DEFINE-CABP: Study to Compare Delafloxacin to Moxifloxacin for the Treatment of Adults With Community-acquired Bacterial Pneumonia

• Sponsor: Melinta Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02679573
• Collaborator: (none)
• Enrollment: 860
• Locations: 90
• Arms: 2
• Actual Duration (Months): 19.7
• Patients Per Site: 9.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of delafloxacin compared to moxifloxacin in the treatment of adult patients with community-acquired pneumonia.

Condition or Disease	Intervention/Treatment	Phase
Community Acquired Bacterial Pneumonia	Drug: Delafloxacin; Drug: Moxifloxacin; Drug: Linezolid	Phase 3

Detailed Description

The purpose of this study is to determine if delafloxacin, an investigational drug, is safe and effective in the treatment of community-acquired bacterial pneumonia compared with moxifloxacin, or linezolid in the case of confirmed MRSA.

Study Design

• Study Type: Interventional
• Actual Enrollment: 860 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-Blind, Comparator-Controlled Study to Evaluate the Safety and Efficacy of Intravenous to Oral Delafloxacin in Adult Subjects With Community-Acquired Bacterial Pneumonia
• Actual Study Start Date: Dec 14, 2016
• Actual Primary Completion Date: Jul 31, 2018
• Actual Study Completion Date: Aug 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Delafloxacin IV delafloxacin with potential to switch to oral delafloxacin	Drug: Delafloxacin; Antibacterial agent, 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total; Other Names: RX-3341
Active Comparator: Moxifloxacin/Linezolid IV moxifloxacin with potential to switch to oral moxifloxacin, and potential to switch moxifloxacin to IV linezolid for confirmed MRSA	Drug: Moxifloxacin; Antibacterial Agent, 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total; Other Names: Avelox ; Drug: Linezolid; Antibacterial Agent, at local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses; Other Names: Zyvox

Outcome Measures

Primary Outcome Measures

1. Early Clinical Response [96 (+/- 24) hours after the first dose of study drug]

   Early clinical response defined as improvement in at least 2 of the following symptoms (as assessed by the investigator): chest pain, frequency or severity of cough, amount and quality of productive sputum, and difficulty breathing, and no worsening of the other symptoms in the ITT population. Symptom severity evaluated by the investigator on a 4-point scale: Absent (0), Mild (1), Moderate (2), Severe (3). Improvement defined as at least a 1-point decrease from baseline.

Secondary Outcome Measures

1. Early Clinical Response Plus Improvement in Vital Signs and no Worsening of the 4 Symptoms [96 (+/- 24) hours after the first dose of study drug]

   Early clinical response with the addition of improvement in vital signs and no worsening of the following 4 symptoms: chest pain, cough, productive sputum, and difficulty breathing in the ITT population. Symptom severity evaluated by the investigator on a 4-point scale: Absent (0), Mild (1), Moderate (2), Severe (3). Improvement defined as at least a 1-point decrease from baseline. Improvement in vital signs defined as a return to normal of any abnormal vital signs at baseline, and no worsening (ie, be abnormal) of any vital sign that was normal at baseline.

2. Clinical Outcome at Test of Cure [5 to 10 days after the last dose of study drug]

   Clinical outcome (Success, Failure, or Indeterminate/missing) based on the investigator's assessment of the patient's signs and symptoms of infection in the ITT population.

3. Clinical Outcome at End of Treatment [Up to 24 (+4) hours after the last dose of study drug]

   Clinical outcome (Success, Failure, or Indeterminate/missing) based on the investigator's assessment of the patient's signs and symptoms of infection in the ITT population.

4. Microbiologic Response [5 to 10 days after the last dose of study drug]

   Microbiological response for subjects in the MITT set will be based on results of the baseline and follow-up cultures and susceptibility testing or serology.

