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Omadacycline vs Moxifloxacin for the Treatment of CABP (EudraCT #2013-004071-13)

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ClinicalTrials.gov Identifier: NCT02531438
Recruitment Status : Completed
First Posted : August 24, 2015
Results First Posted : November 29, 2018
Last Update Posted : January 16, 2019
Sponsor:
Information provided by (Responsible Party):
Paratek Pharmaceuticals Inc

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Bacterial Pneumonia
Community-Acquired Infections
Interventions Drug: Omadacycline
Drug: Moxifloxacin
Enrollment 774
Recruitment Details Participant randomization was stratified by Pneumonia Outcomes Research Team (PORT) Risk Class (II or III/IV), receipt of an allowed antibacterial therapy in the 72 hours prior to study treatment, and geographic region. All participants were expected to present with CABP severe enough to require at least 3 days of intravenous (IV) treatment.
Pre-assignment Details Participants who met inclusion criteria and did not meet exclusion criteria were randomly assigned to a treatment group, and received their first dose of test article within 4 hours after randomization. All participants were expected to present with CABP PORT Risk Class II, III, or IV to require a minimum of at least 3 days of IV treatment.
Arm/Group Title Omadacycline Moxifloxacin
Hide Arm/Group Description Participants received omadacycline 100 milligrams (mg) intravenously (IV) every 12 hours (q12h) (first 2 doses), followed by 100 mg IV every 24 hours (q24h) (starting 24 hours after the first dose), with the option to switch to a 300 mg (two 150 mg omadacycline tablets and 1 over-encapsulated placebo tablet matching moxifloxacin) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days. Participants received moxifloxacin 400 mg IV q24h (with a single placebo infusion to match the omadacycline dosing regimen 12 hours after the first dose on Day 1) with the option to switch to a 400 mg (one 400 mg moxifloxacin over-encapsulated tablet and 2 placebo tablets matching omadacycline tablets) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days.
Period Title: Overall Study
Started 386 388
Completed 356 362
Not Completed 30 26
Reason Not Completed
Adverse Event             7             9
Lost to Follow-up             0             3
Withdrawal by Subject             7             8
Physician Decision             0             1
Death             6             3
Randomized, but Not Treated             4             0
Missed EOT/PTE Visit             5             2
Randomized with Exclusion Criteria             1             0
Arm/Group Title Omadacycline Moxifloxacin Total
Hide Arm/Group Description Participants received omadacycline 100 milligrams (mg) intravenously (IV) every 12 hours (q12h) (first 2 doses), followed by 100 mg IV every 24 hours (q24h) (starting 24 hours after the first dose), with the option to switch to a 300 mg (two 150 mg omadacycline tablets and 1 over-encapsulated placebo tablet matching moxifloxacin) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days. Participants received moxifloxacin 400 mg IV q24h (with a single placebo infusion to match the omadacycline dosing regimen 12 hours after the first dose on Day 1) with the option to switch to a 400 mg (one 400 mg moxifloxacin over-encapsulated tablet and 2 placebo tablets matching omadacycline tablets) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days. Total of all reporting groups
Overall Number of Baseline Participants 386 388 774
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 386 participants 388 participants 774 participants
18 to 45 years old
62
  16.1%
61
  15.7%
123
  15.9%
>45 to 65 years old
172
  44.6%
155
  39.9%
327
  42.2%
>65 years old
152
  39.4%
172
  44.3%
324
  41.9%
>75 years old
75
  19.4%
83
  21.4%
158
  20.4%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 386 participants 388 participants 774 participants
Female
178
  46.1%
169
  43.6%
347
  44.8%
Male
208
  53.9%
219
  56.4%
427
  55.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 386 participants 388 participants 774 participants
American Indian or Alaska Native
0
   0.0%
2
   0.5%
2
   0.3%
Asian
17
   4.4%
18
   4.6%
35
   4.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
11
   2.8%
7
   1.8%
18
   2.3%
White
356
  92.2%
355
  91.5%
711
  91.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
   0.5%
6
   1.5%
8
   1.0%
1.Primary Outcome
Title Number of Participants With Early Clinical Response
Hide Description Early clinical response is defined as clinical success, categorized by survival with improvement of at least 1 level compared to Baseline in at least 2 CABP symptoms (cough, sputum production, pleuritic chest pain, and dyspnea) with no worsening in the other CABP symptoms. Response was determined programmatically using the investigator’s assessment of the CABP symptoms. The severity of the participant's CABP symptoms was evaluated on a 4-point scale (absent, mild, moderate, or severe) based upon the CABP Subject Symptom Severity Guidance Framework for Investigator Assessment. An indeterminate response is defined as one that could not be adequately inferred because the participant was not assessed because they withdrew consent, were lost to follow-up, or other specified reason. Clinical failure is defined as no improvement by at least 1 level in CABP symptoms, worsening of any CABP symptom, alternative antibacterial treatment for CABP, discontinuation due to adverse event, or death.
