AeroVanc in the Treatment of Methicillin-resistant Staphylococcus Aureus Infection in Patients With Cystic Fibrosis

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03181932

Enrollment

188

Registered

2017-06-09

Start date

2017-09-20

Completion date

2021-01-15

Last updated

2022-12-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cystic Fibrosis, MRSA

Brief summary

This is a multi-center, randomized phase III study to evaluate the clinical effectiveness of AeroVanc in persistent methicillin-resistant Staphylococcus aureus (MRSA) infection in patients with cystic fibrosis (CF).

Detailed description

This is a phase III, randomized, multicenter, double-blind, placebo-controlled, parallel-group study to examine the safety and efficacy of AeroVanc in the treatment of persistent MRSA lung infection in patients diagnosed with CF. After the Screening period to confirm study eligibility, participants are 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, participants 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. Participants on a 28-day cyclical on/off anti-Pseudomonal antibiotic regimen enter the Screening period at a time such that the Baseline visit coincide with the end of their anti-Pseudomonas antibiotic cycle. Study drug is thereby administered during the off-cycle, and participants can then resume anti-Pseudomonal therapy during the 28-day observation period. Participants continuing alternating anti-Pseudomonal therapy can continue their treatment during the study drug administration, and observation period. The primary and secondary analyses are conducted in participants ≤21 years old. Subjects \>21 years old are analyzed separately as supportive analyses.

Interventions

DRUGVancomycin inhalation powder

100 participants are to be treated with double-blind vancomycin inhalation powder (75 subjects ≤21 years old, 25 subjects \>21 years old) for 24 weeks during Period 1.

DRUGPlacebo inhalation powder

100 participants are to be treated with double-blind placebo (75 subjects ≤21 years old, 25 subjects \>21 years old) for 24 weeks during Period 1.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

6 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Participants ≥6 years of age at time of informed consent form or assent form signing. 2. Confirmed diagnosis of CF, determined by having clinical features consistent with the CF phenotype, plus one of the following: 1. Positive sweat chloride test (value ≥60 milliequivalent/L), 2. Genotype with 2 mutations consistent with CF (i.e., a mutation in each of the cystic fibrosis transmembrane conductance regulator 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 \>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. FEV1 ≥30% and ≤90% of predicted that is normal for age, gender, race, and height, using the Global Lung Function Initiative 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 study and must be combined with a negative pregnancy test obtained during Screening; sexually active male subjects of reproductive potential who are non-sterile (i.e., 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 study. For purposes of this study, the Sponsor defines acceptable methods of contraception as: 1. Oral birth control pills administered for at least 1 monthly cycle prior to administration of the study drug. 2. A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle prior to the study drug administration but not beyond the 4th successive year following insertion. 3. Intrauterine devices, inserted by a qualified clinician for at least 1 monthly cycle prior to study drug administration. 4. Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 1 monthly cycle prior to administration of the study drug and continuing through 1 month following study completion. 5. Hysterectomy or surgical sterilization. 6. Abstinence. 7. 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 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. Participants with a Pseudomonas 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.

