STOP2: Standardized Treatment of Pulmonary Exacerbations II

• Sponsor: Chris Goss (Other)
• Overall Status: Completed
• CT.gov ID: NCT02781610
• Collaborator: Cystic Fibrosis Foundation (Other), CF Therapeutics Development Network Coordinating Center (Other), Medical University of South Carolina (Other), University of Washington (Other)
• Enrollment: 982
• Locations: 58
• Arms: 4
• Duration (Months): 45.1
• Patients Per Site: 16.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Cystic fibrosis (CF), a life-shortening genetic disease, is marked by acute episodes during which symptoms of lung infection increase and lung function decreases. These pulmonary exacerbations are treated with varying antibiotics for varying time periods based on needs determined by individual patients, their families, and the health care providers. Cystic fibrosis pulmonary guidelines for the treatment of pulmonary exacerbation published by the Cystic Fibrosis Foundation (CFF) in 2009 provided recommendations for treatment and also identified key questions for which additional studies were needed.

A strong desire among clinicians to reduce treatment durations (and reduce cost, inconvenience, and potential toxicities) is in conflict with belief that patients not responding robustly to treatment might benefit from extending treatment.

This randomized, controlled, open-label study is designed to evaluate the efficacy and safety of differing durations of IV treatment, given in the hospital or at home for a pulmonary exacerbation in adult patients with CF.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Cystic Fibrosis	Drug: Standard of care IV antibiotic(s)	Phase 4

Detailed Description

The study will assess the non-inferiority of 10 days versus 14 days treatment duration among patients who have an early robust improvement (ERR subjects) and the superiority of 21 days versus 14 days treatment duration among the subjects who do not meet the definition of ERR (non-ERR; NERR).

Subjects will undergo pulmonary function testing (spirometry) and complete a respiratory symptom score [Chronic Respiratory Infection Symptom Score (CRISS)] at initiation of IV treatment (Baseline/ Visit 1) and at Day 7-10 (Visit 2). At Visit 2, subjects will be allocated to groups ERR or NERR based on their initial clinical response as determined by the change in forced expiratory volume in 1 second (FEV1; percent of predicted) and CRISS from Baseline and then randomized to an IV treatment duration (nested within group).

ERR subjects [≥8% predicted improvement in FEV1 from Visit 1 to Visit 2 and CRISS reduction of ≥11 points from Visit 1 to Visit 2] will be randomized 1:1 to either 10 days or 14 days total IV antibiotic treatment duration. Remaining (NERR) subjects will be randomized 1:1 to receive either 14 or 21 days total IV antibiotic treatment duration. All subjects will be evaluated again at Visit 3, 14 days following scheduled completion of IV antibiotic treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 982 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Standardized Treatment of Pulmonary Exacerbations II (STOP2)
• Study Start Date: Jun 1, 2016
• Actual Primary Completion Date: Mar 6, 2020
• Actual Study Completion Date: Mar 6, 2020

Arms and Interventions

Arm	Intervention/Treatment
Other: ERR-10 ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.	Drug: Standard of care IV antibiotic(s); IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Other: ERR-14 ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.	Drug: Standard of care IV antibiotic(s); IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Other: NERR-14 NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.	Drug: Standard of care IV antibiotic(s); IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Other: NERR-21 NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.	Drug: Standard of care IV antibiotic(s); IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.

Outcome Measures

Primary Outcome Measures

1. Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day [Start of IV antibiotic treatment to 14 days after the end of IV antibiotic treatment]

   Absolute change in FEV1 % predicted from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).

2. Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 [Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment]

   Absolute change in FEV1 % predicted from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).

Secondary Outcome Measures

1. Change in CRISS From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day [Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment]

   Absolute change in respiratory symptoms, as measured by the the Cystic Fibrosis Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment). The Diary asks a participant to state the extent of their 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present 'a great deal' or 'extremely'. A summed score (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms.

2. Change in CRISS From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day [Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment]

   Absolute change in respiratory symptoms, as measured by the the Cystic Fibrosis Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment). The Diary asks a participant to state the extent of their 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present 'a great deal' or 'extremely'. A summed score (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms.