Time Frame Screening; 72 to 120 hours after the first dose of test article
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population: all randomized participants regardless of whether or not the participant received the test article
Arm/Group Title Omadacycline Moxifloxacin
Hide Arm/Group Description:
Participants received omadacycline 100 milligrams (mg) intravenously (IV) every 12 hours (q12h) (first 2 doses), followed by 100 mg IV every 24 hours (q24h) (starting 24 hours after the first dose), with the option to switch to a 300 mg (two 150 mg omadacycline tablets and 1 over-encapsulated placebo tablet matching moxifloxacin) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days.
Participants received moxifloxacin 400 mg IV q24h (with a single placebo infusion to match the omadacycline dosing regimen 12 hours after the first dose on Day 1) with the option to switch to a 400 mg (one 400 mg moxifloxacin over-encapsulated tablet and 2 placebo tablets matching omadacycline tablets) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days.
Overall Number of Participants Analyzed 386 388
Measure Type: Count of Participants
Unit of Measure: Participants
Clinical success
313
  81.1%
321
  82.7%
Clinical failure
49
  12.7%
47
  12.1%
Indeterminate
24
   6.2%
20
   5.2%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Omadacycline, Moxifloxacin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments A non-inferiority margin of 10% was used for the analysis.
Method of Estimation Estimation Parameter treatment difference
Estimated Value -1.6
Confidence Interval (2-Sided) 95%
-7.1 to 3.8
Estimation Comments The 95% confidence interval was constructed based on the Miettinen and Nurminen method without stratification. Treatment difference for a response of clinical success was calculated as omadacycline minus moxifloxacin.
2.Secondary Outcome
Title Number of Participants With the Indicated Investigator Assessment of Clinical Response in the ITT Population at the Post Therapy Evaluation (PTE) Visit
Hide Description At the PTE Visit the investigator indicated one of the following outcomes relating to the primary infection under study: Clinical Success: survival after completion of a test article regimen without receiving any systemic antibacterial therapy other than test article, resolution of signs/symptoms of the infection present at Screening with no new symptoms/complications attributable to CABP and no need for further antibacterial therapy. Clinical Failure: alternative antibacterial treatment for CABP was required prior to the PTE Visit related to either (a) progression/development of new CABP symptoms or (b) development of infectious complications of CABP. Other reasons for clinical failure: participant received antibiotics that may have been effective for the infection under study for a different infection from the one under study; death prior to the PTE Visit. Indeterminate: the clinical response to test article could not be adequately inferred.
Time Frame Screening; 5 to 10 days after the last day of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Omadacycline Moxifloxacin
Hide Arm/Group Description:
Participants received omadacycline 100 milligrams (mg) intravenously (IV) every 12 hours (q12h) (first 2 doses), followed by 100 mg IV every 24 hours (q24h) (starting 24 hours after the first dose), with the option to switch to a 300 mg (two 150 mg omadacycline tablets and 1 over-encapsulated placebo tablet matching moxifloxacin) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days.