Exclusion criteria

1. Use of anti-MRSA treatments prescribed as maintenance therapy (intravenous \[IV\] or inhaled treatment within 28 days; oral treatment within 14 days) prior to the Baseline visit. 2. Use of non-maintenance antibiotic for pulmonary infection or extrapulmonary MRSA infection (IV or inhaled antibiotic within 28 days; oral antibiotic within 14 days) prior to the Baseline visit. 3. History of previous allergies or sensitivity to vancomycin, or other component(s) of the study drug or placebo except for a history of red-man syndrome. 4. Inability to tolerate inhaled products. 5. First time sputum culture or throat swab culture yielding Burkholderia cepacia, or nontuberculous Mycobacteria in the previous 6 months to Screening. 6. History of lung or other solid organ transplantation or currently on the list to receive lung or other solid organ transplantation. 7. Resistance to vancomycin at Screening (vancomycin resistant Staphylococcus aureus, or vancomycin intermediate resistant Staphylococcus aureus, with minimum inhibitory concentration ≥8 μg/mL). 8. Oral corticosteroids in doses exceeding 10 mg prednisone per day or 20 mg prednisone every other day, or equipotent doses of other corticosteroids. 9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid medications within 14 days, or changes in cystic fibrosis transmembrane conductance modulators within 28 days, prior to the Baseline visit. 10. Abnormal laboratory findings or other findings or medical history at Screening that, in the Investigator's opinion, would compromise the safety of the subject or the quality of the study data. 11. Inability to tolerate inhalation of a short acting beta2 agonist 12. Oxygen saturation \<90% at Screening. 13. Changes in physiotherapy technique or physiotherapy scheduled within 1 week of the Baseline visit. 14. Administration of any investigational drug or device within 4 weeks prior to the Screening visit and during the study 15. Female with positive pregnancy test result during Screening, pregnant (or intends to become pregnant), lactating or intends to breastfeed during the study. 16. Renal insufficiency, defined as creatinine clearance \<50 mL/min using the Cockcroft-Gault equation for adults or Schwartz equation for children at the Screening visit. 17. Abnormal liver function, defined as ≥4x upper limit of normal of serum aspartate aminotransferase or serum alanine aminotransferase, or known cirrhosis at Screening. 18. Diagnosed with clinically significant hearing loss. 19. History of positive result for human immunodeficiency virus, hepatitis B virus or hepatitis C virus. 20. Planned hospitalizations for prophylaxis antibiotic treatment within 28 days prior to Baseline visit or during the double-blind period (Period 1).

Design outcomes

Primary

Measure	Time frame	Description
Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	Baseline and Week 4, 12 and 20	The mean absolute change from baseline in FEV1 percent predicted was analyzed sequentially at Week 4 (end of Cycle 1), Week 12 (end of Cycle 2) and at Week 20 (end of Cycle 3).

Secondary

Measure	Time frame	Description
Time to First Pulmonary Exacerbation	Week 20	Time to first pulmonary exacerbation requiring use of another antibiotic medication (oral, IV, and/or inhaled). The Outcome Measure Data presented are the median percentiles and 95% confidence intervals from Kaplan-Meier estimates.
Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Scores	Baseline and Week 4, 12, and 20	The CFQ-R was administered every two weeks using a hand-held e-Diary. CFQ-R scores range between 0 and 100, where higher scores indicate a better outcome. The CFQ-R measures functioning in a variety of domains, including Physical Functioning, Vitality, Health Perceptions, Respiratory Symptoms, Treatment Burden, Role Functioning, Emotional Functioning and Social Functioning. The Outcome Measure Data presented are the Respiratory Symptoms Scores.
Change From Baseline in Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Symptom Score (CFRSD-CRISS) Scores	Baseline and Week 4, 12 and 20	The CFRSD-CRISS was administered every two weeks using a hand-held e-Diary. Scores range between 0 and 100, where higher scores indicate a worse outcome.
Frequency of Pulmonary Exacerbations	Week 20	The number of pulmonary exacerbations during Period 1 adjusted for the length of follow-up.
Number of Successful Response Cycles	Week 20	The number of successful response cycles a participant achieves over Period 1. A response in a cycle is defined by at least a 5 % relative improvement in FEV1 percent predicted at the end of each the respective cycle.
Area Under the FEV1-time Profile	Week 20	The mean treatment difference in FEV1 across all post-baseline visits
Relative Change in FEV1 Percent Predicted	Baseline and Week 4, 12 and 20	The mean relative change from Baseline in FEV1 percent predicted

Countries

Canada, United States

Participant flow

Recruitment details

76 sites in Canada (2 clinics) and US (74 clinics) enrolled participants in the trial. First participant was enrolled on 20 September 2017 and last subject completed the study on 15 January 2021.

Pre-assignment details

A total of 353 participants were screened, and 188 were randomized in Period 1. In total, 165 participants were screen failures and the reasons for screen failure were ineligibility (n=157), exacerbation (n=6), lost to follow-up (n=1) and other reason (n=1).

