IV or IV/PO Omadacycline vs. IV/PO Levofloxacin for the Treatment of Acute Pyelonephritis

• Sponsor: Paratek Pharmaceuticals Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03757234
• Collaborator: (none)
• Enrollment: 201
• Locations: 31
• Arms: 5
• Actual Duration (Months): 8.1
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and efficacy of intravenous (iv) or iv/per oral (po) omadacycline as compared to iv or iv/po levofloxacin in the treatment of female adults with acute pyelonephritis.

Condition or Disease	Intervention/Treatment	Phase
Acute Pyelonephritis	Drug: Omadacycline; Drug: Levofloxacin; Drug: Omadacycline	Phase 2

Detailed Description

This was a randomized (1:1:1:1:1), double-blind, double-dummy, adaptive designed, Phase 2 study. Based on review of the efficacy and microbiology data, the DMC modified the randomization algorithm, and no further participants were enrolled in the following treatment arms after May 2019: the omadacycline 200 iv/100 iv, omadacycline 200 iv/300 po or 100 iv, and omadacycline 200 iv/450 po or 100 iv arms. After this change, participants were randomized in a 1:1 ratio to either the omadacycline 200 iv/200 iv or levofloxacin arms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 201 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blinded, Adaptive Phase 2 Study to Evaluate the Safety and Efficacy of iv or iv/po Omadacycline and iv/po Levofloxacin in the Treatment of Adults With Acute Pyelonephritis.
• Actual Study Start Date: Nov 19, 2018
• Actual Primary Completion Date: Jun 26, 2019
• Actual Study Completion Date: Jul 24, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Omadacycline 200 iv/200 iv On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	Drug: Omadacycline; iv solution; Other Names: Nuzyra
Experimental: Omadacycline 200 iv/100 iv On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	Drug: Omadacycline; iv solution; Other Names: Nuzyra
Experimental: Omadacycline 200 iv/300 po or 100 iv On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams per oral (po). All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	Drug: Omadacycline; po tablets; Other Names: Nuzyra ; Drug: Omadacycline; iv solution; Other Names: Nuzyra
Experimental: Omadacycline 200 iv/450 po or 100 iv On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	Drug: Omadacycline; po tablets; Other Names: Nuzyra ; Drug: Omadacycline; iv solution; Other Names: Nuzyra
Active Comparator: Levofloxacin 750 iv/750 po or iv On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	Drug: Levofloxacin; iv solution/po tablets; Other Names: Levaquin

Outcome Measures

Primary Outcome Measures

1. Number of Participants With an Investigator Assessment of Clinical Response at the Post Therapy Evaluation (PTE) Visit (ITT Population) [Day 21 (A PTE occurred on Day 21 ± 2 days after the participant's first dose of study drug).]

   Clinical response was determined by the investigator at the PTE visit by assessing whether or not the participant met the clinical outcome of Clinical Success, Clinical Failure, or Indeterminate. Clinical Success was defined as the complete resolution or significant improvement of the baseline AP signs and symptoms at the PTE visit such that no additional antimicrobial therapy is required for the current infection. Clinical Failure was defined as no apparent response to therapy or persistence of signs and symptoms of infection or reappearance of signs and symptoms at or before the PTE visit such that use of additional systemic antimicrobial therapy for the current infection was required or death at or before the PTE visit. The clinical outcome was deemed as Indeterminate when the PTE visit was not completed.

2. Number of Participants With a Microbiological Response at the PTE Visit (Micro-ITT Population) [Day 21 (A PTE occurred on Day 21 ± 2 days after the participant's first dose of study drug).]

   Microbiological response was determined programmatically at the PTE visit by assessing whether or not the participant met the microbiological outcome of 'Success', 'Failure', or 'Indeterminate'. Participants were considered to have a microbiological response of 'Success' if the outcomes of each baseline pathogens were eradication at the PTE visit. Participants were considered to have a microbiological response of 'Failure' if the outcome for any pathogen was persistence. Participants were considered to have a microbiological response of 'Indeterminate', if the outcome of at least 1 baseline pathogen was indeterminate and there was no outcome of persistence for any baseline pathogen.

