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

• Sponsor: Savara Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03181932
• Collaborator: (none)
• Enrollment: 188
• Locations: 71
• Arms: 3
• Actual Duration (Months): 39.9
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
MRSA; Cystic Fibrosis	Drug: Vancomycin inhalation powder; Drug: Placebo inhalation powder; Drug: Vancomycin inhalation powder	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 188 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Sep 20, 2017
• Actual Primary Completion Date: Jul 28, 2020
• Actual Study Completion Date: Jan 15, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	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.; Other Names: AeroVanc
Placebo Comparator: 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.	Drug: 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.
Experimental: Open-label vancomycin inhalation powder In the 24-week Period 2, all participants receive AeroVanc 30 mg BID by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation.	Drug: Vancomycin inhalation powder; In the 24-week Period 2, all participants are to be treated with open-label vancomycin inhalation powder.; Other Names: AeroVanc

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Frequency of Pulmonary Exacerbations [Week 20]

   The number of pulmonary exacerbations during Period 1 adjusted for the length of follow-up.

2. 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.

3. 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.

4. 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.

5. Relative Change in FEV1 Percent Predicted [Baseline and Week 4, 12 and 20]

   The mean relative change from Baseline in FEV1 percent predicted

6. 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.

7. Area Under the FEV1-time Profile [Week 20]

   The mean treatment difference in FEV1 across all post-baseline visits

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. 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.

