A Phase III, randomized, double-blind, placebo-controlled study of AeroVanc for the treatment of persistent methicillin-resistant Staphylococcus aureus lung infection in cystic fibrosis patients.
Study ID: STU 092016-033
Randomized, multicenter, double-blind, placebo-controlled, parallel-group study to examine the safety and efficacy of aeroVanc in the treatment of persistent Methicillin resistant Staphylococcus aureus (MRSa) lung infection in patients diagnosed with cystic fibrosis (CF). This study will have to Periods (1 and 2) after the Screening period (up to 42 days) to confirm study eligibility, subjects will be randomly assigned in a blinded fashion to receive either aeroVanc 30 mg twice daily (BiD), or placebo BiD (1:1 active to placebo) by inhalation for 24 weeks or 3 dosing cycles (Period 1). upon completion of Period 1, subjects will receive open-label aeroVanc 30 mg BiD for an additional 24 weeks or 3 dosing cycles (Period 2), to evaluate long-term safety of aeroVanc. a dosing cycle is defined as 28 days of treatment followed by 28 days of observation. Subjects meeting the inclusion / exclusion criteria will be stratified upon randomization on the basis of (a) age (6x21; [Greater Than] 21), (b) Baseline FeV1 ([GreaterThanorequalTo]60%; [Less Than]60%), (c) prior exacerbations treated with antibiotics during the previous 12 months (1-2; [GreaterThanorequalTo] 3) and (d) P. aeruginosa treatment (not treated; treated). Subjects on a 28-day cyclical on/off anti-Pseudomonal antibiotic regimen will enter the Screening period at a time such that the Baseline visit coincides with the end of their anti-Pseudomonas antibiotic cycle. Study drug will thereby be administered during the off-cycle, and subjects can then resume anti-Pseudomonal therapy during the 28-day observation period (Week 5 through Week 8). Subjects continuing alternating anti-Pseudomonal therapy can continue their treatment during the study drug administration, and observation period.
Inclusion Criteria Subjects must meet all of the following criteria to be considered eligible to participate in the study: 1. Subjects >= 6 years of age at time of Informed Consent Form (ICF) or Assent Form signing. 2. Confirmed diagnosis of CF, determined by having clinical features consistent with the CF phenotype, plus 1 of the following: a. Positive sweat chloride test (value >= 60 mEq/L), b. Genotype with 2 mutations consistent with CF (ie, a mutation in each of the cystic fibrosis transmembrane conductance regulator [CFTR] genes). 3. Positive sputum culture or a throat swab culture for MRSA at Screening. 4. In addition to the Screening sample, have at least 2 prior sputum or throat swab cultures positive for MRSA, of which at least 1 sample is more than 6 months prior to Screening. At least 50% of all MRSA cultures (sputum or throat swab culture) collected from the time of the first positive culture (in the previous 1 year) must have tested positive for MRSA.(Note: screening sample may count towards 50% positive count.) 5. Forced expiratory volume in 1 second (FEV1) >= 30% and <= 90% of predicted that is normal for age, gender, race, and height, using the Global Lung Function Initiative (GLI) equation. 6. At least 1 episode of acute pulmonary infection treated with non-maintenance antibiotics within 12 months prior to the Baseline visit. (Initiation of treatment with intermittent inhaled anti-Pseudomonal therapy will not qualify as treatment with non-maintenance antibiotics). 7. If female of childbearing potential, an acceptable method of contraception must be used during the course of the study and must be combined with a negative pregnancy test obtained during Screening; sexually active male subjects of reproductive potential who are non-sterile (ie, male who has not been sterilized by vasectomy for at least 6 months and were not diagnosed with infertility through demonstration of azoospermia in a semen sample and/or absence of vas deferens through ultrasound) must be willing to use a barrier method of contraception, or their female partner must use an acceptable method of contraception, during the course of the study. For purposes of this study, the Sponsor defines * acceptable methods of contraception * as: as: a. Oral birth control pills administered for at least 1 monthly cycle prior to administration of the study drug b. A synthetic progestin implanted rod (eg, Implanon(RegisteredTM)) for at least 1 monthly cycle prior to the study drug administration but not beyond the 4th successive year following insertion c. Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1 monthly cycle prior to study drug administration d. Medroxyprogesterone acetate (eg, Depo-Provera(RegisteredTM)) administered for a minimum of 1 monthly cycle prior to administration of the study drug and continuing through 1 month following study completion. e. Hysterectomy or surgical sterilization f. Abstinence g. Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive foam) NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal contraceptive exposure, reducing the effectiveness and increasing the incidence of menstruation-associated adverse reactions. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi. 8. Able and willing to comply with the protocol, including availability for all scheduled study visits and be able to perform all techniques necessary to use the AeroVanc inhaler and measure lung function. 9. Agree not to smoke during any part of the clinical trial (Screening visit through end of study). 10. Subjects with a P. aeruginosa co-infection must either be stable on a regular suppression regimen of inhaled antibiotics or must be, in the opinion of the Investigator, stable despite the lack of such treatment.