5. All-cause Mortality [Day 28 (+/- 2 days)]

   Time to all-cause Mortality was assessed on Day 28.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female 18 years of age or older

2. Evidence of acute onset of CABP with 2 or more of the following symptoms (new or worsening)

• Cough

• Production of purulent sputum consistent with bacterial infection

• Difficulty breathing

• Chest pain due to pneumonia

AND have at least 2 of the following findings:

• Fever (oral temperature >38.0°C)

• Hypothermia (oral temperature <35.0°C)

• Tachycardia (heart rate >100 beats/min)

• Tachypnea (respiratory rate >18 breaths/min)

AND have at least 1 of the following findings:

• Hypoxemia (oxygen saturation <90% or PaO2 < 60 mmHg) on room air or with subject's baseline (pre-CABP under study) supplemental oxygen

• Clinical evidence of pulmonary consolidation and/or presence of pulmonary rales

• An elevated white blood cell count (WBC) >10,000/mm3 or 15% immature neutrophils (bands), regardless of total peripheral WBC count or leukopenia with WBC <4500/mm^3

1. Presence of lobar, multilobar, or patchy parenchymal infiltrate(s) consistent with acute bacterial pneumonia on a pulmonary imaging study within 48 hours before the first dose of study drug

2. PORT risk class of II to V (PSI score >50)

3. Must be a suitable candidate for possible IV to oral switch antibiotic therapy and must also be able to swallow large tablets/capsules intact without crushing

Exclusion Criteria:

1. A medical history of significant hypersensitivity or allergic reaction to antibiotics of the quinolone or oxazolidinone class or study drug excipients according to the investigator

2. Any infection expected to require other systemic antibiotics in addition to study drug

3. Receipt of systemic antibiotic therapy in the 7 days before enrollment unless 1 of the following is documented:

• Received at least 48 hours of antibiotic therapy for CABP and clinic notes document treatment failure (i.e., not by patient history or pulmonary imaging alone) with new or worsening symptoms while on pre-study therapy

• Received 1 dose of a single, potentially effective, short-acting antibacterial drug or drug regimen for CABP within 24 hours before enrollment (limited to 25% of enrolled patients)

1. Respiratory infection confirmed or suspected to be secondary to hospital-acquired or ventilator-associated pneumonia OR requires treatment in an intensive care setting, OR requires mechanical ventilation

2. Current or suspected diagnosis of viral, fungal, or aspiration pneumonia, noninfectious causes of pulmonary infiltrates, lung cancer, cystic fibrosis, tuberculosis, empyema (not including sterile parapneumonic effusions)

3. Known anatomical or pathological bronchial obstruction OR history of bronchiectasis OR GOLD Stage 4 COPD OR history of post obstructive pneumonia