2. Agree not to smoke during any part of the clinical trial (Screening visit through end of study).

3. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pulmonary Associates of Mobile	Mobile	Alabama	United States	36608
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
3	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
4	Miller Childrens Hospital MemorialCare Health System Pediatric Pulmonology	Long Beach	California	United States	90806
5	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
6	University of Southern California Keck Medical Center of USC	Los Angeles	California	United States	90033
7	UC Davis Medical Center	Sacramento	California	United States	95817
8	Children's Hospital Colorado	Aurora	Colorado	United States	80045
9	National Jewish Health Adult Cystic Fibrosis Center	Denver	Colorado	United States	80206
10	Children's National Medical Center	Washington	District of Columbia	United States	20010
11	University of Florida Pediatrics	Gainesville	Florida	United States	32610
12	Memorial Healthcare System	Hollywood	Florida	United States	33021
13	Nemours Childrens Specialty Care	Jacksonville	Florida	United States	32207
14	University of Miami Bachelor Children's Hospital	Miami	Florida	United States	33136
15	Central Florida Pulmonary Group	Orlando	Florida	United States	32803
16	Arnold Palmer Hospital Pulmonary and Sleep Medical Institute Orlando Health, Inc	Orlando	Florida	United States	32806
17	Nemours Children's Hospital	Orlando	Florida	United States	32827
18	Nemours Children's Specialty Care	Pensacola	Florida	United States	32514
19	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
20	Children's Health Care of Atlanta at Scottish Rite	Atlanta	Georgia	United States	30342
21	Augusta Univ Cystic Fibrosis Center	Augusta	Georgia	United States	30912
22	Chicago CF Care Specialists	Glenview	Illinois	United States	60025
23	NorthSurburban Pulmonary Specialists	Morton Grove	Illinois	United States	60053
24	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana	United States	46202
25	University of Iowa Department of Pediatrics	Iowa City	Iowa	United States	52242
26	University of Kansas	Kansas City	Kansas	United States	66160
27	Via Christi Health Systems CF Clinic	Wichita	Kansas	United States	67214
28	University of Louisville Kosair Charities Pediatric Clinical Research Unit	Louisville	Kentucky	United States	40202
29	Maine Medical Partners Pediatric Specialty Care	Portland	Maine	United States	04102
30	Boston Children's Hospital	Boston	Massachusetts	United States	02115
31	University of Michigan Health System	Ann Arbor	Michigan	United States	48109
32	Wayne State University (HUH)	Detroit	Michigan	United States	48201
33	Children's Mercy	Kansas City	Missouri	United States	64108
34	Cardinal Glennon Children's Hospital /Saint Louis University	Saint Louis	Missouri	United States	63104
35	Washington University	Saint Louis	Missouri	United States	63110
36	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
37	Morristown Medical Center	Morristown	New Jersey	United States	07960
38	Rutgers-Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08901
39	University of New Mexico Pediatric/Pulmonary	Albuquerque	New Mexico	United States	87131
40	Albany Medical College	Albany	New York	United States	12208
41	Northwell Health, Div of Pulmonary, Critical Care & Sleep Medicine	New Hyde Park	New York	United States	11042
42	Columbia University Medical Center	New York	New York	United States	10032
43	Levine Children's Hospital - Atrium Health	Charlotte	North Carolina	United States	28203
44	Duke University Medical Center	Durham	North Carolina	United States	27710
45	Wake Forest School of Medicine	Winston-Salem	North Carolina	United States	27157
46	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
47	University Hospital Cleveland Medical Center	Cleveland	Ohio	United States	44106
48	The Research Institute at Nationwide Children's Hospital	Columbus	Ohio	United States	43205
49	Dayton Children's Hospital	Dayton	Ohio	United States	45404
50	Toledo Children's Hospital CF Center	Toledo	Ohio	United States	43606
51	University of Oklahoma Health Science Center - Pediatric Pulmonary & CF Center	Oklahoma City	Oklahoma	United States	73104
52	Oregon Health and Science University	Portland	Oregon	United States	97239
53	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
54	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
55	Children's Hospital of Pittsburgh of UPMCU	Pittsburgh	Pennsylvania	United States	15224
56	Medical University of South Carolina (MUSC)	Charleston	South Carolina	United States	29425
57	Sanford Childrens Specialty Clinic	Sioux Falls	South Dakota	United States	57105
58	UTHSC Lebonheur Children's Hospital	Memphis	Tennessee	United States	38103
59	Austin Children's Chest Associates	Austin	Texas	United States	78723
60	Children's Medical Center Cystic Fibrosis Clinic	Dallas	Texas	United States	75235
61	Cook Children Medical Center	Fort Worth	Texas	United States	76104
62	Texas Children's Hospital	Houston	Texas	United States	77030
63	The University of Texas Health Science Center at Tyler	Tyler	Texas	United States	75708
64	University of Utah Health Sciences Center	Salt Lake City	Utah	United States	84132
65	University Vermont Medical Center Vermont Lung Center	Colchester	Vermont	United States	05446
66	University of Virginia Health System, Cystic Fibrosis Center	Charlottesville	Virginia	United States	22908
67	Seattle Children's Hospital	Seattle	Washington	United States	98105
68	Providence Medical Research Center	Spokane	Washington	United States	99204
69	West Virginia University	Morgantown	West Virginia	United States	26506
70	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
71	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8

Sponsors and Collaborators

• Savara Inc.

Investigators

• Principal Investigator: Patrick Flume, MD, Medical University of South Carolina

Study Documents (Full-Text)

• Study Protocol - Apr 18, 2018
• Statistical Analysis Plan - Nov 5, 2020

More Information

Publications

None provided.

• Responsible Party: Savara Inc.
• ClinicalTrials.gov Identifier: NCT03181932
• Other Study ID Numbers: SAV005-04
• First Posted: Jun 9, 2017
• Last Update Posted: Nov 8, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Vancomycin

Study Results

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 Detail	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).

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Period Title: Period 1 (Double-blind Period)
STARTED	90	98
COMPLETED	79	85
NOT COMPLETED	11	13
Period Title: Period 1 (Double-blind Period)
STARTED	75	83
COMPLETED	67	70
NOT COMPLETED	8	13