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- PREETI BHATIA SHARMA
The primary objective of the study is to evaluate the efficacy of aeroVanc in improving lung function of CF patients [LessThanorequalTo] 21 years of age with persistent MRSa lung infection. The secondary objectives of the study are: * To evaluate the time to first pulmonary exacerbation requiring use of another antibiotic medication (oral, intravenous, and/or inhaled) and the frequency of pulmonary exacerbations. * To evaluate the efficacy of aeroVanc in the reduction of respiratory symptoms and improvement in quality of life. * To evaluate the safety and tolerability of aeroVanc during 3 treatment cycles (24 weeks Primary and secondary efficacy analyses, for which full control of Type i error will be implemented, will be in the group of patients who are [LessThanorequalTo] 21 years of age. The primary efficacy endpoint is the mean absolute change from baseline in FeV1 percent predicted. The endpoint will be analyzed sequentially at Week 4 (end of Cycle 1), Week 12 (end of Cycle 2) and at Week 20 (end of Cycle 3). if a statistically significant difference is observed in favor of aeroVanc compared to placebo after Cycle 1, then the mean change in the FeV1 percent predicted from Baseline to end of Cycle 2 during Cycle 3 will be analyzed. Similarly, if the effect after Cycle 2 is statistically significant, then the analysis of Baseline to end of Cycle 3 will be reported. The data will be analyzed using an analysis of covariance model with baseline FeV1 percent predicted as a covariate and the stratification factors as fixed effects. For confirmation of the primary endpoint, sensitivity analyses will be conducted where missing data will be imputed in different ways. of the secondary endpoints, the distributions of time to first pulmonary exacerbation will be compared between the treatment arms using a Cox proportional hazards regression model including the effects of treatment group and the stratification factors.The number of days from randomization until the date of first exacerbation will be calculated and summarized using a Kaplan-Meier life table presentation. Subjects who do not experience pulmonary exacerbation prior to discontinuation from the study will be censored at the date of discontinuation of the study. Changes in CFQ-R and , CFRSD-CRiSS score, and relative change from baseline in FeV1 percent predicted, will all be analyzed similarly at Week 4,12, and 20 using an analysis of covariance including baseline covariate and stratification factors. The number of successful response cycles each subject achieves over the 3 cycles of therapy (0, 1, 2 or 3) will be compared using a proportional odds model for ordered categories. Frequency of pulmonary exacerbations will be compared between the groups using a negative binomial model for count data, adjusting for each subjectpatient's length of follow-up. The randomization stratification factors will be included in the model as fixed effects. area under the FeV1xtime profile will be analyzed using analysis of covariance including the patient's baseline FeV1 and the stratification factors. Type i error rate will be controlled by a sequential testing procedure. For patients who are [Greater Than]21 years of age, the above analyses will be repeated but with an emphasis on estimation of the treatment effect, rather than statistical significance testing. no Type i error control will be used for the analyses of these subjects. no interim analyses are planned. The primary analysis will be based on the iTT population of all randomized subjects [LessThanorequalTo] 21 years of age.