3. Change in Weight From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day [Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment]

   Absolute change in weight (kg) from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).

4. Change in Weight From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day [Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment]

   Absolute change in weight (kg) from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Key Inclusion Criteria:

• Male or female ≥18 years of age at Visit 1

• Documentation of a CF diagnosis

• Enrolled in the Cystic Fibrosis Foundation National Patient Registry (CFFNPR) prior to Visit 1 (US sites only)

• At the time of Visit 1, there is a plan to initiate IV antibiotics for a pulmonary exacerbation

• Performed spirometry at Visit 1 and Visit 2 and willing to perform spirometry at Visit 3

• Completed the CRISS questionnaire at Visit 1 and Visit 2 and willing to complete the Cystic Fibrosis Respiratory Symptoms Diary (CFRSD) questionnaire at Visit 3

• Willing to adhere to a specific treatment duration determined by initial response to treatment and subsequent randomization

• Willing to return for follow up Visit 3

• Written informed consent obtained from the subject or subject's legal representative

Exclusion Criteria:

Key Exclusion Criteria

• Previous randomization in this study

• Treatment with IV antibiotics in the 6 weeks prior to Visit 1

• Admission to the intensive care unit for current pulmonary exacerbation in the two weeks prior to Visit 2, unless admission was due to a desensitization protocol

• Pneumothorax in the two weeks prior to Visit 2

• Primary diagnosis for current hospitalization is unrelated to worsening lower respiratory symptoms (e.g., pulmonary clean out, distal intestinal obstruction syndrome (DIOS), sinusitis)

• Massive hemoptysis defined as > 250 cc in a 24 hour period or 100 cc/day over 4 consecutive days occurring in the two weeks prior to Visit 2

• Current pulmonary exacerbation thought to be due to allergic bronchopulmonary aspergillosis (ABPA)

• At Visit 1, receiving ongoing treatment with a duration of more than 2 weeks with prednisone equivalent to >10mg/day

• History of solid organ transplantation

• Receiving antimicrobial therapy to treat non-tuberculous mycobacterium (e.g., M. abscessus, M. avium complex) in the two weeks prior to Visit 2