Baseline Characteristics

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	90	98	188
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	20.2 (12.52)	18.2 (8.70)	19.2 (10.71)
Age, Customized (Count of Participants)
6-21 years	64 71.1%	69 70.4%	133 70.7%
>21 years	26 28.9%	29 29.6%	55 29.3%
Sex: Female, Male (Count of Participants)
Female	45 50%	50 51%	95 50.5%
Male	45 50%	48 49%	93 49.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 4.4%	6 6.1%	10 5.3%
Not Hispanic or Latino	86 95.6%	92 93.9%	178 94.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1%	1 0.5%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 3.3%	1 1%	4 2.1%
White	85 94.4%	94 95.9%	179 95.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 2.2%	2 2%	4 2.1%
Pseudomonas Aeruginosa Infection Present at Screening (Yes/No?) (Count of Participants)
Yes	51 56.7%	45 45.9%	96 51.1%
No	39 43.3%	53 54.1%	92 48.9%
Number of Pulmonary Infections in the Previous Year (infections) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [infections]	2.6 (1.53)	2.6 (1.44)	2.6 (1.48)
Baseline Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted (percent predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent predicted]	65.25 (16.193)	66.32 (16.939)	65.81 (16.550)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Measure Participants	64	69
Week 4	2.39 (8.078)	1.18 (8.581)
Week 12	1.52 (8.414)	0.13 (8.056)
Week 20	1.61 (9.967)	-1.94 (8.924)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Vancomycin Inhalation Powder, Double-blind Placebo Inhalation Powder
	Comments	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%.
	Type of Statistical Test	Superiority
	Comments	The primary efficacy endpoint was tested 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 was observed in favor of vancomycin inhalation powder compared to placebo after Cycle 1, then the mean change in the FEV1 percent predicted during Cycle 2 was to be tested. Similarly, if the effect after Cycle 2 was statistically significant, then the analysis of Baseline to end of Cycle 3 was to be tested.
Statistical Test of Hypothesis	p-Value	0.325
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least square mean difference
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -1.4 to 4.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Frequency of Pulmonary Exacerbations
Description	The number of pulmonary exacerbations during Period 1 adjusted for the length of follow-up.
Time Frame	Week 20

Outcome Measure Data

Analysis Population Description

ITT population (6-21 years).

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Measure Participants	64	69
Mean (Standard Deviation) [exacerbations]	0.9 (1.03)	0.9 (1.02)

3. Secondary Outcome

Title	Time to First Pulmonary Exacerbation
Description	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.
Time Frame	Week 20

Outcome Measure Data

Analysis Population Description

ITT population (6-21 years).

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Measure Participants	64	69
Median (95% Confidence Interval) [days]	38	48

4. Secondary Outcome

Title	Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Scores
Description	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.
Time Frame	Baseline and Week 4, 12, and 20

Outcome Measure Data

Analysis Population Description

ITT population (6-21 years).

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Measure Participants	64	69
Week 4	8.4	3.0
Week 12	6.0	4.3
Week 20	4.6	6.3

5. Secondary Outcome

Title	Change From Baseline in Cystic Fibrosis Respiratory Symptom Diary-Chronic Respiratory Symptom Score (CFRSD-CRISS) Scores
Description	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.
Time Frame	Baseline and Week 4, 12 and 20

Outcome Measure Data

Analysis Population Description

ITT population (6-21 years).

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Measure Participants	64	69
Week 4	-3.2	-5.1
Week 12	-4.7	-8.0
Week 20	-7.3	-5.3

6. Secondary Outcome

Title	Relative Change in FEV1 Percent Predicted
Description	The mean relative change from Baseline in FEV1 percent predicted
Time Frame	Baseline and Week 4, 12 and 20

Outcome Measure Data

Analysis Population Description

ITT population (6-21 years).

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Measure Participants	64	69
Week 4	2.9	1.5
Week 12	1.2	-0.3
Week 20	1.7	-2.2

7. Secondary Outcome

Title	Number of Successful Response Cycles
Description	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.
Time Frame	Week 20

Outcome Measure Data

Analysis Population Description

ITT population (6-21 years).

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Measure Participants	62	66
0 successful response cycles	20 22.2%	24 24.5%
1 successful response cycle	18 20%	27 27.6%
2 successful response cycles	15 16.7%	9 9.2%
3 successful response cycles	9 10%	6 6.1%

8. Secondary Outcome

Title	Area Under the FEV1-time Profile
Description	The mean treatment difference in FEV1 across all post-baseline visits
Time Frame	Week 20

Outcome Measure Data

Analysis Population Description

ITT population (6-21 years).