Participants by arm

Arm	Count
Double-blind Vancomycin Inhalation Powder Vancomycin inhalation powder 30 mg is administered twice daily (BID) during the 24-week double-blind period (Period 1) by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation. Vancomycin inhalation powder: 100 participants are to be treated with double-blind vancomycin inhalation powder (75 subjects ≤21 years old, 25 subjects \>21 years old) for 24 weeks during Period 1.	90
Double-blind Placebo Inhalation Powder Matching placebo is administered BID during the 24-week double-blind period (Period 1) by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation. Placebo inhalation powder: 100 participants are to be treated with double-blind placebo (75 subjects ≤21 years old, 25 subjects \>21 years old) for 24 weeks during Period 1.	98
Total	188

Withdrawals & dropouts

Period	Reason	FG000	FG001
Period 1 (Double-blind Period)	Adverse Event	5	1
Period 1 (Double-blind Period)	Lost to Follow-up	0	1
Period 1 (Double-blind Period)	Protocol Violation	1	2
Period 1 (Double-blind Period)	Withdrawal by Subject	5	9
Period 2 (Open-label Period)	Adverse Event	1	6
Period 2 (Open-label Period)	Lost to Follow-up	0	1
Period 2 (Open-label Period)	Protocol Violation	3	1
Period 2 (Open-label Period)	Reason missing	2	0
Period 2 (Open-label Period)	Withdrawal by Subject	2	5

Baseline characteristics

Characteristic	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder	Total
Age, Continuous	20.2 years STANDARD_DEVIATION 12.52	18.2 years STANDARD_DEVIATION 8.7	19.2 years STANDARD_DEVIATION 10.71
Age, Customized >21 years	26 Participants	29 Participants	55 Participants
Age, Customized 6-21 years	64 Participants	69 Participants	133 Participants
Baseline Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	65.25 percent predicted STANDARD_DEVIATION 16.193	66.32 percent predicted STANDARD_DEVIATION 16.939	65.81 percent predicted STANDARD_DEVIATION 16.55
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	6 Participants	10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	86 Participants	92 Participants	178 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Number of Pulmonary Infections in the Previous Year	2.6 infections STANDARD_DEVIATION 1.53	2.6 infections STANDARD_DEVIATION 1.44	2.6 infections STANDARD_DEVIATION 1.48
Pseudomonas Aeruginosa Infection Present at Screening (Yes/No?) No	39 Participants	53 Participants	92 Participants
Pseudomonas Aeruginosa Infection Present at Screening (Yes/No?) Yes	51 Participants	45 Participants	96 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	3 Participants	1 Participants	4 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants	2 Participants	4 Participants
Race (NIH/OMB) White	85 Participants	94 Participants	179 Participants
Sex: Female, Male Female	45 Participants	50 Participants	95 Participants
Sex: Female, Male Male	45 Participants	48 Participants	93 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 90	0 / 98	0 / 158
other Total, other adverse events	85 / 90	93 / 98	139 / 158
serious Total, serious adverse events	24 / 90	35 / 98	50 / 158

Outcome results

Primary

Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted

The mean absolute change from baseline in FEV1 percent predicted was analyzed sequentially at Week 4 (end of Cycle 1), Week 12 (end of Cycle 2) and at Week 20 (end of Cycle 3).

Time frame: Baseline and Week 4, 12 and 20

Population: Intention-to-treat (ITT) population (defined as all randomized participants). Participants were analyzed according to randomized treatment. The ITT population was also split out by age (≤21 years, \>21 years). The population of participants ≤21 years was used for all main analyses of efficacy endpoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Double-blind Vancomycin Inhalation Powder	Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	Week 4	2.39 Percent predicted	Standard Deviation 8.078
Double-blind Vancomycin Inhalation Powder	Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	Week 12	1.52 Percent predicted	Standard Deviation 8.414
Double-blind Vancomycin Inhalation Powder	Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	Week 20	1.61 Percent predicted	Standard Deviation 9.967
Double-blind Placebo Inhalation Powder	Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	Week 4	1.18 Percent predicted	Standard Deviation 8.581
Double-blind Placebo Inhalation Powder	Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	Week 12	0.13 Percent predicted	Standard Deviation 8.056
Double-blind Placebo Inhalation Powder	Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted	Week 20	-1.94 Percent predicted	Standard Deviation 8.924

Comparison: Based on previous experience, a sample size of 45 participants per arm would provide 89% power to detect a statistically significant difference at alpha level of 0.05. To account for potential dropouts and/or smaller effect size in a 3-cycle trial, a sample size of 75 participants per arm was to be enrolled in the primary analysis population, which if all completed would provide 90% power to detect a difference of 3.4% at 20 weeks assuming the same standard deviation of 6.3%.p-value: 0.32595% CI: [-1.4, 4.1]Mixed Models Analysis

Secondary