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Children's Hospital Alabama	Birmingham	Alabama	United States	35233
2	Providence Alaska Medical Center	Anchorage	Alaska	United States	99519-6604
3	University Medical Center	Tucson	Arizona	United States	85724
4	UC San Diego Medical Center	La Jolla	California	United States	92037
5	Lucile S. Packard Children's Hospital	Palo Alto	California	United States	94304
6	University of California Davis, Health System	Sacramento	California	United States	95817
7	National Jewish Health	Denver	Colorado	United States	80206
8	Hartford Hospital	Hartford	Connecticut	United States	06106
9	Yale New Haven Hospital	New Haven	Connecticut	United States	06520
10	Shands Hospital	Gainesville	Florida	United States	32610
11	Joe DiMaggio Children's Hospital (Adult)	Hollywood	Florida	United States	33021
12	University of Miami	Miami	Florida	United States	33136
13	Emory University Hospital	Atlanta	Georgia	United States	30322
14	Augusta University Medical Center	Augusta	Georgia	United States	30912
15	St. Luke's Regional Medical Center	Boise	Idaho	United States	83712
16	Saint Francis Medical Center	Peoria	Illinois	United States	61603
17	Indiana University Hospital, Indiana University Health	Indianapolis	Indiana	United States	46202
18	The University of Kansas Hospital	Kansas City	Kansas	United States	66160
19	John Hopkins Hospital	Baltimore	Maryland	United States	21205
20	Boston Children's Hospital (BCH)	Boston	Massachusetts	United States	02115
21	University of Massachusetts Memorial Health Care (Worcester, MA)	Worcester	Massachusetts	United States	01655
22	University of Michigan Health System	Ann Arbor	Michigan	United States	48109-5212
23	Detroit Medical Center; Harper University Hospital	Detroit	Michigan	United States	48201
24	Saint Louis University Hospital	Saint Louis	Missouri	United States	63110
25	St. Louis Washington University Adult - Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
26	Billings Clinic	Billings	Montana	United States	59107-7000
27	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
28	Monmouth Medical Center	Long Branch	New Jersey	United States	07740
29	Morristown Medical Center	Morristown	New Jersey	United States	07960
30	Robert Wood Johnson University Hospital (New Brunswick, NJ)	New Brunswick	New Jersey	United States	08903
31	Women and Children's Hospital of Buffalo	Buffalo	New York	United States	14222
32	The Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
33	Beth Israel Medical Center	New York	New York	United States	10003
34	Columbia University Medical Center	New York	New York	United States	10032
35	Highland Hospital; Strong Memorial Hospital	Rochester	New York	United States	14642
36	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
37	New York Medical College	Valhalla	New York	United States	10595
38	North Carolina Children's Hospital	Chapel Hill	North Carolina	United States	27517
39	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
40	Akron Children's Hospital	Akron	Ohio	United States	44308
41	University Hospital of Cleveland	Cleveland	Ohio	United States	44106
42	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
43	Dayton Children's Hospital	Dayton	Ohio	United States	45404
44	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
45	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
46	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
47	Medical University of South Carolina; Medical University of South Carolina Children's Hospital	Charleston	South Carolina	United States	29425
48	University of Texas Southwestern	Dallas	Texas	United States	75390
49	Baylor St. Lukes Medical Center	Houston	Texas	United States	77030
50	University of Texas Health Center at Tyler	Tyler	Texas	United States	75708-3154
51	The University of Vermont Medical Center Inc.	Burlington	Vermont	United States	05401
52	University of Virginia Health System	Charlottesville	Virginia	United States	22908
53	Medical College of Virginia (Richmond, VA)	Richmond	Virginia	United States	23298
54	University of Washington Medical Center	Seattle	Washington	United States	98195
55	Ruby Memorial Hospital	Morgantown	West Virginia	United States	26506
56	University of Wisconsin Hospital Center	Madison	Wisconsin	United States	53792
57	Froedtert Hospital	Milwaukee	Wisconsin	United States	53226
58	Calgary Canada Adult CF Clinic	Calgary	Alberta	Canada	T2N 4N1

Sponsors and Collaborators

• Chris Goss
• Cystic Fibrosis Foundation
• CF Therapeutics Development Network Coordinating Center
• Medical University of South Carolina
• University of Washington

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Nov 2, 2018
• Statistical Analysis Plan - Feb 14, 2017

More Information

Publications

None provided.

• Responsible Party: Chris Goss, Professor of Medicine and Pediatrics, Seattle Children's Hospital
• ClinicalTrials.gov Identifier: NCT02781610
• Other Study ID Numbers: STOP2-IP-15
• First Posted: May 24, 2016
• Last Update Posted: May 19, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Chris Goss, Professor of Medicine and Pediatrics, Seattle Children's Hospital: Cystic fibrosis; Pulmonary exacerbation; Antibiotic; Treatment duration; Lung infection; Cystic Fibrosis Foundation; Cystic Fibrosis Foundation National Patient Registry
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Anti-Bacterial Agents

Study Results

Participant Flow

Arm/Group Title	ERR-10	ERR-14	NERR-14	NERR-21
Arm/Group Description	ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Period Title: Overall Study
STARTED	140	137	353	352
COMPLETED	134	130	336	323
NOT COMPLETED	6	7	17	29

