complete physical examinations include general appearance, head, ears, eyes, nose, throat, thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, back, neck, musculoskeletal, and lymph nodes. |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal pulmonary function tests results | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | Pulmonary function tests will be performed according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) and forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced mid-expiratory flow (FEF25-75) will be measured |
| Safety and Tolerability of SPL84 as assessed by number of participants with abnormal immunogenicity results | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | assessment of anti-SPL84 antibodies will be performed both in serum and sputum |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Characterization of pharmacokinetics (PK) of SPL84: maximum serum concentration (Cmax) | Cohort 1-3: Predose and 15 and 30 minutes and 1, 2, 4, 6, 8, and 24 hours postdose on Day 1 and Day 57; predose on Days 8 and 29; Days 64 and 87; Cohort 4: Predose and 1, 3, and 6 hours post dose on Days 1 and 78 | — |
| Characterization of PK of SPL84: Time to Cmax (Tmax) | Cohort 1-3: Predose and 15 and 30 minutes and 1, 2, 4, 6, 8, and 24 hours postdose on Day 1 and Day 57; predose on Days 8 and 29; Days 64 and 87; Cohort 4: Predose and 1, 3, and 6 hours post dose on Days 1 and 78 | — |
| Characterization of PK of SPL84: terminal elimination half-life (t1/2) | Cohort 1-3: Predose and 15 and 30 minutes and 1, 2, 4, 6, 8, and 24 hours postdose on Day 1 and Day 57; predose on Days 8 and 29; Days 64 and 87; Cohort 4: Predose and 1, 3, and 6 hours post dose on Days 1 and 78 | — |
| Characterization of PK of SPL84: Area under the curve to the final sample (AUC0-t) | Cohort 1-3: Predose and 15 and 30 minutes and 1, 2, 4, 6, 8, and 24 hours postdose on Day 1 and Day 57; predose on Days 8 and 29; Days 64 and 87; Cohort 4: Predose and 1, 3, and 6 hours post dose on Days 1 and 78 | — |
| Characterization of PK of SPL84: Area under the curve to infinity (AUC0-∞) | Cohort 1-3: Predose and 15 and 30 minutes and 1, 2, 4, 6, 8, and 24 hours postdose on Day 1 and Day 57; predose on Days 8 and 29; Days 64 and 87; Cohort 4: Predose and 1, 3, and 6 hours post dose on Days 1 and 78 | — |
| Characterization of PK of SPL84: Apparent clearance (CL/F) | Cohort 1-3: Predose and 15 and 30 minutes and 1, 2, 4, 6, 8, and 24 hours postdose on Day 1 and Day 57; predose on Days 8 and 29; Days 64 and 87; Cohort 4: Predose and 1, 3, and 6 hours post dose on Days 1 and 78 | — |
| Characterization of excretion of SPL84: concentration of SPL84 in urine | Day 1 through Day 87 (Cohort 1-3) or Day 85 (Cohort 4) | — |
| Efficacy of SPL84 as assessed by change from baseline in percent predicted FEV1 | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | Pulmonary function tests will be performed according to the ATS/ERS |
| Efficacy of SPL84 as assessed by change from baseline in percent predicted FEF25-75 | Day 1 to Day 87 (Cohort 1-3) or Day 108 (Cohort 4) | — |
| Efficacy of SPL84 as assessed by change from baseline in Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | The score for is standardized on a 0- to 100-point scale on which higher scores represent a higher quality of life |
| Efficacy of SPL84 as assessed by change from baseline in body weight | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | — |
| Preliminary efficacy of SPL84 as assessed by change from baseline of antibiotic treatment (Cohort 1-3 only) | Day 1 through Day 87 | — |
| Cohort 1-3: Safety and Tolerability of SPL84 as assessed by number of participants with abnormal sputum microbiology results Cohort 4: Exploratory efficacy of SPL84 as assessed by number of participants with change in abnormal sputum microbiology result | Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4) | Sputum microbiology will be performed with a microbiology based assay; organism growth will be identified. |
| Exploratory efficacy of SPL84 as assessed by number of participants with change in Lung Clearance Index at 2.5% of starting concentration (LCI2.5) | Day 1 to Day 85 | Measured using multiple breath washout (at select study sites only) |
Countries
United States
Outcome results
None listed