Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SPL84 in Patients With Cystic Fibrosis

Официальное название

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

Обзор

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.

Вмешательства

• Препарат SPL84
  SPL84 solution for nebulization
• Другое Placebo
  Placebo solution for nebulization

Первичные конечные точки

• 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) [Срок оценки: 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 heart rate [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4)]

Вторичные конечные точки (12)

• Characterization of pharmacokinetics (PK) of SPL84: maximum serum concentration (Cmax) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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-∞) [Срок оценки: 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) [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4)]
• Efficacy of SPL84 as assessed by change from baseline in percent predicted FEF25-75 [Срок оценки: 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 [Срок оценки: Day 1 through Day 87 (Cohort 1-3) or 108 (Cohort 4)]
• Efficacy of SPL84 as assessed by change from baseline in body weight [Срок оценки: 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) [Срок оценки: Day 1 through Day 87]

Критерии участия

Cohort 1-3:

Критерии включения

• 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.

Критерии исключения

• 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:

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 3 центра

• University of Southern California — Los Angeles
• National Jewish Health — Denver
• Boston Children'S Hospital — Boston

Идентификаторы

NCT: NCT06429176 · SPL84-002 · 2024-511184-28

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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