3. Number of Participants With Resolution of All AP Signs and Clinical Symptoms at PTE Visit (ITT Population) [Day 21 (A PTE occurred on Day 21 ± 2 days after the participant's first dose of study drug).]

   Participants recorded their assessments using the Modified Patient Symptom Assessment Questionnaire (mPSAQ), a 6-item questionnaire that assessed the levels of 'severity' and 'bothersomeness' for six pyelonephritis signs and symptoms. The sub-scale responses were recorded as 'did not have', 'mild', 'moderate', and 'severe' for 'severity'; and 'not at all', 'a little', 'moderately', and 'a lot' for 'bothersomeness', both scored 0-3. Total scores were calculated by summing the non-missing scores of the 6 items, divided by the number of non-missing items, and then multiplied by 6. For each sub-scale, the total score ranged from 0 (least Severe/ least bothersome) and 18 (worst severity/most bothersome). Number of participants with resolution of all symptoms, without occurrence of new symptoms is reported. Resolution was defined as absence of all baseline symptoms.

4. Number of Participants With No Worsening and Absence of New AP Signs and Clinical Symptoms at PTE Visit (ITT Population) [Day 21 (A PTE occurred on Day 21 ± 2 days after the participant's first dose of study drug).]

   Participants recorded their assessments using the mPSAQ, a 6-item questionnaire that assessed the levels of 'severity' and 'bothersomeness' for six pyelonephritis signs and symptoms. The sub-scale responses were recorded as 'did not have', 'mild', 'moderate', and 'severe' for 'severity'; and 'not at all', 'a little', 'moderately', and 'a lot' for 'bothersomeness', both scored 0-3. Total scores were calculated by summing the non-missing scores of the 6 items, divided by the number of non-missing items, and then multiplied by 6. For each sub-scale, the total score ranged from 0 (least Severe/ least bothersome) and 18 (worst severity/most bothersome). Number of participants with no worsening and absence of AP signs and clinical symptoms is reported. No worsening meant that each question score is same or better at post baseline.

Secondary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events [up to approximately 28 days]

   An adverse event is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, or laboratory or physiologic observations occurring in a person given a study drug or in a clinical study. A treatment-emergent adverse event was defined as any adverse event that newly appeared, increased in frequency, or worsened in severity on or after the initiation of the study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female participants, age 18-65 years who have signed the informed consent form

• Must have a qualifying acute pyelonephritis

• Participants must not be pregnant at the time of enrollment

• Must agree to a reliable method of birth control during the study and for 30 days following the last dose of study drug

• Must be able to comply with all of the requirements of the study

Exclusion Criteria:

• Males

• Symptoms of acute pyelonephritis present for longer 7 days prior to randomization

• Infections that require antibacterial treatment for greater than 14 days

• Evidence of suspected non-renal source of infections, vaginitis, or sexually transmitted infection

• Evidence of significant immunological disease

• Evidence of liver impairment or disease

• Evidence of unstable cardiac disease

• Severe renal disease or requirement for dialysis

• Evidence of septic shock

• Has a history of hypersensitivity or allergic reaction to any tetracycline or to levofloxacin