Participants received moxifloxacin 400 mg IV q24h (with a single placebo infusion to match the omadacycline dosing regimen 12 hours after the first dose on Day 1) with the option to switch to a 400 mg (one 400 mg moxifloxacin over-encapsulated tablet and 2 placebo tablets matching omadacycline tablets) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days.
Overall Number of Participants Analyzed 386 388
Measure Type: Count of Participants
Unit of Measure: Participants
Clinical success
338
  87.6%
330
  85.1%
Clinical failure
32
   8.3%
42
  10.8%
Indeterminate
16
   4.1%
16
   4.1%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Omadacycline, Moxifloxacin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments A non-inferiority margin of 10% was used for the analysis.
Method of Estimation Estimation Parameter treatment difference
Estimated Value 2.5
Confidence Interval (2-Sided) 95%
-2.4 to 7.4
Estimation Comments The 95% confidence interval was constructed based on the Miettinen and Nurminen method without stratification. Treatment difference for a response of clinical success was calculated as omadacycline minus moxifloxacin.
3.Secondary Outcome
Title Number of Participants With the Indicated Investigator Assessment of Clinical Response in the Clinically Evaluable-Post Therapy Evaluation (CT-PTE) Population
Hide Description At the PTE Visit the investigator indicated one of the following outcomes relating to the primary infection under study: Clinical Success: survival after completion of a test article regimen without receiving any systemic antibacterial therapy other than test article, resolution of signs/symptoms of the infection present at Screening with no new symptoms/complications attributable to CABP and no need for further antibacterial therapy. Clinical Failure: alternative antibacterial treatment for CABP was required prior to the PTE Visit related to either (a) progression/development of new CABP symptoms or (b) development of infectious complications of CABP. Other reasons for clinical failure: participant received antibiotics that may have been effective for the infection under study for a different infection from the one under study; death prior to the PTE Visit.
Time Frame Screening; 5 to 10 days after the last day of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
CE-PTE Population: all participants in the ITT Population meeting additional pre-defined criteria
Arm/Group Title Omadacycline Moxifloxacin
Hide Arm/Group Description:
Participants received omadacycline 100 milligrams (mg) intravenously (IV) every 12 hours (q12h) (first 2 doses), followed by 100 mg IV every 24 hours (q24h) (starting 24 hours after the first dose), with the option to switch to a 300 mg (two 150 mg omadacycline tablets and 1 over-encapsulated placebo tablet matching moxifloxacin) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days.
Participants received moxifloxacin 400 mg IV q24h (with a single placebo infusion to match the omadacycline dosing regimen 12 hours after the first dose on Day 1) with the option to switch to a 400 mg (one 400 mg moxifloxacin over-encapsulated tablet and 2 placebo tablets matching omadacycline tablets) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days.
Overall Number of Participants Analyzed 340 345
Measure Type: Count of Participants
Unit of Measure: Participants
Clinical success
316
  92.9%
312
  90.4%
Clinical failure
24
   7.1%
33
   9.6%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Omadacycline, Moxifloxacin
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments A non-inferiority margin of 10% was used for the analysis.
Method of Estimation Estimation Parameter treatment difference
Estimated Value 2.5
Confidence Interval (2-Sided) 95%
-1.7 to 6.8
Estimation Comments The 95% confidence interval was constructed based on the Miettinen and Nurminen method without stratification. Treatment difference for a response of clinical success was calculated as omadacycline minus moxifloxacin.
Time Frame Adverse events were assessed from the signing of Informed Consent Form to the time of the Final Follow-up assessment (up to 30 to 37 days after the start of the first infusion of test article)
Adverse Event Reporting Description Adverse events are reported for members of the Safety Population, comprised of all randomized participants who received test article (either active or placebo). Treatment-emergent adverse events, defined as events occurring after the first dose of active test article, are reported.
