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

Cystic Fibrosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03181932
• Other study ID #: SAV005-04
• Status: Completed
• Phase: Phase 3
• Start date: September 20, 2017
• Est. completion date: January 15, 2021

Study information

• Verified date: December 2022
• Source: Savara Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 188
• Est. completion date: January 15, 2021
• Est. primary completion date: July 28, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• MRSA

Intervention

Drug:
• 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.
• 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.
• Vancomycin inhalation powder
In the 24-week Period 2, all participants are to be treated with open-label vancomycin inhalation powder.

Locations

Country	Name	City	State
Canada	The Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
United States	Albany Medical College	Albany	New York
United States	University of New Mexico Pediatric/Pulmonary	Albuquerque	New Mexico
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Children's Health Care of Atlanta at Scottish Rite	Atlanta	Georgia
United States	Augusta Univ Cystic Fibrosis Center	Augusta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Austin Children's Chest Associates	Austin	Texas
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Medical University of South Carolina (MUSC)	Charleston	South Carolina
United States	Levine Children's Hospital - Atrium Health	Charlotte	North Carolina
United States	University of Virginia Health System, Cystic Fibrosis Center	Charlottesville	Virginia
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University Hospital Cleveland Medical Center	Cleveland	Ohio
United States	University Vermont Medical Center Vermont Lung Center	Colchester	Vermont
United States	The Research Institute at Nationwide Children's Hospital	Columbus	Ohio
United States	Children's Medical Center Cystic Fibrosis Clinic	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	National Jewish Health Adult Cystic Fibrosis Center	Denver	Colorado
United States	Wayne State University (HUH)	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Cook Children Medical Center	Fort Worth	Texas
United States	University of Florida Pediatrics	Gainesville	Florida
United States	Chicago CF Care Specialists	Glenview	Illinois
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Memorial Healthcare System	Hollywood	Florida
United States	Texas Children's Hospital	Houston	Texas
United States	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana
United States	University of Iowa Department of Pediatrics	Iowa City	Iowa
United States	Nemours Childrens Specialty Care	Jacksonville	Florida
United States	Children's Mercy	Kansas City	Missouri
United States	University of Kansas	Kansas City	Kansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Miller Childrens Hospital MemorialCare Health System Pediatric Pulmonology	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Southern California Keck Medical Center of USC	Los Angeles	California
United States	University of Louisville Kosair Charities Pediatric Clinical Research Unit	Louisville	Kentucky
United States	UTHSC Lebonheur Children's Hospital	Memphis	Tennessee
United States	University of Miami Bachelor Children's Hospital	Miami	Florida
United States	Pulmonary Associates of Mobile	Mobile	Alabama
United States	West Virginia University	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	NorthSurburban Pulmonary Specialists	Morton Grove	Illinois
United States	Rutgers-Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Northwell Health, Div of Pulmonary, Critical Care & Sleep Medicine	New Hyde Park	New York
United States	Columbia University Medical Center	New York	New York
United States	University of Oklahoma Health Science Center - Pediatric Pulmonary & CF Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Arnold Palmer Hospital Pulmonary and Sleep Medical Institute Orlando Health, Inc	Orlando	Florida
United States	Central Florida Pulmonary Group	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Nemours Children's Specialty Care	Pensacola	Florida
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMCU	Pittsburgh	Pennsylvania
United States	Maine Medical Partners Pediatric Specialty Care	Portland	Maine
United States	Oregon Health and Science University	Portland	Oregon
United States	UC Davis Medical Center	Sacramento	California
United States	Cardinal Glennon Children's Hospital /Saint Louis University	Saint Louis	Missouri
United States	Washington University	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	University of Utah Health Sciences Center	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford Childrens Specialty Clinic	Sioux Falls	South Dakota
United States	Providence Medical Research Center	Spokane	Washington
United States	Toledo Children's Hospital CF Center	Toledo	Ohio
United States	The University of Texas Health Science Center at Tyler	Tyler	Texas
United States	Children's National Medical Center	Washington	District of Columbia
United States	Via Christi Health Systems CF Clinic	Wichita	Kansas
United States	Wake Forest School of Medicine	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Savara Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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).	Baseline and Week 4, 12 and 20
Secondary	Frequency of Pulmonary Exacerbations	The number of pulmonary exacerbations during Period 1 adjusted for the length of follow-up.	Week 20
Secondary	Time to First Pulmonary Exacerbation	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.	Week 20
Secondary	Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Scores	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.	Baseline and Week 4, 12, and 20
Secondary	Change From Baseline in Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Symptom Score (CFRSD-CRISS) Scores	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.	Baseline and Week 4, 12 and 20
Secondary	Relative Change in FEV1 Percent Predicted	The mean relative change from Baseline in FEV1 percent predicted	Baseline and Week 4, 12 and 20
Secondary	Number of Successful Response Cycles	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.	Week 20
Secondary	Area Under the FEV1-time Profile	The mean treatment difference in FEV1 across all post-baseline visits	Week 20