• Has received an investigational drug within the past 30 days

• Participants who are pregnant or nursing

• Unable or unwilling to comply with the protocol requirements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 201	Tbilisi		Georgia
2	Site 202	Tbilisi		Georgia
3	Site 203	Tbilisi		Georgia
4	Site 204	Tbilisi		Georgia
5	Site 301	Daugavpils		Latvia
6	Site 304	Liepāja		Latvia	LV-3414
7	Site 302	Riga		Latvia
8	Site 305	Rēzekne		Latvia
9	Site 303	Valmiera		Latvia
10	Site 409	Krasnoyarsk		Russian Federation	660062
11	Site 408	Moscow		Russian Federation	141435
12	Site 410	Moscow		Russian Federation	Moscow
13	Site 415	Penza		Russian Federation	440026
14	Site 407	Rostov-on-Don		Russian Federation	344022
15	Site 405	Rostov-on-Don		Russian Federation	344037
16	Site 411	Saint Petersburg		Russian Federation	194291
17	Site 406	Saint Petersburg		Russian Federation	195067
18	Site 402	Saint Petersburg		Russian Federation	196247
19	Site 412	Saint Petersburg		Russian Federation	197022
20	Site 403	Saint Petersburg		Russian Federation	197374
21	Site 414	Saint Petersburg		Russian Federation	198205
22	Site 401	Saint Petersburg		Russian Federation	198412
23	Site 404	Saint Petersburg		Russian Federation	199106
24	Site 413	Smolensk		Russian Federation	214018
25	Site 502	Chernivtsi		Ukraine	58001
26	Site 506	Dnipro		Ukraine	49005
27	Site 505	Kharkiv		Ukraine	61037
28	Site 504	Kyiv		Ukraine	2660
29	Site 503	Kyiv		Ukraine	4053
30	Site 501	Lviv		Ukraine	79059
31	Site 507	Zaporizhzhia		Ukraine	69600

Sponsors and Collaborators

• Paratek Pharmaceuticals Inc

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 26, 2018
• Statistical Analysis Plan - Jun 4, 2019

More Information

Publications

None provided.

• Responsible Party: Paratek Pharmaceuticals Inc
• ClinicalTrials.gov Identifier: NCT03757234
• Other Study ID Numbers: PTK0796-AP-17202
• First Posted: Nov 28, 2018
• Last Update Posted: Jul 7, 2020
• Last Verified: Jul 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Pyelonephritis; Levofloxacin; Ofloxacin

Study Results

Participant Flow

Arm/Group Title	Omadacycline 200 iv/200 iv	Omadacycline 200 iv/100 iv	Omadacycline 200 iv/300 po or 100 iv	Omadacycline 200 iv/450 po or 100 iv	Levofloxacin 750 iv/750 po or iv
Arm/Group Description	On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.
Period Title: Overall Study
STARTED	75	18	17	17	74
Completed PTE Visit	72	16	17	16	71
COMPLETED	72	16	17	16	70
NOT COMPLETED	3	2	0	1	4

Baseline Characteristics

Arm/Group Title	Omadacycline 200 iv/200 iv	Omadacycline 200 iv/100 iv	Omadacycline 200 iv/300 po or 100 iv	Omadacycline 200 iv/450 po or 100 iv	Levofloxacin 750 iv/750 po or iv	Total
Arm/Group Description	On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	Total of all reporting groups
Overall Participants	75	18	17	17	74	201
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.2 (14.97)	33.9 (14.48)	37.1 (15.97)	38.2 (17.66)	38.8 (14.74)	37.9 (15.07)
Sex: Female, Male (Count of Participants)
Female	75 100%	18 100%	17 100%	17 100%	74 100%	201 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.3%	0 0%	0 0%	0 0%	0 0%	1 0.5%
Not Hispanic or Latino	74 98.7%	18 100%	17 100%	17 100%	74 100%	200 99.5%
Unknown or Not Reported	0 0%	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%	0 0%	0 0%	0 0%	0 0%
Asian	1 1.3%	0 0%	0 0%	0 0%	0 0%	1 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	74 98.7%	18 100%	17 100%	17 100%	74 100%	200 99.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With an Investigator Assessment of Clinical Response at the Post Therapy Evaluation (PTE) Visit (ITT Population)
Description	Clinical response was determined by the investigator at the PTE visit by assessing whether or not the participant met the clinical outcome of Clinical Success, Clinical Failure, or Indeterminate. Clinical Success was defined as the complete resolution or significant improvement of the baseline AP signs and symptoms at the PTE visit such that no additional antimicrobial therapy is required for the current infection. Clinical Failure was defined as no apparent response to therapy or persistence of signs and symptoms of infection or reappearance of signs and symptoms at or before the PTE visit such that use of additional systemic antimicrobial therapy for the current infection was required or death at or before the PTE visit. The clinical outcome was deemed as Indeterminate when the PTE visit was not completed.
Time Frame	Day 21 (A PTE occurred on Day 21 ± 2 days after the participant's first dose of study drug).