Baseline Characteristics

Arm/Group Title	ERR-10	ERR-14	NERR-14	NERR-21	Total
Arm/Group Description	ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	Total of all reporting groups
Overall Participants	107	107	353	352	919
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.6 (6.34)	27.1 (8.89)	31.8 (10.52)	31.5 (9.63)	30.6 (9.79)
Sex: Female, Male (Count of Participants)
Female	46 43%	53 49.5%	192 54.4%	171 48.6%	462 50.3%
Male	61 57%	54 50.5%	161 45.6%	181 51.4%	457 49.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 7.5%	9 8.4%	26 7.4%	20 5.7%	63 6.9%
Not Hispanic or Latino	99 92.5%	98 91.6%	327 92.6%	332 94.3%	856 93.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	3 0.8%	1 0.3%	4 0.4%
Asian	0 0%	0 0%	1 0.3%	2 0.6%	3 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	5 4.7%	3 2.8%	7 2%	17 4.8%	32 3.5%
White	98 91.6%	100 93.5%	335 94.9%	322 91.5%	855 93%
More than one race	2 1.9%	2 1.9%	5 1.4%	4 1.1%	13 1.4%
Unknown or Not Reported	2 1.9%	2 1.9%	2 0.6%	6 1.7%	12 1.3%
Cystic Fibrosis (CF) Genotype (Count of Participants)
Delta F508 Homozygous	46 43%	55 51.4%	171 48.4%	174 49.4%	446 48.5%
Delta F508 Heterozygous	45 42.1%	40 37.4%	127 36%	135 38.4%	347 37.8%
Other/Unknown	16 15%	12 11.2%	55 15.6%	43 12.2%	126 13.7%
Forced Expiratory Volume in 1 second (FEV1) (liters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [liters]	1.9 (0.80)	1.8 (0.83)	1.8 (0.83)	1.8 (0.76)	1.8 (0.80)
FEV1 (% Predicted) Distribution (Count of Participants)
<50%	60 56.1%	61 57%	192 54.4%	194 55.1%	507 55.2%
>=50%	47 43.9%	46 43%	161 45.6%	158 44.9%	412 44.8%
History of PEx in last year (Count of Participants)
0 - 1	43 40.2%	45 42.1%	145 41.1%	144 40.9%	377 41%
>=2	64 59.8%	62 57.9%	208 58.9%	208 59.1%	542 59%
IV Antibiotic Treatment Location Prior to Randomization (Count of Participants)
Any Nights in Hospital	92 86%	90 84.1%	265 75.1%	266 75.6%	713 77.6%
All at Home	15 14%	17 15.9%	88 24.9%	86 24.4%	206 22.4%
Systemic Corticosteroid Use (Count of Participants)
Yes	13 12.1%	10 9.3%	23 6.5%	41 11.6%	87 9.5%
No	94 87.9%	97 90.7%	330 93.5%	311 88.4%	832 90.5%

Outcome Measures

1. Primary Outcome

Title	Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day
Description	Absolute change in FEV1 % predicted from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).
Time Frame	Start of IV antibiotic treatment to 14 days after the end of IV antibiotic treatment

Outcome Measure Data

Analysis Population Description

Includes only participants within the ERR treatment group and per-protocol population, with FEV1 measurements at baseline and last study visit.

Arm/Group Title	ERR-10	ERR-14
Arm/Group Description	ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Measure Participants	107	107
Mean (Standard Deviation) [percentage change]	13.30 (9.65)	13.83 (9.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ERR-10, ERR-14
	Comments	The ERR non-inferiority test was a priori designed to be conducted on the per-protocol (PP) population for 93% power assuming 2-sided alpha=0.05 with 155 PP participants per arm. Difference between ERR treatment duration arms is ERR-10 - ERR-14.
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin is -3.5%.
Statistical Test of Hypothesis	p-Value	0.0164
	Comments
	Method	ANOVA
	Comments	Adjusted for four dichotomous randomization strata.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -3.3 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Absolute Change in FEV1 % Predicted From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21
Description	Absolute change in FEV1 % predicted from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).
Time Frame	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment

Outcome Measure Data

Analysis Population Description

Includes only participants within the NERR treatment group and intent-to-treat population, with FEV1 measurements at baseline and last study visit.