 
Arm/Group Title Omadacycline Moxifloxacin
Hide Arm/Group Description Participants received omadacycline 100 milligrams (mg) intravenously (IV) every 12 hours (q12h) (first 2 doses), followed by 100 mg IV every 24 hours (q24h) (starting 24 hours after the first dose), with the option to switch to a 300 mg (two 150 mg omadacycline tablets and 1 over-encapsulated placebo tablet matching moxifloxacin) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days. Participants received moxifloxacin 400 mg IV q24h (with a single placebo infusion to match the omadacycline dosing regimen 12 hours after the first dose on Day 1) with the option to switch to a 400 mg (one 400 mg moxifloxacin over-encapsulated tablet and 2 placebo tablets matching omadacycline tablets) oral administration q24h after at least 3 days (4 doses) of IV treatment. The total duration of test article therapy (IV plus oral administration) for all participants was at least 7 days and no more than 14 days.
All-Cause Mortality
Omadacycline Moxifloxacin
Affected / at Risk (%) Affected / at Risk (%)
Total   8/382 (2.09%)   4/388 (1.03%) 
Show Serious Adverse Events Hide Serious Adverse Events
Omadacycline Moxifloxacin
Affected / at Risk (%) Affected / at Risk (%)
Total   23/382 (6.02%)   26/388 (6.70%) 
Cardiac disorders     
Acute Myocardial Infarction * 1  2/382 (0.52%)  0/388 (0.00%) 
Cardiogenic Shock * 1  2/382 (0.52%)  1/388 (0.26%) 
Cardiac Arrest * 1  1/382 (0.26%)  0/388 (0.00%) 
Cardiac Failure * 1  1/382 (0.26%)  1/388 (0.26%) 
Cardio-Respiratory Arrest * 1  1/382 (0.26%)  0/388 (0.00%) 
Tachycardia * 1  1/382 (0.26%)  0/388 (0.00%) 
Pericardial Effusion * 1  0/382 (0.00%)  1/388 (0.26%) 
Right Ventricular Failure * 1  0/382 (0.00%)  1/388 (0.26%) 
Gastrointestinal disorders     
Colitis * 1  0/382 (0.00%)  1/388 (0.26%) 
General disorders     
Multi-Organ Failure * 1  1/382 (0.26%)  0/388 (0.00%) 
Hepatobiliary disorders     
Cholecystitis Acute * 1  1/382 (0.26%)  0/388 (0.00%) 
Hepatic Failure * 1  1/382 (0.26%)  0/388 (0.00%) 
Hepatic Congestion * 1  0/382 (0.00%)  1/388 (0.26%) 
Infections and infestations     
Influenza * 1  3/382 (0.79%)  0/388 (0.00%) 
Pneumonia * 1  2/382 (0.52%)  6/388 (1.55%) 
Cellulitis * 1  1/382 (0.26%)  0/388 (0.00%) 
Infectious Pleural Effusion * 1  1/382 (0.26%)  1/388 (0.26%) 
Septic Shock * 1  1/382 (0.26%)  2/388 (0.52%) 
Atypical Mycobacterial Pneumonia * 1  0/382 (0.00%)  1/388 (0.26%) 
Clostridium Difficile Colitis * 1  0/382 (0.00%)  1/388 (0.26%) 
Clostridium Difficile Infection * 1  0/382 (0.00%)  2/388 (0.52%) 
human Immunodeficiency Virus (HIV) Infection * 1  0/382 (0.00%)  1/388 (0.26%) 
Infective Exacerbation Of Bronchiectasis * 1  0/382 (0.00%)  1/388 (0.26%) 
Lung Abscess * 1  0/382 (0.00%)  1/388 (0.26%) 
Pneumonia Viral * 1  0/382 (0.00%)  1/388 (0.26%) 
Injury, poisoning and procedural complications     
Bladder Injury * 1  0/382 (0.00%)  1/388 (0.26%) 
Metabolism and nutrition disorders     