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population consisted of all randomized participants regardless of whether or not the participant received study drug.

Arm/Group Title	Omadacycline 200 iv/200 iv	Omadacycline 200 iv/100 iv	Omadacycline 200 iv/300 po or 100 iv	Omadacycline 200 iv/450 po or 100 iv	Levofloxacin 750 iv/750 po or iv
Arm/Group Description	On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.
Measure Participants	75	18	17	17	74
Clinical Success	68 90.7%	15 83.3%	15 88.2%	16 94.1%	69 93.2%
Clinical Failure	5 6.7%	1 5.6%	2 11.8%	0 0%	1 1.4%
Indeterminate	2 2.7%	2 11.1%	0 0%	1 5.9%	4 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Omadacycline 200 iv/200 iv, Levofloxacin 750 iv/750 po or iv
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin for comparison of the doses was set at 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -12.4 to 6.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and exact 95% confidence intervals for difference from levofloxacin (omadacycline minus levofloxacin) in clinical success rate was estimated.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Omadacycline 200 iv/100 iv, Levofloxacin 750 iv/750 po or iv
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin for comparison of the doses was set at 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-9.9
	Confidence Interval	(2-Sided) 95%; -34.8 to 5.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and exact 95% confidence intervals for difference from levofloxacin (omadacycline minus levofloxacin) in clinical success rate was estimated.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Omadacycline 200 iv/300 po or 100 iv, Levofloxacin 750 iv/750 po or iv
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin for comparison of the doses was set at 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-5.0
	Confidence Interval	(2-Sided) 95%; -30.6 to 8.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and exact 95% confidence intervals for difference from levofloxacin (omadacycline minus levofloxacin) in clinical success rate was estimated.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Omadacycline 200 iv/450 po or 100 iv, Levofloxacin 750 iv/750 po or iv
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin for comparison of the doses was set at 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; -22.4 to 11.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and exact 95% confidence intervals for difference from levofloxacin (omadacycline minus levofloxacin) in clinical success rate was estimated.

2. Primary Outcome

Title	Number of Participants With a Microbiological Response at the PTE Visit (Micro-ITT Population)
Description	Microbiological response was determined programmatically at the PTE visit by assessing whether or not the participant met the microbiological outcome of 'Success', 'Failure', or 'Indeterminate'. Participants were considered to have a microbiological response of 'Success' if the outcomes of each baseline pathogens were eradication at the PTE visit. Participants were considered to have a microbiological response of 'Failure' if the outcome for any pathogen was persistence. Participants were considered to have a microbiological response of 'Indeterminate', if the outcome of at least 1 baseline pathogen was indeterminate and there was no outcome of persistence for any baseline pathogen.
Time Frame	Day 21 (A PTE occurred on Day 21 ± 2 days after the participant's first dose of study drug).

Outcome Measure Data

Analysis Population Description

The micro-ITT population consisted of participants in the ITT population who had an appropriately collected pretreatment baseline urine culture with at least 1 uropathogen at ≥10^5 colony forming unit (CFU)/mL and not more than 2 bacterial isolates at any colony count.