4. Severely compromised immune system

5. Known history of Child-Pugh Class B or C liver disease

6. History of post-antibiotic colitis within last 3 months

7. Other exclusions include those described in the safety label for drugs in the quinolone and/or oxazolidinone classes such as QT prolongation, proarrhythmic conditions, concomitant use of drugs known to cause QT prolongation, peripheral neuropathy, tendon disorders, history of myasthenia gravis, liver disease, severe renal disease, seizures and concomitant use of MAO A or B inhibitor agents and adrenergic serotonergic agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Melinta 306 Study Site	Montgomery	Alabama	United States	36106
2	Melinta 306 Study Site	Newark	Delaware	United States	19718
3	Melinta 306 Study Site	Coral Gables	Florida	United States	33134
4	Melinta 306 Study Site	DeBary	Florida	United States	32713
5	Melinta 306 Study Site	DeLand	Florida	United States	32720
6	Melinta 306 Study Site	Fort Myers	Florida	United States	33901
7	Melinta 306 Study Site	Miami	Florida	United States	33126
8	Melinta 306 Study Site	Miami	Florida	United States	33185
9	Melinta 306 Study Site	Louisville	Kentucky	United States	40202
10	Melinta 306 Study Site	Natchitoches	Louisiana	United States	71457-6215
11	Melinta 306 Study Site	Baltimore	Maryland	United States	21201
12	Melinta 306 Study Site	Boston	Massachusetts	United States	02115
13	Melinta 306 Study Site	Burlington	Massachusetts	United States	01805
14	Melinta 306 Study Site	Saint Paul	Minnesota	United States	55104
15	Melinta 306 Study Site	Saint Louis	Missouri	United States	63110
16	Melinta 306 Study Site	Butte	Montana	United States	59701
17	Melinta 306 Study Site	Omaha	Nebraska	United States	68124
18	Melinta 306 Study Site	Newark	New Jersey	United States	07102
19	Melinta 306 Study Site	Buffalo	New York	United States	14215
20	Melinta 306 Study Site	Charlotte	North Carolina	United States	28203
21	Melinta 306 Study Site	Cleveland	Ohio	United States	44106-5029
22	Melinta 306 Study Site	Dayton	Ohio	United States	45402
23	Melinta 306 Study Site	Rapid City	South Dakota	United States	57702
24	Melinta 306 Study Site	Franklin	Tennessee	United States	37067
25	Melinta 306 Study Site	Corsicana	Texas	United States	75110
26	Melinta 306 Study Site	Buenos Aires		Argentina
27	Melinta 306 Study Site	Córdoba		Argentina
28	Melinta 306 Study Site	La Plata		Argentina
29	Melinta 306 Study Site	Pleven		Bulgaria
30	Melinta 306 Study Site	Ruse		Bulgaria
31	Melinta 306 Study Site	Sofia		Bulgaria
32	Melinta 306 Study Site	Stara Zagora		Bulgaria
33	Melinta 306 Study Site	Barranquilla		Colombia
34	Melinta 306 Study Site	Cali		Colombia
35	Melinta 306 Study Site	Manizales		Colombia
36	Melinta 306 Study Site	Medellín		Colombia
37	Melinta 306 Study Site	Quindío		Colombia
38	Melinta 306 Study Site	Santo Domingo		Dominican Republic
39	Melinta 306 Study Site	Tbilisi		Georgia
40	Melinta 306 Study Site	Leverkusen		Germany
41	Melinta 306 Study Site	Munich		Germany
42	Melinta 306 Study Site	Budapest		Hungary
43	Melinta 306 Study Site	Debrecen		Hungary
44	Melinta 306 Study Site	Deszk		Hungary
45	Melinta 306 Study Site	Miskolc		Hungary
46	Melinta 306 Study Site	Nyíregyháza		Hungary
47	Melinta 306 Study Site	Szombathely		Hungary
48	Melinta 306 Study Site	Daugavpils		Latvia
49	Melinta 306 Study Site	Liepaja		Latvia
50	Melinta 306 Study Site	Riga		Latvia
51	Melinta 306 Study Site	Lima		Peru
52	Melinta 306 Study Site	Chrzanow		Poland
53	Melinta 306 Study Site	Katowice		Poland
54	Melinta 306 Study Site	Lodz		Poland
55	Melinta 306 Study Site	Wroclaw		Poland
56	Melinta 306 Study Site	Braşov		Romania
57	Melinta 306 Study Site	Bucharest		Romania
58	Melinta 306 Study Site	Craiova		Romania
59	Melinta 306 Study Site	Timisoara		Romania
60	Melinta 306 Study Site	Arkhangel'sk		Russian Federation
61	Melinta 306 Study Site	Moscow		Russian Federation
62	Melinta 306 Study Site	Smolensk		Russian Federation
63	Melinta 306 Study Site	St. Petersburg		Russian Federation
64	Melinta 306 Study Site	Vsevolozhsk		Russian Federation
65	Melinta 306 Study Site	Belgrade		Serbia
66	Melinta 306 Study Site	Kragujevac		Serbia
67	Melinta 306 Study Site	Nis		Serbia
68	Melinta 306 Study Site	Sremska Kamenica		Serbia
69	Melinta 306 Study Site	Golnik		Slovenia
70	Melinta 306 Study Site	Ljubljana		Slovenia
71	Melinta 306 Study Site	Benoni		South Africa
72	Melinta 306 Study Site	Chatsworth		South Africa
73	Melinta 306 Study Site	Krugersdorp		South Africa
74	Melinta 306 Study Site	Middelburg		South Africa
75	Melinta 306 Study Site	Phoenix		South Africa
76	Melinta 306 Study Site	Port Elizabeth		South Africa
77	Melinta 306 Study Site	Pretoria		South Africa
78	Melinta 306 Study Site	Worcester		South Africa
79	Melinta 306 Study Site	Badalona		Spain
80	Melinta 306 Study Site	Barcelona		Spain
81	Melinta 306 Study Site	Madrid		Spain
82	Melinta 306 Study Site	Terrassa		Spain
83	Melinta 306 Study Site	Valencia		Spain
84	Melinta 306 Study Site	Dnipro		Ukraine
85	Melinta 306 Study Site	Kharkiv		Ukraine
86	Melinta 306 Study Site	Kyiv		Ukraine
87	Melinta 306 Study Site	Poltava		Ukraine
88	Melinta 306 Study Site	Vinnytsia		Ukraine
89	Melinta 306 Study Site	Zaporizhia		Ukraine
90	Melinta 306 Study Site	Zhytomyr		Ukraine

Sponsors and Collaborators

• Melinta Therapeutics, Inc.

