A Phase 2a, Randomized, Placebo-Controlled, Double Blind Multiple Ascending Dose Study in Patients With Cystic Fibrosis Carrying the 3849 +10 Kb C->T Mutation to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SPL84
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 64
- 试验地点
- 5
- 主要终点
- 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)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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/m
- •FEV1 40-90% predicted at screening.
- •Non-smokers or vapers for at least 180 days (6 months) prior to screening, per participant report.
排除标准
- •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.
- •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/m
- •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.
- •Exclusion Criteria:
- •Previous participation in active arm of SPL84-002 study (Cohort 1-3)
- •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.
研究组 & 干预措施
SPL84
干预措施: SPL84 (Drug)
Placebo
干预措施: Placebo (Other)
结局指标
主要结局
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)
时间窗: Day 1 through Day 87
Incidence, nature, and severity of AEs and SAEs
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal systolic and diastolic blood pressure
时间窗: Day 1 through Day 87
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal heart rate
时间窗: Day 1 through Day 87
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal respiratory rate
时间窗: Day 1 through Day 87
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal oximetry
时间窗: Day 1 through Day 87
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal sputum microbiology results results
时间窗: Day 1 through Day 87
Sputum microbiology will be performed with a microbiology based assay; organism growth will be identified.
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal immunogenicity results
时间窗: Day 1 through Day 87
assessment of anti-SPL84 antibodies will be performed both in serum and sputum
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal temperature
时间窗: Day 1 through Day 87
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal biochemistry lab test results
时间窗: Day 1 through Day 87
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal urinalysis lab test results
时间窗: Day 1 through Day 87
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal hematology lab test results
时间窗: Day 1 through Day 87
Safety and Tolerability of SPL84 as assessed by number of participants with abnormal electrocardiogram (ECG) parameters
时间窗: Day 1 through Day 87
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
时间窗: Day 1 through Day 87
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
时间窗: Day 1 through Day 87
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
次要结局
- Characterization of PK of SPL84: Area under the curve to infinity (AUC0-∞)(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)
- Characterization of PK of SPL84: Apparent clearance (CL/F)(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)
- Preliminary efficacy of SPL84 as assessed by change from baseline in body weight(Day 1 through Day 87)
- Characterization of pharmacokinetics (PK) of SPL84: maximum serum concentration (Cmax)(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)
- Preliminary efficacy of SPL84 as assessed by change from baseline in Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score(Day 1 through Day 87)
- Preliminary efficacy of SPL84 as assessed by change from baseline of antibiotic treatment(Day 1 through Day 87)
- Characterization of PK of SPL84: Time to Cmax (Tmax)(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)
- Characterization of PK of SPL84: terminal elimination half-life (t1/2)(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)
- Characterization of excretion of SPL84: concentration of SPL84 in urine(Day 1 through Day 87)
- Preliminary efficacy of SPL84 as assessed by change from baseline in percent predicted FEV1(Day 1 through Day 87)
- Characterization of PK of SPL84: Area under the curve to the final sample (AUC0-t)(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)