Decreased Appetite * 1  1/382 (0.26%)  0/388 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back Pain * 1  1/382 (0.26%)  0/388 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung Neoplasm * 1  2/382 (0.52%)  2/388 (0.52%) 
Adenocarcinoma * 1  0/382 (0.00%)  1/388 (0.26%) 
Chronic Lymphocytic Leukaemia * 1  0/382 (0.00%)  1/388 (0.26%) 
Colon Cancer Metastatic * 1  0/382 (0.00%)  1/388 (0.26%) 
Pancreatic Carcinoma * 1  0/382 (0.00%)  1/388 (0.26%) 
Nervous system disorders     
Cerebrovascular Accident * 1  2/382 (0.52%)  0/388 (0.00%) 
Psychiatric disorders     
Anxiety * 1  1/382 (0.26%)  0/388 (0.00%) 
Renal and urinary disorders     
Renal Failure Acute * 1  0/382 (0.00%)  2/388 (0.52%) 
Respiratory, thoracic and mediastinal disorders     
Pleural Effusion * 1  3/382 (0.79%)  0/388 (0.00%) 
Acute Respiratory Distress Syndrome * 1  2/382 (0.52%)  0/388 (0.00%) 
Acute Respiratory Failure * 1  2/382 (0.52%)  3/388 (0.77%) 
Acute Pulmonary Oedema * 1  1/382 (0.26%)  0/388 (0.00%) 
Vascular disorders     
Aortic Aneurysm Rupture * 1  1/382 (0.26%)  0/388 (0.00%) 
Peripheral Ischaemia * 1  0/382 (0.00%)  1/388 (0.26%) 
1
Term from vocabulary, MedDRA 17.1
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Omadacycline Moxifloxacin
Affected / at Risk (%) Affected / at Risk (%)
Total   63/382 (16.49%)   94/388 (24.23%) 
Gastrointestinal disorders     
Vomiting * 1  10/382 (2.62%)  6/388 (1.55%) 
Constipation * 1  9/382 (2.36%)  6/388 (1.55%) 
Nausea * 1  9/382 (2.36%)  21/388 (5.41%) 
Diarrhea * 1  4/382 (1.05%)  31/388 (7.99%) 
Investigations     
Alanine aminotransferase increased * 1  14/382 (3.66%)  18/388 (4.64%) 
Gamma-glutamyl transferase increased * 1  10/382 (2.62%)  8/388 (2.06%) 
Aspartate aminotransferase increased * 1  8/382 (2.09%)  14/388 (3.61%) 
Nervous system disorders     
Headache * 1  8/382 (2.09%)  5/388 (1.29%) 
Psychiatric disorders     
Insomnia * 1  10/382 (2.62%)  8/388 (2.06%) 
Vascular disorders     
Hypertension * 1  13/382 (3.40%)  11/388 (2.84%) 
1
Term from vocabulary, MedDRA 17.1
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
The only disclosure restriction on the Principal Investigator 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 from the time submitted to the sponsor for review. The sponsor can request changes to the communication and require the removal of confidential information.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Paul McGovern; Vice President, Clinical Affairs
Organization: Paratek Pharmaceuticals, Inc.
Phone: 484-751-4935
EMail: Paul.Mcgovern@paratekpharma.com
Layout table for additonal information
Responsible Party: Paratek Pharmaceuticals Inc
ClinicalTrials.gov Identifier: NCT02531438     History of Changes
Other Study ID Numbers: PTK0796-CABP-1200
First Submitted: July 14, 2015
First Posted: August 24, 2015
Results First Submitted: November 2, 2018
Results First Posted: November 29, 2018
Last Update Posted: January 16, 2019