Investigators

• Study Director: Sue Cammarata, MD, Melinta Therapeutics, Inc.

Study Documents (Full-Text)

• Study Protocol - Dec 4, 2017
• Statistical Analysis Plan - Oct 2, 2018

More Information

Publications

None provided.

• Responsible Party: Melinta Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02679573
• Other Study ID Numbers: ML-3341-306; 2015-003026-14
• First Posted: Feb 10, 2016
• Last Update Posted: Feb 27, 2020
• Last Verified: Feb 1, 2020

• 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
• Keywords provided by Melinta Therapeutics, Inc.: Pneumonia
• Additional relevant MeSH terms: Pneumonia; Pneumonia, Bacterial; Moxifloxacin; Linezolid

Study Results

Participant Flow

Pre-assignment Detail	860 subjects were planned to be enrolled in the study but 859 are included in the ITT population. One subject mistakenly was randomized into the IXRS but did not provide informed consent; therefore, this subject was not included in the ITT population.

Arm/Group Title	Delafloxacin	Moxifloxacin/Linezolid
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total	Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
Period Title: Overall Study
STARTED	431	428
COMPLETED	394	389
NOT COMPLETED	37	39

Baseline Characteristics

Arm/Group Title	Delafloxacin	Moxifloxacin/Linezolid	Total
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total	Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses	Total of all reporting groups
Overall Participants	431	428	859
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	228 52.9%	249 58.2%	477 55.5%
>=65 years	203 47.1%	179 41.8%	382 44.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.7 (16.06)	59.3 (61.0)	60.0 (16.33)
Sex: Female, Male (Count of Participants)
Female	180 41.8%	175 40.9%	355 41.3%
Male	251 58.2%	253 59.1%	504 58.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	32 7.4%	23 5.4%	55 6.4%
Not Hispanic or Latino	399 92.6%	405 94.6%	804 93.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	4 0.9%	0 0%	4 0.5%
Asian	5 1.2%	5 1.2%	10 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	22 5.1%	33 7.7%	55 6.4%
White	398 92.3%	388 90.7%	786 91.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 0.5%	2 0.5%	4 0.5%
Region of Enrollment (participants) [Number]
Colombia	11 2.6%	9 2.1%	20 2.3%
Argentina	12 2.8%	8 1.9%	20 2.3%
Romania	30 7%	29 6.8%	59 6.9%
Hungary	14 3.2%	12 2.8%	26 3%
United States	1 0.2%	5 1.2%	6 0.7%
Ukraine	84 19.5%	84 19.6%	168 19.6%
Russia	38 8.8%	42 9.8%	80 9.3%
Spain	10 2.3%	14 3.3%	24 2.8%
Latvia	19 4.4%	21 4.9%	40 4.7%
Dominican Republic	2 0.5%	0 0%	2 0.2%
Poland	20 4.6%	8 1.9%	28 3.3%
South Africa	30 7%	41 9.6%	71 8.3%
Georgia	45 10.4%	50 11.7%	95 11.1%
Slovenia	8 1.9%	7 1.6%	15 1.7%
Bulgaria	33 7.7%	25 5.8%	58 6.8%
Serbia	69 16%	73 17.1%	142 16.5%
Peru	4 0.9%	0 0%	4 0.5%
Germany	1 0.2%	0 0%	1 0.1%
PORT Risk Class (Count of Participants)
II	54 12.5%	57 13.3%	111 12.9%
III	258 59.9%	260 60.7%	518 60.3%
IV	115 26.7%	103 24.1%	218 25.4%
V	4 0.9%	8 1.9%	12 1.4%

Outcome Measures

1. Primary Outcome

Title	Early Clinical Response
Description	Early clinical response defined as improvement in at least 2 of the following symptoms (as assessed by the investigator): chest pain, frequency or severity of cough, amount and quality of productive sputum, and difficulty breathing, and no worsening of the other symptoms in the ITT population. Symptom severity evaluated by the investigator on a 4-point scale: Absent (0), Mild (1), Moderate (2), Severe (3). Improvement defined as at least a 1-point decrease from baseline.
Time Frame	96 (+/- 24) hours after the first dose of study drug

Outcome Measure Data

Analysis Population Description

ITT (intent-to-treat) Population is all the randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.