Arm/Group Title	NERR-14	NERR-21
Arm/Group Description	NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Measure Participants	331	322
Mean (Standard Deviation) [percentage change]	3.60 (8.22)	3.53 (7.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ERR-10, ERR-14
	Comments	The NERR superiority test was a priori designed to be conducted on the Intent-to-Treat (ITT) population for 91% power to detect a 2.5% difference, assuming 2-sided alpha=0.05 with 285 ITT participants per arm. Difference between NERR treatment duration arms is NERR-21 - NERR-14.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.568
	Comments
	Method	ANOVA
	Comments	Adjusted for four dichotomous randomization strata.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -1.3 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in CRISS From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day
Description	Absolute change in respiratory symptoms, as measured by the the Cystic Fibrosis Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment). The Diary asks a participant to state the extent of their 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present 'a great deal' or 'extremely'. A summed score (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms.
Time Frame	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment

Outcome Measure Data

Analysis Population Description

Includes only participants within the ERR treatment group and per-protocol (PP) population, with CRISS measurements at baseline and last study visit.

Arm/Group Title	ERR-10	ERR-14
Arm/Group Description	ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Measure Participants	106	107
Mean (Standard Deviation) [score on a scale]	-24.2 (13.21)	-25.3 (12.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ERR-10, ERR-14
	Comments	Difference between ERR treatment duration arms is ERR-10 - ERR-14.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.546
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -2.4 to 4.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in CRISS From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day
Description	Absolute change in respiratory symptoms, as measured by the the Cystic Fibrosis Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CFRSD-CRISS), from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment). The Diary asks a participant to state the extent of their 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present 'a great deal' or 'extremely'. A summed score (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms.
Time Frame	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment

Outcome Measure Data

Analysis Population Description

Includes only participants within the NERR treatment group and intent-to-treat (ITT) population, with CRISS measurements at baseline and last study visit.

Arm/Group Title	NERR-14	NERR-21
Arm/Group Description	NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Measure Participants	335	322
Mean (Standard Deviation) [score on a scale]	-15.1 (13.74)	-16.7 (14.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ERR-10, ERR-14
	Comments	Difference between NERR treatment duration arms is NERR-21 - NERR-14.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.140
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -3.7 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Weight From Visit 1 to Visit 3 Between ERR-10 Day and ERR-14 Day
Description	Absolute change in weight (kg) from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).
Time Frame	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment

Outcome Measure Data

Analysis Population Description

Includes only participants within the ERR treatment group and per-protocol (PP) population, with weight measurements at baseline and last study visit.

Arm/Group Title	ERR-10	ERR-14
Arm/Group Description	ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Measure Participants	107	106
Mean (Standard Deviation) [kg]	1.7 (2.18)	1.5 (2.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ERR-10, ERR-14
	Comments	Difference between ERR treatment duration arms is ERR-10 - ERR-14.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.563
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Weight From Visit 1 to Visit 3 Between NERR-14 Day and NERR-21 Day
Description	Absolute change in weight (kg) from baseline/visit 1 (start of IV antibiotic treatment) to last study visit/visit 3 (14 days after the end of IV antibiotic treatment).
Time Frame	Start of IV antibiotic treatment to14 days after the end of IV antibiotic treatment

Outcome Measure Data

Analysis Population Description

Includes only participants within the NERR treatment group and intent-to-treat (ITT) population, with weight measurements at baseline and last study visit.

