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

• ClinicalTrials.gov Identifier: NCT03757234
• Recruitment Status: Completed
• First Posted: November 28, 2018
• Results First Posted: July 7, 2020
• Last Update Posted: July 7, 2020
• Sponsor: Paratek Pharmaceuticals Inc
• Information provided by (Responsible Party): Paratek Pharmaceuticals Inc

Tracking Information

• First Submitted Date: November 27, 2018
• First Posted Date: November 28, 2018
• Results First Submitted Date: June 8, 2020
• Results First Posted Date: July 7, 2020
• Last Update Posted Date: July 7, 2020
• Actual Study Start Date: November 19, 2018
• Actual Primary Completion Date: June 26, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 8, 2020)

• Number of Participants With an Investigator Assessment of Clinical Response at the Post Therapy Evaluation (PTE) Visit (ITT Population) [ Time Frame: 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.
• Number of Participants With a Microbiological Response at the PTE Visit (Micro-ITT Population) [ Time Frame: 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.
• Number of Participants With Resolution of All AP Signs and Clinical Symptoms at PTE Visit (ITT Population) [ Time Frame: 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.
• Number of Participants With No Worsening and Absence of New AP Signs and Clinical Symptoms at PTE Visit (ITT Population) [ Time Frame: 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.

Original Primary Outcome Measures (submitted: November 27, 2018)

• Investigator's assessment of clinical response at Post Treatment Evaluation (PTE) based on microbiological response. [ Time Frame: 21 days ]
  Clinical success is defined as sufficient resolution of acute pyelonephritis signs and symptoms such that no additional antibacterial therapy is required for the current infection. Clinical response will be determined by the judgement of the investigator at the subject's post-treatment evaluation and will be based on the following factors: Microbiological Response: The subjects will present a urine sample at each visit and pathogen load will be measured via urine culture and urine dipstick analysis. Investigators will examine the results of these tests across all visits and will measure clinical success as a significant reduction in pathogen load such that the subjects do not require additional antibacterial therapy at the end of their 21-day time frame. All of these factors will be aggregated into the clinician's assessment of the subject.
• Investigator's assessment of clinical response at Post Treatment Evaluation (PTE) based on subject's report of acute pyelonephritis signs and symptoms [ Time Frame: 21 Days ]
  Each subject will record her assessment of acute pyelonephritis signs and symptoms severity using the modified Patient Symptom Assessment Questionnaire (mPSAQ) during each visit. The subject will rate the severity and how bothersome each symptom is on a 4-point scale (no symptom, mild, moderate, severe and not at all, a little, moderately, a lot) The investigator will review each subject's responses and decide at the end of their treatment if there is sufficient resolution of AP signs and symptoms.
• Investigator's assessment of clinical response at Post Treatment Evaluation (PTE) based on subject's report of health and adverse events. [ Time Frame: 21 Days ]
  Investigators will interview the subjects at each visit to ask questions about their general health, how they feel, and to report on any adverse events they may be experiencing. Investigators will factor in adverse event reports to their decision on each subject's clinical outcome at the end of their 21-day time frame.

Current Secondary Outcome Measures (submitted: June 8, 2020)

Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events [ Time Frame: 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: IV or IV/PO Omadacycline vs. IV/PO Levofloxacin for the Treatment of Acute Pyelonephritis
• 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.
• 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.
• 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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Acute Pyelonephritis

Intervention

• Drug: Omadacycline
  po tablets
  Other Name: Nuzyra
• Drug: Levofloxacin
  iv solution/po tablets
  Other Name: Levaquin
• Drug: Omadacycline
  iv solution
  Other Name: Nuzyra

Study Arms

• 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.
  Intervention: Drug: Omadacycline
• 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.
  Intervention: Drug: Omadacycline
• 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.
  Interventions:

  • Drug: Omadacycline
  • Drug: Omadacycline
• 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.
  Interventions:

  • Drug: Omadacycline
  • Drug: Omadacycline
• 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.
  Intervention: Drug: Levofloxacin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 8, 2019): 201
• Original Estimated Enrollment (submitted: November 27, 2018): 200
• Actual Study Completion Date: July 24, 2019
• Actual Primary Completion Date: June 26, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Georgia, Latvia, Russian Federation, Ukraine

Administrative Information

• NCT Number: NCT03757234
• Other Study ID Numbers: PTK0796-AP-17202
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Paratek Pharmaceuticals Inc
• Original Responsible Party: Same as current
• Current Study Sponsor: Paratek Pharmaceuticals Inc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Paratek Pharmaceuticals Inc
• Verification Date: July 2020