Arm/Group Title	Delafloxacin	Moxifloxacin/Linezolid
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total	Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
Measure Participants	431	428
Count of Participants [Participants]	383 88.9%	381 89%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delafloxacin, Moxifloxacin/Linezolid
	Comments	The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were: H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm > -0.125 where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively. The treatment difference (delafloxacin - moxifloxacin) were presented, and the Miettinen-Nurminen test, without stratification, was used for the 2 sided 95% CI on the difference in response rate.
	Type of Statistical Test	Non-Inferiority
	Comments	Used on a normal approximation approach (Miettinen and Nurminen's Likelihood Score Test), 860 subjects in the ITT population provided a 90% power to assess non-inferiority of delafloxacin vs. moxifloxacin based on the following assumptions: (1) a rate of ECR for moxifloxacin therapy and delafloxacin of 77% and 74%, respectively; (2) 1 sided type I error (α) of 0.025; and (3) a non-inferiority margin of 12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in responder rates
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -4.4 to 4.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Difference in responder rates (Delafloxacin treatment group minus Moxifloxacin treatment group). Confidence intervals are calculated using Miettinen and Nurminen method without stratification.

2. Secondary Outcome

Title	Early Clinical Response Plus Improvement in Vital Signs and no Worsening of the 4 Symptoms
Description	Early clinical response with the addition of improvement in vital signs and no worsening of the following 4 symptoms: chest pain, cough, productive sputum, and difficulty breathing in the ITT population. Symptom severity evaluated by the investigator on a 4-point scale: Absent (0), Mild (1), Moderate (2), Severe (3). Improvement defined as at least a 1-point decrease from baseline. Improvement in vital signs defined as a return to normal of any abnormal vital signs at baseline, and no worsening (ie, be abnormal) of any vital sign that was normal at baseline.
Time Frame	96 (+/- 24) hours after the first dose of study drug

Outcome Measure Data

Analysis Population Description

ITT (intent-to-treat) Population is all randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.

Arm/Group Title	Delafloxacin	Moxifloxacin/Linezolid
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total	Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
Measure Participants	431	428
Count of Participants [Participants]	227 52.7%	184 43%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delafloxacin, Moxifloxacin/Linezolid
	Comments	The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were: H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm > -0.125 where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively. The treatment difference (delafloxacin - moxifloxacin) was presented, and the Miettinen-Nurminen test without stratification was used for the 2 sided 95% CI on the difference in response rate.
	Type of Statistical Test	Non-Inferiority
	Comments	Used on a normal approximation approach (Miettinen and Nurminen's Likelihood Score Test), 860 subjects in the ITT population provided a 90% power to assess non-inferiority of delafloxacin vs. moxifloxacin based on the following assumptions: (1) a rate of ECR for moxifloxacin therapy and delafloxacin of 77% and 74%, respectively; (2) 1 sided type I error (α) of 0.025; and (3) a non-inferiority margin of 12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in responder rates
	Estimated Value	9.7
	Confidence Interval	(2-Sided) 95%; 3.0 to 16.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Clinical Outcome at Test of Cure
Description	Clinical outcome (Success, Failure, or Indeterminate/missing) based on the investigator's assessment of the patient's signs and symptoms of infection in the ITT population.
Time Frame	5 to 10 days after the last dose of study drug

Outcome Measure Data

Analysis Population Description

ITT (intent-to-treat) Population is all the randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.

Arm/Group Title	Delafloxacin	Moxifloxacin/Linezolid
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total	Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
Measure Participants	431	428
Success	390 90.5%	384 89.7%
Failure	21 4.9%	21 4.9%
Indeterminate/Missing	20 4.6%	23 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delafloxacin, Moxifloxacin/Linezolid
	Comments	The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were: H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm > -0.125 where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively. The treatment difference (delafloxacin - moxifloxacin) was presented, and the Miettinen-Nurminen test without stratification was used for the 2 sided 95% CI on the difference in response rate.
	Type of Statistical Test	Non-Inferiority
	Comments	Used on a normal approximation approach (Miettinen and Nurminen's Likelihood Score Test), 860 subjects in the ITT population provided a 90% power to assess non-inferiority of delafloxacin vs. moxifloxacin based on the following assumptions: (1) a rate of ECR for moxifloxacin therapy and delafloxacin of 77% and 74%, respectively; (2) 1 sided type I error (α) of 0.025; and (3) a non-inferiority margin of 12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in responder rates
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -3.3 to 4.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Clinical Outcome at End of Treatment
Description	Clinical outcome (Success, Failure, or Indeterminate/missing) based on the investigator's assessment of the patient's signs and symptoms of infection in the ITT population.
Time Frame	Up to 24 (+4) hours after the last dose of study drug

Outcome Measure Data

Analysis Population Description

ITT (intent-to-treat) Population is all the randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.