Arm/Group Title	NERR-14	NERR-21
Arm/Group Description	NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.	NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
Measure Participants	333	320
Mean (Standard Deviation) [kg]	0.5 (2.16)	0.8 (2.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ERR-10, ERR-14
	Comments
	Type of Statistical Test	Superiority
	Comments	Difference between NERR treatment duration arms is NERR-21 - NERR-14.
Statistical Test of Hypothesis	p-Value	0.083
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	For Serious Adverse Events (SAEs): Informed consent to final study visit (14 days after the end of IV antibiotic treatment). For all Other (Not Including Serious) AEs: Randomization to final study visit. Final study visit is Day 25 for ERR-10 arm, Day 29 for ERR-14 arm and NERR-14 arm, and Day 36 for NERR-21 arm.
Arm/Group Title	ERR-10		ERR-14		NERR-14		NERR-21
Arm/Group Description	ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.		ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.		NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.		NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. Standard of care IV antibiotic(s): IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.
All Cause Mortality
	ERR-10		ERR-14		NERR-14		NERR-21
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/140 (0%)		0/137 (0%)		0/353 (0%)		0/352 (0%)
Serious Adverse Events
	ERR-10		ERR-14		NERR-14		NERR-21
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/140 (2.9%)		1/137 (0.7%)		19/353 (5.4%)		19/352 (5.4%)
Blood and lymphatic system disorders
Haemolytic anaemia	0/140 (0%)	0	0/137 (0%)	0	1/353 (0.3%)	1	0/352 (0%)	0
Cardiac disorders
Palpitations	0/140 (0%)	0	0/137 (0%)	0	1/353 (0.3%)	1	0/352 (0%)	0
Gastrointestinal disorders
Distal intestinal obstruction syndrome	1/140 (0.7%)	1	0/137 (0%)	0	0/353 (0%)	0	1/352 (0.3%)	1
Gastrointestinal haemorrhage	0/140 (0%)	0	0/137 (0%)	0	1/353 (0.3%)	1	0/352 (0%)	0
Small intestinal obstruction	0/140 (0%)	0	0/137 (0%)	0	0/353 (0%)	0	1/352 (0.3%)	1
General disorders
Fatigue	0/140 (0%)	0	0/137 (0%)	0	1/353 (0.3%)	1	0/352 (0%)	0
Pyrexia	0/140 (0%)	0	0/137 (0%)	0	0/353 (0%)	0	2/352 (0.6%)	2
Infections and infestations
Appendicitis	0/140 (0%)	0	0/137 (0%)	0	1/353 (0.3%)	1	1/352 (0.3%)	1
Gastrointestinal viral infection	0/140 (0%)	0	0/137 (0%)	0	0/353 (0%)	0	1/352 (0.3%)	1
Infective pulmonary exacerbation of cystic fibrosis	1/140 (0.7%)	1	1/137 (0.7%)	1	9/353 (2.5%)	9	9/352 (2.6%)	10
Influenza	0/140 (0%)	0	0/137 (0%)	0	0/353 (0%)	0	1/352 (0.3%)	1
Pneumonia	0/140 (0%)	0	0/137 (0%)	0	0/353 (0%)	0	1/352 (0.3%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/140 (0%)	0	0/137 (0%)	0	0/353 (0%)	0	1/352 (0.3%)	1
Nervous system disorders
Cerebrovascular accident	0/140 (0%)	0	0/137 (0%)	0	1/353 (0.3%)	1	0/352 (0%)	0
Psychiatric disorders
Panic attack	0/140 (0%)	0	0/137 (0%)	0	0/353 (0%)	0	1/352 (0.3%)	1
Renal and urinary disorders
Acute kidney injury	0/140 (0%)	0	0/137 (0%)	0	2/353 (0.6%)	2	3/352 (0.9%)	3
Nephrolithiasis	1/140 (0.7%)	1	0/137 (0%)	0	0/353 (0%)	0	0/352 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/140 (0%)	0	0/137 (0%)	0	1/353 (0.3%)	1	0/352 (0%)	0
Haemoptysis	1/140 (0.7%)	1	0/137 (0%)	0	3/353 (0.8%)	3	0/352 (0%)	0
Pulmonary embolism	0/140 (0%)	0	0/137 (0%)	0	0/353 (0%)	0	3/352 (0.9%)	3
Other (Not Including Serious) Adverse Events
	ERR-10		ERR-14		NERR-14		NERR-21
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/140 (5.7%)		4/137 (2.9%)		4/353 (1.1%)		4/352 (1.1%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	8/140 (5.7%)	8	4/137 (2.9%)	4	4/353 (1.1%)	4	4/352 (1.1%)	4

Limitations/Caveats

Analysis was not done on the combined total of all four treatment duration arms. Interpreting the total column within demographics is inappropriate for this study design.

More Information

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.