Arm/Group Title	Double-blind Vancomycin Inhalation Powder	Double-blind Placebo Inhalation Powder
Arm/Group Description	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.	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.
Measure Participants	64	69
Least Squares Mean (95% Confidence Interval) [percent predicted*hour/liter]	609.7	583.1

Adverse Events

Time Frame	Treatment-emergent adverse events (AEs) were assessed on or after the first dose of trial drug to 28 days after last dose. For all safety analyses, a single set of results was produced including all participants (6-21 and >21 years combined). For the double-blind Period 1, AE data are presented for the vancomycin and placebo groups whereas for the open-label Period 2, AE data for only one combined group is presented.
Arm/Group Title	Double-blind Vancomycin Inhalation Powder		Double-blind Placebo Inhalation Powder		Open-label Vancomycin Inhalation Powder
Arm/Group Description	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 participants ≤21 years old, 25 participants >21 years old) for 24 weeks during Period 1.		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 participants ≤21 years old, 25 participants >21 years old) for 24 weeks during Period 1.		In the 24-week Period 2, all participants receive vancomycin inhalation powder 30 mg BID by inhalation during three dosing cycles, each cycle being 28 days of treatment followed by 28 days of observation. Vancomycin inhalation powder: In the 24-week Period 2, all participants are to be treated with open-label vancomycin inhalation powder.
All Cause Mortality
	Double-blind Vancomycin Inhalation Powder		Double-blind Placebo Inhalation Powder		Open-label Vancomycin Inhalation Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/90 (0%)		0/98 (0%)		0/158 (0%)
Serious Adverse Events
	Double-blind Vancomycin Inhalation Powder		Double-blind Placebo Inhalation Powder		Open-label Vancomycin Inhalation Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/90 (26.7%)		35/98 (35.7%)		50/158 (31.6%)
Blood and lymphatic system disorders
Leukocytosis	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Congenital, familial and genetic disorders
Cystic fibrosis related diabetes	1/90 (1.1%)	1	0/98 (0%)	0	0/158 (0%)	0
Gastrointestinal disorders
Constipation	2/90 (2.2%)	3	4/98 (4.1%)	6	2/158 (1.3%)	2
Abdominal pain	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Distal intestinal obstruction syndrome	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Pancreatitis acute	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
General disorders
Pyrexia	1/90 (1.1%)	1	0/98 (0%)	0	0/158 (0%)	0
Hepatobiliary disorders
Bile duct obstruction	0/90 (0%)	0	1/98 (1%)	4	0/158 (0%)	0
Cholecystitis acute	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	19/90 (21.1%)	24	29/98 (29.6%)	33	38/158 (24.1%)	43
Bronchitis	0/90 (0%)	0	0/98 (0%)	0	3/158 (1.9%)	3
Pneumonia	2/90 (2.2%)	3	3/98 (3.1%)	3	3/158 (1.9%)	3
Pneumonia staphylococcal	1/90 (1.1%)	1	1/98 (1%)	1	0/158 (0%)	0
Appendicitis perforated	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Influenza	1/90 (1.1%)	1	0/98 (0%)	0	0/158 (0%)	0
Peritoneal abscess	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Peritonitis	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Pneumonia bacterial	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Sepsis	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Staphylococcal infection	1/90 (1.1%)	1	0/98 (0%)	0	0/158 (0%)	0