Arm/Group Title	Delafloxacin	Moxifloxacin/Linezolid
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total	Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
Measure Participants	431	428
Success	396 91.9%	390 91.1%
Failure	19 4.4%	20 4.7%
Indeterminate/Missing	16 3.7%	18 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delafloxacin, Moxifloxacin/Linezolid
	Comments	The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were: H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm > -0.125 where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively. The treatment difference (delafloxacin - moxifloxacin) was presented, and the Miettinen-Nurminen test without stratification was used for the 2 sided 95% CI on the difference in response rate.
	Type of Statistical Test	Non-Inferiority
	Comments	Used on a normal approximation approach (Miettinen and Nurminen's Likelihood Score Test), 860 subjects in the ITT population provided a 90% power to assess non-inferiority of delafloxacin vs. moxifloxacin based on the following assumptions: (1) a rate of ECR for moxifloxacin therapy and delafloxacin of 77% and 74%, respectively; (2) 1 sided type I error (α) of 0.025; and (3) a non-inferiority margin of 12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in responder rates
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -3.0 to 4.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Microbiologic Response
Description	Microbiological response for subjects in the MITT set will be based on results of the baseline and follow-up cultures and susceptibility testing or serology.
Time Frame	5 to 10 days after the last dose of study drug

Outcome Measure Data

Analysis Population Description

Microbiological ITT 1 (MITT-1) includes all subjects in the ITT population with a baseline bacterial pathogen identified that was known to cause CABP and against which the study drug had antibacterial activity.

Arm/Group Title	Delafloxacin	Moxifloxacin/Linezolid
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total	Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
Measure Participants	257	263
Count of Participants [Participants]	231 53.6%	235 54.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delafloxacin, Moxifloxacin/Linezolid
	Comments	The null (H0) and alternative (Ha) hypotheses to be tested to establish the noninferiority of delafloxacin were: H0: Pd - Pm ≤ -0.125 Ha: Pd - Pm > -0.125 where Pd and Pm are the probabilities of the ECR for delafloxacin and moxifloxacin, respectively. The treatment difference (delafloxacin - moxifloxacin) was presented, and the Miettinen-Nurminen test without stratification was used for the 2 sided 95% CI on the difference in response rate.
	Type of Statistical Test	Non-Inferiority
	Comments	Used on a normal approximation approach (Miettinen and Nurminen's Likelihood Score Test), 860 subjects in the ITT population provided a 90% power to assess non-inferiority of delafloxacin vs. moxifloxacin based on the following assumptions: (1) a rate of ECR for moxifloxacin therapy and delafloxacin of 77% and 74%, respectively; (2) 1 sided type I error (α) of 0.025; and (3) a non-inferiority margin of 12.5%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in responder rates
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -4.8 to 5.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	All-cause Mortality
Description	Time to all-cause Mortality was assessed on Day 28.
Time Frame	Day 28 (+/- 2 days)

Outcome Measure Data

Analysis Population Description

ITT (intent-to-treat) Population is all the randomized patients with a signed Informed consent form. Subjects were analyzed according to the treatment arm to which they were randomized.

Arm/Group Title	Delafloxacin	Moxifloxacin/Linezolid
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total	Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
Measure Participants	431	428
Count of Participants [Participants]	8 1.9%	6 1.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Delafloxacin, Moxifloxacin/Linezolid
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5951
	Comments	The log-rank test was used to compare the time to all-cause mortality between the 2 treatment groups.
	Method	Log Rank
	Comments