Arm/Group Title	Omadacycline 200 iv/200 iv	Omadacycline 200 iv/100 iv	Omadacycline 200 iv/300 po or 100 iv	Omadacycline 200 iv/450 po or 100 iv	Levofloxacin 750 iv/750 po or iv
Arm/Group Description	On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.
Measure Participants	46	11	14	13	52
Clinical Success	32 42.7%	3 16.7%	9 52.9%	5 29.4%	39 52.7%
Clinical Failure	13 17.3%	7 38.9%	5 29.4%	7 41.2%	11 14.9%
Indeterminate	1 1.3%	1 5.6%	0 0%	1 5.9%	2 2.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Omadacycline 200 iv/200 iv, Levofloxacin 750 iv/750 po or iv
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin for comparison of the doses was set at 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-5.4
	Confidence Interval	(2-Sided) 95%; -23.6 to 12.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and exact 95% confidence intervals for difference from levofloxacin (omadacycline minus levofloxacin) in clinical success rate was estimated.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Omadacycline 200 iv/100 iv, Levofloxacin 750 iv/750 po or iv
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin for comparison of the doses was set at 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-47.7
	Confidence Interval	(2-Sided) 95%; -71.3 to -6.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and exact 95% confidence intervals for difference from levofloxacin (omadacycline minus levofloxacin) in clinical success rate was estimated.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Omadacycline 200 iv/300 po or 100 iv, Levofloxacin 750 iv/750 po or iv
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin for comparison of the doses was set at 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-10.7
	Confidence Interval	(2-Sided) 95%; -40.8 to 15.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and exact 95% confidence intervals for difference from levofloxacin (omadacycline minus levofloxacin) in clinical success rate was estimated.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Omadacycline 200 iv/450 po or 100 iv, Levofloxacin 750 iv/750 po or iv
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority margin for comparison of the doses was set at 10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-36.5
	Confidence Interval	(2-Sided) 95%; -62.6 to -1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and exact 95% confidence intervals for difference from levofloxacin (omadacycline minus levofloxacin) in clinical success rate was estimated.

3. Primary Outcome

Title	Number of Participants With Resolution of All AP Signs and Clinical Symptoms at PTE Visit (ITT Population)
Description	Participants recorded their assessments using the Modified Patient Symptom Assessment Questionnaire (mPSAQ), a 6-item questionnaire that assessed the levels of 'severity' and 'bothersomeness' for six pyelonephritis signs and symptoms. The sub-scale responses were recorded as 'did not have', 'mild', 'moderate', and 'severe' for 'severity'; and 'not at all', 'a little', 'moderately', and 'a lot' for 'bothersomeness', both scored 0-3. Total scores were calculated by summing the non-missing scores of the 6 items, divided by the number of non-missing items, and then multiplied by 6. For each sub-scale, the total score ranged from 0 (least Severe/ least bothersome) and 18 (worst severity/most bothersome). Number of participants with resolution of all symptoms, without occurrence of new symptoms is reported. Resolution was defined as absence of all baseline symptoms.
Time Frame	Day 21 (A PTE occurred on Day 21 ± 2 days after the participant's first dose of study drug).

Outcome Measure Data

Analysis Population Description

The ITT population consisted of all randomized participants regardless of whether or not the participant received study drug. Participants who completed the PTE visit with evaluable data were analyzed for this end point.

Arm/Group Title	Omadacycline 200 iv/200 iv	Omadacycline 200 iv/100 iv	Omadacycline 200 iv/300 po or 100 iv	Omadacycline 200 iv/450 po or 100 iv	Levofloxacin 750 iv/750 po or iv
Arm/Group Description	On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.
Measure Participants	64	16	16	16	66
Count of Participants [Participants]	51 68%	15 83.3%	14 82.4%	13 76.5%	54 73%

4. Primary Outcome

Title	Number of Participants With No Worsening and Absence of New AP Signs and Clinical Symptoms at PTE Visit (ITT Population)
Description	Participants recorded their assessments using the mPSAQ, a 6-item questionnaire that assessed the levels of 'severity' and 'bothersomeness' for six pyelonephritis signs and symptoms. The sub-scale responses were recorded as 'did not have', 'mild', 'moderate', and 'severe' for 'severity'; and 'not at all', 'a little', 'moderately', and 'a lot' for 'bothersomeness', both scored 0-3. Total scores were calculated by summing the non-missing scores of the 6 items, divided by the number of non-missing items, and then multiplied by 6. For each sub-scale, the total score ranged from 0 (least Severe/ least bothersome) and 18 (worst severity/most bothersome). Number of participants with no worsening and absence of AP signs and clinical symptoms is reported. No worsening meant that each question score is same or better at post baseline.
Time Frame	Day 21 (A PTE occurred on Day 21 ± 2 days after the participant's first dose of study drug).

Outcome Measure Data

Analysis Population Description

The ITT population consisted of all randomized participants regardless of whether or not the participant received study drug. Participants who completed the PTE visit with evaluable data were analyzed for this end point.