Systemic viral infection	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Mycobacterial infection	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Pneumonia pseudomonal	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Pseudomonas infection	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Injury, poisoning and procedural complications
Overdose	1/90 (1.1%)	1	0/98 (0%)	0	0/158 (0%)	0
Concussion	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Investigations
Pulmonary function test decreased	1/90 (1.1%)	1	0/98 (0%)	0	0/158 (0%)	0
Nervous system disorders
Loss of consciousness	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Renal and urinary disorders
Nephrolithiasis	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Reproductive system and breast disorders
Testicular torsion	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/90 (1.1%)	1	2/98 (2%)	2	2/158 (1.3%)	2
Asthma	1/90 (1.1%)	1	0/98 (0%)	0	0/158 (0%)	0
Acute respiratory failure	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Dyspnoea	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Pneumothorax	0/90 (0%)	0	0/98 (0%)	0	1/158 (0.6%)	1
Vascular disorders
Venous thrombosis	0/90 (0%)	0	1/98 (1%)	1	0/158 (0%)	0
Other (Not Including Serious) Adverse Events
	Double-blind Vancomycin Inhalation Powder		Double-blind Placebo Inhalation Powder		Open-label Vancomycin Inhalation Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/90 (94.4%)		93/98 (94.9%)		139/158 (88%)
Gastrointestinal disorders
Vomiting	9/90 (10%)	10	11/98 (11.2%)	14	0/158 (0%)	0
Constipation	3/90 (3.3%)	6	7/98 (7.1%)	13	0/158 (0%)	0
Nausea	4/90 (4.4%)	5	10/98 (10.2%)	11	8/158 (5.1%)	8
Abdominal pain	4/90 (4.4%)	4	7/98 (7.1%)	11	0/158 (0%)	0
Diarrhoea	6/90 (6.7%)	6	7/98 (7.1%)	9	0/158 (0%)	0
General disorders
Pyrexia	11/90 (12.2%)	12	8/98 (8.2%)	10	8/158 (5.1%)	9
Chest discomfort	9/90 (10%)	10	8/98 (8.2%)	8	0/158 (0%)	0
Fatigue	3/90 (3.3%)	5	5/98 (5.1%)	5	0/158 (0%)	0
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	51/90 (56.7%)	109	59/98 (60.2%)	116	78/158 (49.4%)	140
Upper respiratory tract infection	6/90 (6.7%)	7	4/98 (4.1%)	5	12/158 (7.6%)	15
Pneumonia	5/90 (5.6%)	7	4/98 (4.1%)	4	0/158 (0%)	0
Sinusitis	5/90 (5.6%)	5	6/98 (6.1%)	6	9/158 (5.7%)	9
Investigations
Blood glucose increased	1/90 (1.1%)	1	7/98 (7.1%)	8	0/158 (0%)	0
Forced expiratory volume decreased	1/90 (1.1%)	1	6/98 (6.1%)	6	0/158 (0%)	0
Glucose urine present	2/90 (2.2%)	2	5/98 (5.1%)	5	0/158 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/90 (1.1%)	1	5/98 (5.1%)	5	0/158 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	6/90 (6.7%)	7	1/98 (1%)	1	0/158 (0%)	0
Nervous system disorders
Headache	9/90 (10%)	13	12/98 (12.2%)	14	12/158 (7.6%)	15
Respiratory, thoracic and mediastinal disorders
Cough	42/90 (46.7%)	62	36/98 (36.7%)	53	40/158 (25.3%)	50
Nasal congestion	7/90 (7.8%)	9	10/98 (10.2%)	15	8/158 (5.1%)	10
Oropharyngeal pain	8/90 (8.9%)	8	12/98 (12.2%)	16	9/158 (5.7%)	9
Sputum increased	7/90 (7.8%)	9	7/98 (7.1%)	10	9/158 (5.7%)	11
Haemoptysis	5/90 (5.6%)	5	6/98 (6.1%)	9	8/158 (5.1%)	9
Wheezing	3/90 (3.3%)	4	8/98 (8.2%)	8	7/158 (4.4%)	8
Dyspnoea	5/90 (5.6%)	5	4/98 (4.1%)	5	8/158 (5.1%)	8
Rhinorrhoea	5/90 (5.6%)	7	2/98 (2%)	3	0/158 (0%)	0

Limitations/Caveats

A total of 200 participants were to be randomized. Consequent to the outbreak of COVID-19, the recruitment was stopped prematurely when 188 participants had been randomized. The CFQ-R and CFRSD-CRISS were administered every two weeks using a hand-held e-Diary. The e-Diary had not been activated at the baseline visit for 39 participants. For these participants, missing baseline measurements were imputed with the population median baseline value for inferential analyses.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.