Adverse Events

Time Frame	All adverse events reported or observed during the study will be recorded from the time that the subject is first administered double-blind study drug through the End of Treatment (5 - 10 days) or Test of Cure visit (5 - 10 days after last dose), whichever is later. All serious adverse events will be recorded from the time the subject or authorized representative signs the informed consent form through the Follow up visit (Day 28).
Adverse Event Reporting Description	Adverse Events are reported in the Safety Population which includes all randomized subjects who received at least 1 dose of study drug. Two subjects in the delafloxacin group and 1 subject in the moxifloxacin group were randomized, but did not receive any study drug.
Arm/Group Title	Delafloxacin		Moxifloxacin/Linezolid
Arm/Group Description	Delafloxacin: 300 mg IV, Q12H for at least 6 doses with potential to switch to 450 mg oral tablet, Q12H for up to 20 doses total		Moxifloxacin: 400 mg IV, Q24H for at least 3 doses with potential to switch to 400 mg oral over-encapsulated tablet, Q24H for up to 10 doses total Linezolid: At local investigator discretion, subjects in the moxifloxacin arm with confirmed MRSA can switch to linezolid 600 mg IV Q12H for all remaining doses
All Cause Mortality
	Delafloxacin		Moxifloxacin/Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/429 (1.9%)		6/427 (1.4%)
Serious Adverse Events
	Delafloxacin		Moxifloxacin/Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/429 (5.4%)		20/427 (4.7%)
Blood and lymphatic system disorders
Agranulocytosis	1/429 (0.2%)	1	0/427 (0%)	0
Cardiac disorders
Cardiomyopathy	1/429 (0.2%)	1	0/427 (0%)	0
Myocardial infarction	1/429 (0.2%)	1	0/427 (0%)	0
Acute myocardial infarction	0/429 (0%)	0	1/427 (0.2%)	1
Atrial fibrillation	0/429 (0%)	0	1/427 (0.2%)	1
Cardiac failure	0/429 (0%)	0	2/427 (0.5%)	2
Cardiac failure acute	0/429 (0%)	0	2/427 (0.5%)	2
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/429 (0.2%)	1	0/427 (0%)	0
Duodenal ulcer	0/429 (0%)	0	1/427 (0.2%)	1
General disorders
Sudden death	0/429 (0%)	0	1/427 (0.2%)	1
Immune system disorders
Hypersensitivity	1/429 (0.2%)	1	0/427 (0%)	0
Sarcoidosis	1/429 (0.2%)	1	0/427 (0%)	0
Infections and infestations
Pneumonia	3/429 (0.7%)	3	1/427 (0.2%)	1
Septic Shock	3/429 (0.7%)	4	1/427 (0.2%)	1
Clostridium difficile colitis	1/429 (0.2%)	1	1/427 (0.2%)	1
Herpes zoster meningomyelitis	1/429 (0.2%)	1	0/427 (0%)	0
Infectious pleural effusion	1/429 (0.2%)	1	0/427 (0%)	0
Lung abscess	1/429 (0.2%)	1	0/427 (0%)	0
Sepsis	1/429 (0.2%)	1	0/427 (0%)	0
Measles	0/429 (0%)	0	1/427 (0.2%)	1
Oral Herpes	0/429 (0%)	0	1/427 (0.2%)	1
Staphylococcal bacteremia	0/429 (0%)	0	1/427 (0.2%)	1
Musculoskeletal and connective tissue disorders
Bursitis	1/429 (0.2%)	1	0/427 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic	1/429 (0.2%)	1	0/427 (0%)	0
Metastatic malignant melanoma	1/429 (0.2%)	1	0/427 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/429 (0%)	0	1/427 (0.2%)	1
Ischaemic stroke	0/429 (0%)	0	1/427 (0.2%)	1
Vertebrobasilar insufficiency	0/429 (0%)	0	1/427 (0.2%)	1
Psychiatric disorders
Delirium	0/429 (0%)	0	1/427 (0.2%)	1
Renal and urinary disorders
Acute kidney injury	0/429 (0%)	0	1/427 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/429 (0.5%)	2	0/427 (0%)	0
Acute respiratory failure	1/429 (0.2%)	1	0/427 (0%)	0
Pulmonary embolism	1/429 (0.2%)	1	4/427 (0.9%)	4
Pleurisy	0/429 (0%)	0	1/427 (0.2%)	1
Pulmonary edema	0/429 (0%)	0	1/427 (0.2%)	1
Vascular disorders
Hypertensive crisis	1/429 (0.2%)	1	0/427 (0%)	0
Other (Not Including Serious) Adverse Events
	Delafloxacin		Moxifloxacin/Linezolid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/429 (9.3%)		30/427 (7%)
Gastrointestinal disorders
Diarrhoea	20/429 (4.7%)	21	14/427 (3.3%)	14
Investigations
Transaminases increased	13/429 (3%)	13	6/427 (1.4%)	6
Nervous system disorders
Headache	8/429 (1.9%)	8	11/427 (2.6%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.