Arm/Group Title	Omadacycline 200 iv/200 iv	Omadacycline 200 iv/100 iv	Omadacycline 200 iv/300 po or 100 iv	Omadacycline 200 iv/450 po or 100 iv	Levofloxacin 750 iv/750 po or iv
Arm/Group Description	On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.
Measure Participants	64	16	16	16	66
Count of Participants [Participants]	62 82.7%	16 88.9%	16 94.1%	15 88.2%	65 87.8%

5. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events
Description	An adverse event is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, or laboratory or physiologic observations occurring in a person given a study drug or in a clinical study. A treatment-emergent adverse event was defined as any adverse event that newly appeared, increased in frequency, or worsened in severity on or after the initiation of the study drug.
Time Frame	up to approximately 28 days

Outcome Measure Data

Analysis Population Description

The Safety population consisted of all randomized participants who received at least one dose of study drug.

Arm/Group Title	Omadacycline 200 iv/200 iv	Omadacycline 200 iv/100 iv	Omadacycline 200 iv/300 po or 100 iv	Omadacycline 200 iv/450 po or 100 iv	Levofloxacin 750 iv/750 po or iv
Arm/Group Description	On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.	On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.
Measure Participants	75	18	17	17	74
Treatment Emergent Adverse Events	23 30.7%	6 33.3%	9 52.9%	8 47.1%	24 32.4%
Treatment Emergent Serious Adverse Events	0 0%	0 0%	2 11.8%	2 11.8%	2 2.7%

Adverse Events

Time Frame	Up to approximately 28 days
Adverse Event Reporting Description	The Safety Population consisted of all randomized participants who received at least one dose of study drug.
Arm/Group Title	Omadacycline 200 iv/200 iv		Omadacycline 200 iv/100 iv		Omadacycline 200 iv/300 po or 100 iv		Omadacycline 200 iv/450 po or 100 iv		Levofloxacin 750 iv/750 po or iv
Arm/Group Description	On Day 1, participants received omadacycline 200 milligrams intravenously (iv). On Days 2 through 7, participants continued to receive omadacycline 200 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.		On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes.		On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 300 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.		On Day 1, participants received omadacycline 200 milligrams iv. On Days 2 through 7, participants received omadacycline 100 milligrams iv or omadacycline 450 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.		On Day 1, participants received levofloxacin 750 milligrams iv. On Days 2 through 7, participants received levofloxacin 750 milligrams iv or levofloxacin 750 milligrams po. All doses were administered once-per-day and iv doses were administered in 150 milliliters of normal saline as continuous infusions over 90 minutes. All oral doses were taken in a fasted state.
All Cause Mortality
	Omadacycline 200 iv/200 iv		Omadacycline 200 iv/100 iv		Omadacycline 200 iv/300 po or 100 iv		Omadacycline 200 iv/450 po or 100 iv		Levofloxacin 750 iv/750 po or iv
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/18 (0%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Serious Adverse Events
	Omadacycline 200 iv/200 iv		Omadacycline 200 iv/100 iv		Omadacycline 200 iv/300 po or 100 iv		Omadacycline 200 iv/450 po or 100 iv		Levofloxacin 750 iv/750 po or iv
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/18 (0%)		2/17 (11.8%)		2/17 (11.8%)		2/74 (2.7%)
Blood and lymphatic system disorders
Anaemia	0/75 (0%)	0	0/18 (0%)	0	0/17 (0%)	0	0/17 (0%)	0	1/74 (1.4%)	1
Gastrointestinal disorders
Duodenal ulcer haemorrhage	0/75 (0%)	0	0/18 (0%)	0	0/17 (0%)	0	1/17 (5.9%)	1	0/74 (0%)	0
Infections and infestations
Renal abscess	0/75 (0%)	0	0/18 (0%)	0	1/17 (5.9%)	1	0/17 (0%)	0	0/74 (0%)	0
Pyelonephritis acute	0/75 (0%)	0	0/18 (0%)	0	1/17 (5.9%)	1	0/17 (0%)	0	0/74 (0%)	0
Pneumonia	0/75 (0%)	0	0/18 (0%)	0	0/17 (0%)	0	1/17 (5.9%)	1	1/74 (1.4%)	1
Escherichia bacteraemia	0/75 (0%)	0	0/18 (0%)	0	0/17 (0%)	0	1/17 (5.9%)	1	0/74 (0%)	0
Other (Not Including Serious) Adverse Events
	Omadacycline 200 iv/200 iv		Omadacycline 200 iv/100 iv		Omadacycline 200 iv/300 po or 100 iv		Omadacycline 200 iv/450 po or 100 iv		Levofloxacin 750 iv/750 po or iv
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/75 (28%)		6/18 (33.3%)		7/17 (41.2%)		8/17 (47.1%)		16/74 (21.6%)
Cardiac disorders
Tachycardia	0/75 (0%)		0/18 (0%)		0/17 (0%)		1/17 (5.9%)		0/74 (0%)
Gastrointestinal disorders
Diarrhoea	1/75 (1.3%)		1/18 (5.6%)		0/17 (0%)		1/17 (5.9%)		5/74 (6.8%)
Nausea	3/75 (4%)		0/18 (0%)		0/17 (0%)		4/17 (23.5%)		5/74 (6.8%)
Vomiting	0/75 (0%)		0/18 (0%)		0/17 (0%)		1/17 (5.9%)		1/74 (1.4%)
General disorders
Asthenia	2/75 (2.7%)		0/18 (0%)		0/17 (0%)		0/17 (0%)		1/74 (1.4%)
Hyperthermia	0/75 (0%)		1/18 (5.6%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Infections and infestations
Asymptomatic bacteriuria	3/75 (4%)		2/18 (11.1%)		2/17 (11.8%)		1/17 (5.9%)		1/74 (1.4%)
Oral herpes	0/75 (0%)		0/18 (0%)		1/17 (5.9%)		0/17 (0%)		0/74 (0%)
Pharyngitis	0/75 (0%)		1/18 (5.6%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Viral rhinitis	0/75 (0%)		0/18 (0%)		1/17 (5.9%)		0/17 (0%)		0/74 (0%)
Vulvovaginal candidiasis	0/75 (0%)		0/18 (0%)		1/17 (5.9%)		0/17 (0%)		0/74 (0%)
Investigations
Alanine aminotransferase increased	1/75 (1.3%)		1/18 (5.6%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Aspartate aminotransferase increased	0/75 (0%)		1/18 (5.6%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Body temperature increased	0/75 (0%)		0/18 (0%)		0/17 (0%)		1/17 (5.9%)		1/74 (1.4%)
Gamma-glutamyltransferase increased	0/75 (0%)		0/18 (0%)		0/17 (0%)		1/17 (5.9%)		0/74 (0%)
Nervous system disorders
Dizziness	3/75 (4%)		0/18 (0%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Dysgeusia	0/75 (0%)		0/18 (0%)		1/17 (5.9%)		0/17 (0%)		0/74 (0%)
Headache	8/75 (10.7%)		0/18 (0%)		2/17 (11.8%)		3/17 (17.6%)		5/74 (6.8%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/75 (0%)		0/18 (0%)		2/17 (11.8%)		0/17 (0%)		0/74 (0%)
Skin and subcutaneous tissue disorders
Rash	2/75 (2.7%)		0/18 (0%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Rash erythematous	3/75 (4%)		0/18 (0%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Urticaria	2/75 (2.7%)		0/18 (0%)		0/17 (0%)		0/17 (0%)		0/74 (0%)
Vascular disorders
Hypertension	0/75 (0%)		0/18 (0%)		0/17 (0%)		1/17 (5.9%)		1/74 (1.4%)

Limitations/Caveats

In May 2019, the DMC modified the randomization algorithm based on their review of the data. After this change, participants were randomized in a 1:1 ratio to either the omadacycline 200 iv/200 iv or levofloxacin arms.

More Information

Certain Agreements

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

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.